FISHMANS MEDICINE

Chapter 1 Sudden Death

Sudden Death

Unconscious
Apnic
Without Blood Pressure
Unexpected

Non traumatic
Instantaneous
300,000 per year

Mechanisms
Smallest Percentage
Respiratory failure
Neurologic (subarachnoid hemorrhage)

Largest Percentages are:

Cardiovascular 4 mechanisms
1. Arrhythmias
a. Mostly Ventricular tachycardia evolving to ventricular fibrillation
b. Bradycardias
i. Sinus e- discharge at sinus node < 60BPM
ii. Junctional
c. Ideoventricular Rhythm
i. An independent cardiac rhythm caused by a repeated
discharge, <100BPM usually between 20-40 BPM, from a
focus within the ventricles
d. Arteriosclerosis
i. 90% of Sudden Death victims have arteriosclerosis of 2 or
more cardiac arteries
e. Prior Infarct in 66%
f. New infarcts are rarely involved in Sudden Death
g. Myocarditis & cardiomyopathies, abnormal conduction systems, some
drugs, electrolyte imbalance, structural abnormalities & inherited
disorders all predispose to Arrhythmic Sudden Death
2. Anatomic Catastrophes
a. Rarely occurs
b. Most common are:
i. Ruptured Ventricle
ii. Ruptured Aorta

iii. Aortic Dissection

iv. Massive Pulmonary Embolism
3. Electromagnetic Dissociation Presence of electrocardiographic activity with
out a detectable blood pressure
a. Can occur with
i. Global myocardial Ischemia
ii. Infarct
b. May be secondary to mechanical obstruction
i. Pericardial Tamponade
ii. Tension pneumothorax Interplueral air from lungs that cant
escape from the pleural linings.
iii. Cardiac rupture
iv. Papillary muscle rupture
v. Aortic Stenosis (critical) Stricture of aortic valve decreasing
cardiac output increasing peripheral vascular congestion
vi. Pulmonary embolus
4. Vasopressor Death
a. Inappropriate reflex decrease of HR, contractility & peripheral vascular
tone
b. Results in precipitous hypotension
c. Triggered by receptors in Coronary Sinus (venous channel in coronary
sulcus that drains 5 veins) and base of heart
d. May be involved in deaths from a hypersensitive carotid sinus baroreflex
or pulmonary thromboembolism

Epidemiology
90% of sudden death associated with coronary artery disease
30% new MI
50% acutely ruptured plaque

Most have history of MI or angina

Many have had chest pain/dypsnea 1 month prior
Risk factors
Hypertension
Smoking
Diabetes Mellitus
Hypercholesterolemia

Younger persons with congenital heart disease

Hypertrophic cardiomyopathy
Small or anomalous coronary arteries
Congenital aortic stenosis

Heritable disorders
Long QT syndrome inherited prolonged QT interval associated with ventricular
tachycardia, cardiac arrhythmias, syncope & sudden death
Mutations in Seven Genes
Encode Ion channels

No Disease
Drugs
Cocaine & ephedrine
Severe psychological or emotional stresses

Prevention
Many present with vague, ill defined symptoms shortly before death
Long term outlook is grim
CPR teaching with sophisticated ambulance teams Resuscitation ~ 40%
Identification of Risk Groups
Young healthy athletes with structural lesions or family history of sudden death

Beta blockers for all s/p MI unless contraindication

Patient resuscitated out of hospital from Heart Attack not precipitated by MI
Resultant from
Heat block
Supraventricular
Bradycardia
arrhythmias
Rapid atrial fibrillation
Patient with conductive bypass tracts
Wolf-Parkinson-White Dual paths of conduction short cut to ventricle
Prolonged QT

24hr ECG may reveal problems, but cant be used to effectively select
antiarrhythmic routine
Better is intracardiac Electrophysiologic (EP) studies
Heart put through programmed rhythms
Arrhythmias identified
Different meds tested to see if arrhythmias are stopped
Invasive
Expensive

Screen for structural heart disease

Stress testing with ECG
Ventricular ectopy alone does not warrant treatment

Symptoms of Ectopy
Palpations, dizziness, syncope
No evidence on routine ECG

Monitor as outpatients

Documented ventricular tachycardia therapy

EP guided antiarrhythmics
Empiric use of Amioderone
Implantation of Automatic Implantable Cardioverter Defibrilator (AICD)

AICD increases survival in

Previous MI
Impaired Left ventriculoar
functioin

Non-sustained ventricular
tachycardia
Inducible ventricular tachycardia
at EP studies

Multicenter Automatic Defibrillator Implantation Trial (MADIT) and

Multicenter Unsustained Tachycardia Trail (MUSTT)
Overall mortality decreased 50% with AICDs

Coronary Artery bypass graft (CABG) Patch trial

Implantation of AICD at time of bypass sx
Patient with abnormal signal-averaged ECG
Reduced antiarrhythmic deaths 45%
No significance in overall mortality

MADIT II stopped
30% decrease in mortality with AICD
No arrhythimic criteria
Included patients with post MI with left vientricular impaiment

Vasopressor syncope
Head up testing
Head up tilt ~60 Degrees precipitates symptomatic hypotension or syncope

CPR
CPR is victims best chance
Every minute lost equates to a 7-10% decrease in survival rate
Airway cleared
Head extended
Mouth to mouth
If AED available, use immediately
If no AED
Brisk chest thump may defibrillate ventricular fibrillation
Try only once
80-100 compressions per minute
At no time other than AED should CPR stop

Arrival at ED
1.
2.
3.
4.
5.

Immediate attempt at cardioversion

Intubate & ventilate with O2 supplemented air
Central Line
Electrical conversion, Lidocaine, Procainamide, Bretylium
EP & more electroconversion

Treatment of Bradycardia, heart block & asystole

Atropine Blocks vagal parasympathetics
Causes tachycardia
Isoproterenol & epinephrine
Stimulate beta adrenergic receptors
Powerful Inotropic & Chronotropic
Beta blockers relax smooth muscle, decreasing peripheral resistance
Should not be used as sole agents to reverse hypotension

Persistent hypotension with sufficient pulse rate

Norepinephrine
Alpha stimulator
Vasoconstriction
Dopamine
Stimulates Alpha & Beta receptors
Low dose stimulates cardiac contractility with less vasoconstriction than
norepinephrine
Helps protect sensitive vascular beds like kidneys

Severe Acidosis
Sodium Bicarb to treat
Dose according to arterial Ph & pCO2
Signs & Symptoms
Headache
Dypsnea
Fine Tremors
Tachycardia
Hypertension
Vasodilitation
May result in if overdose:
Respiratory acidosis
Increased pCO2
Excess carbonic acid
Increase plasma H+ concentrations
Caused by
Decreased alveolar ventilation or suppression of respiratory
reflexes
Increases CO2 combines with water forming carbonic acid that
leads to a decrease in blood pH
5

Hypernatremia
Hyperosmolarity
Electromechanical dissociation (No pressure in presence of electrical
activity)
Treatable causes should be sought
Pericardial tamponade
Tension Pneumothorax
Massive pulmonary emboli
Last ditch pacemaker inserted
Rarely works if already eclectically unexcitablea

Mortality & Prognosis

Due to rapid response
1 in 3 resuscitated
1/3 of these will die with in 2 years

Long-term Prognosis of arrhythmia unrelated to MI is worst

die in 2 years
EP testing may be of help

Chapter 2 Coronary Artery Disease (incomplete)

Angina Pectoris
Distinct variety of heart pain
Myocardium is starved of O2 & nutrients
Inadequate coronary circulation
Most common cause is progressive narrowing of coronary arteries by
atherosclerotic plaques

Lesions are composed of

Intimal foam cells (Macrophages)
Disorganized medial cells
Surrounded by interstitium filled with cholesterol

Symptoms dont occur until >75% of lumina is occluded

Reduced blood flow can lead to
Akinetic (non-contractile)
Dyskinetic (Bulges when the rest of the heart contracts)
Alteration of ST segment & T waves
Abnormalities of cell membrane pumps
Altered ionic permeability
Increase of lactate leaving the heart from anaerobic metabolism

Frequency & Intensity

Do not indicate severity of Coronary Artery Disease (CAD)

Degree of vascular obstruction correlates closely to risk of death

Coronary Vasculature
3 Major Arteries
Right Coronary Artery (RCA)
Left Anterior Descending Artery (LAD)
Left Circumflex Artery (LCx)
In General Left system supplies the Anterior
& lateral of the left ventric

Two coronary ostia

Located just above aortic valve
1 to RCA
90% of people this supplies blood to the AV node as well as posterior &
inferior regions of left ventricle
1 to Left main Coronary Artery
Divides into
LAD & LCx (10% LCx supplies AV node and posterior of left ventricle)

In General Left system supplies the Anterior & lateral of the left
ventricle the Right system supplies the Right ventricle, AV node &
inferior & posterior walls of the left ventricle.

Diagnosis & Clinical Manifestations

Often clear from the characteristic symptoms & physical findings
Confirmed by
ECG changes during episodes of pain
TNG ameliorates pain

Atypical land ECG nonspecific pain does not rule out CAD
Exercise tests
Radionucleotide scans
Angiography
These tests do not correlate pain to angina, but only if the person has CAD

Signs & Symptoms

Squeezing
Pressure
Levine Sign Clenched fist over heart
Relieved by TNG

Risk factors
Smoking
Family hx of premature atherosclerosis
Hypertension
Diabetes
Hypercholesterolemia
Low in women until menopause

During Angina
Reflex hemodynamic changes
Hypertension
Tachycardia

Ischemia of Left Ventricle

S4 Gallop may occur
Abnormal S2 splitting may occur
ECG may reveal
ST depression
T-wave inversion

With out Angina

Physical exam usually normal
Ischemic episodes may occur without pain

Differential Diagnosis
1. Hyperventilation Syndrome
a. Sharp Chest Pain
b. Tingling fingers
c. Lightheadedness
d. T-wave inversion on ECG is common
2. Tietzes Syndrome
a. Arthritis of chest wall
b. Pain can be reproduced by pressure over offending joint
c. Relieved by aspirin or other anti-inflammatory agent
3. Reflux esophagitis
a. When laying flat
b. Esophageal spasm may cause pain after meal
c. Sometimes relieved by TNG
4. Aortic Dissection
a. Aortic intima tear
b. Ripping pain can be projected to back & abdomen
c. Dissection may occlude vessels or cause aortic insufficiency
d. Chest x-ray may reveal widened aortic shadow
Other conditions that may cause chest pain are
Diseases of the lung like pulmonary embolism
Abdominal issues peptic ulcer, choleocystitis (may have inverted T-waves) etc
Diagnostic Tests

Chapter 3 Cardiac Catheterization and Hemodynamic

Measurement
Introduced by Werner Forssman 1929 Tied assistant down
Applications of
Catheterization of the right heart chambers and pulmonary circulation is
performed routinely in many ICU to monitor cardiac function
Catheterization of the left ventricle & coronary arteries is performed in special
labs prior to cardiac Sx & Coronary angioplasty

Right Sided Heart Catheterization

A pulmonary arterial (Swan-Ganz) catheter can be introduced into any large peripheral
vein.
Maneuvered into
Venae Cavae
Right Atrium
Right Ventricle
Pulmonary Artery
Pressures measured during insertion or removal of the catheter:
Pulmonary artery
Right Ventricle
Right atrium
Pulmonary Capillary Wedge Pressure (PCWP)
Balloon floated from R ventricle to wedge in small pulmonary artery
Measures left atrial pressure indirectly Once a pulmonary artery is
occluded, the distal of the balloon measures the pressure of the left atrium.
High PCWP = Cardiogenic Pulmonary edema
Low PCWP = hypovolemia

Indications for the Swan-Ganz

1. Resolution of any uncertainty about filling pressure of Left ventricle
especially hypotensive patients
a. Compromised Left Ventricle who require high filling pressure, but
close to pulmonary edema
b. Patients in shock
c. Large myocardial infarct
d. Patients with heart & lung disease to determine source of
pulmonary edema, i.e. the heart or the lungs.
2. To measure cardiac output
a. Cold water, dye or a solution injected
b. Predicts stroke volume, and cardiac output (SV for 1 minute)
c. Cardiac Index
i. Cardiac output divided by body surface area

10

ii. Normal is 2.5-4.2 L/min/m2

iii. Less than 1.8 implies cardiogenic shock
3. Measure pressures in the right ventricles
a. Evaluate severity of pulmonary hypertension
b. Pericardial disease can be evaluated by pressure contour from right
ventricle
4. To evaluate left-to-right shunts
a. Measure O2 sats from different areas of the heart
b. Right atria & ventricle usually the same

Complications
Not unusual
Balloon tip stuck in wedge pulmonary infarct
Pulmonary artery perforation by tip
Life threatening hemorrhage
Hemoptysis
Kinking
Local infection
Thrombosis
Ventricular ectopy or right bundle branch block as catheter passes through right
ventricle

Left-Sided Heart Catheterization

Brachial or Femoral Artery
Pressure measurements
Injection of dye
Prep for CABG & PTCA dye into coronary arteries

Indications
1. Diagnostic Coronary Angiography
a. Assess degree of blockages
b. Determine health of CABG
2. Left Ventriculography
a. Dye in left ventricle
i. Cineangiography analyses wall motion & abnormalities
ii. Calculated ejection fraction
iii. Reveals presence of
1. aneurysms
2. Intracardiac masses
3. Thrombi
4. Mitral regurgitation
b. Dye in Aortic Root
i. Regurgitiation
ii. Aortic aneurism
iii. Aortic dissection
3. To measure pressures

11

a. Important in
i. Mitral stenosis
ii. Aortic stenosis
4. Perform Therapeutic Percutaneous Coronary interventions
a. PTCA (Percutaneous Transluminal Coronary Angioplasty)
b. Stent placement
c. Valvuloplasty (usually mitral valve)
d. Repair of congenital defect
e. Atrial septal defects

Complications
Vascular damage at insertion site
Arterial thromboembolism
Dye anaphylaxis
Myocardial infarction
Stroke
Death
Complications should not exceed 1%
Transient hypotension or arrhythmias commonly result
Dye may cause intravascular expansion & pulmonary edema
Contrast induced renal failure
Important to monitor urine output of dye

Peripheral Arterial and Central Venous Catheterizations

Radial artery
Continuous monitoring of arterial blood pressure
Access for ABGs
Preferable to repeated arterial punctures
Complications are rare, but include
Exsanguination
Local vasospasm
Thrombosis with ischemia
Pain
Distal tissue necrosis
External Jugular Vein
Referred to as Central Venous Line or Central Line
Stable access for IV infusion
Patients that depend on constant infusion
Meds that are to irritating e.g. catecholamines
Can not determine left ventricular function
Complications are
Pneumothorax
Hemorrhage
Venous thrombosis

12

Chapter 4 Valvular Heart Disease

The most important consideration is timing of surgery
Not every patient with valvular disease requires surgery, but if an opportunity
presents, it should be taken.
Normal valve is diaphanous & wispy.
Two forms of Valvular Disease.
1. Incompetent or regurgitant valves
a. Ruptured chordae tendonae
b. Valve ring loosened by dissecting blood or pus
c. Torn or distorted
2. Stenotic valves
a. Scaring or Congenital

Evaluation of Valvular Heart Disease

Initial evaluation involves five essential areas
1. History
a. Prior rheumatic heart disease
b. Heart failure
c. Endocarditis angina syncope
2. Physical Examination
a. Careful auscultation for clicks or murmurs
b. Palpate precordium for atrial or ventricular hypertrophy
c. Inspect neck veins for distention
d. Right atrial pressure
e. Detect abnormalities of wave form suggestive of tricuspid regurgitation
3. Chest X-Ray
a. Look for chamber enlargement
b. Valve calcification
c. Pulmonary edema
4. Electrocardiogram (ECG)
a. Evaluated for evidence of chamber hypertrophy & arrhythmias
b. Echocardiography
c. Non-invasive visualization of heart & valves
5. Echocardiography
a. Transthoracic echocardiography is non-invasive & painless
b. Imaging of
i. Structures of the heart
ii. Valves
iii. Evaluate blood flow
2-D echocardiography gives real-time view
Quantified flow by Doppler ultrasonography
Transesophageal Echocardiography (TEE)
Minimally invasive
Probe advanced down esophagus
13

Greater sensitivity for

Atrial thrombi
Valvular vegetations
Prosthetic valve dysfunction
Itraoperative use to guide cardiac surgery

Normal Cardiac Cycle

Onset of left ventricular systole
Left ventricle contracts
Pressures in the ventricular chamber rise
Mitral valve closes
Produces the first heart sound
S1
When left ventricular pressure exceeds Aortic pressure
Aortic valve opens
Left Ventricle & aorta have equal pressures during ventricular emptying
When aortic pressure exceeds ventricular pressure
Valve shuts
Produces S2
Two components to S2 sound
Aortic valve closure (A2)
Pulmonic valve closure (P2)
During inspiration, A2 & P2 move slightly apart (normal splitting)
Result of increased venous return to right ventricle and delayed closure of
pulmonic valve
When declining left ventricular pressure drops below the pressure in the left
atrium, the mitral valve opens & the left atrium & ventricle have equal pressure

Heart Murmurs
Character, location, intensity & direction of radiation may be clues to the severity
During systole,
Aortic & pulmonary valves are open
Mitral & tricuspid valves are closed
Systolic murmurs
Result from stenosis of aortic or pulmonic valves
Incompetence of mitral or tricuspid valves
During Diastole
Aortic & pulmonic valves are closed
Mitral & tricuspid valves are open
Diastolic murmurs suggest incompetence of aortic or pulmonic valves
Stenosis of the mitral & tricuspid valves
Murmurs usually radiate along the direction of the jet underlying them
i.e. mitral regurgitation radiates towards axilla
Aortic stenosis radiates towards neck

14

Mitral Stenosis
Hemodynamic Consequences and Natural History
Rheumatic Heart disease accounts for most cases
Lesion runs a leisurely course
Initial symptoms delayed 15-20yrs
Narrowing of mitral orifice
Pressure in Left Atrium Rise
Needed to maintain flow from Left Atrium to Left Ventricle
Left atrium enlarges
Pulmonary venous & pulmonary capillary pressures rise (Sometimes with
pulmonary edema)
Early in course of mitral stenosis
Shortness of breath
Only during strenuous exercise
Later in course
Symptoms even at rest
Laying flat makes worse
7 years from onset to complete incapacity
Advanced mitral stenosis
Two mitral cusps become adherent at the lateral borders
From 4-6 down to 1cm2
Surrounded by calcium deposits
When left atrial pressures rise to ~25mmHg
Pulmonary edema
Dypsnea
Orthopnea
May become high enough to cause right ventricular failure
May appear to be a grace period
Pulmonary edema cease (Right ventricle cant overload left side)
Tricuspid regurgitation may appear
Damage may be too great for surgical intervention to benefit
Oddities
10-15% of patients with mitral stenosis follow different course
Initial stages
Pulmonary vasculature constricts early
Consequent cor pulmonale
Right ventricular failure
Less pulmonary edema
Symptoms & Complications of Mitral Stenosis include:
1. Dyspnea, orthopnea & attacks of frank pulmonary edema
a. Often induced by
i. Exercise
ii. Pregnancy
b. Uncontrolled atrial fibrillation
c. Tachycardia is poorly tolerated

15

i. Reduces the time available for the left atrium to empty (i.e.,
diastolic filling time)
2. Hemoptysis can occur in a variety of forms
a. Pulmonary apoplexy
i. Frank blood is suddenly expectorated
ii. Rupture of bronchial veins
b. Pink frothy sputum
i. Pulmonary edema
c. Blood-tinged sputum
i. Infectious bronchitis
ii. Pneumonia
iii. Upper & lower pulmonary infections
3. Fatigue
a. Prominent symptom in later stages
b. Reflects low-output state
4. Systemic & pulmonary embolization
a. Common
i. Atrial fibrillation patients
Course of Mitral stenosis may be interrupted with bouts of pulmonary edema
Patients who become pregnant
Suffer bronchitis
Atrial fibrillation
Initially sporatic
Advances to chronic
Contributes to pulmonary or systemic embolization
Early death may occur
Pulmonary edema or emboli
Patient endures progressive increments in left atrial & pulmonary arterial
pressures
Symptoms of right ventricular failure become apparent

Physical findings
Mitral facies
Malar flush
Cyanosis of lips
Diastolic murmur of mitral stenosis has several characteristics
1. S1 is accentuated
a. Valve is wide open at onset of ventricular contraction
i. Result of elevated left atrial pressure
b. Snaps shut over wider excursion than normal
c. May be the only ausculatory clue to early mitral
2. Opening snap of stenosed mitral valve
a. Early in diastole
b. Short high-pitched sound following S2
c. Distinguish from
i. Widely split S2 from respirations

16

ii. Loud S3
d. Interval between S2 and opening snap
i. Reflects abnormal pressure gradient across valve
e. As stenosis worsens
i. Atrial pressure rises
ii. Valve opens progressively earlier in diastole
iii. Opening snap moves closer to S2
3. Mid diastolic rumble
a. Result of turbulent flow across valve
b. Low pitched
c. Localized to cardiac apex
d. Best detected using the bell
e. Patient in left lateral decubitus
4. In many patients presystolic accentuation of murmur immediately precedes S1
a. Produced by augmentation of flow during left atrial contraction
b. Usually lost when fibrillation develops

Diagnostic tests
Chest X-Ray
May show large left atrium
Straightening of left-sided heart border
Widening of carinal angle
Displacement of the esophagus on lateral view
May be evidence of pulmonary edema
Late in the disease
Right ventricular enlargement
ECG
Large biphasic P wave
Suggestive of left atrial enlargement
Does not show if atrial fibrillation is present
2-D echocardiography
Stenotic valve can be directly visualized
Tracing to determine area of opening
Reveals degree of calcification
Thickness of valve leaflets
Involvement of subvalvular apparatus
Doppler
Estimates valve area based on blood flow

Therapy
All Mitral Stenosis
Anticoagulants to prevent embolism
Atrial fibrillation control
Digoxin
-blockers or CCBs
Diuretics PRN

17

Relief of dypsnea
Relief of right sided heart failure symptoms
AB prophylaxis for SBE
Surgical intervention
After onset of symptoms before pulmonary hypertension supervenes
Cardiac catheterization
Common intervention
Stenotic Valve Split
Young patient
Noncalcified valve
Without regurgitation
Vavlular replacement is indication majority of time
Operative mortality rate is ~ 5-10%
Higher if Right ventricular failure has developed
Tissue valves
Less risk of thromboembolism
Replaced 7-10yrs s/p
Percutaneous balloon mitral valvuloplasty
Viable alternative to sx commissurotomy
Balloon inflated to mechanically disrupt fused leaflets
Marked improvement in degree of stenosis
Increased functional capacity
Echocardiography is useful for selection
Patients who are good candidates
Thin valve leaflets
Preserved valve leaflet mobility
Less calcification Minimal involvement of the subvalvular
apparatus
May make co-existing mitral regurgitation worse

Mitral Regurgitation
Hemodynamic Consequences & Natural History
Multiple pathologies can cause
Rheumatic mitral valve disease
Papillary muscle dysfunction
Infarct at base of muscle
Distortion of ventricular anatomy
Prevents adequate closure of valve
Endocarditis
Destroys the valve or supporting chordae
Massive calcification of the mitral annulus (rare & unknown reason)
Process of Mitral regurgitation
Left ventricle ejects blood back into left atrium during systole
Left ventricle adapts well to increased volume burden
End-diastolic pressure does not rise until late stages of illness

18

Lower pressures result in less incidence of

Pulmonary edema
Hemoptysis
Systemic embolization
Left Ventricular failure eventually occurs
Low cardiac output
Exhaustion
Exercise intolerance
Can predominate over other symptoms of pulmonary congestion
Acute Mitral Regurgitation
Hemodynamic compensation is not present
Catastrophic
Accompanied by shock & acute pulmonary edema
Surgical intervention may save pt
Caused by
Papillary muscle rupture
Myocardial infarction
Chordae rupture in patients with chronic rheumatic mitral disease
With or without superimposed endocarditis

Physical Findings
Murmur
Holosystolic Murmur
Heard at cardiac apex
Radiates typically posteriorly into axilla
Occasional radiation to base
Confused with aortic stenosis murmur
Accompanied by
Soft or absent S1
Loud S3 that may be followed by short diastolic rumble
Chamber enlargement
Often felt on palpation as a gentle rocking motion

Therapy
Evaluation
Serial assessments of left ventricular size & function
Rate control of atrial fibrillation
-blockers
Digoxin
CCB
Early symptoms treated with
Diuretics
After load reduction
ACE inhibitors
Catheterization with contrast
Needed eventually

19

Evaluate degree of mitral regurgitation

Determine extent of contribution
Disease of Valve
Disease of myocardial muscle
Disease of papillary muscle
Considerations for surgery
1. Patient has symptoms
2. Left ventricular ejection fraction worsens acutely
3. Left ventricular end-systolic dimension approaches 45mm
Goal of timings
Perform surgery before irreversible left or right ventricular failure occurs
Mitral valve may be repaired in some or replaced in others
Acute mitral regurgitation is an emergency
Intra aortic balloon pump if necessary
Urgent surgical correction

Mitral Valve Prolapse

The Click murmur syndrome
Mitral valve produces distinctive systolic murmur
One or more midsystolic clicks
Usually from redundant mitral leaflet tissue
Common syndrome
Up to 5% of adults
Commonly diagnosed in young women
Often asymptomatic
Over diagnosed recently
Potential complications
Endocarditis
Acute fulminant mitral regurgitation
Transient cerebral ischemia from valvular emboli
Ventricular and atrial arrhythmias
Sudden death
Antibiotics prophylaxis for SBE

Aortic Stenosis
Hemodynamic Consequences & Natural History
Three major causes
1. Age
a. Usually over 70
b. Systolic murmur frequently present
c. Calcification & stenosis may result
2. Rheumatic fever
a. Rarely sole involvement of Aortic valve
b. Usually combined with mitral and sometimes tricuspid valve

20

3. Congenitally bicuspid valve

a. Isolated aortic stenosis
b. Usually younger than 60 years old
c. Functions normal at birth
i. Becomes scarred
d. Symptoms onset ~ 4th or 5th decade
During normal systole
Aortic valve is open
Ventricular & aortic pressures are equal
During stenotic systole
Pressure gradient develops across valve
Asymptomatic with early stages of lesion
Critical lesion
Peak systolic gradient may exceed 50mmHg
Pressure in ventricle is 50mmHg>Aorta
Ventricle hypertrophy & myocardial O2 demand increases
End diastolic pressure rises
Loss of left ventricular compliance
When any one of a triad of symptoms occurs
Life expectancy with out surgery is less than 5 years
15-20% will die suddenly
1. Angina
a. Life expectancy ~ 5yrs
b. Reflects inability of coronary flow to meet requirements for hypertrophied
tissues
c. No concurrent atherosclerosis in about of the patients
d. Characteristic similar to CAD angina & responds to TNG
2. Syncope
a. Life expectancy ~ 3 years
b. Accompanies exertion
c. Origin unknown
3. Heart failure
a. Life expectancy ~2 years
b. Most ominous symptoms associated with left ventricular failure
i. Dypsnea on Exertion (DOE)
ii. Orthopnea

Physical findings
Murmur
Rough
Low pitched
Best heard at base of heart
Radiates to neck along carotids
Begins after S1 and peaks midsystole
Crescendo-decrescendo pattern
Impulse of the large left ventricle is

21

Displaced
Discrete
Sustained
Significant stenosis
Systolic thrill palpable at base
Corotid pulses feel weak
Impulses delayed
Non-Compliant ventricle
S4 gallop
As disease progresses
Aortic closure
Progressively delayed
Producing single S2 sound
A2-P2 splitting (paradoxical splitting)
Systolic pressures are not abnormally low
Qualities of murmurs do not correlate to severity of stenosis
Better guide to severity is
Quality of the carotid upstroke
Presence of systolic thrill
Delay of A2

Diagnostic findings
Obstruction of left ventricular outflow produces concentric thickening of ventricular wall
Radiograph appears normal
Left atrium may be enlarged
Non-compliant ventricle
Associated mitral valve disease
ECG findings of left ventricular hypertrophy
Increased QRS voltage
Secondary ST & T wave abnormalities
ST-segment depression
T-wave inversion
In lateral (I & avL)
Apical (V4-V6)
P waves may show evidence of left atrial enlargement
Left bundle branch block
Intraventricluar conduction defects
Echo Cardiogram
Thickened leaflets
Narrowed aortic orifice
Left Ventricular hypertrophy
Doppler Echo
Peak instantaneous gradient
May be different from catheterization values
Superimposition of peak instantaneous & catheterization values gives Peak to
Peak Gradient (difference between aortic & ventricular pressure)

22

Mean gradient is the difference between average ventricular & aortic pressure
during systole
Mean gradient more useful
Basis for management decisions
Once left ventricular dysfunction occurs
Gradient may drop paradoxically
Decompensated ventricular pressure cant sustain as much force
Valve area
Calculated from data derived from cardiac catheterization
Echocardiography
Significant stenosis 0.7cm2
Moderate stenosis 0.7-1.0 cm2
Mild stenosis 1 cm2 or more

