Kidney Diseases - VOLUME ONE - Chapter 06

Disorders of
Acid-Base Balance
Horacio J. Adrogué
Nicolaos E. Madias
M
aintenance of acid-base homeostasis is a vital function of the
living organism. Deviations of systemic acidity in either
direction can impose adverse consequences and when severe
can threaten life itself. Acid-base disorders frequently are encountered
in the outpatient and especially in the inpatient setting. Effective man-
agement of acid-base disturbances, commonly a challenging task, rests
with accurate diagnosis, sound understanding of the underlying
pathophysiology and impact on organ function, and familiarity with
treatment and attendant complications [1].
Clinical acid-base disorders are conventionally defined from the
vantage point of their impact on the carbonic acid-bicarbonate buffer
system. This approach is justified by the abundance of this buffer pair
in body fluids; its physiologic preeminence; and the validity of the iso-
hydric principle in the living organism, which specifies that all the
other buffer systems are in equilibrium with the carbonic acid-bicar-
bonate buffer pair. Thus, as indicated by the Henderson equation,
-
[H+] = 24 PaCO2/[HCO3] (the equilibrium relationship of the car-
bonic acid-bicarbonate system), the hydrogen ion concentration of
blood ([H+], expressed in nEq/L) at any moment is a function of the
prevailing ratio of the arterial carbon dioxide tension (PaCO2,
expressed in mm Hg) and the plasma bicarbonate concentration
-
([HCO3], expressed in mEq/L). As a corollary, changes in systemic
acidity can occur only through changes in the values of its two deter-
minants, PaCO2 and the plasma bicarbonate concentration. Those
acid-base disorders initiated by a change in PaCO2 are referred to as CHAPTER
respiratory disorders; those initiated by a change in plasma bicarbon-
ate concentration are known as metabolic disorders. There are four
6
cardinal acid-base disturbances: respiratory acidosis, respiratory alka-
losis, metabolic acidosis, and metabolic alkalosis. Each can be
encountered alone, as a simple disorder, or can be a part of a mixed-
disorder, defined as the simultaneous presence of two or more simple
6.2 Disorders of Water, Electrolytes, and Acid-Base
acid-base disturbances. Mixed acid-base disorders are frequent- illustrated: the underlying pathophysiology, secondary
ly observed in hospitalized patients, especially in the critically ill. adjustments in acid-base equilibrium in response to the initi-
The clinical aspects of the four cardinal acid-base ating disturbance, clinical manifestations, causes, and thera-
disorders are depicted. For each disorder the following are peutic principles.
Respiratory Acidosis
FIGURE 6-1
Arterial blood [H+], nEq/L Quantitative aspects of adaptation to respiratory acidosis.
150 125 100 80 70 60 50 40 30 20 Respiratory acidosis, or primary hypercapnia, is the acid-base dis-
turbance initiated by an increase in arterial carbon dioxide tension
PaCO2 120 100 90 80 70 60 50
mm Hg (PaCO2) and entails acidification of body fluids. Hypercapnia elic-
40 its adaptive increments in plasma bicarbonate concentration that
50 should be viewed as an integral part of respiratory acidosis. An
immediate increment in plasma bicarbonate occurs in response to
Chron acidosis
Arterial plasma [HCO–3], mEq/L
hypercapnia. This acute adaptation is complete within 5 to 10 min-

40
ic resp
30 utes from the onset of hypercapnia and originates exclusively from

acidic titration of the nonbicarbonate buffers of the body (hemo-
iratory
globin, intracellular proteins and phosphates, and to a lesser extent

30 Acute respira plasma proteins). When hypercapnia is sustained, renal adjust-
tory 20
acidosis ments markedly amplify the secondary increase in plasma bicar-
Normal
bonate, further ameliorating the resulting acidemia. This chronic
20
adaptation requires 3 to 5 days for completion and reflects genera-
10 tion of new bicarbonate by the kidneys as a result of upregulation
of renal acidification [2]. Average increases in plasma bicarbonate
10
and hydrogen ion concentrations per mm Hg increase in PaCO2
after completion of the acute or chronic adaptation to respiratory
acidosis are shown. Empiric observations on these adaptations
6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7
have been used for construction of 95% confidence intervals for
graded degrees of acute or chronic respiratory acidosis represented
Arterial blood pH
by the areas in color in the acid-base template. The black ellipse
near the center of the figure indicates the normal range for the
Steady-state relationships in respiratory acidosis: acid-base parameters [3]. Note that for the same level of PaCO2,
average increase per mm Hg rise in PaCO2
the degree of acidemia is considerably lower in chronic respiratory
[HCO–3] mEq/L [H+] nEq/L acidosis than it is in acute respiratory acidosis. Assuming a steady
Acute adaptation 0.1 0.75 state is present, values falling within the areas in color are consis-
Chronic adaptation 0.3 0.3 tent with but not diagnostic of the corresponding simple disorders.
Acid-base values falling outside the areas in color denote the pres-
ence of a mixed acid-base disturbance [4].
Disorders of Acid-Base Balance 6.3
acid production, leading to generation of new bicarbonate ions

