PHASE 3 NOTES: ACUTE DYSPNOEA AND HAEMOPTYSIS

CONTENTS: Page
Definition and clinical assessment of dyspnoea (history, physical exam key points, differential diagnosis) Clinical assessment of haemoptysis and pathogenetic mechanisms Surface anatomy of the thorax and lungs Examination of the Respiratory system Deep venous thrombosis, pulmonary embolism and case protocol 3 Haematology review- Haemostasis and coagulation pathways Pharmacology- Drugs to treat thrombosis and embolism Heart failure Asthma and case protocol 39 Acute Respiratory Distress Syndrome Arterial Blood gas analysis for acute dyspnoea (laboratory visit) Smoking prevention and lung cancer Lung cancer and case protocol 19 Pneumonia Bronchiectasis Lung abscess Tuberculosis 2 9 14 16 26 42 49 54 80 97 102 109 118

Clinical Assessment & Management of Dyspnoea

History/initial assessment of the presenting problem: dyspnoea:
Dyspnoea is the subjective experience or perception of uncomfortable breathing or short of breath. However, the relationship between the level of dyspnoea and the severity of disease varies widely. Conditions that cause dyspnoea affect the mechanical effort of breathing (e.g. asthma, COPD), or may arise from conditions that necessitate compensatory tachypnoea (e.g. acidosis, hypoxaemia), or from psychogenic causes (e.g. anxiety). When evaluating a patient with shortness of breath, one should first determine the time course over which the symptom has become manifest. Patients who were well previously and developed acute shortness of breath (over a period of minutes to days) may have acute disease affecting either the upper or the intrathoracic airways (e.g., laryngeal edema or acute asthma, respectively), the pulmonary parenchyma (acute cardiogenic or noncardiogenic pulmonary edema or an acute infectious process such as a bacterial pneumonia), the pleural space (a pneumothorax), or the pulmonary vasculature (a pulmonary embolus). A subacute presentation (over days to weeks) can suggest an exacerbation of preexisting airways disease (asthma or chronic bronchitis), an indolent parenchymal infection (Pneumocystis jiroveci pneumonia in a patient with AIDS, mycobacterial or fungal pneumonia), a noninfectious inflammatory process that proceeds at a relatively slow pace (Wegeners granulomatosis, eosinophilic pneumonia, cryptogenic organizing pneumonia, and many others), neuromuscular disease (Guillain-Barre syndrome, myasthenia gravis), pleural disease (pleural effusion from a variety of possible causes), or chronic cardiac disease (congestive heart failure). A chronic presentation (over months to years) often indicates chronic obstructive lung disease, chronic interstitial lung disease, or chronic cardiac disease. Chronic diseases of airways (not only chronic obstructive lung disease but also asthma) are characterized by exacerbations and remissions. Patients often have periods when they are severely limited by shortness of breath, but these may be interspersed with periods in which symptoms are minimal or absent. In contrast, many of the diseases of the pulmonary parenchyma are characterized by slow but inexorable progression. Chronic respiratory symptoms may also be multifactorial in nature, as patients with chronic obstructive pulmonary disease may also have concomitant heart disease. As with all other presenting symptoms, know how to ask relevant questions. Importantly, it is necessary to establish how long the patient has been dyspnoeic. Was the onset of shortness of breath acute or gradual? (i.e. timing of dyspnoea) This is important as the differential diagnosis for acute (e.g. paroxysmal) dyspnoea is different to subacute or chronic progressive dyspnoea. Some causes of acute dyspnoea include bronchospasm, pulmonary embolism (PE), pneumothorax, pulmonary infection, acute respiratory distress syndrome (ARDS), diaphragmatic paralysis, myocardial ischaemia, acute cardiogenic pulmonary oedema, and anxiety/panic attacks. Note that chronic dyspnea can present with an acute exacerbation. Are there any associated symptoms? The patient may focus on the shortness of breath and fail to disclose chest pain, pressure, or discomfort unless specifically asked. Qualify the chest pain; for example, chest pain of a pleuritic nature characterises pneumothorax or PE with infarction. Bear in mind that dyspnoea rather than angina may be the primary or the only symptom of acute myocardial ischaemia. Determination of the effect of positional changes of dyspnoea (i.e. what makes the shortness of breath better or worse? Is the shortness of breath better or worse when you are lying down or sitting up, etc?) is important. Orthopnea (difficulty breathing when lying flat) suggests congestive heart failure, or diaphragmatic dysfunction. Platypnea (difficulty breathing when sitting upright) invokes intrapulmonary or intracardiac shunting. Trepopnea (an inability to lie on ones side) implies pleural effusion or congestive heart failure. Assessment for precipitants, including dyspnoea on exertion (How far can you walk after you feel breathless?) and exposure to chemicals, and other irritants is also helpful (thus a thorough occupational health history, smoking history, and history of drugs & medications and allergies is important). It may also be helpful to ask for other important presenting symptoms including haemoptysis, cough, wheeze, chest pain, fever. Is the patient cyanotic? Hypoxemia is a potentially lethal condition. If there is obvious cyanosis (or evidence of hypoxia, such as by pulse oximetry) noted, then immediate oxygen therapy is indicated.

 Breathlessness: How long have you been short of breath? Important to ask about timing and onset (see below) Was onset of breathlessness gradual, or all of a sudden? What are alleviating and aggravating factors- i.e. what makes it better or worse? Is there a particular time during the day that breathlessness is worse? Are there any other associated symptoms, for example chest pain, discomfort, cough, sputum expectoration, wheeze, haemoptysis? Have you coughed up blood? (80% of cases of haemoptysis may be due to either: bronchitis, bronchial carcinoma, pneumonia and bronchiectasis). Important causes of dyspnoea include airways disease (asthma, chronic bronchitis, Cystic Fibrosis (CF)), parenchymal disease (pneumonia, allergic alveolitis, emphysema, sarcoidosis), Pulmonary circulation (PE), Chest wall & pleura (effusion, massive ascites, tumour). See below for details on dyspnoea. Cough & Sputum production: How long has the cough lasted for and what brought it about, i.e. what do you think caused it? Are you bringing up any sputum with the cough? What is the smell (foul-smelling brown sputum occurs with lung abscess with anaerobic organisms), colour and volume? (i.e. how much sputum- a large volume of purulent yellow to green sputum occurs with bronchiectasis or lobar pneumonia). What makes the cough better or worse; e.g. is the coughing worse or better after drinking or eating? (May be useful to indicate laryngeal pathology or may indicate a tracheo-oesophageal fistula). Have you had a recent fever with the cough (for acute bronchitis & other upper respiratory tract infections, pneumonia?) Have you had a wheeze associated with the cough? (A chronic cough with wheeze could indicate chronic asthma). Is it a dry, chronic cough? (Occurs with oesophageal reflux and laryngeal irritation, late interstitial pulmonary fibrosis with interstitial lung disease, or with use of ACE inhibitors). Do you find that the cough wakes you from sleep, or when do you find that it is worst? (may indicate anything, but specifically it could also point towards cardiac failure or gastrooesophageal reflux disease with laryngeal/tracheobronchial irritation). Have you noticed a change in the character of the cough? (could occur with lung cancer). Can you give me a cough to show me what it is like; is it a productive, dry or barking cough? (Barking cough can occur with pertussis, laryngitis, or epiglottitis; a loud, brassy cough can occur with tracheal obstruction, e.g. due to tumour compression; a hollow sounding cough can be due to recurrent laryngeal nerve palsy). What time of the day do you cough most? With respiratory system questions, time during the day is useful. Cough may indicate the presence of lung disease, but cough per se is not useful for differential diagnosis. The presence of sputum accompanying the cough often suggests airway disease and may be seen in asthma, chronic bronchitis, or bronchiectasis. Haemoptysis can originate from disease of the airways, the pulmonary parenchyma, or the vasculature. Diseases of the airways can be inflammatory (acute or chronic bronchitis, bronchiectasis, or cystic fibrosis) or neoplastic (bronchogenic carcinoma or bronchial carcinoid tumours). Parenchymal diseases causing haemoptysis may be either localized (pneumonia, lung abscess, tuberculosis, or infection with Aspergillus) or diffuse (Goodpastures syndrome, idiopathic pulmonary hemosiderosis). Vascular diseases potentially associated with haemoptysis include pulmonary thromboembolic disease and pulmonary arteriovenous malformations. Chest pain: Use SOCRATES mnemonic, for pain as always. With chest pain associated with the respiratory system, it is pleuritic in nature, which is sharp, stabbing pain that is well localised (to the area of the parietal pleura which has been involved by inflammation or local injury) and is worse on inspiration. Important causes of pleuritic chest pain include Pulmonary Embolism with infarction & pleural involvement, pneumonia with pleural involvement and Pneumothorax. What are relieving factors? Important relieving factors that may give the diagnosis include: rest (most lung diseases), shallow breathing (e.g. with pneumothorax). What are aggravating factors? important aggravating factors to note include: exercise, deep breaths and coughing. Just remember other major types of chest pain including pain from cardiovascular causes including myocardial ischaemia, aortic dissection, musculoskeletal pain, or neuropathic, e.g. herpes zoster shingles. Chest pain caused by diseases of the respiratory system usually originates from involvement of the parietal pleura. As a result, the pain is accentuated by respiratory motion and is often referred to as pleuritic. Common examples include primary pleural disorders, such as

neoplasm or inflammatory disorders involving the pleura, or pulmonary parenchymal disorders that extend to the pleural surface, such as pneumonia or pulmonary infarction. Wheeze: An important presenting problem, that may be associated with dyspnoea, e.g. in the case of asthma or COPD. Again use the SOCRATES mnemonic to ask relevant questions. Note that not just asthma or COPD cause wheeze and other important causes of wheeze include tumours and foreign bodies. Nasal symptoms: An important cause of coughing is a post-nasal drip, in which case the patient has a cough although they have no lower respiratory tract infections, and this is usually worse at night or when they have a runny nose, as in the case with allergies. Other important nasal problems that can cause nasal symptoms include nasal polyps as well as septum deviation. Hoarseness: Many causes, including laryngitis, vocal cord tumours, vocal cord paralysis, recurrent laryngeal nerve palsy. Sleep apnoea symptoms: Importantly, because the patient with sleep apnoea has poor quality sleep, they usually have chronic fatigue syndrome, morning headaches, daytime somnolence (feeling sleepy and having a tendency to sleep), as well as falling asleep- daytime micro-sleep, witness apnoeas (a person such as the wife notices that patient is loudly snoring during the night and suddenly they stop breathing- may cause them to wake up and restart breathing). Usually these patients are overweight/obese. Fever, night sweats: These constitutional symptoms are non-specific, but usually in the case of respiratory system diseases they point-towards infections. Night sweats are an important systemic feature of certain diseases, including haematological malignancies and very importantly tuberculosis. Never forget for a Respiratory System presenting problem other critical components of the medical history, including: Family History (important for many conditions, as diverse as 1-antitrypsin deficiency in COPD to Cystic Fibrosis CFTR mutations), Social history (e.g. ask about how the disease has impacted them and their ADLs, how far they can walk before they become breathless, how many stairs they can climb, do they have any stairs at home, travel history, do they have any pets- specifically birds- as some birds can transmit Chlamydia psittacosis or may be a cause of hypersensitivity pneumonitis), Occupational history is very important with the respiratory system, and obviously a comprehensive smoking history. Family History: Important conditions to ask for include cystic fibrosis, tuberculosis, COPD (1antitrypsin deficiency), pulmonary hypertension, interstitial lung diseases including familial idiopathic pulmonary fibrosis, sarcoidosis and other respiratory diseases including asthma. Interestingly, for patients whose both parents had asthma, they have a 60% risk of acquiring asthma. Social History: Smoking history: how much they have smoked cigarettes and for how long and report this as pack years. Ask if they smoke anything other than tobacco cigarettes, e.g. marijuana. Also if they have ceased smoking, how long it has been since they quit. Exposure to significant second-hand (passive) smoke at home or in the work-place should also be identified with a full respiratory history. Occupational history (e.g. including asbestos exposure, exposure to dusts, e.g. western red cedar for asthma, volatile chemicals, aerosols, dusts in factories etc) This includes both past and current work. Go back ~20 years when asking for occupational history and ask about all work the person has been involved with. Important to ask about construction or insulation work (e.g. electricians, plumbers) and exposure to asbestos, boiler makers (involved with insulation cladding with asbestos) and ship builders and destructors. Also important to assess silicate exposure, important to ask about mining work (hard rocks, minerals/metals including zinc mining, copper, coal (if coal is in a salicaceous deposit- however this causes coal workers pneumoconioses rather than silicosis), tunnelers(underground miners), jack-pick operators, exposure to sandstone and sand-blasting. Also ask for occupations that are risk factors for hypersensitivity pneumonitis (animals, moulds- protein deposits usually in the upper lobes, which infiltrates, causing granulomas with giant cells, pulmonary infiltrates, fever, lung fibrosis with prolonged exposure) including farmers (farmers lung), malt-

workers lung, bird/poultry farmers. For occupational asthma, ask about exposure to paints, spray paints, (asthma induced by di-isocyanates which are volatile chemicals found in 2-pack paints), animal exposure with furs (e.g. lab workers experimenting with mice), aluminium smelters (involves electrolytic production with Bauxite, which uses hydrofluoric acid (HF) and this as well as aluminium metal fumes can cause pot room asthma), exposure to chlorine gas as well as carpenters (red cedar or elm exposure; these woods contain plicatic acid and abietic acids). Travel history & what they did during travel, ask about risk factors for respiratory disease you may be suspecting. Importantly, endemic areas for tuberculosis or geographic locations for certain fungi (e.g. histoplasma, coccidioidomycosis, blastomycosis). Pets and especially birds: Important as they can transmit Coxiella burnetii (Q-fever), Chlamydia psittacosis (Psittacosis), and may cause interstitial lung diseases including hypersensitivity pneumonitis (Type 1 hypersensitivity to avian allergens). Hobbies: May include work that may be contributing to their presenting problem, e.g. wood work/carpentry with extensive dust exposure, spray painting, hence hobbies are also important together with occupational history. Risk factors for HIV/TB: A sexual history may be necessary if HIV is being considered. Travel history to TB endemic areas, exposure to TB, previous TB infection and HIV infection are also important for TB. Home environment & ADLs: Especially in patients with advanced lung disease, it is important to make an assessment of their home and functional status and how well they manage their ADLs. How many stairs do they have in their house; how do they cope with stairs, do they become breathless? How long can they walk before they need to rest? Do they need home oxygen therapy? Obviously a comprehensive drug history is needed and outside the social history, a comprehensive medication and allergies history. Important sites of respiratory diseases include obviously from the nose to the distal airways; the nose, nasopharynx, larynx, trachea, bronchi and smaller airways, alveoli, as well as the pleura, chest wall/respiratory muscles, diaphragm, and the CNS for respiratory regulation (respiratory centres). Allergy history important; do not forget to ask about skin-prick tests (important for asthma & some other conditions). Importantly, dust-mite, cockroach pollen, pet or di-isocyanate allergies. Dont forget past medical history! Especially for rheumatological diseases associated with pleural/lung parenchymal disease. History of previous cancers indicating metastatic disease, HIV/AIDS risk factors, secondary immunoglobulin deficiencies. The lungs are the most common-site for AIDS defining illness. Medications: chemotherapy/radiotherapy, amiodarone, ACE inhibitors, beta-blockers etc.

Physical examination key points:

Vital signs: Fever may signify infection, but can also occur with PE and MI. Tachypnoea occurs most often in cases of dyspnoea; however, dyspnoea can occur with a normal respiratory rate. Hypotension may result from a tension pneumothorax, anaphylaxis, pericardial tamponade, acute MI, or anaemia from haemorrhage. Tachycardia is also seen in the above conditions. Pulsus paradoxus (inspiratory diminution in systolic blood pressure exceeding 10 mmHg) may occur with acute exacerbation of asthma, COPD, constrictive pericarditis, or pericardial tamponade and its significance is established only during normal cardiac rhythm and with respirations of normal tidal rhythm and depth (tidal breathing). Bedside pulse oximetry is a valuable bedside measurement. Lungs: Observe the patient for signs of respiratory distress, including accessory muscle use. Paradoxical abdominal movement during respiration suggests diaphragmatic and respiratory muscle fatigue. Palpate for tracheal deviation, which may be encountered in pneumothorax, large pleural effusion, or pulmonary mass. Percuss the lung fields to survey for asymmetry of resonance as found in pneumothorax. Auscultate for wheezes, stridor, crackles, friction rubs, and absent breath sounds. Heart: Check for elevated jugular venous pressure, displaced apex beat, or an S3 gallop suggests decompensated heart failure. Jugular venous distension on inspiration, a non-palpable apical impulse and muffled heart tones occur with pericardial tamponade. Irregular heart beat and murmurs are also important signs. Extremities: Examine for peripheral oedema or other evidence of deep venous thrombosis, which predisposes to pulmonary embolus. Also, evaluate for pallor and peripheral cyanosis. Clubbing may

be seen in a dyspnoeic patient with chronic suppurative lung disease (e.g. Cystic fibrosis), bronchial carcinoma, cyanotic heart disease, bacterial endocarditis, cirrhosis or Graves hyperthyroidism. Neurologic exam: Confusion and impaired mentation may signify severe hypoxemia or may elucidate the cause of dyspnoea, such as infection.

Differential Diagnosis:
Dyspnoea is the subjective sensation of difficult, laboured, uncomfortable breathing. It may occur through increased respiratory muscle work, stimulation of neuroreceptors throughout the respiratory tract, or stimulation of peripheral or central chemoreceptors. Although many diseases produce dyspnoea, twothirds are caused by pulmonary or cardiac disorders. A. Pulmonary causes: 1) Pulmonary embolism: This diagnosis must be considered in any patient presenting with acute dyspnoea. Also recurrent pulmonary emboli can cause intermittent dyspnoea at rest. This diagnosis should be considered especially in the presence of risk factors such as prolonged immobilisation, recent operative procedure, obesity, malignancy (especially adenocarcinomas which cause migratory thrombophlebitis or Trousseaus syndrome), venous trauma, known venous thrombosis, hypercoagulable risk factors (protein C and protein S deficiencies, Factor V Leiden mutation, prothrombin gene mutation, antithrombin III deficiency- e.g. pregnancy) or hypercoagulable state (such as antiphospholipid antibody syndrome) or high-dose oestrogen therapy, especially in women over 35 years age who take oral contraceptive pills and smoke. 2) Pneumothorax: This can occur after trauma, or spontaneously in patients with bullous emphysema, or in young people- especially males with a tall, thin body habitus. Patients on ventilators are at increased risk. Iatrogenic pneumothoraces may occur after central line insertion, bronchoscopy, positive-pressure ventilation or thoracentesis. 3) Obstructive lung diseases: asthma/Chronic Obstructive Pulmonary Disease (COPD): Sometimes patients with asthma primarily have chest hyperinflation and increased work of breathing before actual wheezing occurs. A careful examination and review of history are important. However, anaphylaxis can also produce wheezing. In addition to bronchospasm, these patients demonstrate other evidence of anaphylaxis such as stridor, wheezing, pruritus, hypotension and urticaria. 4) Asthma: The patient may have developed acute asthma, it is important to ascertain whether they have had asthma in their past medical history. If suspecting asthma, how often do they have symptoms (i.e. what is the frequency of their symptoms)? Do they know what triggers their asthma and have they had exposure to any allergens, such as grass or flower pollens, recent viral infection, exercise induced asthma etc? 5) Aspiration: An altered mental status or advanced age or comorbidities (e.g. neurological deficit in a stroke patient) is often present (e.g. from intoxication, psychosis, delirium); also ask about dysphagia and muscle weakness suggesting an acute cerebral vascular accident. 6) Pneumonia: It is characterised by fever, productive cough, radiographic infiltrates, and either leukocytosis or leukopenia. 7) Interstitial lung disease: This usually produces progressive dyspnoea and is caused by diseases such as sarcoidosis, idiopathic pulmonary fibrosis, collagen vascular disease and occupational lung disease. 8) Pleural effusion: This is more likely to cause chronic or subchronic dyspnoea rather than acute dyspnoea, except in the setting of significant parapneumonic effusion or in association with congestive heart failure, renal failure, or pulmonary haemorrhage. 9) Acute respiratory distress syndrome: This is defined as acute bilateral lung injury with severe hypoxemia and is commonly associated with pneumonia, aspiration, sepsis, trauma, pancreatitis or receiving multiple transfusions. B. Cardiac causes: Acute Myocardial Infarction (MI): Myocardial ischaemia can present primarily with dyspnoea rather than chest pain, which is important to remember. In addition, patients with acute MI can develop acute PE or congestive heart failure with pulmonary oedema as a complication of MI.

 Congestive heart failure: Accumulation of fluid in the interstitial spaces of the lung stimulates neuroreceptors, which produce a sensation of dyspnoea often causing orthopnea and paroxysmal nocturnal dyspnoea. Common causes of Ischaemic heart disease/heart failure include myocardial ischaemia, hypertension, dilated cardiomyopathy and valvular heart disease. Pericarditis/pericardial effusion causing pericardial tamponade: Dyspnoea and fatigue, as well as chest discomfort are frequently significant complaints. Suspect pericardial effusion in a patient with pulmonary malignancy. Cardiac dysrhythmias: Dyspnoea may accompany cardiac tachyarrhythmias (e.g. atrial fibrillation, supraventricular tachycardia, ventricular tachycardia) or bradyarrhythmias (e.g. complete atrioventricular block or sinus bradycardia). Valvular or other cardiac disease: Aortic stenosis, aortic insufficiency, mitral stenosis and mitral insufficiency as well as intracardiac shunt and atrial myxoma can cause dyspnoea. C. Neuromuscular diseases: Dyspnoea can be caused by central nervous system disorders, proximal myopathies, neuropathies, phrenic nerve or diaphragmatic disorders, spinal cord disorders or systemic neuromuscular diseases for example myasthenia gravis, Guillain-Barr syndrome. D. Other organic diseases: Anaemia, gastro-oesophageal reflux, thyrotoxicosis, hypothyroidism, metabolic acidosis (particularly diabetic ketoacidosis), renal failure (with concomitant pulmonary oedema and/or uremic pericarditis), carbon monoxide poisoning, massive ascites (effectively resulting in restrictive lung disease), and deconditioning may all cause dyspnoea. E. Psychogenic breathlessness: Dyspnoea associated with hyperventilation can be difficult to separate from dyspnoea due to organic causes. Typically anxiety, acral paraesthesias and light-headedness are present. The dyspnoea is worse at rest and improves during exercise. A diagnosis of psychogenic breathlessness should not be made until organic diseases have been excluded. These patients often have an increased frequency of sighing.

Relevant investigations for dyspnoea:

Full blood count and blood film: Leukocytosis with an increase in banded neutrophils occurs with pneumonia. Anaemia can cause dyspnoea on exertion and may precipitate myocardial ischaemia in patients with established coronary heart disease. Arterial blood gases (ABGs): These values should be obtained in any patient with significant dyspnoea or when hypoxemia is suspected based on a decreased percentage of oxygen saturation as measured by pulse oximetry. Assess for elevation of the alveolar-arterial (A-a) pO2 gradient. See below for basic ABG interpretation. Sputum gram stain, microscopy, culture and sensitivity: Obtain if pneumonia is suspected. Electrolytes, and renal function tests: Metabolic acidosis or renal failure may be discovered. Potential metabolic causes of cardiac arrhythmias (e.g. hypocalcemia, hypokalemia/hyperkalemia, hypomagnesemia) or diaphragmatic dysfunction (hypophosphatemia) can be uncovered. Thyroid function tests: Obtain if Thyroid disease is suspected. Markers of cardiac disease: Elevations of creatinine kinase (particularly MB fraction) and troponin are supportive of myocardial ischaemia or infarction. Brain natriuretic peptide (BNP) increases in acute ventricular dysfunction, but also may be elevated in chronic heart failure, PE or corpulmonale. Chest x-ray: Obtain a stat portable upright chest x-ray if there is obvious distress. If the patient is unable to sit for an adequate film, obtain lateral decubitus films to rule out the possibility of basilar pneumothorax. A clear chest x-ray raises the possibility of airway obstruction or PE. An increased cardiac silhouette (implies wither cardiomegaly from heart disease or pericardial effusion), pulmonary vascular congestion, infiltrates, pleural effusion, elevated diaphragm (seen in neuromuscular disorders), or pneumothorax may be discovered. See below for chest x-ray basic interpretation.

 ECG: Should always be obtained in evaluating acute dyspnoea to rule out myocardial ischaemia or infarction (ST depression, ST elevation-complex upwards; T-wave inversion; new Q waves); arrhythmias; pericarditis (PR depression, ST elevation-diffuse and concave upward, T-wave inversion), pericardial effusion (low QRS amplitude, electrical alternans); or PE (S1Q3T3, right-axis deviation, right-bundle branch block; T wave inversion). Pulmonary function tests: These are not applicable to the acute situation, but can assist in the evaluation of patients with obstructive or restrictive lung disease. (See below for interpretation of these tests). Bronchial provocation testing, may help increase yield of pulmonary function testing when looking for causes of chronic dyspnoea or cough. Ventilation-perfusion ( V Q ) scan: To evaluate for PE (although PE diagnosis is now made more accurately with CT pulmonary angiography). With underlying cardiopulmonary disease, spiral CT of the chest may be preferred because of the higher rate of ventilation defects, thus lowering the number of high-probability scans. Remember that spiral CT is an excellent rule-in test, but a negative result does not rule out PE and hence CT reader expertise is essential. Pulmonary angiogram: In patients with low or moderate probability V/Q scan, or negative spiral CT in whom there exists a suspicion for PE, this test is the gold standard for diagnosing PE. A venogram or impedance plethysmography and Doppler ultrasound scan of lower extremities may be helpful, potentially obviating the need for pulmonary angiogram if results demonstrate thrombosis. Echocardiography: Should be obtained emergently if there is a strong clinical suspicion for cardiac tamponade/pericardial effusion. Otherwise, echocardiography can be useful for assessing left ventricular function and valvular function and whether or not cardiac disease is responsible for the dyspnoea. Cardiopulmonary exercise testing: Useful if the diagnosis is unclear. It can help determine whether a cardiac or pulmonary abnormality exists. Summary of some important causes of dyspnoea: Type of dyspnoea Pathology in dyspnoea Bronchospasm airway constriction and obstruction Increased mucous secretion obstruction Smooth muscle hypertrophy airway constriction COPD Shunting (bronchitis component) and dead-spacing (emphysema component) leading to ventilation-perfusion mismatch hypoxemia dyspnoea Pneumonia Destruction of lung tissue & inflammation leading to exudation and oedema in small airways decreased effectiveness of gas exchange Pulmonary oedema Alveolar oedema decreased gas exchange Pneumothorax Air in pleural space displacing lung tissue dead-spacing Pulmonary embolism Pulmonary arterial obstruction hypoxaemia/dead-spacing Acute Respiratory Diffuse alveolar damage and hyaline membrane formation Distress Syndrome decreased effectiveness of gas exchange hypoxemia (ARDS) dyspnoea Pleural effusion Displaced lung tissue dead-spacing plus underlying cause of effusion causing dyspnoea (e.g. infection, cancer) Aspiration Foreign object obstruction and associated pneumonitis Myocardial infarction Decreased effectiveness of cardiac output hypoxia CCF Pulmonary oedema Arrhythmia Decreased effectiveness of cardiac output hypoxia Cardiac tamponade Obstruction to cardiac output hypoxia Acidosis/hypercapnea Respiratory compensation tachypnoea & dyspnoea Sepsis Metabolic (lactic) acidosis respiratory compensation Anxiety/Panic Psychogenic (SpaO2 does not decrease despite perception) Asthma Cause

Mechanical

Secondary Cardiac Metabolic Psychiatric

Clinical assessment of presenting problem: Haemoptysis

A 60-year old male smoker comes to the emergency department complaining of spitting up blood for 1 week. Immediate questions: Is the patient truly experiencing haemoptysis? Haemoptysis is defined as the expectoration of blood from the respiratory tract- a spectrum that varies from blood-streaked sputum to large amounts of pure blood. Blood from the nasal, oral or upper GI (i.e. gastro-oesophageal) source may be aspirated to the larynx and then expectorated- dont confuse with epistaxis or haematemesis. Usually, sputum is intermixed with blood in the haemoptysis and is frothy, alkaline and bright red. Haematemesis is acidic and dark. Note: Melaena may occur if blood is swallowed. What is the volume of the haemoptysis? Massive haemoptysis (>100-600ml/24 hours) connotes a lifethreatening problem that demands immediate ICU admission as well as rapid diagnostic evaluation. Although the patients estimates may be notoriously unreliable, but life-threatening nonetheless. Has this happened before? If so, how frequently? Patients with recurrent acute bronchitis or with mitral stenosis may have had multiple episodes or minor haemoptysis. What is the smoking history? The higher the pack years, the more likely the patient has chronic bronchitis or bronchogenic carcinoma. Is there a history of productive cough preceding the haemoptysis? If the answer is yes, then the problem may be an infection, such as acute bronchitis or bronchiectasis. Has there been any history of accompanying chest pain? Pleuritic chest pain may be a symptom of pneumonia, or a pulmonary embolism with infarction. Haemoptysis may accompany pulmonary oedema from any number of causes. Differential diagnosis: A. Pulmonary causes: 1) Infection a) Acute or chronic bronchitis- one of the most common causes of bronchitis, blood-streaks in sputum b) Pneumonia- A necrotising gram negative or staphylococcal pneumonia can cause haemoptysis. Symptoms are acute. c) Lung abscess- Often produces foul-smelling sputum. d) Bronchiectasis- Seen in patients with recurrent episodes of respiratory infections, voluminous foulsmelling sputum production, and intermittent haemoptysis. e) Tuberculosis- Usually apical infiltrates are observed on chest x-ray. Symptoms are often chronic or subacute. f) Parasitic- Paragonimiasis and Hydatid cysts (echinococcosis) (both rare). g) Mycetoma- A ball of Aspergillus fungus may form in a previously formed cavity, blastomycosis. Look for the crescent sign on chest x-ray. Below: PA chest radiograph of a 14-year-old girl with a thinwalled cavity in the right upper lobe (long arrows) containing a fungus ball (short arrows). B: PA chest radiograph after change in patient position shows movement of the mobile fungus ball.

B. Neoplastic causes: a) Bronchogenic carcinoma- Usually, the chest x-ray is abnormal, but it may be normal in up to 13% of patients with early lung cancer and haemoptysis. b) Bronchial adenoma- Carcinoid tumours are notorious for brisk haemoptysis and suspect in a young patient. Chest radiograph may be normal. c) Metastatic disease- A history of cancer should be uncovered during the history. The chest xray will be abnormal, usually with multiple lesions and there may be endobronchial infiltration, causing haemoptysis. d) Kaposi sarcoma- consider in a HIV patient with poorly controlled HIV or AIDS. C. Vascular causes: a) Pulmonary embolism (PE) with infarction- Only 10% of patients with PE present with haemoptysis, but pulmonary emboli are very common and should not be missed. b) Mitral stenosis-May arise from rupture of the pulmonary veins or from frank pulmonary oedema. c) Cardiogenic pulmonary oedema- Surprisingly common, especially now that most cardiac patients are on some form of anticoagulant therapy. d) Pulmonary arteriovenous malformation e) Osler-Weber-Rendu disease (hereditary haemorrhagic telangiectasis) D. Trauma: a) Pulmonary contusion- direct lung injury. b) Bronchial or vascular tear- wounds, post-intubation or thoracic surgery, lung biopsies. c) Retained/aspirated foreign body- Teeth and fillings sometimes find their way down into the bronchi. E. Systemic diseases: 1) Anticoagulation/bleeding diatheses a) Drugs- Warfarin (Coumadin), heparin, aspirin, streptokinase (Streptase), urokinase (abbokinase), tissue plasminogen activator, and APSAC (anisoylated plasminogen streptokinase activator complex) or antistreplase (Eminase). Cocaine is an important drug to remember as it can cause nasal bleeding with intranasal cocaine use (snorting/snuffing). b) Uraemia c) Thrombocytopenia- drugs, idiopathic thrombocytopenic purpura, cancer d) Disseminated intravascular coagulation (DIC) e) Liver disease- Severe liver disease can result in thrombocytopenia and also decrease production of coagulation factors. 2) Autoimmune diseases/genetic/other a) Wegeners granulomatosis- Look for renal changes of glomerulonephritis (red cell casts, haematuria, proteinuria) and upper and lower respiratory tract and sinus disease. The chest x-ray and chest CT is often abnormal. Bilateral nodular densities and cavitation are common. Haemoptysis from small vessel granulomatous vasculitis with necrosis. b) Goodpastures syndrome- This disease often involves the kidney. Proteinuria, haematuria and red cell casts may be present. Diffuse alveolar infiltrates are often present. c) Systemic lupus erythematosis (SLE)- Lupus more frequently involves the pleura, but patients may develop life-threatening haemoptysis from lupus pneumonitis. Pulmonary pathology can include haemorrhage, pleural effusions, pleuritis and interstitial fibrosis. ANA serology positive and often abnormalities are seen on chest imaging (effusions, interstitial infiltrates). d) Cystic fibrosis (CF)- although not an autoimmune condition, haemoptysis can occur in CF. e) Idiopathic pulmonary haemosiderosis- Consider with haemoptysis in children (also predominace in males), exclude all other causes and this requires a tissue biopsy. f) Polyarteritis nodosa- if the vasculitis involves the bronchial arteries and erodes into the airways. g) Sarcoidosis- if there is active granulomatous vasculitis (rare).

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Physical examination key points: 1) Vital signs: Look particularly for fever and signs of impending respiratory failure: tachypnoea with respiratory rate >30 per minute, abdominal paradox with inspiration (Hoovers sign), and accessory muscle use. 2) HEENT: Look carefully for a nasal or oropharyngeal source of bleeding. 3) Chest: Inspect and palpate for signs of trauma such as rib or clavicle fractures. Listen for a pleural friction rub, localised rales, or signs of consolidation. 4) Heart: An irregularly irregular pulse signifies atrial fibrillation and suggests mitral stenosis as a possible cause. Pulmonary embolus can also cause atrial fibrillation. An S3 and jugular venous distension suggest congestive heart failure as a possible cause. Always listen carefully for the low diastolic rumble of mitral stenosis at the cardiac apex with the bell. 5) Abdomen: Palpate the epigastrium, liver and spleen. Peptic ulcer disease or alcoholic liver disease could certainly cause GI bleeding which might be believed to be haemoptysis. 6) Extremities: Examine the lower extremities for signs of deep venous thrombosis or oedema. Look for cyanosis or clubbing. Clubbed fingers associated with haemoptysis generally imply bronchiectasis or pulmonary neoplasm. 7) Skin: Inspect the skin for petechiae, ecchymoses, purpura, angiomata, and rashes. Relevant investigations for a patient with haemoptysis: It is very important to obtain an adequate history and examination to identify the cause and direct investigations. Full blood count and blood film: May reveal anaemia that could be caused by haemoptysis or, more likely, is related to haemoptysis. A normocytic anaemia, with a normal or low reticulocyte count may be secondary to anaemia of chronic disease (e.g. cancer). An elevated reticulocyte count indicates haemolytic anaemia possibly secondary to an autoimmune disease process, consider SLE. An iron deficiency can indicate Goodpastures syndrome. Platelet count, prothrombin time, INR and activated partial thromboplastin time: All are indicated to rule out a coagulopathy as a cause. If platelet dysfunction is suspected, bleeding time will be prolonged in the presence of a normal platelet count. D-dimer: in cases of suspected PE or if the patient is believed to be developing DIC. Group and hold and crossmatch- important if transfusion is needed. Urea, creatinine and electrolytes (UECs): For rapid evaluation of pulmonary-renal syndromes (Goodpastures syndrome, Wegeners granulomatosis, SLE and other forms of vasculitis). Antineutrophil cytoplasmic antibodies (ANCA) and anti-glomerular basement antibody (anti-GBM): May indicate Wegeners granulomatosis (especially cytoplasmic-staining ANCA (C-ANCA)) and anti-GBM Ab is positive in 85% of patients with Goodpastures syndrome. Arterial Blood gases: Check for adequate ventilation and oxygenation. If the patient has underlying pulmonary disease, respiratory failure may be precipitated by haemoptysis. Sputum examination including cytology: If the sputum is purulent, Gram stain and culture and antibiotic sensitivity are helpful. For patients with upper lobe infiltrates or HIV, check sputum samples for acid fast bacilli smear and culture. Sputum cytology is useful in detecting lung cancer, and can be further used with staining techniques including immunohistochemistry, silver or acidfast stains. If blood is mixed with sputum and purulent and the patient is febrile- consider bronchitis or pneumonia. If it is foul-smelling also consider bronchiectasis (especially if chronic and copious) or lung abscess. Blood not mixed with sputum suggests trauma or infarction (sudden pleuritic chest pain with dyspnoea). PPD (tuberculin) skin test: To help rule out tuberculosis. Other autoimmune blood tests: Anti-nuclear antibodies (ANA) for SLE and serum complement levels including C3 and C4, which may also be decreased in Goodpastures syndrome with glomerulonephritis.

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 .Chest x-ray: First and most important radiological test after the history and physical examination. The pattern and location of any infiltrate, combined with the history and physical examination findings will dictate the remainder of the work-up. Ventilation/perfusion ( V Q ) scan: If pulmonary embolism is suspected, a scan must be done. Alternatively a spiral CT may be done or a CT pulmonary angiogram (more sensitive for PE diagnosis). With underlying cardiopulmonary disease, spiral CT/CTPA of the chest may be preferred because of the higher rate of ventilation defects, thus lowering the number of highprobability scans. Remember that spiral CT is an excellent rule-in test, but a negative result does not rule out PE and hence CT reader expertise is essential. Angiography: If PE is suspected and scans are not clearly positive or negative (indeterminate), then pulmonary angiography is indicated. Angiography may also be indicated for the diagnosis of pulmonary arteriovenous malformations. Chest CT including CT angiography: This provides much better anatomic view of pulmonary pathology compared with chest radiographs and also reveals lesions not seen previously. However, the CT pulmonary angiogram is only indicated acutely if looking for an aortic dissection or PE. CT angiography (helical or spiral and electron-beam) are about 90% sensitive and 90% specific for detecting proximal (main, lobar and segmental) pulmonary artery emboli. CT angiography is not good at detecting subsegemental emboli. ECG: May show atrial fibrillation. A right axis shift and/or right bundle branch block may suggest a PE. Classically, a large PE produces an S wave in lead I, and a Q wave and inverted T wave in lead III (S1Q3T3). Bronchoscopy: Patients with unclear sources of haemoptysis, massive haemoptysis, or the suspicion or a neoplasm require fibreoptic bronchoscopy. The earlier it is done, the more likely the source of bleeding will be identified.

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Basic plan for a patient with haemoptysis: 1) ICU admission may be necessary if a. There is massive haemoptysis. b. There is present or impending hypoxemic or hypercarbic respiratory failure. 2) Establish IV access: Death results from asphyxia rather than haemorrhage, but IV access is important for administration of medications. 3) Always protect the airway: This may require early intubation. 4) Correct any coagulopathy 5) Arrange a bronchoscopy: arrange early especially if the diagnosis is unclear or if haemoptysis continues. 6) Consult: Obtain a cardiothoracic surgery consult if the patient has massive or continuous haemoptysis. Medical management of massive haemoptysis is associated with a high mortality rate. 7) Cough suppression: Retard the cough reflex with codeine-based drugs, and place the patient on quiet bed rest. 8) Treat the underlying disease state: a. Lung cancer: Can be treated surgically if there are no metastases present and there is adequate pulmonary reserve. Otherwise, radiation, or laser therapy can control bleeding. b. Infections: Treat with antibiotics as dictated by Grams stain and clinical picture. If a necrotising pneumonia is present, consider methicillin resistant Staphylococcus aureus or Pseudomonas infection and treat accordingly. c. Pulmonary emboli: Treat acutely with heparin or enoxaparin. d. Diffuse alveolar haemorrhage or pulmonary-renal syndrome: 1000mg methylprednisolone (Solu-Medrol) IV may control bleeding, pending definite workup. e. Nonsurgical patients with localised bleeding: Bronchial arteriography followed by embolism may be life-saving. However, collateral circulation to the spinal arteries or carotids must be excluded before embolisation.

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Surface anatomy of the Thorax and lungs

1. Apertures of the Thorax: The superior or thoracic inlet (5 cm anteroposteriorly and 10-11 cm transversely) is bounded by the body of the 1st thoracic vertebra, the medial border of the first ribs and their costal cartilages, and the superior part of the manubrium of the sternum. The inferior or thoracic outlet is bounded by the TV12, 12th pair of ribs, costal margins and the xiphisternal joint. Palpate the superior and inferior apertures. 2. Thoracic vertebrae (TV): Palpate and count the thoracic spines starting from the 7th cervical vertebra (vertebra prominens) which usually is the first prominent lump when palpating from above downward. Make it prominent by having the patient flex their neck. Spinous processes of TV1 to TV4 are easy to feel and see, those of TV5 TV12 are much more difficult to palpate. Also the vertebral border of the scapula can be felt (TV2-TV7 level). 3. Sternum: In the midline, palpate the jugular notch at the upper end of the manubrium and between the sternal ends of the clavicle. The notch is usually at the level of TV2 or TV3. Slide your finger down the midline for ~5cm and this prominence is the site of the sternal angle (of Louis) (at TV4 or a disc between TV4-TV5). It is an important landmark for the lower border of the superior mediastinum and for the level of the 2nd costal cartilage, the starting point from which the ribs should be counted. Palpate the xiphoid process lying at the bottom of the infrasternal fossa (epigastric fossa or pit of the stomach). 4. Ribs: The first rib can be felt below and above the medial 1/3 of the clavicle. The other ribs can be palpated by placing the fingertips in the axilla and slowly drawing them back inferomedially over the ribcage. Note that the spine of the scapula lies over the 3rd rib or 3rd intercostal space and the inferior angle of the scapula is at the level of the 7th rib and it is a good guide to the 7th intercostal space. The costal margins are palpable with ease. The highest part of the costal margin is formed by the 7th costal cartilage and the lowest part by the 10th costal cartilage. Anteriorly, the ribs can be counted, starting from the sternal angle (which is the 2nd costal cartilages), below which is the 2nd intercostal space. This is important for finding the location of the apex cardiac beat & check for its displacement. 5. Diaphragm: The level of the diaphragm on both sides varies in relation to the ribs and to the vertebrae according to the phase of respiration, posture and degree of distension of the abdominal viscera. The diaphragm is highest when the person is supine, lowest when the person is sitting or in an erect position (this explains why patients with difficulties in inspiration prefer to sit up/stand rather than lying down). In an erect position, the right dome of the diaphragm should be at the level of the 5th intercostal space midclavicular line, the central tendon at the xiphisternal junction, and the left dome at the level of the 6th costal cartilage. 6. Trachea, lungs and Pleurae: The bifurcation of the trachea is at or below the sternal angle (TV5 or TV6) and slightly to the right. The bifurcation is not fixed and moves downward with respiration. The main bronchi move obliquely for 2.5 cm. The pleural cavity on each side surrounds a lung and is lined by parietal pleura. These two pleural cavities represent separate and closed potential spaces. The parietal pleura which cover the different parts of the thoracic wall and thoracic content can be divided into: (1) costal pleura, (2) mediastinal pleura, (3) diaphragmatic pleura and (4) cervical pleura. The apex of the lung is covered by cervical pleura (dome or cupola) which extends through the inlet of the thorax upwards to the neck of the 1st rib (level of the spinous process of CV7). Because the 1 st rib slopes downward, the lungs and the pleura rise about 3 cm above the anterior end of the 1st rib and 1 to 2 cm above the middle third of the clavicle, behind the sternomastoid muscle. The lines of pleural reflection are sites at which the costal pleura becomes continuous with the mediastinal pleura anteriorly and posteriorly and with the diaphragmatic pleura inferiorly. The sternal or anterior reflection: a line from the sternoclavicular joint to the median line at the level of the sternal angle. Then the right margin continues down to the xiphisternal joint, the left margin curves out from the 4th costal cartilage along the margin of the sternum to the 6th costal cartilage. The costal or inferior reflection is where the costal pleura is continuous with the diaphragmatic pleura near the costal margin. It passes obliquely across the 8th rib in the midclavicular line , the 10th rib in the midaxillary line and the 12th rib towards the spinous process of TV12 (mnemonic Pleura 8, 10, 12).

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The Lungs: The apex of the lung rises above the clavicle, filling the cupola of the pleural sac. The anterior border of the lung follows the lines of pleural reflection, except for the anterior border of the left lung which deviates ~2.5 cm laterally from the left margin of the sternum to form the cardiac notch. The inferior border of both lungs crosses the 6th rib in the midclavicular line, the 8th rib at the midaxillary line, 10th rib in the midscapular line and ends ~2.5cm lateral to the spinous process of TV10 (mnemonic: Lungs 6, 8, 10). During deep inspiration, the apparent level of the lung descends at least two intercostal spaces. The oblique fissure of the lung can be drawn on the surface of the thorax from a point ~2.5cm lateral to the spinous process of the TV2 to the 6th costochondral junction (~5cm from the anterior median line). When the arm is abducted and the hand on the back of the head, the medial border of the scapula approximately indicates the oblique fissure. The horizontal fissure of the right lung is indicated by a longitudinal line that runs from the anterior border of the lung along the 4th costal cartilage to the oblique fissure.
For the right lung:

For the left lung:

7. Important points for physical examination of the chest: a. By inspection: General contours of the chest, the respiratory movements, the apex beat which may be visible or other pulsations. b. By palpation: The position of the mediastinum can be assessed by determining the position of the cardiac apex beat and the trachea. c. By percussion: By percussion the boundaries between contiguous organs can be determined, and it should be performed from the resonant (e.g. lung) towards less resonant (e.g. heart or liver) organ. Normally lungs are resonant to percussion and there are areas of dullness over the liver and heart. Impaired resonance is found over consolidated or collapsed lungs. The inferior, left and right borders of the heart may be determined by percussion and by this means the cardiac area (area of cardiac dullness) can be outlined. d. By auscultation: The breath sounds are characterised by long inspiratory phase followed by the expiratory phase, which can be heard over the lungs. Bronchial breathing (harsher quality) is heard by listening with a stethoscope over the larynx or trachea.

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Heart sounds: are produced by valve closure, the first heart sound is produced by closure of the atrioventricular valves (tricuspid and mitral valves), the second heart sound is produced by closure of the semilunar aortic and pulmonary valves. The first heart sound is best heard at the cardiac apex (mitral valve area) and over the lower part of the body of the sternum (tricuspid valve area). The second heart sound is best heard at the 2nd right (aortic valve) and 2nd left (pulmonary valve) intercostal space. The first sound corresponds with the beginning of ventricular systole, the second sound is sharper and shorter than the first and marks the beginning of ventricular diastole. In some abnormal conditions abnormal heart sounds can be heard. They may be caused by pathological narrowing of the valves (e.g. mitral stenosis), incompetence of the valves or by distension of the channels.

Examination of the Respiratory system

I. General Inspection: Stand back, inspect for a sputum cup (purulent sputum indicates respiratory infection or bronchiectasis, haemoptysis important), can the patient talk? Dyspnoea, count respiratory rate, check use of accessory muscles of respiration, intercostal in-drawing of lower ribs, cachexia. Inspect for Obvious chest wall abnormalities including thoracic kyphosis, ankylosing spondylitis, increased anteroposterior diameter of chest wall (Barrel chest that occurs in patients with emphysema), Tripod position. Hands: Pick up the patients hands, look for clubbing, peripheral cyanosis, tar staining, palmar erythema, anaemia. Note small muscle wasting of the hands (check for asymmetry, unilateral wasting can occur with a Pancoasts tumour) and weakness of finger abduction (lung cancer involving the brachial plexus, get patient to abduct fingers and then the examiner should try to adduct them against patient resistance). Palpate wrists for tenderness (hypertrophic pulmonary osteoarthropathy). Palpate radial pulse for obvious tachycardia, AF or pulsus paradoxus (a bounding pulse, an exaggeration of the normal variation in the systemic arterial pulse volume with respiration, becoming weaker with inspiration and stronger with expiration; characteristic of cardiac tamponade, rare in constrictive pericarditis; so called because these changes are independent of changes in the cardiac rate as measured directly or by electrocardiogram. In respiratory disease it indicates CO2 retention, there is an increase in pulse pressure as CO2 is a good vasodilator. It can be measured clinically with >10 mmHg difference in systolic pressure). Also make the patient extend their arms at the elbow, with flexed wrists and abducted fingers to check for a flapping tremor (asterixis) of Carbon dioxide narcosis with severe COPD. Also palpate the axillary lymph nodes.

II.

Peripheral cyanosis (look at thumbs)

Nicotine tar stains

Fingernail clubbing (can also occur with toenails) is the exaggerated curvature of nails in all directions, and there is a loss of the angle between the nail and the nail fold and the nail fold feels boggy, these are due to changes in blood flow but exact mechanism is not known. Remember the most important causes of according to different systems: (1) Thoracic causes: Bronchial carcinoma (usually not small cell), chronic lung suppuration including: empyema/abscesses, bronchiectasis, cystic fibrosis, fibrosing alveolitis and mesothelioma. (2) GI causes: IBD (especially Crohns disease), cirrhosis, GI lymphoma, malabsorption disease, e.g. coeliac disease. (3) Cardiac

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causes: Cyanotic congenital heart diseases, Endocarditis, Atrial myxoma. (4) Rare causes include: familial, thyroid acropachy, unilateral clubbing from axillary artery aneurysm or brachial arteriovenous malformations (AVMs).

This image of a patient with emphysema in the Tripod position; where they are leaning forward to increase their ventilatory capacity and this promotes use of accessory muscles. The patient appears cachectic and almost typical appearance of a patient who is a pink puffer. Also when observing, inspect the whole patient and their surroundings, are they sitting up/standing, do they appear comfortable/in distress, do they have ventilatory aids such as a ventilatory mask/Nebuliser (what type is it, e.g. Venturi mask, Hudson mask) attached to an oxygen source, or a metered nose inhaler, nasal prongs, walking aids etc.

III.