Therapy
Complications of surgery & prosthetic valve are significant
Delay catheterization and sx until onset of symptoms
Before evidence of significant left ventricular failure
Exception to the rule
Asymptomatic young patient with significant stenosis
Sudden death may occur if sx is delayed
Catheterization
Determine pressure gradient
Degree of accompanying CAD
Ensure obstruction is valvular and not subvalvular or supravalvular
Medical Management
Diuretics for CHF
Salt restriction for CHF
TNG for angina
Valve replacement once significant stenosis is confirmed
Operative mortality rates
5% patients in good condition
30% patients in heart failure
Good prognosis even in elderly
Percutaneous aortic balloon valvuloplasty for poor sx candidates
Re-stenosis within 6 months
Temporizing procedure only
Unlike mitral valve, aortic valve cant be rx in patients who are sx candidates

Aortic Regurgitation
Hemodynamic Consequences & Natural History
Isolated Aortic regurgitation caused by many of the same disease as aortic stenosis
1/3 are rheumatic in origin
Syphilitic aortitis
Various disorders of the connective tissue

23

Ankylosing spondylitis
Myxomatous degeneration
Distortion of the root of the aortic valve
Marfans Syndrome
Hypertension
Major hemodynamic consequence
Volume overload of left ventricle
Compensates by dilation
Reflex peripheral vasodilation
Eventually left ventricular failure starts to occur
Angina may develop
Medical emergency
Acute aortic regurgitation
Endocarditis
Trauma
Rapid rise in ventricular end-diastolic pressure pulmonary edema and ventricle
may not maintain enough cardiac output

Physical Findings
Murmur
Decrescendo diastolic murmur
Occurring shortly after S2
Rheumatic Valvular disease
Best heard at left sternal border
Austin Flint murmur
May be mixed in with murmur of aortic regurgitation
Timing & quality resemble mitral stenosis
Probably derives from regurgitatant stream striking anterior leaflets of mitral
valve
Long standing aortic regurgitation
Reflexive vasodilation of peripheral arterioles
Widened pulse pressure
Dramatically reduced diastolic pressure
Distinctive pulse that rises & collapses rapidly
Pistol-shot sounds over large arteries
Capillary pulsations
Especially obvious in nailbeds
Called Quinckes Pulses
de Mussets sign
Uvula, head or even whole body to bounce
Duroziers sign
To-and-fro murmur
May be heard on compression of large arteries such as femoral
Cannot correlate signs to severity

24

Diagnostic Findings
Chest X-Ray
Boot-shaped elongation of left ventricle
ECG
May suggest left ventricular hypertrophy
Echo Cardiogram
Indirect evidence of aortic regurgitation
High-frequency stuttering of anterior leaflets of the mitral valve causing
premature closure of mitral valve
Color Doppler technique
Sensitive indication of aortic regurgitation

Therapy
Timing of surgery is critical
Considered when patients develop symptoms
Follow asymptomatic patients closely
Echocardiography
Frequent clinical exams
Surgical indications
Before left ventricle end-systolic dimensions reach 55mm
Left ventricular ejection fraction falls below 55%
Acute Aortic Regurgitation
Aortic dissection
Bacterial endocarditis
Urgent surgery
Medical Therapy
Afterload reducing vasodilators
ACE inhibitors
CCB Nifedipine & nitroprusside to temporize or non-surgical candidates

Rheumatic Fever
Generally disease of childhood & adolescence
Develops after a pharyngeal infection
Group A Streptococci
Reflects immunologic disorder triggered by infection
Immediate symptoms
Fever
Carditis
Migratory polyarthritis
Less common
Chorea neuro disorder of sudden & uncontrollable jerky movements with
emotional lability
Erythema marginatum
Evanescent serpiginous rash (WTF???) - a disappearing skin lesion with a wavy
or indented border.
Subcutaneous nodules found over extensor surfaces of bony prominences
25

Carditis affects the

Pericardium
Myocardium
Endocardium
ECG changes are common
May be a fulminant course leading to death from
Valvular insufficiency
Heart failure
Arrhythmias
More often silent
Damage presents later in life
Recurrent illness
Following acute attack
Monthly intramuscular injections of benzathine penicillin

26

Chapter 5

27

Chapter 6 Cardiac Arrhythmias

28

Chapter 7 Hypertension
Hypertension is associated with increased risk for
Angina
MI
CHF
Renal Failure
Hemorrhagic & thrombotic strokes
Blood Pressures:
Normal 120/80
HTN 140/90
Mild HTN DBP 90-104
Moderate HTN DBP 15-114
Severe DBP >115
JNC = Joint National Commission on Prevention, Detection, Evaluation &
Treatment of increased blood pressure
6th JNC doesnt use term mild or moderate
Labile HTN (BP that fluctuates repeatedly and rapidly) Transient increase in BP
with stress or excitement
Not known if it caries the same risk as sustained HTN or if it will progress to
sustained HTN
Successful Treatment regardless of HTN level all is possible
Decrease incidence & rate of recurrence of stroke
Diminishes Left ventricular hypertrophy
Decrease risk of CAD
Increase survival in patients with renal insufficiency
Decrease chance that patients with hypertension will develop Malignant
Hypertension

COMPLICATIONS
Elevated BP is not symptomatic by itself
No demonstrated correlation to symptoms i.e. headaches etc
Patients should understand treatment of HTN will not address specific complaints
Treatment is to prevent complications of long-term disease

Cardiac complications
Major risk factor in development of
CAD
Consequent Angina & MI
Sustained increase in mean arterial pressure leads to left ventricular hypertrophy
Concentric hypertrophy of left ventricular walls from HTN
Increase in voltage in precordial leads of ECG
Change in the ST & T wave consistent wit left ventricular strain
Echocardiogram shows hypertrophy better than the EKG
29

Evidence of left ventricular hypertrophy

Frequently detected during physical exam
ECG of untreated patients
Palpation may reveal unusually pronounced & prolonged apical impulses
Eventually
Left ventricular dilation & CHF may develop

Aortic Dissection
Serious, but rare complication of long standing HTN
The forward, pulsatile blood blow
Produces intimal tears
Blood dissects between the intima & media
Various distances
Two sites of particular vulnerability
Where Aorta is non-mobile
1. Ascending aorta above aortic valvular ring
2. Immediately distal to the left subclavian artery
Predisposition from
HTN
Marfans or other diseases that affect connective tissue
Clinical characterizations
Acute onset of severe tearing pain in anterior chest
Radiates to the interscapular region
Patients are often
Agitated (extremely)
Anxious
Chest X-Ray
Widening of superior mediastinum
Confirmation of Diagnosis
Contrast arteriography
Demonstrates false lumen
Or narrowing of true lumen
Transesophageal echocardiogram
MRI
Spiral Computed Tomography
Consequences
Potentially sever & fatal depending on location of tear
Three types of aortic dissection
Type I Aortic Dissection The most lethal
Patients younger than 65
Intimal tear in the ascending aorta
Dissection may extend distally to bifurcation
of patients dissection leads proximally
Produces acute regurgitation or hemopericardium
Disasterous if false lumen occludes ostea of major branches
Coronary

30

Carotid
Renal
Can lead to:
MI
Arrhythmias
Stroke
Messenteric Infarct
Acute Renal Failure
Cardiac Tamponade
Type II Aortic Dissection
Major factors
Disease of connective tissue Marfans
Ascending Aorta
Does not extend to origin of great vessels
Type III Aortic Dissection
Tears in descending aorta
Almost always elderly
With atherosclerosis
HTN
Sequelae from HYPOperfusion to vascular tree distal to Left subclavian
arteries
Therapy
Depends on site of tear
Type I & II
Surgical resection of involved portion
Medical therapy alone is dismal
Death results from
Compromise of critical vessels
Rupture of aorta into pericardium
Type III Amenable to medical treatment
Therapy directed to
Rapid reduction in BP
Nitroprusside
Ganglionic Block drugs (Trimethophan)
Reduction of rate of rise in systolic pressure
- Blockers
Surgery for patients with
End organ compromise
Unrelenting pain
Radiographic evidence of progression

Renal complications
Aging leads to:
Progressive thickening of intrarenal arteries
Hyalinization of glomeruli
May be accelerated by HTN

31

Called nephrosclerosis
Small shrunken kidneys & azotemia (Azotemia Def: Retention of
excessive amounts of nitrogenous compounds in the blood. The toxic
condition is caused by failure of the kidneys to remove urea from the
blood & is characteristic of uremia.
HTN is one of the leading causes of renal failure

CNS complications
Devastating affect on intracerebral vasculature
Transient ischemic attacks
Thrombotic strokes
Rupture of intracranial aneurysms
Hypertensive intracerebral hemorrhage
All the above can complicate course of moderate to severe HTN
More common end organ damage in CNS is
Retinophathy of HTN
Fundiscopically detectable vascular changes
Arteriovenous nicking
Hemorrhage
Exudates in a graded fashion

ETIOLOGY
Primary HTN
Origin of 95% HTN unknown
Multifactorial
Involves complex interplay between
Hemodynamic affects of the CNS
Autonomic Nervous System
Its circulating catecholamines
Volume of regulatory effects of Renin-Angiotensin-Aldosterone System
Hemodynamic measurements shows
BP can be increased by decreases in peripheral vascular resistance

Secondary HTN
Problem with one of the control systems (mentioned above)
Less than 5% of cases
Often curable
Most likely young (<25 YO) & elderly (>65YO)
Newly diagnosed HTN
Severe or accelerated HTN
HTN that is refractory with therapy
Only a few causes encountered with regularity
Renovascular disease
Renal parenchymal disease
Disease of adrenal cortex

32

Pheochromocytoma
Coarctation of aorta
Renovacular disease
Goldblatt 1934
Constriction of a single renal artery found to produce chronic hypertension
Renal hypoperfusion leads to an increase in renin release
Renin cleaves angiotensinogen into angiotensin I
Angiotensin I is cleaved again in the pulmonary circulation by ACE enzyme into
angiotensin II
Potent vasoconstrictor
Directly stimulates adrenal cortex to increase production of aldosterone (Na+
retention)
Renal Artery sclerosis is the most common cause of secondary hypertension
Does it through the renin-angiotensin-aldosterone system
Most common cause
Other causes include
Atherosclerotic narrowing (usually in elderly)
Fibromusclular disease of renal arterial wall (young women)
Localized aneurysms
Various space occupying lesions (i.e. cysts & tumors)
If secondary HTN is suspected
Screen for upper abdominal bruits
Best non-invasive test
Renal duplex ultrasound
Magnetic resonance angiography
Sensitivity to above tests is ~90-95%
More invasive tests
Measurement of plasma renin after captopril administration
Rapid sequence IV pyelogram
Sensitivities to only 70-80%
Not as commonly used
Radionuclide renal perfusioin scanning with hippurate (Reflecting renal blood
flow) or diethyl enetriaminepentaacetic acid (DTPA) (Glomerulous filtration)
Extremely sensitive
Stop ACE inhibitors prior
Captopril induced changes are predictive to good response to
revascularization
Renal Digital Subtraction Angiography
Definitive test to confirm or elimate diagnosis
Therapy
Angioplasty for discrete lesions that are accessible
75% 1yr s/p are patent
4/5 have immediate improvement in BP
Medical Therapy
Usually relies on ACE inhibitors

33

Surgical bypass of affected vessels

Effective
Last resort
Only after Angioplasty & medical therapy are unsuccessful
Renal parenchymal Disease
Patients with end stage renal disease often develop volume dependent
hypertension
Less commonly elevated plasma renin concentration is responsible
Medical management with meds & dialysis is usually effective
Nephrectomy rarely needed
Occasionally
Acute glomerulonephritis develops HTN
Screening UA usually suggests
Aldosteronism
Primary Aldosteronism
Excess mineralocorticoid aldosterone
Suspect for in patients that present with
HTN & hypokalemia in absence of diuretic therapy
Most common cause is benign adenoma of the adrenal cortex
i.e. Conns Syndrome
Also caused by bilateral hyperplasia of the zona glomerulsa
Na+ & H2O retention with consequent volume expansion is responsible for the
elevated pressure
Peripheral edema is rare
Diagnosis confirmed by
Elevated levels of aldosterone
Normal levels of
Cortisol
Adrenocorticotropic hormone
Suppressed plasma renin concentration
Result of sustained volume expansion
Treatment
Surgical removal of adrenal adenomas immediately decrease blood pressure
Bilateral hyperplasia better managed medically
Surgery rarely reverses HTN
Patient becomes dependent on glucocorticoids
Spironolactone blocs aldosterone receptors & may normalize BP
Patients with Cushings syndrome may also have HTN
Pheochromocytoma
Adrenal medulla effects BP via production & release of the catecholamines (epi &
norepi)
Pheochromocytoma
Tumor of chromaffin cells of the adrenal medulla

34

Uncontroled production of catecholamines HTN

HTN of pheochromocytoma
Classically paroxysmal
Baseline of sustained HTN for most
Nervousness, palpation & orthostatic hypotension are common
Coarctation of Aorta
Congenital anomaly
Local constriction of aortic lumen
Produces delayed & markedly diminished pulses in the lower extremities & HTN
Uncomplicated coarctation with out any additional anomalies
Complains of headache or exertional claudication
Key findings on exam
Difference in systolic BP between arms & legs
In older children & adults
Musculature of lower extremities may be underdeveloped
Systolic murmur that originates from coarctation
Best heard in back between scapulae
If well developed collateral circulation pulsatile flow in the intercostal region
Chest X-Ray
Aortic constriction adjacent to the silhouettes of Pre & post stenotic dilations (the
3 sign) along the left heart border
Well developed collateral flow erosion of inferior bony margins produce
pathognomonic rib notching
Echocardiogram or MRI can visualize coarctation
Treatment
Surgical correction is curative in most
HTN may persist or reappear years later
Sooner the surgery occurs, the less likely the patient will suffer from residual
HTN
Livelong prophylaxis for infectious endocarditis is mandatory

GENETICS OF HYPERTENSION
Little known about pathogenesis
Several single-gene deficits have been identified
Inherited in Mendelian fashion
Pathophysiologic pathway in the kidneys effected
Alters net renal salt reabsorption
Genetic studies attempting to identify associated genes in general population
unsuccessful

ASSESSMENT
Diagnosis requires confirmation of DBP >90mgHg & Systolic >149mmHg
Two occasions
4 weeks apart
Disagreement about what constitutes a complete physical exam

35

Serum electrolytes
Particularly Potassium level
Adequate screen
End organ assessment with
Retinal exam
Plain chest film
ECG
Urinalysis
Serum creatinine
Further workup for secondary hypertension if
HPI or PE suggests
Member of group at higher risk for secondary
CAD should be assessed with a lipid profile & fasting blood sugar

THERAPY
Weight reduction if obese
Decrease alcohol intake
Moderate level (<1oz/day)
Aerobic exercise
Restriction of dietary Na+
Lifestyle changes may reduce to normal without meds
Goal of treatment
Bring blood pressure to normal range
Most HTN can control with pharmacological intervention
Pharm treatment
Begins with use of first line agents
-blockers
ACE inhibitors
Angiotensin-receptor blockers
CCB
Diuretics
Second agent from different class if non-responsive to above

-Blockers
Used to be first step (JNC VII suggests Thiozides 1st)
Used in CAD & Anginal patients
Propanolol is prototype -adrenergic receptor blocker
Hypertensive result achieved through
Blockade of sympathetically mediated renin release
Reduction of cardiac output
At high dose, it may act at regulatory sites within the CNS
Cautions
Patients with heart block
Left ventricular failure
Decreased cardiac output can compromise the glomerular filtration rate in patients
with renal disease
36

Peripheral -blockade can elevate systemic vascular resistance

Claudication in susceptible persons
Side effects
Various gastrointestinal complaints
CNS issues
Usually transient
Sodium retention
Ameliorated with diuretic
Bronchospasm
Results from the -blockade of 2-receptors on bronchial smooth muscle
Blunting of sympathically mediated S/S of hypoglycemia
Impotence
Urinary retention
Abrupt withdrawal associated with
Rebound hypertension
Angina
Classes of -blockers available
Nonselective -agonists
Pranolol
Nadolol
Timolol
Blocks 1 & 2 receptors
Can exacerbate or induce bronchoconstriction
Selective -agonists
Atenolol
Metoprolol
Select for
Cardiac 1
Minimizes risk of bronchospasm exacerbation
Labetalol
Unique -agonist
Blocks some -adrenergic receptors
Does not raise systemic vascular resistance like other -blockers
- blockade causes vasodilation
Combination of blocking effects offer an advantage in persons with renal
impairment or peripheral vascular disease

Angiotensin-Converting Enzyme Inhibitors

Inhibits enzyme that converts angiotensin I to angiotensin II
Decreases peripheral vascular resistance
Blocks the release of aldosterone
Inhibiting sodium retention
Wide usage for
HTN
CHF
Useful as single-drug therapy when combined with diuretic
37

Contraindications
Patients with underlying renal disease
Can hasten renal failure
Monitor serum creatinine & blood urea nitrogen levels
Usually well tolerated
Captopril was first to be used
Side effects
Disturbances of taste
Proteinuria
Severe neutropenia (Rare)
ACE Inhibitors
Captopril
Lisinopril
Enalapril
Many patients develop chronic cough
Agiotensin Receptor Blockers
Also effective in reducing BP
Losartan
Candesartan
Valsartan

Calcium Channel Blockers

Nifedipine
Verapamil
Diltiazem
Reduce blood pressure by
Blocks the slow Calcium Channels
Decreasing contractile force
Vasodilation

Diuretics
When used alone, can often reduce blood pressure to desired limits
Used often in multidrug regimen
Minimizes sodium retention that occurs with many other antihypertensive drugs
Three classes of diuretics
Thiazides
Loop Diuretics
Potassium Sparing Diuretics
Each act at different site on nephron
Promotes sodium diuresis
Diminishes extracellular fluid volume
Promotes
Transient extracellular fluid decrease
With long-term use returns to normal volume levels
Antihypertensive effect is maintained
Possibly because of the effect of direct vasodilation

38

Thiazides
Act on distal tubule
Prevents sodium reabsorption
Class includes
Chlorothiazide
Hydrochlorothiazide
Closely related
Chlorthalidone
Meolazone
Side effects
Hypokalemia
Significant percentage of patients
Monitor
Serum potassium at start of therapy
Checked at regular intervals
If serum level drops below 3.5mEg/L
Potassium supplements
Sooner if patient is taking digitalis
Hyperglycemia
Hypertriglyceridemia (increase in serum cholesterol levels)
Hypercalcemia
Hyperuricemia
May unmask latent gouty arthritis
Arrhythmias via potassium depletion
Side effects have encouraged treatment with -blockers, ACE inhibitors & CCB
Loop Diuretics
Class includes
Furosemide
Ethacrynic acid
Bumetanide
Acts on ascending limb of the loop of Henle
More potent natriuretic than thiazides
Side effects
Greater electrolyte disturbances
Indications
Patients with impaired renal function
Patients who are relatively insensitive to effect of thiazides
Potassium-sparing diuretics
Act on distal tubule (same area as thiazides)
Three in class
Sprionolactone
Blocks action of aldosterone on distal tubule
May induce gynecomastia & menstrual irregularities
Triamterene

39

Independent of aldosterone
Amiloride
Independent of aldosterone
Side effects
Hyperkalemia
Epigastric distress
Weak diuretics
Rarely used alone
Often incorporated with thiazides in combination tablets to minimize risk
of thiazide induced hypokalemia

Other agents
Methyldopa
Prototype of centrally acting antihypertensive
Suppresses renin release
Produces only minimal orthostatic hypotension
Side Effects
Sedation
Depression
Impotence
Reversible
Hepatic serum transaminases
Hyperprolactinemia
Coombs-positive hemolytic anemia
Usage has declined with availability of better agents
Clonidine
Works through actions on CNS -receptors
Characterized by
Reduction in cardiac output at rest
Reflex control of vascular resistance is not impaired
Orthostatic hypotension is a rare complication
Side effects
Dry mouth
Constipation
Guanabenz & Guanfacine are similar drugs and also act on CNS -receptors
Doxazosin, prazosin & terazosin
-blocking agents
Blockade of postsynaptic 1-receptors
Vasodilation
Drop in blood pressure
Side effects
Orthostatic hypotension that can be severe
Especially with first dose
Syncope may result
Usually combined with diuretic and other first line agents

40

Hydralazine
Vasodilation via direct relaxation of arteriolar smooth muscle
Short acting
Rapidly inactivated by the liver when taken po
Rapid reduction of bp can produce
Profound reflex tachycardia
Fluid retention
Always given in combination with diuretic & sympathetic blocker
Lupus like symptoms with high dosage
Minoxidil
Similar to hydralazine, but is more potents
Combined with furosemide & a sympatholytic agent
Effective at controlling blood pressure where other meds cannont
Does not compromise glomerular filtration
Used in patients with renal disease
Side Effects
Hirsutism
Only used in patients with severe hypertension

HYPERTENSIVE CRISIS
When severe hypertension & end-organ damage evolve over hours
Potentially fatal syndrome
Rare in hypertensive patients
Syndrome is referred to as
Accelerated or Malignant hypertension
Blood pressure that precipitates crisis is variable with each patient
DBP higher than 140mmHg used for convenience
Associated physical findings more important than actual DBP
Physical findings
Severely increased DBP
Advanced retinal changes
Papilledema (optic disc swelling caused by increased intracranial pressure)
Progressive oliguric renal failure
Hypertensive encephalopathy
Clinical presentation
Headache
Seizures
Coma
Agitation
Pulmonary edema
MI
Acute renal failure
Intracranial hemorrhage
Pathogenesis
Unclear
May be associated with

41

Intimal hyperplasia of small renal arteries

Produces fibrinoid necrosis
Leads to high level of circulation renin
Usually no evidence of precipitant
Accelerated hypertension may also be caused by
Pheochromocytoma
Elevated CNS pressures
Eclampsia
Commonly, abrupt withdrawal from some HTN agents
Propranolol
Clonidine
Guanabenzine
MOIs with foods containing tyramine release of catecholamines
Rapid & controlled treatment to prevent renal damage
Stroke & blindness may occur from rapid drop in BP
Initial goal of therapy
Decrease DBP to 100
Treatment
Nitroprusside, only when monitoring is available
Given IV
Metabolized to cyanide & thicyanate
Metabolic acidosis
Weakness
CNS effects that can progress to coma
Labetalol (block both & receptors
Decreases blood pressure by
Reducing peripheral vascular resistance
Cardiac contractility
Patients without neurologic, cardiovascular or renal compromise
Sublingual nifedipine
Successful at reducing high pressures
Followed by several hours of observation
Patients who have had one episode of malignant hypertension are at increased
risk for further episodes

Hypertension Meds
-blockers
Propranolol
Nadolol
Atenolol

Labetalol
Timolol

Vasodilators
ACE inhibitors
Angiotensin receptor blockers
Hydralazine

Prazosin
Doxazosi

42

-Calcium Channel Blockers

Nifedipine
Nicvardipine
Amlodipine

Verapamil
Diltiazem

Diuretics
Thiazides
Loop Diuretics
Potassium-sparring diuretics
Central-acting agents
Methyldopa
Clonidine

JNC VII Guidelines

43

Chapter 10 Pulmonary Function Tests

Used to detect, characterize & quantify pulmonary disease
Basic testing includes
Airflow
Lung volumes
Diffusing capacity
Additional testing
ABGs
Respiratory muscle strength
Bronchial provocation studies
Cardiopulmonary exercise studies

SPIROMETRY
Definitive measurement of airflow
Incomplete measurement of lung volume
Provides information about
Ventilatory or mechanical properties of the lung
Flow rates assessed
Forced Expiratory Volume in 1 second (FEV1)
Volume of air exhaled out of the lung forcefully in the first second of a
maximal expiratory maneuver
Forced Vital Capacity (FVC)
Total Volume of air that can be maximally exhaled during a forced
maneuver
Values that are 80% or greater than predicted normal values are WNL
FEV1/ FVC
Unitless unit
Describes change in expiratory airflow over the course of the maximal
expiratory maneuver
Values greater than 70% are normal
Abnormalities can be broken down into two
Obstructive
Asthma
Emphysema
Chronic bronchitis
Centrally located endobronchial tumors
Restrictive
Interstitial lung disease
Neuromuscular disease
Thoracic cage deformity
Obesity
Alveolar consolidation
Common to all obstruction is a reduction in the airway lumen caliber during
expiration
May be reduced by
Bronchial smooth muscle constriction (asthma)
44

Excess mucus secretions

Mucus plugs (chronic bronchitis)
Increased airway collapsibility secondary to loss of elasticity
(emphysema)
Obstructive lesion (Endobronchial tumor)
Obstructive physiology
Characterized by a reduction of both FEV1 & FEV1/FVC
Restrictive Lung Disorders
Reduce FVC
FEV1/FVC may be normal or increased
Disorders may result from
Neuromuscular diseases (amyotrophic lateral sclerosis)
Thoracic Cage abnormalities (Severe Kyphosis)
Interstitial lung disease (Asbestosis)
Alveolar Disorders (Acute Respiratory distress syndrome)
Neuromuscular insufficiency will also result in reduced maximum inspiratory
force measurement (MIF)
MIF
Easy measurement
Not routinely performed with spirometry
Highly variable results if patient does not give consistent maximal effort

Postbronchodilator Spirometry
Measurements before & after bronchodilator administration
If there is improvement
Indicative of asthma
Increase in FEV1
A positive response is increase of 12% & 200mL 15 min s/p admin
Absence of + response is does not exclude
Ds may be in remission
+Response with obstructive defect confirms
Reversible obstruction
Cardinal feature of asthma
False negative
Patient takes bronchodilator before baseline
Patients should abstain from bronchodilator for 6 hours

DETERMINATION OF TOTAL LUNG CAPACITY

Definitive lung volume measurement
Total Lung Capacity (TLC)
Important when restrictive defect is suspected
All lung volumes including FVC are reduced
Only restrictive defects should result in a reduction of TLC
In obstructive disease, TLC will actually be supranormal due to severe
hyperinflation & gas trapping
Measured by
Gas dilution techniques

45

May underestimate TLC due to gas trapping in obstructive or

mixed disease patients
Results in lower than actual TLC
Body Plethysmography
Measured using Boyles law
Special chamber
Gold Standard for measuring TLC & demonstrating restrictive
disease
Both techniques require special equipment
Not easy to perform

DIFFUSING CAPACITY OF CARBON MONOXIDE

DLCO Also known as: Transfer Factor
Provides measurement of the integrity of the alveolar-capillary interface in the
lungs
Useful information on
How readily gases can cross the interface into pulmonary circulation
Testing
Patient inhales a gas mixture containing CO
Hold a breath with lung fully inflated for 10 seconds
Inspired & expired gas volumes & concentrations are measured
CO has affinity 200 X that of Oxygen
Abnormalities in alveolar-capillary membrane results in decreased transfer
Diseases affecting
Pulmonary vessels (Pulmonary vasculitits)
Interstitium (Pneumoconioses, hypersensitivity pneumonitis, idiopathic
pulmonary fibrosis & sarcoidosis)
Alveloar space (Emphysema or ARDS)
False low
Anemia
False high
Polycythemia
Most labs report corrected value accounting for hemoglobin level
Pulmonary hemorrhage will give supranormal levels because of excess hemoglobin
available for binding
Widespread opacities on chest X-ray & increased diffusing capacity suspect
pulmonary hemorrhage

ARTERIAL BLOOD GASES & PH

ABG & pH provide information about lung function: oxygenation & ventilation
Hypoxemia
Subnormal oxygenation of blood
PaO2 decreases with age
Normal PaO2 in upright position
104-(0.27 X Age)
4 pathophysiologic processes may cause
Hypoventilation
Ventilation-perfusion mismatch (shunting is extreme example)

46

Low inspired fraction of oxygen (15% as opposed to normal 21%)

Low partial pressure of oxygen (High altitudes)
Diffusion abnormalities cause hypoxemia with exercise but less common at rest
Hypoventilation
Has elevated PaCO2
Alveolar ventilation fails to increase sufficiently with CO2 production
Results in hypercapnea
Hypercapnea
Acute or chronic
Common causes
Depressed ventilatory drive
Sedative drugs
Anesthesia
Mechanical abnormalities of lung
COPD
Muscle weakness
Treatment should emphasize restoration of normal ventilation
Ventilation-perfusion mismatch
Most common cause of hypoxemia
Underventilated blood passes back to the heart poorly oxygenated
Low ventilation perfusion [V/Q] ratio
Oxyhemoglobin dissociation curve
Sigmoidal shape
Better ventilated areas of lung cannot make up for poorly ventilated areas
Most obstructive & restrictive disorders due to alveolar filling cause
hypoxemia by this method
Extreme case of low V/Q
Right left shunt
May be intrapulmonary (AV malformations)
May be extrapulmonary (ventricular septal defect)
Refractory to supplemental oxygen
Suspect if + to oxygen in absence of radiographic changes
Diffusion Abnormalities
Destruction of capillary bed
Rapid red cell transit time
Alveolar & erythrocyte partial pressures cannot equalize
Worsens with exercise
Usually successful with supplemental oxygen
Hypercapnia
PaCO2 greater than 44mmHg
May result from compensatory mechanism for metabolic alkalosis pH is
alkaline
May be caused by diminished central respiratory drive
Compromised respiratory mechanisms
Muscle weakness