Eucapnia -
Stable Hypercapnia (HCO3) for the body fluids. Conservation of these new bicarbonate
Net acid excretion
ions is ensured by the gradual augmentation in the rate of renal bicar-

bonate reabsorption, itself a reflection of the hypercapnia-induced
increase in the hydrogen ion secretory rate. A new steady state
emerges when two things occur: the augmented filtered load of bicar-
bonate is precisely balanced by the accelerated rate of bicarbonate
reabsorption and net acid excretion returns to the level required to
offset daily endogenous acid production. The transient increase in
Chloride excretion
net acid excretion is accompanied by a transient increase in chloride

excretion. Thus, the resultant ammonium chloride (NH4Cl) loss gen-
erates the hypochloremic hyperbicarbonatemia characteristic of
chronic respiratory acidosis. Hypochloremia is sustained by the
persistently depressed chloride reabsorption rate. The specific cellular
mechanisms mediating the renal acidification response to chronic
Bicarbonate reabsorption
hypercapnia are under active investigation. Available evidence sup-

ports a parallel increase in the rates of the luminal sodium ion–
-
hydrogen ion (Na+-H+) exchanger and the basolateral Na+-3HCO3
cotransporter in the proximal tubule. However, the nature of these
adaptations remains unknown [5]. The quantity of the H+-adenosine
triphosphatase (ATPase) pumps does not change in either cortex or
medulla. However, hypercapnia induces exocytotic insertion of H+-
0 1 2 3 4 5 ATPase–containing subapical vesicles to the luminal membrane of
Days
proximal tubule cells as well as type A intercalated cells of the cortical
and medullary collecting ducts. New H+-ATPase pumps thereby are
FIGURE 6-2 recruited to the luminal membrane for augmented acidification [6,7].
Renal acidification response to chronic hypercapnia. Sustained hyper- Furthermore, chronic hypercapnia increases the steady-state abun-
-
capnia entails a persistent increase in the secretory rate of the renal dance of mRNA coding for the basolateral Cl—HCO3 exchanger
tubule for hydrogen ions (H+) and a persistent decrease in the reab- (band 3 protein) of type A intercalated cells in rat renal cortex and
sorption rate of chloride ions (Cl-). Consequently, net acid excretion medulla, likely indicating increased band 3 protein levels and there-
(largely in the form of ammonium) transiently exceeds endogenous fore augmented basolateral anion exchanger activity [8].
its development include the magnitude and

SIGNS AND SYMPTOMS OF RESPIRATORY ACIDOSIS time course of the hypercapnia, severity of
the acidemia, and degree of attendant
hypoxemia. Progressive narcosis and coma
may occur in patients receiving uncon-
Central Nervous System Respiratory System Cardiovascular System trolled oxygen therapy in whom levels of
Mild to moderate hypercapnia Breathlessness Mild to moderate hypercapnia arterial carbon dioxide tension (PaCO2)
Cerebral vasodilation Central and peripheral cyanosis Warm and flushed skin may reach or exceed 100 mm Hg. The
Increased intracranial pressure (especially when breathing Bounding pulse hemodynamic consequences of carbon
Headache room air) Well maintained cardiac dioxide retention reflect several mecha-
Confusion Pulmonary hypertension output and blood pressure nisms, including direct impairment of
Combativeness Diaphoresis
myocardial contractility, systemic vasodila-
Hallucinations Severe hypercapnia
Cor pulmonale
tion caused by direct relaxation of vascular
Transient psychosis
Myoclonic jerks Decreased cardiac output smooth muscle, sympathetic stimulation,
Flapping tremor Systemic hypotension and acidosis-induced blunting of receptor
Severe hypercapnia Cardiac arrhythmias responsiveness to catecholamines. The net
Manifestations of pseudotumor cerebri Prerenal azotemia effect is dilation of systemic vessels, includ-
Stupor Peripheral edema ing the cerebral circulation; whereas vaso-
Coma constriction might develop in the pul-
Constricted pupils monary and renal circulations. Salt and
Depressed tendon reflexes water retention commonly occur in chronic
Extensor plantar response hypercapnia, especially in the presence of
Seizures
cor pulmonale. Mechanisms at play include
Papilledema
hypercapnia-induced stimulation of the
renin-angiotensin-aldosterone axis and the
sympathetic nervous system, elevated levels
of cortisol and antidiuretic hormone, and
FIGURE 6-3 increased renal vascular resistance. Of
Signs and symptoms of respiratory acidosis. The effects of respiratory acidosis on the central course, coexisting heart failure amplifies
nervous system are collectively known as hypercapnic encephalopathy. Factors responsible for most of these mechanisms [1,2].
Pump Load
Cerebrum Ventilatory requirement

Voluntary control (CO2 production, O2 consumption)
Controller Brain stem

Automatic control
Spinal cord
Airway resistance
Phrenic and
intercostal nerves
Effectors Lung elastic recoil
Muscles
of respiration ∆V
∆V
Ppl Chest wall elastic recoil
Pabd Diaphragm
Abdominal
cavity
FIGURE 6-4
Main components of the ventilatory system. The ventilatory system is responsible for maintaining
the arterial carbon dioxide tension (PaCO2) within normal limits by adjusting minute ventilation
•
(V) to match the rate of carbon dioxide production. The main elements of ventilation are the res-
piratory pump, which generates a pressure gradient responsible for air flow, and the loads that
oppose such action. The machinery of the respiratory pump includes the cerebrum, brain stem,
spinal cord, phrenic and intercostal nerves, and the muscles of respiration. Inspiratory muscle con-
traction lowers pleural pressure (Ppl) thereby inflating the lungs (V). The diaphragm, the most
important inspiratory muscle, moves downward as a piston at the floor of the thorax, raising
abdominal pressure (Pabd). The inspiratory decrease in Ppl by the respiratory pump must be suffi-
cient to counterbalance the opposing effect of the combined loads, including the airway flow resis-
tance, and the elastic recoil of the lungs and chest wall. The ventilatory requirement influences the
load by altering the frequency and depth of the ventilatory cycle. The strength of the respiratory
pump is evaluated by the pressure generated (P = Ppl - Pabd).
DETERMINANTS AND CAUSES OF CARBON DIOXIDE RETENTION
Respiratory Pump Load