Face: Look for pupil constriction and ptosis (occurs unilaterally from decreased sympathetic activity with Horners syndrome due to n apical Pancoasts lung cancer compressing the cervicothoracic/stellate ganglion). Look at the eyes for conjunctival pallor which may suggest anaemia. Inspect tongue for central cyanosis and the oropharynx to check the tonsils. Examine the inside of the nose and check for visible nasal polyps (if patient has a blocked nose), a deviated nasal septum (have they had nasal surgery?). Does the patient have a hoarse voice (e.g. with recurrent laryngeal nerve palsy)?

IV.

Trachea: Palpate the position of the trachea. If the trachea is displaced, you must concentrate on the upper lobes for physical signs. Tracheal tug (indicates severe airflow obstruction) and feel for the use of the accessory muscles. Ask the patient to speak (hoarseness) and then cough and note whether this is a loose cough, a dry cough or a bovine cough. Measure the forced expiratory time (FET). Tell the patient to take a maximal inspiration and blow out as rapidly and forcefully as possible while you listen. Note audible wheeze and prolongation of the time beyond 3 seconds as evidence of chronic obstructive pulmonary disease. Similarly, peak expiratory flow can be measured using a Peak Flow device, where the patient must be standing and with maximal inspiration they must expire rapidly and forcefully and the best of 3 measurements should be recorded; also make sure that you do not touch the patients mouthpiece (before and after use).

V.

Back of the chest: This is when the patient should be undressed. 1) Inspection: Look for kyphoscoliosis. Do not miss ankylosing spondylitis, which causes decreased chest expansion and upper lobe fibrosis and watch out for any chest wall abnormalities (e.g. pectus excavatum, pectus carinatum). Look for thoracotomy scars and prominent veins. Also note any skin changes for

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radiotherapy markers or radiotherapy scars. 2) Palpation: Palpate first from behind for the cervical and supraclavicular lymph nodes. Then examine for expansion-first upper lobe expansion, which is best seen by looking over the patient's shoulders at clavicular movement during moderate respiration. The affected side will show a delay or decreased movement. Then examine lower lobe expansion by palpation. Note asymmetry and reduction of movement. 3) Percussion: ask the patient to bring his or her elbows together in the front to move the scapulae out of the way. Examine for tactile vocal fremitus first then percuss the back of the chest. Percussion is quite useful for detecting pleural effusions, but it is essential to have appropriate technique, make sure you have flowing, floppy wrists & make sure the finger being struck is placed firmly on the patients chest wall 4) Auscultation usually with the diaphragm in respiratory examination: Note breath sounds (whether vesical or bronchial) and their intensity (normal or reduced). Listen for adventitious (added) sounds (crackles and wheezes). Finally examine for vocal resonance. If a localised abnormality is found, try to determine the abnormal lobe and segment. (It is essential that for a complete respiratory examination, both the anterior and posterior chest wall is examined, importantly because the upper lung lobes are mainly located anteriorly, whilst the lower lobes are mainly located posteriorly- see surface anatomy.)

Note that sometimes chest wall deformities may be subtle, e.g. scoliosis here, so look for it!!

VI.

Front of the chest: 1) Inspection: Inspect again for chest deformity, distended veins, radiotherapy markers and changes (skin may appear erythematous after a course of radiotherapy) and scars. 2) Palpation: Chest wall expansion can be checked, note that it is best to check both upper and lower chest wall expansion. Palpate the supraclavicular and axillary nodes (leave till last if patient sweaty). 3) Percussion: as for back 4) Auscultation: as for back:

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VII.

The heart: In order to examine the heart and JVP, the patient MUST be laying down at 45 degrees. Measure JVP. Examine the praecordium and lower limbs for signs of cor pulmonale. Alternatively, the JVP can be measured after examining the face, just remember to have the patient at the right angle for JVP!

VIII.

The abdomen: Palpate the liver for liver ptosis (due to emphysema, or for enlargement from secondary deposits of tumour in cases of lung carcinoma).

IX. Other: Pembertons sign (ask patient to lift arms over head & wait for 1 minute. In superior vena caval obstruction, patient with have facial plethora, cyanosis, inspiratory stridor & non-pulsatile elevation of JVP). Inspect calves and feet for oedema or cyanosis (cor pulmonale) and DVTs. Measure temperature (infection) & respiratory rate with exercise. Important physical signs related to the respiratory system Signs of respiratory disease: The following are important signs of respiratory disease to be aware of: o Dyspnoea and obvious shortness of breath o Tachypnoea (respiratory rate >25 breaths per minute), Bradypnoea with respiratory rate <8 breaths per minute. Count the respiratory rate surreptitiously as respiration is also under voluntary control and the patient may consciously try to reduce their respiratory rate, or anxiety may increase respiratory rate. Normal range is between 12-20 breaths per minute. Tachypnoea should hence be >20 breaths per minute, but >25 breaths per minute is definite tachypnoea. Note that the respiratory rate in paediatrics is different in adults, as babies have a faster respiratory rate that reduces to the normal adult value over time. o Use of accessory muscles of respiration, including nasal flaring, use of the sternocleidomastoid, scalenus muscles, costal in-drawing; the Tripod position. o Pursed-lip breathing, e.g. in patients with emphysema or any other lung disease. o Cyanosis- central and peripheral cyanosis. o Clubbing of the fingernails. o Wheeze or stridor. o Prolongation of the expiratory phase. Signs of Chest wall hyperinflation: Be able to identify signs of chest wall hyperinflation. This includes a barrel-shaped chest with an increased anteroposterior diameter.

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 Pursed-lip breathing occurs in COPD that is predominantly emphysema (but not in predominantly chronic bronchitis) and this is the expiration through partly closed lips which increases the endexpiratory pressure and helps keep the airways open, which helps minimise air trapping. Use of accessory muscles of respiration and in-drawing of the lower intercostal muscles with inspiration. With palpation one can measure chest wall expansion, and if the chest wall is already expanded, then there will be reduced chest wall expansion and a hyper-inflated chest wall. With percussion, one should classically hear a hyper-resonant note, with decreased liver dullness. Although this is a poor test and hard to discern. Breath sounds: decreased breath sounds (due to less expansion of airways) as well as possibly early inspiratory crackles. In a hyper-inflated chest radiograph, more than six ribs can be seen above the diaphragm in the midclavicular line. There are also flat hemidiaphragms, increased transverse diameters, and a small contour of the heart, as seen below:

Demonstrate signs of abnormalities in chest wall expansion: Place the hands firmly on the chest wall with the fingers extending around the sides of the chest. The thumbs should almost meet in the middle line and should be lifted slightly off the chest so that they are free to move with respiration. As the patient takes a big breath in, the thumbs should move symmetrically apart at least 5 cm. Reduced expansion on one side indicates a lesion on that side. Reduced unilateral chest wall movement (i.e. on one side) may be due to localised pulmonary fibrosis, consolidation, lung collapse/atelectasis, pleural effusion or pneumothorax. Bilateral reduction of chest wall movement indicates a diffuse abnormality such as COPD or diffuse pulmonary fibrosis. Detect abnormalities in the percussion note: The percussion note is affected by the thickness of the chest wall, as well as by underlying structures: Percussion over a solid structure, such as the liver or a consolidated area of lung, produces a dull note. Percussion over a fluid-filled area, such as a pleural effusion, produces an extremely dull (stony dull) note. Percussion over the normal lung produces a resonant note. Percussion over hollow structures, such as the bowel or a pneumothorax, produces a hyper-resonant note.

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Chest Auscultation: Listen to Lung sounds recordings for revision & practice on patients! Be able to understand normal breath sounds. Using the diaphragm of the stethoscope, one should listen to the breath sounds in all zones of the lung. It is important to compare each side with the other. Remember to listen high up into the axillae and, using the bell of the stethoscope applied above the clavicles, to listen to the lung apices. A number of observations must be made while auscultating and, as with auscultation of the heart, different parts of the cycle must be considered. Listen for the quality of the breath sounds, the intensity of the breath sounds, and the presence of additional (adventitious) sounds. Quality of breath sounds: Normal breath sounds are heard with the stethoscope over nearly all parts of the chest. The patient should be asked to breathe through the mouth so that added sounds from the nasopharynx do not interfere. These sounds are produced in the airways rather than the alveoli. They had once been thought to arise in the alveoli (vesicles) of the lungs and are therefore called vesicular sounds. Their intensity is related to total airflow at the mouth (hence patient must take a deep breath in and out through the mouth) and to regional airflow. Normal (vesicular) breath sounds are louder and longer on inspiration than on expiration and there is no gap between the inspiratory and expiratory sound phases. They are due to the transmission of air turbulence in the large airways filtered through the normal lung to the chest wall. The diagram below compares normal vesicular breath sounds with harsh bronchial sounds and where these sounds are normally heard. The numbers suggest an order of where the lungs should be auscultated on the anterior chest, note importantly that each lung should be compared at the same level:

With bronchial breath sounds turbulence in the large airways is heard without being filtered by the alveoli, producing a different quality. Bronchial breath sounds have a hollow, blowing quality. They are audible throughout expiration and there is often a gap between inspiration and expiration. The expiratory sound has a higher intensity and pitch than the inspiratory sound. Bronchial breath sounds are more easily remembered than described. They are audible in normal people, posteriorly over the right upper chest where the trachea is contiguous with the right upper bronchus. Very importantly, bronchial breathing sounds are heard over areas of consolidation, as solid lung conducts the sound of turbulence in main airways to peripheral areas without filtering. Causes of bronchial sounds include: commonly areas of consolidated lung from pneumonia (especially lobar pneumonia) and uncommonly: localised pulmonary fibrosis, above areas of pleural effusion and collapsed lung (adjacent to a pleural effusion). Bronchial breath sounds are also heard in atelectasis and have a high pitched, hollow quality, clearly audible during expiration & inspiration. In pulmonary fibrosis, bronchial breathing is heard usually in the lower lung zones, having a similar quality as in atelectasis and are usually due to interstitial pulmonary fibrosis. Intensity of the breath sounds. It is better to describe breath sounds as being of normal or reduced intensity than to speak about air entry. The entry of air into parts of the lung cannot be directly gauged from the breath sounds. Causes of reduced breath sounds include chronic obstructive pulmonary disease

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(especially emphysema), pleural effusion, pneumothorax, pneumonia, a large neoplasm and pulmonary collapse. Added (adventitious) sounds. There are two types of added sounds-continuous (wheezes) and interrupted (crackles). Crackles are interrupted non-musical sounds. Crackles are probably the result of loss of stability of peripheral airways that collapse on expiration, created when alveoli and small airways open and close with respiration. Typically associated with interstitial lung disease, microatelectasis or filling of alveoli by liquid. Early inspiratory crackles (cease before the middle of inspiration) suggest disease of the small airways, and are characteristic of COPD. The crackles are heard only in early inspiration and are of medium coarseness. They are different from those heard in left ventricular failure, which occur later in the respiratory cycle. Late or pan-inspiratory crackles suggest disease confined to the alveoli. They may be fine, medium or coarse in quality. Fine crackles have been likened to the sound of hair rubbed between the fingers, or to the sound Velcro makes when pulled apart-they are typically caused by pulmonary fibrosis. Characteristically, more crackles are heard in each inspiration when they are due to fibrosis- up to 14 compared with 1 to 4 for COPD and 4 to 9 for cardiac failure. As fibrosis becomes more severe the crackles extend earlier into inspiration and are heard further up the chest. Basal fine crackles are commonly found with pulmonary fibrosis and left ventricular failure and associated pulmonary oedema. Medium crackles are usually due to left ventricular failure. Here the presence of alveolar fluid disrupts the function of the normally secreted surfactant. Coarse crackles are characteristic of pools of retained secretions and have an unpleasant gurgling quality. They tend to change with coughing, which also has an unpleasant gurgling quality. Bronchiectasis is a common cause as well as atelectasis, but any disease that leads to retention of secretions such as infection may produce these features. Pleural friction rub: when thickened, roughened pleural surfaces rub together as the lungs expand and contract, a continuous or intermittent grating sound may be audible (similar to bits of leather rubbing over each other). A pleural rub indicates pleurisy, which may be secondary to pulmonary infarction or pneumonia. Rarely, malignant involvement of the pleura, a spontaneous pneumothorax or pleurodynia may cause a rub. Wheezes are continuous sounds. They are abnormal findings and have a musical quality. Wheezes reflect oscillation of the airway walls as occurs when there is airflow limitation. The wheezes must be timed in relation to the respiratory cycle. They may be heard in expiration or inspiration, or both. Wheezes are due to continuous oscillation of opposing airway walls and imply significant airway narrowing. Wheezes tend to be louder on expiration. This is because the airways normally dilate during inspiration and are narrower during expiration. An inspiratory wheeze implies severe airway narrowing. Inspiratory wheezes are common to have in upper respiratory tract abnormalities, such as in a patient with a large goitre that is obstructing the trachea. The pitch (frequency) of wheezes varies. It is determined only by the velocity of the air jet and is not related to the length of the airway. High-pitched wheezes are produced in the smaller bronchi and have a whistling quality, whereas low-pitched wheezes arise from the larger bronchi. Wheezes are usually the result of acute or chronic airflow obstruction due to asthma (often high pitched) or chronic obstructive pulmonary disease (often low pitched), secondary to a combination of bronchial muscle spasm, mucosal oedema and excessive secretions. Wheezes are a poor guide to the severity of airflow obstruction. In severe airways obstruction, wheeze can be absent because ventilation is so reduced that the velocity of the air jet is reduced below a critical level necessary to produce the sound. A fixed bronchial obstruction, usually due to a carcinoma of the lung (or a foreign body such as a peanut), tends to cause a localised wheeze, which has a single musical note (monophonic) and does not clear with coughing. Wheezes must be distinguished from stridor, which sounds very similar to wheeze but is louder over the trachea and is always inspiratory (wheezes usually occur in expiration-the majority-but can occur in both inspiration and expiration).

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 Egophony is a peculiar broken quality of voice sounds like the bleating of a goat, heard about the upper level of fluid in the case of effusion, or in consolidation or a tumour. Describe patterns of physical signs with consolidation, effusion & pneumothorax: Signs of lung consolidation: Pneumonia is defined as inflammation of the lung which is characterised by exudation into the alveoli. Pneumonia may be classified on an anatomical basis into lobar, segmental or lobular pneumonia (i.e. bronchopneumonia). The signs of lobar pneumonia are characteristic and are referred to clinically as consolidation. Signs of consolidation include as follows: o Reduced chest expansion on affected side. o Vocal fremitus increased on affected side (this is an important examination in pneumonia, in other diseases it is a fairly useless test). o Percussion note dull, but not stony dull. o Breath sounds: bronchial over affected lobe. Bronchial breath sounds are associated with conditions that increase lung tissue density, (e.g. because of consolidation, fluid accumulation, lung collapse or fibrotic scarring.) One of the most common causes of bronchial breath sounds from consolidation is pneumonia and in pneumonia bronchial breath sounds have a hollow or tubular quality, are high pitched and they remain audible during inspiration and expiration. o Vocal resonance: Increased on the affected zones of lung. This is also known as increased bronchophony (or a nasal egophony sound) and the words ninety nine are hence more clearly heard in consolidation. o Pleural friction rub may be present. Important causes of consolidation include: o Lobar pneumonia: pneumococcal (90% of cases), H. influenzae, staphylococcal. o Bronchopneumonia (lobular): bacteria-H. influenzae and S. pneumoniae (commonest), viruses such as influenza virus, adenovirus, measles virus, cytomegalovirus. In bronchopneumonia, crackles are often the only chest sign. o Primary atypical pneumonia: Mycoplasma pneumoniae (majority), Chlamydia psittaci, Legionella spp, Coxiella burnetii (Q fever). Signs of pleural effusion: This is a collection of fluid in the pleural space. Note that pleural collections consisting of blood (haemothorax), chyle (chylothorax) or pus (empyema) have specific names, and are not called pleural effusions, although the physical signs are similar. Important signs of a pleural effusion include: o Trachea and apex beat: displaced away from a massive effusion. o Chest Expansion: reduced on the affected side. o Percussion: Stony dull over the fluid. o Breath sounds: reduced or absent (unlike with a consolidation, in an effusion presence of fluid means there is no net movement of air over the fluid due to acoustical mismatch- hence reduced or no transmission of breath sounds). There may be an area of bronchial breathing audible above the effusion due to compression of overlying lung. o Vocal resonance: reduced. Important causes of pleural effusions include: o Transudate (<30 g protein per litre of fluid): (i) cardiac failure; (ii) hypoalbuminaemia from the nephrotic syndrome or chronic liver disease; (iii) hypothyroidism; (iv) Meigs syndrome (ovarian fibroma causing pleural effusion and ascites). o Exudate: (>30 g of protein per litre of fluid): (i) pneumonia; (ii) neoplasm: bronchial carcinoma, metastatic carcinoma, mesothelioma; (iii) tuberculosis; (iv) pulmonary infarction; (v) subphrenic

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abscess; (vi) acute pancreatitis; (vii) connective tissue disease such as rheumatoid arthritis, systemic lupus erythematosus; (viii) drugs such as methysergide, cytotoxics; (ix) irradiation; (x) trauma. o Empyema (pus in the pleural space): (i) pneumonia; (ii) lung abscess; (iii) bronchiectasis; (iv) tuberculosis; (v) penetrating chest wound. o Haemothorax (blood in the pleural space): (i) severe trauma to the chest; (ii) rupture of a pleural adhesion containing a blood vessel. o Chylothorax (milky-appearing pleural fluid due to leakage of lymph): (i) trauma or surgery to the thoracic duct; (ii) carcinoma or lymphoma involving the thoracic duct. Signs of pneumothorax: Leakage of air from the lung or a chest wall puncture into the pleural space causes a pneumothorax Important signs observed with a pneumothorax include: o Chest expansion: Reduced on the affected side. o Percussion: Hyperresonance over affected are if pneumothorax is large. o Breath sounds: Greatly reduced or absent over affected area. o There may be subcutaneous emphysema. This occurs due to entry of air bubbles in the fascial planes under the skin and it feels like bubble wrap. o There may be no signs if the pneumothorax is small (30% of cases). Important causes include: o 'Spontaneous': (i) subpleural bullae rupture, usually in tall, healthy young males; (ii) emphysema with rupture of bullae, usually in middle-aged or elderly patients with generalised emphysema/COPD; (iii) rarely in asthma, lung abscess, bronchial carcinoma, eosinophilic granuloma, end-stage fibrosis or Marfan's syndrome; (iv) iatrogenic (caused by medical intervention), following the insertion of a central venous catheter. o Traumatic: rib fracture, penetrating chest wall injury, or during pleural or pericardial aspiration Signs of tension pneumothorax: This occurs when there is a communication between the lung and the pleural space, with a flap of tissue acting as a valve, allowing air to enter the pleural space during inspiration and preventing it from leaving during expiration. A tension pneumothorax results from air accumulating under increasing pressure in the pleural space; it causes considerable displacement of the mediastinum with obstruction and kinking of the great vessels, and represents a medical emergency. Important signs to remember include (similar to a normal pneumothorax, however, there may be signs of shock with hypotension, as well as tachypnoea & cyanosis due to impingement/kinking of great vessels in the thorax): o The patient is often tachypnoeic and cyanosed, and may be hypotensive. o Trachea and apex beat: displaced away from the affected side. o Chest Expansion: reduced or absent on affected side. o Percussion: hyperresonance over the affected side. o Breath sounds: absent. o Vocal resonance: absent. Important causes of tension pneumothorax include: o Trauma. o Mechanical ventilation at high positive pressure. o Spontaneous is very rare.

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 The following summarised table indicates the typical chest examination findings in selected clinical conditions, with the detailed table below from Harrisons. TV/VR refers to tactile vocal fremitus and VR to vocal resonance: Condition Pleural Effusion Consolidation Collapse of lung lobe (e.g. lower lobe collapse secondary to pneumonia) Pneumothorax Percussion note Dull (stony) Dull Dull TV/VR Decreased Increased Reduced (little air in collapsed lung, prevents sound transmission) Decreased Breath sounds Reduced Increased, crackles present Reduced

Resonant

Reduced/absent

Types of patients to watch out for that may come up in a station may include (although not limited to) a patient with a pleural effusion, bronchiectasis, lung removal- surgically removed in a patient with lung cancer (patient would obviously have a large sternotomy or thoracotomy scars, with chest wall asymmetry, diaphragm higher up, smaller chest on affected side, abnormal- possibly absent breath sounds). Major categories of respiratory diseases to remember include: 1) Airways disease: Increase in size (bronchiectasis); decrease in size (asthma, chronic bronchitis, local obstruction from: foreign body, carcinoma, mucous plug), disappeared airways (bronchiolitis, small airways disease). 2) Airspace disease: Increased airspaces (emphysema); decreased airspaces (lung fibrosis: rheumatoid disease, cryptogenic fibrosing alveolitis, systemic sclerosis/ scleroderma); airspace disappearance (consolidation/atelectasis: transient- for example pneumonia, infarction; or permanent- e.g. obstruction large infarcts) 3) Pulmonary vascular disease: Increased pulmonary arterial pressure (various lung diseases, hypoxia, primary), decreased pulmonary venous drainage (left ventricular failure), destruction of vessels/lumen (vasculitis, pulmonary emboli). 4) Ventilatory diseases: Pleural disease (pleural effusions, pleural thickening, pneumothorax), chest-wall disease-mechanical defects (skeletal deformities, muscle diseases), diaphragm weakness. 5) Control of ventilation: CNS causes: Efferent pathways (Medulla lesions, cervical spine, neuropathies/poliomyelitis); afferent pathways (hypoxic: carotid or aortic body disease; or hypercapnic: medulla lesions).

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Deep Vein Thrombosis and Pulmonary Embolism

Case protocol 3: Pulmonary thromboembolism
A 52 year old woman suddenly developed breathlessness the day after laparascopic cholecystectomy. The patient, who was previously otherwise well, had a strong family history of ischaemic heart disease and smoked 20 cigarettes per day. Examination revealed an obese, distressed woman with obvious tachypnoea and a productive cough. Auscultation of her chest revealed decreased air entry at the right base. Vital signs also indicate tachycardia and relative hypotension (indicating she is haemodynamically unstable) along with tachypnoea and mild fever. Based on the history and physical examination, there must be some underlying cardiovascular or respiratory complication following her cholecystectomy. As the patient appears haemodynamically unstable and may have developed shock, it is important to identify and exclude serious conditions. She may have developed hypovolemic shock (haemorrhage, dehydration), cardiogenic shock (which may explain some of her symptoms), distributive shock including sepsis (although she is only mildly febrile at this stage, other very unlikely causes of distributive shock: anaphylaxis, neurogenic) and obstructive shock (including pulmonary embolism, other very unlikely causes of obstructive shock include pericardial tamponade and tension pneumothorax). The patient also has developed acute dyspnoea and cough with a mild grade fever after the procedure, along with haemodynamic instability which are more consistent with pulmonary embolism. The decreased air entry at the right base on auscultation is also consistent with a pleural effusion, pneumothorax, atelectasis or pulmonary infarction and/or embolism (due to ventilation-perfusion mismatch). The provisional diagnosis in this case for acute dyspnoea, cough, low-grade fever, haemodynamic instability post-cholecystectomy is pulmonary embolism, secondary to deep venous thrombosis. Other important differential diagnoses include: o COPD exacerbation: Given her history of smoking she may have underlying COPD, and which could be exacerbated by her hospital stay (infections), anaesthesia, intubation and mechanical ventilation and the procedure. o Pneumothorax/tension pneumothorax- this would cause acute dyspnoea and decreased air entry on auscultation and could happen after such a procedure. A tension pneumothorax is very unlikely, given there are no obvious precipitating factors (trauma etc) and it may lead to death very rapidly. These conditions do not explain her cough. o Pneumonia/bronchitis/pleural effusion- this would explain her cough, fever and dyspnoea. But her fever is mild and she is very tachypnoeic at rest, the timeframe for infection is too short following the procedure. Also her fever would be much higher if she had septic shock. o Acute asthmatic attack: Although it was not noted in the history, she may have asthma which was not noted. This could also explain some of her symptoms and would be exacerbated by the anaesthesia/procedure, although she does not have a wheeze or other signs of asthma. o Inhaled foreign body/laryngeal oedema: Would explain sudden shortness of breath, cough, low-grade fever and decreased air-entry. However, if she had aspirated a foreign body or if she had other risk factors for aspiration, it may have been noted on history. Laryngeal oedema usually occurs in the setting of anaphylaxis- does she have any allergies to any medications?

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o o o o

Myocardial ischaemia/infarction/heart failure: Would explain her acute shortness of breath, haemodynamic instability and low-grade fever. Also she has cardiovascular risk factors (smoking) and family history. However, there is no note of chest pain etc. Pericarditis and cardiac tamponade: Important to consider with tachycardia, hypotension and haemodynamic instability (also indicating obstructive shock). Aortic dissection: Can also present with sudden hypotension but also with severe chest pain. Post-operative atelectasis: Especially important post-procedure and intubation/ ventilation. Although would not explain why she has unilaterally decreased air-entry on auscultation, and she has no crepitations/crackles. Does not explain cough, haemodynamic instability, fever. Obesity sleep-apnoea hypoventilation syndrome: A differential to consider given she is obese, but would not explain most of her presentation, and she is currently hyperventilating, not hypoventilating.

If the patient has pulmonary embolism, important risk factors predisposing to her condition can be derived from Virchows triad (see below). In her case, importantly: o Immobility/stasis: obesity, pain related to gallstones and the operation. o Hypercoagulability: smoking, oestrogen (being female and she may be on hormone replacement therapy if she is peri-menopausal), genetic factorsfamily history of IHD, increasing thrombosis related to surgery (related to surgical trauma/haemorrhage leading to increased production of coagulation factors) and she may possibly be dehydrated. o Endothelial damage: surgical trauma Important investigations in this case include: o ECG: Important bedside investigation to quickly check for signs of myocardial ischaemia/infarction, cardiac rhythm abnormalities, and signs of pulmonary embolism. Important ECG changes related to pulmonary embolism to remember include usually a normal ECG or one that shows sinus tachycardia. Sometimes, it may indicate rightventricular strain with a pattern similar to right-ventricular hypertrophy. Look at the following waves and leads: right-axis deviation (S waves in lead I), tall R waves in lead V1, inverted T waves in V1 (normal) spreading across to V2 and V3 and a Q wave in lead III resembling inferior infarction (also known as the S1Q3T3 rhythm), also in some cases you can see right-bundle branch block. This may occur with larger emboli causing strain to the right ventricle. However, an ECG alone is NOT diagnostic for pulmonary embolism.

o o

o o o

Full blood count: to check for signs of infection with high white cell count, and importantly to check for thrombocytosis or anaemia. Urea, electrolytes and creatinine (UECs), calcium, magnesium phosphate and liver function tests: to check post-operatively and compare to baseline, and check if the patient is fluid overloaded or dehydrated, to check if the patient requires IV fluids or diuretics. Arterial blood gases: to check if the patient is hypoxemic, or if there are acid-base abnormalities. D-dimer: sensitive test for identification of pulmonary embolism. Other potentially useful blood tests include Troponin to exclude MI and coagulation studies (PT, APTT and INR) to check for risks of coagulation. Some other predisposing causes of hypercoagulability include Protein C or S deficiency, Antithrombin III deficiency, presence of antiphospholipid antibodies/lupus anticoagulant or Factor V Leidens mutations. This is especially important if the patient is younger and has had a

27

history of repeated miscarriages (20-30 year old female). Blood cholesterol, glucose, HbA1c can be checked as risk factors for IHD, the most common cause for heart failure. Add on Thyroid function tests as hyperthyroidism may lead to high output cardiac failure leading to such a clinical presentation. Chest x-ray (see image below)- a wedge shaped opacity is uncommon. A normal or near normal chest x-ray in a dyspnoeic patient suggests PE. Well established abnormalities include focal oligemia (Westermarks sign), peripheral wedge-shaped density above the diaphragm (Hamptons hump) (or peripheral opacities) or an enlarged right descending pulmonary artery. Also may see pleural effusion or atelectasis. V/Q scan: the main value of this technique is in the detection of pulmonary thromboemboli, as it shows reduction of segmental perfusion and normal ventilationventilation-perfusion mismatch (atelectasis: no ventilation, PE: no perfusion). In pneumonia there may be good perfusion, lobar area of poor ventilation. A high probability scan is diagnostic if the clinical suspicion is also high (i.e. a classic story for PE in a patient with risk factors). A low-probability scan can rule out PE only in the low clinical suspicion patient, whilst an indeterminate-probability scan is indeterminate. Pulmonary angiography or CT pulmonary angiogram: CTPA is now the gold standard for diagnosis of pulmonary emboli, particularly in the acutely ill and shocked patient or when ventilation-perfusion scans are equivocal (it shows filling defects corresponding to thromboemboli). A pulmonary angiogram is the gold standard for diagnosis. This procedure is generally safe (0.3% mortality) and indicated if the diagnosis remains uncertain after non-invasive testing.

o o

Doppler and ultrasound scan: to check for DVT, and venous Doppler to exclude venous flow occlusion. Bedside pulmonary function tests: If the patient is asthmatic, check peak expiratory flow rate. Spirometry is also useful to check underlying airways disease to discriminate between obstructive and restrictive disease.

A chest x-ray was performed which showed an area of opacification at the right base, together with a small right pleural effusion. Important causes of the chest x-ray features together with her clinical presentation include pulmonary embolism and infarction, which can cause opacification and pleural effusion. With infarction, red infarction occurs at the initial stages of embolic impaction in the lungs, as the embolus obstructs the pulmonary circulation to that zone in the lung, but because of the lungs dual blood supply from the bronchial arteries, blood can extravasate to that area. A pale infarct occurs when there is no secondary blood supply to an affected zone. With PE, chest x-ray most often shows atelectasis, seen in 60-70% of patients. Other less common signs include (also see image on pages below): increased lung lucency in the area of the embolus (Westermark sign), abrupt cutoff of vessel, wedge-shaped pleural based infiltrate (Hamptons hump) and pleural effusion which can appear bloodstained if sampled with thoracentesis. Pleural effusion and wedge-shaped areas of infarction usually occur 12-36 hours after symptoms begin and usually indicate pulmonary infarction. An area of confluent consolidation or atelectasis can also cause the chest x-ray features.

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Arterial blood gas was performed:

The patient appears to have uncompensatory respiratory alkalosis (high pH and hypocapnia) due to her hyperventilation. She is also hypoxemic due to the ventilation-perfusion mismatch and shunting. The ABG abnormalities of hypoxemia can be explained due to the pulmonary infarction and pleural effusion and pulmonary arterial obstruction. The hypocapnia is due to her hyperventilation which was the result of increased respiratory drive because of the hypoxemia leading her to blow off excess CO 2. ABGs typically show hypoxemia, hypocarbia and a respiratory alkalosis. However, a normal ABG does NOT conclusively rule out pulmonary embolus. Because of the diagnosis of pulmonary embolism, the patient obviously requires urgent anticoagulation therapy, with either o Fibrinolytic agents: Tissue plasminogen activator (alteplase, duteplase), streptokinase. o IV Unfractionated Heparin: use a loading dose of 60U/kg bolus, a maintenance dose of 12U/kg/hr IV infusion. But must monitor APTT levels every 4-6hours, ensure that it is 1.5-2 times the patients baseline, normal is ~30 seconds). Mechanism of action: potentiates the activity of the endogenous anticoagulant antithrombin III. This in turn inactivates thrombin (factor IIa) and other clotting factors (IX, X, XI, XII) and plasmin. Be aware of the heparin induced thrombocytopenia syndrome (HITS) or other signs of bleeding, reversal is with protamine sulphate. Other contraindications include undiagnosed or active bleeding, haemorrhagic stroke or allergies. o SC low molecular weight heparin (Enoxaparin (Clexane))- use 1mg/kg bd or 1.5mg/kg once daily. No monitoring is required. Mechanism of action: inactivates thrombin to a lesser extent than unfractionated heparin because smaller molecules (2000-6000 molecular weight vs. 5000-30 000) cannot bind to both antithrombin and thrombin simeoultaneously.Enoxaparin has a better bioavailability compared to unfractionated heparin, so one does not have to monitor levels and there is less bleeding than warfarin. o PO warfarin (Coumadin): dose varies with individual, but start with 5-10mg dose and titrate to INR 2-3 as needed (INR for AF, DVT, PE is 2-3; mechanical prosthetic heart valve 3-4.5). Monitor until the patient has 2 theapeutic INRs, then check 2-3 times/week for 1-2 weeks, once the patient is stable can decrease monitoring to every 4-6 weeks. Also monitor for signs of bleeding. Reversal is with vitamin K (INR > 6.0). Initially monitor INR and PT levels 4-5 days after starting (half-life is 36 hours), so cover with heparin as initially prothrombotic and to prevent further PE. PT should be 1.3-1.5 times the control. INR = (PTobs/PTcontrol) ISI of thromboplastin agent being used in the lab. ISI = International sensitivity index. Mechanism of action: vitamin K reductase inhibitor, inhibits synthesis of vitamin K dependent factors II, VII, IX, X) and antagonises protein C and S. Contraindications: undiagnosed bleed, haemorrhagic episode over last 6 months, haemorrhagic stroke (most thrombotic), allergy or drug interactions. o Surgical management: Insertion of IVC filter for patients with high risk of developing PE from DVTs and bilateral DVTs (e.g. cancer patients) and in which anticoagulation is contraindicated. Also can operate- and remove thrombosis, for example with pulmonary embolectomy or thrombectomies. o Prophylaxis: Mobilise, prevent dehydration, use of compression stockings (TEDS). Also refer to old Phase 2 notes from HM3 week 7on GI bleeding for more information on disorders of haemostasis and treatment.

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The patient was sent for a ventilation-perfusion lung scan, but during transport she developed central chest pain, increasing dyspnoea and cyanosis. Her blood pressure fell to 70/40 mmHg and her JVP was elevated to 7cm. Despite attempting resuscitation, the patient died in ICU four hours later. Clinical signs of massive pulmonary embolism include intense chest pain, acute/worsening dyspnoea, cyanosis and circulatory collapse. Note that pulmonary embolism can have the following effects: o Increased pulmonary vascular resistance due to vascular obstruction. o Impaired gas exchange due to ventilation-perfusion mismatch o Alveolar hyperventilation due to reflex stimulation of irritant receptors, and hypoxemic drive. o Increased airways resistance due to bronchoconstriction. o Decreased pulmonary compliance due to lung oedema, haemorrhage, and loss of surfactant. o Right ventricular dysfunction- which can manifest as ECG changes and chest x-ray features. Sequence of events: o Thrombosis: Usually arises from a vein (DVT) in the deep venous muscular plexus of the leg. The thrombus may be attached to the endothelial wall and there may be partial or complete occlusion. o Embolism occurs when a mobile segment of the thrombus dislodges and passes up to the lungs via the IVC and right-side of the heart. o Depending on the size of the embolism, degree of collateral blood supply several outcomes can occur. In this case massive pulmonary saddle embolism may have occurred, leading to acute obstruction of right cardiac outflow (acute cor pulmonale) leading to obstructive shock (she was very hypotensive) and rapid death. Before this, she would have had smaller emboli, which caused pulmonary infarction, which was evident on chest x-ray. Small pulmonary thromboemboli occur in 60-80% of cases and are asymptomatic, and they can cause chronic right heart strain, chronic thromboemboli and pulmonary arterial hypertension. Medium-sized emboli occur in 20-30% of cases, which can be a primary presentation which leads to sudden-onset shortness of breath, pleuritic chest pain, can develop into chronic pulmonary arterial hypertension and the patient may have many risk factors. Large-sized emboli occur in 5-10% of cases and can lead to sudden death (saddle embolus), the release of vasoactive amines and pro-inflammatory cytokines can also lead to circulatory collapse and uncorrected shock and low-grade fever. Progressive right heart failure is the usual immediate cause of death from PE. As pulmonary vascular resistance increases, right ventricular wall tension rises and perpetuates further right ventricular dilatation and dysfunction. Consequently, the interventricular septum bulges into and compresses an intrinsically normal left ventricle. Increased right ventricular wall tension also compresses the right coronary artery and may precipitate myocardial ischaemia and right ventricular infarction. Decreased filling of the left ventricle may lead to a fall in left ventricular output and systemic arterial pressure, thereby provoking myocardial ischaemia due to compromised coronary artery perfusion. Eventually, circulatory collapse and death may ensue (In this case the patient died from saddle embolus, not RHF). In this case of death a post-mortem examination is mandatory. Importantly this is because the patient was <24 hours post-op (<24 hours of admission to hospital, nursing home, post-surgery or major procedure) and was relatively young (52 years old). However, the death in this case was not unexpected (given she developed acute PE) and the death was not unexplained. A post-mortem examination in this case would provide a definite diagnosis of the cause of death in this patient. Important major pathological findings one would expect at autopsy would include: o DVTs: on inspection there may be unilateral/bilateral oedema in the lower limbs and on autopsy there may be propagating deep venous thrombosis in the lower limb.

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Lungs: There may be a large saddle embolus obstructing the pulmonary artery. There may also be smaller pulmonary emboli (as opposed to a post-mortem clot) in the smaller branches of the pulmonary arteries. As this was acute on onset there may not be any other major pathological changes. However, there may be wedge-shaped infarction in the lower lobes, (as seen on chest x-ray) with apex pointing towards the lung hila with haemorrhage and fibrinous exudation or fibrosis (long-standing) from previous PE. If the patient also had pulmonary arterial hypertension, there may be atherosclerosis in the pulmonary arteries. There may also be changes in the lungs related to COPD if the patient was a long-standing smoker and the pleural effusion may also be noted. Heart: There may be evidence of right heart failure and right heart strain (increased thickness of the right heart muscle wall). There may also be atherosclerotic changes in the coronary arteries (related to smoking).

Pulmonary wedge-shaped haemorrhagic infarction on pleural surface of lung (left), which is hard and elevated above adjacent lung surface. Right, pulmonary embolus in supplying artery (black arrow) at the apex of a distal wedge-shaped haemorrhagic infarct.

Pulmonary thromboemboli at autopsy (arrow)

If the patient had survived, important long-term complications that may have developed would include: o Pulmonary arterial hypertension, this could lead to right heart strain and development of cor pulmonale (right heart disease which is a sequelae of chronic pulmonary disease). o Other important long-term complications could include repeated thromboemboli if the patient is not adequately given anticoagulants. o Unilateral peripheral oedema (from recurrent DVT) o If emboli do not resolve, smooth muscle proliferation and intimal thickening associated with other possible outcomes will cause decreased vessel compliance. This results in decreased flow in the affected vessel and predisposes to thrombus formation on top of emboli. o Ventilation-perfusion mismatching alters the function of Type 2 pneumocytes, which subsequently produce less surfactant and this decreases lung compliance.

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Case: Pulmonary thromboembolism

A 73 year old woman with long-standing congestive cardiac failure presented to her GP with sudden onset of dyspnoea at rest, associated with haemoptysis and pleuritic chest pain. In the preceding week, she had experienced several short-lived episodes of dyspnoea at rest. Her GP organised admission to hospital, concerned about the possibility of pulmonary thromboemboli. A provisional diagnosis of pulmonary embolus (PE) is reasonable, based on all the clinical features and the timing onset of the dyspnoea. Pleuritic chest pain and haemoptysis indicate the possibility of pulmonary infarction from PE. The episodic shortness of breath over the preceding week indicates possible showers of emboli to the lungs and hence persistence of pleurisy and dyspnoea. Her risk factors include: her long-standing congestive cardiac failure which predisposes to venous stasis from poor systemic circulation & venous return; which can cause deep-vein thrombosis formation and hence PE. This is one element of Virchows triad (which includes changes in blood flow: stasis/turbulence in aneurysms or vessel branch points), vessel/endothelial injury (ruptured atherosclerotic plaques, trauma, vasculitis) and changes in blood constituents (hypercoagulable stateshyperviscosity of blood from erythrocytosis/polycythemia, dehydration, impaired synthesis of coagulation factors by the liver- with systemic inflammation, oral contraceptive pills/hyper-oestrogenic states, cancer, inherited deficiencies of anti-clotting agents such as antithrombin III, protein C, protein S; Factor V Leidens genetic mutations). Another important risk factor is potential hypercoagulability due to reduced mobility from cardiac failure and drugs to treat her condition such as diuretics causing hyperviscosity of her blood. Note that in 50% of cases of DVT, patients are asymptomatic; whilst 36-84% of patients may have dyspnoea, pleuritic chest pain or cough (most common features), leg pain is present in 25%; and haemoptysis, palpitations, wheezing and anginal pain in <25%. Also importantly, syncope and sudden death and worsening of underlying heart failure or lung disease. Important signs to identify include tachypnoea (very common), crackles and tachycardia (very common) including supraventricular tachycardia (40-90%), S4 accentuated S2P (pulmonary component of second heart sound) (~25%), lowgrade fever (variable), Homans sign (pain in the calf or popliteal region with abrupt dorsiflexion of the patients foot at the ankle, while the knee is flexed to 90 degrees), pleural rub, third heart sound (S3) and cyanosis. Investigations which might assist in establishing the diagnosis include: o AP chest x-ray: With PE a chest x-ray is not diagnostic or very helpful as the film may be normal or may have subtle changes, some signs of possible PE include linear collapse lines from atelectasis, and pleural effusions. A chest x-ray is helpful to rule out other causes of chest pain differential diagnoses such as pneumonia, pneumothorax or exacerbations of cardiac failure. o ECG: a relatively simple investigation, usually ECG is normal or shows sinus tachycardia in PE. Sometimes, it may indicate right-ventricular strain with a pattern similar to right-ventricular hypertrophy. Look at the following waves and leads: right-axis deviation (S waves in lead I), tall R waves in lead V1, inverted T waves in V1 (normal) spreading across to V2 and V3 and a Q wave in lead III resembling inferior infarction. However, an ECG is NOT diagnostic for pulmonary embolism.

o D-dimer (Fibrin degradation product), a small protein product present in the blood after a thrombus has been degraded by fibrinolysis, and a positive result is useful in the diagnosis of thrombosis and DIC. If a D-dimer reading is high, then further imaging with venous ultrasonography, or lung scintigraphy or CT pulmonary angiography is indicated. o CT pulmonary angiogram (or helical CT with contrast): this is performed with contrast and is now the gold-standard for diagnosing PE, the path of contrast is followed with the scanner to look for pulmonary emboli and wedge shaped areas of haemorrhagic infarction. This is now more commonly used (contraindicated in pregnancy) rather than a V Q nuclear lung scan, which reports the probability of the patient having a PE as either low, medium or high probability- this modality also requires a high index of clinical suspicion as well as looking for ventilation-perfusion ( V Q ) mismatch on this scan. In a V Q lung scan radio-labelled particles are inhaled and segmental areas where there is ventilation but

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no perfusion of the particles are observed for and this calculates a low, moderate or high probability of PE. o DVT venogram: In a DVT venogram look for filling defects in the lower limb veins, and this requires IV radio-contrast. Also a simple Venous Doppler study is also very useful for visualising thrombosis in the lower limb veins. o Pulmonary angiography: These are very invasive procedures but can very accurately diagnose PE, they are usually performed when surgery is required, e.g. surgical embolectomy to treat a PE. Pulmonary angiography is very invasive as it requires cardiac catheterisation, to check for a cut-off of perfusion blood supply to a lung segment, it is only used in patients where other investigations were not helpful in diagnosing PE when a strong clinical suspicion of PE still remains. If PE is the cause of her symptoms, she could have still potentially experienced multiple episodes of painless dyspnoea, which could have been the result of smaller showers of emboli that did not cause pulmonary infarction and pleural involvement. Hence pleuritic chest pain is significant in pulmonary thromboembolism as it indicates pulmonary haemorrhagic infarction which very often involves the pleura, causing inflammation and irritation of the parietal pleura. The following specimens are taken from another patient that died from PE. On the left-hand side, there is recognisable alveolar tissue, the right-hand side is haemorrhagic (it has jitter artefact with a banding wavy pattern), it also has a ghost pattern of alveoli with a loss of nuclei- indicating coagulative necrosis and hence haemorrhagic pulmonary infarction. An example of thromboembolism is seen with a fragment impacting in a pulmonary artery on the right-side of the field. The actual embolus that caused infarction, however, would have impacted proximally in the supplying branch of the pulmonary artery. In the left-hand side there are areas of necrotic alveoli and red material (hemosiderin) in macrophages from long-standing congestion of the vessels from chronic congestive cardiac failure and increased pulmonary vascular resistance indicating pulmonary artery congestion. On the pleural surface, there is evidence of inflammation, in most cases one would expect to have a fibrinous pleural exudate, although fibrin is not present in the pleura in this slide. There may be insufficient time (less than a few hours) or insufficient stimulus to cause a fibrinous exudate not observed here:

The possible outcomes of DVTs and pulmonary thromboembolism include:

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o Saddle embolism: occurs in ~10% of cases, causing sudden death, as it causes sudden obstruction to right-ventricular outflow, (also known as acute cor pulmonale), hence there is no venous return to the left ventricle and hence sudden loss of cardiac output, loss of perfusion to the heart and brain and sudden death. Saddle emboli are associated with recurrent multiple emboli that precede the massive embolus. A large saddle embolus impacts into the pulmonary trunk, where >60% obstruction results in acute hypotension & breathlessness causing sudden death. o Paradoxical embolism: this is rare, but is due to left-right shunting of the heart, e.g. in patients with atrioventricular septal defects (hole in the heart) this can mean that an embolus from a DVT can cause systemic embolic phenomena, such as TIA/stroke, splenic, renal or bowel ischaemia/infarction, or embolisation to the lower limbs. o ~65% of pulmonary embolism is asymptomatic, or has subtle signs such as mild-shortness of breath. These are due to small-sized emboli. o Pulmonary infarction: this occurs as a result of mild-moderate sized emboli, e.g. in the case of this patient with congestive cardiac failure. However, in young people with good bronchial collateral circulation, infarction would not be likely to occur. o Pulmonary arterial hypertension: this can occur as a result of permanent narrowing of the vessel wall due to embolus organisation and recanalisation, which can predispose to PE. The permanent narrowing of the pulmonary vessel wall increases vessel resistance and hence causes chronic pulmonary arterial hypertension. o Most emboli go to the bases of the lungs due to the effects of gravity. Thus pulmonary embolism requires fast treatment & management, as well as prevention as soon as possible, which is what the GP did in this case to prevent massive PE. In venous thrombosis, the majority of DVTs form in the deep veins of the calf, that extend in length (propagate) in direction of blood flow to the heart. On microscopy (see below) it is seen to be mainly made up of laminations of red blood cells with small amounts of fibrin & platelets- hence known as a red thrombus. Note that not all microemboli cause pulmonary infarction, as the lungs have a dual blood supply via the bronchial arteries, which may not allow gas exchange but allows appropriate pulmonary perfusion. ~50-65% of DVTs are silent, hence in such immobilised, dehydrated & post-operative hospitalised patients, must have high suspicion for DVTs. The rest of patients with DVTs may have swelling & pain in their legs (unilaterally generally).

The following specimens display a lung at autopsy, which shows a massive recent infarct in the lower lobe and embolus can be seen in branches of the pulmonary artery.

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 The following specimen displays a circumscribed area of infarction in the mid-zone of the right upper lobe, dark red in the centre, with pale areas at the margin. Thrombus is present in small vessels, and on the pleural surface there is quite marked fibrinous pleurisy- a frequent reaction to infarction.

Massive pulmonary thromboembolism:

A 68 year old man was diagnosed with primary pancreatic cancer, which was found to be inoperable. He underwent a course of chemotherapy, but developed sudden severe dyspnoea and collapsed in a cardiorespiratory arrest, from which he could not be resuscitated. The following specimens were obtained at autopsy: The patients pancreatic cancer diagnosis is important, as he would have most-likely had Trousseau syndrome of migratory thrombophlebitis (or Trousseau sign of malignancy). Pancreatic cancers and some visceral adenocarcinomas/GI cancers produce mucin, which predisposes to coagulation and hence thromboembolic phenomena. All other cancers that cause loss of mobility also predispose to hemostasis, DVT formation and pulmonary embolism. Furthermore, cancers produce a hypercoagulable state.

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 The specimen shows the left and right lungs, with the pulmonary valve, pulmonary trunk and bifurcation. There is a pulmonary embolus straddling the pulmonary artery bifurcation- a "saddle" of embolus, extending into the intrapulmonary portion of both right and left pulmonary arteries. The upper lobes of both lungs are pale, but there are no localised areas of infarction in this specimen, indicating it is a saddle embolus with no evidence of lung infarction. Also on the left, there is an image of a large DVT, which grows in the direction of venous flow towards the inferior vena cava & right ventricle. The slide below displays embolus in a pulmonary artery, an embolus is different to a post-mortem clot as emboli contain laminations of fibrin/platelets and red cells. The presence of a semilunar valve indicates that this specimen is from a large vein (e.g. femoral or iliac vein). There are bands of eosinophilic red cells with darker bands indicating laminations so this is a thrombus rather than a postmortem clot, particularly in conditions of stasis.

Thrombus organisation is occurring, with granulation tissue occurring around the sides of the valves indicating this thrombus is a few days old, this also indicates that this process occurred during life and is not a post-mortem clot (which would consist of two separated distinct layers of red currant jelly with red-cells and a supernatant of plasma and fibrin overlying it, known as chicken fat). An old infarct is shrunken in appearance, fibrotic/scarred; a new infarct is haemorrhagic and hard. Remember that ~50% of DVTs are asymptomatic; others may cause localised heat, swelling and pain due to venous congestion or thrombophlebitis. One must be very vigilant to investigate for DVTs when these signs are seen. Virchows triad of changes in the vessel wall, changes in the constituency of blood and endothelial injury describes factors that contribute in the formation of thrombosis. Thrombosis in the deep venous

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plexus of the calf increases risk of embolism into the pulmonary circulation. Clinically this is results in a ventilation/perfusion mismatch, due to the blockage of blood to the pulmonary circulation via the pulmonary arteries. It is often clinically asymptomatic (50%) and is an important cause of mortality. Other symptoms include chest pain, dyspnoea, haemoptysis, faintness + collapse and signs of right heart failure. Signs reveal circulatory collapse tachycardia, hypotension, elevated JVP, decreased urinary output and gallop rhythm and loud P2. Confirmation is firstly based on history and examination, and investigation using arterial blood gas, with addition of D-dimer, ECG, lower-limb Doppler studies, V/Q scan, CTPA [and pulmonary angiography] as required.