BRONCHIAL PROVOCATION STUDY

47

Used to detect presence of airway hyperreactivity

Most commonly used on suspected asthma patients with normal spirometry
Most common agent used is methacholine (cholergenic drug
bronchoconstricition)
Delivers drug over timed intervals
Spirometry performed within 5 minutes of each does
Serial testing continues until FEV1 is decreased by 20%
A low PC20 is suggestive of asthma
A high PC20 rules out asthma
Bronchodilators administered at end to reverse

CARDIOPULMONARY EXERCISE STUDY

Assessment of cardiovascular-pulmonary response to exercise
Only test that assesses exercised lung
Complicated procedure
Indications
Unexplained dypsnea
Assess work capacity
Assess factors limiting exercise tolerance
Evaluate disease progression & treatments over time
Measures
CV & ventilatory parameters
Oxygen consumption most important measurement
Determinants of the pulmonary response to exercise include
Central respiratory drive
Neuromuscular function
Thoracic cage anatomy
Conducting airways
Gas exchanging units (alveolar ducts & sacs)
Interstitium
Pulmonary vasculature
Determinants of Cardiovascular response
Heart rate
Stroke volume response
Integrity of peripheral vasculature
Ability of muscle beds to utilize delivered oxygen
Normal Cardiac response to exercise
Progressive increase in
Minute ventilation
Heart rate
Stroke volume
Oxygen consumption
Should be able to exercise beyond anaerobic threshold
Abnormal cardiovascular response
HR response excessive for workload
Early lactic acidosis
Abnormal pulmonary response

48

>50 breaths per minute (virtually dx of restrictive lung ds)

Desaturation (interstial lung disease & emphysema)
Inability to reach anaerobic threshold (emphysema)
development of post exercise obstructive ventilatory defects (exercise induced
asthma)

49

Chapter 11 Asthma
7% of US population
NAEPP National Asthma Education & prevention Program
Characterized by
Airway obstruction
Airway inflammation
Increased response to airway stimuli
Prevalence is on the rise
PATHOGENESIS & PATHOLOGY
Contributions
Genetics
Heredity
Associated with chromosome 5q31-q33 bronchial hyperreactivity and
elevation of IgE
Environment
Tobacco smoke
Possibly infectious components
Asthma is an inflammatory response
Influx of inflammatory cells tendency for bronchospasm
Bronchial hyperreactivity present in all cases of asthma
Relevant inflammatory cells
Bronchial mucosal mast cells
TH2 Helper lymphocytes
Eosinophils
Interaction via
Proinflammatory cytokines
Leukotrienes
Adhesion molecules
Growth factors
Physiological findings
Acute & chronically inflamed airways
Thickened airway mucosa
Desquamated epithelial cells
Hypertrophy of smooth muscle
Thickened basement membrane
Increased number of inflammatory cells
CHRONIC ASTHMA
Clinical & laboratory presentation
Triad of chronic Asthma symptoms
Episodic dypsnea
Cough
Wheezing in response to diverse stimuli
Mild end of spectrum
Exercise induced asthma
Respiratory symptoms 15-20 minutes s/p exercise

50

Putative triggers
Respitory tract heat
Water loss
Exercise in cold, dry air
Cough variant asthma
Seldom or never notices wheezing or SOB
Methacholine challenge to prove bronchial hyperresponsiveness is
responsible for cough
Occupational asthma
Difficult to dx
Confirmed with portable peak flow meter
Rare patient with years of untreated airway inflammation
Structural remodeling of the airway
fixed obstruction
Mimics COPD
Nocturnal Asthma
Brittle disease
Propensity for fatal result
Marked diurnal swings in airway caliber (peak flow variability >30%)
Early morning cough, dypsnea & wheezing
Responsive to bronchodilators
Morning dipper
Unstable asthmatic
Demands aggressive therapy
Rarely is distinction made between extrinsic & intrinsic asthmatics today
Search for precipitants is still vital
Asthma precipitants
Pollen
The house dust mite
Animal dander
Iodine
Change in air quality
Yellow dye
NSAIDS
Aspirin sensitivity associated with the syndrome of nasal polyposis &
sinusitis
Extrapulmonary disease may mimic or complicate asthma
CHF
Pulmonary embolism
Upper airway obstruction
COPD
Bronchiectasis
Cystic fibrosis
Nasal disease
GERD
Family hx is helpful in dx

51

Physical Examination
Supports diagnosis
Assess the possibility of other disorders
Skin may show eczema
ENT exam
All make treatment more difficult
Rule out nasal polyps
Sinus Ds
Cobblestoned posterior nasopharynx suggestive of postnasal drip
Diffuse polyphonic expiratory wheezes with prolonged expiratory phase is typical
of asthma
Cardiac exam
Possible left ventricular failure or pulmonary hypertension
Finger clubbing not indicative of asthma, but may show coexistent interstitial
lung disease
Laboratory work
CBC with Wrights Stain for determining total eosinophils
>450/mm3 should prompt test for plasma IgE levels & consideration of
bronchopumonary aspergillosis
Treatment of increased IgE with corticosteroids preemptively improves outcome
Pulmonary function tests
Should confirm reversible airway obstruction
Asthmatics with chronic oral corticosteroids & a propensity for nocturnal asthma
should record peak flows twice a day
Persistent small airway inflammation causes a decrease in flow rates at low lung
volumes, hyperinflation & hypoxemia
Management
Goals of treatment include
1. Prevent chronic & troublesome symptoms
2. Maintain (near) normal activity levels
3. Prevent recurrent exacerbations of asthma & minimize the need for ED visits or
hospitalizations
4. Provide optimal pharmacotherapy with minimal or no adverse effects
5. Meet patients & families expectations of and satisfaction with asthma care
Attainment extends beyond pharm & includes
1. Education
2. Need for objective measures of airways obstruction
3. Moderation compliance, proper use of inhaler devices
4. Environmental controls
5. Self management plans to be followed at home if need arises
Asthma severity
Classified based on symptoms into 4 categories
1. Mild intermittent
2. Mild persistent
3. Moderate persistent
4. Severe persistent

52

Therapeutic recommendations
Based on a stepwise approach
Attempt to taper down to lower classification
Pharmacotherapy of asthma is divided into two broad classifications
Quick-relief medications treats symptoms & exacerbations
Selective short-acting 2 agonists
Long-term controller medications to achieve & maintain control
Corticosteroids
Long-acting 2 agonists
Cromolyn
Nedocromil
Antileukotriene agents
Infrequent symptoms
2 agonists on an as needed basis
MDI Metered Dose Inhaler
Acceptable 2 specific agents
Albuterol
Salmeterol
Pirbuterol
Toxicity
Thrush
Dysphonia
Obviated by proper inhaler technique
Cromolyn & nedocromil alternative anti-inflammatory agents virtually free of
toxicity

53

Chapter 14 Deep Venous Thrombosis and Pulmonary

Thromboembolism
PREVALENCE AND PATHOGENESIS
100K deaths per year
30-50% recurrence in untreated patients
Occurs in setting of
Vichows Triad
1. Endothelial Damage (Trauma to venous intima)
2. Venous stasis
3. Hypercoagulable state
Single most important risk factor is previous DVT or PTE
Hypercoagulable States
Cancer
Oral BCP
Age
Certain myeloproliferative conditions
Familial hypercoagulable states
Deficiency in proteins C & S
Deficiency in antithrombin III
Antiphospholipid antibody syndrome
Prolonged aPTT (activated partial thromboplastin time)
10% of patients with heparin induced thrombocytopenia
Presence of intravascular devices

PATHOPHYSIOLOGY
Once established tend to drift proximally
If free floating can cause problem in pulmonary circulation
If large clot moves through right ventricle systemic hypotension may result
Most originate from deep venous system of thighs
Origination below popliteal fossa
Low risk for propagation & embolism
Still require anticoagulation
Other sources
Pelvic & renal veins
Right atrium & ventricle
Central Venous Catheters
Clinical & Laboratory Manifestations
Result from obstruction of pulmonary vasculature by clot
Pulmonary vasoconstriction
Mediated by platelet-derived substances
Serotonin
Possibly by imbalance between
Vasoconstrictor endothilin
Endothelium-derived nitric oxide

54

Resultant increase varies depending on the presence or absence of

preexisting pulmonary vascular disease
Normal individuals may show no changes until 40% occlusion
COPD may have greater disproportionate changes after small embolism
Risks for hemodynamic compromise from PTE are greatest in
Patients with existent compromise right ventricular function i.e. cor
pulmonale secondary to primary pulmonary hypertension or global
cardiomyopathy
Pulmonary Vascular Obstruction
Compromises cardiac output and causes gas exchange abnormalities
The obstruction
Creates areas with high V/Q ratios (wasting ventilation)
Increases ventilatory requirements
Large saddle emboli may cause frank hypercapnia
More common
Hypoxemia
Vascular obstruction has diverted blood to normal (low V/Q)
regions of the lung
As a result of vascular injury from mediator release (vasc perm)
Ischemic atelectasis leading to right-to-left shunt fraction
Occasionally
Profound and refractory hypoxemia develops
Increase in right atrial pressure drives blood through potentially
patent foramen ovale
Normally
Emboli resolve over days to weeks via endogenous thrombolysis
1% large proximal clots fail to resolve and recanalize
Develop slowly progressive pulmonary hypertension cor
pulmonale

CLINICAL AND LABORATORY PRESENTATION

HPI
Leg pain
Swelling
PE
Ipsilateral
Edema
Erythema
Tenderness
Palpable venous cord
DVT cases are clinically silent
Negative D-dimer test usually rules out large clot, but can be negative for smaller
ones
Contrast Venography
Gold standard for dx
Other sensitive tests do exist that are less invasive

55

Equally useful & less invasive tests

Serial Impedance plethysmography (IPG)
Ultrasound (US) both color flow & duplex
Sensitive enough for non-calf thrombosis in the lower extremities
Initial Rx Dx Test
If negative in high risk patient repeat every 3 10 days
CT & MRI are being integrated
Signs & Symptoms
Depend on
Antecedent cardiopulmonary reserve
Clot load
Presence of pulmonary infarction
Recurrence of PTE
Degree of endogenous thrombolysis that follows embolic event
Rare variants
Chronic recurrent small emboli & chronic large vessel pulmonary emboli
Present with
Insidious onset of dyspnea on exertion
Mimic primary pulmonary hypertension
10% of acute cases imply pulmonary infarction has occurred. Common in CHF
where bronchial artery & collateral blood flow is compromised
Fever
Occasional
Rarely higher than 39 C (102.2 F)
Peaks on hospital day 1
Tachypnea
Rate less than 16 can rule out PTE
Hypotension suggestive of massive PTE
Also
Right-sided ventricular heave
Third heart sound
Tricuspid regurgitation murmur
Increased P2
JVD (Jugular Venous Distention)
If pulmonary infarct has occurred
Pleural friction rub
Dullness to percussion at site of associated pleural effusion
Consolidation above
Occasional overlying tenderness
Lab tests
None are sufficiently sensitive or specific to confirm dx
D-dimer by ELISA (Enzyme linked Immosorbent Assay)
May have negative predictive value, but cant rule out definitively
PaO2 is normal in 10% of patients
Alveolar-arterial O2 gradient is usually widened

56

EKG Abnormalities
Sinus tachycardia is most common
New atrial fibrillation may be present
P pulmonale and right ventricular strain with massive PTE
Right bundle branch block
Right ventricular hypertrophy
Classic S1Q3T3 pattern
Chest X-ray is usually normal
2-3 days post infarct, may show atelectasis
Westermarks Sign
Loss of vascular markings in the same area as the involved vessel
Hamptons Hump
Radiopaque density abuts the posterior diaphragm and protrudes
towards the heart
Lung Perfusion Scan
Screening test of choice
Injection of radioactive albumin macroaggregates into venous circulation
Slightly larger than pulmonary capillaries
Areas of under perfusion are absent of radioactivity
Normal essentially rules out PTE
Abnormal means only there is a process compromising perfusion & not
necessarily a PTE
Inhalation of radioactive gas
Increased specificity
Continued ventilation to a segment absent perfusion is highly suggestive
of PTE
Positive test treatment without further testing
High probability V/Q lung scans are one of the following
1. Two or more large segmental perfusion defects
a. Without corresponding ventilation or roentgenographic
abnormalities
2. Two or more moderate segmental perfusion defects
a. Without matching ventilation or xray abnormalities
b. Plus one large mismatched segmental defect
3. Four or more moderate segmental perfusion defects without ventilation or
x-ray abnormalities
Significant numbers of patients with low & intermediate V/Q have PTE
documented by pulmonary angiography
Patients with high suspicion for PTE should have further testing to r/o PTE
Serial non-invasive tests to rule out DVT in extremities
Pulmonary angiography
Definitive test for PTE
Most specific radiographic signs of acute PTE
Intraluminal filling defect
Vessel cutoff

57

Chronic large vessel PTE difficult to detect

Recanalization of vessel mimics normal blood vessels
Spiral high-resolution CT & Magnetic resonance angiography
Shows promise for dx of acute PTE
Valuable in ID of large-sized central or lobar PTE
Sensitivity for smaller clots is lower
Dont use to exclude dx
Chronic large vessel PTE
Pulmonary angioscopy procedure of choice

PREVENTION AND THERAPY

Prophylaxis
Several regimens can be used
Nature & number of risk factors should influence
Young patient with uncomplicated illness & postop patient at risk for wound
hematoma
Elastic stokings
Pneumatic compression of lower extremities
Decrease stasis
Activates endogenous thrombolytic pathways
Pharmacology
Low-dose (5000 units bid) of subcutaneous heparin
Heparin-induced thrombocytopenia is a contraindication.
Ineffective after surgery where large amounts of tissue
thromboplastin are released (hip & knee sx)
Patients with multiple risk factors should receive both mechanical and medical
therapy
Patients with hip & knee replacements have VTE incidence between 50-70%
Aggressive therapy
Low Molecular weight heparin (LMWH) subcutaneous or oral warfarin
started pre-op

Anticoagulation
Inhibition of the cascade prevents propagation of the clot
Endogenous thrombolytic mechanisms work to dissolve it
All patients with suspected or documented DVT or PTE should receive heparin
Heparin
Combines with antithrombin III & prolongs the aPTT
Therapeutic range is 1.5-2.5 X control
Failure to move into the therapeutic range within 24 hrs of presentation increases
incidence of recurrence
IV bolus between
5000 1000 IU
IV drip to maintain levels
Checked initially q4h and adjustments made
LMWH
Also approved therapy

58

Advantages are
Higher bioavailability
Less protein binding
Decreased clearance
Prolonged half-life
More reproducible anti-coagulant activity
No need for serial monitoring
Warfarin therapy
5-10mg qd
With not before heparin
Inhibits coagulation by depletion of vitamin k-dependent pathway
Factor II, VII, IX & X
Endogenous anticoagulants protein C & S
Transient hypercoagulable state may result transiently without starting heparin
first
PT time reflects extrinsic pathway
Dependence on factor VII (reflects index of warfarin anticoagulation)
INR
Goal is 2.0-3.0
Takes 3-4 days after initiation of therapy to be in therapeutic range
Heparin & warfarin therapy should overlap for 5 days
Complication of anticoagulation therapy is bleeding
Poorly predicted by aPTT
Well correlated with warfarin
At risk if:
INR over 4.0
Increased Age
CNS ds
Peptic ulcer ds
Trauma
Prior surgery
LMWH & bleeding is controversial
If anticoagulation is contraindicated IVC filter
Heparin can induced Immunoglobulin Thrombocytopenia (HIT)
1-3%
5-15 days s/p initiation of therapy
More common in those receiving heparin in previous 3 months
More common with unfractionated than LMWH
5% of HIT patients have disseminated intravascular coagulation
Platelet count monitored qd in patients receiving heparin
Discontinue if HIT develops
Two agents used to treat
Danaparoid sodium
Ancrod (snake venom in trials in Europe)

59

Additional complications of warfarin

Bleeding
Skin necrosis (vit C deficiency and malignancy)
Teratogenesis
Systemic anticoagulation should continue for 3-6 months after DVT or PTE
Life long in presence of
Persistent hypercoagulability
Chronic autoagglutination

Thrombolysis
Agents dissolve thrombi by
Activating plasminogen to plasmin
Degrades fibrin
To soluble peptides
Thrombolytic Agents
Streptokinase (SK)
Urokinase (UK)
Tissue Plasminogen Activator (tPA)
Activates plasminogen associated with clot
All above are equally effective in treatment of DVT & PTE
Anistreplase (APSAC)
Less systemic effect than SK
Less depletion of circulating plasminogen
Expensive & no proven benefit over SK
Thrombolytic therapy
Decreases the frequency of the postphlebotic syndrome assoc with DVT
Most physicians use thrombolysis in PTE if
Clot burden is high
Hemodynamic instability refractory to volume resuscitation
SK is cheaper than UK use if no streptococcal antibodies
SK
IV bolus followed by 24 hour infusion for PTE (48-72 hrs for DVT)
tPA
2hour 100mg infusion
When aPTT or thrombin time has returned to less than 1.5 X the control heparin is
started without a bolus
Major complication of thrombolysis
Bleeding
Primarily at venipuncture sites
Trauma sites
Recent Sx or internal bleeding is absolute contraindication
Surgical Embolectomy
Patients with massive pulmonary embolism
Persistent shock
Hypoxemia
Requires cardiac bypass
Mortality rate 50%

60

Chapter 16 Acute Respiratory Failure

Divide ARF (Acute Respiratory Failure)
Hypoxemic/Nonhypercapnic
Hypercapnic/Hypoxemic
The two above have different etiologies, findings & therapeutic ramifications

HYPOXEMIC RESPIRATORY FAILURE

Occurs with combo of
Low V/Q
Elevated Right-To-Left shunt
DepressesPaO2
Alveolar space with
Pus
Edema
Fluid
Blood
Hypercapnia generally not associated
Usually overcome with supplemental oxygen

HYPOXEMIC RESPIRATORY FAILURE

Pathogenesis
Associated Ds
CHF
Cardiogenic pulmonary edema
Pneumonia
Acute lung injury (ALI)
Acute (or Adult) Respiratory Distress Syndrome (ARDS)
ALI & ARDS
Fluid infiltrate from capillary leak of noncardiogenic protein-rich edema
Differentiated by PaO2/FiO2 ratio (Arterial Oxygen level/Inspired
Oxygen) 300-200 mmHg respectively
Clinical Scenario one or more of the following risk factors
Aspiration
Pneumonia
Sepsis
Multiple blood transfusions
Drug overdose
Drowning or trauma
There may be a 24-36 hour delay before appreciation
Overall mortality is 50%
Normal lung function with appropriate therapy
Extremely aggressive treatment

Clinical & Laboratory Manifestations

Physical findings of cyanosis when desaturated hemoglobin is > 5mg/dl
Check tongue, cheek etc to r/o acral cyanosis
As PaO2 decreases the following occur
Confusion
Somnolence
61

Significant hypoxemia
Dyspnea
Tachypnea
Tachycardia
Bradycardia (if hypoxemia is profound)
Emergent settings Arterial oxygenation should be determined
Non-emergent SaO2 is fine
Treatment endpoints
SaO2 > 90

TREATMENT
Treatment of Adult Respiratory Distress Syndrome
Successful outcome is removal &/or appropriate treatment of the underlying cause

Oxygen Therapy
Goal is to restore adequate oxygenation
Using minimal possible concentration of exogenous oxygen
Avoid pulmonary oxygen toxicity (occurs at concentrations greater than
50%)
Stable patient
0.5-6 L/min via nasal canula
FiO2 via nasal canula depends on amount of entrained room air
Determined by an individual patients breathing pattern
Estimate is
FiO2 = 0.20 + 0.4 X O2 flow (L/min)
FiO2 between 0.24 to 0.40 have proved to be useful in oxygen
sensitive patient

Mechanical Ventilation & Positive End-Expiratory Pressure (PEEP)

Endotracheal intubation & mechanical vent is necessary
If patient is
Tachypneic (>35)
Worsening hypercapnia
Hypoxemia is refractory to supplemental oxygen
Best Peep trial
Intubated patient with hypoxemic respiratory failure
Goal is to maintain adequate tissue oxygenation at minimum FiO2
In general FiO2 of 1.0 & PEEP of 5 cmH2O immediately after intubation
If FiO2 is greater than 0.55
PEEP increased 2.5cmH2O increments
q30-60minutes
20 cmH2O is the maximum
Higher risks barotraumas
Before each change the following should be checked
SaO2
Cardiac output (Qt)
Mixed venous O2 (SvO2)
Static lung compliance (Cstat)

62

PEEP may decrease cardiac output & decrease systemic O2 delivery (DO2 =
CaO2 X Qt)
Mechanical ventilation of the patient with airspace ds, stiff lungs & hypoxemic
resp failure is different than obstructed patient
Some degree of respiratory acidosis is OK
Previous thought unacceptable
PaCO2 = 70 torr, pH = 7.2
Small tidal volumes 6-8 mL/kg
Peak airway pressure < 40 cm water
Adjust freq to keep pH > 7.2
A 20-30 torr change in PaCO2 has minimal effect on arterial oxygenation
Some patients cant get enough oxygen at non-toxic levels
Change vent mode
Intermittent Mandatory Ventilation (IMV) to Pressure Control-inverse
Ratio Ventilation (PC-IVR)
Applies pressure in a square wave fashion
Combine with prolonged >1.0) ratio of insp to expir
Can mimic PEEP by keeping atelectic portions open longer
May need to place pt in prone to improve V/Q matching
Patients with high mean pulmonary artery pressure
Inhaled nitric oxide (2-3 weeks)
Low concentration 20 ppm
Increases blood flow to ventilated alveoli
Improve matching
Decrease FiO2 requirements
Mixed venous oxygen tension or saturation has been used for years as index of
global oxygenation
Septic patient will shunt
Normal SvO2 doesnt mean there isnt a problem
SvO2 < 60% ([PvO2] < 30 torr) should be corrected

Weaning the patient

When cause has been treated & all extrapulmonary functions are stable & if:
1. Right to left shunt fraction (Qs/Qt) < 0.20, when the pt has been place on an FIO2
of 1.0 for at least 30 minutes
2. The Cstat is greater than 20mL/cmH2O
First FiO2 is decreased to 0.5 then PEEP to 5 cmH2O
Extubate to humidified face mask with FiO2 ~ 0.10 higher than the vent
May require CPAP for SaO2 > 90%

HYPERCAPNIC RESPIRATORY FAILURE

Clinical & Laboratory Manifestations
PaCO2 > 44mmHg assoc. with an acid arterial pH is suggestive that
Alveolar respiration is unable to keep up with production of CO2
Most patients with hypercapnic respiratory failure
Sever peripheral airway obstruction
If FEV1 > 30% predicted clinician should look for
Upper airway obstruction

63

Respiratory muscle weaknessdepression of central respiratory drive

Obesity-hypoventilation syndrome (assoc with sleep apnea)
Drugs
Hypothyroidism
Metabolic alkalosis
As PaCO2 Rises
Decrease in cognitive fxn
Headaches
Hypersomnolence
Asterixix & tremor appear
Occasionally accompanied by diaphoresis & conjunctival suffusion
Onset of symptoms
Chronicity of hypercapnia
Presence of cellular adaptive mechanisms
Treatment must address cause

Treatment
Mechanical Ventilation
Mainstay of tx is adequate alveolar ventilation
Immediate goal should be an arterial pH >7.20
If PaCO2 elevated for more than 3 days
Compensatory renal retention of bicarbonate makes abrupt lowering of
PaCO2 to normal values dangerous
Resultant metabolic acidosis
In AOX3 patient without signs of resp muscle failure
Addition of low flow oxygen to correct hypoxemia is initial therapy of choice
Clinically relevant danger of oxygen therapy is
Worsening respiratory acidosis
In chronic alveolar hypoventilated patient
Blunted response to hypercapnia
Elevated CNS bicarb
Relies on hypoxic drive to breathe
Incremental increase in oxygen
20 min intervals
pH < 7.20 & SaO2 < 90%
Facemask ventilation
Non-invasive ventilator modes
Bilevel positive pressure (BiPAP)
If patients continue to decompensate mechanical ventilation is required
Assist ctrld or volume-cycled synchronized intermittent mandatory ventilation
(SIMV) is first choice
Larger tidal volume is used than for hypoxemic patient (10-12) mL/kg
If peak pressure is > 40 cmH2O
Permissive hypercapnia
Decrease tidal volume to 4-8 mL/kg
IV bicarb
Be careful with increasing frequency of breathes > 14

64

Insufficient time for exhale

Breath stacking
Results in auto or occult PEEP
All the risks of iatrogenic PEEP
Barotrauma
Decreased cardiac output
Increased wasted ventilation
Increased inspiratory workload
AutoPEEP treatment
Tidal volume < 12mL/kg
Decrease insp/expir ratio
Increase flow rate to 80 from 40 L/min
If patient fails to respond to therapy inordinate CO2 production sources should be
sought
Overfeeding
With or without excessive carbohydrate
Fever
Heliox blend may help
Used in acute asthma
After stabilization
SIMV changed to Pressure support Ventilation (PSV)
Pt determines inspiratory flow rate, tidal volume & frequency

Weaning From the Ventilator

Confirmation of readiness includes
1. Inspiratory force more negative than -25 cmH2O
2. Vital capacity > 15 mL/kg
3. Dead space/Vt ratio < 0.6
a. This can be measured by (PaCO2 PECO2)/PaCO2 where PECO2 is the
PCO2 of the expired gas collected over 3 minutes
Classically weaned from IMV of 10-12 breaths per minute to unsupported over
several days
Other techniques may shorten duration of mechanical ventilation
1. Increasing periods of spontaneous T-piece trials off the ventilator
2. Gradual or intermittent reduction of PSV to a level that just overcomes the
resistive work of breathing imposed by the endotracheal tube & ventilator circuit
(usually 8 cm H2O)
Rapid shallow breathing reasonable predictor of failure to successfully wean
An acid change in gastric aspirate can also be predicted
Occasionally pts require long term CPAP

65

Chapter 17 Fluids, Electrolytes, and PH Homeostasis

WATER AND SODIUM
Fluid in two compartments
Intracellular
Extracellular
70Kg man
50-60% water
60% Intracellular
40% Extracellular
20% of ECF is in blood plasma
Sodium Chloride
Mostly restricted to ECF
Most abundant EC cation
Main determinant of ECF volume
ECF & Intracellular fluid in osmotic equilibrium

Extracellular Volume
Positive Sodium Balance
The amount of sodium ingested exceeds amount excreted
Excess sodium retains water in ECF
Glomerular filtration rate increases
Excess sodium & water are excreted
Excess ECF sodium stimulates enhanced urinary sodium excretion
Negative Sodium Balance
If fall is precipitous or severe
Signs of hypovolemia
Orthostatic hypotension
Dry mucous membranes
Resting tachycardia
Absent axillary sweat
Poor skin turgor (degree of resistance to deformation)
Low jugular venous pressure
Signs are a reflection of bodies attempt to maintain blood pressure in the
face of acutely decreased intravascular volume
Infusion of isotonic saline (0.9% sodium chloride) expands ECF & provides
volume replacement

Serum Sodium Concentration

The concentration of sodium reflects the bodys state of water balance
A measure of how much the sodium has been diluted by water
Serum sodium concentration
Accurate measure of serum osmolality
The two are used interchangeably
Hyperosmolar states are often hypernatremic states
Important Exception HYPERGLYCEMIA
Hyperosmolality from increased [glucose]
Regulation of [sodium] is usually from pathways that adjust water balance
66

Arise from osmoreceptors of the brain

Stimulate release of ADH from posterior reservoir of pituitary
Sensitive to even minute shifts
Receptors in atria sensitive to changes in intravascular volume may
also stimulate ADH release
Stimulate thirst mechanism
Hyper/hypoVOLEMIA
Reflects problems in total body SODIUM
Hyper/hypoNATREMIA
Reflects problems in total body WATER

HYPONATREMIA
Symptoms become noticeable when
[Sodium] < 125mEq/L
Mild confusion
Vomiting
Anorexia
Convulsions
Nausea
Eventually coma & death
Hyponatremia
Indicates only that there too much fluid in relation to amount of solute in the body
Usually reflects hypo-osmolality
Can occur with
Euvolemia
Hypovolemia
Hypervolemia

Hyponatremia with hypervolemia

Three edematous states are associated with hyponatremia & hypervolemia
Severe CHF
The Nephrotic Syndrome (damaged kidneys proteinuria & hypervolemia
Hepatic Cirrhosis
Leads to sodium retention by the kidneys
Effective volume depletion ensues (more ECF than intracellular)
ADH secretion
Retained water dilutes sodium leading to a hyponatremia

Hyponatremia with Euvolemia Syndrome of Inappropriate

Antidiuretic Hormone (SIADH)
Causes
1. Inappropriate secretion of ADH
a. Oat cell carcinomas of lung
b. Lung infection (unknown mechanism)
c. Disorders of CNS
i. Meningitis & encephalitis
d. Postoperative state
2. Drugs (enhance secretion of ADH or potentiates kidneys response
a. Prolonged use of thiazide diuretics
b. Clofibrate (topical corticosteroid)
c. Cyclophospamide (alkylating agent for tx of neoplasm &
immunosuppressant s/p organ transplant