Depressed Central Drive Abnormal Neuromuscular Transmission Increased Ventilatory Demand Lung Stiffness
Acute Acute High carbohydrate diet Acute
General anesthesia High spinal cord injury Sorbent-regenerative hemodialysis Severe bilateral pneumonia
Sedative overdose Guillain-Barré syndrome Pulmonary thromboembolism or bronchopneumonia
Head trauma Status epilepticus Fat, air pulmonary embolism Acute respiratory
Cerebrovascular accident Botulism Sepsis distress syndrome
Central sleep apnea Tetanus Hypovolemia Severe pulmonary edema
Cerebral edema Crisis in myasthenia gravis Atelectasis
Augmented Airway Flow Resistance
Brain tumor Hypokalemic myopathy Chronic
Acute
Encephalitis Familial periodic paralysis Severe chronic pneumonitis
Upper airway obstruction
Brainstem lesion Drugs or toxic agents eg, curare, Diffuse infiltrative disease eg,
Coma-induced hypopharyngeal obstruction alveolar proteinosis
Chronic succinylcholine, aminoglycosides,
Aspiration of foreign body or vomitus Interstitial fibrosis
Sedative overdose organophosphorus
Laryngospasm
Methadone or heroin addiction Chronic Chest Wall Stiffness
Angioedema
Sleep disordered breathing Poliomyelitis Acute
Obstructive sleep apnea
Brain tumor Multiple sclerosis Rib fractures with flail chest
Inadequate laryngeal intubation
Bulbar poliomyelitis Muscular dystrophy Pneumothorax
Laryngeal obstruction after intubation
Hypothyroidism Amyotrophic lateral sclerosis Hemothorax
Lower airway obstruction
Diaphragmatic paralysis Abdominal distention
Generalized bronchospasm
Myopathic disease eg, polymyositis Ascites
Airway edema and secretions
Muscle Dysfunction Peritoneal dialysis
Severe episode of spasmodic asthma
Acute Chronic
Bronchiolitis of infants and adults
Fatigue Kyphoscoliosis, spinal arthritis
Chronic
Hyperkalemia Obesity
Upper airway obstruction
Hypokalemia Fibrothorax
Tonsillar and peritonsillar hypertrophy
Hypoperfusion state Hydrothorax
Paralysis of vocal cords
Hypoxemia Chest wall tumor
Tumor of the cords or larynx
Malnutrition Airway stenosis after prolonged intubation
Chronic Thymoma, aortic aneurysm
Myopathic disease eg, polymyositis Lower airway obstruction
Airway scarring
Chronic obstructive lung disease eg, bronchitis,
bronchiolitis, bronchiectasis, emphysema
FIGURE 6-5
Determinants and causes of carbon dioxide retention. When the res- muscle dysfunction. A higher load can be caused by increased venti-
piratory pump is unable to balance the opposing load, respiratory latory demand, augmented airway flow resistance, and stiffness of
acidosis develops. Decreases in respiratory pump strength, increases the lungs or chest wall. In most cases, causes of the various determi-
in load, or a combination of the two, can result in carbon dioxide nants of carbon dioxide retention, and thus respiratory acidosis, are
retention. Respiratory pump failure can occur because of depressed categorized into acute and chronic subgroups, taking into consider-
central drive, abnormal neuromuscular transmission, or respiratory ation their usual mode of onset and duration [2].
FIGURE 6-6
Spontaneous Mechanical ventilation
breathing Posthypercapnic metabolic alkalosis. Development of posthypercap-
nic metabolic alkalosis is shown after abrupt normalization of the
arterial carbon dioxide tension (PaCO2) by way of mechanical ven-
80
tilation in a 70-year-old man with respiratory decompensation who
PaCO2, mm Hg
has chronic obstructive pulmonary disease and chronic hypercapnia.

-
The acute decrease in plasma bicarbonate concentration ([HCO3])
60
over the first few minutes after the decrease in PaCO2 originates
from alkaline titration of the nonbicarbonate buffers of the body.
When a diet rich in chloride (Cl-) is provided, the excess bicarbon-
40
ate is excreted by the kidneys over the next 2 to 3 days, and acid-
base equilibrium is normalized. In contrast, a low-chloride diet sus-
tains the hyperbicarbonatemia and perpetuates the posthypercapnic
40
metabolic alkalosis. Abrupt correction of severe hypercapnia by
way of mechanical ventilation generally is not recommended.
[HCO–3], mEq/L
Low-Cl– diet
–
Rather, gradual return toward the patient’s baseline PaCO2 level
30 Cl - rich diet should be pursued [1,2]. [H+]—hydrogen ion concentration.
20 Cl–- rich diet
7.60
[H+], nEq/L
7.50 30
pH
7.40 40
7.30 50
7.20 60
0 2 4 6 8
Days
FIGURE 6-7
No Remove dentures, foreign bodies, or food particles; Heimlich maneuver Acute respiratory acidosis management.
Airway patency
secured? (subdiaphragmatic abdominal thrust); tracheal intubation; tracheotomy Securing airway patency and delivering an
oxygen-rich mixture are critical initial steps
ent
Yes
ay pat in management. Subsequent measures must
w • Administer O2 via nasal mask or prongs to maintain
Air PaO2 > 60 mm Hg. be directed at identifying and correcting the
Oxygen-rich mixture • Correct reversible causes of pulmonary dysfunction underlying cause, whenever possible [1,9].
delivered with antibiotics, bronchodilators, and PaCO2—arterial carbon dioxide tension.
corticosteroids as needed.
• Monitor patient with arterial blood gases initially at
Alert, blood pH > 7.10, intervals of 20 to 30 minutes and less frequently
or PaCO2 <60 mm Hg thereafter.
Mental status and
blood gases evaluated • If PaO2 does not increase to > 60 mm Hg or PaCO2
rises to > 60 mm Hg proceed to steps described in
the box below.
• Consider intubation and initiation of mechanical