Mechanisms of Thrombosis and pathogenesis of PE

Virchows triad

Endothelial damage is an important factor causing thrombosis; important causes include post-MI mural thrombus, valve inflammation, endothelial injury leading to exposure of subendothelial collagen (vessel wall damage- infections/sepsis, trauma, burns, systemic vasculitides), atherosclerosis, smoking. Hypercoagulability is the imbalance between anticoagulant (e.g. PGI2 and plasminogen activator) and pro-coagulant (tissue factor, plasminogen activator inhibitor and adhesion molecules binding to platelets (e.g. vWF and subendothelial collagen)) factors. These can be affected by certain disorders, e.g. consumption of factors that occurs in DIC, hypercoagulable states in certain cancers, pregnancy, hyperviscosity syndromes, e.g. polycythemia, sickle cell anaemia etc. Normal blood flow is laminar; abnormal blood flow results from turbulence from stasis, vessel branch points, aneurysms, MI mural thrombus, atrial fibrillation, mitral valve stenosis (e.g. after rheumatic heart disease). Some important causes and risk factors of hypercoagulability include: Factor V Leiden Prothrombin mutation (G20210A), hyperhomocystinemia Antithrombin III deficiency Protein C or S deficiency Venous stasis: prolonged bed rest, immobilisation, dehydration Myocardial infarction, heart failure Tissue damage (fractures, surgery, burns, major trauma) Cancer DIC Prosthetic valves Secondary Heparin-induced thrombocytopenia syndrome (HITS) SLE (lupus anticoagulant, anti-cardiolipin antibodies) Atrial fibrillation Nephrotic syndrome Cardiomyopathy Hyperoestrogenic states (e.g. pregnancy, oral contraceptive pill) Sickle cell anaemia Smoking Primary

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 Risk factors predispose to the formation of a DVT and this can then lead to one of the four paths: o o o o DVT propagation- thrombus grows proximally, obstructing a critical vessel Embolisation- impacts the lung vasculature, resulting in infarction, right to left shunting and obstructive shock Dissolution of thrombus- fibrinolysis Organisation and recanalisation and incorporation of thrombus into the vessel wall

DVT leasing to PE accounts for 75-90% of all PE. Also consider other emboli- amniotic fluid, fat, foreign bodies, air, parasites, septic emboli, cholesterol emboli or tumour emboli. Important risk factors for DVT formation include: Surgery Major abdominal/pelvic surgery Hip/knee surgery Post-operative care/intensive care COPD Congestive cardiac failure Pregnancy/peurperium Varicose veins Fracture Stroke/spinal cord injury Abdominal/pelvic Advanced metastatic Concurrent with chemotherapy Previous proven venous thromboembolism Immobility Thrombotic disorders Trauma Increasing age

Cardiorespiratory disease Obstetric Lower limb disorders

Malignant disease

Other

Some chest radiograph changes to note (although not commonly present) in pulmonary embolism and infarction include:

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Management of pulmonary embolism

Anticoagulant therapy is required in the treatment of pulmonary thromboembolism. Heparin, both unfractionated and low-molecular weight heparin may be used, fibrinolytics and warfarin are indicated. Fibrinolytics include alteplase and streptokinase, and in the scenario of heparin complications, lepirudin or danaparoid may be used. Warfarin is a standard for long-term therapy if indicated. Heparin potentiates antithrombin III and antagonises factors II, IX, X, XI and XII in the coagulation pathway. Fibrinolytics are analogues of tissue plasminogen activator or have similar activity such that plasminogen is activated into plasmin, which catalyses the degradation of fibrin fibres. Warfarin is a vitamin K reductase inhibitor which inhibits the formation of factors II, VII, IX and X (vitamin K-dependent factors) in the coagulation cascade. Heparin/warfarin treatment: 1) Enoxaparin 1.5mg/kg SC daily or 1mg/kg SC BD for 5 days 2) Start warfarin 5 mg PO daily, titrate to INR 2-3. 3) Maintain enoxaparin for at least 5 days, and for two days of stable INR with warfarin. Use compression stockings as an adjunct. Also an inferior vena caval (IVC) filter may be used in patients with confirmed DVTs who are at high risk of developing massive or significant PE, this requires ultrasound or CT guidance for insertion via a femoral venous catheter. Consider DVT in the axillosubclavian veins, mesenteric veins and cerebral sinuses. The following is a guide for the management of DVT/PE depending on clinical circumstances:

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 The molecular mechanisms of the common anti-coagulant medications are highlighted below:

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Summary of important features to remember about the pathogenesis and complications of DVT/PE:

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Haematology: Haemostasis & coagulation pathways

Haemostasis: Haemostasis is the normal physiological response to stop bleeding after rupture in blood vessel walls. It consists of three parts: 1) Vasoconstriction of the damaged vessel, 2) Platelet activation that forms a plug around the site of vessel damage, which leads to 3) formation of an insoluble fibrin clot. These processes together help to prevent bleeding. It is most effective in controlling small vessel injuries. Since veins contain blood at lower pressures, hence venous bleeding is less rapid and more easily controlled. Sometimes venous bleeding can be controlled simply by lifting the limb involved, i.e. above heart level. Also internal venous bleeding can be controlled by the accumulation of pressure from accumulated blood in the tissues. A collection of blood in tissues is known as a haematoma. The following describes haemostasis in more detail: It is actually a five-stage procedure, involving the following processes: Vascular spasm & vasoconstriction. Formation of a platelet plug Formation of a blood clot through coagulation Clot retraction Replacement of the clot with fibrous tissue Immediately after trauma (i.e. cut or rupture) to a blood vessel, the trauma to the vessel wall causes vasoconstriction or spasm, which will instantly reduce blood flow (and hence blood loss) to that vessel. Vascular contraction usually results from a combination of local smooth muscle spasm, nervous reflexes initiated by pain nociceptive fibres and local chemical factors produced by traumatised tissues to cause vasoconstriction. In smaller vessels, platelets are responsible for most of vasoconstriction, as they release the vasoconstrictor substances with the main vasoconstrictor being Thromboxane A2. Note that the greater the damage, the greater the degree of vascular spasm. Hence a cut vessel will bleed greater than a crushing injury, as the crushing injury has a greater deal of damage, to surrounding tissue and hence greater vascular spasm preventing (further) bleeding, cuts have relatively less damage. Local vascular spasm can last for many minutes or even hours during which time the wound can be sealed by a blood clot. Platelets generally have a lifetime of ~8 days and are then eliminated from the circulation by tissue macrophages. Cell membranes of platelets are important, for clotting as they have a glycoprotein coat, which allows platelets to slide past vessel walls, but adhere to tissue factor in injured areas. Platelets have secretory vesicles containing adrenaline, serotonin, ADP and Thromboxane A2. If the hole in the damaged vessel wall is relatively small, it can be sealed by the platelet plug. The glycoprotein coat is hence important in the formation of a platelet plug for adhesion to the damaged vessel wall. Processes involved in formation of the platelet plug include: The damaged vessel disrupts the endothelium and exposes subendothelial connective tissue and collagen. When platelets encounter the defect in the blood vessel and collagen, platelets swell, forming irregular shapes with numerous pseudopods and attach to exposed collagen- platelet adhesion. Once attached, contractile proteins in the platelet contract forcefully, releasing multiple active factors from storage granules. Platelet substances released from the granules include Thromboxane A2, adrenaline and serotonin which cause vasoconstriction and minimise blood loss. ADP is released from platelets causing the platelets to become sticky and adhesive which causes another layer of platelets to adhere to the first layer of platelets. These platelets also release ADP causing a platelet adhesion/pile-up through receptor/ligand interaction via GPIb/IX and vWF or GPIIb/GPIIIa receptors and further platelet aggregation, until a platelet plug is formed. Hence platelet adhesion to the vessel wall occurs first, then followed by platelet aggregation & plug formation. Platelets also release Thromboxane A2, which also directly causes vasoconstriction but also directly promotes platelet aggregation and triggers the release of more ADP from platelet granules. Thromboxane A2 and ADP hence promotes platelets plug formation to stop bleeding. Note that the platelet plug is limited to the site of vessel injury; the normal endothelium releases prostacyclin (PGI2), which profoundly inhibits platelet aggregation, which limits platelet plug formation to the area of the defect. Hence it prevents the extension of the plug out into areas of

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normal endothelium. Prostacyclin hence prevents clotting from occurring. The body is hence in a balance whereby procoagulant and anticoagulant factors and states are normally balanced. Note that however, Prostacyclin and Thromboxane A2 are related as they are both Eicosanoids derived from Arachidonic acid. Nevertheless thromboxane A2 causes vasoconstriction and platelet aggregation, whilst prostacyclin causes vasodilatation and inhibits platelet aggregation. If a defect in the vessel wall is small enough, then the platelet plug by itself can stop blood loss. If the hole in the vessel wall is large, then a blood clot rather than a platelet plug is required. Transformation of blood into a solid gel or clot/thrombus occurs mainly through the formation of the polymer protein fibrin. Blood coagulation occurs around the formed platelet plug, it serves to reinforce the plug and solidify the blood that remains in the wound channel. This process involves several stages and is known as the coagulation pathway. Platelets contain actin and myosin contractile proteins, which allows platelets to pull the edges of the damaged vessel wall back together once the platelet plug has been formed. This process is known as clot retraction. As a result serum (plasma minus fibrinogen) is exuded out of the bloodstream at the damage site, this is the fluid exuded in this shrinking process. Following this there is a process of replacing the clot with fibrous tissue. Platelets secrete growth factor proteins stimulating the growth of arterial smooth muscle and skin fibroblasts; this begins after the first few hours of clot formation. Serotonin stimulates fibroblasts to secrete collagen. As a result the blood clot is converted to fibrous tissue. This process takes about 1-2 weeks. There are three major stages in blood coagulation; 1) injury to the vessel wall leads to a chemical reaction cascade that leads to the formation of prothrombin activator. 2) prothrombin is then converted to thrombin, catalysed by prothrombin activator. 3) Thrombin acts as an enzyme which converts fibrinogen to fibrin fibres which trap platelets, blood cells and plasma to form a clot. There are ~50 substances in blood which affect coagulation; some are procoagulants, others are anticoagulants. There is a balance between these to determine clotting. In the normal state anticoagulants are more active, preventing blood clotting, with damaged vessels there is procoagulability. Prothrombin activator is the rate-limiting step in blood-coagulation. Prothrombin activator can be formed in two ways; by an extrinsic pathway involving factors present in damaged tissue and by an intrinsic pathway involving coagulation factors already present in plasma. In both pathways of prothrombin activator formation, plasma proteins known as blood clotting factors, play major roles. Most are inactive forms of proteolytic enzymes. When active, their enzymatic actions cause the next cascading reactions of the clotting process. Most clotting factors are designated by roman numerals, i.e. Factor VIII (complexes with von Willebrands factor), factor X, etc. A small a is written after the number to indicate the active form of the factor, e.g. Factor Xa. The following image displays the intrinsic clotting pathway. It is initiated by inactive Factor XII (Hageman factor) coming into contact with a foreign surface, i.e. collagen for example from a damaged blood vessel. This pathway finishes off with prothrombin activator being activated. Ionic calcium, Ca 2+ and platelet factor (a phospholipid) are needed for this clotting pathway to occur, hence in hypocalcaemia, patients may also have blood clotting abnormalities. If no anticoagulants are used and blood is taken into a glass tube, for example, due to Factor XII coming into contact with this foreign surface, blood then quickly coagulates via this intrinsic clotting pathway:

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 The extrinsic clotting pathway begins with a damaged vascular wall or extravascular tissue that comes into contact with blood. The damaged tissue releases several factors into the blood, which include Factor III (also known as tissue factor or tissue thromboplastin) which complexes with Factor V and Factor VII to form extrinsic thromboplastin catalysed by Ca2+. Hence the extrinsic clotting pathway starts with tissue damage and ends with prothrombin activator activation and requires Ca2+ in several steps.

With the formation of prothrombin activator, the intrinsic and extrinsic pathways converge and afterwards it is a common coagulation pathway. Thus after a blood vessel ruptures, blood starts to clot via both the intrinsic & extrinsic pathways. An important difference in both pathways is that the extrinsic clotting pathway is much shorter, taking ~15 seconds. The intrinsic clotting pathway is much slower, requiring 1-6 minutes to cause clotting. Hence both occur simultaneously but one occurs much more faster than the other. The common coagulation pathway is depicted as follows, after prothrombin activator has been formed:

Fibrin is the end-product of the common clotting pathway and it is important in forming the framework of the clot. Fibrinogen is the precursor, a high molecular weight protein synthesised by the liver. Thrombin changes fibrinogen into a smaller monomer which then polymerises with other fibrin monomers to form long fibrin fibres that form the reticulum (meshwork) of the clot. Initially fibrin fibres are held together by weak hydrogen bonding that is easily broken. Thrombin activates platelets to release a fibrin stabilising factor; that causes covalent bonding between fibrin monomers; adding strength and cross-linkages between the fibres to form the fibrin meshwork. The final clot consists of fibrin fibres running in all directions, entrapping blood cells, platelets and plasma. The fibrin fibres adhere to the damaged areas of the blood vessels therefore the clot adheres to any vascular opening, preventing further blood loss. Most procoagulant molecules are synthesised in the liver and some are vitamin K dependant, including Factors II, VII, IX, X; anticoagulants protein S and protein C (vitamin K -carboxylation is vital for biological activity). von Willebrands factor (factor VIIIR) is complexed with factor VIII and is synthesised by megakaryocytes and endothelial cells. Factor VIII circulates complexed with vWF, as vWF protects it from proteolytic degradation. Anticoagulation: Dissolving the clot: The fibrin meshwork is not meant to last forever and is broken down after a certain time, where new skin and blood vessel growth occurs and hence is a temporary measure to allow blood vessel regeneration and healing.

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 In a system analogous to the clotting pathways, the anti-clotting system dissolves the clot. This occurs when plasminogen is converted to the active enzyme plasmin, which digests fibrin and other clotting factors to dissolve the clot. Note other inhibitors of blood coagulation include dilution of procoagulants (e.g. with liver disease, haemophilia & other coagulopathies), secretion of prostacyclin and nitric oxide by neighbouring endothelial cells (vasodilators); removal of particulate matter and activated factors by the reticuloendothelial system. There are also specific inhibitors to coagulation pathways including tissue factor pathway inhibitor; protein C and protein S and antithrombins. (Remember Protein C and S deficiencies predispose to thrombosis). Antithrombin, Protein C and protein S are formed by the liver as well; hence the liver is important in forming both coagulant & anticoagulant molecules. Heparin is an important anticoagulant used clinically but also occurs as an endogenous molecule on the surface of endothelial cells, which functions physiologically by binding to antithrombin III thus forming an antithrombin IIIheparin complex that inactivates factors XI, IXa, Xa or IIa). The drug form of heparin exists as a free molecule that also binds to circulating antithrombin III and the resultant complex inhibits the same clotting factors.

The tissue factor pathway inhibitor (TFPI) is also an important endogenous molecule that inhibits coagulation by binding to factor Xa inhibiting it and subsequently also inhibiting the tissue factor-factor VIIa complex:

Also do not forget fibrinolysis via the activation of plasminogen to plasmin, which breaks down/dissolves fibrin strands in a clot. Investigations for Coagulation: Activated Partial Thromboplastin Time (APTT): this test is performed by adding kaolin to patient plasma to provide surface activation of factors XII and XI. Platelet lipid surrogate is then added and the time taken to produce fibrin is recorded. In other words, it measures the clotting time after the addition of contact factors (e.g. factors V, VIII, IX, X, XI, XII, prothrombin and fibrinogen), but without added tissue thromboplastin. APTT is affected by deficiencies of factors which precede to the activation of Factor X (i.e. it measures the intrinsic pathway coagulation time); i.e. it is sensitive to the action of heparin, and it is used to monitor heparin therapy. APTT is also prolonged in the haemophilias. Prothrombin time (PT): In this test a tissue extract such as thromboplastin/tissue factor (Factor III) is added to patient plasma and the time taken to produce fibrin is recorded, hence measuring clotting time of the extrinsic

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coagulation pathway. It is then reported as a corrected prothrombin ratio (PR), expressed as the INR (International Normalised Ratio) which is corrected to take account of the differences in the thromboplastins. It is hence sensitive to abnormalities of the extrinsic coagulation pathway (e.g. abnormalities with Factors I, II, V, VII and X) and hence INR is used to monitor patient warfarin therapy. D-Dimer (Fibrin/fibrinogen Degradation Products): This is a latex agglutination test, which detects the crosslinked fibrin degradation fragment, D-dimer. Elevations in this fragment are seen in primary and secondary fibrinolysis; during thrombolytic or defibrination therapy with tissue plasminogen activator (tPA); as a result of thrombotic disease, such as deep-vein thrombosis, pulmonary embolism or DIC; in vaso-occlusive crisis of sickle cell anaemia; in malignancies; and in surgery. Platelet function tests: Tests for platelet function include checking the platelet count in the FBC, checking blood films, checking patient bleeding time and aggregometry. Factor assays can be done if there are unexplained reasons why a patient has abnormalities with blood coagulation based on other tests. It can be useful for bleeding disorders, e.g. Factor VII deficiency and testing other factors. Disorders of too little coagulation: Important disorders of too little clotting include Thrombocytopenia, platelet function defects, coagulation factor deficiencies (of these, they are inherited, and they involve either failure to synthesise factors or failure to consume factors) and vascular purpura (e.g. due to endothelial defects, for example in Ehlers Danlos syndrome or acquired conditions, e.g. corticosteroid excess, senile purpura, leukocytoclastic vasculitis).
Thrombocytopenia:

This is abnormally low platelet numbers and hence a tendency to bleed, usually bleeding from capillaries and venules. Clinically, the skin may develop small purplish patches which is venule bleeding into the skin and is known as purpura (lower limbs or upper limbs), or ecchymoses (bruising). It may also present with petechiae- capillary bleeding usually in the lower limbs, buccal mucosa, or with abrasions. The patient may also have menorrhagia, or mucosal bleeding, e.g. bleeding gums. The cause of platelet disorders should be categorised into either quantitative platelet disorders (thrombocytopenia) or qualitative platelet defects. Thrombocytopenia occurs mostly as a result of formation of antibodies which react against platelets to destroy them, hence most commonly it has an autoimmune cause; other times it is due to blood transfusions and formation of antibodies against donor platelets. Important ways of classifying causes of thrombocytopenia includes: Platelet production defects: -Due to bone marrow ablation from radiation or cytotoxic drugs. - Bone marrow infiltration (due to infection or malignancy) - Selectively impaired platelet production from drugs (e.g. gold, ethanol, sulphonamides, thiazides etc) - Ineffective megakaryopoiesis (due to B12 or folic acid deficiency or myeloproliferative disease). - Congenital defects of platelet production (Fanconis anaemia). Accelerated platelet removal: - Immunological causes (e.g. Idiopathic Thrombocytopenic Purpura, SLE, Non-Hodgkin Lymphoma, drug induced immune reactions, heparin, infections, HIV, sepsis) -Non-immune causes, e.g. Disseminated Intravascular Coagulation, Haemolytic-uraemic syndrome, transfusion induced platelet destruction. Platelet sequestration: Hypersplenism & any causes of hypersplenism, e.g. Malaria, portal hypertension. Idiopathic thrombocytopenic purpura (ITP) is caused by platelet associate-IgG (this is often directed against the platelet surface glycoprotein molecules GP-IX or GPIIb-GPIIIa complexes). These platelets are tagged by these IgG antibodies for destruction in the spleen by the reticuloendothelial cells. It is often a self-limiting disorder (acute) with remission in <3 months, it usually occurs in children/young adults and follows Epstein-Barr virus & other viral infections. Chronic ITP however, can occur and when it does it is in adults. Management of ITP involves anti-inflammatory drugs including corticosteroids, intravenous -globulin and in severe chronic cases splenectomy may be necessary.

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 Platelet functional disorders: These can be separated into either 1) Hereditary diseases that involve genetic mutations in platelet membranes, platelet granules and von Willebrands disease (failure of platelet adhesion via GPIb-IX glycoproteins); or 2) Acquired platelet disorders including bone marrow disorders such as Myelodysplasia, Uraemia or drug induced such as through NSAIDs and aspirin.
Vascular Purpuras:

This occurs as a result of leakage of blood from terminal arterioles, capillaries and post-capillary venules. For example this can occur with Scurvy, as vitamin C is needed for normal collagen metabolism (formation of hydroxylysine/hydroxyproline for collagen) and hence smaller blood vessels are weak & susceptible to bleeding. Vascular Purpuras can also occur with corticosteroid excess (see House season 1 Cushing syndrome episode.) Also caused by senile purpura and leukocytoclastic vasculitis (immune complex deposition in smaller blood vessels).
Vitamin K deficiency:

Vitamin K is important for the formation of 5 blood clotting factors. It is required by the liver to synthesis these clotting factors including prothrombin. Hence Vitamin K deficiency can lead to serious bleeding disorders. Vitamin K is fat soluble, continuously synthesised in the GI tract by gut flora. Hence it requires bile salts for absorption in the small intestine. Vitamin K deficiency can hence occur with cholestasis, which prevents the liver releasing bile into the gut preventing vitamin K (and other fat soluble vitamins A, D and E) being absorbed. Warfarin is a competitive inhibitor of Vitamin K hence preventing blood clots. It competes with vitamin K for active sites in the enzymatic process of prothrombin and other clotting factor synthesis. It is hence a competitive antagonist of vitamin K and has anticoagulant effects.
Von Willebrands Disease:

This is caused by a deficiency of vWF, the carrier of Factor VIII. vWF is needed for platelet adhesion via the GPIb receptor. This is usually an autosomal dominant disorder. Patients with this disease have a lifelong history of mucosal bleeding, severe bleeding during surgery or trauma. Relevant investigations to diagnose this condition include prolonged bleeding time, increased APTT, decreased antigenic vWF, decreased Factor VIII to protein C ratio and abnormal ristocetin-induced platelet aggregation.
Haemophilia:

This is a hereditary disease characterised by uncontrolled bleeding, even with minor injuries. In ~80% of haemophiliacs, it is due to Factor VIII deficiency. Haemophilia A is caused by defective/deficient Factor VIII to protein C ratios. Haemophilia B is caused by Factor IX deficiency. It is inherited as sex-linked recessive, carried by the mother on the X-chromosome, hence predominantly males are affected and females are carriers. There are over 600 genetic mutations identified with Haemophilia A, including insertions, deletions and point mutations. The severity of haemophilia is very variable, it can range from excessive bruising, persistent bleeding after a simple cut to haemorrhage into joints or muscles, which can be painful and disabling, causing arthropathy. Relevant investigations that provide diagnosis of a suspected Haemophilia patient include increased APTT (as mentioned previously), decreased Factor VIII to protein C ratio but normal vWF levels (unlike von Willebrands disease). Haemophiliacs used to require frequent blood transfusions, nowadays it is treated by synthetic factor VIII, which is synthesised by genetic engineering. With diagnosis patients also require genetic counselling. It is also important to prevent and manage possible complications of Haemophilia, including arthropathy/myopathy from intraarticular or intramuscular bleeding; analgesic dependence and prevention of blood-borne infections (e.g. Hepatitis C, HIV etc) in patients requiring regular transfusions.

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Other acquired disorders of coagulation:

Again this may be due to decreased production of clotting factors, as can occur with: i. Vitamin K deficiency (affects Factors II, VII, IX, X) as a result of low dietary vitamin K or with Warfarin therapy. ii. Hepatic disease causing decreased Factor II, V, VII, IX, X and protein C. iii. Disseminated intravascular coagulopathy, e.g. either as a result of massive tissue damage, burns, tumours, amniotic fluid embolus, sepsis etc. With investigations there will is usually thrombocytopenia, prolonged APTT, elevated INR, decreased fibrinogen levels, elevated D-Dimer. iv. Inhibition of clotting factor production: for example with antibodies to clotting factors, or with Antiphospholipid antibody syndrome. Hypercoagulable states: Important hypercoagulable states occur with Antiphospholipid antibody syndrome; or deficiencies of anticoagulant molecules: o An important deficiency of an anticoagulant molecule is antithrombin III deficiency (also known as heparin resistance). o Protein C or protein S deficiency (hence the loss of the ability to inactivate Factor VIIIa or Va). Activated Protein C (APC) resistance (resistance of factor Va to activated Protein X)- also known as Factor V (Leiden) mutations, an important cause of hypercoagulable states to be aware of, that for example is associated with cerebrovascular accidents. Prothrombin gene variants can also cause hypercoagulability. Trousseaus syndrome an important eponymous syndrome which included migratory thrombophlebitis associated with malignancy, especially pancreatic cancer and other glandular mucin/tissue factor producing adenocarcinomas. Obesity, immobility, pregnancy and other hyper-oestrogenic states are other important causes of a hypercoagulable state.

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Pharmacology: Treatment of Thrombosis

Arterial thrombosis mainly occurs as a result of atherosclerotic disease, for example in the coronary arteries which leads to myocardial infarction; or in the cerebral circulation causing cerebral infarction & stroke, this is usually a white thrombus that consists predominantly of fibrin and platelets. Venous thrombosis is mainly the result of stasis of blood flow & hypercoagulable states, for example, deep vein thrombosis and subsequently pulmonary embolism, in cases of venous thrombosis there is usually a red thrombus. Thrombosis can be treated with either: anti-platelet, anti-coagulant or thrombolytic drugs. Anti-platelet drugs: Many factors released by platelets and some clotting factors act on platelet G-protein coupled receptors, e.g. P2Y, Thromboxane A2 receptor, PAR-1 etc. Platelet adhesion contributes to thrombus formation. Activation of platelet surface G-protein coupled receptors (e.g. the Adenosine diphosphate activated P2Y receptor) activate intracellular platelet-signalling pathways, that up-regulates the dimeric platelet glycoprotein IIb/IIIa receptor complex binding to the platelet surface. This causes the platelets to form pseudopodia on their surface, which can help platelet clumping or binding to vWF or fibrinogen. The GPIIb/IIIa is the platelet receptor for fibrinogen or vWF and can hence bind to fibrinogen and hence other platelet GPIIb/IIIa complexes causing platelet adhesion, as shown below:

Protease-activated receptor-1 (PAR-1) does not have a circulating ligand; however, thrombin can cleave part of its end-terminus, causing PAR-1 activation. Note that platelets produce Thromboxane A2 via break-down of arachidonic acid (AA) to prostaglandins via cyclooxygenase. This formed Thromboxane A2 can activate the Thromboxane A2 receptors usually found on platelets. Note that intra-platelet AA is modulated by levels of cyclic AMP; where high levels of cAMP decreases AA levels. cAMP levels are regulated by conversion of AMP to cAMP via phosphodiesterases. The following diagram indicates where the major anti-platelet drugs act on these biochemical platelet pathways:

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 Aspirin is an oral anticoagulant drug, which inhibits the formation of Thromboxane A2 by inhibiting cyclooxygenase (but not prostacyclin), low doses of 300mg/day prevents thrombus formation and embolisation. Aspirin is rapidly absorbed from the GIT with a peak concentration achieved after 30-40 minutes. It takes about one week for platelet function to come back after ceasing aspirin. Contraindications for aspirin use include NSAID hypersensitivity/allergies, peptic ulcer disease, severe hepatic/renal disease. Adverse effects of aspirin are obviously (like any anticoagulant) haemorrhage and also upper GI toxicity/gastritis/ulceration. Dipyridamole: mainly inhibits platelet cAMP formation and hence decreases the formation of Thromboxane A2, furthermore, it can also inhibit platelet adenosine binding. Dipyridamole is mainly used in the clinical use in combination with aspirin in patients with transient ischaemic attacks (TIA) and also patients with thrombotic strokes. Dipyridamole can be administered orally or IV. It is contraindicated in patients with hypertension, angina, asthma and syncope. Adverse effects of dipyridamole include headache, dizziness, hypotension (hence can cause syncope). Clopidogrel: inhibits the action of the ADP activated P2Y receptor, hence preventing GPIIb/IIIa upregulation and hence prevents platelet activation and adhesion. Clopidogrel is used in combination with aspirin in patients with unstable coronary syndromes (e.g. unstable angina pectoris) to prevent platelet aggregation & coronary thrombus formation. It is actually a pro-drug and hence is given orally to be converted to active form. Contraindications of Clopidogrel include bleeding and adverse effects include rash and diarrhoea. Abciximab: This is a synthetic antibody that is used to bind to the GPIIb/IIIa receptor complex, thus blocking fibrinogen or vWF binding and hence preventing platelet adhesion & aggregation. A similar drug is Eptifibatide, which is derived from snake venom and also inhibits this receptor. Abciximab is clinically used in coronary artery angioplasty/stenting to prevent coronary thrombosis. It is administered as an IV bolus followed by continual infusion up to 72 hours. Platelet function recovers after 2 days of infusion cessation. Contraindications of Abciximab include active bleeding, concurrent warfarin use and previous thrombocytopenia with use of GPIIb/IIIa antagonists. Adverse effects include thrombocytopenia, bleeding, nausea, fever, headache, rash. Anticoagulant drugs: Refer to the coagulation cascade described previously. There are many different anticoagulant drugs which inhibit clotting factors in both the intrinsic and extrinsic coagulation pathways. Major drugs in this category include Warfarin, Heparin, Hirudin, Rivaroxaban and Dabigatran etexilate. Warfarin has many effects on the coagulation cascade, but mainly inhibits the extrinsic pathway (hence affects PT and thus INR monitoring is required). The following displays coagulation cascade factors that are inhibited by warfarin:

Warfarin can be taken orally and is a competitive inhibitor of vitamin K, it lowers levels of prothrombin and other clotting factors, reduces clotting by 20% in 24 hours. Note that warfarin was discovered after the use of Coumarin as a rat poison (very similar to warfarin) and subsequently side chains were added to make it safer for humans and

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hence Coumadin (also known as warfarin) was made. Vitamin K is needed by the liver for the production of the active forms of: prothrombin, Factor VII, IX and X. Since warfarin inhibits the enzymes synthesised from vitamin K; it is thus a competitive inhibitor of vitamin K and thus inhibits formation of prothrombin, Factor VII, IX and X as described earlier. The following depicts the vitamin K cycle, importantly warfarin inhibits formation of vitamin K hydroquinone; as well as inhibiting the Quinone reductase and Vitamin K epoxide reductase enzymes. The vitamin K cycle is needed to form circulating clotting factors from precursors:

There are MANY drugs which can interact with warfarin and affect warfarin activity; thus affecting patient INR. Important agents which can increase warfarin INR response include: SSRIs, MAOIs, NSAIDs, analgesics, penicillins, Quinolones, Tetracyclines, Sulfonamides and beta-blockers. Drugs which can decrease warfarin INR response include: foods high in vitamin K (i.e. green leafy vegetables), antacids, antihistamines, oral contraceptives, immunosuppressive drugs. Heparin mainly inhibits the intrinsic coagulation pathway, inhibiting Factor IXa, Xa and thrombin and thus it has its major effects in increasing APTT. Large molecular-weight Heparin inhibits thrombin binding via long chains needs to bind to BOTH thrombin and Antithrombin III, which once bound to antithrombin III can then inhibit thrombin. Large molecular-heparin can also after binding to antithrombin III bind to Factor Xa, thus inhibiting coagulation via that pathway. However, the risk associated with Large molecular-weight heparin is that by inhibiting thrombin and Factor Xa, it can cause a tendency to bleed and the syndrome (Heparin-induced thrombocytopenia) HITS:

Low molecular-weight heparins are relatively safer in that they do not cause HITS as often, since the low molecular weight heparin binds only to antithrombin III, but as it does not have a long chain, it cannot bind to & inhibit thrombin. However, its action of factor Xa is unaffected, as shown below. The incidence of HITS is much less with low molecular-weight heparin as there is less thrombin activity:

Heparin-induced thrombocytopenia initially causes thrombosis that is then followed by bleeding and thrombocytopenia. HITS usually manifests as a dramatic drop in platelets 1-20 days after initiation of therapy and is believed to be an autoimmune destruction mediated through IgG. An immune thrombocytopenia also occurs with GPIIb/IIIa antagonists such as Abciximab also causing thrombocytopenia. Heparin must be given IV, it is a naturally occurring chemical; produced by Basophils and Mast cells, inhibiting thrombin formation and reduces

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platelet function. Heparin injection can increase blood clotting time almost 5 times, hence has a fast & immediate effect, slowing the process of embolisation. Heparin can also be used as an in-vitro anticoagulant, preventing blood coagulation outside the body as well, also it is useful in surgery, i.e. cannulas and heart lung machines storing blood. The ideal anticoagulant should be a medication that can be administered orally (unlike heparin), one tablet once daily (unlike warfarin). It should be highly effective in reducing thromboembolic events, with predictable dose response and kinetics and a low incidence of bleeding events. It should also not need routine monitoring of coagulation (unlike warfarin) or platelet count required. It must also have a wide therapeutic window, with no dose adjustment required and little interaction with other drugs (again a problem with warfarin); it should also have low, non-specific plasma protein binding (problem with heparin only binding to antithrombin III) and inhibition of both free and clot-bound activated coagulation factors. It can be seen how difficult it is to produce such an ideal drug. Direct thrombin inhibitors include (large molecular-weight heparins are indirect thrombin inhibitors); include Dabigatran etexilate and Melagatran which inhibit thrombin at its catalytic site; and also Hirudin which binds to the thrombin substrate recognition site. Hirudin is a peptide molecule derived from medicinal leaches. Hirudin is not available orally and it is used as the replacement anticoagulant in patients with HITS. Dabigatran is used mainly in patients with major orthopaedic surgery of the lower limb, for example, total hip or knee replacement surgery. Unlike Hirudin, Dabigatran is given orally, and contraindicated in patients with active bleeding, renal impairment (due to renal clearance), and has adverse effects including haemorrhage, anaemia and abnormal liver function tests. Melagatran and Ximelagatran are both derived from Naja Naja cobra venom, but have both been withdrawn due to hepatotoxicity. Direct Factor Xa inhibitors include Rivaroxaban and Apixaban. Major clinical use of Rivaroxaban include major orthopaedic surgery of the knee or lower limbs, e.g. total hip replacement surgery or knee replacement surgery. It is administered orally, and contraindicated in patients with active bleeding and other drugs which are inhibitors of CYP3A4 inducers. Rivaroxaban can cause GI upsets, haemorrhage, anaemia, cramping, syncope and jaundice. The following compares warfarin with new oral anticoagulants:

There are also some new experimental drugs that are being tested that are thrombin-like enzymes. These are basically competitive antagonists of thrombin, which hence causes a decrease in formation of fibrin strands. Thrombolytic drugs: Refer to the fibrinolytic pathway described previously, where fibrin strands are broken down by plasmin. Tissue Plasminogen activator (tPA): Unlike warfarin & heparin, tPA is a thrombolytic, when delivered directly to an area of thrombosis, it activates plasminogen to plasmin, dissolving clots. Heparin & warfarin prevent clot formation. tPA is naturally occurring, but is produced synthetically by genetic engineering, directly dissolving a thrombus hence can be rapidly used to treat acute Ischaemic Heart Disease. With ischaemic stroke, tPA must be

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prescribed within the first three hours of stroke, since it rapidly causes thrombolysis and hence even in thrombotic stroke if end-organ vessels have become ischaemic and necrotic, tPA could rapidly cause bleeding into the stroke penumbra zone causing neuronal excito-toxicity. Furthermore, it is very important to establish that the cause of the patients stroke was not due to a haemorrhagic stroke; thus an early head CT within 3 hours is required to exclude haemorrhage. Hence even though this is a very effective drug in preventing damage from thrombotic stroke, it must be administered carefully to prevent further neurological damage. It is hence is not given as commonly as it should with thrombotic stroke due to the short timeframe that it should be administered; so only 1-5% of patients with ischaemic stroke receive tPA due to delayed hospital presentation. There are many contraindications for tPA in this setting, including subarachnoid haemorrhage or intracerebral haemorrhage, raised PT, hypertension, seizures (as tPA also acts on excitable NMDA receptors in the brain), haematuria, thrombocytopenia, GI bleeding etc. Streptokinase: Has the same action as tPA, removing clots once they have formed, it is produced by Streptococcal bacteria. Similarly urokinase can also be used which is also a plasminogen activator. Desmotoplase is a new drug, which can also be used in ischaemic stroke and unlike tPA has a larger window of opportunity, allowing up to six hours after stroke onset. This is because it has similar mode of action as tPA, however, it does not cause NMDA excito-toxicity. It is derived from vampire-bat saliva, but still is under trials. In-vitro clotting agents include tubes coated with silicon, which also prevents Factor XII activation and the intrinsic clotting pathway. Ca2+ binding substances include chelating substances, which prevent Ca2+ activating reactions in the clotting pathways, these include oxalate, citrate and EDTA. These chemicals bind Ca2+ to testtubes preventing blood coagulation.

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Physiology of oedema and cardiac failure

Oedema is basically caused by water & salt loss from capillaries. Capillaries are exchange vessels, containing diameters of between 5-10m and re important in controlling nutrient and waste exchange. Capillaries contain a single endothelial layer on a basement membrane. The number of pores varies between tissues, with the liver and kidneys containing many fenestrations in their capillaries, whist the brain contains low numbers. Fluid enters and leaves the capillaries from the bloodstream via filtration. This is determined by the rate and direction of water passage through pores/fenestrations. Filtration is in turn, determined by various forces acting on fluid within the capillary, these are known as Starling forces. Starling forces and equation in trans-capillary exchange: outward forces driving filtration include: hydrostatic pressure of blood in capillary (Pc), interstitial fluid colloid osmotic pressure (if). Inward forces driving absorption of fluid back into the capillary bloodstream include: hydrostatic pressure of interstitial fluid (Pif) and colloid plasma osmotic pressure (c). The net movement of fluid is given by the following equation:

Using this equation, it can be found that at the arteriole end of a capillary there is net filtration of 13mmHg; this is then collected by lymphatic vessels; whilst at the venule end there is a net absorption of fluid of -8mmHg. The fluid flux/filtration equation takes into account the capillary filtration coefficient, hydrostatic forces and colloid osmotic forces. Capillaries are exchange vessels, and hydrostatic forces pull water out, lymphatics drain this excess interstitial fluid and proteins. Plasma colloid osmotic forces from plasma proteins pushes water back into the capillaries, preventing leakage of fluid. As plasma proteins are not exchanged out of capillaries, that is why they tend to keep water with them and prevent it leaking. Only some low molecular weight proteins may leak out, however, these would be removed by the lymphatics. Thus the amount of water moving in and out of capillaries is balanced, otherwise oedema occurs. The hydrostatic pressure in the capillary is a key factor for this equation, which is why when capillary fluid overload occurs in heart failure that causes increased hydrostatic pressure, which leads to oedema. Capillary hydrostatic pressure may be increased by: o Increased arteriole pressure, as in hypertension. o Increased venous pressure, such as in heart failure. o Increased blood volume, such as in heart failure. Congestive heart failure: Heart failure definition: The situation when the heart is incapable of maintaining a cardiac output adequate to accommodate the metabolic requirements and the venous return. Basically, the heart fails to maintain a cardiac output of 5L/minute. Heart failure is a complex clinical syndrome with typical symptoms that can occur at rest or with exertion, including fatigue, dyspnoea, orthopnoea and paroxysmal nocturnal dyspnoea and fluid retention. The main physiological consequences of LV failure is low cardiac output and elevated pulmonary venous pressure (dyspnoea), whereas RV failure there is low pulmonary artery output and thus elevated systemic venous pressures (JVP, hepatojugular reflux, hepatic congestion, ascites, peripheral pitting oedema). Radiographic appearances are related to the dominant sided pathology which includes pulmonary oedema (left-sided) and primary pathologies in right-sided heart failure. Heart failure is characterised by objective evidence of underlying structural abnormality or cardiac dysfunction that impairs the ability of the ventricle to fill with or eject blood (particularly during physical activity). A diagnosis of heart failure can be strengthened by improvement in symptoms in response to treatment. Heart failure with preserved systolic function (diastolic heart failure) (i.e. impaired relaxation of the ventricle with inability to fill with blood, leading to cardiac dysfunction is associated with LVEF > 40% ~300 000 Australians have heart failure, causing ~90 000 annual hospitalisations, with ~75% of admissions being in those aged over 70. The average length of hospital stay from heart failure is ~10 days and there is a readmission rate of 30% within 28 days. The 1 year mortality is very high at ~30%. This is the only cardiovascular disorder that is increasing in prevalence.

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 The aetiology of cardiac failure (impaired ability to eject blood, LVEF40%) includes: o Coronary artery disease with prior MI (ischaemic heart disease) in 2/3 cases, patients may have had prior MI; this is the most common cause. IHD is present in over 50% of new cases. o Valvular heart disease/Endocarditis- aortic/mitral incompetence/stenosis. o Hypertension- present in about 2/3 cases. o Cardiomyopathy- restrictive (sarcoidosis, amyloidosis), dilated (cytotoxic agents- (doxorubicin, cyclophosphamide, paclitaxel), viral myocarditis- HIV, CMV, Coxsackie virus, pregnancy-related), hypertrophic (HOCM, autosomal dominant genetic causes, familial especially in those with younger age) o Alcoholic dilated cardiomyopathy- also associated with wet beriberi from thiamine (B1) deficiency. o Chronic cardiac arrhythmias e.g. AF o Thyroid disease (hyper-/hypothyroidism) o Myocarditis o Living at high altitudes increases intrathoracic pressure & can cause heart failure. o Idiopathic causes. Important symptoms and signs of decreased ventricular pump function include: Symptoms Dyspnoea Fatigue (these are signs of left ventricular failure). Signs of congestion Oedema (RHF) Weight gain (RHF) Ascites (RHF) Increased JVP (RHF) Pulmonary congestion (LHF)

The New York Heart Association (NYHA) classification of dyspnoea is useful to know for classifying differing degrees of dyspnoea:

Relevant physical examination in a patient with congestive cardiac failure includes: o Appearance: distressed patient, exhaustion, tachypnoea, cyanosis, Cheyne-Stokes breathing (endstage heart failure breathing, near time of death). o Pulse: weak, tachycardia, atrial fibrillation, pulsus alternans. o BP: low, possibly hypotensive o Face: cyanosis, look for myxoedema, malar flush of mitral stenosis. o JVP: elevated, large v waves suggest tricuspid regurgitation. o Carotids: low volume in character. o Praecordium: apex beat displaced and dyskinetic, right ventricular parasternal lift. o Auscultation: Third heart sound (sign of heart failure in those aged over >30 years), gallop rhythm, functional mitral regurgitation due to mitral annular dilatation. o Lung fields: Pleural effusions, bilateral basal crackles, check for sacral oedema. o Legs: Peripheral pitting oedema, establish the level. o Abdomen: Hepatomegaly, ascites. The acute response to cardiac failure is: o Strong sympathetic stimulation (baroreceptors/chemoreceptors) to increase heart rate and contractile force, in order to improve systemic perfusion.

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o Thus the heart rate and contractile force increase, and peripheral vasoconstriction occurs. o Overall, the capillary pressure falls (peripheral pressure falls overall). The delayed response to heart failure (>1 day) is: o An attempt to conserve volume to maintain pressure. o This leads to a fluid overload and hence peripheral oedema. The following diagram displays the forces driving peripheral oedema in ongoing heart failure:

When left-ventricular failure occurs, the heart does not pump sufficient blood as it should and this could be due to several reasons as mentioned above, such as cardiomyopathy, which results in a drop in cardiac output and hence a drop in BP. This would lead to a drop in renal blood flow. This activates the renin-angiotensin-aldosterone system, which hence leads to renal reabsorption of salt and water, subsequently, this results in an increase in blood volume. As a result of this increase in blood volume, the venous system becomes congested, and engorged with a greater blood volume. Also as the left ventricle is not sufficiently pumping blood away, this leads to pressure build-up in the pulmonary veins and pulmonary capillary beds, as there is now a greater end-diastolic volume of blood in the left-heart. This subsequently leads to increased pulmonary venous pressure. Increased pulmonary venous pressure will lead to pulmonary oedema, which can be heard as crackles on auscultation of the lung bases. Pulmonary oedema makes gas-exchange much more difficult and hence this will lead to the symptom of dyspnoea. The gases would diffuse through liquid before entering the alveoli, hence compromising oxygenation and carbon dioxide removal. Preload or end-diastolic volume (EDV) is determined by the extent of ventricular filling (end-diastolic volume). The Frank-Starling mechanism or relationship relates the increased force of myocardial contraction with increased stretch on the fibres, which occurs with increased pre-load; energy of contraction of the ventricle is a function of the initial length of fibres in its walls. In other words, the ventricle automatically adjusts to increased pre-load with increased force of contraction, so that blood in = blood out. Note that however, there is a limit to how much the cardiac muscle fibres can be stretched, after which the contractile force decreases. This is shown below (see curve on right for instance) and is seen as an upside down parabola curve. For example, end-diastolic volume is normally ~120mL, however, it could be increased to 300ml, and the ventricular output, or stroke volume also increases proportionally. However, after 300ml end-diastolic volume, the stroke volume decreases, as the cardiac muscle fibres are over-stretched, from the Frank-Starling mechanism.

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 In an attempt to maintain cardiac output and myocyte contractility, this leads to hypertrophy of the existing myocyte mass, leading to increased oxygen requirements and increased energy usage, acute ischaemia is more likely (large mass for coronary arterial perfusion) and ventricular enlargement can lead to mitral regurgitation, which further facilitates heart failure End-diastolic volume is determined primarily by venous return. Factors influencing venous return include: o Pressure at the end of capillaries o (Right) atrial pressure o Blood volume, since ~60-70% of blood volume is stored in the venous system o Venous tone o Muscle, respiratory and abdominal pumps to help venous return The following pressure-volume curve displays the effects of increased pre-load on left ventricular pressure:

The following diagram displays the distribution of blood volumes in the circulation and the relative mean pressures at different sites in a normal circulation with normal cardiac function:

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 However, when congestive cardiac failure occurs, with right-heart failure there is an increase in RAP, which forces more blood into the ventricle but also increases blood pooling in the veins, this increases mean capillary pressure, Pc. The following is again the same diagram, but with cardiac output 50% of normal:

The following chart displays the effects of acute cardiac failure and how increasing right atrial pressure is related to cardiac output, with increasingly severe degrees of heart-failure and different compensatory mechanisms:

One of the compensatory responses to oedema includes increased lymphatic drainage, although lymphatics have limited ability to cope with excess fluid. Late-stage heart-failure may cause death by acute pulmonary oedema. Some important processes in heart-failure include: there may be a temporary cardiac overload, through exercise, stress/anxiety, or severe cold, this puts increased stress on the heart and blood pools in capillaries (pulmonary), pulmonary oedema occurs as fluid accumulates in the lung tissues and alveoli. There is hence decreased ability for gas-exchange and hypoxemia develops. Decreased oxygen absorption leads to peripheral vasodilation, lowered BP and thus more blood pools in the capillaries and hence oedema becomes worse and progressive. A summary of heart failure from Phase 1 medicine notes: In heart failure, the left-ventricle is not clearing blood that is collecting in the lungs. Hence the veins develop venous congestion in the lungs, as a result of back-pressure from the heart. In the microcirculation and veins, the increased blood and congestion in veins leads to failure of venous valves and this causes an increased blood pressure back to the capillaries. As capillaries are not resistance vessels, this venous congestion results in a dramatic increase in capillary pressure. As a result of this venous congestion, hydrostatic driving forces are increased. However, as plasma protein levels remain the same, osmotic driving forces are approximately the same. This increased hydrostatic pressure leads to a greater amount of fluid diffusing out of capillaries and into the interstitium. Some fluid enters the lymphatics, which removes it. The excess fluid remains in the tissues, causing it to swell and become oedematous. Oedema may also result from increased vascular permeability, i.e. if the endothelium is damaged or as a result of exudation in inflammation, for example. This leads to leakage of plasma proteins. As there will be fewer plasma proteins in the blood, this would mean that they would not be able to exert their capillary plasma colloid osmotic pressure and thus there would be little driving force opposing outward hydrostatic force. Increased capillary permeability may be the result of, for example: o A bee sting, or insect bites, which causes increased histamine release, which increases vascular permeability and exudation of inflammatory proteins/molecules and inflammation occurs. o Severe burns, a state with increased vascular permeability, which leads to severe exudation into the skin and low protein and dehydration/hypovolemia, as a complication of severe burns.

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 Another cause may be a low protein oedema, i.e. protein deficiency from chronic liver failure or Kwashiorkor or protein losing enteropathy, where there is hence lowered osmotic pressure and the patient is more prone to oedema. Lymphatic obstructions- can severely cause lymphoedema and tissue oedema (non-pitting gross oedema) as excess fluid is not drained out of tissues and remains in tissues causing swelling. Lymphatic obstruction can be caused by surgical damage to lymphatics, parasitic infections (e.g. lymphatic filariasis from Wuchereria bancrofti infection) or congenital lymphatic disorders, such as Milroys syndrome.

Pathology of Ischaemic Heart Disease & Congestive Cardiac Failure

Case: Paroxysmal nocturnal dyspnoea and heart failure A 75 year old man with a history of long-standing ischemic heart disease with a MI severeal years ago, was brought to ED by ambulance at 3 am because of acute shortness of breath, which had woken him from his sleep. A chest x-ray was taken in the ED and is shown below. New S-T segment depression was seen in the anterior leads of his ECG, which reverted following sublingual glyceryl-trinitrate therapy. He was also treated with oxygen by mask and diuretics, and recovered rapidly. Serial ECGs and measurements of serum Troponin levels excluded acute MI. The acute shortness of breath which suddenly woke him from sleep, was most likely paroxysmal nocturnal dyspnoea from pulmonary oedema, due to left-sided ventricular failure, which causes upper lobe blood diversion, which can be seen on the chest x-ray below. These vessels appear more dilated than vessels at the hilum of the lungs. This is a case of unstable angina, stable angina normally occurs with exertion and is relieved by rest. On the other hand, unstable angina occurs in patients that are at rest. In this case, unstable angina indicates possible plaque rupture that has not completely occluded the coronary arteries, although there is a very high risk of myocardial infarction and this is an important sign that the patient may develop MI. The chest x-ray appearances show upper lobe blood diversion, interstitial alveolar oedema with a spider-like appearance of the lung fields- Kerley B lines indicate interstitial oedema, cardiomegaly (on a PA chest x-ray view, there is >50% maximal cardiac diameter relative to the transthoracic diameter). With severe pulmonary oedema, alveolar oedema may also be seen patchy shadows around hila, may be unilateral, that is high in the upper lobes, with a bats wings appearance and also keep an eye out for pleural effusions which usually occur on the right side in heart failure, remember the features as A, B, C, D, E. Note that it is however, difficult to comment on cardiac size on an AP film. In right failure, signs of pulmonary hypertension and respiratory causes (COPD, other lung pathologies such as interstitial lung disease) may be present.