67

d. Chlorpropamide (oral hypoglycemic)

e. Carbamazepine
f. NSAIDs
3. Pregnancy
SIADH is the most common cause of hospital acquired hyponatremia
Diagnosis
Low sodium level/osmolality
Inappropriate high urine osmolality (usually > 100mOsm/kg)
Urine sodium usually > 20 mEq/L
Renal fxn must be normal
Hypothyroidism must be R/O
May have increased ADH secondarily
Water restriction often only therapy required
Demeclocycline
Renders kidneys resistant to ADH may help

Hyponatremia with Hypovolemia

Clinical evidence of dehydration
Sodium loss may occur by
Renal or non-renal route
With severe volume depletion, regulation of volume takes precedence over
osmolality regulation
ADH increases
If free water is not restricted hyponatremia results
Renal sodium loss may result from
Urine sodium levels are high 20 mEg/L
Diuretics
Adrenal insufficiency
Thought to explain hyponatremia in AIDS patients
Salt-losing renal ds (rare)
Hyponatremia with urine sodium < 10 mEq/L
Non-renal source is likely
Vomiting
Diarrhea
Excessive sweating
If fluids are replaced solely by water
Hyponatremia may result
Important causes of hyponatremia that should be considered in all patients is
Pseudohyponatremia & hypothyroidism
Low serum sodium can be a measurement artifact
Hyponatremia assoc with normal or high serum osmolality
Psueudohyponatremia
May not reflect plasma osmolality when plasma water is reduced
Conditions such as
Hyperlipidemia
Myeloma
Condition requires no direct treatment

68

Corrected calculation
Add 1.6 mEq/L to measured sodium for every 100 mg/dL
elevation in serum glucose

Therapy
Often discovered only incidentally
Usually no specific therapy is required
Euvolemic & hypervolemic patients
Water restriction usually sufficient
Hypovolemic/hypotensive
Isotonic solution for volume repletion & maintenance BP
Severe systemic hyponatremia
Infusion of hypertonic (3%) saline
Serum sodium level should be returned slowly to ~125 mEq/L

HYPERNATREMIA
Develops when water loss exceeds sodium loss
Water may be lost
Through the kidneys by
CENTRAL diabetes insipidus Inadequate ADH secretion
Any process that interrupts or destroys the hypothalamic-pituitary
axis
Trauma
Tumors
Strokes
Infiltrative diseases
Sarcoidosis
NEPHROGENIC diabetes insipidus Poor renal response to ADH
Caused by anything that affects renal response to ADH
Renal disease
Hypokalemia
Hypercalcemia
Meds
Lithium & demeclocyline
Skin
Sweat or burns
Through the lungs
Normal thirst mechanisms usually lead to free water replacement and reduction
of hypernatremia
Develops when the patient is
Obtunded
Comatose
Institutionalized without access to water
High risk patients
Infants
Patients with stroke
Neurosurgical patients who have acquired diabetes insipidus from intracranial
event (or from cognitive & mobility compromise)

69

Responds to slow replacement of lost water

Central diabetes insipidus can be treated by ADH analogs
Nephrogenic diabetes insipidus
Resistant to ADH
Respond to free water replacement or thiazide diuretics

POTASSIUM
Main intracellular cation
Preferentially restricted to intracellular space by
Na+-K+-ATPase Pump
EC [Potassium] 3.5-5 mEq/L
Cells are large reservoir
Gradient from intracellular to EC is basis for resting membrane potential of cells
Normal gradients are important for
Secretory activity
Electrical activity
Small changes to ECF [K+]
Large effect on cardiac & neuronal cells
Major determinants of concentration in ECF
Distribution of potassium between cell & ECF
Renal excretion of potassium
Dietary intake
Cellular breakdown
Distribution between cell & ECF
Determined by
Sympathetic nerve
pH of EC space
activity
EC potassium levels
Insulin
Acidosis
Leads to hyperkalemia
H+ enters cells K+ leaves to maintain electrical neutrality
Alkalosis
K+ enters cell & H+ leaves
Leads to hypokalemia
Things that drive potassium into the cell
Alkalosis
Insulin
Used to tx hyperkalemia
Sympathetic nerve activity
Potassium intake
Buffered by cells
Cells act as buffer & reservoir
Kidneys excrete excess
Massive cell death
Releases large amounts of potassium
Kidneys cant keep up
Hyperkalemia can rapidly develop

70

Total amount of potassium is regulated by renal excretion

Under several controlling influences
1. A fall in the glomerular filtration rate reduces potassium excretion
2. Aldosterone increase potassium secretion
3. Delivery of Sodium to the distal tubule enhances potassium secretion
4. The [K+ & H+] in the renal tubular cell also contribute to regulation of
potassium secretion
a. Alkalosis increases the intracellular [potassium]
i. Provides more potassium for secretion
b. Concomitantly there are fewer intracellular H+ competing with the
potassium for the same or similar pumps
5. Increased tubular flow causes increased potassium secretion
Maximal potassium secretion
Associated with
High aldosterone levels
High delivery of sodium to the distal tubules
Alkalosis
Common in patients receiving diuretics
Why hypokalemia is side effect

Hypokalemia
Generally well tolerated
Increases risk of digoxin toxicity
Competes with K+ for the Na+-K+-ATPase Pump
Profound or rapid hypokalemia
Nausea
Aryrhythmias
Impaired gastrointestinal motility
Carbohydrate intolerance
Impaired urine-concentrating
Skeletal muscle weakness
ability
Potassium may be lost via
Kidneys
GI tract
Shift into cells
Clinical situations associated with renal potassium loss
1. Use of diuretics
a. All except triamterene cause severe loss
2. Osmotic diuresis
a. May occur with hyperglycemia
i. Hypokalemia via increasing distal sodium delivery & flow rate
3. States of primary or secondary hyperaldosteronism increases secretion
4. Renal tubular acidosis
Gastrointestinal causes associated with hypokalemia
Prolonged vomiting
Results in poor renal potassium conservation
Diarrhea
Fistulous drainage

71

Hypokalemic periodic paralysis

Familial disorder
Attacks of weakness or complete paralysis
Accompanied by transient mvmt of potassium into cells
Initiated by high carbohydrate meal
Hypokalemic therapy
Proceed slowly
Employ oral & IV supplementation with potassium chloride
IV must be done cautiously
No greater than 10 mEq/hr
To prevent arrhythmias from transient hyperkalemia

Hyperkalemia
Significant hyperkalemia
Serum [potassium] > 6.5 mEq/L
Ventricular fibrillation
Cardiac standstill
Evident on EKG
Changes are neither invariable nor specific
T wave moves in a progression
Tall peaked
PR interval prolongs
P wave diminishes
QRS complex widens
P wave disappears
QRS complex & T wave merge
Portends cardiac arrest
Causes of hyperkalemia are
Inadequate renal excretion
Movement of potassium out of the cells
Causes of inadequate secretion
1. Renal failure (especially with low urine flow)
2. Absence of aldosterone
a. Hyporeninemic hypoaldosteronism
i. Diabetes, chronic renal failure & adrenal insufficiency
3. Drugs that reduce potassium excretion
a. Potassium sparing diuretics
b. ACE inhibitors
c. Cyclosporine
d. NSAIDS
Anuric renal failure patients
[potassium] increases ~ 0.5 mEq/L/day
If patient has compromised renal fxn administration of potassium loads may
cause an iatrogenic hyperkalemia
Acute hyperkalemia
Massive cell death
Source is usually muscle from crushing injury, etc

72

Less often is RBC from internal hemorrhage

Death of rapidly growing tumor cells
Result of chemotherapy
Apparent hyperkalcemia
Result of cell lysis in sample from patients with thrombocytosis or
leukemic leukocytosis
Therapy
Adjusted for severity of electrolyte disturbance
Severe cases
[potassium] > 8mEq/L
EKG changes to QRS complex or P wave
Toxicity countered by
Calcium Gluconate infusion
Effect almost immediate
Excess potassium moved back into cells
By alkalinization with sodium bicarbonate
Insulin given to enhance mvmt of potassium into cells
Noticeable in 1 hour
Glucose is given also to prevent hypoglycemia
Excretion
Stimulate urine flow with diuretics
Potassium-trapping resins
Kayexalate (polystyrene sulfonate)
Chelates
May cause overload by increasing [sodium]
Exchanges sodium for potassium
Sorbitol given to induce diarrhea
Use sparingly and for temp measure only
Dialysis
Impaired renal function
Massive load of potassium
Less acute cases
Diuretics suffice
[Potassium] < 6.5 mEq/L
Underlying cause may be treated first

PRINCIPLES OF SALT AND WATER THERAPY

Basal requirements
Normally can be met with appropriate combinations of
Saline
Glucose
Potassium chloride
Allow for a loss of 1000mL of water per day
Kidneys 500ml
Insensible loss 500ml
Lungs & skin
Increase with fever & hyperventilation

73

20 mEq/day potassium loss

Obligate loss from kidneys
150-200 g/day carbohydrates to prevent protein catabolism
Sodium is flexible
Patients with normal renal fxn loss decreased to almost zero with dietary
restriction
Estimation of losses
Direct measurement of [ionic] from lost fluids
Vomitus, diarrhea, etc
Standard estimates
ESTIMATING ELECTROLYTE LOSSES (mEq/L)
Route of
Na+
K+
H+
loss
Gastric
40
10
90
secretion
Diarrheal
50
35
fluid

Cl-

HCO3+

140

45

40

45

If patients lose more than 0.3 kg/day it may represent fluid loss or severe
catabolism

REGULATION OF PH
Acidosis & Alkalosis
Virtually all fxns directly or indirectly depend on regulation of pH
pH
Acidosis < Normal 7.4 < Alkalosis
Acidemia Arterial pH < 7.36
Alkalemia Arterial pH >7.44
A pt may have acidosis without acidemia
Two concurrent acid-base disorders coexist
If there is no counterbalancing action
Acidosis results in at least a slight acidemia
pH regulatory mechanisms
Buffering
Extracellular
Intracellular
Excretion
Lungs as CO2
From kidneys

Buffers
Each buffer has a unique affinity for H+ ion
All body buffers are in equilibrium at all times
If ratio of protonated buffer to nonprotonated buffer is known
Predict
The pH

74

The ratio of any other buffer system

Predictions via Henderson-Hasselbach equation
pH = pKb + log (B)/(B X H+)
B = [nonprotonated buffer]
(B X H+) = [protonated buffer]
pKb = constant that is characteristic of, and describes each buffers H+
affinity
Most used ratio is the bicarbonate-carbonic acid buffer system
CO2 + H2O H2CO3 HCO3- + H+
pK is 6.1
Formula for calculation is
pH = 6.1 + log (HCO3+) / (constant X PaCO2)
HCO3+ is [bicarbonate] in blood
PaCO2 is the partial pressure of CO2 in the blood
Increasing PaCO2 lowers the pH
Increase in HCO3+ raises the pH
The total buffer store is ~ 12 15 mEq/kg body weight
Severe acidosis releases of calcium salts from bone may help
To restore buffer system
Body must excrete excess acid
Lungs
Kidneys

Lungs
Metabolism of fats & carbs
Dissolved CO2
Carbonic anhydrase enzyme readily hydrates
Produces ~ 13,000 mEq/day of carbonic acid
Excretion of CO2 by the lungs drives rxn to the left
Decreasing [carbonic acid]

Kidneys
Chronic source of acid
Nonvolatile e.g. non-CO2
Results from fat & carb metabolism
H2SO4, H3PO4 & uric acid
Produces ~ 70 mE1/day of acid
Handled in two ways
H+ ions into tubules
Binds with appropriate anion
+
H in the form of ammonium (NH4+)
Generates new bicarb
Reclaimed in the proximal tubule

Interpreting Acid-Base disturbances

First step is to assess 3 things
pH
[HCO3+] Metabolic acidosis
PaCO2 - Respiratory acidosis

75

Metabolic acidosis
Fall in [bicarbonate] partially counterbalanced by hyperventilation
Decreases PaCO2

Respiratory acidosis
Rise in PaCO2 counterbalanced by renal retention of bicarbonate
A rise in the pH can be from
HCO3- Increase (Metabolic Alkalosis)
Counterbalanced by hypoventilation
PaCO2 Decrease (Respiratory Alkalosis)
Counterbalanced by renal bicarb wasting
pH DISTURBANCES
pH
Metabolic

Acidosis
Respiratory

Acidosis
Metabolic

Alkalosis
Respiratory

Alkalosis

Primary Disturbance

Compensatory response

HCO3(Bicarb)

PaCO2

Ventilation

Renal
Bicarb

Respiratory Acidosis
PaCO2 > 45
Ventilatory system can no longer compensate for metabolic production of CO2
Acidosis
Buffering of resultant acid occurs in two phases
Acute respiratory
Carbonic acid levels rise & H+ dissociates
Buffered by cellular proteins
H+ enters cells & is exchanged for
Sodium
Potassium
Completed in ~ 10 minutes
Cellular systems only partially buffer
There is still a large change in the [acid] for each increment of
change in the PaCO2
Chronic respiratory
Increase in the [H+] excretion via formation of urinary ammonium
pH change is less for the same change in PaCO2 than in acute
respiratory acidosis
Kidney cannot fully compensate
pH does not return to 7.4

76

Chronic hypercapnia
Better able to prevent [acid] changes
Chronically elevated HCO3- levels
Prior degree of renal compensation and acute changes do not affect as
much
Any disorder compromising ventilation
Can produce respiratory Acidosis
Leading causes are
COPD
Neuromuscular disorders affecting diaphragmatic excursion
Thoracic cage deformities
Anything causing CNS depression with consequent hypoventilation

Respiratory Alkalosis
Acute Respiratory Alkalosis
Hyperventilation
Decrease PaCO2 < 36 mmHg
Results from
Anxiety
Pain
Salicylates
Intracranial heme
Fever
Sepsis
Symptoms
Lightheaded
Paresthesias
Numbness
Tingling (Mouth & fingers)
Severe May cause unconsciousness
Tx
Rebreathing (paper bag)
Find underlying cause & fix
Chronic Hyperventilation
Causes
Stiff lungs interstitial lung ds
Hypoxemia of high altitude
Cyanotic congenital heart ds
Thyroid or liver ds
High serum progesterone during pregnancy
Bodys Response
Asymptomatic
Renal compensation returns pH to normal
Tx - None

Metabolic Acidosis
Low arterial pH assoc. with low [bicarb]
Compensatory hyperventilation

77

Many causes
Calculation of anion gap essential for dx
Anion Gap
The sum of chloride + bicarb (EC Anions) is usually less than predominant EC
Cation (sodium)
This difference
[Na+ - (Cl- + HCO3+)]
Expressed as mEq/L is the anion gap
Normal is < 12 14 mEq/L
Represents
Phosphate
Sulfate
Protein
Other endogenous & exogenous anions
Metabolic acidosis can present with normal or widened anion gap
Acidosis with a widened anion gap
Only ltd # of disorders causes a metabolic acidosis with widened anion gap
H+ ion and accompanying anion produces the widened gap
Disorders include
Toxic ingestions
Salicylates
Concomittant respiratory alkalosis
Paraldehyde
Unmistakable odor (hypnotic partially secreted through lungs)
Methanol
Blindness & optic disc hyperemia
Ethylene glycol
Metabolized to oxalate calcium oxalate crystals in urineStates of
acid retention
States of acid retention
Uremia
Widened anion gap only late in course
Diabetic ketoacidosis
Acidosis results from production of
Acetoacetic acid
-hydroxybutyric acid
S&S of diabetes
Bedside detection relies on
Calorimetric reaction of nitroprusside with acetoacetate
Acidosis may be underestimated when -hydroxybutyrate
is predominant ketone
Lactic acidosis
Occurs with tissue hypoxia
Shock or respiratory failure
Several poorly understood states

78

Frequently acidemia of diabetic ketoacidosis has a component of

lactic acidosis
Acidosis With A Normal Anion Gap
Results from a loss of bicarbonate
From
Kidney
GI tract
Balanced by increase in serum chloride
Hyperchloremic acidosis
Chloride rises as bicarb declines
Anion gap doesnt change
Bicarb depletion
Loss of bicarb-rich fluids
Diarrhea
Pancreatic fistulas
Ureterosigmoidostomy
Ureter implanted into sigmoid colon
Urinary chloride exchanges for serum bicarb
Alkaline urine
Normal kidney
90% of bicarb resorbed in proximal tubules
Generation of new bicarb
Dissociation of H2CO3 into H+ and HCO3H+ secreted into lumen trapped as NH4+
Or trapped with other buffers (Phosphate)
HCO3- resorbed into blood
Production of ammonia by kidney is flexible
Can be stimulated over several days to handle increased acid load
Renal Tubular Acidosis (Normal urine pH is 4.8-5.2)
Three major subtypes
Type I Distal Renal Tubular Acidosis
Proximal reabsorption of bicarb adequate
Distal tubule H+ Secretion compromised
Produces a decreased serum potassium level
Urine pH > 5.5 even with an acid load
Accompaniment of the defect in urinary acidification
Hypercalciuria
Osteomalacia weakening of bones from mineralization problems from
type 1 renal tubular acidosis
Renal stone formation
Causes
Idiopathic
Distal renal tubular damage from
Multiple myeloma
Hyperthyroidism
Drug toxicity

79

Amphotericin B
Vitamin D
Lithium
Treatment
Moderate amounts of oral bicarb corrects acidosis
Type II Proximal Renal Tubular Acidosis
Ability of proximal tubule to reabsorb HCO3- is compromised
HCO3- is lost
Increased serum potassium levels
Limited capacity of distal tubule to reabsorb flood of bicarb is overwhelmed
Serum bicarb levels drop to where proximal tubules can reabsorb the decreased
load & remainder is claimed in distal tubule
Urine acidified to pH < 5.5
Caused by
Damage to the proximal tubules
Heavy metals
Bence Jones proteins (Multiple myeloma)
Generalized disorder of proximal tubular function (more common)
Fanconi Syndrome
Lose bicarb, glucose phosphate, urate & aa in the urine
Tx
Large quantities of oral bicarb to correct
Readily spill any administered bicarb
Type III Renal Tubular Acidosis
Hyporenimic hypoaldosteronism
Characterized by
Mild Acidosis
Elevated serum potassium levels
The elevated potassium levels
Suppresses the production of ammonia
Contributes to sustaining acidosis
Diabetics are most commonly afflicted
Metabolic Acidosis
In General
pH > 7.2 is well tolerated
Allows focus on tx of underlying disorder
pH < 7.2
Bicarb may be administered as temporary tx only
Underlying disorder still must be corrected

Metabolic Alkalosis
Kidney is responsible for most cases of metabolic alkalosis
Secretion of H+ ions
Rarely does alkali ingestion or injection underlie cause
Lab tests to differentiate causes for treatment
Most common cause
Contraction Alkalosis

80

Urine chloride < 10 mEq/L

Reflects renal salt retention to restore normal volume
Combination of volume depletion & chloride depletion
Diuretics
Vomiting
Kidneys attempt to maintain volume by reabsorbing sodium
Electrically neutral mechanism
Absorbing a chloride ion with
Secreting a hydrogen or potassium ion in exchange
Chloride depletion from prolonged diuretic use or vomiting results in
H+ ion secretion to maintain volume
Results in and maintains the alkalosis
Volume regulation trumps pH homeostasis
Tx
Lungs play small role with hypoventilation
Limited by hypoxemia
Administration of sodium chloride with potassium chloride is
curative
Less common causes
Chloride-resistant Alkalosis
Urine chloride > 10 mEq/L
Hypokalemia
Depletion of intracellular potassium leads to increased H+ ion
secretion by renal tubular cells
Adrenal Cortical over activity
Directly stimulate H+ ion & potassium secretion
Tx
Treatment of adrenal disease
Repletion of potassium
Metabolic alkalosis by itself doesnt have obvious signs & symptoms
If hypocalcemia is present
Tetany may result
Alkalosis decreases the portion of ionized calcium present
Rarely so severe and refractory to volume 7 potassium chloride replacement that
acid administration is needed
Dilute hydrochloric acid (0.1N)
Acetazolamide

Mixed Acid-Base Disorders

Patients may present with multiple acid-base disturbances
Common combo
Respiratory acidosis & metabolic alkalosis
COPD
Respiratory Acidosis
CHF tx with salt restriction & diuretics
Metabolic Alkalosis
pH is variable

81

Depends on predominant process whether it is acidotic, alkalotic or normal pH

All cases
PaCO2 & Bicarb are high
Any combination of disorders is possible with exception of respiratory alkalosis
and respiratory acidosis
Existence of mixed disturbances complicates the interpretation of alterations in
the pH, PaCO2 & Bicarb

82

Chapter 18 Acute Renal Failure

ARF occurs mostly in hospitalized patients with other conditions
First signs of ARF
Oliguria - < 400mL/day
Minimum amount to clear produced metabolites
Detection of ARF
Increase in BUN (Blood Urea Nitrogen)
Increase in serum creatinine
BUN & Creatinine
Products of normal metabolism
Indirect markers of Glomerular Filtration Rate (GFR)
Produced at a constant rate
Freely filtered
Not significantly resorbed or secreted
Any decrease in GFR leads to retention & elevation of [serum]
ARF that occurs in the community usually result from
Hypovolemia
Drugs
Especially NSAIDs
ACE inhibitors
Obstruction
ARF that occurs in the hospital
Combination of factors
Hypovolemia
Drugs
Sepsis
Underlying medical condition
Results in development of Acute Tubular Necrosis (ATN)
Increase in BUN & Creatinine
Not specific for intrinsic renal failure
Must rule out
Prerenal failure
Most common cause of nosocomial renal insufficiency
Condition that compromises renal fxn
Reduced renal perfusion
Postrenal failure
Also common
Obstruction of urine flow

PRERENAL FAILURE
AKA Azotemia (Retention of excessive amounts of nitrogenous compounds in
the blood)
Reversible renal compromise
Diminished renal perfusion
Any disorder that inhibits blood flow to kidney can be responsible
Volume depletion due to
1. Hemorrhage

83

a. Dehydration
b. Surgery
c. Cardiac dysfunction resulting in decreased cardiac output
2. Diminished intravascular volume
3. Redistribution of intravascular fluid into the EC space
a. Hepatic cirrhosis
b. Nephrotic syndrome
c. Sepsis
d. Burns
Prerenal failure exacerbated by inhibition of adaptive mechanisms or decreased
renal perfusion from
Diuretics
NSAIDs
ACE inhibitors

POSTRENAL FAILURE
Bilateral or unilateral outflow obstruction
Pelvic pathology
Men Enlarged prostate
Women gynecologic ds
Bilateral ureter blockage is uncommon
Extrinsic compression
Lymphoma
Fibrosis
Intrinsic obstruction may cause total anuria
Stones
Crystals
Blood clots
Diagnosis
Abdominal ultrasound
Dilated collecting system (Hydronephrosis)

ACUTE INTRINSIC RENAL FAILURE

Grouped into three categories based on pathology
1. Glomerular disease
2. Vascular disease
3. Tubulointerstitial disease

Glomerular Disease
Uncommon cause of ARF
Follows a subacute or chronic course
When fulminant enough ARF
Always associated with a active urinary sediment
Term Rapidly Progressive Glomerulonephritis (RPGN)
Prominent findings
Oliguruia
Proteinuria
Hematuria
RBC casts

84

Several disorders can cause sudden renal deterioration

Goodpastures Ds antibodies directed against cross-reacting antigens in
basement membranes of glomeruli & pulmonary alveoli responsible for
organ damage
Glomerulonephritis associated with systemic vasculitis
o Wegeners Syndrome
o Microscopic polyarteritis
o Idiopathic RPGN
Glomerulonephritis associated with infection
o Poststreptococcal disease
o Abscesses
o Endocarditis
o Shunt infections
Glomerulonephritis associated with systemic disease
o Systemic Lupus Erythematosus (SLE)
o Henoch-Schnlein purpura A self limiting hypersensitivity
vasculitis chiefly of children
Glomerulonephritis associated with primary glomerular diseases
o Membranoproliferative glomerulonephritis
o Membranous glomerulonephritis
Pathogenesis
Immunologic mechanism
Poststreptococcal glomerulonephritis
Lupus nephritis
Many other glomerular disorders
Immune complexes & complement (responsible for lysis) are responsible
for much of the damage

Vascular Diseases
Diseases responsible include vascular occlusive processes
Renal artery dissection
Thrombosis or embolism
Renal vein thrombosis
Present with a clinical triad
1. Sudden & severe low back pain
2. Macroscopic hematuria
3. Severe oligura that borders on anuria
Rare but should be suspected in patients with Severe atherosclerotic peripheral
vascular Disease
Renal vein thrombosis considered for underlying hypercoagulable state
Nephrotic syndrome
Diagnosis
Renal perfusion scan is best
Other vascular diseases that can lead to ARF
Vasculitis
Scleroderma
Malignant hypertensionThrombotic thrombocytopenic purpura

85

In the above diseases intravascular thrombosis of small & medium-sized vessels

lead to glomerular & tubular ischemia

Tubulointerstitial Diseases
Most common causes of acute intrinsic renal disease
Subdivided
Acute interstitial nephritis
Acute tubular Necrosis (ATN)
Interstitial Nephritis
Caused by
1. Systemic diseases
a. Sarcoidosis
b. Sjgrens
c. Lymphoma
2. Systemic infections
a. Syphilis
b. Toxoplasmosis
c. Cytomegalovirus
d. Epstein-Barr
3. Drugs
a. -lactam intibiotics
i. PCN & Cephalosporins
b. Diuretics
c. NSAIDs
Drug induced
Eosinophils in urine & other systemic manifestations of hypersensitivity
reaction
Returns to normal after cessation of drug
Steroid therapy may help resolve more quickly
NSAIDs
Rarely by induction of interstitial nephritis
More common
ARF in pt with
Underlying renal ds
CHF
Hepatic cirrhosis
NSAID inhibition of prostaglandin synthesis
Used in role of renal hemodynamic regulation
Chronic interstitial nephritis & papillary necrosis
Prolonged use
When induce acute interstitial nephritis
Often no clinical evidence of hypersensitivity reaction
Acute Tubular Necrosis
Major cause of acute intrinsic renal failure is with hospitalized patients
Clinical more than pathologic diagnosis with causes from
Renal ischemia
Sepsis

86

Nephrotoxins
Histologic confirmation in only a few patients
Most who survive recover renal function
Many causes can be grouped into two categories
Ischemic from
Shock
Hypoxia
Trauma
Sepsis
Should suspect if positive hx of ischemic event, oliguria or
increased creatinine
Toxic
Heavy metals
Ethylene glycol
Paraquat A pesticide
Contrast media
Dye induced renal failure
Prognosis
With good renal function before
Good prognosis
Creatinine peaks 1 week s/p & renal fxn
returns
With poor renal function before
Possible irreversible renal shutdown
Risk factors increase for
Underlying renal dysfunction
Diabetes is major
Multiple myeloma
Hepatic failure
Aminoglycoside renal toxicity
Usually reversible
Toxicity is dose related
Close monitoring is necessary
Increased incidence with concomitant use of
Diuretics
NSAIDs
Contrast Media
Other nephrotoxic drugs
Rhabdomyolysis
Increased myoglobin in blood for filtering
Cannot differentiate from heme with dipstick
Must differentiate from heme with
Electrophoresis
Immunoassay
Causes
Trauma
Burns
Alcoholism

87

Seizures
Violent exertion
Prolonged muscle ischemia from arterial embolus
Pressure over bony prominences in comatose or bedridden
Myoglobin
Doesnt cause damage serves as a marker for rhabdomyolysis
Other intracellular muscle enzymes are released
Creatine kinase & aldolase
May exceed 100,000 IU/L
Also common
Hyperkalemia
Hyperuremia
Hyperphosphatemia
Calcium Decrease
Tumor lysis
May cause ARF
Especially in hypovolemic
Phosphate & potassium may rapidly rise
Tx at risk patients with Allopurinol
Diuresis initiated
Volume replacement & diuretics
Dialysis for early hyperkalemia
Differential Dx ARF
Determine first
Prerenal failure
Intrinsic renal disease
Post renal blockage
Exclude post renal obstruction
Renal ultrasound to dx
False neg may occur 48 hrs for collecting sys dialation
Retrograde pyelogram
Dye introduced transurethrally
Differentiate prerenal Disease from intrinsic renal disease
Prerenal usually positive for hypovolemia
Support differential dx with labs
BUN & Creatinine levels
Intrinisic
Both rise together
Prerenal failure
Both rise, but
BUN >Creatinine
Urea can be resorbed from renal tubules, but
creatine cannot
BUN:Creatinine 20:1 ratio
Incr BUN:Creatinine in pt with renal
impairment also