Obtunded, blood pH < 7.10, ventilation.
or PaCO2 > 60 mm Hg • If blood pH is below 7.10 during mechanical
ventilation, consider administration of sodium
bicarbonate, to maintain blood pH between 7.10
and 7.20, while monitoring arterial blood gases closely.
• Correct reversible causes of pulmonary dysfunction
as in box above.
FIGURE 6-8
Severe Chronic respiratory acidosis management.
hypercapnic Therapeutic measures are guided by the
encephalopathy No Yes presence or absence of severe hypercapnic
PaO2 > 60 mm Hg Observation, routine care.
or hemodynamic on room air encephalopathy or hemodynamic instability.
instability An aggressive approach that favors the
• Administer O2 via nasal cannula or Venti mask early use of ventilator assistance is most
No • Correct reversible causes of pulmonary appropriate for patients with acute respira-
dysfuntion with antibiotics, bronchodilators,
and corticosteroids as needed.
tory acidosis. In contrast, a more conserva-
tive approach is advisable in patients with
Mental status deteriorates

Hemodynamic instability
chronic hypercapnia because of the great
CO2 retention worsens

PaO2 < 55 mm Hg
Yes difficulty often encountered in weaning
PaO2 ≥ 55 mm Hg, patient stable
these patients from ventilators. As a rule,

the lowest possible inspired fraction of
oxygen that achieves adequate oxygenation
(PaO2 on the order of 60 mm Hg) is used.
Contrary to acute respiratory acidosis, the
underlying cause of chronic respiratory aci-
• Consider intubation and use of • Consider use of noninvasive nasal mask ventilation dosis only rarely can be resolved [1,9].
standard ventilator support. (NMV) or intubation and standard ventilator support.
• Correct reversible causes of
pulmonary dysfunction with
antibiotics, bronchodilators,
and corticosteroids as needed. • Continue same measures.
Respiratory Alkalosis
FIGURE 6-9
Arterial blood [H+], nEq/L Adaptation to respiratory alkalosis. Respiratory alkalosis, or
150 125 100 80 70 60 50 40 30 20 primary hypocapnia, is the acid-base disturbance initiated by a
decrease in arterial carbon dioxide tension (PaCO2) and entails
PaCO2 120 100 90 80 70 60 50
mm Hg
alkalinization of body fluids. Hypocapnia elicits adaptive decre-
40 ments in plasma bicarbonate concentration that should be viewed
50 as an integral part of respiratory alkalosis. An immediate decre-
ment in plasma bicarbonate occurs in response to hypocapnia. This
acute adaptation is complete within 5 to 10 minutes from the onset

40 30 of hypocapnia and is accounted for principally by alkaline titration
of the nonbicarbonate buffers of the body. To a lesser extent, this
acute adaptation reflects increased production of organic acids,
30 notably lactic acid. When hypocapnia is sustained, renal adjust-
20 ments cause an additional decrease in plasma bicarbonate, further
Normal
Acut
e resp ameliorating the resulting alkalemia. This chronic adaptation
Ch
alkalo iratory
ro alk
20 sis requires 2 to 3 days for completion and reflects retention of hydro-

nic al
res osis
gen ions by the kidneys as a result of downregulation of renal acid-

pir
10
ato
ification [2,10]. Shown are the average decreases in plasma bicar-

ry
10 bonate and hydrogen ion concentrations per mm Hg decrease in

PaCO2after completion of the acute or chronic adaptation to respi-
ratory alkalosis. Empiric observations on these adaptations have
been used for constructing 95% confidence intervals for graded
6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7
degrees of acute or chronic respiratory alkalosis, which are repre-
Arterial blood pH sented by the areas in color in the acid-base template. The black
ellipse near the center of the figure indicates the normal range for
Steady-state relationships in respiratory alkalosis: the acid-base parameters. Note that for the same level of PaCO2,
average decrease per mm Hg fall in PaCO2 the degree of alkalemia is considerably lower in chronic than it is
[HCO–3] mEq/L [H+] nEq/L in acute respiratory alkalosis. Assuming that a steady state is pre-
Acute adaptation 0.2 0.75 sent, values falling within the areas in color are consistent with but
not diagnostic of the corresponding simple disorders. Acid-base
Chronic adaptation 0.4 0.4
values falling outside the areas in color denote the presence of a
mixed acid-base disturbance [4].
FIGURE 6-10
Eucapnia Stable Hypocapnia Renal acidification response to chronic hypocapnia. A, Sustained
Net acid excretion
hypocapnia entails a persistent decrease in the renal tubular secretory

rate of hydrogen ions and a persistent increase in the chloride reab-
sorption rate. As a result, transient suppression of net acid excretion
occurs. This suppression is largely manifested by a decrease in
ammonium excretion and, early on, by an increase in bicarbonate
excretion. The transient discrepancy between net acid excretion and
endogenous acid production, in turn, leads to positive hydrogen ion
Sodium excretion
balance and a reduction in the bicarbonate stores of the body.

Maintenance of the resulting hypobicarbonatemia is ensured by the
gradual suppression in the rate of renal bicarbonate reabsorption.
This suppression itself is a reflection of the hypocapnia-induced
decrease in the hydrogen ion secretory rate. A new steady state
emerges when two things occur: the reduced filtered load of bicar-
Bicarbonate reabsorption
bonate is precisely balanced by the dampened rate of bicarbonate

reabsorption and net acid excretion returns to the level required to
offset daily endogenous acid production. The transient retention of
acid during sustained hypocapnia is normally accompanied by a loss
of sodium in the urine (and not by a retention of chloride as analogy
with chronic respiratory acidosis would dictate). The resulting extra-
cellular fluid loss is responsible for the hyperchloremia that typically
0 1 2 3
accompanies chronic respiratory alkalosis. Hyperchloremia is sus-
Days
tained by the persistently enhanced chloride reabsorption rate. If
Km Vmax
dietary sodium is restricted, acid retention is achieved in the compa-
ny of increased potassium excretion. The specific cellular mecha-
NS P<0.01 nisms mediating the renal acidification response to chronic hypocap-
10 1000 nia are under investigation. Available evidence indicates a parallel
decrease in the rates of the luminal sodium ion–hydrogen ion
nmol/mg protein × min
(Na+-H+) exchanger and the basolateral sodium ion–3 bicarbonate