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 Apart from ischaemic heart disease, which is the most common cause of left-ventricular failure, other causes include the following list. These can either cause concentric hypertrophy (this usually occurs with increased pressure load, without chamber dilation) or eccentric hypertrophy (usually occurs with volume overload with chamber dilation) to compensate for loss of heart muscle. o With a pressure overload- hypertension, or aortic stenosis, mitral stenosis. o With a volume overload- mitral and aortic regurgitation, patent ductus arteriosus. o Intrinsic disease of heart muscle: Dilated cardiomyopathy- with impaired systole for example, caused by viral myocarditis such as from HIV, CMV, enteroviruses such as Coxsackie virus, influenza or genetic causes, pregnancy (dilated cardiomyopathy), alcohol, cytotoxic agents. Restrictive cardiomyopathy- from toxic conditions such as sarcoidosis, amyloidosis, or haemochromatosis. Hypertrophic cardiomyopathy: HOCM, autosomal dominant genetic diseases of heart muscle. Important causes of right ventricular failure include cases of volume overload (atrial septal defects, tricuspid regurgitation), pressure overload (pulmonary stenosis, pulmonary hypertension), myocardial disease (secondary to LV failure, or RV infarction (uncommon)). The important short and long-term complications of left-sided cardiac failure includes those of eccentric or concentric hypertrophy; or in the long-term it can also cause right-ventricular failure, due to interventricular interdependence. Since both ventricles lie in a common pericardial sac, ventricular interdependence means that the right-ventricle will fail from long-standing left-ventricular failure. Case: Complications of right ventricular failure A 73 year old man with a long-history of hypertension had suffered from repeated episodes of shortness of breath over many years. These episodes had increased in severity following a myocardial infarction three years previously. Prior to his death he had also suffered from significant swelling of his ankles. The following specimens were obtained at autopsy: The history indicates that he had congestive cardiac failure due to progressively worsening shortness of breath, and peripheral oedema on a background history of myocardial infarction and a long-standing hypertension. He may also have had a raised JVP, hepatosplenomegaly, as well as ascites, sacral & peripheral oedema.

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 The macroscopic specimens consist of slices of liver and heart. The liver weighed 1350g, and the heart, 837g. The heart shows areas of greyish-white fibrous tissue on the interventricular septum, and the posterolateral wall of the left ventricle. The anterior part of the left ventricle shows almost complete replacement of the myocardium by greyish-white fibrous tissue, with the formation of an aneurysm of the wall. The heart shows eccentric hypertrophy on the posterior left ventricle, thinned anteriorly due to aneurysmal dilatation, with white-silvery areas of scar tissue. The liver shows the typical appearances of chronic passive venous congestion ("nutmeg liver"), the small red foci representing the central areas of congestion of the lobule, surrounded by a yellow zone representing the peripheral zone of each lobule. This is the appearance of cardiac hepatomegaly or nutmeg liver, and on close inspection the liver has a mottled, tanned, yellowish appearance and is plumpish in some areas.

On microscopic examination of the heart, there are collagenous bands of connective tissue, which may represent fibrosis/scar tissue which is evidence of old infarction and organisation, with patchy areas of fibrosis- focal bands of connective tissue. The surviving myocytes have undergone hypertrophy- they have larger bore-like nuclei, this is a subtle appearance, not seen on the magnification below (need higher magnification of individual cells), this is compensatory hypertrophy of remaining cardiac myocytes.

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 On microscopic examination of the liver, the portal tracts appear abnormal, there is mild centrilobular hepatic steatosis from intracellular hepatocyte triglyceride accumulation that is secondary to vascular congestion from heart failure. Steatosis is the response to chronic hepatocyte hypoxia, due to a chronic lack of venous return from venous congestion; there is poor hepatic oxygenation and thus impaired -oxidation of triglycerides which hence accumulate in hepatocytes. Thus chronic heart-failure or passive venous congestion of the liver leads to mild to moderate hepatic steatosis. A summary of the main clinical features of left-ventricular cardiac failure are summarised below: Pulmonary oedema: Left heart failure Symptoms - Exertional dyspnoea - Fatigue - Othopnoea - Paroxysmal nocturnal dyspnoea Signs - Tachypnoea (due to raised pulmonary pressures - Tachycardia (increased sympathetic tone) - End-inspiratory basal crackles - LV S3 heart sound - Functional mitral regurgitation (secondary to valve ring dilatation) - Pulsus alternans (alternating large and small pulse pressures rare) - Cardiomegaly - Wheeze (cardiac asthma) - Cough (pink froth) - Haemoptysis (pink coloured) - Displaced apex beat with LV dilation (dyskinetic in anterior MI or dilated cardiomyopathy) - Palpable gallop rhythm - Central cyanosis (pulmonary oedema) - Hypotension (low cardiac output) - Cardiac cachexia - Pleural effusion - Peak expiratory flow rate may be low, but if it is <150L/min, suspect COPD or asthma -

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 Important signs and symptoms of right-ventricular failure are summarised below: Pulmonary oedema: Right heart failure
Symptoms Peripheral pitting oedema (ankle/sacral/scrotal/ascites) Dyspnoea Abdominal discomfort Nausea Fatigue Wasting and often weight gain Raised JVP - Due to raised venous pressure (right heart preload) - Large v waves (functional tricuspid regurgitation secondary to valve ring dilation. Kussmauls sign - JVP rises with inspiration (normally falls) - Due to poor RV compliance (e.g. RV MI) RV heave, S3, pansystolic murmur of functional TR (murmur absence does not exclude TR) Tender hepatomegaly - Due to raised venous pressure transmitted by hepatic veins - Pulsatile if TR is present Oedema - Due to sodium and water retention plus raised venous pressure - Pitting ankle and sacral oedema or pleural effusions (small) Low volume arterial pulse (due to low cardiac output), reduced peripheral pulses

Signs

Important investigations to perform in clinically suspected cardiac failure includes: o Full blood count: (anaemia is an adverse prognostic marker) o UECs: (check renal function for cardiorenal syndrome, responses to and maintenance of therapy, especially diuretics and ACE inhibitors) o LFTs: Check for cardiac hepatomegaly/cardiac cirrhosis o Thyroid function tests (TFTs): check thyroid function as an underlying treatable cause o Atrial or brain natriuretic peptide (ANP/BNP): quantification may be of prognostic value. o ECG: check for conduction abnormalities, arrhythmias, MI o CXR: exclude pulmonary oedema, look for other signs of cardiac failure o Trans thoracic or trans-oesophageal Echocardiography: must perform to characterise cardiac failure, calculate LV ejection fractions (%) as a marker for degree of heart failure and for prognosis. May also be able to identify underlying cause or anatomical anomalies. o Coronary angiography: consider if the patient has IHD. o Nuclear medicine scan: May also be useful to perform a Sestamibi nuclear medicine scan with/without dipyradimole stress or if not contraindicated other physical stress, to evaluate degree of ischaemia. Spirometry: Exclude concurrent respiratory causes for airflow limitation.

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Pharmacology for treatment of hypertension

Hypertension is defined clinically as a blood pressure greater than 140 mmHg systolic or greater than 90 mmHg diastolic pressure. There are in fact only few recognisable, treatable causes for hypertension, and most cases have a multifactorial aetiology. 90% of hypertension is essential (i.e. of unknown aetiology). The remainder of causes are secondary causes, e.g. endocrine (such as hyperaldosteronism- Conn syndrome) or renal causes (e.g. renal artery stenosis or a renin producing tumour, for example). The diagnosis of hypertension is very important, as hypertension can lead to microcirculatory damage (i.e. hyaline arteriolosclerosis) and hence this can lead to chronic vascular and end-organ damage. The following are WHO-ISH definitions and classifications of BP levels for adults aged 18 years and older:

Apparently the lower the BP is reduced, the better the prognosis and hence BP is now aggressively attempted to be reduced to 120/80 mmHg by most primary health care physicians. Indications for ambulatory blood pressure monitoring include: 1) Possible white coat hypertension- i.e. hypertension in clinic only. 2) Patients with variable blood pressure. 3) Evaluation of the efficacy of treatment over 24 hours. 4) Evaluation of drug resistant hypertension. 5) Evaluation of patients with nocturnal hypertension. Before proceeding with exploration of pharmacology, it is essential to explore non-pharmacological treatment of hypertension, which may greatly help reduce BP to normotensive levels, however, mainly involve life-style changes which are hard to sustain: 1) Weight loss may lead to a 5-10mmHg drop in BP/10kg weight loss, although this may be difficult to sustain. 2) Limit alcohol, reduces BP by 2-4mmHg. 3) Diet- DASH diet, high in complex carbohydrates (e.g. fruits & vegetables) and potassium, can reduce BP by 6mmHg. 4) Physical activity of at least 30 minutes/day, can reduce BP by 4-9 mmHg. 5) Reduce sodium to <100 milliequivalents/day reduces BP by 2-8mmHg. However, drugs are consistently better than lifestyle changes in head to head comparisons. Remember that blood pressure is actually the product of the persons cardiac output (cardiac output itself is the product of heart rate & stroke volume) and total peripheral resistance. Blood pressure regulation involves different mechanisms, including short term controllers (such as the baroreceptors, autonomic nervous system, catecholamines etc.) and long-term controllers (i.e. the kidneys- reninangiotensin-aldosterone system). This also involves various adrenergic receptors as shown below:

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 The most important classes of antihypertensive agents include the following: 1) Diuretics (osmotic diuretics, carbonic anhydrase inhibitors, loop-diuretics, thiazides, potassiumsparing diuretics(subdivided into aldosterone antagonists and sodium-channel blockers) 2) -adrenergic antagonists 3) -adrenoreceptor antagonists, calcium channel blockers 4) Drugs acting on the renin-angiotensin system 5) Centrally acting drugs, methyl-dopa, clonidine 6) Renin inhibitors 7) Osmotic diuretics, mannitol 8) Other anti-hypertensives- e.g. hydralazine, nitrates. Diuretics: (Refer to the chapter 31 in Guyton & Halls Physiology for a more detailed discussion on diuretics) These drugs increase the rate of urine flow. Most diuretics actually increase Na+ excretion. There are several different groups of diuretics with different mechanisms and sites of action. A diuretic is a substance that increases the rate of urine volume output, as the name implies. Most diuretics also increase urinary excretion of solutes, especially sodium and chloride. In fact, most diuretics that are used clinically act by decreasing the rate of sodium reabsorption from the tubules, which causes natriuresis (increased sodium output), which in turn causes diuresis (increased water output). That is, in most cases, increased water output occurs secondary to inhibition of tubular sodium reabsorption, because sodium remaining in the tubules acts osmotically to decrease water reabsorption. Because the renal tubular reabsorption of many solutes, such as potassium, chloride, magnesium, and calcium, is also influenced secondarily by sodium reabsorption, many diuretics raise renal output of these solutes as well. The most common clinical use of diuretics is to reduce extracellular fluid volume, especially in diseases associated with oedema and hypertension. A loss of sodium from the body mainly decreases extracellular fluid volume; therefore, diuretics are most often administered in clinical conditions in which extracellular fluid volume is expanded. Some diuretics can increase urine output more than 20-fold within a few minutes after they are administered. However, the effect of most diuretics on renal output of salt and water subsides within a few days. This is due to activation of other compensatory mechanisms initiated by decreased extracellular fluid volume. For example, a decrease in extracellular fluid volume often reduces arterial pressure and glomerular filtration rate (GFR) and increases renin secretion and angiotensin II formation; all these responses, together, eventually override the chronic effects of the diuretic on urine output. Thus, in the steady state, urine output becomes equal to intake, but only after reductions in arterial pressure and extracellular fluid volume have occurred, relieving the hypertension or oedema that prompted the use of diuretics in the first place. The many diuretics available for clinical use have different mechanisms of action and, therefore, inhibit tubular reabsorption at different sites along the renal nephron. The general classes of diuretics and their mechanisms of action are shown below:

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 The diuretics used to treat hypertension include loop diuretics, thiazides and potassium sparing diuretics.
Loop diuretics:

The mechanism of action of loop diuretics is that they inhibit Na + and Cl- reabsorption in the thick ascending limb of the loop of Henle, via the Na+/2Cl-/K+ cotransporter. The main examples include furosemide (Lasix), ethacrynic acid and bumetanide. Furosemide, ethacrynic acid, and bumetanide are powerful diuretics that decrease active reabsorption in the thick ascending limb of the loop of Henle by blocking the 1-sodium, 2-chloride, 1-potassium co-transporter located in the luminal membrane of the epithelial cells. These diuretics are among the most powerful of the clinically used diuretics. Illustrated below are the electrolytes that are reabsorbed in the loop of Henle and also the mechanism of action of the loop diuretics:

By blocking active sodium-chloride-potassium co-transport in the luminal membrane of the loop of Henle, the loop diuretics raise urine output of sodium, chloride, potassium, and other electrolytes, as well as water, for two reasons: (1) they greatly increase the quantities of solutes delivered to the distal parts of the nephrons, and these act as osmotic agents to prevent water reabsorption as well; and (2) they disrupt the counter-current multiplier system by decreasing absorption of ions from the loop of Henle into the medullary interstitium, thereby decreasing the osmolarity of the medullary interstitial fluid. Because of this effect, loop diuretics impair the ability of the kidneys to either concentrate or dilute the urine. Urinary dilution is impaired because the inhibition of sodium and chloride reabsorption in the loop of Henle causes more of these ions to be excreted along with increased water excretion. Urinary concentration is impaired because the renal medullary interstitial fluid concentration of these ions, and therefore renal medullary osmolarity, is reduced. Consequently, reabsorption of fluid from the collecting ducts is decreased, so that the maximal concentrating ability of the kidneys is also greatly reduced. In addition, decreased renal medullary interstitial fluid osmolarity reduces absorption of water from the descending loop of Henle. Because of these multiple effects, 20 to 30 per cent of the glomerular filtrate may be delivered into the urine, causing, under acute conditions, urine output to be as great as 25 times normal for at least a few minutes.

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 As a result important side effects to be aware of include hypokalemia and thus metabolic alkalosis (as hydrogen ions

tend to follow potassium). As with all other drugs, patients may have allergies to loop diuretics. Loop diuretics also cause hearing loss and there are drug interactions.
Thiazide diuretics:

The Thiazide diuretics inhibit Na+ and Cl- reabsorption in the early distal convoluted tubule via inhibition of the Na+/Cl- co-transporter at the basolateral membrane of these epithelial cells. An important example is chlorothiazide. The Thiazide derivatives, such as chlorothiazide, act mainly on the early distal tubules to block the sodium chloride co-transporter in the luminal membrane of the tubular cells. Under favourable conditions, these agents cause 5 to 10 per cent of the glomerular filtrate to pass into the urine. This is about the same amount of sodium normally reabsorbed by the distal tubules. Thiazides are also useful in hypertension as they cause vasodilation. The following is an image of the electrolytes that are reabsorbed in the early distal convoluted tubule and the mechanism of action of Thiazide diuretics:

Important adverse effects of Thiazide diuretics include hypokalemia, hyponatremia (more so than the loop diuretics), hyperlipidemia, hyperglycaemia (with ~1% risk of developing Diabetes Mellitus with Thiazide diuretic use), uric acid retention and obviously allergic reactions may occur.
Potassium-sparing diuretics:

Note that there are two major subtypes, which are the aldosterone antagonists (such as spironolactone) and the sodium-channel blockers (such as amiloride). Spironolactone, Aldactone and eplerenone are aldosterone antagonists that compete with aldosterone for receptor sites in the cortical collecting tubule epithelial cells and, therefore, can decrease the reabsorption of sodium and secretion of potassium in this tubular segment. As a consequence, sodium remains in the tubules and acts as an osmotic diuretic, causing increased excretion of water as well as sodium. Because these drugs also block the effect of aldosterone to promote potassium secretion in the tubules, they decrease the excretion of potassium. Aldosterone antagonists also cause movement of potassium from the cells to the extracellular fluid. In some instances, this causes extracellular fluid potassium concentration to increase excessively. For this reason, spironolactone and other aldosterone inhibitors are referred to as potassium-sparing diuretics. Many of the other diuretics cause loss of potassium in the urine, in contrast to the aldosterone antagonists, which spare the loss of potassium. Spironolactone could also be used effectively to treat Conn syndrome, as it is an aldosterone antagonist, perfect for hyperaldosteronism. Aldosterone antagonists have been shown to improve survival in randomised controlled trials, with up to 30% reduction in the risk of death and hospitalisation in patients with heart failure. Amiloride and triamterene also inhibit sodium reabsorption and potassium secretion in the collecting tubules, similar to the effects of spironolactone. However, at the cellular level, these drugs act directly to block the entry of sodium into the sodium channels of the luminal membrane of the collecting tubule epithelial cells. Because of this decreased sodium entry into the epithelial cells, there is also decreased sodium transport across the cells basolateral membranes and, therefore, decreased activity of the sodium-potassium adenosine triphosphatase pump. This decreased activity reduces the transport of potassium into the cells and ultimately decreases the secretion of potassium into the tubular fluid. For this reason, the sodium channel blockers are also potassium-sparing diuretics and decrease the urinary excretion rate of potassium. Amiloride blocks Na+ channels and hence spares K+ in the late distal convoluted tubules or collecting tubules.

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 The following image displays the mechanism of action of the potassium sparing diuretics- the aldosterone receptor antagonists (spironolactone and eplerenone) and the sodium channel blockers (amiloride and triamterene). There is also an image of the electrolytes that are reabsorbed/secreted at the level of the late distal convoluted tubules and collecting tubules (note the intercalated cells reabsorb potassium and exchange this with hydrogen and the principal cells reabsorb sodium and chloride but secrete potassium and reabsorb water under the influence of ADH):

-adrenoreceptor antagonists: -blockers inhibit the sympathetic activity of noradrenaline/adrenaline on -adrenoreceptors. They reduce cardiac output by decreasing the heart rate and force of contraction. It also affects heart activity even during exercise. Furthermore, they also act on -adrenoreceptors in the kidneys, reducing renin release thus decreasing blood volume and vascular tone. The juxtaglomerular cells of the kidney have 1-adrenoreceptors, which stimulates the release of renin under sympathetic control. -blockers also have some effect on the central nervous system, possibly relevant to BP reduction. These drugs are useful to circumvent sympathetic response (i.e. if a 1st line antihypertensive does not work in reducing BP in the long-term). However, there is variation, with 1 and 2-selective adrenoreceptor antagonism. There is also variation between these drugs in their intrinsic sympathomimetic activity and their lipid solubility. Non-selective 1 and 2 receptor antagonists include propranolol, pindolol and timolol. It is very important to avoid these drugs and not to prescribe in asthmatics, as they cause 2-receptor antagonism which could lead to bronchospasm in asthmatics. Furthermore, these non-selective -blockers can also cause effects on the liver. 2adrenoreceptors are found in the lung, the liver and peripheral vessels. 1-selective receptor antagonists include atenolol, bisoprolol and metoprolol, which are more useful for treating hypertension (effects on cardiac output and renal renin release) compared with the non-selective -blockers. For treatment of hypertension, it is thus preferred to have -blockers that are more 1-selective and have less 2receptor activity. Note that in the human heart the ratio of -adrenoreceptors in cardiac muscle is (1: 2 75:25). The kidney predominantly contains 1 adrenoreceptors. However, the bronchi, peripheral vessels and some other tissues predominantly have 2 adrenoreceptors. 2-receptors are similar to 1 and hence 2-selective drugs may have slight 1-affinity. Thus even with a 1-selective antagonist, such as atenolol, there is a risk of bronchoconstriction/spasm for asthmatics. Important adverse effects from -blockers to remember include those from -adrenoreceptor blockade, such as cold hands and feet, bronchospasm, increased triglycerides (effects on the liver), CNS effects: dreams, insomnia, syncope and fatigue.

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/-adrenoreceptor antagonists: Carvedilol and labetolol are examples of non-selective adrenoreceptor blockers, so it has effects on both and adrenoreceptors, and it has no intrinsic sympathomimetic activity. Carvedilol is used for the treatment of mild to moderate congestive cardiac failure. Labetolol is frequently used for pregnancy-induced hypertension and preeclampsia and also for acute hypertensive crisis or pheochromocytoma. The effects of blocking 1 receptors include vasodilatation, 1-antagonism as mentioned before blocks reflex tachycardia (through reduced heart rate & force of contractility) and reduced renin release. -adrenoreceptor antagonists: Important drugs include Prazosin and terazosin, which are 1-selective adrenoreceptor antagonists, which blocks post-synaptic 1-receptors, so noradrenaline cannot bind. The mechanism of action includes peripheral vasodilatation (just like calcium channel blockers), both arterial and venodilation, due to blockade of postsynaptic 1 receptors. These are however, NOT 1st line antihypertensives. They are also used for benign prostatic hyperplasia. They have side effects including postural hypotension, and this is a 1st-dose effect; it is not a good idea to prescribe in the elderly geriatric population, due to risks of orthostatic hypotension and syncope. These drugs can also cause weakness and drowsiness/dizziness/presyncope. Calcium channel blockers: Calcium has a pivotal role as an intracellular 2nd messenger. Transient increases in calcium concentration can be initiated by: 1) Increased release from intracellular storage sites 2) Increased Ca2+ permeability of the plasma membrane- opening of channels. Note that many cells have voltage sensitive Ca2+ channels (VOCC). Calcium concentrations are also very important in controlling smooth muscle tone and there is a 1000 times gradient from extracellular to intracellular Ca2+ concentration (being highest in the extracellular compartment). Note that in arterial smooth muscle a special type of calcium channel the L-type exists (different from cardiac muscle T-type). All L-type Ca channel blockers relax arterial smooth muscle by preventing Ca2+ entry into smooth muscle cells, thus causing vasodilation and decreasing blood pressure. The site specificity varies, and important drugs include: The dihydropyridines, such as nifedipine and amlodipine (Norvasc) which are vascular smooth muscle Ca2+ channel-selective (L-type channel-selective). Diltiazem is a calcium channel blocker of the benzothiazepine class which is both vascular and cardiac muscle selective. However, verapamil is completely cardiac muscle selective. For a patient with cardiac failure and hypertension, you should NOT give verapamil or diltiazem as it can further compromise cardiac function (due to negative inotropic effects), instead nifedipine or amlodipine may be given. Verapamil is a calcium channel blocker of the phenylalkylamine class and also a Class IV anti-arrhythmic agent that acts on cardiac L-type calcium channels, which slows conduction in the SA and AV nodes where action potential propagation depends on slow inward Ca2+ slowing the heart and terminating SVT rhythms by causing partial AV block. They shorten the plateau of the action potential and thus reduce the force of contraction. Reduced Ca2+ entry reduces after-depolarisation and thus suppresses premature ectopic beats. The main clinical indication for verapamil is for treatment of dysrhythmias, in particular to slow ventricular rate in rapid atrial fibrillation, to prevent recurrence of supraventricular tachyarrhythmias (SVT) (given IV to terminate SVT, although now largely replaced by adenosine). The main clinical use for dihydropyridines is for treatment of hypertension, and according to the National Heart Foundation guidelines, it is considered a first-line anti-hypertensive together with either an ACE inhibitor or AT II antagonist. Dihydropyridines may also be used to prevent angina, which is also the main clinical indication for diltiazem. Clinical uses: 1) Hypertension (mainly dihydropyridines) 2) Angina (mainly diltiazem, some use for dihydropyridines) 3) Dysrhythmias (rapid AF and SVTs, mainly verapamil) Important adverse effects of the dihydropyridines include: oedema, flushing, headaches, and reflex increase in sympathetic activity.

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 Important adverse effects of diltiazem and verapamil include cardiac bradyarrhythmias. Side effects of the dihydropyridines include oedema, flushing, headaches, constipation (with verapamil) and reflex increase in sympathetic activity- as the baroreceptors return BP to previous levels- dihydropyridines would not be effective in this case. Drugs affecting the Renin-Angiotensin system: Remember the basics of the renin-angiotensin-aldosterone system, highlighted below:

Note that angiotensin II has two ways of increasing BP, it can act as a powerful vasoconstrictor, or it can lead to increased adrenal production of aldosterone, which causes water and salt retention thus also increasing BP. The following highlights the mode of action of angiotensin converting enzyme (ACE) inhibitors, note that they are also involved blocking the in breakdown of bradykinins (bradykinin breakdown is an important role of ACE).

The ACE inhibitors:

Enalapril and perindopril are important ACE inhibitors (ACEI) that block the conversion of angiotensin I to angiotensin II, therefore it causes a decrease in vascular tone and BP and also decreases aldosterone production. However, the adverse effects of the ACE inhibitors include severe hypotension, acute renal failure, hyperkalemia, cough (associated with decreased break down of bradykinins, ACE is commonly found in the lungs and on endothelium), loss of taste (dysgeusia), rash and fetal malformations (highly teratogenic). ACE inhibitors hence contraindicated in pregnancy and in people with pre-existing renal disease.
Angiotensin II antagonists:

Angiotensin receptors are widely distributed; in vascular smooth muscle, adrenal cortex, kidney and brain. There are two types of angiotensin II receptors identified, AT1 and AT2 receptors. AT2 receptors are found in blood vessels. However, most known actions of angiotensin II are mediated through the AT1 receptor, which are involved in increasing adrenal aldosterone secretion and causing vasoconstriction via angiotensin II. Angiotensin II is ~40 times more potent than noradrenaline. In the near future renin inhibitors will hopefully be a new future possibility for treatment of hypertension. The following image summarises the mechanism of action of the Angiotensin II receptor antagonists:

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 Important angiotensin II receptor antagonists include losartan (Cozaar), candesartan (Atacand) and irbesartan (Avapro), which are all selective for AT1 receptors, and inhibit the cardiovascular effects of angiotensin II, and have similar efficacy as ACE inhibitors. Note that these drugs have the same adverse effects as ACEI, however, unlike ACEI they are not involved in the break-down of bradykinins, and so they do not produce a cough. So, adverse effects include: hyperkalemia, headaches, dizziness, etc. It is important just like with ACEI to avoid angiotensin II receptor antagonists in pregnancy (due to teratogenicity) and also in patients with renal impairment. Note however, that diabetics may in fact benefit from use of ACE inhibitors/angiotensin II receptor antagonists. Centrally acting antihypertensives: Note that it is the baroreflex that increases BP when the BP is detected as being low in the carotid sinus. This then causes increased descending sympathetic outflow from the medulla oblongata that then acts on the heart, blood vessels & kidneys to increase blood pressure. Centrally acting antihypertensives act by decreasing sympathetic outflow from brain centres and thus decreasing vascular tone. Important drugs to remember include -methyldopa which is converted to -methyl noradrenaline (which is an 2-receptor agonist) in the brain that then decreases sympathetic outflow and also clonidine- an 2receptor agonist. These drugs hence act at the brainstem level on 2-receptors (agonists). The following reactions display the conversion of -methyldopa to -methyl noradrenaline:

However, adverse effects of centrally acting antihypertensives include sedation, sleep disturbance, dreams, depression, xerostomia. Also -methyldopa side effects include hepatotoxicity and haemolytic anaemia. Clonidine is also associated with a withdrawal syndrome which is a detrimental rebound increase in sympathetic activity. Overview of treatment for hypertension: benefits are unequivocal with reducing BP. Lifestyle measurements may be useful, although there are a diverse range of drugs that aim to normalise BP. However, adverse effects of these drugs may preclude use. Note also that 50-75% of patients will not respond adequately to monotherapy, so combination therapy is used. Note that a larger reduction in BP produces a larger reduction in risk of end-organ and vascular diseases. From randomised controlled trials, there was no significant differences in outcome in the total number of major cardiovascular events between ACEI, calcium antagonists, diuretics or beta blockers. Hypertension is a common cause of morbidity, but too few patients are adequately treated. A reduction in cardiovascular disease mortality and morbidity can be achieved through improved treatment and control of hypertension. A choice of drugs is available for hypertension, systematic trial and error may be necessary for each individual. An estimated 50-75% of patients with hypertension will not achieve BP targets with monotherapy. For most patients, a combination of anti-hypertensive drugs from two or more pharmacological classes is needed. Occasionally a combination of three or more may be required to achieve adequate BP control.

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 With combination therapy, it is important to use drugs from different groups. Based on current evidence, the use of an ACE inhibitor or AT II antagonist in conjunction with a calcium channel blocker is the most effective combination in most people and has particularly beneficial effects for diabetics and those with lipid abnormalities. Aim for at least additive effects, for example, use one of the following: 1) ACEI or ARA & calcium channel blocker 2) ACEI or angiotensin II receptor antagonist (ARA) & a Thiazide diuretic (effective for heart failure or post-stroke) 3) ACEI or ARA & beta blocker (useful in the setting of heart failure) 4) Beta blocker & Ca channel blocker (DHP) 5) Thiazide diuretic & Ca channel blocker 6) However AVOID: ACEI and K+ sparing diuretic (as it would cause hyperkalemia), and beta blocker with either verapamil or diltiazem (causes severe bradycardia/bradyarrhythmia). 7) Also large-scale trials have shown that combination therapy with ACE inhibitors in conjunction with AT II receptor antagonists are not more effective in reducing cardiovascular death or morbidity in patients with vascular disease or diabetes, however, increased the risks of hypotensive symptoms, syncope and renal dysfunction. The following table gives the advantages & disadvantages of different drugs:

AE refers to adverse effects, adv- advantages, TG- triglycerides, C/I-contraindicated

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Pharmacological management of heart failure

ACE inhibitors and AT II receptor antagonists, -blockers and diuretics are the mainstay of therapy. Nitrates are useful if the cause is MI (for coronary artery vasodilation and prophylaxis), and while digoxin improves symptoms and reduces hospitalisation, they have yet to be shown to improve mortality. Other medication such as direct vasodilators (hydralazine) and calcium channel blockers may be used but have yet to be shown to improve mortality. -blockers are used in the treatment of cardiac failure to decrease cardiac work, pre-load and after-load to decrease heart contractility. However, in late stages of cardiac failure, there must be an increase in contractility to keep the patient alive and then this would involve use of inotropic agents to increase heart contractility and includes the cardiac glycosides and catecholamines. Important non-pharmacological management includes physical activity and rehabilitation, nutrition (optimise weight), saturated fat intake, fibre intake, malnutrition (cardiac cachexia, anaemia), reduce sodium intake, refer to specialised dietician. With fluid management, be aware of weight gain (>2kg over 2 days prompts medical attention). Also avoid >2Lfluid intake/day, with restrictions liberalised with warmer weather. Abstain from alcohol if alcoholic cardiomyopathy, otherwise limit to 1-2 standard drinks/day. Reduce caffeine intake, limit to 1-2 beverages/day. Smoking cessation important and education regarding condition, monitoring, beneficial lifestyle changes, medication side-effects, signs of deterioration, importance of adherence to therapy and psychosocial support. Sleep apnoea, vaccination (influenza and pneumococcal) and counselling in travel (DVTs) and in pregnancy (high morbidity and mortality). Heart failure aims of treatment include: To improve cardiac function Reduce symptoms and improve quality of life, including fatigue, dyspnoea and oedema. Prevent progression and increase survival rate by ~10% even with mild or moderate heart failure. Inotropic agents are used last, as they are administered intravenously for acute exacerbations of heart failure or for advanced chronic heart failure. Heart failure is defined as insufficient cardiac output from the heart to meet the perfusion requirements of the body. It has multiple causes: Ischaemic heart disease/coronary heart disease Long-standing hypertension Valvular heart disease/endocarditis Cardiomyopathy- think in terms of hypertrophic, restrictive or dilated, but other important categories of causes include infectious, inflammatory, familial, metabolic, toxin-related, idiopathic. Myocarditis- inflammatory In a normal heart, as ventricular end-diastolic volume (pre-load) increases, stroke-volume also increases to compensate, as the heart pumps more forcefully to remove the blood. In cardiac failure, despite increasing enddiastolic volume (because of volume overload), stroke volume does not increase and the heart compensates by trying to work harder as a result of stretching of the fibres (Frank-Starling mechanism), which eventually leads to cardiac hypertrophy (and/or dilation also ensues as a result of higher end-diastolic volume). Hence treatment must also include decreasing pre-load (load placed on myocardium due to venous return- the end diastolic volume), or reducing after-load (the pressure at which the heart has to contract) in accordance with Laplaces law. By decreasing pre-load and after-load, pressure on the myocardium is reduced and this decreases symptoms of congestive cardiac failure (CCF). In cardiac failure there is increased sympathetic overdrive due to low BP stimulating baroreceptors (low BP from low cardiac output). This leads to increased sympathetic drive with chronic over-action of 1-adrenoreceptors. This

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leads to impaired 1-adrenoreceptor coupling and reduced 1-adrenoreceptor expression that can lead to reduced sensitivity to 1-receptor antagonists. Disease/damage to the myocardium leads to decreased cardiac output and hence cardiac failure. Then compensatory mechanisms are activated; e.g.: Increased sympathetic activity Activation of the renin-angiotensin-aldosterone system Cardiac hypertrophy to try to increase cardiac output In the long-term, these compensatory mechanisms are disadvantageous, i.e.: It leads to sodium and water retention leading to oedema Cardiac hypertrophy due to increased cardiac muscle work, this increased cardiac muscle mass also has greater requirements for oxygenation Treatment strategies thus are aimed at these compensatory responses, i.e. to remove salt and water with diuretics, reduce pre-load and after-load by vasodilators and improvement of cardiac muscle work/contraction with inotropic agents. Also a number of non-pharmacological strategies may be employed such as salt and water restriction. Thus drugs for heart failure include: Diuretics as discussed above ACE inhibitors/Angiotensin II AT1 receptor antagonists Vasodilators -blockers Cardiac glycosides Phosphodiesterase inhibitors Sympathetic stimulants- sympathomimetics Some of the previous discussion is repeated for diuretics, -blockers, ACE inhibitors/AT II antagonists but now for the context of heart failure. Diuretics in heart failure: Loop diuretics are particularly useful for removing excess fluids and these include furosemide (Lasix), bumetanide and ethacrynic acid. They are particularly useful for removing excess extracellular fluids, such as in peripheral oedema, ascites, pleural effusions and pulmonary oedema which occurs in heart failure. Loop diuretics act on the thick ascending limb of the loop of Henle, by inhibiting the Na +/K+/2Cl- co-transporter, which leads to natriuresis and diuresis but may lead to hypokalemia and metabolic alkalosis, hearing impairment as an adverse-effect. This can be controlled by giving the patient IV fluids supplemented with potassium or also using a potassium-sparing diuretic. Thiazides such as chlorothiazide act on the luminal side of the distal convoluted tubules, and inhibit the Na+/Cl- cotransporter and thus decreasing NaCl reabsorption. Again, hyponatremia, hypokalemia are important side effects. Many people taking diuretics will need supplements due to electrolyte imbalances. Also, many patients with chronic heart failure will need chronic loop diuretics. Potassium sparing diuretics such as spironolactone act on the collecting ducts and tubules and is an aldosterone antagonist, it has been shown that aldactone has similarly reduced mortality in cardiac failure by up to 30%. These diuretics spare potassium excretion and hence there are no side-effects of hypokalemia, however, it can induce lifethreatening hyperkalemia. Spironolactone antagonises the action of aldosterone on the aldosterone nuclear receptor, which inhibits its transcription of the ENaC channels (epithelial Na + channels) as well as luminal Na+/K+ transporters. It thus leads to sodium and chloride excretion, but spares potassium excretion. This is a weak diuretic, that blocks aldosterone and hence prevents K+ loss but enhances Na+ removal.

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ACE inhibitors in heart failure: Inhibition of ACE leads to inhibition of angiotensin II production, leading to decreased aldosterone release, which leads to decreased fluid retention (thus reducing preload); and it also inhibits the vasoconstriction from angiotensin II, which leads to decreased arteriolar tone and constriction (thus reducing afterload). Examples include enalapril and perindopril, which inhibits conversion of angiotensin I to angiotensin II, suppressing aldosterone production by the adrenal medulla which dilates arteries and thus reduces afterload. Some ACE inhibitors may cause venodilation and are used for early and moderate cardiac failure, but may also decrease cardiac hypertrophy due to decreased preload and afterload. Hence ACE inhibitors may improve survival, but have the side-effects of hyperkalemia, first-dose hypotension, renal impairment, dry cough, and teratogenicity. Renal impairment may be an important co-morbidity to consider especially if the patient has cardio-renal syndrome with renal failure secondary to heart failure. Angiotensin II AT1 receptor antagonists in heart failure: Common examples include losartan and candesartan. These drugs block the action of angiotensin II on vessels, and avoids some of the side-effects of ACE inhibitors. These drugs are useful for mild to moderate heart failure. They may also decrease cardiac hypertrophy by decreasing heart preload and afterload. Important side effects however, to remember include hypotension, teratogenicity, hyperkalemia and renal impairment. Renal impairment may be an important co-morbidity to consider especially if the patient has cardio-renal syndrome with renal failure secondary to heart failure. Vasodilators in heart failure and angina: These drugs act by decreasing peripheral resistance and hence decreasing BP. In the setting of heart failure, they decreased preload by venous dilatation and afterload by arterial dilatation. This leads to decreased cardiac workload. Important examples include nitrates, hydralazine, ACE inhibitors and angiotensin II AT1 receptor antagonists. These drugs have been shown to improve survival in heart failure. Nitrates: Nitric oxide donors stimulate guanyl cyclase, which leads to calcium being held in smooth muscle cells in the blood vessel wall and leads to vasodilation. Examples include nitroglycerin (glyceryltrinitrate) and isosorbide dinitrate. Nitrates predominantly lead to venous dilatation, thus reducing pre-load. Glyceryl trinitrate (GTN) is used to treat acute cardiac failure and myocardial ischaemia (angina) and it is given sublingually or with a translingual spray. It leads to relaxation of vascular smooth muscle and dilation of coronary arteries. Isosorbide dinitrate is used more for the treatment of longer term cardiac failure as well as angina. Important side effects of nitrates include flushing, headaches, hypotension and reflex sympathetic tachycardia. They may be contraindicated in postural hypotension, head trauma and cerebral haemorrhage. Importantly, tolerance may develop to nitrates within 1-2 weeks of chronic use, which can be avoided with a nitrate-free period each day, using shorter acting nitrates and removing longacting patches. Hydralazines: an example being apresoline. These are direct vasodilators, which increase guanosine monophosphate levels, thus decreasing the action of the secondary messenger IP 3, which limits calcium release from smooth muscle sarcoplasmic reticulum and tis hence leads to blood vessel relaxation and dilation. It has also been identified as a nitric oxide donor. Hydralazines can be used in combination with isosorbide dinitrate to reduce the mortality of cardiac failure. Side-effects include hypotension, reflex tachycardia, but it is a useful vasodilator to give in conjunction with -blockers, as the compensatory sinus tachycardia can be eliminated with a -blocker. They may also induce an SLE-like syndrome, SVT and peripheral neuropathy and may lead to hepatic impairment in pre-existing liver disease.

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-blockers in heart failure and angina: Important examples include carvedilol- a non-selective adrenoreceptor antagonist, which blocks 1, 1 and 2 adrenoreceptors. These drugs have no intrinsic sympathomimetic activity. Carvedilol blocks 1, receptors, which leads to peripheral vasodilatation (and decreased preload), 1 receptors, which leads to decreased heart rate and cardiac output and the reflex sympathetic tachycardia response is also blocked and additionally, it inhibits renin release by the juxtaglomerular apparatus cells of the kidney. With inhibition of 1, 1 and 2 receptors stroke volume is reduced. The important side effect of carvedilol is that it causes hypotension, dizziness and fatigue. Inotropic agents: Inotropic agents act by increasing the force of cardiac contraction and thus increasing cardiac output. This includes: The cardiac glycosides Phosphodiesterase inhibitors Adrenoreceptor agonists with (sympathomimetic activity) Some of these drugs work by increasing sympathetic activity, which in an acutely failing heart can improve contractility. The cardiac glycosides: include digoxin, or digitalis and ouabain, which is derived from the Foxglove plant and has been used for many years, and can also be used in conjunction with diuretics and ACE inhibitors. In addition to contractility, it decreases sympathetic drive, which enhances parasympathetic activity causing vasodilation and reduces resting heart rate along with increasing force of contraction. Thus it has a POSITIVE inotropic effect, but a NEGATIVE chronotropic effect. Cardiac glycosides inhibit the Na+/K+ ATPase pump; hence Na+ build up occurs inside myocytes; this then reduces Ca2+ efflux as it then INCREASES activity of the Na+/Ca2+ symport exchanger. The diagram on the left shows in a cardiac myocyte that digitalis inhibits the Na+/K+ ATPase pump and hence Na+ builds up in the myocyte. This subsequently increases Na+/Ca2+ re-entry via a Na+/Ca2+ exchanger, keeping Ca2+ with it, this leads to increased contractility. Digoxin, however, has a small safety margin and increased toxicity with lowered plasma K+ in cardiac failure and atrial fibrillation (thus one must NOT use digoxin in conjunction with most diuretics in these situations). A severe adverse effect is that it could cause ventricular arrhythmias and hence digoxin is used for advanced heart failure. As almost all cells in the body have a Na+/K+ ATPase pump and hence digoxin has many widespread adverse effects, including diarrhoea, drowsiness, confusion, psychosis and arrhythmias. Phosphodiesterase inhibitors: Phosphodiesterase inhibitors prevent cyclic AMP breakdown (as phosphodiesterase breaks down cAMP), which increases Ca2+ entering into the cell. Intravenous milronone is used for acute cardiac failure, and in cardiogenic shock. These drugs may cause GIT symptoms, hepatotoxicity and ventricular arrhythmias. Hence these drugs cannot be used chronically due to their toxic effects and increased mortality.

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-adrenoreceptor STIMULANTS in heart failure: These drugs are catecholamines with sympathomimetic activity, which also cause cardiac myocyte cAMP increase, which increases Ca2+ entry into cells leading to increased contractility, along with increased rate of contraction and can be used to treat acute heart failure and cardiogenic shock. Intravenous dobutamine (low dose dobutamine) is one example, which causes direct stimulation of 1adrenoreceptors (cardiac contractility effects are hence similar to specific 1 receptor stimulation. These drugs, including dopamine (a sympathomimetic) can also increase renal perfusion, as they act on dopaminergic DA receptors. 1-adrenoreceptor agonists are only used in the acute care setting (e.g. coronary care units), as these drugs may cause arrhythmias, they can down-regulate 1-receptors and can lead to an increased rate of cardiac work and need for oxygen consumptions (can predispose to myocardial ischaemia).

The following table summarises the main forms of treatment in cardiac failure: Drug class Diuretics Spironolactone Mechanism Decrease oedema Aldosterone antagonist Effects Decreased preload Decreases preload, reduces heart failure-related cardiac fibrosis Decreased preload Decreased afterload Increased stroke volume, decreased preload Increased cardiac output

ACE inhibitors/AT II receptor antagonists Non-selective / blockers

Vasodilation, and decreases extracellular fluid volume Vasodilation, no reflex increases in heart rate Increased contractility

Inotropic drugs

Hence these drugs help to decrease mortality associated with heart failure. Heart failure treatment involves many drugs, which may not improve disease progression; but can improve symptoms and morbidity. Other measures (discussed earlier) such as salt and water retention are also required. Compliance with medications and fluid/salt restrictions is very important. Other important treatment strategies include pacing with a pacemaker, or with a left or bi-ventricular assist device, use of implanted cardioverters (expensive) and surgery (LV excisions, aneurysmectomy, and heart transplantation). There are many flowcharts/guidelines for the pharmacological treatment of CCF, based on the New York Heart Association functional status score. In short, if there is no functional limitation from diagnosed heart failure (LVEF<40%) then use ACE inhibitors and -blocker.

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 If there is functional limitation, start ACE inhibitors and diuretic, add a -blocker and consider adding spironolactone, digoxin and AT II inhibitors to achieve symptomatic improvement.

Summary of the mechanisms of heart failure and sites of target for pharmacological agents:

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 The following is a related-aside topic that is very important to understand for management of acute pulmonary oedema: in the emergency situation:

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Asthma
Case protocol 39: Asthma
A 35 year old woman was seen by her local doctor because of increasing dyspnoea over the previous 12 hours. She had suffered from asthma since childhood, requiring numerous hospital admissions, and consequently was reluctant to consult doctors or to go to hospital. Her only medication was a salbutamol puffer, used as required. She had been suffering from an upper respiratory tract infection for the past three days and had a cough productive of yellow sputum. On examination, the woman was dyspnoeic at rest, having difficulty in carrying out a conversation. She was pale but not cyanosed, the chest was hyperinflated with prominent tracheal tug, and she was using accessory muscles of respiration. Bilateral inspiratory and expiratory wheezes were heard on auscultation. She was commenced on antibiotics, nebulised salbutamol and prednisone tablets, but refused admission to hospital. On examination, the patient is also tachycardic and tachypnoeic. Also importantly, she is afebrile, with an elevated systolic blood pressure. Based on the history and physical examination findings, the provisional diagnosis is an acute exacerbation of asthma or an asthma attack and possibly development of status asthmaticus, secondary to a recent upper respiratory tract infection (likely viral) along with poor compliance with medical treatment. Respiratory infections are the most common of the stimuli that evoke acute exacerbation of asthma. It has been shown that viruses (Influenza, parainfluenza, coronaviruses, respiratory-syncytial virus, rhinovirus, adenovirus etc) are a major aetiological factor. In older children and adults, rhinoviruses and influenza viruses predominate as pathogens. Differentials to consider (although asthma is very likely the cause in her presentation) include lower respiratory tract infection including bronchitis, bronchiolitis or pneumonia (although she is afebrile) secondary to the upper respiratory tract infection or bronchiolitis obliterans organising pneumonia (BOOP) (idiopathic and rare). Given her young age, it would be extremely unlikely for her to have cardiac failure and acute pulmonary oedema, or upper airway obstruction from a tumour. She may also have laryngeal oedema, recurrent pulmonary embolism, or a large pulmonary embolus (she may be a smoker on the oestrogen contraceptive pill) carcinoid tumour or even eosinophilic pneumonia, or diffuse vasculitic lung disease (e.g. Churg-Strauss syndrome). Appropriate pharmacotherapy must be given (see discussion on following pages), basically with reliever medications (bronchodilators) and preventers (e.g. steroids). Antibiotics may not be necessary as it appears that she is now recovering from a viral infection. Her treatment should be monitored in terms of her lung function: pulmonary function tests should be performed along with a challenge test with a bronchodilator response (>15% increase in FEV 1 in asthma after bronchodilators). This can be followed-up as an outpatient and she can also do peak-expiratory flow measurements at home using a peak flow meter to assess the severity of her asthma as well as response to medications. Her compliance to medications needs to be checked along with adequate education regarding her puffer use and how to take it properly. Other inhaler devices can be used as necessary (puffers/metered dose inhalers, turbuhalers, spacers, nebulisers etc). This woman exhibited features indicative of severe asthma, including dyspnoea at rest, tachypnoea (RR 26) with tracheal tug and hyperinflated chest (indicating air trapping from severe airways obstruction leading to increased anteroposterior diameter), bilateral inspiratory and expiratory wheezes. Important investigations to assess the nature of her disease would include: i. Peak expiratory flow rates ii. Pulmonary function tests- spirometry to check lung volumes and flow rates iii. Chest x-ray (showing hyperinflation, air trapping, mucous plugging) iv. Arterial blood gases v. Sputum sample to check for microscopy (Gram stain), culture and sensitivity and to check for sputum and blood eosinophil count. vi. Serum IgE levels

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Twelve hours after her initial consultation she was admitted to hospital following a respiratory arrest at home. Examination in the Emergency Department revealed a drowsy, cyanosed woman in severe distress and unable to talk. Respiratory effort was poor, the pulse rate was 180 beats per minute, the blood pressure 140/60 mm Hg with 30 mm Hg of paradox (pulsus paradoxus), and the chest was silent. Important questions to ask the carer/family would be the progression of what happened after she returned home. It is also important to ask about her medication use: compliance, how much she takes and how often. This is to check the effectiveness of her medications (in terms of reversibility) because if she took too much salbutamol often previously it may have induced tachyphylaxis and thus now there could have been a poor response to the bronchodilators, which is why she did not get better after her first ED admission. Otherwise, there may also have been worsening of infection with sepsis, development of ARDS, progression of asthma with a delayed asthma attack, a cardiac tachyarrhythmia or a rapid progression of some other unknown/rare condition such as Churg-Strauss syndrome etc. Important investigations would be to: i. recheck her vital signs (also check for fever, check oxygen saturation with pulse oximetry and check her arousal with Glasgow Coma Scale). ii. Also do an urgent arterial blood gas analysis iii. Urgent chest x-ray. iv. Collect blood cultures if she is febrile v. Also obtain IV access with a cannula to start her on IV medications if indicated and check her FBC, CRP. vi. She will also require urgent ventilation with oxygenation and if she is not breathing may need intubation with positive pressure ventilation and ICU admission.