88

Incr Nitrogen burden

GI Hemorrhage
Hypercatabolic states
Sepsis
High dose roids
Incr. protein load
Sodium
Prerenal failure
Permits sodium reabsorption while [urine]
Urine sodium < 15 mEq/L
Osmolality is high > 500 mOsm/L
Specific gravity ~ 1.02
Intrinsic Renal Disease
Urine sodium > 15 mEq/L
Osmolality low < 400mOsm/L
Specific gravity ~ 1.010
Fractional excretion of sodium best determinant
1% in intrinsic Far less in prerenal
Calculated by:
_____(Urine Sodium/Plasma Sodium)_____X 100
(Urine Creatinine/Plasma Creatinine)
Can be confused by:
Diuretics
Dopamine
Manitol
Saline
Examination of urinary sediment
Prerenal failure
Fairly benign appearing
A few scattered hyaline or finely granular
casts (molds of tubules from cell &
protenacious debris)
Hyaline casts
Non-specific
Healthy persons
Active sediment
Intrinsic renal ds
Marked hematuria
Proteinuria
ATN Sedimentation
Epithelial cells
Pigmented granular casts
Course & Complications

89

Period of renal failure

Lasts usually 1-2 weeks (may persist for months)
Must receive intensive medical support for survival
50% of ATN do not have oliguria (<400mL/day) during acute phase
Non-oliguric likely from nephro toxic agents
Not able to predict who will have oliguria or not
Non-oliguric pts usually have milder symptoms and lower
mortality rate
Major complications are
Fluid & electrolyte imbalances
Infection
Uremia
Volume overloads & water intoxication pose serious dangers
Most hyponatremia & circulatory overload are iatrogenic
Serum Potassium
Increase ~ 0.5 mEq/L/day
Rate increased by fever or injury from breakdown of tissue
Hyperkalemic symptoms will occur
Metabolic Acidosis
All ATN pts experience
Normal metabolism 1 mEq/kg/day of acid
Severe
Coma
Shock
Heart failure
Phosphate
Absorbed from gut
Released from bone
Accumulation enhanced by tissue (esp muscle) breakdown
Infection
Rate is 35-75%
Urinary & respiratory tracts are common
Sepsis account for highest percentages of death
Uremic Syndrome
Pericarditis
Anemia
Bleeding tendencies
GI disturbances
CNS disorders
NOT SEEN IN ATN
Peripheral neuropathy
Renal osteodystrophy
Recovery phase
Serum BUN & creatinine plateau & decline
Urine output increases in oliguric patients
Diuresis may be profound

90

Not usually seen in non-oliguric patients

Hypercalcemia may occur & enhance diuresis
Care must be taken to avoid hypovolemia
Patients are often left with little or no residual effects
Prevention & Therapy
Proper hospital management
Creatinine checked for patients recv nephrotoxic drugs
If a patient suffers renal failure after hypotensive episode
Correction of cardiac output should be primary therapeutic maneuver
Early stages of ARF
IV diuretics (furosemide)
Next stage of management
Match fluid & salt I/O
Limit dietary potassium
Mild metabolic acidosis is usually tolerated
Severe metabolic acidosis should be treated
ARF pts should have 1000-2000 cal/day of carbohydrate with minimal potassium
Minimum 800 cal/day or protein catabolism ensues
Small amount of protein should be included for
Better survival of sepsis
Better recovery of function

ACUTE VERSUS CHRONIC RENAL FAILURE

Uremic syndrome that occurs in chronic renal failure can occur in acute renal
failure as well except renal osteodystrophy & peripheral neuropathy (also not
seen in ATN)
Renal ultrasound
Small shrunken kidneys indicate chronic
Not foolproof test
False negatives
Diabetes mellitus
Amyloidosis

OTHER MANIFESTATIONS OF RENAL DISEASE

Outpatients dont have the same oversight as hospitalized
Vague complaints of
Lethargy & fatigue
Routine urinalysis and measurements of
BUN
Creatinine
Electrolytes
Hallmark of renal dysfunction
Hematuria
Proteinure

Hematuria
Results from bleeding anywhere along urinary tract
Rarely signifies important renal ds
>40yrs old usually benign

91

Some rare disorders are ruled out by sediment & other testing
In older persons must R/O
Prostatic hypertrophy
Bladder & prostatic neoplasms
Cultures to R/O infection
Other testing as necessary

Proteinuria
Most sensitive sign of renal dysfunction
Specificity is low
Benign causes
Fever
Exercise
Stress
Orhtostatic proteinuria
Idiopathic proteinuria (young adults & children)
Spontaneous resolution
If persistent
Repeat test
24hr collection
Upper limit of normal
150mg/day
Both glomerular & tubulointerstial ds can be associated with excretion of up to 3
gm/day of protein
>3gm/day (The nephrotic syndrome) indicative of glomerular pathology

Nephrotic Syndrome
Any glomerular lesion that produces more than 3 gm / day of protein in the urine
All of the diseases that cause the nephrotic syndrome enhance the permeability
of the glomerulus to plasma proteins
Hypoproteinemia leads to decline in plasma oncotic pressure
Edema
Serosal effusion
Hypercholesterolemia is often seen
Maltese crosses of urinary cholesterol
Polarized light examination of urine sediment
Differential diagnoses is vast
Common causes
Nil disease
Minimal change disease
Usually idiopathic
Associated with
Hodgkins ds
NSAID use
Electron microscopy needed to show loss of epithealial foot
Usually steroid responsive
Good prognosis
Doesnt progress to chronic renal failure

92

Focal glomerulosclerosis
Characterized by an obliterative glomerulosclerosis (scaring of the
renal glomeruli
Involves only a ltd # of glomeruli
Deposition of immunoglobulin & complement can be detected
Immunofluorescene
Focal glomerulosclerosis
IV drug users
AIDS patients
Most experience hypertension & chronic renal failure
Steroids benefit only some
Membranous glomerulonephritis
Manifestation of immune complex deposition
Responsible for of the cases of nephrotic syndrome in adults
May be idiopathic
May occur in association with
SLE
Certain chronic infections (HepB)
Certain solid tumors
Putative agents
Penicillamine
Gold
Captopril
Variable course of ds
Steroids are tx of choice
Especially Chlorambucil
Systemic causes
Sickle cell anemia
Medullary & papillary damage occur because of
hypertonic medullary interstium causes the RBCs to
sickle in the vasa recta
Can lead to urinary concentrating defect and
recurrent bouts of papillary necrosis
Diabetes Mellitus
Predispose to papillary necrosis & nephrotic
syndrome
Multiple myeloma
Bence-Jones proteinuria

93

Chapter 19 Chronic Renal Failure

The main dysfxn in CKD is related to diminished glomerular filtration & loss of
tubular fxn. The renal endocrine fxn (erythropoietin) & enzymatic fxn(25-OH-VitD
1,25(OH)2 VitD) is impaired. Metabolism of insulin & gastrin by the beans is
decreased leading to hypoglycemia especially in those who take oral
hypoglycemic agents and increase in peptic ulcers.
RENAL FUNCTION IN CHRONIC RENAL FAILURE
Intrarenal compensation for nephron loss
Good fxn until most of parenchyma is destroyed
Remaining nephrons Increase their GFR increase stress and destruction of remaining
nephrons
GFR decrease of 50% show no evidence renal dysfxn
Evidence of early CKD
HTN
Inability to compensate for H20 or solute loading
80-90% loss of fxn cant control with dietary maneuvers and replacement of kidneys is
needed.
Water & Sodium
Early renal insufficiency
Decreased ability to excrete maximum concentrated urine & conserve water may be first
sign
Excretion of maximal h20 load also impaired
Lose Na+ in urine
Potassium
GFR must be severely limited to decrease excretion of K+ Secreted by distal tubule
Susceptible to hyperkalemia in course of CKD
Be aware of diuretics, ACEi
Acid-Base Homeostasis
Excess acid excreted into urine with filtered:
Phosphate or sulfate (titratable acid)
Ammonia (NH3)
Tubule cells make ammonia prn by deamination of glutamine
When kidney fails
pH maintained until about 50% decrease in GFR
Eventually cant keep up with H+ production
Mostly because NH3 production is insufficient
Early acidosis is normal anion gap
Later acidosis increased anion gab
Manifestations of academia
Anorexia
Nausea
Weakness
Fatigue
Kussmaul respirations - very deep, gasping, desperate breathing in severe acidosis
Calcium & phosphate

94

Bone demineralization 2/2 altered Ca++ & PO43- metabolism

Hyperphosphatemia (cant excrete it) Hypocalcaemia 2 hyperparathyroidism
Cant activate VitD adds to Hypocalcaemia
2 hyperparathyroidism Osteitis fibrosa & metastatic calcifications
Creatinine Clearance
Constant rate of production ant secreted or reabsorbed
Expect a rise in level with decrease of GFR
Blood Urea Nitrogen
Decreased GFR incr BUN
Less precise guide to extent of renal compromise
The Uremic Syndrome
Pathogenesis unknown
Metabolic byproduct accumulation may be source
No systemic toxin ID
Some manifestations may be due to retention of filterable molecules, esp neuro
Signs & symptoms
Sallow complexion
Wasting
Purpura & excoriation
Pruritus
Polydipsia
Nausea
Loss of appetite
Lassitude
Vomiting
Urine lab findings
Isosthenuria urine has specific gravity the same as protein free plasma (kidney cant
make adjustments) and is fixed at ~1.010
Proteinuria
Abnormal sedimentation
Neurologic Manifestations
PNS & CNS derangements are prominent
Sensory polyneuropathy usually present
Bilateral foot drop early sign
Progressive
Carpal tunnel syndrome common
Initial CNS
Insomnia
Difficulty with concentration
Late signs
Clonus
asterixis
Seizures
Cardiopulmonary manifestations
Consequence of systemic HTN
Left ventricular hypertrophy

95

Left ventricular dysfunction

Accelerated atherosclerosis
Development of ischemic heart ds & arrhythmias
HTN common complication with ESRF
Mostly from volume overload

96

Chapter 25 Diabetes Mellitus

General information
4.5% of population
1/6th of all healthcare costs
Can affect every organ system
At a cellular level
Result of insufficient insulin action
Insulin is an anabolic hormone
Regulates fuel economy
Stimulates glucose uptake by
Muscle
Liver
Adipose Cells
Stimulates synthesis within the above cells of
Protein
Glycogen
Triglycerides
Without Insulin
Catabolic state
Breakdown of
Glycogen
Protein
Fat
Liver makes glucose from amino acids from muscle proteolysis
(gluconeogenesis) inducing hypoglycemia
Deficiency in adipocytes produces lipolysis releasing fatty acids into
circulation
Glucose lowering by insulin is counterbalanced by regulator hormones
Glucagon
Epinephrine
Growth hormone
Cortisol
All have overlapping effect in increasing hepatic glucose production via
Glycogenolysis & Gluconeogenesis
Inhibiting insulin secretion & action

CLASSIFICATION & PATHOPHYSIOLOGY OF DIABETES

MELLITUS
Four Division of Diabetes
Absolute Deficiency of insulin secretion
Type 1 Diabetes Mellitus (IDDM)
Target tissue resistance to insulin
Type 2 Diabetes Mellitus (NIDDM)
Diabetes recognized during pregnancy
97

Gestational Diabetes
Increased chance for diabetes later in life
Secondary Diabetes Directly attributable to another systemic illness
Sepsis
Cushings syndrome
Acromegaly
Pheochromocytoma
Severe & Chronic pancreatitis
Produce endocrine & exocrine insufficiency
Requires insulin therapy

Clinical Consequences of Deficient Insulin Action

When degree of hyperglycemia is greater than ability of kidneys tubular
reabsorption of glucose
Glucose appears in urine
Osmotic diuresis ensues
Results in polyurea
If volume depletion is not replaced, dehydration may occur
Early symptoms of Type 1 can include
Extreme fatigue
Weight loss
Common to Type 1 & II
Polyurea
Polydipsea
Polyphagia
Blurred vision
Result of osmotic changes
Poorly diffusible polyols (e.g. sorbitol) accumulate
Changes resolve as hyperglycemia is controlled
Yeast infections

Type 1 Diabetes Mellitus

Absence of Insulin
Destruction of insulin-producing -cells of the pancreatic islets of Langerhans
Ketoacidosis
Develops in absence of insulin therapy
Exogenous insulin essential
Autoimmune disorder
Not clearly understood
Islet cell antibodies usually appear before the onset of frank diabetes
Strong association with
Human Lymphocyte antigens (HLA) alleles
DR3
DR4
DQ
Familial history is lacking
50% for identical twins
15% for HLA identical siblings

98

Viral etiology has been argued, but specific causal relationship not found
Some develop as part of a polyglandular autoimmune syndrome associated with
Autoimmune thyroid disease
Adrenal insufficiency
Gonadal failure
Hypoparathyroidism
Pernicious anemia
Subclinical until 90% of -cells function is lost
The release of counter-regulatory hormones with stress of concurrent illness may
reveal illness earlier and have a honeymoon period before re-onset of
symptoms.

Type 2 Diabetes Mellitus

Accounts for 90% of DM in the US
Etiology
Resistance to the effect of target cells to insulin
It is a relative insulin insufficiency
80-90% of Type 2 patients are obese
Insulin resistance without hyperglycemia for years
Ultimately & unknown mechanism
-cells cease producing enough insulin to over come the insulin resistance
Insulin resistance & -cell failure
Lead to Increased hepatic glucose production
Glycogenolysis & gluconeogenesis
Disease progressively worsens over the years
Ketoacidosis is rare
Residual insulin production usually can prevent
Management
Early in disease
Diet
Weight loss
Exercise
Pharmacologic therapy later in disease
Strong genetic component
NOT HLA-linked
Family history of diabetes for most patients
90-100% among identical twins
30-40% in first degree relatives

DIAGNOSIS OF DIABETES MELLITUS

Diagnosis in a non-pregnant adult by any one of the three criteria
1. Random plasma glucose exceeds 200mg/dL & pt has signs & symptoms of
diabetes
2. Fasting glucose is >125mg/dL on two separate occasions
3. Plasma glucose >200mg/dL 2 hours after ingestion of 75g of glucose
Fasting glucose between 110-125 mg/dL or 2 hour between 140-200mg/dL
Has Impaired fasting glucose or Impaired glucose tolerance respectively

99

These patients are at increased risk for atherosclerotic disease &

developing overt diabetes mellitus

CHRONIC COMPLICATIONS OF DIABETES MELLITUS

DM is risk factors for
MI
Stroke
End-stage renal disease

Nontraumatic amputation
Blindness among 25-75Y/O in
the US

Diabetic Nephropathy
Chronic renal failure
Major problem in type 2
Leading cause of death in type 1
At autopsy
25% diabetic kidneys reveal Kimmelstiel-Wilson Lesions
Nodular glomerulosclerosis consisting of
Acidophilic
Spherical
Hyaline glomerular lesions
Diffuse hyaline thickening of glomerular capillary basement
membrane
May be a more significant pathology
Glomerular hyperfiltration occurs early in the course of diabetic nephropathy
Development of persistent microalbuminuria
Albumin excretion >50mg/day
Not detected by standard urine dipsticks
Predicts ultimate progression to gross proteinuria
>500mg/day
The nephrotic syndrome may develop in patients with severe proteinuria
Diabetics with mild renal insufficiency are at risk for
Developing acute renal failure after administration of radiological contrast media
Oliguric or nonoliguric
Usually transient
In a significant number of patients the creatinine clearance does not return
to baseline
Aminoglycoside antibiotics & NSAIDS are hazardous to
Insulin has an increased half-life
Insulin requirements decline during acute renal failure
Other causes of uremia
Papillary necrosis
Neurogenic bladder (dysfunction of the bladder caused by lesion of nervous
system)
Hyporeninemic hypoaldosteronism manifested by
Kyperkalemia
Hyperchloremic acidosis
Controlling hyperglycemia & hypertension
Paramount to delay & slow progression of diabetic nephropathy
Treatment

100

ACE inhibitors
Especially effective both hypertensive & normotensive
Other classes of antihypertensive agents also effective
Well controlled blood sugar
Low protein diet
Dialysis and renal transplant

Diabetic Retinopathy
Diabetics are at increased risk for developing
Open-angle glaucoma
Cataracts
Retinopathy
Most common cause of blindness
develop within 20yrs of disease onset
Pathogenesis
Divided into two broad categories
Nonproliferative (background) retinopathy
Proliferative retinopathy
Nonproliferative retinopathy
Develops first
Microaneurysms
Earliest lesion
May remain unchanged for months or years
Generally pose no threat to vision
Dot-blot hemorrhages
Common in non-proliferative stage
Increased capillary permeability produces
Retinal edema may impair vision if involves macula
Hard exudates (i.e. sharply demarcated white or yellow lesions)
Pre-proliferative phase
Progressive closure of capillaries produces
Retinal ischemia
Infarction
Manifested by soft exudates i.e. cotton wool spots
Large blot hemorrhages
Pan-retinal laser photocoagulation helps prevent sight loss
Also effective for patients with macular edema
Proliferative phase
Retinal ischemia ultimately develops
Stimulates angioneogenesis
This proliferative retinopathy represents the principal threat to vision
patients are blind within 5 years of diagnosis
Proliferative retinopathy also associated with
Diabetic nephropathy
CAD
Due to associated diseases average survival is less than 6 years after onset of
proliferative phase

101

Neovascularization is the hallmark of proliferative retinopathy

Vessels may sprout anywhere on the surface of the retina
Especially common near optic disk
Poor prognosis at this location
Neovascular vessels
Have little supportive connective tissue
Liable to hemorrhage into vitreous
Reorganization of vitreous hemorrhages produces fibrous tissue
Fibrous tissue contracts
Exerts traction on the retina
Leads to further hemorrhage or retinal detachment
The repeated hemorrhaging & fibrosis eventually cause severe retinal detachment
& sight loss
Screening
Retinopathy rarely occurs at the onset of type 1 diabetes
Type 2 diabetics or any diabetic patient over 30yrs of age
Baseline ophthalmologic examination scheduled with several months of diagnosis
Most lesions can be detected during routine fundoscopy
Exception is Retinal Edema
Onset of background retinopathy warrants referral to ophthalmologist
Fluorescein angiography
Dye injected IV & photographs taken of retina
Reveal macular edema
Delineate extent of retinopathy
Management
Glucose control & blood pressure control are necessary
Early detection is essential
Preventive therapy is necessary
Studies have shown that application of laser photocoagulation to
Macular edema
Proliferative retinopathy
Inhibits progression & spares vision
Laser therapy
Decreases vitreous hemorrhages

Diabetic Neuropathy
Includes a variety of neurologic lesions
Pathogenesis is unclear
Various theories
Microvascular lesions
Metabolic derangements
Accumulation of sorbitol in peripheral nerves
Axonal degeneration
Any peripheral nerve may be affected
Most conform to one of the following common syndromes
Distal Sensory Polyneuropathy
The most common neuropathic syndrome

102

Bilateral, symmetric, distal sensory impairment

Usually found in the lower extremities
Signs & symptoms
Diminished vibratory sensation
Decreased response to pinprick
Ankle reflexes are lessened or absent
Patients may experience as a result of C fibers (Pain fibers) being least affected
Pain
Paresthesias
Hyperesthesia
Often manifested as burning or lancinating pain
Especially at night
Painful neuropathies respond well to
Improved glycemic control
Tricyclic antidepressants
Gabapentin
Carbamazepine
Eventually C-fibers are affected
Pain replaced by hypoesthesia
Sequelae of chronic hypoesthesia
Painless ulcers
Un-noticed minor trauma
Because of lower extremity vascular deficiencies common in diabetics
Lesions are predisposed to infection
Decreased effectiveness of antibiotics
Infection may spread to surrounding tissues & bone
Osteomyelitis is difficult to treat in diabetics
Amputation may be required
Charcot Joint (i.e. neuropathic athropathy)
Patients may unknowingly damage their relatively anesthetic feet
Degenerative changes may develop in the tarsal & ankle joints
Prolonged & repetitive trauma may destroy joint surface
Dramatic physically & radiographically, but painless
Diabetic foot ulcers
Polymicrobial
Secondarily colonized
Superficial wound cultures rarely useful
Treatment
Superficial wound care
Collaboration with podiatrist
Empiric broad-spectrum antibiotics
Cephalexin
Clindamycin
Fluoroquinolone with one of the above
Recommended outpatient therapy
Failure to respond is indication for admission for

103

Parental antibiotics
Consideration for
Debridement
Hyperbaric oxygen
Upper extremity lesions are rare
Some patients may have atrophy of interosseous muscles of the hands
Diabetic Mononeuropathy
Mononeuropathy may present as
Simplex (single nerve)
Multiplex (Several nerves)
Caused by infarction of a peripheral nerve due to
Insufficiency of the vasa nervorum
Any nerve may be affected
Rapid onset of
Pain
Palsy of the oculomotor nerve (cranial nerve most affected)
Classically spares pupil function
Other nerves affected
CN VI
CN VII
Large nerves of the extremities
Radial
Ulnar
Median
Femoral
Radiculopathies can mimic abdominal crises
May take months to recover
Prognosis is excellent
Autonomic Neuropathy
Diabetic Cardiovascular autonomic neuropathy
Manifested by
Resting tachycardia
Absence of normal beat-to-beat variation of sinus rhythm that
accompanies respiration
Many have impaired baroreceptor reflexes
Do not display normal increase in heart rate after standing
Do not show slowing heart rate after Valsalva maneuver
Severe cases
Syncope may occur
Managed with support stocking
Increased salt intake
Aldosterone agonist Fludrocorticsone
Most Silent MI in diabetics is result of
Neuropathy of cardiac nerves
Autopsy reveals
Changes in sympathetic & parasympathetic nerves

104

Similar to neuropathic changes seen in bladder and elsewhere

GI tract can also be affected
Gastroparesis diabeticorum
Stomach emptying is delayed
Mimics gastric outlet obstruction
Metoclopramide or erythromycin
Increases gastric emptying & GI motility
Syndromes of
Gustatory sweating
Hyperemesis
Intractable diarrhea
Constipation
Fecal incontinence
75% of men with longstanding diabetes experience erectile dysfunction
Irreversible from DM
Neurogenic Bladder
Common in patients with diabetic neuropathy
Often asymptomatic
Increased residual urinary volume & bladder atony predispose to
Acute urinary retention
Urinary tract infection
The complications may worsen renal insufficiency in patients with
diabetic nephropathy

Macrovascular Complications
Patients are at increased risk for
CAD
Cerebrovascular disease
Peripheral vascular disease
Type 2 diabetics
Macrovacular complications twice as likely
type 2 diabetics succumb to CAD or its sequelae
Risk of CAD in Type 2 diabetics
2X in Men
3X in female
Diabetes is more important a risk factor than smoking
Greater risk of recurrent MI & cardiac failure
Pathogenesis of diabetic atherosclerosis
Multifactorial
LDL levels similar to non-diabetics
Increased oxidation of LDL particles increases atherogenicity
Microalbuminuric stage of diabetic nephropathy associated with increased
cardiovascular morbidity & mortality via unknown mechanism
Increased platelet aggregation
Microvascular abnormalities
Increased incidence of hypertension

105

Syndrome X
Well-recognized association of
Obesity
Hypertension
Dyslipidemia
Elevated VLDL
Decreased HDL
CAD
Insulin resistance & hyperinsulinemia of type 2 diabetes may be underlying cause
Insulin resistance is associated with low HDL levels
Low HDL is an independent risk factor for CAD
Small vessel disease has also been implicated in diabetic cardiac disease
Microaneurysm (A hallmark) has been found on autopsy
Diabetic Cardiomyopathy (Congestive heart failure)
Diffuse small vessel disease implicated
Clinical syndromes of small vessel disease
Claudication
More often in the diabetic than the non-diabetic
Surgical bypass is more difficult

EFFECTS OF GLYCEMIC CONTROL ON CHRONIC

COMPLICATIONS
Improved glycemic control delays onset & slows progression of diabetic
complications
Both type 1 & 2
Diabetes Control & Complications Trial (DCCT) in type 1 diabetics & United
Kingdom Prospective Diabetes Study (UKPDS) in type 2
Intensive glucose lowering therapy reduced development of
Retinopathy
Nephropathy
Neuropathy
No threshold for risk reduction
The greater the improvement in HgbA1c the lower the risk of
complications
The more intensively controlled patient has more incidences of hypoglycemic
reactions
Mild hypoglycemic reactions are unavoidable
As long as autonomic warning symptoms occur during waking hours and resolve
with glucose
Mild reactions are an acceptable trade off for tight control
Hypoglycemia that occurs
During sleep
Produce mental status changes
Asymptomatic
Significant immediate & long-term threat
Glycemic goals must be relaxed

106

Goal of therapy should be

Glycosylated hemoglobin <7
If it is <8.0 additional measures should be taken
Between 7-8 is a grey zone and stricter control is weighed against risks
Young patients stand to benefit the most from strict control
In older patients, the risk of recurrent hypoglycemia do not exceed the benefit of
tight control
To achieve tight control in type 1 patients
Insulin in multiple injections
Insulin pump
Aggressive control prevents & slows microvascular & macrovascular disease
Blood pressure must be controlled in these patients
ACE inhibitors are standard
Retards nephropathy
Other meds work
BP 135/80 or lower

MANAGEMENT OF PATIENTS WITH DIABETES MELLITUS

Principal goal of therapy is to ameliorate
Hyperglycemia & associated symptoms
Prevent hyperglycemic crisis, e.g.
Ketoacidosis
Hyperosmolar coma
Prevent or retard chronic complications of the disease
Neuropathy
Retinopathy
Nephropathy
Cardiovascular disease
All type 1 require insulin
Most type 2 can achieve control initially from a combination of or alone
Diet control
Exercise
Oral meds
As disease progresses, increasing pharmacologic therapy is needed

Nonpharmacologic measures
Burden of care is on the patient
Patient education is crucial
Must learn self monitoring techniques
Type 1 - Finger sticks 4 or more times a day (before meals & at bedtime)
Type 2 taking the meds
Dietary management
Emphasizes regularity of caloric intake & unsaturated fats
Type 1 timing & meal size matches insulin regimen
Type 2 Can reverse insulin resistance
Consistent exercise regimen
Aids in weight control & cardiovascular fitness
Exercise increases sensitivity to insulins effect independent of effect on weight

107

Glycosylated hemoglobin represents the duration of exposure to glucose

Reflects about 2-3 months
Surveillance & monitoring is important in all patients
Tests
HgbA1c q3mos
Microalbuminuria or 24-hour urine collection Annually
Fasting lipids - Anually

Pharmacologic measures
Oral antidiabetic agents
Prior to 1995 type 2 diabetics only had sulfonylureas & insulin preps with 3
different pharmacokinetic profiles.
Sulfonylureas
Increase pancreatic insulin secretion
Independent of blood glucose concentration
1st generation
Tolbutamide
Tolazamide
Chlorpropamide
nd
2 generation
Glipizide
Glyburide
Glimepiride
Benefits
Shorter duration of action
Reduced incidence of adverse effects
Among the most potent oral agents
Lowers HgbA1c by 1.5-2%
Complications
Weight gain
Hypoglycemia
Biguanides
Metformin is only one in class
Derivative of French lilac
Used for centuries as folk remedy in Europe
Inhibit hepatic glucose production
Modest increase in insulin sensitivity
Lowers HgbA1c by 1.5-2.0%
Favorable action on lipid profiles
Lowers LDL & VDL
Increases HDL
Complications
Most common is diarrhea
Minimized by starting with a low dose & gradually increasing
Rare to produce hypoglycemias
Modest weight loss (mild anorexigenic effect)
Lactic acidosis is most dangerous

108

Rare 0.03cases/1000 patient-years

50% mortality rate
Predisposing risk factors
Renal insufficiency
Serum creatinine >1.5 mg/dL in men, 1.4 mg/dL in
women
Liver dysfunction
Alcohol binges
Chronic Alcohol abuse
CHF or other conditions prone to hypoxia
Thiazolidinediones
New class of drug
Interacts with
Cell nuclear receptor
Peroxisome proliferator activating receptor (PPAR-)
Unknown gene transcription
Increases sensitivity to insulin in
Muscle
Fat
Possibly liver
Gradual decrease in glucose
4-6 weeks
Agents
Rosiglitazone
Pioglitazone
Lowers HgbA1c by 1.0-1.5%
Side effects
Volume expansion with edema may occur
Increase activity of hepatic P450 enzymes drug interactions may occur
Meglitinides
Derivative of benzoic acid
Acts on pancreatic -cells to augment insulin secretion
Repaglinide
First of class available
Short duration of action
Effective at lowering postprandial glucose levels
Modest effect on fasting glucose
Lowers HgbA1c by 0.7 1.3%
Generally well tolerated
Alpha-glucosidase inhibitors
Alpha-glucosidase
Family of enzymes on brush border of the small intestine
Cleave disaccharides & Polysaccharides into monosaccharides
Facilitates absorption
Inhibition of these enzymes decrease carbohydrate absorption
Greatest effect on postprandial levels of glucose