-
ion (Na+-3HCO3) cotransporter in the proximal tubule. This parallel
mmol/L
decrease reflects a decrease in the maximum velocity (Vmax) of each

transporter but no change in the substrate concentration at half-
5 500 maximal velocity (Km) for sodium (as shown in B for the Na+-H+
exchanger in rabbit renal cortical brush-border membrane vesicles)
[11]. Moreover, hypocapnia induces endocytotic retrieval of H+-
adenosine triphosphatase (ATPase) pumps from the luminal mem-
brane of the proximal tubule cells as well as type A intercalated cells
of the cortical and medullary collecting ducts. It remains unknown
Control Chronic Control Chronic whether chronic hypocapnia alters the quantity of the H+-ATPase
hypocapnia hypocapnia pumps as well as the kinetics or quantity of other acidification trans-
(9% O2) (9% O2) porters in the renal cortex or medulla [6]. NS—not significant. (B,
From Hilden and coworkers [11]; with permission.)
FIGURE 6-11
SIGNS AND SYMPTOMS OF RESPIRATORY ALKALOSIS Signs and symptoms of respiratory alkalo-
sis. The manifestations of primary hypocap-
nia frequently occur in the acute phase, but
Central Nervous System Cardiovascular System Neuromuscular System seldom are evident in chronic respiratory
alkalosis. Several mechanisms mediate these
Cerebral vasoconstriction Chest oppression Numbness and paresthesias clinical manifestations, including cerebral
Reduction in intracranial pressure Angina pectoris of the extremities hypoperfusion, alkalemia, hypocalcemia,
Light-headedness Ischemic electrocardiographic changes Circumoral numbness hypokalemia, and decreased release of oxy-
Confusion Normal or decreased blood pressure Laryngeal spasm gen to the tissues by hemoglobin. The car-
Increased deep tendon reflexes Cardiac arrhythmias Manifestations of tetany diovascular effects of respiratory alkalosis
Generalized seizures Peripheral vasoconstriction Muscle cramps are more prominent in patients undergoing
Carpopedal spasm mechanical ventilation and those with
Trousseau’s sign ischemic heart disease [2].
Chvostek’s sign
CAUSES OF RESPIRATORY ALKALOSIS
Central Nervous
Hypoxemia or Tissue Hypoxia System Stimulation Drugs or Hormones Stimulation of Chest Receptors Miscellaneous
Decreased inspired oxygen tension Voluntary Nikethamide, ethamivan Pneumonia Pregnancy
High altitude Pain Doxapram Asthma Gram-positive septicemia
Bacterial or viral pneumonia Anxiety syndrome- Xanthines Pneumothorax Gram-negative septicemia
Aspiration of food, foreign object, hyperventilation syndrome Salicylates Hemothorax Hepatic failure
or vomitus Psychosis Catecholamines Flail chest Mechanical hyperventilation
Laryngospasm Fever Angiotensin II Acute respiratory distress syndrome Heat exposure
Drowning Subarachnoid hemorrhage Vasopressor agents Cardiogenic and noncardiogenic Recovery from metabolic acidosis
Cyanotic heart disease Cerebrovascular accident Progesterone pulmonary edema
Severe anemia Meningoencephalitis Medroxyprogesterone Pulmonary embolism
Left shift deviation of Tumor Dinitrophenol Pulmonary fibrosis
oxyhemoglobin curve Trauma Nicotine
Hypotension
Severe circulatory failure
Pulmonary edema
FIGURE 6-12
Respiratory alkalosis is the most frequent acid-base disorder to permit full chronic adaptation to occur. Consequently, no
encountered because it occurs in normal pregnancy and high- attempt has been made to separate these conditions into acute
altitude residence. Pathologic causes of respiratory alkalosis and chronic categories. Some of the major causes of respiratory
include various hypoxemic conditions, pulmonary disorders, cen- alkalosis are benign, whereas others are life-threatening. Primary
tral nervous system diseases, pharmacologic or hormonal stimu- hypocapnia is particularly common among the critically ill,
lation of ventilation, hepatic failure, sepsis, the anxiety-hyper- occurring either as the simple disorder or as a component of
ventilation syndrome, and other entities. Most of these causes mixed disturbances. Its presence constitutes an ominous prog-
are associated with the abrupt occurrence of hypocapnia; howev- nostic sign, with mortality increasing in direct proportion to the
er, in many instances, the process might be sufficiently prolonged severity of the hypocapnia [2].
FIGURE 6-13
Respiratory alkalosis Respiratory alkalosis management. Because chronic respiratory alka-
losis poses a low risk to health and produces few or no symptoms,
measures for treating the acid-base disorder itself are not required. In
Acute Chronic contrast, severe alkalemia caused by acute primary hypocapnia
requires corrective measures that depend on whether serious clinical
No manifestations are present. Such measures can be directed at reducing
Manage underlying disorder. -
Blood pH ≥ 7.55 plasma bicarbonate concentration ([HCO3]), increasing the arterial
No specific measures indicated.
carbon dioxide tension (PaCO2), or both. Even if the baseline plasma
Yes bicarbonate is moderately decreased, reducing it further can be partic-
ularly rewarding in this setting. In addition, this maneuver combines
Hemodynamic instability, No • Consider having patient rebreathe effectiveness with relatively little risk [1,2].
altered mental status, into a closed system.
or cardiac arrhythmias • Manage underlying disorder.
Yes
Consider measures to correct blood pH ≤ 7.50 by:

• Reducing [HCO–3]:
acetazolamide, ultrafiltration and normal saline
replacement, hemodialysis using a low bicarbonate bath.
• Increasing PaCO2:
rebreathing into a closed system, controlled hypoventilation
by ventilator with or without skeletal muscle paralysis.
FIGURE 6-14
Lungs Pseudorespiratory alkalosis. This entity
develops in patients with profound depres-
sion of cardiac function and pulmonary
perfusion but relative preservation of alveo-
Normal lar ventilation. Patients include those with
advanced circulatory failure and those
undergoing cardiopulmonary resuscitation.
The severely reduced pulmonary blood flow
limits the amount of carbon dioxide deliv-
pH 7.40
LV RV
pH 7.38 ered to the lungs for excretion, thereby
PCO2 40 PCO2 46 increasing the venous carbon dioxide ten-
– –
[HCO3 ] 24 [HCO3 ] 26 sion (PCO2). In contrast, the increased ven-
PO2 95 PO2 40
FiO2 0.21 tilation-to-perfusion ratio causes a larger
Peripheral tissues than normal removal of carbon dioxide per
unit of blood traversing the pulmonary cir-
culation, thereby giving rise to arterial
hypocapnia [12,13]. Note a progressive
Arterial Venous widening of the arteriovenous difference in
compartment compartment
pH and PCO2 in the two settings of cardiac
dysfunction. The hypobicarbonatemia in
the setting of cardiac arrest represents a
Circulatory Failure
complicating element of lactic acidosis.
Despite the presence of arterial hypocapnia,
pseudorespiratory alkalosis represents a
special case of respiratory acidosis, as
pH 7.42 pH 7.29 absolute carbon dioxide excretion is
PCO2 35 LV RV PCO2 60 decreased and body carbon dioxide balance
– –
[HCO3 ] 22 [HCO3 ] 28
is positive. Furthermore, the extreme oxy-
PO2 80 PO2 30
FiO2 0.35 gen deprivation prevailing in the tissues
might be completely disguised by the rea-
sonably preserved arterial oxygen values.
Appropriate monitoring of acid-base com-
position and oxygenation in patients with
advanced cardiac dysfunction requires
mixed (or central) venous blood sampling
in addition to arterial blood sampling.
Management of pseudorespiratory alkalosis
Cardiac Arrest must be directed at optimizing systemic
hemodynamics [1,13].
pH 7.37 pH 7.00
PCO2 27 LV RV PCO2 75
[HCO3– ] 15 [HCO–3 ] 18
PO2 116 PO2 17
FiO2 1.00
Metabolic Acidosis
FIGURE 6-15
Arterial blood [H+], nEq/L
Ninety-five percent confidence intervals for metabolic acidosis.
150 125 100 80 70 60 50 40 30 20 Metabolic acidosis is the acid-base disturbance initiated by a
-
PaCO2 120 100 90 80 70 60 50 decrease in plasma bicarbonate concentration ([HCO3]). The resul-
mm Hg tant acidemia stimulates alveolar ventilation and leads to the sec-
40 ondary hypocapnia characteristic of the disorder. Extensive obser-
50
vations in humans encompassing a wide range of stable metabolic
acidosis indicate a roughly linear relationship between the steady-
state decrease in plasma bicarbonate concentration and the associ-

40 30 ated decrement in arterial carbon dioxide tension (PaCO2). The
-
slope of the steady state PaCO2 versus [HCO3] relationship has
been estimated as approximately 1.2 mm Hg per mEq/L decrease
30
20
in plasma bicarbonate concentration. Such empiric observations
Normal have been used for construction of 95% confidence intervals for
20
graded degrees of metabolic acidosis, represented by the area in
sis c
ido oli
color in the acid-base template. The black ellipse near the center of
ac tab
e
M
10 the figure indicates the normal range for the acid-base parameters
10 [3]. Assuming a steady state is present, values falling within the
area in color are consistent with but not diagnostic of simple meta-
bolic acidosis. Acid-base values falling outside the area in color
denote the presence of a mixed acid-base disturbance [4]. [H+]—
6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 hydrogen ion concentration.
Arterial blood pH
FIGURE 6-16
SIGNS AND SYMPTOMS OF METABOLIC ACIDOSIS Signs and symptoms of metabolic acidosis.
Among the various clinical manifestations,
particularly pernicious are the effects of
Respiratory Central severe acidemia (blood pH < 7.20) on the car-
System Cardiovascular System Metabolism Nervous System Skeleton diovascular system. Reductions in cardiac
output, arterial blood pressure, and hepatic
Hyperventilation Impairment of cardiac Increased Impaired metabolism Osteomalacia and renal blood flow can occur and life-
Respiratory distress contractility, arteriolar metabolic demands Inhibition of cell Fractures threatening arrhythmias can develop. Chronic
and dyspnea dilation, venoconstriction, Insulin resistance volume regulation
and centralization of
acidemia, as it occurs in untreated renal tubu-
Decreased strength Inhibition of Progressive obtundation lar acidosis and uremic acidosis, can cause
of respiratory blood volume anaerobic glycolysis Coma calcium dissolution from the bone mineral
muscles and Reductions in cardiac Reduction in adenosine
promotion of output, arterial blood and consequent skeletal abnormalities.
triphosphate synthesis
muscle fatigue pressure, and hepatic
Hyperkalemia
and renal blood flow
Increased
Sensitization to reentrant
protein degradation
arrhythmias and reduction
in threshold for ventricular
fibrillation
Increased sympathetic
discharge but attenuation of
cardiovascular responsiveness
to catecholamines
Normal Metabolic acidosis