Arterial blood gases were obtained and they show obvious respiratory acidosis, with severe hypoxemia, hypercarbia, and there may be some degree of metabolic compensation (positive numbers for base excess indicates excess base and negative indicates a deficit- a high base excess usually involves a high level of bicarbonate and can be caused by metabolic compensation for respiratory acidosis). This is due to her asthma and hypoventilation. Refer to the discussion on the following pages for detailed description of the aetiology and pathogenesis of asthma. Asthma is a very common condition. Bronchial asthma occurs at all ages, but predominantly early in life. Half of all cases develop before age 10, one-third before age 40. Asthma is a heterogeneous disease, it would be useful to classify asthma by principal stimuli that incite or are associated with acute episodes. Atopy is the largest risk factor for development of asthma but a significant number suffer from idiosyncratic asthma. Asthma that has its onset in early life tends to have a strong allergic component. Asthma that develops late tends to have a non-allergic or mixed aetiology. The hallmark pathological features of asthma to note include reduction in airway diameter brought about by contraction of smooth muscle, vascular congestion, oedema of bronchial wall, thick tenacious secretions and mucous plugging. These pathological changes result in increased airways resistance, with decreased forced expiratory volume and flow rates. This can lead in respiratory muscle function to air-trapping in the lungs and hence hyperinflation of the lungs and thorax, increased work of breathing and alterations in respiratory muscle function and changes in elastic lung recoil. There can also be impaired distribution of both ventilation and pulmonary blood flow with V/Q mismatch and hence altered blood gas concentrations.

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 In acutely ill patients: Residual volume can reach 400% of normal Findings of metabolic acidosis signifies severe airways obstruction. Hypoxemia is a universal finding during acute exacerbations, but frank ventilatory failure such as in this case is relatively uncommon (10-15%). Despite all attempts at resuscitation, the patients condition continued to deteriorate, and six hours later she had a cardiac arrest and died. Important macroscopic pathological findings would include obvious gross distension of the lungs, the lungs may also fail to collapse after the pleural cavities are opened due to air-trapping with airways obstruction and mucous plugging. When the lungs are cut, gelatinous plugs of exudates and mucous plugs in the bronchial tree down to the terminal bronchus may be observed. Below: The following image is of a lung at autopsy from a woman who had
chronic asthma, but who died from an acute asthmatic attack. The lung specimen shows complete occlusion of some of the respiratory passages in the lungs by thick, tenacious mucous (arrows).

Important histopathological changes that could be observed (see detailed description and images below) would include: Bronchial smooth muscle hypertrophy Hyperplasia of mucosal and submucosal vessels (angiogenesis). Mucosal oedema due to exudation Thickening of the basement membrane Mucous plugs in airways Eosinophillic infiltrates in bronchial wall, along with lymphocytes and plasma cells. Absence of any well-recognised forms of destructive emphysema.

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Asthma case 2::

A 42 year old man who had a long history of intermittent dyspnoea associated with expiratory wheezing and chest tightness presented to the emergency room of his local hospital. He had developed a cold 3 days earlier and during the night he had become very short of breath. His regular medications did not seem to have any effect. The man had never smoked. On examination, his respiratory rate was 30/min and widespread wheezing was audible in both lung fields. The following investigation results were obtained: Spirometry (after usual medications) 0.9L FEV1 4.2 L FVC Arterial blood gases (on room air) pH pO2 (mmHg) pCO2 (mmHg) Bicarbonate (mmol/L) O2 saturation Expected FEV1 Expected FVC 7.38 (7.36-7.44) 55* (80-100) 45 (35-45) 24 (24-32) 85* (95-100) 4.0L 5.0L

Since his shortness of breath is noticeable, this is evidence of respiratory distress. Other signs of respiratory distress may include costal in-drawing and subcostal recession, use of accessory muscles of respiration, tachypnoea, tachycardia and cyanosis. The spirometry illustrates an obstructive pattern of lung disease. The FEV1 is severely reduced, the FEV1/FVC ratio is ~20% which is very seriously reduced, even after he has taken his regular medication, which indicates he is not responding to his medications. Spirometry is the way that lung air volumes & lung capacity can be measured. The normal Forced Vital Capacity (FVC) is 5.0L, i.e. the lungs can hold (on average) a maximum volume of ~5.0L. Forced Expiration Volume in 1 second (FEV1) is used to identify how much air one can expire in one second. In people with normal lung function, forced expiration leads to an exponential decrease of air over time, with ~4.0L of FVC expired within 1 second. The normal ratio of FEV1/FVC should hence be ~80%. In asthmatics FEV1/FVC ratio is however <40%, although this is not necessarily diagnostic of asthma. This ratio can be increased (hence reversing bronchoconstriction) with the use of bronchodilator drugs, particularly 2-adrenergic agonist such as Salbutamol, which acts on bronchiolar smooth muscle, relaxing this smooth muscle & hence dilating airways. In this patient the FEV1/FVC ratio is ~0.21, which seems to be a grim outlook for the patient. The cold was most likely the result of a viral infection, which is a major trigger for exacerbating asthma. This led to seriously impaired air flow, & low oxygen status. This leads to the central nervous system respiratory centres increasing respiration rate to 30/min, compared to a normal 12-20/min. The viral infection was possibly complicated by spreading & causing a lower respiratory infection that triggered serious asthma. The bronchoconstriction, increased mucous output & airway oedema would have caused the audible wheezing sounds to be heard on both lung fields. Arterial blood gas is an invasive method of measuring arterial oxygen saturation levels. A less invasive method to monitor oxygen saturation would be with a pulse oximetry. The results of his ABGs indicates that he is hypoxemic, his O2 saturation is markedly reduced, since a normal O2 saturation should be ~98%. His pCO2 is in the upper range of normal, which is a bad sign of decompensated lung disease, since he is hyperventilating but not able to blow-off excess CO2. His bicarbonate is in the lower range of normal, he is not acidotic, as his pH is still in the normal range. The possible provisional diagnosis in this case is that (although we have not ascertained that he has a previous diagnosis of asthma in his medical history), this is a severe case of asthma; based on his history and physical examination findings, his ABGs and spirometry, and his unresponsiveness to his (asthma) medications. The differential diagnosis of a wheeze in this case is as follows: o The provisional diagnosis is severe asthma, secondary to a recent viral infection. The viral upper respiratory tract infection precipitated acute asthma. o Acute exacerbation of COPD, in a patient that has a background history of chronic bronchitis or emphysema, although he has never smoked. o Other obstructive lung diseases: small airways lung disease/bronchiolitis, bronchiectasis (irreversible ectasis or enlargement of the larger airways).

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If there is a localised wheeze, rather than a diffuse bilateral pattern, consider the possibility of lung cancer. If there is a unilateral/localised wheeze consider foreign bodies, such as coins, toys, food etc.

The man was commenced on salbutamol, a 2-adrenergic agonist, by nebuliser & given an intravenous dose of hydrocortisone, a corticosteroid The pathogenesis of asthma includes acute inflammation (from an irritant agent leading to acute bronchoconstriction), non-specific hyperactivity of chronic inflammation & airway remodelling (with metaplasia & hyperplasia of goblet cells, hypertrophy of bronchial smooth muscle, increased vascularity & subepithelial fibrosis). Hence asthma has an acute on chronic pattern of pathogenesis. Treatment is thus targeted at both arms of this pattern of inflammation.

Some triggers for asthma include house dust mite, pollens, animal fur & feathers, some chemical, insects (i.e. cockroaches), dust, fungal spores, some drugs (e.g. aspirin), exercise, cold weather, tobacco smoke, viruses. This leads to an acute inflammatory response initiated by Helper-T cells that sample the presented antigen from epithelial antigen presenting (dendritic) cells. These cells then release TH2 cytokines (namely IL-4, IL-5 and IL-13), which activate IgE secreting B lymphocytes (which could be formed at any stage of antigenic exposure), they secrete IgE, which activates Mast cells. Mast cells then secrete IL-3 & IL-5 which activates & recruits epithelial eosinophils (which are also activated by other pro-inflammatory factors from T helper cells). Eosinophilic major basic protein and Eosinophilic cationic proteins then lead to epithelial damage and acute inflammation. This also contributes to the chronic process of airway remodelling.

The 2-adrenergic agonist (Salbutamol, note also Terbutaline can be given) given to the patient is an important reliever medication, that relieves symptoms; by causing bronchodilatation. These drugs function via physiological antagonism, whereby these 2-receptor agonists oppose the parasympathetic effects of muscarinic

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M1, 2 & 3 receptors stimulated by acetylcholine from the parasympathetic vagus nerve branches. Salbutamol & Terbutaline, are 2-adrenergic agonists, short-acting bronchodilators (hence relievers), acting on smooth muscle cells in the airways to cause bronchodilatation. In this case it was given by nebuliser, as this gives better respiratory absorption (with vapour) of the drugs. The vapour allows mucous plugs to become softened and hence expectorated. Note that the nebuliser increases deposition of anti-asthmatic drugs into the bronchi & lungs. However, note that with puffers/inhalers only ~10% of the drug enters the lungs, the rest is deposited into the stomach. IV 2-adrenergic agonists are given in status asthmaticus- severe prolonged asthma episodes. Note that salbutamol/terbutaline are short acting (4-6 hours) and relieve the symptoms of bronchoconstriction & hence decrease hypoxemia. Tremors & tachycardia are a side effect, as these drugs have partial effects on other types of -adrenergic receptors in other sites of the body (i.e. 1 receptors). However, overuse, which may have been the case in this patient leads to development of tolerance. Hence a higher dose would be needed to reach a therapeutic effect. A 2-adrenergic agonist with longer lasting activity that could be used includes salmetrol. Asthma has an acute/early phase characterised with bronchospasm (acute inflammation), and a late inflammatory phase 5-8 hours after contact with initial stimuli. It is important to characterise the pathological changes observed in the acute and chronic phases of asthma. Important changes in the early phase include: o Initiation of an acute inflammatory response with symptoms, 30-60 minutes after inhalation of antigen. o Initial triggering of Mast cells, which release mediators such as histamine, which increases cell-junction permeability, which leads to more exposure of antigen to mucosal mast cells, histamine also affects Mast cell degranulation. o Parasympathetic stimulation also occurs leading to bronchoconstriction. o Mast cells release: o Leukotrienes C4, D4 and E4: bronchoconstriction, mucin secretion o Prostaglandin D2, E2, F2: bronchoconstriction, vasodilation, increased vascular permeability o Histamine: bronchospasm, increased vascular permeability o Platelet activating factor: recruits platelets to release histamine o Mast cell tryptases: inactivation of normal bronchodilatory peptide (VIP) Important changes in the late-phase of asthma include: o Usually occurs 4-8 hours after inhalation of antigen/allergen o It is dominated by leukocytes: basophils, neutrophils and eosinophils o Late-phase cells release: o Eosinophilic and neutrophilic chemotactic factors and leukotriene B4 o IL-4, IL-5, which augment the TH2 response, increases IgE synthesis and chemotaxis and proliferation. o Platelet activating factor and IL-5: recruits platelets for chemotaxis o TNF- up-regulates adhesion molecules on vascular endothelium and on inflammatory cells.

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 IV hydrocortisone was also given to the patient, which is the most potent naturally occurring anti-inflammatory drug. The intended action of this corticosteroid is to reduce the general inflammation in the lungs. The action of the hydrocortisone is to improve airway wall function, decrease airway hyper-reactivity by reducing inflammation, mainly by reducing oedema, mast cell degranulation and eosinophil recruitment. This functions by reducing cytokines & pro-inflammatory interleukins & inhibits leukocyte influx into lungs. A good method of administration would be inhaled glucocorticoids (i.e. budesonide, beclomethasone, fluticasone) for quick deposition of steroids into the lungs. Other possible potent anti-inflammatory drugs that could be used include leukotriene receptor antagonists, as the pathogenesis of asthma is also mediated by leukotrienes. Also apart from these treatments, it is important to give the patient O2 ventilation to improve their hypoxemia and give them IV rehydration. Also for management, it is important to do physiotherapy (e.g. breathing exercises with a bag) to allow expectoration of mucous plugs, preventing secondary infection & relieving airways obstruction. In severe cases of asthma, adrenaline is given, and one can try to reassure the patient. Adrenaline is very rarely used as a treatment nowadays; it is given for patients in the case of either anaphylaxis or croup/epiglottitis in children. Asthma has a: 1 in 6 prevalence in children, and a lower 1 in 10 prevalence in adults in Australia. However, importantly, asthma nowadays has a low mortality rate. The man did not respond to these medications & was transferred to the ICU. He died several hours later with respiratory failure. The following on the right is from tissues prepared at autopsy: This macroscopic specimen is from a lung in a patient that died from severe asthma. The lung appears collapsed, hyperaemic and congested, consistent with asthma. The segmental large and medium-sized bronchioles are thick-walled & their lumina are occluded by greyish-white, opalescent, jelly-like mucous plugs. It is these plugs, rather than bronchospasm that have caused lung collapse (due to air trapping- air is absorbed by alveoli and then there is atelectasis, with hyperinflation in other areas), unconsciousness, hypoxemia, acidosis & death in this patient. The pulmonary vessels in the vicinity of the bronchi contain post-mortem clot. A histological specimens below displayed the following:

The main features seen in this slide which are suggestive of long-standing asthma includes smaller bronchiole lumens, eosinophil influx- characteristic of asthma, with intraepithelial eosinophils; mucous plug obstruction of airways (which could have led to respiratory failure from status asthmaticus). Also seen is subepithelial fibrosis & hypertrophy of bronchiole smooth muscle both indicative of a chronic asthma. Furthermore, goblet cell metaplasia & hyperplasia is observed in the bronchiole lumen. Also significant lymphocytic infiltrate is observed indicating chronic inflammation of asthma.

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 Note that the reduced lumen size is due to the mucous plugs. The lumen is highly folded, due to increased number of goblet cells being accommodated by the bronchi, i.e. goblet cell hyperplasia which is abnormal. The subepithelial fibrosis indicates a chronic inflammatory process. Also lymphoid aggregates present with prominent germinal centres, these are CD4+ T lymphocytes and activated B cells, Plasma cells. Vascular changes from inflammation & oedema are also observed; as well as compensatory hyperinflation of the alveolar acini. Note that mast cell proteases (e.g. tryptases) on immunohistochemistry stain can be used to detect mast cells in asthma.

Asthma assessment & management

Asthma is chronic airway inflammation, with increased airway responsiveness. This results in the symptoms of wheeze, cough, chest tightness and dyspnoea. Asthma is airways obstruction which is variable over short periods of time or reversible with treatment. Asthma is a common condition, affecting many Australians. It has a multifactorial complex aetiology, with genetic and environmental factors causing the disease. Indoor environmental agents that can predispose or induce asthma include house dust mite pellets (dust), pet derived allergens, fungal spores, pollutants and cigarette smoke. In the outdoor environment, the role of agents in initiating asthma is small, although these agents/allergens have an important role in triggering exacerbations of existing asthma; including grasses and flower pollens as well as air pollution gases (e.g. Oxides of Nitrogen etc). Occupational asthma is also important, with major work environments that can predispose/induce asthma including people who are spray painters (exposure to diisothiocyanates), hard wood dusts (e.g. carpenters working with red cedar woods), laboratory-workers working with animals. In these cases, the patient is characteristically only affected when at work (e.g. not on weekends) or if the agent is removed within the first six months of symptoms there is usually no persistent pathology. More persistent symptoms can lead to irreversible airways changes. In some patients, chronic inflammatory stimuli cannot be identified, yet they have severe airway inflammation. These patients have intrinsic asthma (non-allergic), which separates them from allergic asthma, but they have all the classic features of airway hyper-responsiveness and obstruction. A number of other factors influence the development of asthma. For example, infections, e.g. viral, Mycoplasma and bacterial infection provoke a transient increase in airway responsiveness in normal people and in asthmatics, as well as cigarette smoke, cold air, exercise (induced asthma) etc. Breastfeeding may offer some protection against development of asthma. For asthma pathogenesis, a series of factors combined lead to asthma, including: increasing airway inflammation and responsiveness, followed by bronchoconstriction and symptoms of asthma. With inhalation of an allergen, this leads to a sensitised atopic individual. In acute asthma, there is then a two-phase response; 1) and early asthmatic response maximum of 20 minutes after allergen exposure, followed by 2) a late asthmatic reaction from ongoing/late inflammation- about 6-12 hours later. Clinical features of asthma include that of: o Episodic asthma: which is the pattern observed in children and young adults; patients are generally asymptomatic between episodes, they then suffer an asthma attack- e.g. during a viral upper respiratory tract infection or exposure to allergens, such as pets, pollen. o Persistent asthma: this is adult onset asthma, which is characterised by a chronic wheeze and dyspnoea. It is more common in older patients. There is a variable nature of symptoms, which is characteristic in asthma, e.g. there may be a diurnal pattern (symptoms and peak flow measurements being worse in the early morning, improving during day); some patients may have nocturnal symptoms, some patients have a cough variant asthma, some patients have an exercise-induced asthma. The pattern of asthma is important to ask for: what is the frequency of symptoms, i.e. how often and when do you have these symptoms (daily, monthly)? What triggers your asthma? Important trigger factors include upper respiratory tract infections, cold air, dusts/dust mites (dermatophagoides)/vacuuming, allergen exposure such as cockroaches, cats, furs, feathers/birds, stress-induced, seasonal triggers such as grasses and pollen, exercise-induced asthma, drugs such as -blockers (systemic or topical or selective 2-blockers), aspirin (aspirin-sensitive asthma), ACE inhibitors (associated with inhibited break-down of kinins, which are bronchoconstrictors), gastro-oesophageal reflux, premenstrual asthma (related to a fall in progesterone levels, also associated with thyrotoxicosis or hypothyroidism). Exercise-induced asthma is common in children and

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typically begins after exercise has ended and normally recovers spontaneously after 30 minutes. Exerciseinduced asthma is worse in cold and dry climates more than hot and humid climates. Exercise-induced asthma can be inhibited by -blockers, anti-leukotrienes and glucocorticoids. Exercise leads to hyperventilation, which leads to increasing osmolarity in airway lining fluids and mast cell mediator release and bronchoconstriction. Other similar mechanisms in asthma include cold-air and hyperventilation, laughter (hyperventilation), weather changes, strong smells and perfumes. Mechanisms of food-induced asthma may be related with anaphylactic/anaphylactoid reactions leading to wheezing, rather than foods that genuinely increase asthma symptoms, some examples include: aspirin-induced, shellfish, nuts, food preservatives and colouring agents. Air-pollution may also induce asthma, related to increased levels of sulphur-dioxides, ozone, nitrogen oxides and dusts. Also importantly, occupational-asthma. It is important to ask: do you have pets? Also have you had any allergy or skin-prick tests? What were the results of the skin-prick tests and what are your allergies? Another important clinical feature to ask about is their response to treatments, which should be asked with their medications history. What is your response to treatment, or how well do you respond to treatment? This is important as it provides clues to the reversibility of the disease, and is important to ask in elderly people who have had chronic asthma. Other important questions to ask for in the history include a comprehensive occupational history (remember occupational risk factors), what was your age when you first developed asthma? This is important, as generally most children with childhood asthma become better and their asthma gradually improves becoming milder or disappears during the teens; at least in one-thirds of patients the asthma will go away, although some people develop asthma in their 20s. It is also important to ask about past hospitalisations and past asthma history, especially important are any ICU visits that may have been the result of severe asthma and these patients are at higher risk of dying from asthma. Have you been admitted to hospital before for asthma, when was this etc? It is important to ask about what medications the patient uses for asthma and how they respond to treatment, what do you take for your asthma and do medications/inhalers/nebulisers improve their symptoms? Take a good detailed medications history; ask about preventers, relievers (SABA, LABA, muscarinic receptor antagonists etc.). What investigations/tests have you had done? Important tests to ask for and check results include Peak flow charts documenting changes in Peak Expiratory flow, lung-function tests (has there been any improvement in obstructive lung patterns, FEV1/FVC with medications?), chest x-rays, bronchial challenge tests (nebulised histamine, hypertonic saline or methacholine) and was there any changes/fall in FEV1 with bronchial challenge? Have they done an exhaled Nitrous oxide test? Also important to ask in patients is their family history, have they had a family history of asthma or lung diseases?

Physical examination key points: Typically with asthma, there is a diffuse, bilateral polyphonic wheeze heard on auscultation. Furthermore, as asthma is an obstructive lung disease, one would expect a prolonged forced expiratory volume in one second (FEV1) which would result in a low peak expiratory flow measurement. These are important signs of severity of asthma. Important investigations for asthma: Spirometry is a good test for checking lung function and degree of obstruction. Typically with asthma, there is a reduced peak expiratory flow rate measurement, a reduced FEV1, which thus causes a reduced FEV1/FVC ratio. Note that the patients lung function test results may be normal in between attacks in patients with episodic asthma. Also note that it is important to demonstrate disease reversibility with administration of bronchodilators. A methacholine, hypertonic saline or histamine challenge test (bronchial provocation tests) is also useful for investigating the patients acute asthma. It is very important that bronchial provocation tests are performed with careful supervision and available medications as this test may involve precipitating bronchospasm. Skin prick tests are very useful in determining if the patient has hypersensitivity reactions to certain allergens and identifying which allergens they should try to stay away from. Acute severe asthma: In acute severe asthma, the patient may be significantly short of breath that they may be unable to complete a normal sentence (speaking in short sentences, increased work of breathing). The patient is usually tachypnoeic with respiratory rate >25/minute and with other signs of respiratory distress. The patient may also be tachycardic, with a pulse rate >110/minute. Reduced peak flow measurements are usually <50% of the predicted value for their gender, age and height. The patient with severe asthma may also

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have pulsus paradoxus, which is a fall in the systolic blood pressure of ~10mm Hg during inspiration, although it can disappear with respiratory muscle fatigue, as the patient can no longer generate intrapleural pressure. It is very important to recognise life threatening signs of severe acute asthma including: 1) 2) 3) 4) 5) 6) 7) 8) Peak flow <33% of predicted A silent chest with reduced or absent breath sounds PaO2 <60 mm Hg (Normal) or high PaCO2 pH decreased, patient acidotic Patient hypotensive and possibly in shock A decreased heart rate. Patient comatose or with other signs of respiratory failure.

Treatment of acute asthma: basic principles: Oxygen therapy is very important, to prevent hypoxemia. Bronchodilators especially the use of salbutamol (or salmetrol in severe asthma) is important to reverse the symptoms of acute respiratory distress. Steroids such as prednisolone, or IV hydrocortisone are necessary to reduce airway inflammation and prevent a late-phase inflammatory response. Xanthines: Theophylline. Treatment of chronic asthma: basic principles: 1) Reliever medications useful with asthma episodes/acute attacks which are basically bronchodilators- Short acting bronchodilators (SABA) (salbutamol (Ventolin), albuterol, terbutaline (Bricanyl or Terbulin)). Muscarinic receptor antagonists (ipratropium bromide, terpatropium). 2) Preventer medications: are important, as they stabilise the airways, preventing inflammation; these are inhaled corticosteroids including fluticasone (Flixotide and Seretide: fluticasone/salmetrol), budesonide (Pulmicort and Symbicort: budesonide/formoterol) and beclamethasone. 3) Long acting bronchodilators (LABA) (Salmetrol, Formoterol). 4) Combined preparations: a combination of inhaled corticosteroids together with long-acting bronchodilators is useful in controlling asthma, e.g. Seretide (salmetrol & fluticasone) and Symbicort (budesonide & formoterol). See below for pharmacology of medications used to treat asthma & COPD.

Pharmacology: Drugs to treat COPD & asthma

COPD or also known as Chronic airways limitation (CAL) is a disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious gases or particles such as cigarette smoke. Clinical features may include a productive cough, dyspnoea, recurrent low grade infective exacerbations. Respiratory failure is the leading cause of death. COPD aetiology is complex, involving bronchoconstriction, inflammation, airway structural changes, that all contribute to causing airflow limitation. Other factors that can contribute to development of CAL include occupational dust and fume exposure, air pollution, alpha-1 antitrypsin deficiency (which is involved in inhibiting neutrophil elastase), genetic predisposition, recurrent respiratory infections in childhood and bronchial hyper-responsiveness. The following diagram summarises the very basic pathogenesis of COPD:

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 Note that proteinase inhibitors are a potential new drug class being investigated for treatment of COPD. Bronchoconstriction in CAL may be partially reversible in many patients, however, not all patients respond to pharmacotherapies. Airway hyper-responsiveness may develop after exposure to tobacco smoke or environmental irritants. Chronic inflammation is associated with an increase in the amount of smooth muscle in the airway wall. Note that there is some overlap between asthma and CAL (asthmatic bronchitis or chronic asthma), otherwise they are almost two separate obstructive lung diseases. o COPD usually affects the elderly, it is slowly progressive, it has an inflammatory component that is mediated by CD8+ T cells, macrophages and neutrophils, and is usually only partially reversible. o Asthma can affect all ages, especially children, it has an episodic course with triggering factors, the inflammatory component comprises of CD4+ lymphocytes, eosinophils and mast cells and it can be fully reversible although there are exceptions in some patients (such as decreased responsiveness to medications). The efferent pathways or receptors present in the smooth muscle of the airways includes: 1) 2 adrenergic receptors which respond to circulating adrenaline. 2) Muscarinic receptors (M1, 2, 3), the M2 receptor is a presynaptic inhibitory auto-receptor. Muscarinic receptors have parasympathetic effects and respond to Acetylcholine. 3) Non-adrenergic non-cholinergic nerves (NANC): inhibitory nerves (relaxant) which are acted on by nitrous oxides, and stimulant nerves which increase vascular permeability acted on by Substance P and bradykinins/neurokinin A (a potent spasmogen).
Treatment of COPD

It is important to help the patient to stop smoking and help them on the path to quitting. This has been definitely shown to improve survival, as there is prolonged life expectancy after stopping smoking, it is never too late to stop smoking. Smoking impairs mucociliary transport and contributes to mucous gland hypertrophy and altering the structure of alveolar macrophages in COPD. Pharmacological management of COPD involves three main types of treatment: o Bronchodilators these are reliever medications, including 2 adrenergic agonists, xanthines (which tend to be used when other drugs do not work, due to xanthine side-effects), muscarinic receptor antagonists. o Symptom controllers: namely Long-acting 2 adrenergic agonists o Anti-inflammatory drugs: glucocorticoids/oral steroids, leukotriene receptor antagonists. Other important therapies for management not discussed here include antibiotics for treating recurrent infections, vaccinations as prophylaxis against influenza and pneumococcal infection to prevent a major exacerbation of COPD and also in patients with COPD exacerbation that require oxygen therapy.
2 adrenergic agonists: reliever medication

2 adrenergic agonists dilate bronchial smooth muscle by a direct action on 2 adrenergic receptors. These drugs help antagonise bronchoconstriction of the smooth muscle irrespective of the spasmogen involved, they are a form of physiological antagonism. 2 adrenergic agonists also inhibit the release of inflammatory mediators by mast cells. Common 2 adrenergic agonists that are short acting include salbutamol and terbutaline, which have a duration of action of 4-6 hours and a maximum effect after 30 minutes (by inhalation). These drugs are resistant to enzymatic degradation; they are excreted largely unchanged in the urine. Long-acting 2 adrenergic agonists include salmetrol, which is more effective in treating COPD, but it is more expensive and has duration of action of ~12 hours, useful for the late-inflammatory stage of acute asthma. Side-effects and problems of 2 adrenergic agonists include those of increased sympathetic responses, such as tremor and tachycardia. Another important problem is that patient overuse leads to tolerance and desensitisation. Hence bronchodilator drugs should be used on an as need basis during the early stages of disease. Also very importantly, they should be used with caution in patients with cardiovascular disease and one must be aware of potential drug interactions, e.g. they should not be used in patients that are taking 1-antagonists for hypertension/heart failure.

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Muscarinic receptor antagonists:

Ipratropium bromide (Atrovent) antagonises bronchial constriction and mucous production caused by parasympathetic stimulation from acetylcholine acting on muscarinic M2 and M3 receptors. It is more effective in treating patients with CAL than for asthma, as it also inhibits mucous secretion (feature of chronic bronchitis). The onset of duration is often slow, with maximum effect after 30-60 minutes and duration of action 3-5 hours. They can be used in combination with a short-acting 2 adrenergic agonist. Side-effects are those that cause inhibition of the parasympathetic nervous system, including nervousness, nausea and vomiting, dry mouth and tachycardia. Another important muscarinic receptor antagonist used to treat COPD is tiotropium bromide (Spiriva).
Xanthines:

Theophylline (Nuelin-SR) or aminophylline are examples of a xanthine, which can act as a bronchodilator; xanthines are used when 2 adrenergic agonists are ineffective. These drugs are well absorbed, given orally, using slow-release preparations. A sustained blood level is achieved in up to 12 hours. The mechanism of action of Theophylline is by inhibiting phosphodiesterase (which metabolises cAMP) thus increased intracellular cAMP which could inhibit the activation of inflammatory cells and cause bronchodilatation. However, an effective concentration is needed which exceeds the therapeutic dose. The side effects of theophylline includes that it has a poor therapeutic index and hence blood plasma levels should be monitored. Theophylline has many side-effects and many drug interactions. There is a need for individual monitoring of blood levels because of side effects and the narrow therapeutic window. Theophylline causes CNS stimulation (think of side effects of caffeine!); causing reduced fatigue, improvement in mental and motor tasks, tremor, seizures, nervousness and sleep interference, diuresis, dry throat. It can also cause cardiac stimulation; with a positive inotropic effect (i.e. increases the force of contraction) and positive chronotropic effect (increase in heart rate) due to its action on phosphodiesterase inhibitors. Gastrointestinal symptoms include: nausea, vomiting and anorexia. Major drug interactions include with oral contraceptives, erythromycin, calcium channel blockers and cimetidine (a histamine receptor antagonist) and these interactions are all because these drugs reduce CYP450 activity, which is needed to metabolise theophylline.
Glucocorticoids:

Glucocorticoids have an anti-inflammatory and by similar mechanisms immunosuppressant activity. These drugs are NOT bronchodilators, but they may reduce bronchial hyper-reactivity. They can result in a significant increase in FEV1, in responsive CAL patients, but non-responsive CAL patients can also benefit by reducing exacerbations of CAL through reducing inflammation. Important inhaled glucocorticoids used for treatment of asthma and COPD include budesonide, beclomethasone and fluticasone. Immunosuppressant activity of glucocorticoids is via inhibition of the influx of inflammatory cells into the lung. This involves inhibition of the activation of macrophages and inhibition of the release of inflammatory mediators from leukocyte including eosinophil major basic protein and major cationic proteins. Glucocorticoids also reduce the formation of pro-inflammatory cytokines and reduction in the synthesis of IL-3. Glucocorticoids also have anti-inflammatory actions by inhibiting the induction of cyclooxygenase (COX), specifically COX-2 (inhibition of pain and inflammatory pathways, as opposed to COX-1 which is responsible for maintaining and protection of the gastrointestinal tract). Remember that cyclooxygenase is responsible for
catalysing the conversion of arachidonic acid to prostaglandin H 2. Three main isoenzymes of COX exists, COX-1, COX-2 and COX-3. (Note that the -coxib drugs are COX-2 selective inhibitors). This is as opposed to non-selective COXinhibitors (the classical NSAIDs), which inhibit prostoglanding and thromboxane synthesis and they thus have reduced inflammation, antipyretic effects, antithrombotic and analgesic effects. The most frequent effect of NSAIDs however, is irritation of the gastric mucosa/gastritis and gastric bleeding due to the inhibition of prostaglandins which normally have a protective role in the GI tract. Selectivity for COX-2 is the main feature of celecoxib and rofecoxib and as COX-2 is usually specific to inflamed tissue there is much less gastric irritation associated with COX-2 inhibitors. The selectivity for COX-2 inhibitors however, does not negate other side effects including increased risk of renal failure, and also increased risks associated with thrombosis including thrombosis, myocardial infarcts and strokes through an increase in thromboxane A2 unbalanced by prostacyclin (which is reduced by COX-2 inhibitors).

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 Glucocorticoids also inhibit the formation of arachidonic acid by inducing the synthesis of Lipocortin. Lipocortin inhibits phospholipase A2 and the subsequent formation of both prostaglandins and leukotrienes. Refer to the Eicosanoid biosynthesis diagram:

Important side-effects of glucocorticoids to remember include immunosuppression; causing vaginal or oral thrush that causes hoarseness and they can also precipitate infections that could potentially exacerbate COPD. They also have systemic effects such as bruising, dermal thinning, adrenal suppression and altered bone metabolism (causes catabolism that can cause osteoporosis), impaired wound healing, development of diabetes (causes gluconeogenesis and glycogenolysis and decreases insulin resistance) and peptic ulcers (from effects on cyclooxygenase on prostaglandin synthesis and hence disrupts gastric mucosa), and can cause iatrogenic Cushings syndrome. The side effects are more likely to occur with the oral glucocorticoids such as prednisone, hence inhalation is the preferred method of administration to transfer medication directly to sites of inflammation in the lung. Sodium chromoglycate and nedocromil are two related non-steroidal anti-inflammatory agents that are able to blunt the effect of inflammatory inducers and certain bronchospastic triggers (especially cold air and exercise). They are particularly effective in patients with a significant allergic component to their asthma. The precise mechanism of action of these drugs is not clear.
Leukotriene-receptor & synthesis antagonists:

Leukotriene receptor antagonists: leukotrienes are potent bronchoconstrictors that amplify the inflammatory processes, competitive antagonists of the cysteinyl-leukotrienes LTC4, LTD4 and LTE4 include Montelukast and Zafirlukast. Leukotriene synthesis inhibitors: block the formation of LTB4 as well as LTC4, LTD4, LTE4. These drugs also inhibit 5-lipoxygenase (refer to diagram above) and includes Zileuton.
Monoclonal antibodies:

Omalizumab is a humanised monoclonal antibody that selectively binds to the Fc portion of human IgE and designed for those with moderate to severe or very severe asthma which is triggered by hypersensitivity reactions to harmless environmental substances. Like other biological, the cost can be extremely high and as a result is reserved for patients with severe asthma whose disease cannot be controlled by high-dose glucocorticoids and other simple medications. A major risk side-effect of Omalizumab is anaphylaxis or the development of cancer in very few cases.

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Summary of important medications to treat asthma:

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Acute Respiratory Distress Syndrome

Case: ARDS:
A 63 year old woman developed Gram-negative sepsis following a urinary tract infection. She was admitted to the ICU, but developed rapidly worsening dyspnoea. Arterial blood gases were as shown: Arterial blood gases pH PaO2 (mmHg) PaCO2 (mmHg) Bicarbonate (mmol/L) O2 saturation (%)

7.30* 45* 48* 18* 75*

(7.36-7.44) (80-100) (35-45) (24-32) (95-100)

The ABGs display mixed acidosis, that is both respiratory and metabolic in origin, i.e. she is hypercapnic indicating a respiratory component to the acidosis (although not severely hypercapnic), together with a metabolic component with decreased bicarbonate (note if this were respiratory acidosis with metabolic compensation, one would expect bicarbonate to be elevated (not decreased) with low pH). The whole ABG pattern indicates respiratory failure, with hypoxemia and hypercapnia one would expect more ventilationincreased ventilatory drive to blow-off CO2 which is not occurring in this case. Hence the primary problem in this case is hypoventilation. Furthermore, sepsis causes shock and loss of ventilation-perfusion to tissues and hence peripheral tissues begin to utilise anaerobic metabolic pathways, and hence there is a build-up of lactic acid, with lactic metabolic acidosis which hence decreases bicarbonate buffering. Thus this metabolic acidosis together with the respiratory acidosis indicates mixed acidosis from respiratory failure. This patient has obvious severe hypoxia from possible acute-respiratory distress syndrome (ARDS); and her survival probability is very poor. Also even in those who survive the prognosis is still poor, with persistent morbidity/disability from pulmonary fibrosis. If this really is ARDS, then a chest x-ray would demonstrate diffuse bilateral oedema, with an acute onset. It must be distinguished from acute cardiogenic pulmonary oedema from CCF, which is done by inserting a Swan-Ganz catheter, which is inserted into a major vessel and a balloon is blown to measure capillary wedge pressure to exclude acute congestive cardiac failure causing pulmonary oedema. The patients chest x-ray is displayed below.

The chest x-ray appears to have a classical pattern indicating diffuse bilateral pulmonary oedema and together with her acute progression to respiratory failure may indicate that this is ARDS. This is life-threatening, associated with complications and is caused by hyaline glassy membranes which form in the alveoli that prevent gas-exchange.

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She was intubated and ventilated with 100% oxygen, but her arterial oxygen saturation remained dangerously low. A diagnosis of acute respiratory distress syndrome (ARDS) was made. Treatment was ineffective and she died in the Intensive Care Unit several days later. The following tissues were obtained from autopsy.

Interstitial inflammation and interstitial oedema is observed, with neutrophil and lymphocytic infiltrate. There is obvious diffuse eosinophilic material in the lung alveoli, which are hyaline membranes that have replaced alveolar epithelium. Hyaline membranes are created from epithelial cell necrotic debris, surfactant and fibrin. There is a diffuse pattern of alveolar pneumocyte and endothelial damage, indicating ARDS. On higher magnification:

She would have had a very poor lung compliance and hence poor lung expansion. The loss of surfactant would cause lung collapse and hence would make lung expansion difficult, causing excessively hard work needed for breathing. Hyaline membranes and interstitial oedema would have caused hypoxia due to poor gas exchange. This explains her respiratory failure; the grossly decreased compliance of the lungs and lack of surfactant causing atelectasis would mean that she cannot hyperventilate to blow-off CO2.

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 ARDS is due to primary epithelial/endothelial injury causing inflammation and alveolar & interstitial oedema. ARDS is defined as a clinical syndrome characterised by severe dyspnoea of rapid onset, with hypoxemia, diffuse bilateral pulmonary infiltrates leading to respiratory failure. It is characterised as an interstitial lung disease of acute origin, with acute lung injury. The other form of acute interstitial lung disease is of less severity than ARDS but may evolve to become ARDS. ARDS is also characterised by a ratio of PaO2/FiO2 200 mmHg, and a PaO2/FiO2 between 200-300mmHg identifies patients with acute lung injury. Causes of ARDS can be divided into environmental & non-environmental (or direct and indirect lung injury). Non-environmental causes include: 1) Burns and severe trauma including pulmonary contusions and near drowning 2) Aspiration of gastric contents 3) Endothelial injury from Gram-negative septicaemia, the bacterial lipopolysaccharide binds to neutrophils and macrophages increasing TNF-, and pro-inflammatory mediators; these cells injure alveolar epithelial and endothelial cells and thus cause ARDS 4) Diffuse pulmonary infections, such as with pneumonia 5) Obstetric complications such as DIC and endothelial injury as a result of amniotic fluid emboli. 6) Acute pancreatitis 7) Uraemia Environmental causes of ARDS include: 1) Inhalation of smoke, toxic noxious gases 2) Ingested toxic chemicals 3) Heroin or methadone overdose 4) Acetylsalicylic acid injury 5) Amiodarone induced lung injury

Management of ARDS is to recognise and treat the underlying cause, with supportive care through mechanical ventilation, nutritional support and preventing complications. Based on the case above, it can be note that important diagnostic criteria for ARDS includes: o An acute clinical onset o With PaO2/FiO2 200mmHg (as opposed to acute lung injury (ALI) which has PaO2/FiO2 300mmHg) o A chest x-ray indicating bilateral alveolar or interstitial infiltrates. o Also importantly, with a pulmonary capillary wedge pressure 18mmHg or no clinical evidence of increased left atrial pressure. o The underlying pathology is diffuse alveolar damage, with three characteristic phases: Exudative, proliferative and fibrotic:

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 The exudative phase is characterised by: o Capillary endothelium and alveolar type I pneumocyte (alveolar epithelial cell) injury o Loss of cellular junctions/alveolar barrier o Exudation and development of alveolar and interstitial oedema o Production of pro-inflammatory cytokines, chemokines and arachidonic acid derivatives by cells in the local milieu in the zone of active inflammation, including IL-1, IL-6, IL-8/CXCL-8, TNF- and leukotriene B4, to increase the inflammatory response in response to the inciting agent and also to recruit more inflammatory cells. o This leads to a chemotactic, inflammatory response, with associated vascular obliteration and this leads to microthrombi formation. o The chemotactic signals lead to neutrophil infiltration and exudation of acute-phase proteins into the alveolar spaces and interstitium. Neutrophils secrete proteases, reactive oxygen species (oxidants) and platelet activating factor, which leads to more local tissue destruction and necrosis. o The accumulation of proteinaceous exudates including fibrin, necrotic pneumocyte and endothelial cell debris together with surfactant leads to the development of hyaline glass membranes. o Dependent alveolar oedema also leads to atelectasis, which together with interstitial oedema decreases lung compliance. As a result, there is also shunting and hypoxemia worsens.

During the proliferative phase: o Patients clinically recover rapidly and usually do not require mechanical ventilation, but still experience dyspnoea, tachypnoea and hypoxemia. o Histologically, there is resolution of inflammation and initiation of lung repair, organisation of alveolar exudates. o There is a transition from acute inflammation mediated predominantly by neutrophil infiltration to more of a chronic inflammatory picture, with increasing numbers of lymphocytes infiltrating the lungs. o As part of the healing response, there is a compensatory proliferation of Type II pneumocytes, which produce new pulmonary surfactant. o There is also an increase of alveolar Type III pro-collagen peptide, which is produced in response to increased levels of TGF-1 and other pro-fibrotic cytokines including Fibroblast growth factor (FGF),

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platelet-derived growth factor (PDGF), fibronectin, insulin-like growth factor etc. Note that type III pro-collagen peptide is a marker of increased mortality. In the fibrotic phase: o A small percentage of patients progress and become more dependent on mechanical ventilation or supplemental oxygen. o Histologically, the alveolar oedema and inflammatory exudates become organised and at this stage it is converted into alveolar and interstitial fibrosis. The acinar architecture becomes markedly disrupted, with emphysema-like changes with large bullae. There is also fibrous proliferation in the microcirculation which leads to vascular occlusion and development of pulmonary hypertension. o These patients are at increased risk of developing pneumothorax (increased rates of positive-pressure ventilation with background lung injury and bullae which can rupture), decreased lung compliance and increased pulmonary dead space volume. o If the patient survives, this can hence progress to chronic interstitial lung disease with pulmonary fibrosis. Other important complications after survival include psychiatric disorders such as depression, post-traumatic stress disorder. Management of ARDS is individualised depending on the patients underlying condition, along with ICU supportive care, with the following principles in mind: 1) Recognise and treat the underlying medical/surgical disorder 2) Important fluid management: Increased pulmonary vascular permeability leading to interstitial and alveolar oedema rich in proteins is characteristic of ARDS. In addition, impaired vascular integrity augments the normal increase in extravascular lung water that occurs with increasing left atrial pressure. Maintaining a normal or low left atrial filling pressure minimizes pulmonary oedema and prevents further decrements in arterial oxygenation and lung compliance, improves pulmonary mechanics, shortens ICU stay and the duration of mechanical ventilation, and is associated with a lower mortality. Thus, aggressive attempts to reduce left atrial filling pressures with fluid restriction and diuretics should be an important aspect of ARDS management, limited only by hypotension and hypoperfusion of critical organs, such as the kidneys. 3) Glucocorticoids: Inflammatory mediators and leukocytes are abundant in the lungs of patients with ARDS. Many attempts have been made to treat both early and late ARDS with glucocorticoids to reduce this potentially deleterious pulmonary inflammation. Few studies have shown any benefit. Current evidence (2009) does not support the use of glucocorticoids in the care of ARDS patients. 4) Minimise invasive procedures and complications 5) Prophylaxis against venous thromboembolism, gastrointestinal bleeding and catheter/cannula-related infections. 6) Recognition of hospital-acquired infections, with multi-drug resistant organisms, hospital acquired pneumonia, or central venous access related. 7) Provision of adequate nutrition, use total parenteral nutrition if required. 8) Manage mechanical ventilation: o Prevent ventilator-induced injury: barotrauma/volutrauma o Prevention of alveolar collapse, use judicious positive end expiratory pressure (PEEP), inspiratory-time and expiratory-time. o Use novel therapies, including nitric oxide and sildenafil etc.

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Role of arterial blood gas analysis in dyspnoea (laboratory visit)

Some revision:

Composition of dry air is ~218% oxygen; 78% nitrogen and 0.04% carbon dioxide, atmospheric pressure at STP is 760mmHg and the partial pressure of water vapour is 47mmHg at body temperature. Normal respiratory rate is 12-20 breaths per minute, tidal volume is 0.5L, minute volume is 6-8L/min depending on sex, height & chest size etc. The normal anatomical dead space volume is 150mL. Thus with each tidal volume, only ~350mL are exchanged at the alveoli and hence alveolar volume is 4.2L/min. Rapid, shallow breaths can rapidly reduce alveolar minute volume. Oxygen reduction, hypoxemia is rapidly detected by the aortic and carotid bodies and this increases respiratory drive. However, reduction of carbon dioxide with hypocapnia can limit the hypoxemic respiratory drive. Decreased pH (i.e. increased H+ concentration) and increased carbon dioxide in hypercapnia also stimulates the respiratory centre to change respiratory rate. In general alveolar minute volume is inversely proportional to carbon dioxide levels and hypercapnic drive is important for control of respiration.

Remember the haemoglobin-oxygen dissociation curve; which is recorded when pH = 7.4, Pco2 = 40 mmHg, temperature 37C and Haemoglobin concentration 15g/100mL. Useful points to remember from the graph include: Po2 (mmHg) 0 20 27 40 100 %Sat 0 35 50 75 97.5

This can be used to solve the alveolar gas equation, PA O2 PI O2 Pa CO2 respiratory quotient . The respiratory quotient is averaged to ~0.8. Hence for example, 100 = 150 40mm/0.8, which determines the A-a gradient, is important to know and should normally be less than 25. The effects of oxygen therapy are as follows; 30% FiO2 is equivalent to PiO2 = 214 mmHg; 40% FiO2 is equivalent to PiO2 = 285 mmHg (e.g. calculate the PiO2 from 760mm 47mm (H20) 0.4). With arterial blood gases, the PaO2 must be compared with PAO2 in order to determine the A-a gradient. The ABG must also be assessed firstly for acidosis or alkalosis. Base excess is useful to determine if there is a metabolic or respiratory problem. Some examples for ABGs: in a patient with narcotic overdose; this patient will have a depressed respiratory drive from opioids and as such their minute volume will be reduced. Hence their PaCO2 is reduced and PAO2 reduces as per the alveolar gas equation.

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 In atelectasis there is collapse of the lower lung alveoli, however, perfusion still occurs in the unventilated lung (causes a ventilation-perfusion mismatch). The degree of hypoxemia is proportional to the amount of lung collapse. The patient hence becomes short of breath, but the PaCO2 remains the same or slightly reduced. In pulmonary embolism, there is reflex shallow rapid respiration. A V/Q mismatch occurs because of poor perfusion to well ventilated lung. Hence PaO2 is reduced, although PaCO2 is normal or slightly reduced from rapid respiration. In ARDS, ventilation & perfusion is uneven in the lungs; there is alveolar-capillary block and hence perfusionventilation mismatch, PaO2 is low and PaCO2 may be normal. However, if the lungs become very stiff, as occurs with hyaline membrane formation, then the PaCO2 can rise. In a patient with emphysema, the lungs lose their elastic tissue and alveoli breakdown forming large air sacs and as a result the dead space volume is greatly increased. The alveolar ventilation is poor and uneven, resulting in perfusion to unventilated areas. As a result severe hypoxia occurs. Hypercarbia develops due to poor ventilation mechanics. Hypoxia in the lungs also causes pulmonary vasoconstriction, leading to development of pulmonary hypertension, which can lead also contribute to V/Q mismatch. The following displays the characteristics of primary acid-base disorders:

The clinical causes of acid-base abnormalities are described below. The major cause of respiratory acidosis is decreased rate of pulmonary ventilation, which increases PCO2, which causes increased H2CO3 and thus increased H+ concentrations. Respiratory acidosis can occur from pathological conditions that damage the respiratory centres (damage to the medulla oblongata) or that decreases the ability of the lungs to eliminate CO2, such as with airway obstruction with pneumonia, emphysema, or decreased pulmonary membrane surface area; or any other factor that interferes with gas exchange between blood & alveolar air. In respiratory acidosis, the compensatory responses include (1) body fluid buffers and (2) the kidneys, which require several days to compensate by increasing acid secretion & an increase in bicarbonate. Respiratory alkalosis results from increased ventilation and decreased PCO2. The causes include overventilation by the lungs. This rarely occurs because of organic pathological conditions, however, psychoneurosis (anxiety- panic attacks) can occasionally cause hyperventilation to the extent that the person becomes alkalotic. Physiologic type respiratory alkalosis can occur with ascent to high altitude. The low atmospheric oxygen stimulates respiration (hypoxic drive), which causes excess loss of CO 2, and development of mild respiratory alkalosis. The major means of compensation are chemical body fluid buffers, and the ability of the kidneys to increase excretion of bicarbonate. Metabolic acidosis results from decreased extracellular fluid bicarbonate concentration. This refers to all other types of acidosis besides those caused by excess CO2 in the body fluids. Metabolic acidosis can result from several causes: 1) failure of the kidneys to excrete metabolic acids from the body, 2) formation of excess quantities of metabolic acids in the body, 3) addition of acids to the body by ingestion or infusion, 4) or loss of base from the body, which has the same effect as addition of acid. Some specific conditions are described as follows; 1) Renal tubular acidosis results from a defect in renal secretion of acid or reabsorption of bicarbonate, or both. Some causes include chronic renal failure, insufficient aldosterone secretion (Addisons disease), and several inherited or acquired disorders that impair tubular function, such as Fanconis syndrome. 2) Severe diarrhoea is probably the most common cause of metabolic acidosis, caused by the elimination of large quantities of sodium bicarbonate into the faeces (see diarrhoea notes). As the

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gastrointestinal secretions normally contain large amounts of bicarbonate, this results in a loss of bicarbonate & hence acidosis. This is especially serious and is a cause of death in young children. 3) Vomiting of intestinal contents: as intestinal secretions are basic, this leads to a net loss of base from the body & hence acidosis, similar to diarrhoea. 4) Diabetes mellitus: this is caused by a lack of pancreatic insulin secretion (type I) or insufficient secretion of insulin to compensate for decreased sensitivity to the effects of insulin (type II). In the absence of sufficient insulin, normal glucose metabolism is prevented. Instead some fats are split to acetoacetic acids (ketone bodies) and this is metabolised in tissues for metabolic fuel rather than glucose. With severe diabetes, blood acetoacetic acid levels can rise significantly, causing metabolic acidosis. In an attempt to compensate for this acidosis, large amounts of acid are excreted in the urine, sometimes as much as 500ml/day. 5) Chronic renal failure: When kidney function declines significantly, there is a build-up of the anions of weak acids in the body fluids that are not being excreted by the kidneys. In addition decreased glomerular filtration rate reduces the excretion of phosphates and ammonium, which reduces the amount of bicarbonate added back to the body fluids. Thus, chronic renal failure can be associated with severe metabolic acidosis. 6) Ingestion of acids: rarely large amounts of acids are ingested in the diet, although severe metabolic acidosis can result from ingestion of certain acidic poisons such as acetylsalicylic acid (aspirin) and methyl alcohol (forms formic acid when metabolised). Metabolic alkalosis is caused by increased extracellular fluid bicarbonate concentration. This is not nearly as common as metabolic acidosis but can occur in the following conditions: 1) Administration of diuretics (except carbonic anhydrase inhibitors); all diuretics lead to increased flow of fluid along the tubules, usually causing increased flow in the distal and collecting tubules. This leads to increased reabsorption of Na+ from these parts of the nephrons. Because sodium reabsorption here is coupled with H+ secretion, enhanced sodium reabsorption also increases hydrogen secretion and an increase in bicarbonate reabsorption. These changes lead to the development of alkalosis, characterised by increased extracellular fluid bicarbonate concentration. 2) Excess aldosterone (Conn syndrome): When large amounts of aldosterone are secreted, mild metabolic alkalosis occurs as aldosterone promotes extensive reabsorption of sodium from the distal and collecting tubules and at the same time stimulates secretion of hydrogen (and potassium) by the intercalated cells of the collecting tubules. This increased hydrogen secretion leads to its increased excretion by the kidneys and therefore metabolic alkalosis. 3) Vomiting of gastric contents: causes loss of HCl secreted by the stomach mucosa and hence development of metabolic alkalosis. This type metabolic alkalosis occurs especially in neonates who have pyloric stenosis caused by hypertrophied pyloric sphincter muscles. 4) Ingestion of alkaline drugs: A common cause of metabolic alkalosis is ingestion of alkaline drugs such as sodium bicarbonate for the treatment of gastritis or peptic ulcers.