109

Lowers HgbA1c by 0.7-1.0%

Side effects
Flatulence
Nonabsorbed carbohydrates
Fermentation by colonic flora
Limiting factor in use & acceptance of drug
Combination therapy
Because the above drugs have distinct mechanisms of actions they can be used in
combination to achieve desired effects
Common Combinations
Sulfonylureas + metformin
Metformin + thiazolidinediones
Sulfonylureas + thiazolidinediones
Repaglinide + metformin
Patients on maximum oral agents with persistent hyperglycemia
Single injection of NPH insulin qs can lower fasting glucose levels to near
normal
Avoid weight gain of multiple injections
Diabetics who are poorly controlled despite large levels of insulin
Addition of thiazolidinediones & lesser extent metformin is beneficial
Insulin sensitizing effect
Combination of may predispose to cardiac complications
No formal approval from FDA yet
Insulin therapy
Does not restore euglycemia or prevent chronic complications of diabetes
Cannot control as finely as the pancreas can
Several types of insulin with different pharmacokinetic profiles are available
Wide range of onset, peak & duration of action
Absorption may vary with dose & site of injection
All type 1 diabetics require insulin
Must have onboard at all times
Insulin onboard prevents ketoacidosis.
General Insulin Schedule
Regular or lispro insulin (short acting)
Before meals
NPH or lente Insulin (Intermediate acting)
Once or twice each day
In the morning & with supper or before bed
Given at supper, peak is ~ early morning
Patient at risk for nocturnal hypoglycemia
Given at bedtime, peak is ~ breakfast time
Glargine or ultralente (long acting)
Have no specific peak
More physiologic basal level
Supplementation before meals with regular insulin

110

DIABETIC CRISIS
Diabetic Ketoacidosis (DKA)
Pathophysiology
Potentially life threatening complication from type 1 & occasionally type 2
Absence of insulin
Increased secretion of stress hormones that impair insulin action
Increase in Glucagon:Insulin ratio
Activates ketogenic mechanisms in the liver
Leads to production of the ketones
Acetone
Acetoacetic acid
111

-hydroxybutyric acid
Fatty acids are the substrate for ketone production
Derived from increased lipolysis
Ketones are normally metabolized by cardiac & skeletal muscle
Lack of insulin impairs ability to metabolize
Accumulate in the blood
High concentrations of ketoacids produce metabolic acidosis
Characterized by increase in the anion gap
Na+ - [Cl- + HCO3-] > 15mEq/L
Missing anions are negatively charged ketones
Electrolyte panel reflects changes in ketotic process in addition to the specifically
measured analyst
Insulin deficiency diminishes uptake of glucose
Increased glucagon stimulates
Hepatic glucose production
Glycogenolysis
Gluconeogenesis
Results in severe hyperglycemia
Glucose spills into urine
Osmotic diuresis
Volume depletion is severe
8-10 liters
Osmotic diuresis
Depletes total body potassium stores
Average of 3-5 mEq/kg body weight
Combo of acidemia & insulin deficiency
Increases extracellular potassium
Hyperkalemia
Can produce life threatening dysrhythmias when severe
Rapidly reversed with treatment
Hypokalemia if stores are not replenished
Clinical features
Typical prodrome of DKA
12-24 hours of
Weakness
Plyuria
Polydipsia
Deep & rapid breathing
Kussmaul hyperventilation
Fruity breath
Blurred vision
Abdominal pain with emesis
All patients are volume depleted
Treatment of DKA is important, but underlying cause should be found as well
Underlying infection is leading cause
Careful & thorough exam is necessary

112

Hypothermia common in ketoacidosis

Leukocytosis of 15,000 cells/mm3 is common in acidosis uncomplicated by
infection
Hyperventilation & tachycardia of sepsis mimic ketoacidosis
Other precipitants
Forgotten insulin dose
Pregnancy
Stress of MI
Dont forget silent MI of diabetics
MI in presence of DKA has poor prognosis
Abdominal pain in patients with DKA
Potential causes
Gastric distention
Swelling of the hepatic capsule
Pancreatitis
Neuropathy
Acidemia
May be difficult to determine if symptoms are from ketoacidosis alone or
underlying infection that may have initiated decompensation
Potential underlying initiators
Cholelithiasis
Atherosclerotic mesenteric insufficiency
Pyelonephritis
Peritonitis
Peptic ulcer disease
Complications of sever ketoacidosis
Altered mental status
Stupor
Coma
When blood osmolality increases rapidly
Water drawn out of CNS neurons
Cellular dehydration
Changes in conciousness
Hyperglycemia eventually stimulates intracellular production of large molecules
that cannot diffuse outside the cell
Idiogenic osmoles (some are polyols such as sorbitol)
Allow brain to resorb water from the extracellular space & become
rehydrated
Coma in patients who
Initial serum osmolality is less than 340 mOsm/L
Indicate another underlying issue
Consider meningitis or other CNS disorder
Diagnosis
At arrival to ED
Initial assessment of clinical status
Med Hx

113

Testimony of family & friends

Finger stick blood sample
ABG
To assess acid-base status
Urine dip stick for presence of glucose & ketones
Allows a rapid presumptive diagnosis of ketoacidosis
Initiate rapid therapy
Blood sent to lab for
Confirmation
Measurement of electrolytes
Blood urea nitrogen levels
Creatinine
CBC
EKG mandatory to rule out MI
Many require constant cardiac monitoring to detect arrhythmias
Resultant from hyperkalemia or hypokalemia
Cultures of
Blood, sputum, urine and pleural & ascetic fluid (if any)
Regardless of patients temperature or leukocyte count
Any alteration of consciousness
Urgent CT or MRI of brain
Consideration of lumbar puncture
Additional lab & radiologic studies as warranted by presentation
Treatment
Cornerstone of DKA therapy
Prompt administration of IV fluids
Insulin
Search for precipitating cause
Fluids
Present with substantial volume depletion
8-10 liters down
In absence of contraindications (CHF or Renal failure)
1-2 L normal saline immediately
After diagnosis of DKA
Vigorous saline infusion
estimated fluid loss replaced in first 4-8 hours
Depletes glucose & ketoacids concentrations via dilution
Via enhanced renal clearance
Later in therapy hypotonic solutions may be necessary to replace free water
deficits
Measured serum sodium concentrations
Often underestimate true [sodium]
Water redistribution from hyperglycemia results in
Dilutional hyponatremia
Requires no specific therapy

114

Insulin
Absolutely essential to reverse hepatic ketogenesis
Administration should be as soon as diagnosis of DKA is made
Initial IV bolus of insulin 0.1 U/kg
Given to saturate insulin receptors
Rapidly achieve maximal effect
Low dose constant infusion
0.1U/kg/hour
Once shown to be effective, leave unchanged
Never give Modified (NPH or lente) IV or in initial course of ketoacidotic therapy
Subcutaneous insulin slow & erratic absorption makes inappropriate
Potassium
Although potassium losses can be huge
Initial potassium concentration is usually above normal
Patients who present with normal or below normal levels of potassium are
severely depleted
Best to delay potassium replacement until lowered serum potassium levels are in
the high normal range by
Dilution
Insulin
Improving acid base balance
ECG can be useful in diagnosis
Hyperkalemia
Peaked T waves
Widened QRS complex
Hypokalemia
Flat T Waves
U waves
Patients may require several days of oral potassium to restore balance
Phosphate
Depletion of phosphate can complicate therapy of DKA
Leaves the cells during acidemia
Excreted in urine
Diabetic catabolic decompensation augments phosphate loss
DKA may have normal, low or high serum levels but all are total body depleted
Repletion within 2-3 days with normal diet
Alkali
Bicarbonate administration is not indicated in most patients
Recommended only in severe cases of acidemia (pH<7.0)
Administered if indicated for cardiac dysrhythmias or hypotension from
large volume replacement
Monitoring the response to therapy
During initial therapy
Hourly monitoring of blood glucose & electrolytes
If extreme abnormalities were present

115

Redo serum ketones & ABG only if extreme abnormalities present or

symptoms worsen
Flow sheet charting
Lab results
Insulin dose
Fluid therapy
Success is gauged by
Reduction of the anion gap
Use of serum bicarb to assess resolution of acidosis can be misleading
The saline administered to replace volume provides chloride as
The anion to replace [diminished] of negatively charged ketoacids
Hyperchloremia develops with an artificially low [bicarbonate]
May persist past closure of anion gap, restoration of normal pH &
resolution of ketosis
When blood sugar is <250-300mg/dL
Dextrose should be added to IV to prevent hypoglycemia
Maintained until patient can eat
If blood sugar falls to low levels
50% dextrose administered
Glucose infusion rate increased
Insulin infusion should not be stopped
Worsen the ketoacidotic state
If treatment is not succeeding
Increase hourly dose of insulin
Intensify search for causative factor
When the patient starts to eat
Subcutaneous NPH insulin morning of
With or without regular insulin
Continue insulin infusion for another 2-4 hours
Without infusion, patient will slip back into ketoacidosis while
waiting for NPH insulin to onset
Complications of Diabetic Ketoacidosis
Infection is principal source of morbidity
Medical advancements have limited infectious complications
Mucormycosis
Rare but often lethal complication of DKA
Fungal infection affects
Hard palate
Nasal turbinates
Sinuses
Ultimately CNS
Black eschar on palate or nares suggests diagnosis
Aggressive therapy is necessary
Surgery
Antifungals
Not always successful

116

Coma
Result of cerebral edema during treatment
If serum osmolality declines to quickly
Water flows from brain to the brain cells
Brain cells have accumulated nondiffusible idiogenic osmoles
Limit use of hypotonic fluids
Careful attention to blood glucose level
Generally good prognosis for recovery
Worse for
Elderly
Unconscious
Hypotensive
Bradycardic
Levels of below correlate with increasing mortality
Hyperglycemia
Hyperosmolality
Azotemia retention of excess nitrogen compounds in blood
Extent of ketosis & acidosis do not carry a similar risk as above
Most deaths result from precipitating or coexisting illness

Hyperosmolar nonketotic coma

Pathophysiology
Type 2 diabetics
Different presentation
Extreme dehydration
Crazy big blood sugars
1000-2000 mg/dL
Serum ketones are absent or trace
Acidosis, if present, is mild
Syndrome can be seen in severe dehydrated non-diabetics & burn patients or
hyperalimentation (eating too much)
Pathogenesis is not fully understood
Postulated
-cells cannot produce enough insulin into circulation to prevent
ketogenesis in the liver and to shunt free fatty acids into triglyceride rather
than ketone synthesis
Because the peripheral circulation is left without enough insulin
Gluconeogenesis is stimulated
Peripheral glucose metabolism is inhibited
Serum glucose levels therefore rise
Patients have usually been ill for several days with complaints of
Polyuria
Polydpsia
Most cases a concurrent infection triggers the hyperglycemia
Pneumonia
Infection
Renal failure

117

Stroke
GI hemorrhage
Occasionally drugs are implicated in hyperosmolar coma
Thiazide diuretics
Steroids
Stress of surgery
Diagnosis
Patients often are
Obtunded
Confused
Stuporous
Focal neurologic signs are not unusual
Diagnosis often delayed because signs & symptoms are often non-specific
Prolonged period of hyperglycemia & consequent osmotic diuresis
Profound dehydration
Volume depletion
Prerenal azotemia
Hemoconcentration
Abnormal high hematocrit
Promotes sludging & intravascular thrombosis
Level of consciousness, as in DKA is function of degree of hyperosmolality
Cerebral vascular accident is a common diagnosis suggested by
Paresis
Aphasia
Babinski signs
Focal seizures that are refractory to anticonvulsants further complicate
diagnosis
Phenytoin makes hyperglycemia worse
Inhibits insulin release
Serum osmolality in hyperosmolar state
Usually higher than in DKA
Blood sugar is almost always greater than 600
Serum sodium is also higher because deficit of free water than in DKA
Treatment
Repletion of extracellular volume & free water is the most important
Fluid replacement alone will decrease blood sugar levels (much faster than in
DKA)
IV insulin
Accumulation of idiogenic osmoles in brain predisposes to cerebral edema during
fluid resuscitation
Potassium depletion is not as profound as in DKA
Mortality rate is greater
Older patients in poorer health
Attributable to comorbid conditions

Special Situations
Inpatient management of diabetic patients

118

Blood glucose levels must be monitored

Insulin requirements may change due to stress & illness
Glycemic goals should not be as strict
Between 150-250mg/dL usually safe margins
Oral therapy held or decreased with supplemental insulin
Sliding scale insulin implemented for type 1
Rarely used for type 2
Surgery in diabetic patient
Vital that glucose & insulin requirements be provided throughout the operation
Variety of protocols can be used
Continuous IV glucose & insulin
IV glucose & subcutaneous or IV regular insulin
Glucose levels should be monitored at frequent intervals

119

Chapter 26 Hypoglycemia
Inevitable with good control
Symptoms
Palpitations
Mild anxiety
Seizures
Coma

NORMAL REGULATION OF GLUCOSE LEVELS

Liver maintains glucose levels between meals
Hepatic glycogen levels depleted several hours after last meal
Body requires active gluconeogenesis after liver glycogen stores depleted
Livers ability to manufacture glucose
Availability of substrate (proper amino acids)
Proper hormones
Hypoglycemia may occur when
Substrates are not ingested or not available to liver
Glycogenolysis is impaired
Gluconeogenesis is impaired
Hormone imbalance
Glucose Levels
Low Normal 65-70mg/dL
Hypoglycemic 40-45mg/dL
Healthy may maintain lower without signs & symptoms of hypoglycemia
Plasma glucose ~ 10-15% > than blood glucose measured with finger stick
Symptoms may depend on rate of fall & duration of hypoglycemia than actual
glucose levels
Clinically significant hypoglycemia
Whipples Triad
1. Low Blood Sugar
2. Simultaneous symptoms of hypoglycemia
3. Resolution of symptoms with glucose administration

CLASSIFICATION & CLINICAL SYMPTOMS

Hypoglycemia is often over diagnosed & not well understood
Reactive hypoglycemia (postprandial)
Occurs 2-5 hours after last meal
Autonomic Nervous System Manifestations
Palpitations
Tremors
Tachycardia
Weakness
Diaphoresis
Hunger
Anxiety
Nausea
Hyperventilation
Symptoms are strictly postprandial
Resolve spontaneously with ingestion of food
Fasting Hypoglycemia
120

Symptoms of glucose deficiency in CNS (Neuroglycopenia)

Disorientation
Focal Neurologic deficits
Dipolpia
Seizures
Hallucinations
Obtundation
Bizarre behavior
Coma
Amnesia
Usually6hrs after eating
May be precipitated by exercize in late posprandial period
Symptoms resolve with ingestion of glucose or food
Distinction between fasting & reactive is crucial
Fasting
May be caused by underlying systemic disease
Reactive
Usually functional & not from an identifiable cause

ETIOLOGY & TREATMENT

Fasting Hypoglycemia
Insulinoma
Primary diagnostic focus in patients with fasting hypoglycemia is an insulinoma
Must rule out potential overt causes first
Drugs
Ethanol
Organ failure
Hormone deficiencies

Insulin secreting tumors

Sporadic
Associated with

Parathyroid & pituitary neoplasms in the Familial Multiple Endocrine Neoplasia

Syndrome (MENS) Type I
Tumor is rare
<1:100,000
75% of patients insulinoma is benign
Diagnosis of insulinoma
Documented hypoglycemia with inappropriate high insulin
Patient fasted for 72hrs
Documented response to glucose
Level of proinsulin is usually elevated
Ratio of proinsulin/insulin ratio
Small & difficult to image
Intraoperative ultrasound most sensitive
Therapy
Surgical excision of tumor
Some patients unable to effectively remove all sites
Somatostatin analog Ocreotide is administered

Suppresses insulin secretion

Oral diazoxide
Malignant disease responds poorly
Factitious Hypoglycemia (Pharmacologically self induced)
Insulin usage (inappropriate)

121

No C-Peptide increase as in insuloma

Cleavage product of proinsulin
Sulfonylurea Use
Distinguish from insuloma by urine & serum assays
Drugs
Ethanol
Alcoholics are 1/3 of all drug induced hypoglycemics
Inhibits gluconeogenesis
Nothing other than EtOH for nutrition
Liver glycogen is depleted
Hypoglycemia may mimic acute EtOH intoxication
Presentation
Diminished sensorium
Agitated delusional state
Treatment
IV glucose after hypoglycemia confirmation
100mg Thiamine to prevent Wernickes encephalitis
Hospitalize for observation

Insulin
Hypoglycemia in insulin treated diabetics may be seen in both fasting & fed state
Skipping meals
Failure to titrate insulin appropriately

After several years of diabetes, 2 factors increase dangers of hypoglycemia

1. Severe Diabetic Autonomic Neuropathy with hypoglycemic unawareness
2. May have impaired glucagons & epinephrine response to hypoglycemia,
impairing the bodys ability to respond

Sulfonylureas & other oral anti-diabetic meds

Sulfonylurea
Stimulates production of insulin
2 fold danger
Blood sugar greatly depressed
Duration of action can be prolonged
May be refractory to treatment requiring multiple administrations of 50% dextrose
Metformin & thiozides may contribute when used with sulfonylureas

Other Agents

-blockers
Have caused hypoglycemia in fasting & fed states
Probably through inhibition of glycogenolysis
Can mask symptoms of hypoglycemia
Used with caution in diabetics
Other meds that have been reported to cause hypoglycemia
Sulfonamides
Systemic Pentamidine
Quinine
High doses of salicylates

Severe Illness
Severe liver disease
Decreased or absent glycogen stores
Impaired gluconeogenesis
Usually encountered with fulminant hepatic failure
Viral, cardiac cirrhosis, alcoholic

122

Renal failure
Reduced clearance of insulin
Gluconeogenic potential of kidney is lost
Sepsis & CHF may also cause

Hormone deficiencies
Adrenal insufficiency
May have hypoglycemia during an addisonian crisis
Hypothyroidism
Occasionally associated through unknown mechanism

Inanition
Hospitalized & severely ill
Result of depleted muscle mass
Inadequate glycogen stores
Inadequate nutrition

Non-islet cell tumor Hypoglycemia

Nonpancreatic tumors associated
Most are
Mesenchymal (Sarcoma)
Located in thorax or peritoneum
Also other tumors including hepatomas
Produce prohormone form of Insulin Like Growth Factor II (IGFII)
Hypoglycemia by
Stimulates tumor & peripheral glucose uptake
Inhibits hepatic glucose production

Autoimmune hypoglycemia
Rare instances of fasting hypoglycemia may result in
Auto antibodies
Against insulin & insulin receptors
Insulin induced inactivation of the receptor

Reactive hypoglycemia
Theory is excessive release of insulin in response to meals
Whipples triad is the only way to diagnose it is not by patient report
Management
Reassure patient that disease is not progressive or dangerous
Dietary changes for patient
Avoidance of simple sugars
Multiple meals/day
Many present with stated hypoglycemia and fail Whipples triad

Alimentary Hypoglycemia
1/3 of patients who have had
Gastrectomy
Vagotomies
Jejunostomy
Billroth II anastamoses*
Pyloroplasty
Dumping syndrome
Rapid emptying of stomach into small intestines leads to premature absorption of
glucose
The exaggerated insulin response leads to hypoglycemia
Signs/Symptoms
Abdominal fullness
Weakness
Nausea
Palpitations

123

Within first few hours of eating

Followed by 2-3 hours of reactive hypoglycemia
Treatment
Most adjust in a few months
Anticholinergics help some patients

124

Chapter 34 Hepatitis
Biosynthesis of
Albumin
Clotting factors
Lipoproteins
During early phase of liver injury
Release bilirubin
Increase in serum bilirubin jaundice
Intracellular enzymes
Aspartate aminiotransferase (AST)
Alanine aminotransferase (ALT)
Lactate dehydrogenase (LDH)
Protracted injury leads to scarring & cirrhosis
Cirrhosis is characterized by
Damage of portal circulation
Portal hypertension
Ascites
Development of porosystemic collaterals
Esophageal varices

JAUNDICE
Cardinal sign of liver & biliary tree ds
Bilirubin at 2-3 mg/dL
Jaundice
Light colored stool
Dark urine
Gilberts syndrome
Chronic hyperbilirubinemia
Healthy no tx needed

Bilirubin Metabolism
Reticuloendothelial system
Fxnl rather than anatomic made up of macrophages, kupfer cells of the
liver, reticulum cells of lungs, marrow, spleen & lymph nodes that breaks
down RBCs and releases the heme moiety
Heme moiety Biliverdin Bilirubin
Bilirubin conjugated with glucuronic acid bilirubin glucuronide
Bilirubin glucuronide can be excreted into the bile
Gut flora can change to urobilinogen that can be reabsorbed &
appear in urine
Unconjugated hyperbilirubinemia
Results from Severe hemolysis may overload ability to convert
Unconjugated bilirubin binds to serum proteins not filtered by
kidneys
Bilirubinurea does not occur
Conjugated hyperbilirubinemia
125

Results from Liver disease or extrahepatic obstruction

Conjugated bilirubin leaks back into system
Does not bind to serum proteins can be filtered by kidneys
Characteristic dark urine
Acholic stools (lighter colored due to less bilirubin in
feces)

Diagnosis
Differential Diagnosis
Extrahepatic biliary obstruction
Can be surgically corrected
Common causes
Bile duct stones
Duct strictures
Carcinoma of pancrease
Carcinoma of ampulla of Vater (union of pancreatic & bile duct)
Medical causes of icterus
Severe hemolysis
Sepsis
Viral & toxic hepatitis
Infiltrative ds of liver
Cirrhosis
Method to differentiate
History
Labs
Physical exam
Abdominal ultrasound
Associated symptoms
Epigastric pain radiating to the back
Characteristic of pancreatic carcinoma
Acute pancreatitis
Colicky abdominal pain
URQ occasionally assoc with enlarge gall bladder
Obstruction of biliary tree
Chills & fever
Cholangitis
Duct obstruction from stones
Patients with viral
Part of anicteric prodrome
Severe alcoholic hepatitis
Chills, fevers & abdominal pain
Laboratory Tests
Most helpful to differentiate between surgical & medical causes of jaundice
Elevation of Aminotransferases AST & ALT
Extremely high
Parenchymal liver damage
Cholestasis
Alkaline phosphatase & bilirubin
Out of proportion to changes in aminotransferases
Ratio of conjugated bilirubin to total serum bilirubin

126

Unconjugated hyperbilrubinemia (<15%) in patients with massive

hemolysis
>40% - Conjugated hyperbilirubinemia
Medical or surgical causes of jaundice
Parenchymal ds
PT & INR values
Oral vit K doesnt help
Other Tests
Abdominal ultrasound can show
Dilated intrahepatic ducts obstructive ds
Dilated common bile duct obstructive ds
CT
MRI
Endoscopic Retrograde Cholangiopancreatography (ERCP)
Percutaneous Transhepatic Cholangiography (PTHC)
Liver Biopsy gold standard for parenchymal liver ds

ACUTE VIRAL HEPATITIS

Diagnosis and Clinical Features
Clinical Syndromes
Range from asymptomatic to debilitating
No therapy for routine cases & usually is self limiting
Viral agent determines route of transmission, immune response & prognosis
Must rule out toxic or pharmacologic cause for treatment
Viral hepatitis has distinct prodrome
Arthralgias
Anorexia
Myalgias
Nausea
Headache
Vomiting
Photophobia
Weight loss
Complaints may be mild malaise & weakness and taste & smell alterations
HAV
2-5 days in length
HBV
Up to 1 month
Jaundice phase
Just prior to icteric phase
Darkened urine or lightened stool
Associated with
Anorexia
Fatigue
Pruritis
Some patients remain anicteric throughout
Infected liver large smooth & tender
Histologic exam
Cell necrosis
Mononeuclear inflammatory infiltrate
URQ tenderness

127

Palpable splenomegaly (small number)

Spider angiomas
Increased effective dose of meds due to inability to detox
Most patients recover
Laboratory Findings
Dramatic in AST & ALT
Elevation may persist for months
No correlation between enzymes & severity of clinical illness
Alkaline phosphatase
Small increase with hepatitis
Dramatic increase with obstruction
May decrease albumin & clotting factor synthesis
Low albumin & PT & INR
Severe cases
Hypoglycemic & anorectic
Mild leukocytosis
Fulminant Hepatitis
Many Causes viral, drugs and mushrooms
Mild neuropsychiatric changes prior to severe hepatic decompensation
Irritability & inappropriate behavior
Rapid cellular necrosis
Liver shrinks
AST, ALT & bilirubin rise fast and then fall just before death
After bulk of hepatocytes destroyed
Clotting factors decline PT/INR
Transplantation only hope of survival

Hepatitis A
No chronic carriers No chronic liver ds
Fecal/oral x-mission route
Incubation
10-15 days
HepA antigen detected in stool
Once jaundice occurs, antigen usually absent from feces
IgM antibody soon after infection
Anti-HAV IgG follows & long term immunity
Health care no higher risk than regular population active virus gone when help
is sought
Tx
Immune serum globulin for household contacts of pts with HAV
Vaccine now available

Hepatitis B
DNA virus
Most are asymptomatic
Persistent & heavy viremia
Routes of x-mission
Blood x-fusions decreasing due to testing

128

Homosexuals with multiple partners

IV drug abusers
Tattooing & piercing
Hemodialysis
Acupuncture
Serologic testing
Virus in all body fluids
Jaundice 2-3 months S/P exposure
Antigens can be detected earlier after exposure
HBsAg 1-2 weeks after exposure. Disappears in 90% of patients during
or after acute hepatitis
HBeAg correlates with infectivity and appears soon after HBsAg
Anti-HBc detectable for life
Anti-HBe heralds remission of active hepatitis
Anti-HBs appears later in course 6-20 weeks after acute hepatitis and
persists for life. Never develops in chronic carriers
Period of time weeks to months after infection
Only anti-HBc will show
Chronic Carriers
Never develop anti-HBs
Increased risk of chronic liver ds & primary hepatocellular carcinoma
Symptomatic flare-ups
The delta Agent
Defective RNA virus
Requires simultaneous or antecedent HBV infection
More fulminant course & worse prognosis
Dx
IgM or IgG to HDV in pts who are HBsAg positive
Increased risk for
HIV patients
IV abusers
Multiple blood x-fusions
Extrahepatic Complications
Immunologic response is responsible for most extrahepatic manifestations
Two categories
Antigen-antibody complexes activate complement system
Arthritis
Urticaria
Angioedema
Chronic carriers chronic immune-complex ds
Chronic interstitial nephritis
Polyarteritis nodosa
Essential mixed cryoglobulinemia
Prevention
Blood precautions for all seropositive patients
Vaccination

129

Recombinant
3 injections over 6 months
Anti-HBs levels diminish immunity persists
Routine vaccination for all & part of vaccine panel
Immune globulin with high titers of anti-HBs within 7 days of exposure
In conjunction with hepB vaccine

Hepatitis C
RNA virus
Milder acute illness
Mode of x-mission & symptoms similar to hep B
X-mission
Blood transfusion is rare now
IV abusers
50% develop chronic ds
50% positive hx for exposure 50% unknown
Dx
ELISA
Antibody to HCV (anti-HCV)
Negative in acute
Seroconversion confirms dx
Polymerase chain reaction

Management of Acute Hepatitis

Symptomatic tx
Caution with meds due to impaired detoxification
No EtOH use
Hospital admission for
Low serum albumin
Prolonged INR
Hepatic encephalopathy
Elderly who are anorectic
Fulminant hepatitis
X-fered to hospital capable of transplant if needed

TOXIC HEPATITIS
Drugs or toxins can cause a symptomatically indistinguishable hepatitis
Directly toxic drugs
Carbon tetrachloride
Certain mushrooms
Acetaminophen in high doses
Evident after 1-2 days
Unpredictable & idiosyncratic toxic drugs
Halothane
Rare 2wks s/p acute hepatitis with severe liver damage & high
mortality rate
Isoniazid
1:10 in AST >35YO risk of hepatitis
1% acute symptomatic hepatitis

130

Phenytoin
Various NSAIDs
Anabolic roids
Reversible increase in alkaline phosphatase & transaminases
Rarely
Peliosis (blood filled hepatic cysts)
Hepatic tumors
Estrogen may cause
Cholestasis
Benign hepatic adenomas

CHRONIC HEPATITIS
Diagnosis is from lab values
Severity is from liver biopsy

Diagnosis
Inflammatory lesion doesnt resolve after 6 months
May be based only on persistent elevation of ST or ALT
Regardless of symptoms
Biopsy
Determines severity
Mild chronic hepatitis
Nonspecific reactive & inflammatory changes
Severe Chronic hepatitis
Inflammatory rxn bridges portal tracts
Disturbs architecture
Bridging necrosis & fibrosis
Hepatitis B & C are the most common causes of chronic hepatitis, hepatocellular
carcinoma, and cirrhosis
Other causes
Chronic autoimmune hepatitis
Drug induced chronic hepatitis
May also be seen as a precirrhotic lesion in Wilsons ds (decreased ceruloplasm
copper accumulates in lever, hemolysis & hemolytic anemia liver cirrhosis)
& 1-antitrypsin deficiency
Chronic hepatitis
Often symptomatic
Hepatosplenomegaly
Jaundice
Spider angiomas
Dramatic biopsy
Chronic active hepatitis accompanied by
Interstitial nephritis
Hemolytic anemia
Polyarteritis nodosa
Mixed cryoglobulinemia
Arthralgias
Other systemic disorders