FIGURE 6-17
Normal anion gap High anion gap Causes of metabolic acidosis tabulated according to the prevailing
(hyperchloremic) (normochloremic) pattern of plasma electrolyte composition. Assessment of the plas-
A– 10 –
A 10 ma unmeasured anion concentration (anion gap) is a very useful
HCO3– HCO3– 4 A– 30
first step in approaching the differential diagnosis of unexplained
24 HCO3– 4
metabolic acidosis. The plasma anion gap is calculated as the dif-
ference between the sodium concentration and the sum of chloride
Na+ Cl– Na+ Cl– Na+ Cl–
140 106 140 126 140 106
and bicarbonate concentrations. Under normal circumstances, the
plasma anion gap is primarily composed of the net negative
charges of plasma proteins, predominantly albumin, with a smaller
contribution from many other organic and inorganic anions. The
normal value of the plasma anion gap is 12 ± 4 (mean ± 2 SD)
Causes Causes mEq/L, where SD is the standard deviation. However, recent intro-
Renal acidification defects Endogenous acid load
Proximal renal tubular acidosis Ketoacidosis duction of ion-specific electrodes has shifted the normal anion gap
Classic distal tubular acidosis Diabetes mellitus to the range of about 6 ± 3 mEq/L. In one pattern of metabolic aci-
Hyperkalemic distal tubular acidosis Alcoholism dosis, the decrease in bicarbonate concentration is offset by an
Early renal failure Starvation increase in the concentration of chloride, with the plasma anion
Gastrointestinal loss of bicarbonate Uremia
gap remaining normal. In the other pattern, the decrease in bicar-
Diarrhea Lactic acidosis
Small bowel losses Exogenous toxins bonate is balanced by an increase in the concentration of unmea-
Ureteral diversions Osmolar gap present sured anions (ie, anions not measured routinely), with the plasma
Anion exchange resins Methanol chloride concentration remaining normal.
Ingestion of CaCl2 Ethylene glycol
Acid infusion Osmolar gap absent
HCl Salicylates
Arginine HCl Paraldehyde
Lysine HCl
Lactic acidosis
duce lactate during the course of glycolysis, those listed contribute
Glucose substantial quantities of lactate to the extracellular fluid under nor-
mal aerobic conditions. In turn, lactate is extracted by the liver and
Gluconeogenesis to a lesser degree by the renal cortex and primarily is reconverted to
glucose by way of gluconeogenesis (a smaller portion of lactate is
oxidized to carbon dioxide and water). This cyclical relationship
Cori between glucose and lactate is known as the Cori cycle. The basal
cycle turnover rate of lactate in humans is enormous, on the order of 15
to 25 mEq/kg/d. Precise equivalence between lactate production and
its use ensures the stability of plasma lactate concentration, normally
Muscle Brain Skin RBC Liver Kidney cortex ranging from 1 to 2 mEq/L. Hydrogen ions (H+) released during lac-
tate generation are quantitatively consumed during the use of lactate
Anaerobic glycolysis
H+ + Lactate such that acid-base balance remains undisturbed. Accumulation of
lactate in the circulation, and consequent lactic acidosis, is generated
Overproduction Lactic acidosis Underutilization whenever the rate of production of lactate is higher than the rate of
utilization. The pathogenesis of this imbalance reflects overproduc-
tion of lactate, underutilization, or both. Most cases of persistent lac-
tic acidosis actually involve both overproduction and underutiliza-
FIGURE 6-18 tion of lactate. During hypoxia, almost all tissues can release lactate
Lactate-producing and lactate-consuming tissues under basal condi- into the circulation; indeed, even the liver can be converted from the
tions and pathogenesis of lactic acidosis. Although all tissues pro- premier consumer of lactate to a net producer [1,14].
reduces the availability of adenosine triphosphate (ATP) and NAD+

Glucose (oxidized nicotinamide adenine dinucleotide) within the cytosol. In
PFK turn, these changes cause cytosolic accumulation of pyruvate as a
+ low ATP consequence of both increased production and decreased utiliza-
ADP
Glycolysis
tion. Increased production of pyruvate occurs because the reduced
NAD+
cytosolic supply of ATP stimulates the activity of 6-phosphofruc-
tokinase (PFK), thereby accelerating glycolysis. Decreased utiliza-
tion of pyruvate reflects the fact that both pathways of its con-
NADH
sumption depend on mitochondrial oxidative reactions: oxidative
Pyruvate LDH decarboxylation to acetyl coenzyme A (acetyl-CoA), a reaction cat-
Lactate
Gluconeogenesis + alyzed by pyruvate dehydrogenase (PDH), requires a continuous
high NADH
NAD+ Cytosol supply of NAD+; and carboxylation of pyruvate to oxaloacetate, a
Mitochondrial membrane reaction catalyzed by pyruvate carboxylase (PC), requires ATP. The
increased [NADH]/[NAD+] ratio (NADH refers to the reduced
Mitochondria
form of the dinucleotide) shifts the equilibrium of the lactate dehy-
PD – high NADH+ drogenase (LDH) reaction (that catalyzes the interconversion of
low ATP – H NAD
PC
ADP NAD+ pyruvate and lactate) to the right. In turn, this change coupled with
Acetyl-CoA
NADH the accumulation of pyruvate in the cytosol results in increased
Oxaloacetate TCA – accumulation of lactate. Despite the prevailing mitochondrial dys-
cycle function, continuation of glycolysis is assured by the cytosolic
regeneration of NAD+ during the conversion of pyruvate to lactate.
Provision of NAD+ is required for the oxidation of glyceraldehyde
FIGURE 6-19 3-phosphate, a key step in glycolysis. Thus, lactate accumulation
Hypoxia-induced lactic acidosis. Accumulation of lactate during can be viewed as the toll paid by the organism to maintain energy
hypoxia, by far the most common clinical setting of the disorder, production during anaerobiosis (hypoxia) [14]. ADP—adenosine
originates from impaired mitochondrial oxidative function that diphosphate; TCA cycle—tricarboxylic acid cycle.
FIGURE 6-20
CAUSES OF LACTIC ACIDOSIS Conventionally, two broad types of lactic
acidosis are recognized. In type A, clinical
evidence exists of impaired tissue oxygena-
Type A: tion. In type B, no such evidence is apparent.
Impaired Tissue Oxygenation Type B: Preserved Tissue Oxygenation Occasionally, the distinction between the
two types may be less than obvious. Thus,
Shock Diseases and conditions Drugs and toxins inadequate tissue oxygenation can at times
Severe hypoxemia Diabetes mellitus Epinephrine, defy clinical detection, and tissue hypoxia
Generalized convulsions Hypoglycemia norepinephrine, can be a part of the pathogenesis of certain
Vigorous exercise Renal failure vasoconstrictor agents
causes of type B lactic acidosis. Most cases
Salicylates
Exertional heat stroke Hepatic failure of lactic acidosis are caused by tissue hypox-
Hypothermic shivering Severe infections Ethanol ia arising from circulatory failure [14,15].
Massive pulmonary emboli Alkaloses Methanol
Severe heart failure Malignancies (lymphoma, Ethylene glycol
Profound anemia leukemia, sarcoma) Biguanides
Mesenteric ischemia Thiamine deficiency Acetaminophen
Carbon monoxide poisoning Acquired Zidovudine
Cyanide poisoning immunodeficiency syndrome Fructose, sorbitol,
Pheochromocytoma and xylitol
Iron deficiency Streptozotocin
D-Lactic acidosis Isoniazid
Nitroprusside
Congenital enzymatic defects
Papaverine
Nalidixic acid
FIGURE 6-21
• Antibiotics (sepsis) Lactic acidosis management. Management
• Dialysis (toxins) of lactic acidosis should focus primarily on
• Discontinuation of incriminated securing adequate tissue oxygenation and on
drugs
No • Insulin (diabetes) aggressively identifying and treating the
Inadequate tissue Cause-specific measures underlying cause or predisposing condition.
oxygenation? • Glucose (hypoglycemia, alcoholism)
• Operative intervention (trauma, Monitoring of the patient’s hemodynamics,
tissue ischemia) oxygenation, and acid-base status should be
Yes
No • Thiamine (thiamine deficiency) used to guide therapy. In the presence of
• Low carbohydrate diet and
Oxygen-rich mixture antibiotics (D-lactic acidosis) severe or worsening metabolic acidemia,
and ventilator support, Circulatory failure? these measures should be supplemented by
if needed judicious administration of sodium bicar-
Yes
bonate, given as an infusion rather than a
bolus. Alkali administration should be
regarded as a temporizing maneuver adjunc-
• Volume repletion tive to cause-specific measures. Given the
• Preload and afterload
No • Continue therapy ominous prognosis of lactic acidosis, clini-
reducing agents Severe/Worsening
• Myocardial stimulants • Manage predisposing cians should strive to prevent its develop-
metabolic acidemia?
(dobutamine, dopamine) conditions ment by maintaining adequate fluid balance,
• Avoid vasoconstrictors optimizing cardiorespiratory function, man-
Yes aging infection, and using drugs that predis-
pose to the disorder cautiously. Preventing
Alkali administration to the development of lactic acidosis is all the
maintain blood pH ≥ 7.20
more important in patients at special risk
for developing it, such as those with dia-
betes mellitus or advanced cardiac, respira-
tory, renal, or hepatic disease [1,14–16].
Diabetic ketoacidosis and nonketotic hyperglycemia