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 In some instances, acid-base disorders are not accompanied by appropriate compensatory responses. When this occurs, the abnormality is referred to as a mixed acid-base disorder. This means that there are two or more underlying causes for the acid-base disturbance. For example, a patient with a low pH would be categorised as acidotic, and if they had low plasma HCO3- concentration associated with elevated PCO2, one would suspect a metabolic and respiratory component to the acidosis, which could occur for example in a patient with acute bicarbonate loss from the GI tract because of diarrhoea who also had emphysema. A convenient way to diagnose acid-base disorders is to use an acid-base nomogram. When using this diagram, one must assume that sufficient time has elapsed for a full compensatory response, which is 6-12 hours for a respiratory compensation in primary metabolic disorders and 3-5 days for metabolic compensations in primary respiratory disorders. A mnemonic to remember causes of metabolic acidosis is LUSK: Lactic acidosis, Uraemia, Salicylates/Severe diarrhoea, Ketoacidosis. Ketoacidosis can be the result of starvation, diabetes mellitus or excess alcohol intake.

Laboratory visit notes: Arterial blood gas (ABG) analysis

Measurement of ABG tensions will detect a disturbance of gas exchange and indicate likely mechanisms, if hypercapnia is present (PaCO2> 45 mmHg), then alveolar ventilation is inadequate for the bodys metabolic rate. If hypoxemia is present and it cannot be accounted for solely by hypoventilation then there is disease of the lung (i.e. airways, parenchyma, and/or pulmonary vasculature). Measurement of ABG tensions allows assessment of the severity of the patients gas exchange disturbance. For example, for any given metabolic production of carbon dioxide, a halving of alveolar ventilation will double PaCO2. ABGs also indicate the presence of an acid-base disturbance of the blood and allow assessment of the metabolic component of the disturbance. However, ABGs cannot: o Diagnose the patients underlying disease, nor differentiate between different lung diseases. o ABGs cannot indicate the severity of the patients underlying disease. For example, spirometry should be used to assess the mechanical disturbance of the lungs in asthma. o The decision to administer oxygen to a sick patient is a clinical decision and should not be delayed until the PaO2 is available. Conversely, some patients with low PaO2, e.g. those with Type II respiratory failure from stable COPD do not require oxygen therapy. Interpreting ABGs, for alveolar ventilation: Is a disturbance of gas exchange present , and if so, what is its type? o First look at arterial PaCO2 (gives indication of respiratory component is primary or secondary). If PaCO2 is high (>45mmHg hypercapnia), the alveolar ventilation is inadequate to excrete carbon dioxide produced by metabolism. Normally ventilation is driven by arterial PaCO2. Therefore, a rise in metabolic CO2 production, e.g. by exercise is followed by a compensatory rise in ventilation. Thus elevations of PaCO2 marginally above normal are significant and usually indicate severe disease of the brain (e.g. medulla), respiratory muscles, chest wall or lungs. Now look at arterial PaO2: o Is it normal (assuming PaCO2 is normal)? PO2 = 100 (age 0.25). If the arterial PO2 is lower than expected for the patients age, hypoxemia is said to be present and the mechanism needs to be elucidated. If the alveolar ventilation is adequate (i.e. arterial PaCO2 is normal or low) hypoxemia is almost certainly due to a disturbance of ventilation/perfusion ratio in the lungs. o Is it normal (assuming PaCO2 is elevated)? Alveolar ventilation is not adequate and so it is necessary to assess whether: i) hypoventilation accounts for the hypoxemia, or whether ii) there is also a disturbance of the ventilation/perfusion ratio. This is done by estimating the difference between alveolar PaO2 and the arterial PaO2 (A-a gradient) using the alveolar air equation: = FiO2 [Patm - 47] 1.25[PaO2] Where Patm is atmospheric pressure (760mmHg), Partial pressure of water vapour is 47mmHg).

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Example: PaCO2 = 62mmHg (hypercapnia) PaO2 = 69mmHg (borderline hypoxemia) FiO2 = 0.28 (on 28% oxygen) = 0.28 [760 - 47] 1.25(62) = 122 Therefore the A-a gradient is 122 -69 = 53mmHg. A value >15-20mmHg means there is a ventilation-perfusion mismatch and consequently there is disease of the airways, lung parenchyma or vasculature (nonspecific). N.B. This alveolar-arterial gradient cannot be used to assess the size of ventilation perfusion inequality. pCO2 is the partial pressure of carbon dioxide that is being carried in the blood stream to the lungs for excretion by respiration. This hence represents the respiratory component of ABGs, with normal levels being 3545mmHg. Most CO2 is carried as carbonic acid (H2CO3) which is converted back to CO2 for excretion in the lungs. Any excess is excreted through the kidneys via the bicarbonate buffer system. Respiratory excretion of carbon dioxide assists us in maintaining a normal pH by eliminating the body of the vast amounts of CO2 produced daily as a result of normal cellular metabolism. pO2 is the partial pressure of oxygen dissolved in the blood, which normally is 80-100mmHg. This only represents ~2-3% of the oxygen actually in the body, but it is an important indicator of potential tissue oxygenation. Without sufficient partial pressure, oxygen is unable to bind to Haemoglobin where the majority of the oxygen is carried to the body tissues. Bicarbonate plays a role as the metabolic component of acid-base regulation, with normal levels being 2228mmol/l. In acidosis, bicarbonate acts as a buffer throughout the body, while the kidney excretes hydrogen ions and reabsorbs the bicarbonate. In alkalosis, bicarbonate is excreted while hydrogen ions are retained to maintain balance. Acid-base status: ABGs are also used to evaluate pH, which gives an indication of the primary process- acidosis or alkalosissince compensation is never complete. An abnormal pH indicates the presence of an acidosis or alkalosis and the extent of the acid-base disorder. It may suggest that compensation has occurred. However, pH alone does not indicate whether a mixed disorder is present. For example: o pH 7.20 indicates that a severe acidosis is present and that compensation is either not present or has not controlled the acidosis. Further investigation is needed to determine the origin of the acidosis and whether more than one acidotic process is present. o pH 7.48 indicates a mild alkalosis is present. Further investigation is needed to determine the cause of the alkalosis, whether it is in its early stages, has been nearly compensated or is part of a mixed disorder. A normal pH may indicate that a patient has no acid-base disorder. On the other hand, the patient may have a mix of acidotic or alkalotic events (primary or compensatory) that have offset each other. In addition to the patients history, HCO3- and PaCO2 must be considered. For example: o pH 7.45 with elevated HCO3- and PaCO2 suggests that a primary metabolic alkalosis has been compensated by an appropriate respiratory acidotic response. Similarly, a pH of 7.45 with decreased HCO3- and PaCO2 suggests a primary respiratory alkalosis has been compensated by a metabolic acidotic response. o pH 7.40 with both HCO3- and PaCO2 abnormal indicates that a mixed acidosis and alkalosis are present that are offsetting each other to give a normal pH.

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Graphical presentation of the acid-base status of blood: Evaluation of acid-base data is often difficult because of the presence of mixed respiratory and metabolic acidbase disturbances. Hence the graphical diagram (nomogram) on the following page may prove helpful in identifying the type of disturbance in a particular patient. The chart refers to the acid-base status determined in arterial blood or arterialised capillary blood. Each point in the chart is characterised by four different coordinates representing the acid-base values in a given blood sample: o The acid-base nomogram shows arterial blood pH, arterial plasma HCO3- and PCO2 values. The central open circle shows approximate limits for acid-base status in normal people. The shaded areas in the nomogram show the approximate limits for the normal compensations caused by simple metabolic disorders. For values lying outside the shaded areas, one should suspect a mixed acid-base disorder.

Why is the test performed? An ABG may be requested to evaluate symptoms of lung disease, such as a chronic cough or dyspnoea. It is also used to monitor the effectiveness of oxygen therapy. The acid-base component also gives information on how well the kidneys are functioning. Blood gases are important in determining the oxygen status of patients who present with conditions such as chronic emphysema, pneumonia and asthma. Symptoms of hypoxemia include cyanosis and visual hallucinations. Oxygen therapy is usually given to correct a low pO2. Symptoms of hypercarbia include drowsiness, bounding pulse, headaches and tremors (carbon dioxide narcosis). A low pCO2 may suggest a metabolic condition such as acute and/or chronic renal failure, or diabetes mellitus. Congestive cardiac failure also causes a low pCO2. How is the test performed? Pulse oximeters are used to monitor the oxygen saturation of the blood and pulse rate in patients undergoing surgery. An oximetry device is usually placed on the patients finger and measures the transmission of light through the tissues as a marker of oxygen saturation. A blood sample is required for analysis on a blood gas analyser. Using a small needle, the sample is usually collected from the radial artery in the wrist, after performing Allens test to check for vascular insufficiency of the hand. The blood is collected in a heparisinised tube and excess air is removed from the syringe with an air cube. OR this can be performed from sampling blood via syringe from a site of patient vascular access, such as a central or peripheral arterial line. At least 500l of blood is needed to be analysed in the reader and thus collection requires a special syringe. After collecting blood, it should be well mixed in its heparisinised tube, and any air bubbles fully expelled to remove any excess oxygen (as air bubbles may falsely elevate the pO2 measurement). Remove the needle to prevent a needle-stick injury, remove excess air with the air cube and then attach the syringe cap.

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 Note that an arterial blood sample for an ABG measurement is stable for ~10 minutes at room temperature, and hence it must be sent to the lab immediately (via a carrier, as the hospital vacuum pathology tube transport system may also decrease pO2), or placed on ice (which can increase viability to 30 minutes- although this can lyse cells and this can hence falsely elevate serum potassium readings for example). The requesting medical officer must make sure that they have checked the following: o Correctly labelled the sample, with the patients details and medical record number, check patient labels. o Appropriately fill in any pathology request forms, with brief history of clinical case. o Provide your own contact details (pager etc.) The sample is then introduced to the analyser where specific electrodes measure the partial pressures of gases, pH and concentrations of other analytes in the blood. The syringe is placed in a specific part of the machine and a small lever draws up a blood sample by suctioning. There is then protein removal/washout of the analyser after the sample has been analysed and after these washing and calibrator reagents are finished, the analysers calibrator reagents must be replaced. Results take about 2 minutes to obtain after placing the sample in the analyser. Some of the important measurements obtained include pH, pO2, pCO2, lactate, glucose, total creatinine, Haemoglobin (Hb), carboxy-Hb, met-Hb, total Hb, sodium, potassium, chloride, bicarbonate and calcium. One important source of pre-analytical error is leaving the patient tourniquet on for too long (falsely elevates potassium and some other ions), sample clotting due to poor heparin mixing and not analysing the sample immediately/efficiently. The role of ABGs in investigating acute dyspnoea A patient presenting with acute dyspnoea can be due to several major mechanisms: decreased inspired PO2, hypoventilation, shunting and V/Q mismatch (*decreased diffusion is also a cause). Through history/examination and use of the A-a gradient, you can determine the nature of acute dyspnoea. The clinical situation contributes greatly in decreased inspired PO2 and hypoventilation since there is no intrinsic pulmonary defect, there is no dysfunction in gas exchange. In a patient with raised A-a gradient, organic causes of shunting and V/Q mismatch should be considered and further investigated. These may include airways disease, ILD, alveolar collapse amongst others. ABG (+A-a gradient) should not be considered diagnostic, rather, guides clinical thinking and directs further investigations (e.g. PE: (?)D-dimer, ECG, lowerlimb Doppler study, V/Q scan, CTPA) Acute dyspnoea has many causes: o Asthma o Pneumonia (with or without aspiration) o Pulmonary oedema o Pneumothorax o Pulmonary embolism o Metabolic acidosis o Acute respiratory distress syndrome o Panic attack Other causes include: o Pulmonary: obstructive (asthma, COPD, foreign body); restrictive (ILD, pleural effusion, respiratory muscle weakness, obesity); aspiration o Cardiac: MI, CCF (orthopnoea, paroxysmal nocturnal dyspnoea), arrhythmia, cardiac tamponade o Neuromuscular: diaphragm dysfunction, phrenic nerve palsy, Guillain-Barre syndrome, Myasthenia gravis, brainstem and upper spinal cord segment injuries. o Metabolic: acidosis, hypercapnea, sepsis o Haematological: anaemia, methaemoglobinaemia o Psychiatric: anxiety The Clinical presentation gives many clues, ABG (and A-a gradient) guides further investigations. The alveolararterial oxygen gradient (A-a gradient) is useful in determining the type of respiratory failure. Determined by the equation:

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 Using the A-a gradient equation, one can determine whether hypoxia is due to a problem at the pulmonary or the extrapulmonary level (760 mmHg is atmospheric pressure at the sea level, 47 mmHg is the pressure displaced by water vapour, 0.8 is the respiratory quotient). The normal A-a gradient is around 10 mmHg (Normal PAO2 = 105 mmHg, normal PaO2 = 95 mmHg). This figure increases with age and should increase with an increasing FiO 2 (because you are increasing the PAO2). This figure stays the same in an extrapulmonary event (e.g. hypoventilation: there is no issue with the lungs). This figure increases in a pulmonary event (e.g. ventilation/perfusion mismatch, Pa O2 drops, PaCO2 stays roughly the same: CO2 diffusion is 20 better than oxygen, hence PAO2 stays the same, A-a gradient increases). Defects in diffusion, ventilation-perfusion, and left-to-right shunting is suggested by an increased A-a gradient. You can differentiate V/Q mismatch with shunting by increasing FiO2, and in V/Q mismatch there should be an improvement in PaO2 (increase in FiO2 increases PAO2, and in mismatch improves the diffusion across the areas which are exchanging: the exchange cannot be further improved when it is a left-to-right shunting problem, such as in congenital cyanotic heart disease- e.g. atrioventricular/ventricular septal defects or patent ductus arteriosus). There are various ways to estimate an age-adjusted A-a gradient (to determine an actual rather than background increase): use 15 mm Hg for <30 yo and +3 mm Hg per decade beyond 30 (Harrisons). Below is a flow diagram from Harrisons which is useful in determined the causes of acute dyspnoea with hypoxemia:

Pathology of Lung Cancer:

Lung cancers can basically be divided into either small-cell lung cancers or non-small cell lung cancers. The main treatment for small cell lung cancers is chemotherapy, which includes Etoposide. Non-small cell lung cancers basically represent all other types of lung cancer besides small-cell and are broadly divided into the following three categories: 1) Adenocarcinomas. 2) Squamous cell carcinomas. 3) Large cell/undifferentiated lung cancers. Other important but less common forms of lung neoplasms include bronchoalveolar cancers (usually encountered in non-smokers), mesotheliomas and carcinoid tumours. As with all other cancers, it is important firstly to diagnose and identify what the type of cancer is and identify grade, and then stage. Basic staging involves: A CT scan of the chest and abdomen, PET scan with 18fluorodeoxyglucose is also very important for staging and identifying other areas of metastatic disease that may not be seen on other scans. It is also perform lung-function tests and check cardiovascular health/coronary arteries for atherosclerotic disease & check for myocardial ischaemia, which is important to identify cardiopulmonary reserve to see if the patient may be suitable for surgery, if the cancer is not advanced or is a well localised. Note that of all lung cancers, only ~5% require surgery. After staging and checking patient lung

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and cardiac function, one must then decide for surgery, or if this is not suitable, appropriate chemotherapy or radiotherapy or both. Smoking is the most important epidemiological risk factor by far for the development of lung neoplasms. 10 pack years of smoking increases risk of lung cancer 10-fold. With a >40 pack year history, ~20-30% develop COPD, but also have a higher risk of developing lung cancer. Also note that 80-90% of lung cancers occur among smokers, but there is only a 10% mortality of lung cancer from smoking (i.e. only 10% of smokers die from lung cancer, whereas the mortality amongst nonsmokers is 1%). In non-smokers, this is usually amongst women and may be related to hormonal factors causing cancer. The major determinants of risk among smokers are the number of cigarettes smoked per day as well as the total number of years smoked (usually expressed in pack years, that is the number of packs of cigarettes smoked per day multiplied by the number of years smoked). The risk of lung cancer, however, falls progressively in the decade following discontinuation of smoking, and loss of lung function above the expected age-related decline ceases with the discontinuation of smoking. However, the risk of developing lung cancer is still present and is just slightly above the risk for the normal non-smoker population. If a person quits smoking, risk thus declines and by 10 years the lung cancer risk is only slightly above that of someone who has never smoked, but the risk never returns to baseline. Other important carcinogenic exposures that can lead to lung cancer includes: o Radon gas or uranium exposure (Radon is a naturally occurring radioactive gas) o Asbestos (increases risks of lung cancer and mesothelioma, apart from asbestosis). o Environmental pollutants (e.g. airway pollution, vehicle exhaust fumes). o Second hand (passive) smoke o Silica and silicosis o Heavy metal exposure- Arsenic, beryllium, cadmium, chromium, haematitie, nickel, tin mining. o Man-made mineral fibres- polycyclic aromatic hydrocarbons, diesel exhaust fumes, cooking oil vapours. o Adenomatous hyperplasia of the lung is a precursor for lung adenocarcinoma.

These other carcinogens may be involved with some of the non-smoking related lung cancers that are encountered. Even though COPD and neoplasia are the most important respiratory complications of smoking, other respiratory disorders, e.g. spontaneous pneumothorax, bronchiolitis-interstitial lung disease, pulmonary Langerhans cell histiocytosis and pulmonary haemorrhage with Goodpastures syndrome are also associated with smoking. Evidence on a biological and molecular level as well as an epidemiological level confirms pathogenesis of lung cancer from cigarette smoking. From the biological perspective activation of dominant oncogenes and inactivation of tumour-suppressor genes in cells leads to dysplasia and neoplasia. Activation of autocrine growth factors and increased cell turnover related to chronic inflammation and irritation increases the likelihood of neoplastic transformation. From the epidemiological perspective cigarette smoking, first- or second-hand, exposure duration and intensity are all linked to increased risk for developing lung cancer.
Basic biology of lung cancers and pathogenesis

Lung cancer cells have multiple gene mutations (perhaps 20) Once cells have acquired necessary mutations to have acquired malignant behaviour leading to cancer stem cell and then this leads to clonal proliferation. The bulk of a lung cancer is likely to contain a large proportion of sub-malignant cells. Cancer stem cells must be eradicated to cure disease, but cancer stem cells likely to be more resistant to chemotherapy. Lung cancer pathogenesis is associated with activation of many oncogenes: o o RAS family of oncogenes leads to formation of the onco-protein KRAS in adenocarcinoma (KRAS causes increased GTPase siganalling related cell growth, differentiation and survival; and unregulated increase in cell function). Tyrosine kinase domain of the epidermal growth factor receptor (EGFR) in adenocarcinoma from nonsmokers) leads to unregulated increase in growth. In lung cancer other EGFR family members including Her2/neu and ERB3 may also be upregulated.

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o o o o

The BRAF, PIK3CA, PIK3CA/AKT/mTor pathway may also increase in amplification, with rearrangement and loss of transcriptional control of myc family of oncogenes. There are C-myc changes found in non-small cell lung cancer and N-, L-myc changes found in small cell lung cancer. Some cancers also have Bcl-2 over-expression (oncogene) which has anti-apoptoic functions (also has a role in granuloma survival in sarcoidosis). There may also be an increase in telomerase activation, which increases telomere repair of DNA, leading to immortality of DNA. Important tumour suppressor genes involved include TP53 (p53- the protector or guardian of the genome, which can be due to an inherited loss of one copy of the gene, and predisposing to carcinogenesis with mutations in the second copy (e.g. p53 mutations or RB in retinoblastoma). There may be tumour-acquired inactivation via DNA methylation, or both. The normal function of the p53 protein is indicated below and indicates how p53 functions when DNA damage or cell cycle abnormalities occurs. p53 can induce to apoptosis, or cell cycle arrest:

There are also tumour suppressor genes on chromosome 3p, which can also be mutated. Autocrine growth factors: Theory holds that lung cancer arises from a progressive, multistep process that involves carcinogens causing mutation (initiating the neoplastic process), and promoters of the neoplastic process. Lung cancer cells produce many peptide hormones and express receptors for hormones which leads to autocrine stimulation; nicotine is an extrinsic example. Cigarette smoke has carcinogenic derivatives of nicotine which leads to lung cancer cells expressing nicotinic acetylcholine receptors that are responsible for promotion of tumour formation and reduction in apoptosis. Inherited/genetic syndromes associated with lung cancer include: p53: Li-Fraumeni syndrome which causes lung and breast cancer. Chromosome 6p23 mutations, polymorphisms of cytochrome P450 enzymes which cause decreased metabolism of carcinogens and chromosome fragility (mutagen sensitivity) which increases potential for chromosomal changes. Targeted therapy is thus directed against VEGF (Avastin), EGFR (ERBB/Her family) ligands : Her2/neu (Herceptin- trastuzumab), Her3, Her4, tyrosine kinase inhibitors etc., which specifically antagonise oncogene associated proteins. Old Phase 1 revision notes for molecular biology: Oncogenes are formed from proto-oncogenes either by deletions (in-dels) or point mutations of DNA coding sequence leading to a hyperactive protein being formed, or gene amplification whereby a normal protooncogene protein is overproduced. Another mechanism of oncogene formation is that chromosomal rearrangement occurs (i.e. translocations, deletions, duplications, inversions) that affects a nearby promoter region of the DNA segment that causes transcription to become overactive & hence proteins overproduced; or fusion occurs of the proto-oncogene segment to a gene that is actively transcribed (house-keeping genes) that hence causes the proto-oncogene to also be actively transcribed, which leads to formation of a fusion protein which is hyperactive (see image below).

o o

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 Oncogenes that are formed as a result of genetic mutations include genes that code for growth factors, growth factor receptors, intracellular signal transduction proteins & transcription proteins. Hence these mutations ultimately affect gene expression. Note that mutation in only ONE COPY of a proto-oncogene can have disastrous effects that lead to the oncogene to abnormally cause cell proliferation. Hence most oncogenes behave as dominant alleles. Examples of proto-oncogene mutations that lead to abnormal onco-proteins includes dimerising cell surface receptors. For example, Her2/neu receptors (in some breast cancers) are growth factor receptors on the cell surface, which are encoded by proto-oncogenes. A single point mutation leads to the formation of an abnormal Neu onco-protein receptor that dimerises without the need for external growth factors (see below). This leads to a receptor that is always active and when it is normally activated, it is a kinase that phosphorylates signal transduction proteins that leads to a response by the cell nucleus to cause transcription. Since it is now always active & dimerised, it can readily phosphorylate signal transduction proteins & hence cause the cell to abnormally produce proteins. Another example is epidermal growth factor receptors, that when mutated become ErbB onco-protein receptors that also causes abnormal signal transduction; the beginning of cancer development.

Ras is a G-protein that is involved in the signal transduction pathway for epidermal growth factor receptors (tyrosine kinase dimerising receptors) by activating downstream proteins with GTP (it is a GTPase switch protein- hence G protein). It is also a proto-oncogene protein that when a single point-mutation occurs at a particular codon (glycine at position 12) leads to formation of the mutant K-Ras oncogene that is involved in continual stimulation of the growth signalling pathways regulated by Ras & hence continual cell growth. K-Ras is also involved in colorectal carcinomas & involved in ~30% of all cancers. It is possible to detect Ras protooncogene mutations by PCR using primers which will only anneal to the gene if the correct sequence is present. Following detection of mutant genes by PCR, it is possible to perform DNA sequencing to confirm this finding.

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Diagnostic techniques are being developed to identify mutant K-Ras in both patient stool samples & serum for colorectal adenocarcinoma, although no. of cancer cells are very low & hence detection methods must be extremely sensitive. Tumour suppressor genes are genes that have a normal role in producing inhibitory proteins that inhibit cell division & the cell cycle, in response to DNA damage. This inhibition allows the cell to repair DNA damage via ligases & DNA polymerases. Other tumour suppressor gene proteins are involved in directly repairing damaged DNA, preventing the cell from accumulating cancer causing mutations. Other tumour suppressor genes are involved in detecting cell DNA damage at restriction points of the cell cycle (i.e. between G1 & S phases) & if there is significant damage it leads to formation of death activators & proteins that induce apoptosis. However, cancer predisposition occurs if tumour suppressor genes are mutated, since the cell will continue proliferating despite accumulated mutations which are thus not repaired; initiating cancer development. Unlike oncogenes, tumour suppressor alleles behave recessively; hence mutation in both tumour-suppressor genes is required to block tumour suppression, as one functioning allele has the capacity to repair cell damage. One of the most important of tumour-suppressor genes in the p53 gene, which is involved in stopping the cell cycle (by activating cyclin-dependent kinase inhibitors) if there exists DNA damage & activating repair mechanisms to repair DNA. Also if DNA damage is irreparable, then the p53 protein is involved in activating apoptosis. p53 is one of the most important of tumour suppressors as it is mutated in ~50% of cancers & when damaged (TP53) it can lead to more aggressive, metastatic cancers with worse prognosis. Some hereditary cancer syndromes are the result of inheritance of one defective tumour suppressor allele; hence these people are thus one step closer to accumulating the necessary mutations for cancer development. Examples include children that have inherited one abnormal Rb tumour-suppressor gene, whose protein is involved in inhibiting a transcription factor for cell proliferation. Upon acquiring another mutation in the second Rb allele, these children are thus prone to retinoblastoma (as well as some other cancers, such as osteosarcoma) at a younger age compared to normal individuals.

Other hereditary cancer syndromes include certain pancreatic cancers, ~1-5% of breast cancers (& some ovarian cancers) that involve BRCA1 & BRCA2 tumour suppressor gene mutations, which also explains incidence of male breast cancers. Other acquired mutations include tumour suppressor genes involved in nucleotide excision repair, repairing DNA strand breakage from UV light. These people with Xeroderma Pigmentosum & who are at great risk with minimal UV radiation & hence acquire melanomas & other skin cancers at a young age & most die by age 20. DNA mismatch repair is employed by cells to maintain the fidelity of DNA replication by correcting nucleotide mispairing & small insertions or deletions caused by errors from DNA polymerase during replication. In the mismatch repair system, a protein called MutS scans the DNA for mismatches by recognising them due to the distortion they cause to the DNA backbone (e.g. pyrimidines paired with pyrimidines). A second protein, MutL searches for the damage & triggers degradation of the damaged area, removing strands from the vicinity of the damage. Then DNA polymerases can repair this segment of DNA by synthesising the correct DNA sequences. Because of their importance in DNA repair, mutations in mismatch repair genes lead to over a hundred fold elevation in mutation rate & hence genetic instability leading to cancer.

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 Inherited loss of the gene mismatch repair system hence predisposes to colorectal cancer, particularly hereditary non-polyposis colon cancer (HNPCC). HNPCC is an autosomal dominant disorder, which accounts for ~3-5% of all colorectal cancers, with most cases occurring as a result of mutations to the MutL & MutS genes. Individuals with HNPCC hence have a high 70-80% lifetime risk of developing colorectal carcinomas as well as ovarian cancers (known as the Lynch syndrome) & hence must be screened often for development of malignancy. Note that MMR gene mutations may be sporadically acquired that predispose to bowel cancer. Detection of mismatch repair defects can be performed by assays for protein or also by instability of microsatellite DNA. Microsatellite DNA is found in the DNA of colorectal cancers in individuals with mismatch repair gene mutations, as mismatch repair mutations leads to accumulation of nucleotide repeats & hence abnormal microsatellite DNA. The Adenomatous Polyposis Coli tumour suppressor gene APC, is a tumour suppressor gene involved in APC is involved in the Wnt signalling transduction pathway. Binding of Wnt proteins by a cell is a signal for cell cycle progression. -catenin is a protein that mediates Wnt protein signalling. When -catenin is in the cytoplasm, it however, becomes bound to the APC protein, which targets it for destruction, hence APC inhibits cell proliferation. Wnt signalling however, causes APC to release -catenin, which then moves to activate Wnt proteins to increase transcription factors of growth promoting genes. Thus if APC is mutated, -catenin is free to activate Wnt proteins that continuously promotes cell growth. APC mutations have a very important role in colorectal carcinomas, as mutations occur in over 60% of tumours. There is also an autosomal dominant syndrome called Familial adenomatous Polyposis (FAP), where a mutation in APC is inherited. This is uncommon, but like HNPCC it is important in predisposing to colorectal cancers & accounts for <1% of all colorectal neoplasms. FAP is characterised by the development of hundreds of intestinal adenomatous polyps (unlike HNPCC) & extra-colonic tumours. Sporadic APC mutations are also involved in the adenoma-carcinoma sequence, which can lead to a hyperproliferative epithelium with increased genetic instability & activation of K-Ras, loss of Smad4 (another tumour suppressor) & other tumour suppressors (i.e. mismatch repair etc.), loss of p53 & telomerase activation, which leads to carcinoma formation. It is important to note that the accumulation of mutations, rather than their occurrence in a specific order is more significant. The adenoma-carcinoma sequence (in colorectal cancer) was discovered by analysis of intermediate stagesincluding polyps, benign adenomas & carcinomas isolated by surgeons, allowing major mutations within each stage to be identified.

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Smoking, and its link to lung cancer

There is a decreasing trend amongst all smoking populations. Males smoke more than females in most age groups. There are a substantial proportion of secondary school students smoking. Like other developed countries, prevalence of smoking is inversely proportional to educational qualification and occupational status. Aboriginal and Torres Strait Islander populations smoke more in total (>50%) and as age-adjusted populations. Nicotine replacement therapy serves to replace the cravings of smoking and combat nicotine withdrawal. There are currently many methods for delivery; including gum, patches, lozenge, inhaler and sublingual tablets.

Currently, about 19% of the Australian adult population are smokers, according to the 2007 data. There is a significant proportion of adult smokers leading to a high burden of disease (prevalence in males is 21%, females 18%). The following figure indicates that smoking has become a decreasing trend in all age groups, however, the peak smoking rate is in the 25-29 year old age group:

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 Tobacco companies target 18-24 year olds, indicating smoking is fashionable and this has led to a rise in smoking prevalence especially in developing countries. The prevalence of smoking is inversely related to occupational and socioeconomic status. Also there is a greater number of smokers amongst those with mental illness and people with substance abuse disorders. Smoking cessation is critical in preventing lung cancer and other cancers (oropharyngeal, gastro-oesophageal, renal, urothelial, gynaecological etc). reducing risks of aggravating other respiratory diseases (COPD, asthma, infections etc) and increasing cardiovascular disease risk (myocardial infarcts, ischaemic strokes, deep venous thrombosis & pulmonary embolus, peripheral vascular disease in conjunction with other cardiovascular disease risk factors). Apart from the numerous health benefits, there are also many economic benefits for the patient. The major benefits according to timeframe after quitting si summarised below:

Smoking and smoking-related harm prevention is practiced at 3 levels: o Primary (preventing initiation of tobacco use) o Secondary (identifying disease related to tobacco use early, and treating it) o Tertiary (rehabilitation after a tobacco-related disease sets in) The strategies used include (1) government/community legislation (e.g. taxation, pricing, advertising laws, restrictions on tobacco companies), (2) community actions (e.g. no-smoking laws at public places etc, community perceptions), (3) education (community and individual level, advertising of smoking related harms etc.), (2) treatment (individual smoking cessation) Many of the prevention strategies are employed in Australias target at-risk groups: o Taxation: increasing price has a stronger effect on younger smokers who are less addicted, may inhibit tobacco sales if expensive o Laws: regarding age at which one can buy, laws preventing tobacco smoking advertising. o Introduction of community programs: (Quitline) aimed at encouraging smokers to quit. o Smoking cessation clinics: with smoking cessation counsellors, multi-language resources are available, e.g. brochures, advertisements, interpreters for non-English speaking background patients. o Anti-smoking campaigns: promoted in a variety of media sources. Smoking cessation should be managed with the 5As approach: o Ask: about and document tobacco use at every opportunity o Assess: the willingness and motivation to change and confidence to quit- are you interested in quitting? o Advise: the smoker to stop o Assist: the smoker to stop (education; Quit-line, counselling, smoking cessation counsellor, nicotine replacement therapy) o Arrange follow-up: to maintain smoking cessation and prevent relapse
Pharmacological management of smoking cessation:

Smoking cessation essentially requires providing a gradual reduction to nicotine intake rather than cold turkey and this leads to reversal of neurological changes in the dopaminergic reward pathways of the brain: which has shown to improve quit rates.

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 From eTG: Dependence on cigarettes has both ritual and addictive components. If judged by quit rates in motivated individuals, nicotine seems to be one of the most addictive substances yet discovered. Nicotine replacement therapy (NRT) approximately doubles quit rates compared with controls, irrespective of the intensity of other support and non-pharmacological intervention- in primary care, quit rates are doubled from approximately 5% to 10%, and in more intensive settings from approximately 10% to 20%. All patients with high or moderate nicotine dependency, or whose previous attempts to quit have failed because of nicotine withdrawal symptoms, should be offered NRT. Consider the level of nicotine dependence when selecting NRT for those who smoke at least 10 cigarettes daily: o High: waking at night to smoke, or within the first 5 minutes after waking; usually smokes more than 30 cigarettes daily. o Moderate: smoking within 30 minutes of waking; usually smokes 20 to 30 cigarettes daily. o Low-to-moderate: not needing to smoke within the first 30 minutes of waking; usually smokes 10 to 20 cigarettes daily o Low: not needing to smoke in the first hour after waking; usually smokes fewer than 10 cigarettes daily *NRT for quitting should start at the quit date, not while the patient is still smoking. Important methods in NRT include: o Nicotine patches: which are easy to use, contain half the nicotine concentration of normal cigarettes, no need to taper dose. However, can be associated with itching/scratching. o Nicotine gum: 1/3rd to 2/3rd nicotine concentration of cigarettes. Should be used for 3 months before tapering. Possible adverse effects include GIT disturbances, dyspepsia, nausea. o Nicotine inhaler: Plastic cylinder with cartridge containing 10mg nicotine. 1/3rd nicotine concentration of cigarettes, good for smokers who miss the hand-to-mouth action. o Nicotine lozenge: Absorbed from oral mucosa, good for smokers who like the quick onset form of nicotine. o Sublingual tablets: Tablet is placed under the tongue & disintegrates over 30 minutes. Nicotine concentration is comparable to gum & lozenges. o Combination therapy; patches are probably easiest but choice is a personal one. o Must start after smoking cessation; cannot start while still smoking. The aim of NRT is to reduce withdrawal symptoms, by providing some of the nicotine from cigarettes but without the harmful components of tobacco smoke. NRT is available over-the-counter and can be used in all groups of smokers, including children/adolescents, pregnant women and patients with cardiovascular disease. As above, evidence shows that: o All forms of NRT are equally effective for long-term smoking cessation o NRT helps smokers unwilling or unable to stop smoking to decrease smoking consumption o There are no real risks of use, using NRT to quit is always safer than continuing to smoke Other important pharmacotherapies include: o Varenicline (Champix): Nicotinic acetylcholine receptor partial agonist, which decreases cravings and withdrawal symptoms. o Bupropion (Zyban): Selective catecholamine (noradrenaline/dopamine) reuptake inhibitor with minimal indolamine (serotonin) reuptake and no inhibitory effect on monoamine oxidase (MAO) and hence avoids side-effects of other SSRIs including weight gain and loss of libido and has a role in smoking cessation, by decreasing the urge to smoke and nicotine withdrawal symptoms. o Nortriptyline: Tricyclic anti-depressant, normally for major or worsening depression, also has some role in smoking cessation. o These other pharmacotherapies may be of adjunct use with NRT.

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Case Protocol 19: lung cancer

A 61 year old woman presented to her LMO with a three-week history of cough and chest pain. She had coughed up a small amount of blood-stained sputum. There was no history of fever or night sweats. Examination revealed a thin woman with dyspnoea on mild exertion. There was decreased expansion of the left side of the chest and the percussion note at the left base was stony dull. Auscultation revealed expiratory rhonchi, and there was no friction rub. Further information from history would include asking about: o Ask questions based on the differential diagnosis: infective (sputum colour, fever, infectious contacts (e.g. TB), COPD. Neoplastic: (systemic symptoms, smoking history, family history, past medical history, asbestos); pulmonary thromboembolism: recent surgery/trauma, acute onset, unilateral calf/leg swelling, leg pain. o The nature of her cough, presence of mucous, how many previous episodes of haemoptysis, has she had a cough previously or previously diagnosed CAL/bronchitis/asthma/tuberculosis? How long has she had the cough? (acute<3 weeks, or chronic>8 weeks?) Is there a constant (intrinsic) or intermittent (extrinsic) cough? Blood streaked sputum: infection, bronchiectasis, lung cancer, pink & frothy: APO, frank haemoptysis: TB, lung cancer, PE, bronchiectasis, Wegeners, Goodpasures (rare). Timing of cough: asthma worst at night, APO or GORD worse at night whilst lying supine, special triggers, e.g. pets, cold, exercise, indicates asthma. Character: wheezy, if airway obstruction, bovine vocal cord paralysis, dry if pulmonary fibrosis, gurgling if bronchiectasis, whooping. o Also need to ask about the chest pain- characterise the type and locate the site of pain, location- is it a visceral or more somatic type of pain? Has she had any other associated symptoms, for example the dyspnoea- severity of dyspnoea on exertion, does she take any regular medications for her dyspnoea, orthopnoea, trepopnea (together with the stony dullness on percussion & reduced chest wall expansion may suggest a pleural effusion), paroxysmal nocturnal dyspnoea (does she have underlying heart failure?), what relives/aggravates her dyspnoea and chest pain, has she required any medications for the chest pain, any radiation of the pain. o Ask about any other systemic symptoms- fever, night sweats, fatigue, weight loss, anorexia, lymphadenopathy, malaise, any other aches/pains. Weight loss of >10% over 3 months is an important sign that may indicate a neoplastic, a chronic infectious or inflammatory state or associated malnutrition. Associated with the weight loss should ask about anorexia with decreased appetite being due to infection/inflammation, malignancy, or a metabolic/endocrine condition such as poorly controlled advanced diabetes with ketosis, thyroid or adrenal dysfunction. o It is also important to ask about similar past episodes, past medical history (may suggest previous history of cancer, tuberculosis etc), current medications. o Obviously with any respiratory disease process, a smoking history is critical, quantify pack years smoked and if currently smoking. o A family history is also very important, particularly to ask about previous cancers indicating genetic predisposition. o Occupational history- asbestos, dust/silica, radiation exposures, exposure to tuberculosis, any pets such as birds. o Travel history: where and how recent, travel to TB endemic countries, and any infectious contacts. The full blood count appears relatively normal, except with haemoglobin/haematocrit in the lower range of normal. ESR is elevated, indicated a chronic inflammatory/infectious/neoplastic process- it is non-specific. Anything that causes inflammation and an increase in serum acute-phase proteins or proteins related to inflammation can cause red cells to stick and hence sedimentation rate is faster.

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 Provisional diagnosis appears to be lung cancer. Differential diagnosis includes: o o o o o o o o Lung metastases (secondary tumours in lung) Lower respiratory tract infection (pneumonia, bronchitis) Acute exacerbation of COPD Bronchiectasis Pulmonary embolism Tuberculosis Ischaemic heart disease with angina and related haemoptysis, (e.g. acute pulmonary oedema) Systemic inflammatory disorder- sarcoidosis, other interstitial lung disease, Wegeners, Goodpastures etc.

Important investigations to performo Initially obtain the patients vital signs- haemodynamic status, respiratory rate, oxygen saturation. o ECG- should be performed in any case of chest pain and even if the pain is atypical for coronary heart disease it is worthwhile as the patient may have multiple risk factors including age. o Other bedside tests: spirometry may be performed to identify if there is an obstructive or restrictive cause for her dyspnoea, peak flow for asthma. o Full blood count (performed) check for elevated white cell count, especially neutrophilia if bacterial. o Inflammatory markers- (ESR performed, could also check for elevated CRP) o EUC- check for signs of dehydration and third-space volume loss (related to the pleural effusion, and check baseline renal function if she may require a procedure such as a bronchoscopy or surgery or if she requires contrast injection for a CT scan). May also check baseline calcium, magnesium phosphate later. o Liver function tests: not particularly indicated but may be useful to obtain a baseline in case she requires medications or requires a procedure with anaesthetics. o Arterial blood gas- may be required if the patient is dyspnoeic, cyanotic or in respiratory distress. o Sputum microscopy, culture, sensitivity, cytology and special acid-fast stains- check for signs of infection including TB and malignancy. Also may require special fungal stains if the patient is immunocompromised. o Imaging- chest radiograph (check for signs of a pleural effusion, consolidation, cardiomegaly, masses/lesions (e.g. coin lesions, cavitations) suggestive of cancer, enlarged hilar nodes (lung cancer, infection, sarcoidosis); atelectasis (obstructive lesions, basal if fluid is from below), wedge-shaped consolidation/opacification- Hamptons hump suggestive of PE with infarction. May later require a CT scan of the thorax if a mass is found for staging and high resolution images of the mediastinum and lymph nodes, assess severity of COPD, bronchiectasis, pleural effusions. Although not indicated here, if there was as greater clinical suspicion of PE she may require a lower limb Doppler, CTPA or V/Q scan. Further enquiry revealed that the patient had lost 6 kg in weight during the preceding 3 months. She had smoked 40-50 cigarettes a day since she was 18 years old. A chest x-ray revealed a left pleural effusion. Sputum culture was negative, as was microscopy for AFBs. Important further investigations to now consider would include firstly identifying the cause of the pleural effusion. Hence a thoracentesis could be performed to obtain a pleural aspirate- and check again for microscopy, culture, sensitivity and importantly cytology. Depending on the clinical suspicion for TB, a acidfast stains may also be performed. If suspecting a neoplastic process, a pleural biopsy may also be obtained. Note that the thoracentesis and drainage of effusion may be therapeutic, as it may also relieve her symptoms. A CT scan of the thorax may be performed to identify the extent of the effusion, and identify a possible cause for the effusion. Depending on the results of the previous investigations, a bronchoscopy may also be performed, and any lesions identified with endobronchial biopsy excision, brushings or washings for cytology. If considering interstitial lung diseases such as sarcoidosis or even atypical forms of lung cancer, a bronchoalveolar lavage may be required. Bronchoscopy has the benefit of also allowing sampling of underlying nodes with a transbronchial biopsy or even use of the new technique of endobronchial ultrasound (EBUS) for biopsy. Further basic imaging, such as a chest x-ray may be needed after draining the effusion- to check position of chest tube and identify if an underlying lesion can now be seen on chest x-ray.

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 These investigations may allow for a definitive diagnosis of lung cancer, TB, other infection, abscess, vascular causes etc. The patient was admitted to hospital for aspiration of the effusion. Cytological analysis of the aspirated pleural fluid revealed malignant cells. A subsequent chest x-ray revealed a 2cm coin lesion in the left lower lobe near the hilum. Bronchoscopy and biopsy were performed. The lesion is very likely a lung cancer, and it is important to note general patterns of where these lesions arise from. Small cell cancers are mainly found in the upper lobes and can be multiple lesions, at an advanced stage when first diagnosed. Squamous cell cancers are often found in the peripheries, or also on the surfaces of the respiratory tract (e.g. oropharynx, larynx, trachea, bronchi etc.). Adenocarcinoma is often peripheral. Large cell/undifferentiated cancers can arise anywhere. Bronchial carcinoma: is by definition, a malignant epithelial tumour arising from the bronchi or lung parenchyma. It is the leading cause of death due to cancer in Australia and is the 5th most common cancer. Cigarette smoking is the most important factor. On macroscopic examination, it appears as a firm, grey/white mass arising close to the origin of the main bronchi, presenting as a stenotic ulcerating mass, an infiltrating peribronchial mass, or a cauliflower like intra-parenchymal tumour growing from the bronchus. A few (mainly adenocarcinomas) arise peripherally, and are often associated with areas of scarring; one variant (bronchoalveolar) grows along the alveolar walls with mucin secretion producing a mucoid grey cut surface. There are 4 principal histological types of lung cancer: o Squamous cell carcinoma (30%): composed of malignant epithelial cells showing keratinisation, with keratin pearl formation and/or intracellular bridges (desmosomes/hemidesmosomes). o Adenocarcinoma (30%): takes two forms, either acinar adenocarcinoma, with a predominance of glandular structures, or bronchoalveolar carcinoma in which the cylindrical malignant epithelial cells grow on the walls of pre-existing alveoli. Both principal types produce variable amounts of mucin. o Small cell carcinoma (25%): composed of loosely aggregated round or oval cells about 2 times the size of lymphocytes with scanty indistinct cytoplasm (oat cell carcinoma). Usually centrally located, and widely disseminated when diagnosed, the primary tumour is often small and inconspicuous, but may produce systemic effects from inappropriate hormone production (paraneoplastic syndromes). These cancers are usually only responsive to chemotherapy (and may relapse quickly after which they are resistant to chemotherapy) and are usually not resectable (due to spread at presentation). o Large cell carcinoma (15%): constitute a group of neoplasms that lack cytologic differentiation. The cells are large, usually anaplastic and have large vesicular nuclei. Usually centrally located, and metastasise early in their course so have a poor prognosis. Clinically it is important to make the distinction between small cell and non-small cell tumours. Non-small cell cancers are potentially curable if localised with no evidence of metastases (in which they are surgically resectable, and such localised stage I tumours may be curable with 30-50% 5 year survival). Carcinoid tumours are rare, neuroendocrine tumours, and may present with serotonin syndrome, which may present with personality changes, diarrhoea and flushing. The natural history of lung cancer is a typically early metastases to local nodes (with increased hilar shadows), and this may be spread by either the lymphatic or haematogenous route. Some cancers may cause paraneoplastic effects (effects of a neoplasm not related to either the primary tumour mass or metastatic tumour deposits, e.g. abnormal hormone production, cachexia etc.), for example hypercalcaemia due to Parathyroidhormone-related peptide, Cushings syndrome due to a ectopic ACTH producing small cell tumour, syndrome of inappropriate ADH secretion (SIADH) which can cause hyponatremia. Important causes of hyponatremia include: low volume (diuretics, Addisons, vomiting/diarrhoea), normal volume (SIADH, e.g. chest malignancy, head infection, head trauma (including neurosurgery), high volume (renal failure, CCF, liver failure); cachexia/wasting due to systemic inflammatory effects. Neuromuscular effects- e.g. Lambert-Eaton Myasthenia syndrome, increased risk of DVTs and PE, e.g. migratory thrombophlebitis with Trousseaus syndrome. In lung cancer the overall outlook is generally poor. Surgical resection offers the best hope of cure, but the majority are inoperable. Survival rates for the following includes: o Non-small cell: 50% 2 year survival without spread, 10% with spread. o Small cell: median survival is 3 months if untreated, 1-1.5 years if treated.

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Two weeks later she complained of further left-sided pleuritic chest pain and fever. Important causes for her fever and pleuritic chest pain would include pneumonia (with pleural involvement), or pulmonary abscess (with pleural involvement) or empyema secondary to abscess/pneumonia. Pneumonia or lung abscess may be secondary to bronchial obstruction. This usually results from impaired fluid/lymphatic drainage, distal atelectasis (from radiotherapy, surgery), and aspiration of blood, tumour fragments or even food from broncho-oesophageal fistula all contribute to the development of pneumonia or lung abscess. Lateral confluence pneumonia may be due to obstructive lesion setting off pleural inflammatory response (lesion centrally, which produced obstruction distally, and because of the atelectasis, a fertile ground for developing secondary pneumonia). This presentation may also have developed secondary to a pulmonary thromboembolism, due to her immobility, hypercoagulable state (increased risk with adenocarcinomas, large cell), post-surgical (or with trauma). There may also be progression or extension of the tumour. Other important complications of lung cancer include: o Local: recurrent laryngeal nerve palsy (causing hoarseness of the voice), phrenic nerve palsy (leading to dyspnoea, chest pain/shoulder pain or sensory loss of C3-C5 dermatomal distribution), Superior Vena Cava obstruction (check with Pembertons sign), Horners syndrome (due to an apical Pancoasts tumour impinging on the superior cervical ganglion), rib erosion due to local spread and tissue breakdown as well as PTH-related peptide effects, pericarditis and atrial fibrillation. o Metastatic: brain (neurological deficits, headaches, seizures), bone (bone pain, anaemia, hypercalcaemia, pathological fractures spinal cord compression), liver (hepatomegaly), adrenals (Addisons disease), local satellite spread within the lungs, lymph nodes (ulcerating masses from lymph nodes). o Endocrine: ectopic hormone secretion, e.g. SIADH (hyponatremia, and increased ADH), ACTH (Cushings) by small cell tumours, PTH-related peptide (hypercalcaemia) by squamous cell tumours and adenocarcinoma.
The patient's condition deteriorated over the following three months and she eventually died at home.