Treatment
Only tx effective for chronic hepatitis B or C
Interferon (IFN)-

131

For pts with replicating viruses

These patients have
aminotransferases
Positive HBeAg (absent in rare cases)
Positive HBV DNA
Chronic Hep C
IFN administered for inflammation of liver
ALT level
Not for normal (ish) ALT levels and little inflammation
Not all patients respond to IFN
+ Response in ~ 50%
Ribavirin (antiviral usually RSV) may be added
Duration of therapy 6-12 months
40% persistent negative HCV RNA
Side effects of IFN therapy
Flu-like
Hair loss
Fatigue
Depression
Malaise
Mood swings
Fever
Chills
Decreased WBC & platelets may also occur resultant from
antiproliferative effect of IFN & occasionally thyroid problems with HepC

Chronic Autoimmune Hepatitis

Characterized by histologic evidence chronic liver ds in association with serologic
evidence of antinuclear antibody & antismooth muscle antibody in high titers
Cause unclear
Immunosuppressive therapy helps
Corticosteroids & azathioprine commonly used
Liver transplant has been successful
Drug induced resolves after offending drug dced

ALCOHOLIC HEPATITIS
Spectrum of alcoholic liver ds includes
Fattly liver
Alcoholic hepatitis
Commonly seen in malnourished, but not always
Women are more susceptible
Cirrhosis

Diagnosis
Based on
History
Physical Exam
Characteristic lab abnormalities
Biopsy definitive, but not necessary
Clinical hallmarks
Abdominal pain
Jaundice

Nausea
Vomiting

132

Fever
Leukocyte count elevation
Aminotransferases
Elevated but rarely over 300
AST usually higher than ALT
Indicators of significant loss of hepatic fxn and poor prognosis
PT & INR after Vit K supplementation
Hypoalbuminemia
[Bilirubin] > 20mg/dL
Fatty infiltration
Early sign
Hepatomegaly
Biopsy
Cytoplasmic alcoholic hyaline bodies
Mitochondria are swollen
Endoplasmic reticulum increased
Pronounced
Hepatocellular necrosis & polymorphonuclear inflammatory infiltrate
Nonalcoholic steatohepatitis (NASH)
Common condition characterized by
Steatosis
PMN infiltration
Necrosis of liver parenchyma
All without EtOH intake
Risk factors
Obesity
Diabetes mellitus
Hyperlipidema
Drug use
Medical therapy to control causes to prevent fibrosis & cirrhosis

Treatment
Abstinence
Rest
Proper nutrition
For very ill high dose corticosteroids
Mild cases reversible
80% who continue to drink develop cirrhosis in 5 years
Poor prognostic signs
Ascites
Encephalopathy
Renal failure
Severe leukocytosis
Fatty liver
Universal finding in all excessive EtOH consumption

133

Chapter 35 Cirrhosis & Liver Failure

CIRRHOSIS
Widespread hepatocyte loss & diffuse proliferation of connective tissue & fibrosis
destroy the vascular & lobular architecture of the liver
Results in
Shrunken & scarred liver
Patchy, nodular areas of hepatocyte regeneration
If patients continue to drink EtOH
Alcoholic hepatitis & fatty infiltration can be found
Three hallmarks of cirrhosis
Parenchymal necroisis
Hepatocyte regeneration
Scarring
Three pathologic types
1. Micronodular cirrhosis
i. Small uniform nodules
1. <3mm in diameter
ii. Seen in chronic alcoholics
1. Longstanding biliary or venous obstruction
2. Hemochromatosis
2. Macronodular cirrhosis
i. Nodules vary in size from 3mm several cm
ii. Associated with chronic hepatitis
3. Mixed cirrhosis
i. Elements of micro & macronodular cirrhosis
Etiology
Most common cause in US is alcoholic liver ds
Women more prone to cirrhosis than men
Worldwide the two leading causes are
Alcoholism
Chronic hepB infection
Other causes
Hep C
Primary biliary cirrhosis
Wilsons Ds
Hemochromatosis
Primary sclerosing cholangitits
Right sided heart CHF hepatic congestion cirrhosis
Nutritional deprivation
Clinical manifestations
Totally asymptomatic to severe
Typically
General deterioration of health
Wight loss
Loss of muscle mass
Weakness
Anorexia
Fatigue

134

Jaundice results from inability to metabolize bilirubin

Fever without chills
Other features may include
Hepatic encephalopathy
Ascites
Stigmata of portal hypertension
Parotid gland enlargement
Physical findings
Firm shrunken liver (may be enlarged with fatty liver of EtOH)
Splenomegaly
From portal hypertension
May be hard to palpate in patients with ascites
Spider angiomas
Radiate from central point
Blanch when pressed
Palmar erythema
Gynecomastia
Testicular atrophy
Clubbing of digits
Dupuytrens contractures
Fibrosis of palmar fascia
Laboratory findings
Several serum tests provide measure of dysfunction
End stage cirrhosis
Few functional liver cells
May have normal serum aminotransferases
Early cirrhosis
Increased serum enzymes
Alcoholic hepatitis
AST > ALT
Decrease in BUN
<4mg/dL characteristic of cirrhosis
If patient has cirrhosis normal BUN = renal failure
Significantly compromised livers
Low albumin level
Low cholesterol
Elevated INR
Biopsy
Confirms dx
Establish cause
Stage the progression
Biopsy may have therapeutic implications also
Complications
Major Complications
Portal hypertension
Hepatic encephalopathy

135

May cause life threatening hemorrhages

Esophageal & gastric varices
Portal hypertensive gastropathy diffuse mucosal ds of stomach
Portal hypertension + low albumin
Results in massive ascites
Compromise pulmonary fxn
Fluid & electrolyte mgmt difficulties
Encephalopathy
Liver doesnt detoxify so toxins go straight to the brain
Renal failure
Potassium deficiencies & hyponatremia
Cause is unknown
Hepatorenal syndrome The kidneys work fine if implanted to another
Spontaneous & unexplained renal failure
Oliguria < 500 mL urin/day
Progressive azotemia
Unremarkable urinary sediment
Low urinary sodium concentration
A dismal prognosis
Diagnosis
Biopsy is definitive dx test
Percutaneously
Laproscopically
Transjugular route
Other tests
Ultrasound
CT
MRI
Nuclear medicine studies
Mortality
Without liver transplant
8% alive after 5 years
Graded using Childs Criteria
Basis of
Serum bilirubin
Albumin levels
Severity of ascites
Encephalopathy
State of nutrition
Higher the number the worse the prognosis
Poor prognoses
Onset of jaundice
25% are alive after 1 year
Varices
Encephalopathy
Ascites

136

Spider Angiomas
Hypoalbuminemia
Severely prolonged PT time
Most die of hepatic failure often complicated by GI bleeds
40% non liver related
Cardiac DS
Extrahepatic infection
Extrahepatic malignancies
4% primary liver cancer
When complicated by ascites
90% die from liver causes
PRIMARY BILIARY CIRRHOSIS
Chronic progressive cholestatic ds of the liver characterized by destruction of
extrahepatic bile ducts
90% affected are female
Autoimmune phenomena prevalent
Elevated
Alkaline phosphatase
Antimitochondrial antibodies
Both appear before symptoms
Antimitochondrial antibody titers
Levels do not correlate with severity of ds
Bilirubin concentration > 2mg/dL
Extensive disease
Predicts early mortality
Usually within 2 years
On Biopsy
Chronic cholangitis early
Bile stasis
Granulomas
Ultimately periportal fibrosis & end-stage cirrhosis appear
The sicca syndrome
Scleroderma
Rheumatoid arthritis
Thyroiditis
Most common presentation
Anicteric pruritis
Jaundice several years after pruritis
Symptomatic course
Downhill
Rate varies
Patients suffer from
Xanthomas
Severe osteoporosis
TX
Cholestyramine

137

Effective for itching & xanthomas

Colchicine improves biochemical abnormalities & may slow progression
Ursodeoxycholic acid
May improve function
No cure for illness
Liver transplantation for patients with end-stage liver failure
WILSONS DISEASE

138

Chapter 41 Transfusions
Whole Blood
Components of whole blood
Blood Values
RBCs
Blood measure
Male
Female
Platelets
Hematocrit
39-49%
34-45g/dL
WBCs
(Hct)
Plasma cryoprecipitate
Hemoglobin
13.612.0Clotting factors
(Hb)
17.5%
15.5g/dL
Immunoglobulin
Whole blood is given only when patient is at risk for rapid exsanguinations
Can usually use IV crystalloid & blood components
Admin of blood components is called
Component therapy
Risks of administration
Transfusion reactions

Hb X 3
= Hct

RED BLOOD CELL TRANSFUSIONS

One unit of packed red cells (PRCs)
Represents RBCs from 450ml of whole blood
When given to a pt without underlying problems (rbc destruction or sequestrum)
3% increase in hematocrit
1 g/dL increase in hemoglobin
Indicated to restore oxygen-carrying capacity
Losses
Healthy person
RBCs & keep sufficient oxygen delivery
Volume must be maintained
Cardiopulmonary or respiratory ds
Cant increase cardiac output or alveolar ventilation
30% may be minimum hematocrit to sustain
Anemia
Rapidity of onset may affect how well or poor a pt may tolerate loss
Chronic anemia
Hematocrit of 15% may notice only fatigue
Acute anemia
Immediate hospitalization & replacement

139

140

Red Blood Cell Component Preparations

Variety of different preps by removal of different components
Separation of non-erythrocyte components
Increases cost
Diminishes allergic reaction
PRC (Packed Red Blood Cells)
1 Unit (300ml)
60-90% hematocrit
Only erythrocytes in concentration
Leukocyte-Poor RBCs
Prevent febrile, non-hemolytic transfusion reactions
Most common form of transfusion rxn
Prevent alloimmunization (The body gains immunity against itself) to
human lymphocyte antigens (HLAs)
Coombs test to dx
Methods for removal
Microaggregate filter
In-line leukocyte filter
Effectiveness
98% effective at removing leukocytes
<106 WBC per unit remain
Washed RBC
Saline Rinse
Best way to remove allergens like plasma proteins
Some leukocytes & platelets are removed
Prevents allergic rxn
Mediated by recipients IgE against donor plasma proteins
Very severe allergic rxn if
Recipient is IgA deficient
Must be used soon after processing due to bacterial contamination risk
Frozen RBC
Stored for years
Little biodegradation
Poor in leukocytes & plasma proteins
Can be washed for further purification
Low hepatitis transmission
Unknown reason
Expensive
Irradiated RBCs
Good for immunocompromised patient
Decreases risk of graft-versus-host ds
Destroys stem cells & lymphocytes

141

Adverse Effects From Transfusions

Transfusion Reactions
Three forms
1. Febrile & non-hemolytic
2. Hemolytic
3. Immediate hypersensitivity reactions
Febrile reactions
Most common rxn
Caused by leukoagglutinins
Antibodies against donor WBC
Pyrogen release from reaction of above
Risk increases with number of previous transfusions
6-12 hours before reaction
Rxns are usually mild
Chills are usual, but rarely substantial rigors
Core temp increases by 1C or more
No evidence of hemolysis
Treatment
APAP
Transfusion may continue, but patient should be observed
If additional transfusions are required premed with APAP
Prevention
Use of leukocyte poor RBCs
APAP premed

142

Hemolytic Reactions
Acute hemolytic reaction
Transfusion of immunologically incompatible blood
Results of host antibodies binding to transfused blood
Intravascular hemolysis
Destruction of the antibody or complement coated cell in
Spleen
Liver
Bone marrow
Rare due to cross matching
Signs & symptoms
Fever & chills usually early symptoms
May be indistinguishable from
Common benign febrile reactions
Check details of
Infused product
Identification
Crossmatching
Slow rate of transfusion & monitor patient
Acute intravascular hemolysis
Results in transfused RBCs with preformed antibodies capable of fixing
complement against the major ABO blood groups
Produces lysis (from the complement)
Signs & Symptoms
Back & flank pain
Hypotension
Bleeding from IV sites
Nausea & vomiting
Diagnosis
Plasma should be examined visually for Hemoglobin (red plasma)
Urine examined for hemoglobin
Repeat blood group determination & crossmatching
Direct test of recipients RBC
Pre & post
Pt blood sample tested for
HCT
Platelet count
Haptoglobin
Prothrombin time
Partial thromboplastin time
Fibrin Split Product & fibrinogen
Action
Transfusion stopped as soon as signs & symptoms appear
Sequelae
Catastrophic chain of events
Disseminated intravascular Coagulation (DIC)

143

Vascular collapse
May be caused by activation of inflammatory
pathways
Renal failure
Acute tubular necrosis
Possibly caused by effects of antigen
antibody complexes or both
In an anesthetized patient
Bleeding from DIC may be first sign
Treatment
After transfusion is stopped
Support blood pressure
Controls bleeding
Maintains renal circulation
Monitor urine output
Loop diuretics (furosemide)
Help establish renal blood flow & incr urine output
Acute extravascular hemolysis
Transfused RBCs react with recipients antibody
Recipients antibodies are
Incapable of fixing complement
Capable of fixing only early components (C3b)
Presence of IgG &/or C3 on the donor RBC clearance of the coated cells
Macrophages clear the donor RBCs
Signs & symptoms
More subtle than in intravascular hemolysis
Fever may be only symptom
Lab values
Less than expected increment in HCT post transfusion
Elevation of indirect serum bilirubin
Increase in lactate dehydrogenase
Positive direct antiglobulin test
Tx
Stop the transfusion
Repeat crossmatch

Immediate hypersensitivity reactions

Variety of reactions seen
Local urticaria
Angioneurotic edema
Anaphylaxis
Rxns are unusual & usually milde
IgA-deficient patients
<1 of every 500 persons
Predisposed to allergic rxns
Circulating anti-IgA antibodies in some patients
Small amount of IgA results in hypersensitivity rxn
Washed RBCs usually prevent rxns in these patients

144

TX
Stop transfusion
Antihistamines
Diphenyhydramine is used in IgE-mediated allergic rxns such as urticaria
Sympathomimetics

Complications
Fever during transfusion is first clue of bacterial contamination
Severe rxn may mean serious septicemia
Symptoms
Fever
Chills
Rigors
Nausea & vomiting
Followed by
Hypotension
DIC
Circulatory collapse
Mortality rate >50%
Rxns are rare
TX
Stop transfusion
Two sets of blood cultures from recipient
Untransfused blood gram stain & culture
Broad spectrum Abx before culture results is available
Other immediate complications
Circulatory overload in pts with cardiac ds
Precipitate CHF
Give blood slow
Diuretics prn
Hypothermia
Massive transfusion of cold blood
Hypocalcemia from massive transfusion
Electrolyte imbalances
[Potassium] & [free ammonia] rise in non-frozen blood during storage
Large x-fusion can deliver dangerous potassium loads in patients with
renal failure
Hyperammonemia bad for pts with marginal liver fxn

Autologous Blood Transfusion

Pt donates own blood 42 days prior to sx
Iron and erythropoietin may be necessary to prevent anemia
Cell Savers
Intraoperatively machines filter RBCs from suctioned blood & return to pt

PLATELET TRANSFUSIONS
Effective in stopping bleeding in thrombocytopenic patients
For every transfused unit
Platelet count increase of 5,000 to 10,000 platelets/L

If there is no source of platelet destruction

Circulate in progressively smaller #s for ~ 1 week

Platelets are usually restricted to several defined groups of patients

Bone marrow aplasia or failure

145

Due to infiltrative ds
Transfuse if <10,000 platelets/L
Thrombocytopenic patients
When risk of bleeding is increased
Immune thrombocytopenic purpura (ITP)
Routine transfusion of platelets is not indicated
Continuous destruction of platelets
Reserved for active bleeding & emergency sx
Give with high-dose gamma-globulin
Increases platelet survival time
Strictly contraindicated in patients with
Thrombotic thrombocytopenic purpura (TTP)
A hemolytic anemia with neurologic abnormalities, generalized purpura
& deposition of microthrombi within capillaries & smaller arterioles
A platelet x-fusion would exacerbate this condition

Long term platelet transfusions

4-8 weeks of regular x-fusion platelet live will diminish
Secondary to alloimmunization (The body gains immunity against itself) of

HLA antigens carried on donor platelets

Signs and symptoms of alloimmunization
Marked decrease in peak platelet response & life span of x-fused platelets
Frequency of alloimmunization decreased by use of ABO compatible platelets &
leukocyte filters & HLA matched donors

WHITE BLOOD CELL TRANSFUSIONS

Expensive
Few indications for use
Life span is only hours after harvest
Given only to patients
Documented bacterial infections in the setting of persistent neutropenia
<500/L neutrophils
Especially Gram-negative infections
No response to Abx therapy
Components of WBC transfusions
1010-11 granulocytes
1 hour s/p x-fusion
WBC count increases by 0-1000/L
Side effects
Mild fever
With our without chills
Few patients
High fever
Hypotension
ARDS

HEPATITIS & ACQUIRED IMMUNODEFICIENCY SYNDROME

Screening has greatly reduced transmission of viral ds in blood products
Hepatitis
Screened but risk is from when antibody titers are too low to detect

146

Other causes of post x-fusion hepatitis

Cytomegalovirus
Epstein-Barr virus
Clinical syndromes are similar to hepatitis acquired through other modes
Acute icteric symptomatic illness
Anicteric asymptomatic hepatitis
Chronic liver disease
Cirrhosis
HIV
Screened for
HIV virus
HIV RNA
HIV p24 antigen
Exclusion of high risk donors has helped
Problems with screens is time frame
HIV for 3 weeks before development of measureable antibodies
16 days for p24 antigen to show
11 days for HIV RNA to be measured
Human T-Cell Lymphotropic Viruses I & II (HTLV-1 & HTLV-2)
Can be transmitted
Associated with
Peripheral T-cell leukemias
Lymphomas
Endemic myelopathies
Predominantly found in
Japan
Caribbean
Southern US
Risks associated with transfusions
HepB
HepC
HIV
HTLV I &
Virus
II
Risk 1 in 200,000 1 in 100,000 1 in 656,000 1 in 600,000
units
units
units
units

147

Chapter 42 Anemia
Definition a reduction in the oxygen carrying capacity of blood as a result of
decreased [hemoglobin]
Measurements
Decreased hematocrit usually
[Hemoglobin] is a more accurate gauge of oxygen transport capacity
Many causes
Dx possibilities reduced by
Reticulocyte count
Examination of a peripheral blood film
Anemia stimulates the synthesis & release of
Reticulocytes (immature RBCs)
Basophilic densities
Count is expressed as a percent of total RBCs
Corrected for hematocrit
Fewer mature RBC reticulocytes percentage will be apparently
increased
Formula
Measured reticulocytes count X (Measured hematocrit/45)
Elevated corrected reticulocytes count
>2.5%
Anemia is result of peripheral RBC destruction or
exsanguinations
Bone marrow is functioning normally
Called hyper-regenerative anemia
Low or normal corrected reticulocytes count
Failure of RBC production
Called hyporegenerative anemia
Morphology of RBCs further subcategorizes RBC indices quantitative
description
1. Mean Corpuscular Volume (MCV)
a. Average size of RBC defined as: Vol of packed RBC per L of Blood/#
RBCs (millions/mm3)
b. Normal value is 90m3/RBC
2. Mean Corpuscular Hemoglobin (MCH)
a. Amount of hemoglobin per cell calculated as: hemoglobin (g/L)/#RBC
(millions per mm3)
b. Normal value ~ 30 pg/RBC
3. Mean Corpuscular Hemoglobin Concentration (MCHC)
a. Percentage measure of how much of the RBC is hemoglobin calculated as:
Hemoglobin (g/dL) X 100/ hematocrit
b. Normal value ~ 34%
4. Red Cell Distribution Width (RDW)
a. Measure of the coefficient of variations in the sizes of RBC calculated as:
Coefficient of variation = Standard deviation of RBC siz/MCV

148

b. Normal value ~ 11.5 14.5

Hyporegenerative anemias three morphologic categories
1. Macrocytic anemias
a. Vitamin B12 deficient
b. Folate deficient
2. Normochromic normocytic anemias
a. Renal failure
b. Marrow aplasia
3. Microcytic hypochromic anemias
a. Iron deficient
b. Thalassemia syndromes
One of the most common forms of anemia has an underlying inflammatory
process
Present as normocytic or slightly microcytic
Anemia from hemolysis in peripheral circulation
Corrected reticulocytes count is elevated
Peripheral blood film may reveal
Sickled cells
Spherocytes of immune hemolysis
Schistocytes (RBC fragments) of mechanical hemolysis prosthetic valve
pts
Other laboratory abnormalities
Increased plasma lactate dehydrogenase
Increased plasma indirect [bilirubin]
Decreased plasma [haptoglobin]
RDW (Red cell distribution width)
Ancillary role in differential dx of anemia
Normal RDW accompanies anemias of
Thalassemia trait
Aplastic anemia
Anemia of chronic ds or inflammation
Elevated RDW
Anemias of iron, B12 or folate deficiencies
Can help differentiate microcytic hypochromic anemias of iron deficiency &
thalassemia trait
RBC indices can be misleading
Since they are averages, two concurrent processes may be occurring, but
averaging each other out on the numbers
Review of peripheral smear is therefore essential

HYPOREGENERATIVE ANEMIAS
Can be classified as to whether or not there is increased death of RBC
precursors in the marrow
Prevention of adequate hemoglobinized precursor development
Hypoplastic abnormalities
Nutritional deficiencies
Stem cell abnormalities

149

Bone marrow replacement abnormalities

Ineffective erythropoiesis
Hemoglobinized RBC precursors are formed but die within the marrow before
they can be released as reticulocytes
Some chemistry tests consistent with hemolysis
Low [LDH & haptoglobin]
High indirect [bilirubin]
Corrected reticulocyute count is low to normal
Examples of anemias of ineffective erythropoiesis
Thalassemia major & intermedia
Sideroblastic anemia
Congenital dysterythropoietic anemias
Ineffective erythropoiesis is associated with increased iron absorption & risk of
iron overload

Macrocytic Anemia
Causes
Cobalamin (Vit B12) or folate deficiency is the most common macrocytic anemia
EtOH abuse
Liver ds
Hypothyroidism
Myelodysplasia of many causes
Reticulocytosis
Cobalamin folate deficient anemias are called megaloblastic
Marrow examination reveals developing erythroid & meloid series cells to be
exceptionally large
Secondary to delayed nuclear maturation & cell division
The PMN in peripheral blood
Larger than normal
Increased number of lobes
>5 lobes = hypersegmented
Characteristic metamyelocytes (sometimes >30 m in size are seen in marrow
Morphologic changes in marrow & blood from lack of cobalamin & folate are
identical
Only cobalamin deficiency causes neurologic problems
Cobalamin (Vitamin B12) Deficiency
Caused by
Pernicious anemia
Gastrointestinal bacterial overgrowth
Loss of ileal fxn
In these conditions
Cobalamin poorly absorbed by gut
Vegan diet may also cause
Pernicious Anemia
Result of loss of intrinsic factor activity
Intrinsic factor is a glycoprotein normally secreted into gut
Gastric parietal cells secrete

150

Responsible of binding cobalamin & facilitating uptake

Uptake is in the terminal ileum
Gastric parietal cells
Deficient in secretion of hydrogen ions
Achlorhydria is typical finding in patients
Tested by measuring gastric acid output in response to histamine
Concurrent problems
Variety of immune abnormalities
90% humoral (antibody-mediated) or cellular autoimmunity
against parietal cells
have anti-intrinsic factor antibodies
Gastric histology is consistent with immune process
Lymphocytic infiltrate
Absence of parietal & chief cells
Gastrointestinal Bacterial Overgrowth
Result of bacterial competition for cobalamin
Inflammatory Bowel Disease, Tropical Sprue or Ileal resection
Failure to absorb
Intrinsic factor-cobalamin complexes
Abnormal or absent enterocytes of terminal ileum
Iatrogenic cause Nitrous oxide chemically inactivates the vitamin
Diagnosis Lab confirmation
Serum cobalamin levels
Deficiency of cobalamin
Elevated serum or urine methylmalonic acid level
Ineffective erythropoiesis in bone marrow
Abnormalities on peripheral blood film
Megaloblastic anemia (may be associated with glossitis)
Elevated levels of
LDH of erythrocyte origin
LDH-1 isoenzyme frequently is > LDH-2
Plasma indirect bilirubin & iron
Neurologic symptoms of cobalamin deficiency can be subtle or devastating
May occur late with severe megaloblastic anemia
May occur with lack of cobalamin in absence of anemia
Subacute combined degeneration
Demyelinating changes in dorsal & lateral spinal cord
Symptoms
Symmetric paresthesias
Loss of proprioception & ataxia
Megaloblastic madness
Disturbed cerebral function
Course of anemia & neurological decompensation are usually independent
Cobalamin deficiency can cause dementia in absence of anemia
Replacement therapy beneficial for early neurologic changes
Cause is usually learned from history

151

Schilling test may also help

Test dose of cobalamin
Intestinal absorption measured
With & without exogenous intrinsic factor
Test dose of cobalamin alone
Pernicious anemia not absorbed
Severe ileal disease not absorbed
Test dose with cobalamin & intrinsic factor
Pernicious anemia absorbed
Ileal disease not absorbed
Large test dose of cobalamin
Bacterial overgrowth syndrome patients may be able to absorb
Greater amount of substrate than bacteria can use
Megaloblastic anemia in pernicious anemia
Responds to intramuscular injections of cobalamin
Morphologic changes in the bone & blood resolve rapidly
Reticulocytosis begins after 72 hrs
Serum uric acid rises
Hypokalemia may develop from erythropoietic usage of potassium
Severe hypokalemia & cardiac arrhythmias may occur
Serum potassium must be monitored & replaced prn
Large doses of folate may transiently improve or correct anemia of cobalamin
deficiency
Folate alone
Does not prevent progression of neurologic symptoms
May actually hasten
Folate therapy
Started on a daily basis
Change to monthly after hematocrit returns to normal
Neurologic abnormalities from advanced subacute combined degeneration are
probably not reversed by subsequent cobalamin administration
Folate Deficiency
Also causes megaloblastic anemia
Peripheral blood film & bone marrow appear identical as cobalamin deficiency
Lack neurologic syndrome
Caused by
Poor absorption of folic acid in the presence of
Phenytoin & other drugs
Malabsorption syndromes
Inadequate dietary intake (Most Common)
In the alcoholic the following combine to produce anemia
Poor diet
Inability of marrow to use folate
Distinction between folate and cobalamin deficiency is made in the lab
Low RBC folate levels reveal deficiency
Confused if already transfused

152

Anemia of alcoholic person resolves quickly on admission

When alcohol is halted
Patient begins to eat folate rich food\
Folate deficient anemia is completely curable with oral replacement therapy

Microcytic Hypochromic Anemias

Iron deficient anemia
Thalassemia
Other causes
Iron Deficiency
Most common cause
Usually result of blood loss
Often combined with inadequate dietary intake
Common in children & menstruating women
When occurs in men or non-menstruating females
Specific site & cause must be sought
Most likely blood loss site is the GI tract
Clinical features
Fatigue
Angular cheilitis
Irritablility
Palor koilonychias (nail
spooning)
Headaches
Paresthesias
Pica (eating weird stuff)
Glossitis
Mild iron deficiency may be asymptomatic
Diagnosis
Suggested by microcytic, hypochromic anemia on blood film
Transferrin saturation may not be reliable for dx
Low or normal reticulocytes count
The ratio of serum iron to total serum iron-binding capacity (i.e.
transferrin saturation) of less than 15%
Normal reticulocyte count is 20-40%
Decreases
Acute or chronic inflammation
Raised with
Marrow dysfunction from
Alcohol
Cancer chemotherapy
Megaloblastic processes
Diurnal variations
Helpful measure of total body iron stores
Low (<12 g/L) diagnostic of iron deficient anemia
Serum transferritin
Positive acute-phase reactant
May not reflect iron deficiency in a patient with lack of iron &
inflammatory process
Early in the course of iron deficiency
RBC normochromic & normocytic

153

If everything else is normal

Transferrin saturation & serum ferritin are low
If serum ferritin is > 12 g/L
Bone marrow stained to reveal presence or absence of iron stores
If macrophages are absent of iron it is an iron deficient anemia
Presumptive diagnosis is enough to start treatment
Oral iron therapy
Patients with negative history for
Gastrointestinal bleeding
Microcytic hypochromic indices
Low reticulocyte count
Low serum ferritin level
Guaiac-negative stools
i.e. menstruating females absent history
Response to oral iron therapy
Moderate reticulocytosis
Increase in [hemoglobin]
Within 10 days
Response confirms diagnosis
Patients who have no clear source of bleeding
If stool is guaiac positive safe to assume that is the cause of anemia
If no blood loss is detectable, but lab findings indicate iron deficiency
Bone marrow exam
If there is a decrease in stainable iron stores
Suspect colorectal cancer
History suggesting a potential bleeding source
Alcohol abuse
NSAID usage
Peptic ulcer disease
Treatment
Oral iron replacement
Ferrous sulfate is the most common
Well absorbed
Most patients respond well
Leading cause of medicinal iron poisoning in children
Iron dextran
Rarely necessary
IM or IV
Parenteral route higher incidence of severe allergic rxns
All patients should be monitored for anaphylaxis
Thalassemia
Any of several genetic defects in the production of the globin chains of
hemoglobin
-chain (-thalassemia)
-chain (-thalassemia)
Clinical syndromes understood by corresponding genotypes