Likely causes of death in this patient includes: o Pneumonia: if she had pneumonia in the previous episode it may have worsened, and the infection may have spread causing severe infection including an acute respiratory distress syndrome and sepsis. She may also develop febrile neutropenia if she is on chemotherapy, which can lead to sepsis. o Pulmonary thromboembolism: again due to her risk factors, which could have led to acute respiratory failure. o Disseminated Intravascular Coagulation (DIC): due to Hypercoagulability, leading to widespread micro-emboli within the circulation. o Progression/expansion of tumour: metastases to the central nervous system, leading to raised intracranial pressure and herniation syndromes. Extensive metastases to the liver (>90% involvement) may lead to liver failure which can lead to death including hepatic encephalopathy (due to ammonia and toxic nitrogenous waste metabolite build-up). o Phrenic nerve impingement: May lead to diaphragm paralysis and hence the patient would not be able to breathe unassisted. o Spinal cord compression: An emergency situation in oncology, if there are metastases and pathological fractures, may lead to spinal cord compression and hence can lead to neurogenic shock. o Cachexia: malnutrition, dehydration or electrolyte imbalances, may predispose to dysrhythmias, and can occur with hyperkalemia or hyponatremia. o Pericarditis (dysrhythmias): Patient may die from fatal abnormal heart rhythms such as VT and VF. Important findings on autopsy include: o Brain- metastases, oedema with flattened gyri and sulci. o Lungs- evidence of pneumonia, PTE, bony changes in underlying ribs, identify the primary lesion if still present (if has not been removed). o Abdomen: metastases to the liver, renal and adrenals. Also consider spinal metastases.

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Case: Bronchial squamous cell carcinoma:

A 65 year old man presented to his local doctor complaining of worsening dyspnoea, cough and haemoptysis over the past 6 weeks. He had smoked a packet of cigarettes per day for over 40 years. The patient has presented with a long smoking history and is at major risk for lung cancer development; it is also important to know his past medical history/background including pulmonary comorbidities, as he may have developed emphysematous changes after smoking for so long. Furthermore, if he has COPD he may have predominantly chronic bronchitis (develops in smokers) and they may present with a productive blood-stained cough. What is really important in these patients is if they have noticed a change in the character of their sputum (colour, smell, volume etc.). If the haemoptysis is more frequent & copious with a larger amount of blood-stained mucous it is important to have it investigated as it may no longer be just bronchitis. Based on the history given, a differential diagnosis can be formulated for what appears to be a sinister underlying cause: o Lung cancer (Bronchial neoplasms): The time-frame at which his symptoms have occurred as well as the constellation of symptoms is highly suggestive of lung cancer. Also he has risk factors including his age, and his long, >40 pack year smoking history. o Pulmonary Embolism: Although he has had these symptoms over 6 weeks, it does not exclude medium to small-sized pulmonary thromboemboli. Worsening pain, cough and haemoptysis can all occur with PE, however, he may also have pleuritic chest pain, which is important to ask for. o Pneumonia complicated by an abscess: Worsening symptoms of shortness of breath and cough can occur with a lower respiratory tract infection such as pneumonia. If the pneumonia was complicated, such as with abscess formation, this could explain the haemoptysis and chronicity of his symptoms. However, he may have a putrid smelling purulent yellow-brown, blood-stained sputum on expectoration. Common causes of haemoptysis include bronchitis or lower respiratory tract infection, as well as PE, bronchiectasis and lung carcinoma. o Bronchiectasis: Bronchiectasis would explain the chronic symptoms of dyspnoea and often the cough is blood stained, this is because there is necrosis of airway walls which occurs with dilatation of the airways often secondary to airway obstruction. o Cardiac causes: Mitral stenosis/left ventricular failure: In cases of pulmonary oedema and pooling of fluid in the lungs, there may be a pink tinge in the patients sputum. o Other infections such as Tuberculosis. Uncommon, but must never simply rule out TB until certain. This clinical picture does not necessarily indicate tuberculosis but it is low in the differential diagnosis. Also with TB there would be other constitutional symptoms, such as possible fever, night-sweats, lymphadenopathy, unexplained weight-loss etc. o It is important to exclude haematemesis or haematemesis with aspiration as a cause of the patients haemoptysis. Have the patient cough and check if they expectorate any blood in the sputum. Important features to look for in the patients physical examination re outlined as follows: o Start at the hands: look for clubbing (occurs in lung cancer, bronchiectasis), wrist tenderness from hypertrophic pulmonary osteoarthropathy, check for signs of anaemia, signs of brachial plexus involvement if there is cancer. Check the head for central cyanosis, the face for pallor, jaundice etc. If there is a known apical lung cancer check for signs of Horners syndrome (ptosis, miosis, anhidrosis) due to compression of nerves of the sympathetic trunk or compression of the stellate ganglion. o Examine the lymph nodes of the head and neck region, including the supraclavicular lymph nodes. o If worried about mitral stenosis check for a Diastolic murmur. o Important signs to note for the rest of the examination with respect to lung cancer includes: pleural effusion (stony dullness to percussion, reduced breath sounds, reduced vocal resonance), consolidation (may also indicate pneumonia developing). Yield in physical examination may not be that high in the lungs.

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The GP organised a chest x-ray, which is shown below:

This x-ray appearance is typical of a pleural effusion. Mitral stenosis/heart failure will give bilateral pleural effusion, so some other underlying pathology would have caused this unilateral pleural effusion, such as lung cancer. If TB is suspected one may see apical cavitation. Unusual to see one lung completely unaffected. Would have to proceed with further investigations as this does not .indicate any specific underlying pathology. Further investigations to be organised include: o A Full blood count (anticipating an elevated WCC and PMN leukocytosis in pulmonary infection, lymphocyte count in possible Tuberculosis, RBC erythrocytosis in COPD, check for anaemia of chronic disease). o Check the patients clinical chemistry including urea, creatinine & electrolytes, to check renal function, as well as liver function tests. o Since the patient is coughing, it is important to obtain a sputum sample for sputum microscopy/cytology, culture and sensitivity. Multiple samples are required, to check cytology for possible neoplastic cells, similar to a Pap smear for cervical cancer screening, this can be useful for ruling in lung cancer, and can identify malignant cells. A separate specimen could be used for gram stain microscopy, culture & sensitivity to check for possible pneumonia/lower respiratory tract infection. Similarly, if Tuberculosis is suspected, then it is important to perform an acid-fast stain (Ziehl-Neelson stain) to check for presence of mycobacteria, as well as mycobacterial Lowenstein-Jenson culture & sensitivity (although results take many weeks to obtain). A special fluorescent stain may also be used. o Since the patient also has a large left pleural effusion, it is important to assess and manage this; a pleural aspirate/thoracentesis should be performed. Cytology should be performed on the aspirate to check for malignant cells, e.g. in the case of mesothelioma, as well as gram-stain microscopy, culture and sensitivity testing for the possibility of infections such as in empyema thoracis. o If there is a strong index of suspicion of lung cancer, it is important to organise a bronchoscopy, with bronchial lavage and excision biopsy if a tumour is identified. Bronchoscopy is important, as it allows the identification of any exophytic bronchial lesions that may have caused the patients cough & haemoptysis. It also allows the sampling of cells either for cytology in the case of lavage, or histopathology with excision biopsy. o Further imaging can be performed, with a chest CT scan, if one is suspecting malignancy; also apart from diagnosis, it is important for staging cancers. The greater anatomical detail of a CT scan allows the observation of airways and identifying which airways are involved in cancer, lymphadenopathy from spread to lymph nodes (hilar, mediastinal etc.). One may be able to see metastases in the liver, in scans involving the abdomen.

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 The following table summarises the patients clinical chemistry results: Clinical Chemistry Sodium (mmol/L) Potassium (mmol/L) Chloride (mmol/L) Bicarbonate (mmol/L) Calcium (mmol/L) Phosphate (mmol/L) Urea (mmol/L) Creatinine (mol/L) Bilirubin (mmol/L) Alkaline phosphatase (U/L) -glutamyltransferase (U/L) AST (U/L) ALT (U/L) Total protein (g/L) Albumin (g/L) 141 3.7 105 27 3.2* 0.57* 3.8 90 15 85 25 31 26 64 43 135-145 3.5-5.0 95-110 24-32 2.10-2.55 0.8-1.50 3.0-8.0 60-110 2-20 38-126 <30 <45 <45 62-80 33-48

The clinical chemistry displays that the patient has hypercalcemia and hypophosphatemia. The causes of these electrolyte abnormalities usually include: o Hyperparathyroidism, which increases excretion of phosphate by the renal tubules and increases calcium absorption from intestine, bone calcium resorption. or something behaving like parathyroid hormone. This can also occur with any peptide that acts similar to parathyroid hormone (PTH); such as PTH-related peptide, which is secreted by some cancer cells and causes this paraneoplastic effect. Bronchial carcinoma may also be releasing PTH -related peptide classically produced by squamous cell lung carcinoma. o Calcium may also be elevated in malignancy and could possibly be the result of bony metastases, which may stimulate local destruction of bone by osteoclasts (causing osteolytic bony metastases), releasing calcium and phosphate. Sometimes in the absence of bony metastases, tumours secrete IL-1 and TNFalpha which stimulates osteoclasts and causes this paraneoplastic effect. The results of sputum cytology and an aspirate of pleural fluid are displayed below. Following this, bronchoscopy and biopsy of a lesion in the left main bronchus was also performed. On the basis of all the investigations undertaken it was decided the patient should have a pneumonectomy:
Non- keratinising normal epithelium

PMNs Malignant cell, keratinising

Cytology report: Papanicolaou stain used for sputum cytology. Large, irregular cells with eosinophilic cytoplasm observed, these are cancer cells. They are a little pleomorphic, with central nuclei. These are carcinoma cells (malignant tumour of epithelial origin). Different forms of epithelial differentiation can be picked up on sputum cytology. Although no architecture is preserved here. The redness in the cells with this stain is keratin. Hence these malignant cells are showing squamous cell differentiation. Not all are accumulating keratin. Small cells appear to be neutrophils.

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 The pleural aspirate above displays epithelial cells, which display a high nuclear to cytoplasmic ratio, the cells have irregular nuclear membranes, indicating nuclear pleomorphism. The cells have not accumulated keratin & are quite convincingly malignant cancer cells. The patient underwent bronchoscopy with a biopsy and following staging, it was decided that a pneumonectomy would be performed for curative intent: The following slide displays a histopathological section from the neoplasm removed after pneumonectomy:

The histological section contains all sectioned borders, and has been taken from bronchi, as there is cartilage evident. The lesion appears ulcerated, haemorrhagic and the tumour appears to be invading from the epithelial layer to the lung parenchyma, characteristic of a bronchial squamous cell carcinoma. The section on the following page displays higher magnifications of the specimen:

The slide above shows a higher magnification displaying normal respiratory (pseudo-stratified ciliated columnar epithelium) and a section of cartilage is seen, there is no evidence of neoplasia observed here. The rest of the specimen does not display this normal pattern of differentiation, the slide below displays abnormal epithelial proliferation in one of the large airways:

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 The slide above displays (with arrow) abnormal epithelial proliferation; squamous metaplasia. It is stratified squamous, and this metaplastic change occurs to protect against smoke. The epithelial cells lose cilia, and this interferes with mucus clearance, causing mucous build-up and the smokers cough. Smokers are thus at increased risk of lung infection due to mucous build-up. The next step along for metaplasia may then be to turn to dysplasia (cytological features of malignancy). The cells become darker staining, larger, with a higher nuclear to cytoplasmic ratio etc. It may just be that the lower lung lobes are affected, or all areas in the lungs etc. If dysplasia is full-thickness- this is a bad sign, but if it has not appeared to have invaded then by definition this is carcinoma in situ. This is not carcinoma in situ because there is invasion. Evidence of invasion can be seen in the following higher magnification.

On this higher magnification, it is very obvious that the bronchial cartilage is being invaded by malignant epithelial cells (which are normally very resistant to tumour invasion, it requires tumour cells to have matrix metalloproteinases and collagenases to degrade and invade the cartilage matrix), which display squamous cell differentiation. The darker malignant epithelial cells are invading in sheets/nests and cords of cells and the local invasion suggests malignancy. In order to determine the cell type of the cancer, to distinguish it from other lung cancers, in this case it is useful to find extracellular keratin blobs, not necessarily small keratin whorls.

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 The specimen has an eosinophilic surface, indicating keratin accumulating on the surface of lesion (this was an exophytic lesion growing into the lumen of the airway). Malignant cells can be observed underneath the surface keratin (there is fair amounts of stroma underneath it, which indicates the tumour has stimulated a desmoplastic fibroblast response). The section below also shows this and indicates a substantial amount of material occluding an airway lumen (hence causing the patient to cough up mucus with inflammatory cells and blood).

Hence the histopathological diagnosis in this case is an ulcerating squamous cell carcinoma of the bronchus that is moderately well differentiated. There is evidence of intracellular bridging (a feature of squamous cell differentiation) and hence this is moderately well differentiated. After histological typing it is very important to comment on any local invasion or the presence of tumour adjacent or near lymphatics & blood vessels, or if tumour cells are present near surgical margins, which can affect patient management. There appears to be some lymphatic infiltration (difficult to see). There is obvious formation of an invasive carcinoma around the lumen of this bronchus.

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Case 10: Metastatic small cell carcinoma:

A 59 year old woman presented with unproductive cough and chest pain. Bronchoscopy and biopsy revealed small cell (also known as oat cell) carcinoma of the bronchus. It was decided that an operation was not appropriate and the woman was treated with chemotherapy. In spite of this treatment she gradually deteriorated over the following 3 months. The following biochemical profile was obtained. Unfortunately, she died 1 week after this investigation.
Clinical Chemistry Sodium (mmol/L) Potassium (mmol/L) Chloride (mmol/L) Bicarbonate (mmol/L) Calcium (mmol/L) Phosphate (mmol/L) Urea (mmol/L) Creatinine (mol/L) Bilirubin (mmol/L) Alkaline phosphatase (U/L) -glutamyltransferase (U/L) AST (U/L) ALT (U/L) Total protein (g/L) Albumin (g/L) Glucose (mmol/L) 144 2.9* 108 37* 2.4 1.2 4.6 90 35* 156* 78* 70* 68* 65 43 10.3* 135-145 3.5-5.0 95-110 24-32 2.10-2.55 0.8-1.50 3.0-8.0 60-110 2-20 38-126 <30 <45 <45 62-80 33-48 3.0-6.5

Based on her known metastatic disease that was unresponsive to chemotherapy, some abnormalities that would be expected at autopsy and the basis of the biochemical abnormalities shown above are as follows: o The biochemical profile displays the patient had hypokalemia and metabolic alkalosis (Hypercarbia) (although it does not indicate if metabolic acidosis was the original insult or if there was compensation for it) as well as hyperglycaemia. o In the liver function tests it should be noted that protein and albumin are in the normal range (as albumin has a half-life of ~3weeks, this short time span is a marker of chronic liver damage, indicating that chronic liver damage has not occurred). Note that AST and ALT are mildly elevated, indicating hepatocellular damage or dysfunction (not in the 1000s as in acute hepatitis). o These tests also indicate biliary duct obstruction- a cholestatic picture. Intrahepatic biliary duct obstruction is most likely to have been caused by liver metastases. ALP and -GT are also raised which is also consistent with liver metastases. o Is there a possibility that the patient may have had excess glucocorticoids in the bloodstream? This could explain her hyperglycaemia and other possible metabolic abnormalities. Furthermore, it is important to remember that she has small cell carcinoma. Small cell cancers sometimes do produce excess ACTH and more commonly they secrete ADH. Hence in small cell cancers abnormalities observed include Syndrome of Inappropriate ADH secretion (SIADH) and adrenal cortex hyper-stimulation with ACTH. Excess ACTH can stimulate the adrenal cortex to produce both glucocorticoids and mineralocorticoids, which could cause mixed features of Cushings and Conn syndrome. In particular, ACTH can cause hypercortisolism (especially in stress situations) and this can elevate blood glucose. Hypercortisolism can also cause mineralocorticoid effects, such as those caused by aldosterone. Hence hypercortisolism (and possible hyperaldosteronism) explains why the patients sodium is in the upper-range of normal and with there is hypokalemia. o Metabolic acidosis can be explained by the fact that the patient has low serum and extracellular fluid potassium levels.This causes movement of large amounts of reserve potassium from the intracellular fluid, and this requires exchange with hydrogen ions (remember from physiology, hypokalemia leads to movement of hydrogen ions into the cell). As a result, the extracellular fluid hydrogen ion concentration decreases, pH increases and this leads to a metabolic alkalosis as a compensation for hypokalemia. Note that this can occur the opposite way with hypoaldosteronism in Addisons disease & the patient develops metabolic acidosis. Thus there is hypokalemic metabolic alkalosis from paraneoplastic effects of the small cell lung cancer.

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 Based on her histopathological findings, the reason why she was not treated surgically is explained as follows. There is a clinical division of lung carcinomas into either small cell or non-small cell carcinomas. Surgical treatment is not usually used in patients with small cell carcinoma as it is usually a very aggressive cancer that metastases early. The usual anatomical distribution of lung cancers is that cancers originating in the lung hila are commonly small cell, squamous cell or large cell carcinomas. Carcinomas originating from the lung periphery are commonly adenocarcinomas. Hence with small cell carcinomas, there is usually no point in attempting surgical resection. Patients are thus likely to be treated palliatively, with chemotherapy or adjuvant radiotherapy with metastatic disease or to relieve symptoms. Palliative chemo-radiotherapy may increase patient survival time and rarely in some cases may lead to a cure. Abnormalities that can be found at autopsy are outlined as follows: o In the lungs: one would most likely find neoplastic lesions in the larger airways (e.g. in the lung hila). The primary lesion may be either reasonably large or small. Proximal to the primary tumour, the hilar lymph nodes may be engulfed by local invasion or the nodes may be affected by metastatic disease. The hilar lymph nodes are usually not the only nodes affected, and other mediastinal nodes may be affected. o On the lungs: Small cell carcinoma may also spread along the lung surface as a result of intrapleural spread on the visceral and parietal pleural surface. Cancer at the pleural surface may stimulate pleural effusion. Inside the lung the tumour may protrude into airways, causing collapse/atelectasis and prevent drainage of secretions and lymph from the airways, which would predispose to bronchopneumonia. Most patients would have this once died from cancer, and this will be in both lungs, not just the lung with the primary lesion. Also one may find on autopsy deposits of metastatic lung cancer in both lungs. o Metastases: Cancer spread may be identified in lymph nodes, liver, brain, bone and adrenals. Though small cell carcinoma is not aggressive as melanoma this is still a very aggressive cancer. The following specimens display sections of lung and liver in a patient who had small cell carcinoma. There is a small, greyish neoplasm arising from a large bronchus in the upper lobe. Note that even though the primary cancer is small, it has metastasised extensively. Scattered nodules of metastatic carcinoma are seen on the pleural surface and multiple metastases are seen throughout the liver:

The following histological sections were taken from the patient at autopsy. It can be seen that there is a large malignant tumour with irregular borders that appears to be spreading on the lung pleural surface and into the parenchyma.

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 On higher magnification; the neoplastic cells are highly basophilic, with very little cytoplasm (hyperchromasia- increased chromatin), these are small cell carcinoma cells, which do not display much pleomorphism (they mostly appear similar). They differentiate to be of the neuroendocrine type (and are hence associated with ACTH and ADH secretion).

The lung is the only significant site of small cell carcinomas. The following was also taken from the patients liver indicating distant metastases. It can be seen that on the left there are normal liver sinusoids, however, invading the liver is small cell lung cancer on the right of the field.

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Case 11: Lung adenocarcinoma:

The following lung neoplasm was identified as a coin-lesion on chest x-ray in the peripheral lung of a different patient. The differential diagnosis of lung coin lesions on chest x-ray includes tuberculosis cavitations, lung abscess where the pus has not been drained, lung metastases (canon-ball metastases), pulmonary infarction, patchy pneumonic consolidation, hamartomas, granulomatous inflammation of the lung (e.g. sarcoidosis), and may even be a primary cavitating lung cancer.

This is a section from the lung, since on the top-right hand corner normal lung tissue can be seen. This is a neoplastic lesion, since clusters of cells can be seen with loss of differentiation; it is malignant because it is invading lung tissue. This is an example of small cell carcinoma, which when very poorly differentiated is termed anaplastic. Athough not well differentiated, this is not anaplastic small cell lung cancer, as seen below on higher magnification:

On higher magnification, this does not appear to be small cell carcinoma, as there is nuclear pleomorphism (unlike previous slides), and cells are obviously apparent here. There is also attempt at lumen formation by some neoplastic cells.

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 The cells are not hyperchromatic, although there is only a slightly higher nuclear to cytoplasmic ratio but there are prominent nucleoli. These cells are still trying to make lumens. There is some wispy material in the lumen of these glands, this represents mucin. The malignant tumour is actually an adenocarcinoma. There are sheets of epithelial-type cells making lumens, hence this has glandular differentiation and is thus adenocarcinoma. It is invasive. One would expect to see this in periphery of lung, as was seen on the chest x-ray, although they can occur at the lung hila. Note that there is a lot of connective tissue surrounding the tumour, which is a desmoplastic reaction (stroma induced by carcinoma). Also quite a common host response seen with malignancy and observed here is lymphocytic infiltration. Epidemiologically, smoking is the most important risk factor for bronchial squamous cell and small-cell carcinomas. It is also a risk factor in adenocarcinomas, however, adenocarcinomas also arise in patients who have never smoked before and this usually occurs in women, so smoking is not as much of a significant risk factor for adenocarcinomas.

Case 12: Disseminated malignancy of unknown primary:

In this case tissue was prepared from a 56 year old woman who died from disseminated malignancy, with the primary tumour unknown. The following lung specimen shows malignancy, with an unknown primary. On autopsy, a pathologist can search for the primary, although this may take several days of searching. If the patient is alive, histological samples are the best specimens that can be used to identify tumour differentiation. Special stains, such as immunohistochemical tests can then be used to identify where the tumour cells originated from. With epithelial tumours, use cytokeratins, mucin stains are useful for adenocarcinomas, breast cancer may be positive for oestrogen or progesterone receptors. For mesenchymal tumours use special proteins. Receptors can narrow down certain types of adenocarcinomas to primary sites. Usually melanomas may be a cause of unknown primaries, although it may be possible to use special stains for melanoma (e.g. cytokeratins etc). Tumour markers may also be helpful.

This specimen is taken from lung tissue. There appears to be abnormalities in the blood vessels of the lung. There are islands of cells which are well adherent to each other, and may be trying to form lumens (rounded

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spaces as opposed to artefacts) and are hence possibly epithelial cells. These appear to be metastatic tumour emboli that have lodged/arrested in the blood vessels of the lung. They may try to extravasate, like little tongues trying to push through vessels walls to set up secondary metastatic deposits, these usually do not survive for long but can kill the person. These tumour emboli can sit there for quite a while in the vessels in a dormant state (e.g. a breast carcinoma, which may arise many years later. These tumour emboli will not kill a patient immediately. Hence treatment is with chemotherapy, aimed at destroying micro-metastatic lung deposits. The following is a higher magnification of a tumour embolus in the lung:

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Case 7: Bronchopneumonia:
A 78 year old woman, debilitated by congestive cardiac failure, was admitted to hospital with a 4 day history of cough and fever. The cough had become productive of yellow sputum over the last 2 days. She also complained of increasing weakness and lassitude. Examination revealed signs of patchy lower lobe consolidation. The yellow sputum indicates purulent sputum containing inflammatory cells, predominantly neutrophils. Important signs not to miss of a patchy lower lobe consolidation include reduced/asymmetric chest expansion on affected lobe, dullness to percussion, decreased breath sounds, harsh bronchial breath sounds in areas of consolidation and increased vocal resonance as solid material conducts sound better and additional sounds would include crackles due to the presence of exudate in the alveoli with pneumonitis. The following investigations were performed:

Full Blood Count Haemoglobin (g/L) RCC (1012/L) Platelet Corpuscle Volume (PCV) Mean Corpuscle Volume (fl) (MCV) MCH (pg) MCHC (g/L) WCC (109/L) Neutrophils Lymphocytes Monocytes Eosinophils Platelets (109/L) ESR (mm/hr) C0reactive protein (mg/L)
Arterial blood gases pH PaO2 (mmHg) PaCO2 (mmHg) Bicarbonate (mmol/L) O2 saturation (%)

118 4.0 0.38 86 28 308 20.8* 18.5* 1.5 0.2 0.1 270 63* 1200*
7.49* 58* 33* 24 80* (7.36-7.44) (80-100) (35-45) (24-32) (95-100)

115-165 4.5-6.5 0.40-0.54 80-100 27-32 300-350 4.0-11 2.0-7.5 1.5-4.0 0.2-0.8 0.04-0.4 150-400 2-15 <5

Sputum culture results: Gram stain: Polymorphs +++, Gram positive diplococci in chains Culture: Pure growth of Streptococcus pneumoniae Blood culture: Pure growth of Streptococcus pneumoniae in 2 of 2 bottles. The full blood count displays a neutrophil leukocytosis which is consistent with a systemic inflammatory response that could have occurred due to infection such as in pneumonia. Also consistent with this is the increase in acute-phase inflammatory markers such as ESR and C-RP. The arterial blood gases indicate that the patient has alkalosis. Also importantly, she is hypoxemic and hypocapnic and this indicates a picture of respiratory alkalosis due to decreased PaCO2, and as the bicarbonate is normal, there is no metabolic compensation. This pattern of ABGs is consistent with systemic hypoxemia due to lobar pneumonia. There is thus increased ventilatory drive (which causes her to blow-off CO2 which causes hypocapnia) due to hypoxia sensed by the central chemoreceptors. Hypoxia occurs due to a V Q mismatch in the lungs from reduced gas-exchange in consolidated alveoli, which causes hypoxia.

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 It is difficult to obtain a good sputum culture, for example if the patient has difficulty expectorating or if they contaminate the specimen by holding sputum in their mouth, they must expectorate directly into the sputum sample cup. The patients blood culture is consistent with bacteremia and sepsis, and as there is a pure growth of Streptococcus pneumoniae in sputum culture and blood culture, she most likely has a community-acquired pneumococcal pneumonia. Based on the history, examination and investigation results the provisional diagnosis would be pneumonia. She also has risk factors for developing community-acquired pneumonia. Congestive cardiac failure produces a good culture medium for bacterial growth if the patient has pulmonary oedema. Also oedema causes impaired function of alveolar macrophages; they have impaired phagocytic ability in a fluid-medium. There is also an increased risk of pneumonia in patients with disseminated malignancy. A chest x-ray was requested to investigate for possible pneumonia:

An examination of the chest x-ray displays an abnormally shaped mediastinum, with a boot-shaped heart from congestive cardiac failure. Also in both lung fields there are multifocal areas of patchy consolidation, consistent with bronchopneumonia. The woman died the next day due to sepsis and hypoxemia; the combination causing septic shock. The following specimens were obtained from tissues removed at autopsy:

The specimen consists of a section of the left lung and shows extensive consolidation of most of the upper lobe. The lesions are confluent, and the specimen shows something of the appearance of "lobar" pneumonia. The lower lobe shows the typical patchy appearance of bronchopneumonia. The middle part of the lobe displays

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confluence pneumonia, which is a poor prognostic marker, as it indicates that the patches of bronchopneumonia have become confluent as there is spread of inflammation between the patches, which is hard to distinguish from lobar pneumonia. This is a poor host response to bronchopneumonia. The following slides were also obtained:

On higher magnification:

On low magnification, the alveoli appear like pieces of popcorn, indicating areas of alveoli that are not consolidated and expanded with air. The popcorn alveoli mean that increased oxygen saturation occurs in the well-ventilated areas, but there is not enough to obtain an oxygen concentration any higher in these areas as there is saturation (from the Hb-O2 saturation curve) and this compensation is not enough to overcome poor ventilation in the consolidated areas. The net effect is hence hypoxemia. The bronchioles are filled with neutrophils, necrotic debris and exudate, which is pus. Surrounding the pus filled bronchioles, there are areas of marked consolidation in the surrounding alveoli, due to spread of a fibrinosuppurative exudate meshwork (causing consolidation of airspaces and bronchopneumonia) and spread of necrotic material into the smaller distal airways. Hence there is a spread of inflammation out from the small airways or a bronchocentric inflammation, which causes patchy consolidation which is in differing stages in different parts of the lung in this specimen.

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 Some of the non-consolidated alveoli have oedema, possibly from congestive cardiac failure. In other parts of the lung haemorrhage can be observed. Classically in a lung with bronchopneumonia, the histological appearances are as follows: the bronchioles are filled with pus caused by inflammation from pyogenic bacteria, so-called suppurative bronchiolitis with neutrophil infiltrate, necrotic tissue and exudation. In acute bronchopneumonia the significant features that are seen include vasodilatation, congestion of blood vessels, exudation of fluid and proteins, infiltration of inflammatory cells and epithelial damage. The alveolar structure remains, however, there are suppurative collections- abscesses. Consolidation of alveoli in acute bacterial pneumonia occurs due to accumulation of fibrinosuppurative exudate, along with vascular changes of acute inflammation in alveolar blood vessels. In acute bronchopneumonia, the alveoli are consolidated by fibrinosuppurative exudate, hence expectorated sputum will be purulent (yellow-green) not mucoid (white). Of the other features: fever is a systemic response (mediated by the hypothalamic synthesis of Prostaglandin E2, from systemic release of cytokines including Interleukin-1 and TNF- from inflamed lung tissue. Bronchial breath sounds are heard on auscultation over areas of consolidated alveoli. A neutrophil leukocytosis is caused by the release of a reserve pool of neutrophils from the bone marrow, in response to a systemic increase in IL-1 and TNF-, from the inflamed lung tissue. Consolidation is also evident on chest x-ray, which is the most important investigative finding in establishing the diagnosis of bacterial pneumonia (sputum culture is required to determine causative agent(s)). However, one must distinguish between different types of pneumonia; alveolar pneumonitis or interstitial pneumonitis. They cause reduced lung compliance and hence interference with gaseous diffusion. Some extra information of pneumonia: Pneumonia is the most common cause of infection-related death, with ~50% of cases and the majority of deaths due to bacteria. It is the 6th leading cause of death in western countries and occurs in patients with CCF or cancer. Transmission of organisms occurs due to inhalation, aspiration, haematogenous spread, direct infection extension into the lungs or exogenous penetration and contamination (i.e. foreign bodies). Remember the common clinical features including cough with purulent sputum, shortness of breath, fever, chest pain, respiratory distress namely tachypnoea. Diagnosis of pneumonia is based on history, examination and diagnostic investigations- where chest x-ray and sputum culture being very important in identifying the organism. Common aetiological agents of pneumonia include: o Bacterial: 1) Gram positive bacteria: Streptococcus pneumonia & Staphylococcus aureus 2) Gram negative bacteria: Haemophilus influenzae, Pseudomonas aeruginosa (e.g. in patients with cystic fibrosis), Klebsiella pneumoniae, Legionella pneumophila, E. coli, Enterobacter sp. 3) Moraxella catarrhalis o Bacterial-like agents: 1) Mycoplasma pneumoniae 2) Chlamydia pneumoniae; Chlamydia psittaci 3) Coxiella burnetti (the cause of Q-Fever in farmers) o Mycobacteria: e.g. Mycobacterium tuberculosis or Mycobacterium avium o Viral (viral infection is usually complicated by bacterial pneumonia): 1) Respiratory syncytial virus (RSV), parainfluenza virus, influenza virus, adenovirus. o Fungal: Aspergillus species (common in neutropenic patients such as those with leukaemia), Cryptococcus neoformans or Pneumocystis jirovecii (e.g. in HIV patients). o Protozoal There is also a pattern of typical and atypical pneumonia. Typical pneumonia has an abrupt onset of productive cough with purulent sputum, pleuritic chest pain, impressive physical findings, leukocytosis or leukopenia. Atypical pneumonia has a gradual onset, non-productive cough, substernal chest pain, unimpressive physical examination, white blood cell count normal. Other important classification schemes for pneumonia include either acute or chronic pneumonia (chronic e.g. in atypical pneumonias), Community acquired or nosocomial pneumonia (also known as health-care associated pneumonia as occurs in hospital settings, dialysis centres, nursing homes etc) (which is a good classification system as it can distinguish between organisms and hence the treatment varies with community or nosocomial pneumonia). Also pneumonia can occur in a normal or immunocompromised host, or it can be classified

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according to microbiological agent (although this is not easy to identify), and radiological/pathological features (lobar or bronchopneumonia). Aspiration pneumonia: this usually involves aspiration of oropharyngeal contents. The organisms involved usually include oropharyngeal flora, anaerobes (from non oropharyngeal secretions), enteric bacteria. Chest xrays show consolidation dependent at the time of aspiration. Sputum culture in these cases is unreliable, with growth of oral anaerobes, hence it is also important to do blood cultures or cultures of pleural fluid. Pneumonia can be either classified as community-acquired or hospital acquired (nosocomial) pneumonia.
Community Acquired pneumonia:

The most common causative agents, such as in this ladys case is Streptococcus pneumoniae. Other important major causes include in terms of most-common to less-common: Mycoplasma pneumoniae, Chlamydia pneumoniae, Haemophilus influenzae, Legionella pneumophila and other organisms. Community acquired pneumonia usually occurs with certain age groups (e.g. increased risk at extremes of age although all ages can be affected), environmental factors (mid-winter, or such as transmission via airconditioning towers or cooling towers as in the case of Legionella pneumophila which like aquatic environments) or with certain lifestyles/diseases (such as alcoholics, with aspiration pneumonia, who develop Klebsiella pneumonia). The following table displays the most-likely organisms with community-acquired pneumonia in different age-groups: Age Neonatal (0-1 month) Most likely organisms E. coli (faecal contamination), Group B streptococcus (intrapartum infection, part of vaginal flora in a mother that is GBS positive, they need prophylactic antibiotics before delivery) Chlamydia trachomatis, Respiratory Syncytial virus (once they develop RSV antibodies, they acquire life-long immunity to RSV) Respiratory Syncytial virus, Parainfluenza viruses Mycoplasma pneumoniae, Influenza type A Mycoplasma pneumoniae, Streptococcus pneumoniae Streptococcus pneumoniae, Haemophilus influenzae

Infants (1-6 months) Children (6months to 5 years) Children (5-15 years) Young adults (16-30) Older adults

Important symptoms include: chills, rigors, productive cough and pleuritic chest pain. Signs include: fever, tachypnoea, dullness to percussion, bronchial breathing an/or crackles, pleural friction rubs. Laboratory findings may include: neutrophil leukocytosis, hypoxemia, sputum with PMN and causative organism found on Gram stain. With bacterial pneumonia, anatomically it can cause either lobar or bronchopneumonia patterns, suppurative inflammation and the classical stages of 1) lung congestion, 2) red hepatisation, 3) grey hepatisation and finally 4) resolution. In initial congestion, there is exudation of acute-phase proteins into the alveolar spaces, with few inflammatory cells and one would hear crackles/crepitations as a result of fluid filling the alveoli. With red hepatisation, a fibrin meshwork forms and solidifies the exudate, which makes the lung appear red, also suppuration occurs with neutrophil infiltrate; the redness is from the dilatation of the alveoli and some exudation of red blood cells which makes the lung red liver-like. With grey hepatisation, the red blood cells degrade and hence the lung appears grey; macrophages remove the exudate and debris and are also removed via the lymphatics or the patient coughs this up as sputum; no ventilation occurs at this stage or in the earlier stages. With resolution the lung finally returns to normal. Microscopically in early bacterial pneumonia, the alveolar capillaries become dilated and hence alveolar walls are more prominent and congested with blood. There are also neutrophils in the alveolar spaces, also red cells and proteinaceous exudate which forms a fibrin meshwork that helps consolidate the alveoli. As a result of this pathology, virulence of causative agents and their ability to spread and also depending on the host response, this leads to either lobar or bronchopneumonia. Bronchopneumonia appears as patchy areas of consolidation, with other areas of lung being unaffected and is usually caused by less virulent organisms. Streptococcus pneumoniae causes a brisk exudative response and spreads quickly, resisting phagocytosis due to its polysaccharide capsule and hence this agent commonly causes lobar pneumonia. Clinicopathological correlation in community acquired pneumonia, the cause of symptoms is explained below: o Cough: is caused by the stimulation of the cough reflex by the inflammatory process in the airways.

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o Dyspnoea: hypoxemia due to ventilation/perfusion mismatch and subsequent blood shunting. This can be life-threatening in pneumonia and it can cause cyanosis. In the affected bronchi, dyspnoea is caused by low PaO2, due to a combination of ventilation/perfusion mismatch and shunting of blood- due to a lack of ventilation in the consolidated alveoli blood shunting occurs to other alveoli. o Pleuritic chest-pain: stimulation of somatic sensory nerve endings in the parietal pleura by the inflammatory products on the visceral pleura. The cause of important signs in pneumonia are explained below: o Tachypnoea: this is the result of increased ventilatory drive from a chemoreceptor mediated response to hypoxemia. There is increased saturation of O2 in the well ventilated areas, but not enough to obtain a O2 concentration that is any higher in these areas due to saturation (from the Haemoglobin-oxygen saturation curve) and this is not enough to overcome the poor ventilation in the poorly ventilated areas thus resulting in hypoxemia. o Fever: due to resetting of the hypothalamic thermostat by IL-1, TNF-. o Crepitations/crackles: this is due to opening of fluid/pus filled alveoli. o Dullness to percussion: loss of resonance in the consolidated alveoli. Important investigations to perform in a patient with suspected community-acquired pneumonia include: o Imaging: chest x-ray is the most important diagnostic investigation. Without a chest x-ray one cannot make a diagnosis that the infection is in the lung parenchyma or in the bronchi etc. Check for lobar or bronchopneumonia, an air bronchogram suggests consolidation rather than effusion or collapse. The following is a chest x-ray of middle lobe consolidation (check for silhouette sign at right cardiac border) in a patient with lobar pneumonia:

Cultures: Sputum Gram stain, culture, antibiotic sensitivities; and blood culture (which is positive in 20-30% cases). With microbiology, Streptococcus pneumoniae is the most common, Haemophilus influenzae is commonly found in patients with COPD or with previous viral infections, Staphylococcus aureus is common after viral infections such as influenza. Legionella pneumophila typically occurs in epidemic settings. Ancillary tests: full-blood count: look for neutrophil leukocytosis; inflammatory markers: check CRP & other acute-phase proteins; arterial blood gases/pulse oximetry: check for hypoxemia, if hypoxemic use ventilatory oxygen.

Bronchopneumonia occurs more commonly in debilitated people such as those with cancer or CCF, it more commonly occurs in the lung bases, due to static secretions and impaired cough reflexes; it is typically bilateral and caused by low virulence organisms. Certain features which suggest certain causative agents include with lung consolidation (either lobular, segmental or lobar) this is most likely Streptococcus pneumoniae, or diffuse/bronchopneumonia is commonly due to Mycoplasma pneumoniae, Chlamydia pneumoniae, Staphylococcus aureus. Important microbiological investigations for pneumonia include: sputum direct gram stain, culture (enables antibiotic sensitivity testing, although difficult to interpret if contaminated & many cannot produce sputum), blood cultures (High specificity with bacteremia/sepsis, although it has a low sensitivity of 20-30%). A urine sample may be useful for detecting microbial antigens filtered in the kidneys such as streptococcus pneumoniae urinary antigen and Legionella urinary antigen. Serology tests may also be useful for certain organisms such as Legionella, Chlamydia and Mycoplasma.

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 Important ways to prevent pneumonia include with influenza vaccination: pneumonia is a common complication of influenza. Pneumococcal vaccination: is important for patients who are at risk who have chronic illnesses such as COPD, are recovering from severe illnesses, are in nursing homes or other chronic care facilities and are aged 65 years and older.
Hospital Acquired pneumonia:

This usually occurs in patients that have underlying respiratory disease, such as COPD or bronchiectasis, or in the elderly and unwell. It occurs in hospitals, nursing homes, patients with recent surgery, intubation (gramnegatives common cause of ventilator-associated pneumonia, they are good colonisers of ventilatory equipment) and with broad-spectrum antibiotic use causing resistance organisms. Symptoms include fever and deterioration in clinical course. Signs include tachypnoea and basal crackles. Laboratory findings include leukocytosis and hypoxemia and there is chest x-ray evidence of consolidation, or variable, often patchy, widespread bronchopneumonia. Drug-resistant organisms may be cultured, such as MRSA. Usual infective agents include aerobic gram negative bacilli in 60% of cases including Klebsiella pneumoniae, E. coli, Serratia species, Enterobacter species and pseudomonas aeruginosa. Other organisms include Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae. Neonatal hospital acquired pneumonia infective agents commonly include Group-B streptococcus, Chlamydia trachomatis, both from intrapartum vertical transmission. Other causes of hospital acquires pneumonia include transmission from medical equipment, such as in those requiring assisted ventilation, common causative agents include Klebsiella pneumoniae, Staphylococcus aureus (a very common nosocomial infection, also dont forget MRSA).
Pneumococcal pneumonia:

Clinical features include an abrupt onset of symptoms, with fever, rigor and chills, productive cough with purulent sputum, pleuritic chest pain, dyspnoea, tachypnoea and hypoxemia. Risk factors for pneumococcal pneumonia include patients that have chronic illnesses such as lung disease, heart disease, kidney disorders, diabetes, or sickle-cell anaemia. Also in patients recovering from serious illnesses. Some patients developing pneumococcal-pneumonia are living in nursing homes or other chronic care facilities, and are usually aged 65 years and older.
Mycoplasma pneumoniae:

This organism lacks a true cell wall and hence does not gram stain. It is a fastidious organism, that is slow growing and may take >7 days to grow in culture. Also since this organism does not have a cell-wall, beta lactam antibiotics are ineffective, hence specific antibiotics are needed, and thus there is slow eradication. Mycoplasma pneumoniae are the smallest self-replicating organisms which grow on special media and are never found freely in nature. They can not be seen by simple light-microscopy. Infection usually occurs in children >5 years of age and young adults, Mycoplasma pneumonia is the most common cause of pneumonia in school children, contributing to 15-20% of community acquired pneumonias, with an incubation period of 1-3 weeks and symptoms developing over 2-4 days. The symptoms may persist for a few days to more than a month. Laboratory diagnosis of Mycoplasma pneumoniae pneumonia is with serology, Mycoplasma PCR and a sputum culture.
Atypical pneumonia:

Atypical pneumonia is more common in children, adolescents, young adults; institutions as a year round occurrence, and it has specific risk factors. Atypical pneumonia or interstitial pneumonia, is more commonly caused by intracellular organisms e.g. Chlamydia, viruses, Toxoplasma. Symptoms of atypical pneumonia include a 3-4 day prodrome of malaise, then headache, fever and dry cough. Signs are typically sparse. Hence atypical pneumonia may be mistaken for non-specific viral bronchitis or other viral illnesses. Laboratory findings are typically limited. Inflammatory products are in the lung interstitium rather than in the alveolar air spaces. There is limited or no lung signs, cultures are negative.

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 Atypical pneumonia pathology: It is an interstitial pneumonia, where inflammation predominantly occurs within the alveolar septa, there is mononuclear leukocyte infiltrate including macrophages, lymphocytes, plasma cells rather than neutrophils observed with typical pneumonias, as this is predominantly a cell-mediated immune response, needed to overcome intracellular organisms that have infected alveolar macrophages and alveolar pneumocytes. There is usually an intraalveolar proteinaceous exudate in many cases, leading to signs of crackles, although this is not consistent. As a result of intraalveolar proteinaceous exudation and inflammation, there is hyaline membrane formation, which reflects alveolar damage. The following displays a microscopic image of atypical pneumonia, indicating thickening of the alveolar septa and epithelial debris, which can form hyaline membranes from surfactant and exudate. The hyaline membranes form barriers to gaseous diffusion:

In atypical pneumonia, ~70% of cases are due to Mycoplasma pneumoniae, Chlamydia (Chlamydophila) pneumoniae, viral causes: Influenza A and B, Coxiella burnetii (Q fever), Chlamydia (Chlamydophila) psittaci. On radiology there is typically a diffuse, interstitial pattern:

Pneumonia pathogenesis:

Pneumonia occurs as a result of failure of host defences, such as humidification and filtration of inspired air, epiglottic or cough reflexes, mucociliary transport, innate immunity (alveolar macrophages, neutrophils and complement), humoral immunity (B lymphocytes, immunoglobulin and complement all from the Bronchialassociated lymphoid tissue) and cellular immunity (T lymphocytes). Pathogenesis also depends on the virulence factors of the organism and sufficient inoculum. Remember important lung defences such as mucociliary transport in large airways, IgA secretion by mucosal plasma cells, regional lymph nodes and alveolar macrophages in smaller airways and alveoli.

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 Impaired defences include: extremes of age (paediatric & geriatric populations- who have the inability to mount adequate responses), impaired drainage of secretions (cystic fibrosis, bronchiectasis, obstructive neoplasm, foreign body); impaired mucociliary transport (congenital immotile cilia, cigarette smoking and post-viral) impaired consciousness (suppression of the cough reflex with anaesthesia, coma, narcotic drugs, alcohol), static fluid in alveoli, e.g. pulmonary oedema, which impairs macrophage phagocytosis and immunodeficiency (innate, humoral or cell-mediated). Pneumonia syndromes include: acute, community acquired pneumonia; atypical pneumonia, nosocomial (health-care associated) pneumonia and pneumonia in the immunocompromised.
Pneumonia in the immunocompromised:

Features are closely related to the immunodeficiency; o HIV: there is diffuse, interstitial pneumonia, of insidious onset, commonly due to Pneumocystis jirovecii (usually with CD4 T cell count <400) or Cryptococcus neoformans. o Acute leukaemia: there is focal pneumonia also of insidious onset with fever and productive cough, often due to Aspergillus fumigatus. o Bone marrow transplantation: severe, diffuse interstitial pneumonia, often due to Cytomegalovirus.
Pneumonia complications:

Abscess formation. This most commonly occurs due to aspiration of infective material, such as oropharyngeal material, commonly in people that have lost consciousness such as patients on anaesthetics, alcoholics, people taking narcotics, etc or can occur from sepsis from teeth or gum infections. Certain bacteria are associated with bronchopneumonia, especially Staphylococcus aureus, Klebsiella pneumoniae and type 3 pneumococcus. Lung abscesses can also cause septic embolism. It can be caused by airways obstruction, penetrating injury to the lungs, spread from adjacent organs or it can lead to haematogenous spread to the lungs. Signs and symptoms of lung abscesses include high spiking fevers, copious amounts of purulent sputum when the lung abscess communicates with the airways, and this may lead to resultant haemoptysis due to erosion into blood vessels and this may lead to sinus formation to the pleural surface, leading to spread of infection/inflammation into the pleural sac, causing empyema thoracis. The following chest x-ray depicts a lung abscess, which appears as a cavitating lung lesion. There is an area of cavitation, surrounded by opacification:

Empyema (thoracis) formation. The following chest x-ray is from a patient with empyema thoracis:

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 Disseminated infection, particularly with bacterial infections, including meningitis, septic arthritis, infective endocarditis, septic shock and multiple organ failure- the inflammatory response to sepsis can cause multisystem failure. Respiratory failure and the ARDS. Organisation of exudate: Permanent loss of lung-function due to organisation of granulation tissue, rather than resolution. If the exudate is not coughed-up, or phagocytosed by macrophages or drained by lymphatics, then the exudate may organise into granulation tissue. This granulation tissue can permanently impair gas exchange.

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Principles of O2 therapy & basic respiratory physiology (revisited)

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Bronchiectasis

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Arterial Blood Gas interpretation

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Oxygen therapy clinical tutorial & Revise respiratory physiology and include arterial blood gas tutorial & importantly clinical interpretation of ABGs based on respiratory physiology

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Pathology of tuberculosis infection

Case : Tuberculosis
A 48 year old man, who had recently emigrated from Cambodia, presented with a three month history of fever, night sweats and 6kg weight loss. He spoke little English and used his 16 year old son as an interpreter. He had a chronic cough, productive of mucoid sputum. On occasion he had noticed haemoptysis and more recently complained of right sided pleuritic chest pain. He smoked 40 cigarettes and consumed 50g of alcohol per day. Abnormalities on examination included fever (38.3C), obvious wasting, and reduced expansion of the right lung with bronchial breath sounds over the right apex. A chest x-ray taken at the time is shown below (left).

The projected x-ray on the left shows opacification in the apex of the right lung, with radiolucent areas in the centre of the lung indicating cavitation. The chest radiograph on the right also shows a right upper lobe infiltrate with the appearance of apical cavitation with an air-fluid level in a patient with active tuberculosis. The x-ray on the right also shows small scattered nodules in the upper zone of the left lung which appear calcified (and a calcified nodule behind the heart on the left side). Mucoid sputum indicates a clear coloured of sputum. Note that pleuritic chest pain is characterised as a sharp, stabbing type of chest pain that is worse on inspiration/coughing, that is indicative of pleural irritation, as the parietal pleura is supplied by somatic sensory nerve fibres. 3 common lesions that could present with these chest x-ray appearances could include: 1) Tuberculosis: Chronic inflammation associated with TB; this would be high on the differential diagnosis in this case, based on most of the clinical features in the history. Opacification may be associated with concurrent fibrosis, granulomatous tissue and caseous necrosis. 2) Pulmonary abscess: Acute inflammation from a lung abscess could also produce a cavitating lesion, in this case possibly a communicating lung abscess that has been drained into a bronchus via a draining sinus. This could produce a similar chest x-ray image, although the duration of illness would not be 3 months. 3) Lung cancer: An apical lung cancer could also cause similar opacification in the lungs, with central necrosis causing cavitation. Such a tumour could also cause airway obstruction leading to secondary destruction of lung tissue from pneumonia. One should always suspect tuberculosis in such a clinical presentation with signs/symptoms of fatigue, nightsweats, chest pain, dyspnoea, weight loss, cough/haemoptysis and this type of x-ray appearance. Other important clinical factors to note in a patient with suspected tuberculosis include if they are immunosuppressed (for example, HIV positive patients), and also patients from certain endemic regions (or with significant travel history) including China, South-East Asia, South Asia/subcontinent and Central-West Africa.

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 The patients full blood count results were as follows:

Full Blood Count Haemoglobin (g/L) RCC (1012/L) Packed Corpuscle Volume (PCV) (Haematocrit) Mean Corpuscle Volume (fl) (MCV) MCH (pg) MCHC (g/L) WCC (109/L) Neutrophils Lymphocytes Monocytes Eosinophils Blood Film Platelets (109/L) ESR (mm/hr) 112* 4.0** 0.35** 130-180 4.5-6.5 0.40-0.54

88 80-100 28 27-32 317 300-350 13.7* 4.0-11 6.8 2.0-7.5 6.5* 1.5-4.0 0.3 0.2-0.8 0.1 0.04-0.4 Normochromic, normocytic 346 52* 150-400 1-10

The full blood count indicates a normocytic, normochromic pattern of anaemia; commonly caused by anaemia of chronic disease due to impaired haematopoiesis from chronically elevated levels of circulating TNF-. Again, this could be due to a chronic pulmonary abscess, tuberculosis/chronic inflammation or cancer- it does not help with the differential diagnosis. However, the elevated lymphocyte count (lymphocytosis) is significant, as it indicates that the patients disease is most likely not due an acute inflammation due to a pyogenic bacteria (i.e. most likely not abscess). ESR is also elevated indicating chronic inflammation. Other investigations that may now be performed: 1) Sputum cytology to rule out tuberculosis or cancer. Cytology is important to identify dysplastic or neoplastic changes in the airway epithelial cells. 2) Rapid Mycobacterium tuberculosis PCR can also be performed to identify mycobacterium tuberculosis DNA either in a lung biopsy sample or on sputum. 3) Mycobacterium tuberculosis culture on Lowenstein-Jenson medium; this takes ~6 weeks to grow, while the more modern BacTec culture takes about 2 weeks to culture. Culture is important to perform if a diagnosis of TB is to be made since it also allows for determination of organism antibiotic sensitivities. 4) Ziehl-Neelson acid-fast stain of sputum or lung biopsy specimen; a stain to identify acid-fast organisms (i.e. Mycobacteria). An auramine-rhodamine fluorescent stain is also used to visualise Mycobacteria and although cheaper and more sensitive, is not as specific as the ZN stain for mycobacteria. Below is a ZN stain from sputum, showing red-coloured acid-fast mycobacteria, and a auramine-rhodamine fluorescent stain of sputum, indicating yellow fluorescent mycobacteria.

5) Gram stain, microscopy and culture of sputum to identify organisms that may cause acute inflammation and abscess formation. However, this would not be useful for detection of mycobacteria.

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6) Repeat chest x-rays, or thoracic CT scan may be indicated following treatment to assess for clinical improvement. A CT scan may be performed if the diagnosis was initially unclear. 7) QuantiFERON TB Gold or other interferon- release assays may also be performed in cases of patients with suspected TB, and this is more sensitive than a Mantoux test, and this involves mixing a patients blood sample overnight with Mycobacterium tuberculosis antigenic proteins including purified-protein derivative (PPD), early-antigenic target-6 (ESAT-6) and culture-filtrate-protein-10 (CFP-10) and then measuring the amount of interferon- produced by the patients lymphocytes and comparing to non-stimulated and control patient blood. Unfortunately, before the diagnosis could be confirmed, the man discharged himself from hospital. The man returned by ambulance two weeks later, having collapsed after a massive haemoptysis. Unfortunately, he could not be resuscitated. The following slides were prepared from tissues removed at autopsy.

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 The patient may have died as a result of aspiration of blood (and hence hypoxia) or as a result of massive haemorrhage that could have caused hypovolemic/haemorrhagic shock and hence death. The slides display multifocal abnormalities due to the presence of chronic granulomatous inflammation, with some granulomas exhibiting central foci of caseation. Most granulomas in the slide are necrotising (indicating it is most likely caused by tuberculosis; i.e. as non-caseating granulomas in the lung have other causes such as chronic beryllium disease, hypersensitivity pneumonitis, some fungal infections and sarcoidosis). A granuloma is a focal aggregate of macrophage derivatives. Giant epithelioid cells make up most of the granuloma, due to shrinkage of tissue they appear stringy and oedematous. They are formed due to activation of macrophages (from interferon- activation) fusing together to form a syncytium. They wall-off spherical areas of M. tuberculosis infection. There are also Langhans multinucleated giant cells that have horseshoe shaped nuclei located peripherally and these are morphologically different from the foreign body type of giant cells. Note that caseous (cheese-like) necrosis is a type of necrosis that is intermediate between the liquefactive and coagulative types. Casseous necrosis undergoes liquefaction if it erodes into the airways and if neutrophil infiltration enters leading to tissue liquefaction. This pattern of granuloma formation is the manifestation of a cell-mediated response to a poorly removed pathogen (M. tuberculosis) and is an example of a type IV or delayed hypersensitivity reaction. Cell-mediated immune response by T cells leads to macrophage activation and granuloma formation. When cell mediated immunity wanes, e.g. due to HIV/AIDS, alcoholism, diabetes, age etc., granulomatous inflammation can spread to the airways via bronchogenic spread. Latent tuberculosis infection usually remains in the lung apex due to higher oxygen tension in the upper lungs. The pathogenesis of granuloma formation in response to a poorly solubilised antigen is summarised in the diagram below:

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 Within each tuberculous granuloma, there is a zone of casseous necrosis, surrounded by a syncytium of epithelioid cells interspersed with Langhans-type multinucleated giant cells. Surrounding the granuloma is a cuff of T-lymphocytes, which are driving the TH1 immune response to Mycobacterium tuberculosis, as well as a peripheral zone of granulation tissue. The granulation tissue (mature scar tissue) is composed of fibroblasts, new blood vessel formation and macrophages.

The slide below also shows the presence of an acute fibrinous pleuritis (which would have caused the patients pleurisy, i.e. pleuritic chest pain), representing the pleuras reaction to the chronic inflammatory response in the underlying lung parenchyma. Characteristic microscopic features include: 1) Vasodilatation and vascular congestion. 2) Fluid exudation (indicated by clear spaces within tissue) and protein (fibrin) deposition. 3) Infiltration by inflammatory cells. This would have undergone reorganisation and thickening of the pleura. However, it could also be associated with tuberculous empyema and spread of granulomas over the pleural surface. Acute inflammation is also seen in the pleura (hence this is an acute-on-chronic inflammation) due to increased vascular permeability with oedema, proteinaceous exudates; neutrophil infiltration; increased vascularity; some angiogenesis and early granulation tissue formation. This is a non-specific response in the pleura to inflammatory mediators from the lung parenchyma:

A granuloma is a focal lesion, consisting of an aggregate of chronic inflammatory cells, principally macrophages, epithelioid cells, giant cells and lymphocytes. It exhibits the following classic features of chronic inflammation: 1) Ongoing tissue injury (necrosis) 2) Concurrent attempts at healing by repair (i.e. organisation and formation of granulation tissue). 3) Mononuclear cell (i.e. monocyte/macrophage & lymphocyte) infiltration.

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 The slides above display a lymph node, it is identified as a lymph node by the high concentration of lymphocytes and the lymph node capsule. Casseous necrosis in granulomas is present with a rim of giant epithelioid cells and some multinucleate giant cells. TB spread to lymph nodes occurs due to macrophages transporting mycobacteria to lymph nodes for T-cell presentation. Lymph nodes are the most common extra-pulmonary site of infection, although it can spread to other tissues.

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 Tuberculosis is a major health problem, ~1/3 or the worlds population has been infected with Mycobacterium tuberculosis, with ~2million deaths/year worldwide. That does not mean that 1/3 of the world population have the disease, and fortunately there is a big difference in being infected with M. tuberculosis and actually having the disease, however, once infected, one is at higher risk of developing disease. Thus there are many people at high risk of disease worldwide. ~1.5 million people worldwide have active tuberculosis at any one time. In Australia, tuberculosis is not a health problem as much as it is in other regions of the world. In Australia, the case rate declined from ~50 patients/100000 population in the 1950s to ~5cases/100 000 currently. Australia has also very much survived the surge of tuberculosis that has been associated with the HIV epidemic. HIV AIDS is substantially related to the development of tuberculosis, as tuberculosis is an interaction between the organism and the host immune response. Since HIV-AIDS destroys the host immune response, this provides a good environment for tuberculosis to cause disease. Australia is very lucky to have low rates of incidence of tuberculosis/HIV coinfection. Hence in Australia, tuberculosis is not always considered in a differential diagnosis, when it is considered likely in other parts of the world. Hence this may be a problem, as the right diagnosis may not be achieved on time in Australia, although it is fortunate that tuberculosis does not occur commonly in Australia. In Australia, there is ~8 times higher incidence of tuberculosis in indigenous Australians and certain migrants compared with non-indigenous Australians, illustrating that even still the same level of healthcare and health outcomes are not achieved in Australia, in indigenous communities. Mycobacterium tuberculosis is a remarkable organism in two main ways: 1) it does not produce any real toxins, 2) it is extraordinarily difficult to destroy this organism, at least by normal immune cells, although it is susceptible to dessication and UV radiation and this is also a fastidious organism, growing in oxygen-rich environments- it is a strict aerobe. However, due to its outer waxy coat; it can survive phagocytosis and reside within macrophages. Natural history of tuberculosis: The natural history of tuberculosis illustrates the relationship of Mycobacterium tuberculosis and the host immunological response. Tuberculosis is always about the balance between organism and host.

In a typical tuberculosis reaction, the pattern of disease is a function of time and level of immune response. When the immune reaction is really good, there is effective localisation of the infection, perhaps so effective that

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infection is wiped out although not necessarily so, and the process of removing the organism results in tissue destruction- resulting from immunologically driven granulomatous responses, complete with necrosis. The necrotising granulomas have a pattern of caseous necrosis. Hence there is a trade-off; a good immune response to tuberculosis will be localised although it results in tissue destruction. Whereas, in a poor immune response there is little tissue destruction and caseation, and also spreading of infection. A good immune response damages the host tissue (resulting in caseation) but also destroys the organisms within the cells and hence infection becomes localised. Tissue destruction is a price to pay to eliminate M. tuberculosis. At the bottom end of the y-axis of the graph above, the poor immune response means that there are many macrophages infected by the organism, however, these are ineffective and the organism is not eliminated and there is infection spread and no tissue damage. Even with a slowly replicating organism, such as M. tuberculosis, in a poor immune response and given enough time, the organism can spread and disseminate within the body. Referring to the previous chart, a person with a PRIMARY INFECTION is a nave host that is exposed to M. tuberculosis for the first time and has not developed an adaptive immune response. The infection usually occurs via inhalation of the organism with dust particles or respiratory droplets containing the organism- hence primary infection is mainly a pulmonary infection. Hence primary infection results in an initial innate immune response- although it does NOT trigger a neutrophilmediated response, hence this organism is a low intensity irritant, as there is no significant inflammatory response occurring at all. Then macrophages resident in local tissues phagocytose the mycobacteria, but these are only internalised and not killed by the macrophages, as mycobacteria are normally resistant to being killed by macrophages, as the organism has an outer waxy-coat that resists normal macrophage lysosomal enzymes. To kill a Mycobacterium tuberculosis inside a phagolysosome, it must essentially be nuked, by high-energy, highly reactive molecular species, that combine with the bacterial lipid coat and destroy it. These include reactive oxygen species or free radicals, to kill the organism within the phagolysosomes. Whereas neutrophils produce oxygen-free radicals, macrophages when activated can produce both oxygen and nitrogen free radicals that can destroy the mycobacteria. However, unlike neutrophils, macrophages must be activated to kill effectively. Therefore as the macrophages are not initially activated, the mycobacteria acquire a new mobile home, by preventing fusion of the phagosome and lysosome, allowing mycobacterial migration elsewhere. Hence after primary infection, in a nave host, there is a period when mycobacteria can proliferate both intracellularly and extracellularly and even though numbers may be small and it is slow dividing, it will find its way into the bloodstream, causing a pre-immune low-level bacteraemia. This first stage of infection is a completely asymptomatic initial period of infection, but the organisms are slowly dividing and disseminate. After a few weeks, the immune response is activated, as this occurs the destructive process also occurs. In an ideal word the immune response should move up vertically in the chart to remove the organism. What occurs with the initial immune activation is a TYPICAL PRIMARY COMPLEX- a focal localisation of organisms in the site where they were first lodged, or a focal proliferation of organisms in a draining lymph node. There is hence an inflammatory response in this primary site of focal proliferation- there is thus a granulomatous lesion with caseous necrosis at this site of primary proliferation and this typical primary complex is also referred to as a Gohn complex. This indicates that an immune response has kicked-in and the organism is being destroyed, if no problems/complications occur, this primary gohn complex progresses towards healing- with healed lesions and the organisms may hence lose viability. However, as not all cases are ideal, some organisms may evade the immune response and the organisms may remain dormant in the latent pulmonary or extra-pulmonary lesions. The organism can remain in a dormant state in these sites for decades, non-replicating after the primary immune response. The organism is waitingin latent lesions. The immune response may then decline for various reasons (old age, HIV infection etc.) and the organism is then reactivated. However, the vast majority, or ~95% of people develop an effective primary response against the organism and will progress towards healing. However, ~5% of people may not have an effective primary response and they may develop PROGRESSIVE PRIMARY TUBERCULOSIS. To develop progressive primary tuberculosis means that the host immune response is not very effective. A good immune response will develop highly localised lesions, with marked caseation, a poor response will not be limited, with organism spread and less caseation developing primary progressive tuberculosis during the primary response.

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 With a very poor immune response, this can then lead to massive haematogenous dissemination of the organism- the slowly replicating organisms keep spreading but given time this leads to infection spread massively throughout the body via the bloodstream. Massive haematogenous dissemination is also referred to as MILIARY TUBERCULOSIS. Development of primary progressive tuberculosis and then miliary tuberculosis may be the outcome of <5% of infections. For most people ~90-95%, there is a good immune response that progresses to healing and a loss of viable organisms, and that is where the story ends. However, for some people, the organisms remain dormant and the proportion is not well known. It appears that most people with primary infection are at risk, as there are some residual viable organisms remaining. In these people with latent lesions, there may be reactivation of tuberculosis and re-infection. This may occur from a decreased host-immune response due to HIV, or from impaired macrophage function, e.g. in the case of diabetes. The organisms make a comeback and this reactivation and reinfection results in POST-PRIMARY TUBERCULOSIS. The attenuated immune response results in what appears to be the same as in a failed primary response to tuberculosis. This hence results in some localisation of the lesions with caseation. Post-primary tuberculosis is the most common clinical form of tuberculosis, which results from a drop in the host immune response. A more severe drop in the host immune response e.g. with AIDS leads to PROGRESSIVE POST-PRIMARY TUBERCULOSIS; similar to progressive primary tuberculosis that results from primary infection. Just like in progressive primary tuberculosis, there is also the possibility of massive haematogenous dissemination/miliary tuberculosis during post-primary tuberculosis. Note that post-primary tuberculosis should not be called secondary tuberculosis (see the same graph from Robbins Pathology below, note that they refer to post-primary tuberculosis as secondary) as this confuses it with secondary spread to extra-pulmonary sites (e.g. like with secondary cancer spread). Also primary tuberculosis occurs at a much different timescale to post-primary tuberculosis, which can occur years to decades after primary infection. It is NOT secondary spread from the primary infection, hence avoid calling this secondary TB. Note the y-axis in the graph below is the same as in the previous chart (represents the host immune response).

Also note that over time, there may be increased tuberculin reactivity, against M. tuberculosis antigenic proteins (heightened Type IV delayed-type hypersensitivity reactions); this can also occur in some cases with BCG vaccination and is generally measured with a Mantoux test.

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Tuberculosis: Sites of primary lesions: In a normal tidal inspiration, there is not much ventilation of the apex and base of the lungs, most ventilation occurs in the middle 2/3rds or more of the lung. Thus with primary pulmonary tuberculosis infections, they mostly occur in the middle 2/3rds of the lungs (as shown in the diagram on the right), as a result of multiple exposures with the organism and inhalation of the organisms through dust particles or respiratory droplets. Hence a typical Gohn focus of caseation occurs in the middle 2/3rds of the lung, spreading out to the pleura with associated hilar/paratracheal adenopathy and caseation in these draining lymph nodes (together these two features is referred to as a Gohn complex). The organisms replicate at these primary foci within macrophages and can spread to draining lymph nodes- pulmonary, hilar, tracheobronchial and paratracheal lymph nodes. As a result of the host immune response, there is resulting caseation in the lung periphery and caseation in the draining lymph nodes (forming the primary complex). By observing the gohn complex primary focus of caseation, under high magnification, it can be observed that there would be numerous macrophages. Using special stains that identify acid-fast mycobacteria (ZN and auramine-rhodamine), it can be seen that these macrophages are laden with intracellular bacilli. The image below is an acid-fast stain, which demonstrates foamy histiocytes (tissue macrophages) laden with hundreds of acid-fast mycobacterial organisms:

As mycobacteria have a waxy lipid coat; the special stains, e.g. Ziehl-Neelson stain binds to this lipid coat, but after treatment of the histological section with acid, the dye is removed from all tissue except the mycobacteriaresulting in observable residing mycobacteria within the macrophages, as above. Acid-fast organisms retain dye even after treatment with acid and alcohol. M. tuberculosis is weakly gram positive. The image below is from primary pulmonary tuberculosis, with a Gohn-complex. The gray-white parenchymal focus is under the pleura in the lower part of the upper lobe. Hilar lymph nodes with caseation are shown on the left. During primary infection, there is also caseation necrosis in the primary local site of infection and in a draining lymph node- indicating immune activation/responsiveness. The primary infection is usually subclinical, similar to an upper respiratory tract infection.

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 If all goes well, that primary lesion heals and scars and what occurs is that a small area of scar tissue that is observed years on, with no viable organisms, this area may become calcified as a Ranke complex, which is radiographically observable and appears white on gross-examination. There would be scar-tissue deposition, with abundant collagen fibres and as there might be lymphatic obstruction, there may also be peripheral aggregates of carbon around the scar, where the carbon is not removed by the lymphatics (patchy areas of anthracosis, which may be observed on histology) and there may be central areas of necrosis. However, within such a scar in some cases there may be remnant necrotic debris, which would provide evidence of mycobacterial DNA from PCR analysis. With culture of this sample of tissue, it may be possible to demonstrate that there may be viable organisms present. Given the right circumstances, these could cause post-primary TB. Hence, what appears to be calcified scar tissue may contain viable organisms present- hence these lesions are referred to as latent lesions. Progressive-primary tuberculosis If the individual does not mount an adequate immune response to primary infection, this could lead to progressive primary tuberculosis. Instead of nice localisation in a typical primary complex lesion, there would be progressive spread and enlargement of the pulmonary lesion, as shown in the section of lung below:

As there may be some host immune responses occurring, there would be caseation necrosis present, as it is not a runaway lesion. However, the host immune response may not be effective, leading to development of pulmonary satellite lesions. There could be poor outcomes for such individuals. One poor outcome would result from spread of the caseating lesions and hence mycobacteria into the circulation, which could lead to massive haematogenous dissemination. Massive haematogenous dissemination Despite slow growth of mycobacteria, spread of caseation into vascular tissues may lead to tremendous haematogenous spread and dissemination. The dissemination could spread tuberculosis lesions locally and the pulmonary tissue-forming small foci of granulomatous lesions, which do not have much caseation, as there is a poor host immune response. Within these granulomatous lesions, there are many macrophages that are full of hundreds to thousands of mycobacteria, however, as there is no significant host immune response, there is not much caseation. Massive haematogenous dissemination of TB lesions is what kills people, as it can spread to distant sites, such as the central nervous system and meninges- the most dangerous site of spread of massive haematogenous dissemination. It is also an overwhelming infection that can kill in part because of the systemic inflammatory consequences. The following shows disseminated TB in the lung (miliary TB- with appearance of millet seeds):

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Post-primary tuberculosis For most people, primary infection is a terminating event, with a host immune response; localisation of the lesion, with caseation and then progression to healing and repair (with calcification). For some people, this is not the case. In some people, their immune response drops over the course of their life for various reasons, e.g. age may be a predisposing factor, malnutrition (especially in chronic alcoholics in Australia), which impairs cell-mediated immune responses and diabetes mellitus, which impairs phagocyte function are major predisposing factors. These are all predisposing factors as CD4+ T-cells are involved in producing cytokines (hence HIV which destroys these cells leads to poor TB outcomes), such as IFN- and macrophage activating factors (macrophage inflammatory proteins (MIPs), and macrophage inflammatory activating factors (MIFs)) that cause macrophages to produce reactive oxygen and nitrogen species. The T H1 CD4+ cells drive macrophage activation in response to M. tuberculosis, this TH1 activation results in activated epithelioid giant cells and multinucleated giant cells that are designed to kill mycobacterial organisms. Epithelioid giant cells are mycobacterial killers, as they upregulate reactive oxygen and nitrogen species and multinucleated giant cells also have a higher capability for phagocytosis and mycobacterial destruction. The following diagram highlights the important sequence of immunopathologic events in primary pulmonary tuberculosis, commencing with inhalation of virulent M. tuberculosis and culminating with the development of cell mediated immunity to the organism. A. events occurring within the first 3 weeks after exposure B. events thereafter. The development of resistance to the organism is accompanied by appearance of a positive tuberculin (Mantoux) skin test. Cells and bacteria are not drawn to scale, iNOS (inducible nitric oxide synthase); NRAMP1, natural resistance-associated macrophage protein.

Note the important roles of IL-2, IL-12, IFN- and TNF- in mediating this inflammatory pathway. iNOS induction is also very important, to counteract mycobacterial phagocytosis evasion, and leads to increased intracellular nitric oxide and reactive oxygen species to destroy the bacilli.

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 Thus in a person with an impaired immune response, e.g. in HIV AIDS, there is no or limited cytokine production and hence the macrophages are not activated. But in a diabetic, it would not matter what signals are given to the macrophages, their phagocytic capability would be compromised. The end result is that the latent organisms are no longer held under control. When reactivation occurs, this leads to bacterial colonisation at sites that suit them best- this means that mycobacterial colonisation occurs most often at the lung apices (below)- this is because the lungs are an oxygen rich environment, but most enter the bloodstream due to gas exchange. At the apices, there is not much gas exchange as there is lower blood-flow perfusion due to gravitational effects on blood flow (pulmonary blood flow is greatest at lung bases). As Mycobacterium tuberculosis is a strict aerobe, it hence grows more readily in the lung apices when reactivation occurs in post-primary TB lesions, as there is higher oxygen tension than compared with the lung bases.

On microscopic examination of post-primary TB lesions, there is caseation present, with a lot of necrotic debris, surrounded by granulomatous inflammation with numerous epithelioid giant cells, multinucleate giant cells that in TB have a characteristic appearance with apically located nuclei arranged in a horse-shoe shape, which are referred to as Langhans giant cells. It is possibly the driving cytokines that causes a different morphological appearance as that of foreign-body type giant cells. There are also lymphocytes, indicating cell-mediated immune responses activating the macrophages (these lymphocytes are located more peripherally in the granuloma). Peripherally, fibroblasts may also be prominent and a major feature of granulation tissue, which can also contribute to development of pulmonary fibrosis if there is extensive attempt at healing.

An area of caseous necrosis is NOT an abscess, as there is no suppuration and neutrophils present. But a strange phenomenon can occur with apical post-primary TB lesions in that a secondary wave of neutrophil infiltration can occur, the trigger for this is not well known. However, when the neutrophils appear, they can liquefy the necrotic material, that does not mean it became an abscess, as the neutrophils did not appear first.

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 Nevertheless, like an abscess, the liquefied material can be discharged elsewhere and in the case of the lung, the liquefied necrotic debris can discharge into the airways, such as a bronchus. If that occurs, i.e. the area of necrosis has gained access to an airway and then this can lead to: 1) Dispersal of organisms, e.g. with coughing there is dispersal of organisms, and hence there is high potential of spread of organisms into the environment. 2) The necrotic debris may drain out of the airways forming cavities- cavitating lesions, which are remnants of caseous TB lesions. Apical cavitations are a classical presentation of post-primary TB, in someone whose immune response has dropped modestly.

Apical cavitations may then heal and then scar. As carbon deposition may occur around these areas of healing, this leads to the appearance of fibrocaseous tuberculosis. However, in someone who had a poor immune response, or whose immune response dropped significantly, there would be worse outcomes. The apical cavitation may lead to progressive post-primary TB, this progression may not only involve massive haematogenous spread, but also bronchogenic spread, where the TB lesions spread via the small airways- the bronchioles and some smaller divisions of bronchi. This would form patchy areas of caseation and TB lesions that appear larger than those of miliary tuberculosis. Note that on top of bronchogenic spread, in post-primary tuberculosis, there may also be massive haematogenous spread. The following CT scan displays the appearance of miliary and bronchogenic tuberculosis.

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Extra-pulmonary tuberculosis Extra-pulmonary TB can result from massive haematogenous dissemination of pulmonary TB, or it may occur without evidence of pulmonary TB, although it is fairly uncommon. It may be the case that pulmonary TB leads to healing and was subclinical, whilst the extra-pulmonary TB was not. In Australia, ~40% of cases of reported TB are now extra-pulmonary. Common sites of extra-pulmonary TB include: 1) Lymph nodes 40% 2) Pleura 14% (not part of lung parenchyma) 3) Skeletal 9% 4) Genitourinary tract 7% 5) Central nervous system 5% (meningitis or tuberculoma) 6) Miliary spread 2% (massive haematogenous dissemination) Lymph node involvement is common, usually presents with lymphadenopathy that is often discrete and nontender, rarely inflammatory with fistula formation. Typically the cervical lymphadenopathy (scrofula), supraclavicular and axillary nodes and is associated with HIV. Many people with post-primary TB reactivation who develop extra-pulmonary TB occur as a result of the preimmune bacteraemia from primary infection, or seeding of infection, the organisms which spread via the bloodstream are not eliminated at distant sites and hence remain latent until reactivation of post-primary TB. In pleural TB spread, as it is a mesothelial surface, the vascular response of inflammation leads to exudation (not commonly seen in TB chronic inflammation), causing tuberculous pleurisy (with or without pain) and can lead to pleural effusions, tuberculous empyema and fever. There is a mixed acute and chronic inflammatory response in the pleura, whilst in the lung parenchyma there is a chronic granulomatous inflammatory response. Aspiration reveals straw-coloured aspirate, may be haemorrhagic exudates (protein > 50% than that of serum), low glucose, pH 7.3, detectable WBC (neutrophils and mononuclear cells). Pleural biopsy reveals granulomas, acid-fast bacilli. Fistulae may form with tuberculous emphysema. The upper airways may be involved in advanced disease, with involvement of the larynx, pharynx and epiglottis. This may have a mass effect: altered phonation, hoarseness, dysphagia, due to spread of organisms by lymphatics or expectoration of infective matrial. Smear masses for AFBs. Caseous necrosis can also spread to the urinary tract, effacing the kidneys for example below. Important features include renal impairment, frequency, dysuria, pyuria, haematuria, obstruction, calcifications, strictures, mass effect and tissue destruction:

With CNS tuberculosis, typically TB spreads to the grey-white junctions, forming caseous necrotic granulomas in this area of the cerebral cortex. It can also lead to tuberculous meningitis with leptomeningeal involvement. (Important differentials to consider: neurosarcoidosis, multiple sclerosis, CNS abscesses, lymphoma/malignancy). It is this involvement of critical organs and the difficulty of organism elimination that makes TB such a worrisome and deadly disease. Diagnosis is with obtaining a biopsy specimen from necrotic tissue, or identifying

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AFB on lumbar puncture. Can present with meningism and mass-occupying lesions. Neurological deficits may persist in 25% of cases.

Skeletal tuberculosis often involves weight bearing joints and forms joint/bony abscesses and osteomyelitis. Spinal tuberculosis is referred to as Potts disease, shown here to involve the right pedicle of a vertebra:

Gastrointestinal/tuberculous peritonitis is not very common (~3.5%), but can present with terminal ileal, caecal masses, appendicitis, with intestinal wall involvement, ulcerations and fistulae likened to Crohns disease. It causes abdominal pain (similar to appendicitis) and swelling, obstruction, haematochezia and a palpable mass, which are common findings on presentation. Fever, weight loss, anorexia, night sweats are common. TB peritonitis may also occur via rupture of lymph nodes, abdominal organs and haematogenous spread. Confirm with peritoneal biopsy. Oropharyngeal and intestinal tuberculosis contracted by drinking contaminated milk containing M. bovis is now rare in developed countries, but is still seen in countries that have tuberculous dairy cows and unpasteurised milk. The organisms may also be transmitted by swallowing coughed sputum and organisms may accumulate in Peyers patches in the GI tract, undergo caseating necrosis and ulcerate. Pericardial: rare, but can lead to pericardial effusions and cardiac tamponade, diagnosed on pericardial biopsy. Others: chorioretinitis, uveitis, otitis, congenital, dissemination in organs in miliary, e.g. with hepatosplenomegaly. Splenic involvement (below) in miliary disease, cut-surface shows numerous grey-white tubercles:

Miliary TB is most prominent in the liver, kidneys, spleen, adrenals (formerly an important cause of Addisons disease), bone marrow and bone (tuberculous osteomyelitis), meninges (tuberculous meningitis), fallopian tubes (tuberculous salpingitis) and epididymis and can spread to the skin (lichen scrofulosorum).

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 Summary of tuberculosis pathogenesis: 1) Primary infection is seeding of the organism (common organisms include: Mycobacterium hominis tuberculosis, M. bovis tuberculosis, M. avium tuberculosis, M. intracellulare tuberculosis. 2) Organism lodges in the alveoli (seeding in the lungs) and divides in alveolar macrophages, enters lymphatics and causes a low-level bacteraemia (as opposed to sepsis). There may be seeding to: lymph nodes, bone, urinary tract, genital tract. 3) A T-cell mediated response develops against TB organisms, which leads to delayed-type hypersensitivity reactions (Type IV DTH). This can lead to control of the organisms with a chronic granulomatous inflammatory response, in lung parenchyma and hilar/tracheobronchial lymph nodes. Fibrosis occurs to wall off immune response and gohn complex formation. 4) Reactivation of the organism after many years and with reduction of immune response. 5) Organism causes caseating post-primary TB in lung apices. This may lead to either: a. drainage via the airways with liquefaction; hence cavitations form; a poor immune response may lead to bronchogenic spread. b. Or it may erode into blood vessels, leading to massive haematogenous spread (which may present as haemoptysis. This may lead to death from haemoptysis. 6) Massive haematogenous spread leads to miliary TB, which can lead to extra-pulmonary TB spread to vital organs and this can lead to death.

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Microbiology, diagnosis and management of tuberculosis

Summary: Investigation of tuberculosis is dependent on the stage or extent of the disease. In primary pulmonary tuberculosis, investigations include sputum microscopy, culture and sensitivities, acid-fast stains, PCR amplification, chest x-ray, Mantoux test and, QuantiFERON TB Gold. Rarely does post-primary tuberculosis present with only extrapulmonary signs. In this setting, the particular system should be investigated with tuberculosis in mind (e.g. lymph node, pleural etc.). Treatment of tuberculosis is based on the Direct Observed Treatment Short-course (DOTS) with the four mainstay drugs of rifampicin, isoniazid, pyrazinamide and ethambutol. Under the Therapeutic Guidelines, this is recommended for 6 months, either once daily or three times weekly (at different doses). Important symptoms of tuberculosis include: 1) Coughing- may be associated with haemoptysis in cavitatory TB 2) Chest pain: may be pleuritic due to pleural involvement 3) Weight loss: effects of chronic inflammation, cachexia 4) Fever/Night sweats: effect of inflammation, pro-inflammatory cytokines (TNF-, IL-1) increases PGE2 in hypothalamus, increasing thermoregulatory set-point and hence causes fever. 5) Malaise: General feeling of being unwell due to inflammation 6) Signs are variable and may also depend on extra-pulmonary features noted previously. Mycobacterium genus contains >70 known species: Mycobacterium tuberculosis complex (M. TB complex): Mycobacterium tuberculosis hominis- causes human TB M. africanum- also causes TB, limited to Africa, less common M. canettii- also found in Africa, causes human TB, less common M. bovis- Causes TB in cows and humans M. microti- TB in rodents, rare in humans, only immunocompromised Mycobacterium avium complex (MAC) includes: M. avium species Immunocompromised patients (e.g. HIV AIDS) M. avium intracellulare Immunocompromised patients (e.g. HIV AIDS) M. avium paratuberculosis species- affects cattle Mycobacterium leprae (Hansens bacillus) causes leprosy Properties of M. tuberculosis Mycobacteria are strict aerobes, and they must require oxygen for growth. They are slightly curved or rod shaped bacilli. Mycobacteria are very slow growing, e.g. M. tuberculosis doubling time is ~15-20 hours, M. leprae is a few weeks. This is in comparison to E. coli, which has a doubling time of 20-40 minutes. The mycobacterial cell wall is complex, composed of many lipids, mycolic acid, which causes acid-fast staining, plasma membrane and polysaccharides. The outer waxy coat of mycobacteria is what gives them their special properties. The mycobacterial cell wall is complex; waxy, with a high lipid content, which is why it is resistant to chemical agents and desiccation- organisms can hence survive for weeks in dry sputum. Cell wall components of mycobacteria powerfully stimulate the immune system, e.g. Mannan and lipopolysaccharide. The cell wall is also resistant to decolourisation with acid and ethanol. Diagnosis of M. tuberculosis It is important to obtain the appropriate specimens for investigation. For pulmonary tuberculosis, a sputum sample is taken. This is usually digested with enzymes first to break down the mucous and then examined for mycobacteria. Extra-pulmonary tuberculosis requires lymph node and tissue biopsies, CSF and blood samples. Sputum/tissue microscopy: Direct microscopy is useful for rapid diagnosis, because it allows rapid diagnosis and also detection of AFBs with a Ziehl-Neelson stain is diagnostic, as this stain does not stain other organisms. An acid-fast stain- Zhiel-Neelson staining of the tissue/sputum sample involves initial staining with carbol-

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fuschin (the primary stain, red colour), while heating tissues/sputum with steam. The sample is then decolourised with a mixture of hydrochloric acid and ethanol. Then there is counter-staining with methylene blue (blue colour). Standard protocols may call for examination of 100 fields of view. The identification of a single acid-fast bacillus is diagnostic of infection. Despite the identification of only one acid-fast bacillus, to obtain smear positivity, high bacterial numbers are required (with ~104 organisms/ml). Hence care must be taken with the reporting of negative results, it should be stated that NO acid-fast bacilli were observed on microscopy. Also note that all mycobacteria are acid-fast bacilli, not just M. tuberculosis complex, as other bacilli, such as nocardia are also weakly acid-fast. Fluorescent staining involves the use of mycobacterial antibodies that have fluorescent proteins attached. This type of stain is much more efficient and more sensitive to identify organisms than conventional acid-fast staining. This includes auramine-rhodamine or auramine-o stains, and fluorochrome smears with a fluorescent microscope (expensive) are needed. Mycobacterial cultures and sensitivity: A sample must be cultured to properly identify the organism and also to obtain antibiotic sensitivity results. This involves the use of either a solid media or liquid media. With solid media, commonly Lowenstein-Jensen medium is used and growth occurs in 2-6 weeks. An additional 2-6 weeks afterwards is needed for species identification. With liquid media, the BACTEC radiometric system allows faster, more rapid detection of ~2 weeks. With solid cultures, malachite green is added to inhibit growth of other organisms yet assists in isolation of mycobacterial species. M. tuberculosis is grown on a capped bottle and not on an agar plate as there is a risk of infection via the air, aerosol spread to prevent infection spread. Also it allows aerobic growths of culture media or contamination. Molecular methods: Polymerase chain reaction (PCR) amplification of mycobacterial DNA is performed using patient tissue samples, sputum or cultures. PCR then involves 1) denaturing of DNA, 2) primer annealing to relevant DNA sequence sites, then 3) amplification of DNA sequences and extension. Then the amplified DNA is separated using gel electrophoresis with ethidium bromide gel and staining to identify electrophoretic bands that correspond to M. tuberculosis DNA sequences. Nucleic acid probes may also be used, which involves hybridisation using specific mycobacterial DNA probes, similar to fluorescent in-situ hybridisation. Sputum should be obtained if the patient is competent, otherwise use nebulised hypertonic saline to obtain induced sputum, or seek physiotherapy aid, or can investigate bronchoalveolar lavage samples. A Mantoux test, also referred to as the tuberculin test or purified protein derivative (PPD) test can be used. PPD is a crude extract of M. tuberculosis antigens. In the Mantoux test there is intradermal injection of PPD. As tuberculosis results in a delayed-type (IV) hypersensitivity reaction, hence measurement of the size of induration occurs 48-72 hours later, to determine if a delayed-type hypersensitivity response has been elicited, as it stimulates specific CD4+ TH1 cells. A positive test signals previous TB organism or M. avium complex exposure, latent disease or BCG vaccination, not necessarily an active TB case. Exposure to mycobacterium species other than M. tuberculosis can be (weakly) skin positive. Note that it takes ~4 weeks to convert to test positive, so Mantoux test may be negative with a recent infection. Also false negatives can occur in immunocompromised patients with TB infection, or those with active disease with peripheral anergy. With the Mantoux test, if the subject has circulating mycobacteria-specific memory T-cells, these cells are activated at the site of intradermal injection and release cytokines, including interferon-. The cytokines attract and activate macrophages. The resulting inflammation is slow in onset and persists for several days (delayed). Mantoux tests are assessed 48-72 hours after injection, when the reactions peak and other types of hypersensitivity have subsided. Events that occur with the Mantoux test include increased adhesiveness of the local endothelium (within 12 hours after injection) and then influx of leukocytes into the skin. There is then activation of specific T-cells by local dendritic cells or infiltrating macrophages. This leads to release of factors including IFN- by T-cells. There is then a further influx and activation of macrophages (peaking at 48 hours). Interferon- release assays: such as the QuantiFERON TB Gold are also useful diagnostic tests. Whole blood is incubated with TB antigens (synthetic recombinant TB peptides including ESAT-6, PPD and CFP-10). Dendritic cells or macrophages in the blood activate specific T-cells and this leads to release of IFN- ~24 hours later. The plasma is then separated and collected and the amount of released IFN- is later measured by ELISA; the presence of IFN- is indicative of latent and active disease. This is a useful test compared to Mantoux, as it eliminates false-positive results by non-tuberculous mycobacterial infections and cross-reactivity to previous BCG vaccination. Similarities of the Mantoux and IFN- release assays includes that they both assess for whether antigen-specific memory T-cells are present. Therefore the tests are useful to assess whether the patient has latent TB infection,

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but they do not distinguish between latent and active TB infection. They may also be negative in advanced TB or in immunocompromised patients (for example, patients with HIV and TB). The advantages of Mantoux over IFN- release assays is that Mantoux is inexpensive and there is no need for a sophisticated laboratory for investigation. Advantages of IFN- release assays includes that it is much more specific for M. tuberculosis; IFN- release assays are negative after BCG vaccination and in most other mycobacterial infections, whereas Mantoux may be positive. IFN- release assays are probably more sensitive than Mantoux, especially in the immunocompromised and it does not require the patient to be injected or to return for assessment Chest x-ray: Some important features to note include a calcified/fibrotic Gohn complex: check hilar/paratracheal lymphadenopathy with a calcified focus in the lung periphery. Atelectasis secondary to lymphadenopathy may be found in children. Fibrocaseous cavitating lesion in the apical region is found in post-primary tuberculosis. If a patient has no respiratory symptoms, a normal chest x-ray almost excludes pulmonary tuberculosis. Chest x-rays are valuable for detecting pulmonary lesions of tuberculosis, however, activity of disease cannot be judged with certainty. Classic upper-zone changes can be due to other pathology, and pulmonary tuberculosis can have many other non-classic presentations with broad differential diagnoses. Unusual chest x-ray appearances (including normal chest x-ray) are more common in people with immune deficiencies and other comorbidities. Once pulmonary TB is suspected, the most appropriate initial investigation is sputum analysis and not further imaging, even if chest x-ray shows fibrosis which appears to be radiologically inactive. Investigations for post-primary (secondary) TB: Lymph nodes: Fine needle aspirate and/or biopsy. Biopsy obviously more sensitive Pleural: Thoracentesis: microscopy, culture, sensitivities, acid-fast stain and check appearance, protein, glucose concentration, LDH, white blood cells. Also obtain a pleural biopsy Upper airways: Sputum acid-fast stain, laryngoscopy and biopsy Genitourinary: IV pyelogram, abdominal CT/MRI may show deformities, obstructions, calcifications and ureteral strictures. Culture 3 morning specimens of urine. Skeletal: Obtain a synovial aspirate, microscopy, culture and sensitivities, acid-fast stain, check appearance, protein, glucose concentration, white blood cells. Relevant imaging (x-rays, CT/MRI, bone scans). Rarely arthroscopy and synovial biopsy. Meningitis/tuberculoma: LP microscopy, culture and sensitivities, acid-fast stains and appearance, protein, glucose concentration, white blood cell count; PCR. CT/MRI may show hydrocephalus or spaceoccupying lesions. Gastrointestinal: Paracentesis, microscopy, culture, sensitivities, acid-fast stain and appearance, protein, glucose concentration, white cell count and peritoneal biopsies with laparoscopy. Biopsy as part of surgery, endoscopy; anal fistula, inflammation and ulceration. Pericardial: Pericardiocentesis, microscopy, culture and sensitivities, acid-fast stain, appearance, protein, glucose concentration, white cell count. Miliary: Chest x-ray, sputum and bronchoalveolar lavage. Haematology: anaemia with leukopenia, lymphopenia, neutrophilic leukocytosis and polycythemia, DIC. Blood culture for mycobacteria. LFT abnormalities: liver and bone marrow biopsies may be needed. CD4+ T-cell count. Other: chorioretinitis, uveitis, otitis (congenital), investigate as required. ENT/ophthalmology referral. Key factors in Tuberculosis management Requires at least 6 months of treatment, the first- line drugs used include isoniazid, rifampin/rifampicin, pyrazinamide, ethambutol and occasionally streptomycin. The second-line of drugs are less effective and have more toxic/side-effects. Also non-compliance is a major problem with TB prevention/treatment. WHO advocates the DOTS programme; which is Directly Observed Therapy Short Course; to ensure a full course is taken by the patient and to avoid relapse and discourage emergence of drug-resistance. Prevention: vaccination? The BCG vaccine was developed from M. bovis, when administered it enters macrophages, elicits a response and is killed. It is a safe and cheap vaccine but is it effective? This is controversial, as it has a wide range of efficacy, 0-80%; it does not prevent reactivation of pre-existing infections. Patients become Mantoux skin test positive, hence BCG vaccines are not routinely used in USA and Australia (since 1950s).

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 Multi-drug resistant TB (MDR-TB) is resistant to at least isoniazid and rifampicin. Extensively drug resistant TB (XDR-TB) is MDR-TB that is resistant to quinolones and also to any one of kanamycin, capreomycin or amikacin. XDR-TB is almost untreatable and a serious public health threat. There was an outbreak in South Africa in 2006 with 53 cases of XDR-TB. The average time to death was 16 days after sputum sample was taken and all cases were HIV positive. HIV and TB: HIV infection is a potent risk factor for TB, not only does HIV increase risk of reactivating latent TB, it also increases risks of rapid TB progression soon after infection or re-infection with M. tuberculosis. In persons infected with M. tuberculosis only, lifetime risk of developing TB ranges from 10-20%. In persons coinfected with HIV and M. tuberculosis, however, the annual risk can exceed >10%, i.e. 10% risk/year. The TB burden in countries with a generalised HIV epidemic has therefore increased rapidly over the past decade, especially in severely affected regions of Eastern and Southern Africa. TB is one of the most common causes of morbidity ad most common cause of death in HIV-positive adults living in less-developed countries. Also in HIV patients, M. Avium Complex (MAC) can occur, which is similar to M. tuberculosis in many ways, but resistant to conventional drugs used to treat TB. There is a large link between poverty, overcrowding, poor health services and other social/cultural factors that affect rates in countries; as well as factors such as migration, air travel, access to treatment, preventative public health measures, vaccination rate, compliance to treatment (DOTS), patients follow-up, housing, employment and education, environmental factors etc. Treatment of Tuberculosis: TB was regarded as a treatable disease from the 1960s after introduction of rifampicin and ethambutol. However, there was a TB re-emergence in the late 1980s, with increased virulent strains, multi-drug resistant strains are now common. Primary TB is mostly asymptomatic, and may be similar to a respiratory tract infection. TB disease is associated with: persistent cough, haemoptysis, lethargy/fatigue & malaise, anorexia and weight loss, low grade fever and night sweats. Mycobacterial cell walls are impenetrable to antibacterial agents due to presence of a waxy coat. Also as some mycobacteria reside within macrophages, this aids in protection of the organism from anti-bacterial agents. These organisms easily develop resistance against single antibiotic agents. Thus effective therapy requires a prolonged course of multiple drugs with different mechanisms. Problems arising from combination therapy include: compliance, drug toxicity/side effects and drug interactions- particularly in patients who are also being treated for HIV at the same time. First-line therapy: Includes four drugs; isoniazid, rifampicin, ethambutol and pyrazinamide given for two months. In HIV patients there is substitution of rifampicin with rifambutin, which minimises drug interactions with HIV protease inhibitors and HIV non-nucleotide reverse transcriptase inhibitors. Then rifampicin and isoniazid are continued for another 3-6 months. This regimen has the greatest level of efficacy, with acceptable levels of toxicity. It is assuring to find that the majority of patients can be treated successfully with these drugs. Total treatment course for non-resistant TB is 6 months; but this is extended to 9 months in patients who are HIV infected or have meningitis. Therapy may depend on whether drug-resistance is found, second-line drugs may then be added. Principles of pharmacological therapy includes that successful treatment of any infection relies on the principle of selective toxicity: Ideally drugs would be toxic to the invading organism and not harmful to the hostselective toxicity, but in reality this is only relative. Hence generally, selective toxicity relies on some process that is essential to the organism but not the host. Common mechanisms of action of antibacterial agents include: inhibition of cell wall synthesis, cell wall permeability, protein synthesis, nucleotide synthesis, and also anti-metabolites which interfere with metabolic processes. Important pre-treatment screening includes checking baseline weight, liver & renal function tests, visual acuity and colour vision testing and recording, full blood examination, testing for HIV (after appropriate counselling), and contraceptive advise for fertile female patients. Isoniazid: the activity of this drug is limited to mycobacteria and it was discovered in 1945 and used in clinical practice later, it is a hydrazide of isonicotinic acid. Its mechanism of action is unclear, there is evidence of

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inhibition of cell wall constituents- a glycopeptide-like action. Isoniazid is special in acting as a bacteriostatic for resting bacteria and a bacteriocidal for growing bacteria. Allergic skin reactions can occur as well as hepatitis. Ethambutol: is a tuberculostatic drug that inhibits cell wall synthesis by inhibiting cell wall arabinosyl transferase of M. tuberculosis. Important adverse effects include optic neuritis causing visual disturbances, colour blindness and also peripheral neuropathy. Resistance occurs as a result of bacterial modification of target arabinosyl transferase, resulting from genetic mutations. Rifampicin: Is also known as rifampin the USA and its mechanism of action is that it inhibits bacterial DNA dependent RNA polymerase activity (present in prokaryotic cells only), which suppresses chain formation in RNA synthesis. It is active against most gram positive bacteria. It is absorbed well from the gut after oral administration, it has a wide distribution and it is excreted via the liver into bile. Adverse effects include: nausea, vomiting, diarrhoea; rash, fever, red tears & urine, drug interactions. Bacterial resistance occurs via modification of the antibiotic target, resulting from bacterial gene mutations. Pyrazinamide: Is a nicotinamide analogue; which affects fatty acid synthase; thus affecting mycobacterial cell wall synthesis and ATP synthesis. However, pyrazinamide is ineffective at neutral pH and kills bacteria in acidic conditions, thus it is effective against intracellular mycobacteria within macrophages. It is well absorbed in the gut, with wide distribution. Adverse effects include: liver damage (with high doses), gout and GI upsets. The mechanism of action of the main first-line drugs for tuberculosis are shown below:

Streptomycin: was the first available drug used for TB (used rarely now). It is bactericidal in-vitro, but bacteriostatic in-vivo. Its mechanism of action is that it inhibits protein synthesis by binding to the ribosomal 30S subunit (it is an aminoglycoside). It is poorly absorbed in the gut and hence needs to be administered IV or IM and has renal excretion. Adverse effects include those of aminoglycosides: ototoxicity, tinnitus, vertigo and renal impairment. Resistance occurs via many different mechanisms including failure of permeation, reduced ribosomal affinity and drug interactions. Pharmacological prophylaxis: is usually with isoniazid, as this is specific for mycobacteria and is used in high risk groups only, including household exposure in family members of those infected, those with infection with evidence from a Mantoux test (10mm induration, or 5mm induration in immune suppressed or HIV infected) or in whom disease is latent/inactive.

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 Important public health issues include those of treat, trace, educate and notify. Public heath detention is only applicable to those who are not complaint with therapy. Screen people at high risk (e.g. from TB endemic areas) and liaise with national/international groups to improve surveillance and control. Summary of TB drugs: 1) Rifamipicin: inhibits DNA dependent RNA polymerase activity 2) Isoniazid: inhibits cell-wall synthesis 3) Pyrazinamide: impairs cell-wall and ATP synthesis, has activity in acidic pH (important for intracellular macrophage penetration) 4) Ethambutol: inhibits cell wall synthesis 5) No difference in treatment of pulmonary and extra-pulmonary disease 6) Precautions to adverse reactions, epilepsy (isoniazid), renal and hepatic impairment (all), pregnancy (rifampicin), diabetes (rifampicin), optic neuritis (ethambutol), gout (ethambutol), monitor changes in colour vision, check Snellen chart every 3 months (ethambutol). Some doses to remember:

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