154

-thalassemia
Mutation on the -globin gene impairs the level of protein expression
Less severe in heterozygous state
AKA -thalassemia minor
More severe in homozygous state
AKA -thalassemia major
-thalassemia
More genetic possibilities because locus is duplicated
Absence of -globulin genes (--/--)
Incompatible with life (hydrops fetalis)
Death in utero
1 functional gene (--/-)
Severe anemia with microcytic cells
Hemolysis
Called hemoglobin H disease
2 functional genes (-/- or /--)
-thalassemia minor syndrome
Mild anemia
3 functional genes clinically silent
Most common form is -thalassemia minor
Normal life expectancy
Populations most affected
Mediterranean regions of
Middle East
Southern Europe
Africa
Southeast Asia
Sub-Saharan Africa
Blood information
5.5
million RBCs/L (Contrast with iron deficiency where
RBCs are not elevated)
Basophilic stippling is common
Mild reticulocytosis may be present
Cells are more uniform in size than in iron deficient anemia
Suspect Thalassemia minor when
Microcytosis & hypochromia present combined with a borderline
or slight anemia
Serum ferritin levels are in the normal range (16-300 g/L)
Diagnosis
-thalassemia minor
Hemoglobin electrophoresis
Elevated percentage of Hemoglobin A2 (4-6%)
Elevated hemoglobin F (5-20%)
-thalassemia minor
DNA analysis
Globin chain analysis

155

Condition often dx by exclusion

If question is between iron deficient or thalassemia
Bone marrow exam & stain
Iron stores normal thalassemia
Other causes
Microcytic hypochromic anemia could also be cause by
Lead poisoning
Hereditary sideroblastic anemia
Anemia of chronic inflammation

Normochromic Normocytic Anemias

Anemia of Chronic Inflammation
AKA Anemia of chronic disease
Chronic inflammation is most common cause in western countries
Characterized by
Increased accumulation storage iron in macrophages
Decreased delivery of iron to the erythroid precursors in the marrow
Inflammatory cytokines i.e. Tumor Necrosis Factor
May directly inhibit erythropoiesis
Circulating RBCs have slightly decreased survival
Anemia of inflammation
Generally mild
Rare for hematocrit to go below 28%
General decrease in
Serum iron
Total iron binding capacity
Transferrin saturation
Serum Ferritin is normal or increased
Can occasionally mimic iron deficient anemia on blood film
Serum ferritin then makes the dx
Remember, iron deficient anemia serum ferritin levels is <12 g/L
Prolonged Inflammatory States
Examples of
Tuberculosis
Malignancies
Rheumatologic disorders
May be complicated by iron deficiency
GI loss
NSAID usage
30% of rheumatoid arthritis patients are iron deficient
To confirm Iron deficiency in chronic inflammation
Demonstrate lack of iron staining in bone marrow
Anemia of Renal Failure
Uremia always associated with anemia
Extent of anemia
Only rough correlation with degree of renal impairment
Result of

156

Failure of erythropoietin production

Suppression of marrow from uremic toxins
Decrease in lifespan of circulation RBCs from uremic toxins
Frequently patients with renal failure have blood loss
Impaired hemostasis form abnormal platelet fxn
GI bleeds
Must rule out iron deficiency
Severe hypoproliferative anemia in a patient with uremia
Bone marrow exam
Determine if oral iron is indicated
Recombinant human erythropoietin
Treatment of choice for patients with anemia of renal failure
Marrow Aplasia
Common cause of normochromic, normocytic anemia
Presents as a pancytopenia
Immediately suggesting total bone marrow failure
Testing
Bone marrow aspirate
May produce only spicules devoid of hemopoietic cells
Marrow biopsy
Confirms hypocellularity & fatty replacement
Pure RBC aplasia
Rare disorder
Only marrow erythroid forms are diminished or absent
Marrow aplasia & Pure RBC aplasia
Serum [iron] is elevated
Transferrin saturation is high
Marrow reveals adequate or increased iron stores
Etiology
~1/2 are attributable to marrow toxic drugs
Chloramphenicol
Marrow aspirate has characteristic vacuolization of marrow cells
Chemical exposure also implicated
Benzene
Insecticides
Toluene
Viral hepatitis
Infiltrative diseases of bone marrow can look like marrow failure
Myelofibrosis
Leukemia
Bone marrow examination to differentiate between
Aplasia & infiltrative disease
Cease potentially offending drugs or chemicals
Recovery
Ranges from full to none
Bone marrow transplants have been successful

157

Anemia in Patients With Acquired Immunodeficiency Syndrome (AIDS)

Cause is multifactorial and may include
Suppression of erythropoiesis related to infection with HIV
Metabolic changes from chronic inflammation
Examination
Bone marrow typically shows
Increased plasma cells
Fibrosis
Iron stores
Plasma erythropoietin levels may be inappropriate low for degree of anemia
Treatment with Zidovudine causes myelodysplastic changes and ineffective
erythropoiesis
Infiltration of the marrow by infections, lymphoma cells or mycobacterial
granulomas
Chronic Diarrhea syndromes may cause lack of folate
Evaluation
Cultures
Histologic exam of bone marrow
Treatment
Good response with Erythropoietin
Iron deficiency is rare with AIDs so dont start empiric treatment with iron
replacements

ANEMIAS OF RED BLOOD CELL DESTRUCTION

Anemias with
No blood loss & plenty of reticulocytes (marrow is working normal & trying to
compensate)
Implies peripheral RBC destruction
Four major causes of destructive anemias
1. Immune hemolysis
2. Mechanical hemolysis
3. Sickle cell anemia
4. Glucose-6-phosphate dehydrogenase (G6PD) deficiency

Immune Hemolysis
Etiology
Generally caused by warm reacting (>31 deg C) immunoglobulin
IgG anti-RBC antibodies
Test
Direct antigblobulin test
Determines presence of bound immunoglobulin or complement on a
patients RBCs
Demonstrates agglutination of RBCs with anti-immunoglobulin or antcomplement antibody
20-30%
Immune hemolysis not associated with underlying ds
Considered idiopathic
30-40%

158

Immune hemolysis is associated with underlying ds

Chronic lymphocytic leukemia
Other lymphoproliferative ds
Underlying lymphoproliferative ds should be suspected if
Development of warm-reacting autoimmune hemolytic anemia
develops
30%
Result of drug use
Most common drugs are
Quinidine
Sulfonamides
Methyldopa
PCN
Cephalosporins
Mechanisms
1. PCN induced immune hemolysis
a. PCN attaches to RBC membrane & acts as a haptan
b. Substantial hemolysis usually with only high doses
c. Strong positive Coombs test (+agglutination with antibodies)
2. Quinidine & many other drugs
a. Stimulate production of antibodies
i. These drug antibody complexes attach nonspecifically
to RBC
1. This is the most common mechanisms
b. Immune complexes can activate the complement pathway
i. Leads to acute hemolysis
ii. May be so severe it causes renal failure
iii. The complex can migrate from cell to cell
c. Low drug doses can cause
3. + Coombs to Anticomplement antibodies
4. Other mechanisms are more speculative
Regardless of mechanism & drug
Remission usually occurs after removal of the drug
Clinical Manifestations
Depends on acuteness & severity of anemia
Fulminant cases present with
Jaundice
Pallor
Cardiopulmonary collapse
Other cases may be asymptomatic
Hepatosplenomegaly occurs in 1/3 1/2 of patients
Thrombophlebitis may also occur
Testing
Peripheral blood film reveials
Microspherocytes

159

Spherocytosis presumably result of inability of IgG to opsonize the

RBCs
Results in partial phagocytosis of macrophages in spleen
Progressive loss of RBC membrane makes it more round
Direct Coombs test reveals on patients RBCs
Immunoglobulin
Complement
Or both
Labs
Elevated LDH level
Indirectly reacting bilirubin
Decreased [haptoglobin]
Increased plasma levels of free hemoglobin & hemoglobinuria
With rapid hemolysis
Lab abnormalities are not specific & are seen with any hemolytic anemias
Therapy
Discontinue all drugs
Search for lymphoma or leukemia started
Corticosteroids are usually helpful in controlling hemolysis
Other immunosuppressants
Splenectomy if drug therapy fails
Cold-Reacting Antibodies
Cold agglutins
Generally the IgM antibodies
Maximal reactivity when < 31 deg C
Can occur in patients with
Lymphoproliferative ds
Certain infections
Mycoplasma
Falciparum malaria
Epstein-Barr virus
Idiopathic
Because responsible antibody is a multivalent IgM molecule
Hemolysis is mediated by complement activation or agglutination dominate
Predominant features of erythrocyte agglutination
Symptoms of vascular occlusion occur
Pain
Ulceration in chilled areas of the body
Usually fingers or toes
Mechanical Hemolysis
Caused by turbulent blood flow across
Abnormal heart valves
Partially obstructed vessels
Through hemangiomas
Macroangiopathic hemolysis is associated with
Tight aortic stenosis

160

Prosthetic heart valves

Microangiopathic hemolysis can be caused by
Disseminated intravascular coagulation
Thrombotic thrombocytopenic purpura
Malignant hypertension
Hemangiomas
The blood film is distinctive
Schistocytes & RBC fragments

Sickle Cell Anemia

Genetic ds caused by substitution of valine for glutamine
Occurs in 6th position of the -hemoglobin chain
Altered chain called hemoglobin S
Strong tendency to form long crystalline aggregates when deoxygenated
Distorts into sickle shape
May not be apparent if blood is not deoxygenated
Sodium metabisulfite is used
Heterozygous persons
Sickle trait
Rarely experience symptoms
RBCs can be demonstrated to sickle when deoxygenated
[Hemoglobin S] is low enough it doesnt occur at normal oxygen tensions
Homozygous
Sickle Cell Disease
Dx is almost always in childhood
More common in blacks than whites
May protect against malaria
Peoples from
Africa
Mediterranean
Middle East
India
Clinical course
Reflects chronic consequences of anemia
Tissue infarct
Punctuated by acute recurrent symptomatic periods
Sickle Cell Crisis
Life expectancy is reduced
Patients adapt well to chronic anemia (results in fatigue)
Develop hyperdynamic circulations & almost always have cardiac flow murmurs
Problems arise from
Vascular sludging
Thrombosis
Produces gradual but widespread tissue infarct
Likely a result of intravascular sickling
Chronic Problems
Leg ulcers

161

Ankles
Anterior tibial regions
May be sites of infection
Chance for healing incr with x-fusion
Maintains hemoglobin level between 9-10 g/dL
Skin grafts may be required
Chronic hematuria & hyposthenuria (excretion of urine w/ low specific gravity)
Occurs in both sickle disease & sickle trait
Vascular sludging may be marked in the kidney
Infart & necrosis may occur
Renal medulla has low oxygen tension & is particularly susceptible
Renal papillary necrosis w/ urinary obstruction may manifest as
Acute
Painful renal crisis
Unilateral renal shutdown
Hematuria
Chills
Chronic renal failure requiring hemodialysis develops in a few patients\
Functional asplenism
From repeat infarction
Contributes to increased susceptibility to infarction
Therefore polyvalent pneumococcal & haemophilus influenza vaccines given as
soon as dx
Prophylactic PCN may be indicated
Priapism not uncommon
Bilirubin released by hemolysis
Pigmented gallstones
Source of sepsis
Elective cholecystectomy
Removes possible source of sepsis
Simplifies differential of an acute abdominal crisis
Aseptic necrosis of the femoral heads
Increased incidence with sickle cell patients
Likely secondary to bone infarcts
Advanced aseptic necrosis consider hip replacement
Osteomyelitis
Salmonella is the putative organism
Failure of patients immune system
Predisposition to bone infection is thought to be from
Poor blood supply
Vascular sludging
Possibly the presence of infarcts in the bone
Sickle Cell Crisis
Acute painful attack often with fever
Pain crisis
Most common cause for hospitalization

162

Pain in
Back & joints
May migrate
Abdominal pain may accompany
May present as a surgical abdomen
Infection should be suspected if
Fever
Leukocytosis
Acute debility
Empiric abx is not indicated
Tests
Blood cultures
Chest x-ray
Urine examined for
Leukocytes
Bacteria
Presumptive broad spectrum abx for high fever and sepsis appears likely
Tx
Generally symptomatic therapy
Abate over several days
Narcotic analgesia for pain
Precipitants for crisis
Cold
Hypoxia
Acidosis
Use of supplemental oxygen without hypoxia has no benefit
Pulmonary infarction
Common problem
Clumps of sickled cells occlude pulmonary system
May have concurrent pneumonia
Administer Abx to pts with acute chest syndrome
Aplastic crisis
Less common than pain crisis
Precipitated by parvoviral infection
Short duration but aplasia can persist for longer
Reticulocyte count monitored
Transfusions until marrow recovers
Hyperhemolysis crisis
Therapeutic regimens have not been successful
Hydroxyurea recently tried
Increases hemoglobin F
Chronic administration reduces hemolysis
Allogeneic bone marrow transplants have been curative in selected patients
Sickle Cell-Hemoglobin C Disease
Patients possess
One gene for the -chain of hemoglobin of disease

163

One gene for the normal where glutamic acid from the 6th position has
been replaced by lysine
Called the c gene
Share some of the clinical features of sickle cell
Less severe
Most common symptom is pain in
Abdomen
Chest
Bones
Joints
Chest symptoms of
Pain
Cough
Fever
Probably caused by small pulmonary infarcts
Most have splenomegaly
Target cells can be seen on blood film
Dx considered in patients with sickle disease like symptoms but without severe
anemia & sickling
Confirmed by electrophoresis

Glucose-6-Phosphate Dehydrogenase Deficiency

Enzyme G6PD is protective
Prevents RBC from oxidative damage
Intracellular reducing agent is
Nicotinamide adenine dinucleotide phosphate (NADPH)
Patients with ds are less able to deal with oxidative stresses & hemolysis can
occur
10% of black men have ds
Called A form
Self limiting because effect is greatest on older RBCs
Hemolysis only kills the old & weak, not the young
Quantitative tests after crisis are usually normal
Detected by serum electrophoresis
Mediterranean type
White populations
No detectable G6DP
Heinz bodies
Small densities in RBC visualized with special stain
They are denatured hemoglobin
Can be seen before onset & early in hemolysis
Later nothing on the peripheral film is suggestive
Drugs are the most common initiators
Typically produce lysis in 24 hrs
Previous sensitization is not required
Most common cause is
Sulfonamides

164

Febrile illnesses of any sort can induce hemolysis

Usually mild
Absence of reticulocytosis in the presence of infection can exacerbate the
resultant anemia
Fava bean ingestion
Can cause severe RBC lysis
May require x-fusion therapy

165

Chapter 43 Abnormalities of Hemostasis

Hemostatic defects are from abnormalities of
Platelets
Blood vessels
Coagulation factors
Platelet disorders & vascular abnormalities
Superficial vessel involvement
Petechiae
Skin
Mucus membrane
Coagulation defects
More prominent bleeding in deep tissues
Atraumatic hemarthroses
Characteristic of severe coagulation abnormalities
Most bleeding disorders can be classified by lab tests
Bleeding time
Measures how long it takes for a standardized skin incision to stop
bleeding
Time is
Prolonged with platelet or vascular abnormalities
Normal in coagulation disorders
PT (Prothrombin) Time & PTT (Patial Thromboplastin) time
Detect most coagulation disorders
Coagulation Cascade
Complex series of biochemical rxns that trigger the next rxn
End result is a fibrin clot
All coagulation factors are proteins
Most exist in inactive form in plasma
Final step is Fibrinogen Fibrin
Mediated by protein thrombin
Generated from prothrombin
Mediated by activated factor X(Xa)
Factor X(Xa) has two pathways of generation
4. Intrinsic pathway
i. Factor XII exposure to a variety of surface agents (e.g. collagen)
initiates cascade
5. Extrinsic pathway
i. Involves Factor VII
ii. Complexes with calcium & a tissue factor
PTT (Partial thromboplastin time)
Measures the ability to form a fibrin clot by the intrinsic pathway
Doesnt test Factor VII
PT (Prothrombin Time)
Measures the extrinsic pathwy

166

Test measures time to clot

Calcium & a tissue extract added to plasma
Normal Normal level of factor VII
Normal fxn of factors common to both pathways
Factor V
Factor X
Thrombin
Fibrinogen
In Vivo Coagulation initiated by Tissue factor/factor VIIa complex
Factor X directly or through mediation of factor IX
Thrombin Factor VII to VIIa & then the IXa/VIIa complex amplifies the
formation of additional Xa
Limitation of clot spread
Inhibitors in the clotting cascade
Arrest coagulation & limit to site of vascular damage
i.e. Antithrombin III circulates
Inactivates thrombin
Rxn enhanced by heparin
Factor C & S
Inactivate cofactors involved in production of thrombin
Endothelial cells secrete prostacyclin
Limits size of platelet aggregates

167

PLATELET DISORDERS
Bleeding can result from
Thrombocytopenia
Most common cause of bleeding
Abnormal platelet fxn
Normal platelet count - ~ 250,000/L
Thrombocytopenic bleeding does not occur until
< 20,000/L
Initial screen is a blood film
Examination will reveal
True thrombocytopenia or Artifactual clumping of platelets
Normal v. abnormal platelet morphology
Normal platelet count with bleeding disorder & PT & PTT normal
Bleeding test
If prolonged
Abnormal platelet fxn or abnormal blood vessel
Aspects of platelet fxn that can be tested in the laboratory
1. Platelet adhesiveness The ability to adhere to a foreign surface

168

2. Platelet aggregation the ability to induce platelet aggregation via several

substances
a. Adensodine diphosphate
b. Epinephrine
c. Collagen
Common Causes of Thrombocytopenia
Drug-induced thrombocytopenia
Immune thrombocytopenic purpura (ITP)
Thrombotic Thrombocytopenic purpura (TTP)
Bone marrow failure

Drug-Induced Thrombocytopenia
Thrombocytopenia via
Marrow toxicity
Platelet destruction
Most common drugs implicated in suppressing production of megakaryocytes
EtOH
Thiazide diuretics
Alcoholic thrombocytopenia
Result of folate deficiency & hypersplenism
Usually mild & chronic
Rarely results in bleeding
Counts return to normal 1-2 weeks after EtOH cessation
Associated with thiazides also & resolves after stopping drug
Drug related peripheral platelet destruction
Immunological mechanism
Many drugs implicated
Most common
Heparin
Quinidine
Quinine
Others
Gold
Para-aminosalicylic acid
Methydopa
Sulfonamides
Heparin-induced thrombocytopenia
Frequent due to common use in hospitals
1%-3% incidence in patients tx for 7-14 days
Mechanism of action
Heparin-dependent IgG antibodies recognize complex of
Heparin & platelet factor 4
Antiboides activate platelets via
FcIIa receptors & endothelial cells bound by factor 4
Can lead to thrombosis
5-10 days later thrombocytopenia develops after starting heparin
Usually mild to moderate

169

 - 1/3 patients will develop thrombosis

Venous or arterial
Devastating consequences
Bleeding complications are uncommon
Tx
Cease heparin if suspected
Alternative anticoagulants
Danaparoid
Recombinant hirudin
Argatroban
Dont use LMWH can also induce thrombocytopenia
Thrombocytopenia associated with quinidine or quinine
Sudden & severe
Results in bleeding
Admit these patients
Halt all drugs & avoid trauma
Platelet transfusion
Rapid recovery normal 7-10 days
Gold induced may last for months

Immune Thrombocytopenic Purpura

Common disorder antiplatelet antibodies implicated in massive peripheral
destruction
Acute ITP
Any age, but mostly pedo
Also AIDs
Bleeding occurs acutely & often several weeks after a viral illness or
immunizations
Pt is well despite dramatic petechiae & pupra
Slightly enlarged spleen & liver (small percentage)
Lab findings are normal except thrombocytopenia
Differential dx
Acute ITP & sepsis (meningococcemia)
Generally benign
Tx
Corticosteroids
High dose gamaglobulins
80% recover within 6 moths
Refractory cases
Splenectomy
Azathioprine & vincristine
X-fusion doesnt increase platelet count
Chronic ITP
Usually adult female
Less severe & an insidious onset
Low spontaneous remission
Same tx as acute

170

Associated diseases
Chronic lymphocytic
leukemia
Lymphoma

SLE
Sarcoidosis
Tuberculosis

Thrombotic Thrombocytopenic Purpura

Uncommon middle aged females, HIV pts
Clinical Pentad of thrombocytopenic purpura characterizes
1. Thrombocytopenic purpura
2. Anemia
3. Fluctuating neurologic signs
4. Renal deterioration
5. Fever
Hemolytic-uremic syndrome is closely related disorder
TTP characterized by
Platelet rich thrombi
Damaged endothelium
Unknown cause
May be related to abnormally large von Willenbrand factor (vWF) molecules that
promote shear
Some patients have a deficiency in vWF cleaving protein
Anemia
Microangiopathic hemolytic anemia
Wide spread arteriolar inclusions may cause renal dysfxn
Frequent abdominal pain
Neurologic signs & symptoms
Headache
Acute psychosis
Seizures
Coma
Rapid & dramatic fluctuations
Hemorrhagic complications
Cutaneous purpura
GI & genitourinary bleeding
Without tx
Aggressive
Fatal
Tx
Plasmapheresis
90% improvement
Long term remissions still occur
30% will relapse
Auxillary treatment that can be tried in refractory cases or in conjunction with
plasmapheresis
Antiplatelet agents
Corticosteroids
Vincristine
Splenectomy

171

Bone Marrow Failure

Thrombocytopenia is often severe enough to cause bleeding
Leukemia usual cuase
Other causes
Aplastic anemia
Myelofibromosis
Drugs
Dx
Blod film
Marrow aspirate biopsy
Other causes of thrombocytopenia due to bone marrow dysfxn
Vitamin B12 or folate deficiency
Paroxysmal nocturnal hemoglobinurea

Thrombocytopenia and AIDs

Common findings in HIV
ITP syndrome may an acute antibody-mediated occur
Respond to
Prednisone & high dose IV gamma globulin
Zidovudine may remit ds
TTP Also reported
Suppression may be from infection
Abnormal fxn may be result of
Meds
Malignancies
Drug-related immune mechanisms
Disseminated intravascular coagulation (DIC)
Marrow infiltration by lymphoma or granuloma
Megaloblastic changes from zidovudine therapy

VASCULAR ABNORMALITIES
Various abnormalities associated
Normal PT & PTT
Prolonged bleeding time
Helps point to dx
Principle manifestation may be purpura
Examples of conditions
CT disorders Ehlers-Danlos
Scurvy
Autoimmune vascular disorders
Henoch-Schnlein purpura
Rocky Mountain spotted fever
Meningocococemia
Tx
Tx underlying infection
Administer Vitamin C for scurvy pts
Treatment of the above disorders is difficult

172

COAGULATION DISORDERS
Suspect if
Bleeding times & platelet counts are normal
Investigate coagulation pathways
Clinical sign suggesting coag disorder
Deep tissue bleeding without skin or mucosal petechiae

Acquired Coagulation Disorders

Vitamin K deficiency
Most common
Vit K dependent factors
Are made in the liver
Vit K required for synthesis
The Vit K factors are
Factor II (Prothrombin)
VII
Shortest half life (3-5 hours)
IX
X
Prolonged PT is 1st evidence of Vit K deficiency
Can be caused by
Intestinal malabsorption
Oral anticoagulants interfere
Treatment with some broad spectrum antibiotics
Oral Anticoagulants
Warfarin
Completely inhibits action of vitamin K
Bleeding can occur through accidental or intentional ingestion
Pharmacodynamics
Bound to albumin
Metabolized in liver
Some agents can displace warfarin from albumin
Accidental overdose by increasing free drug
Excessive anticoagulation
Prolonged PT
Prolonged PTT
May experience bleeding
TX
Administer vitamin K
Returns to normal ~ 6-14 hours
Drawback
Days to return pt to therapeutic coagulation levels
If bleeding is severe
x-fusion of missing factors

173

Malabsorption
Vitamin K
Fat soluble
Requires bile acids for absorption
Disruption of bile acid synthesis Disruption of K absorption
Broad spectrum antibiotics may kill vitamin K producing bacteria
May lead to deficiency
Protracted periods of therapy parenteral vitamin K may be needed
Response to parenteral vitamin K differentiates from liver failure patients
Liver Disease
Deficiencies of
Vitamin K dependent factors
II
VII
IX
X
Other Factors
I
V
Independent of vitamin K levels
Also
Hypoalbumenemic
Thrombocytopenia concurrent hypersplenism from portal hypertension
Other Causes
Circulating antigoagulant to factor VIII (hemophilia receiving x-fusion therapy)
Amylidosis
Factor X absorbed by extracellular amyloid

Inherited Coagulation Disorders

Hemophilia
Hemophilia A
Factor VIII
1:10,000 affected in US
Sex-linked Recessive
Various deficiencies
Failure to produce factor VIII
Altered, non-functional factor VIII
Severity dependent on amt of normal VIII circulation
Mild 5-25% normal
Bleeding when exposed to hemostatic stress
Moderate 2-5% normal
Severe - <2% normal
Moderate & severe patients
Deep-tissue bleeding
Intramuscular
Serious contracture deformities
Intra-articular

174

Hemarthrosis hospitalization
Preceded by trauma or exercise
Spontaneous
Usually knee, but any large joint
S&S
Painful
Tender
Swollen
Repeated may destruction with cystic subchondral changes &
osteoporosis
Neurologic problems
Compression of peripheral nerves by muscle heme
May lead to atrophy
Intracerebral hemorrhage secondary to trauma
Often fatal
Empiric VIII replacement
Variety of syndromes from deep tissue heme
Mimic non-vascular problems
Retroperitoneal bleeding
Painful abdominal syndrome
Oropharyngeal
Airway obstruction
Periureteral
Spasms & obstruction
Hematemesis & hemoptysis are rare to occur with hemophilia
Therapy
Replacement therapy (VIII)
Much reach a level of 25% normal VIII for hemostasis
Several days of replacement
Prophylactic replacement therapy for invasive procedures
Recombinant VIII
Low HIV risk
Hemophilia B
Factor IX deficiency
Sex linked
Recessive
Tx recombinant factor IX
von Willebrands Disease (vWD)
2nd most common
Autosomal dominant
Rare recessive variety as well as acquired
S&S
Severe mucosal bleeding
Bruis easily
Prolonged bleeding
Epistaxis

175

Most common manifestation

75% of patients
Generally improves with age
Lack of, or abnormality in a protein complex called von Willebrand factor
Glycoprotein complex
Three fxns
1. Associates with factor VIII & stabilizes it
2. Enhances platelet aggregation
3. Contributes to platelet attachment to injured vascular
endothelium
Two types of von Willebrands disease
1. Type I
a. Decreased amount of vWF
b. More severe disease
2. Type II
a. Abnormal (variant) vWF
Pregnancy & liver ds elevate the serum levels
S&S
Evidence of abnormal platelet fxn (i.e. prolonged bleeding time)
Measure platelet dysfunction via ristocetin aggregation test
Measures ability of the antibiotic ristcetin to aggregate platelets
Platelet counts are normal
Therapy
Correct both the bleeding time & coagulation abnormalities
Infusion of preparations that contain
Highest molecular weight vWF multimers
Factor VIII
Intermediate-purity factor VIII concentrates such as Humate-P and Alphanate can
be used
Cryoprecipitate
Fxnal vWF & VII
1-desamino-8D-arginine vasopressin (DDAVP) for patients with type I Disease
Works only on deficiency not deformity

Disseminated Intravascular Coagulation

DIC is primarily a coagulation disorder, but severe thrombocytopenia may occur
& exacerbate the tendency to bleed
Pathophysiology
Results from widespread activation of coag sys
Depletion of factors bleeding
Fibrin-split product (FSP)
From widespread fibrinolysis
Product enhances bleeding
Microangiopathic hemolysis
From deposit of fibrin in microvascular
Schistocytes detected on peripheral smear film
Prolonged

176

PT
PTT
Thrombin time
Decreased fibrinogen levels
Effects of
Small vessel emboli and thromboses
Tissue bleeding
Severe anemia
Etiology
Infection the most common
Abnormal production or release of procoagulant patient
Severe bacterial sepsis with Gm + & GmTx
Find the source of infection
Empiric broad spectrum parenteral Abx
Etiology
Thought to be caused by liberation of tissue factors
Cancer
Fat emboli
Massive acute hemolysis
Necrotic tissue
Obstetric catastrophes
Therapy
Tx underlying disorder
x-fusions occasionally
Balance with potential to worsen condition
IV heparin to interrupt cycle of coagulation
Could make patient bleed even more than they already do

Hypercoagulable States
Heterogeneous group of disorders
Tend to form venous or arterial thromboses
Heredity or acquired defects of factors that
Inhibit the coag cascade (eg, protein C, protein S, antithrombin III)
Promote fibrinolysis
Plasminogen
Tissue plasminogen activator
Inherited abnormalities of factor V or II
Assoc with thrombotic tendencies
Certain systemic conditions that may lead to thromboisis
Vasculitis
Malignancy
Hyperviscosity
Nephrotic syndrome
Increase risk of thrombosis from stasis
Pregnancy
Heparin use

177

Lupus anticoagulant
Antiphospholipid antibody
Leads to an elevated PTT
Inhibits the assay in vitro, but leads to hypercoagulable state in vivo
Therapy rarely needed unless thrombosis evidence
Managed by immediate heparin & long term Coumadin

178