FIGURE 6-22
A
Increased hepatic Role of insulin deficiency and the counter-
glucose production regulatory hormones, and their respective
Glucagon sites of action, in the pathogenesis of hyper-
Increased hepatic Cortisol glycemia and ketosis in diabetic ketoacido-
ketogenesis Counterregulation
Epinephrine sis (DKA).A, Metabolic processes affected
Insulin Growth hormone
deficiency Norepinephrine by insulin deficiency, on the one hand, and
Increased lipolysis excess of glucagon, cortisol, epinephrine,
in adipocytes
norepinephrine, and growth hormone, on
the other. B, The roles of the adipose tissue,
B Decreased glucose
utilization in skeletal
liver, skeletal muscle, and kidney in the
Triglycerides muscle pathogenesis of hyperglycemia and ketone-
Increased mia. Impairment of glucose oxidation in
lipolysis
most tissues and excessive hepatic produc-
tion of glucose are the main determinants
Increased ketogenesis Decreased ketone uptake
of hyperglycemia. Excessive counterregula-
Ketonemia tion and the prevailing hypertonicity, meta-
(metabolic acidosis) bolic acidosis, and electrolyte imbalance
superimpose a state of insulin resistance.
Increased gluconeogenesis Prerenal azotemia caused by volume deple-
Increased glycogenolysis Decreased glucose excretion
Decreased glucose uptake
tion can contribute significantly to severe
Hyperglycemia hyperglycemia. Increased hepatic produc-
(hyperosmolality) tion of ketones and their reduced utilization
by peripheral tissues account for the
ketonemia typically observed in DKA.
Increased protein breakdown Decreased glucose uptake
Decreased amino acid uptake

FIGURE 6-23
Insulin deficiency/resistance
Clinical features of diabetic ketoacidosis (DKA) and nonketotic
Severe Mild
hyperglycemia (NKH). DKA and NKH are the most important
acute metabolic complications of patients with uncontrolled dia-
betes mellitus. These disorders share the same overall pathogene-
Pure DKA Pure NKH sis that includes insulin deficiency and resistance and excessive
Mixed forms
profound DKA + NKH profound counterregulation; however, the importance of each of these
ketosis hyperglycemia endocrine abnormalities differs significantly in DKA and NKH.
As depicted here, pure NKH is characterized by profound hyper-
glycemia, the result of mild insulin deficiency and severe coun-
Mild Severe terregulation (eg, high glucagon levels). In contrast, pure DKA is
Excessive counterregulation characterized by profound ketosis that largely is due to severe
insulin deficiency, with counterregulation being generally of less-
Feature Pure DKA Mixed forms Pure NKH er importance. These pure forms define a continuum that
includes mixed forms incorporating clinical and biochemical fea-
Incidence 5–10 times higher 5–10 times lower
Mortality 5–10% 10–60%
tures of both DKA and NKH. Dyspnea and Kussmaul’s respira-
Onset Rapid (<2 days) Slow (> 5 days) tion result from the metabolic acidosis of DKA, which is general-
Age of patient Usually < 40 years Usually > 40 years ly absent in NKH. Sodium and water deficits and secondary
Type I diabetes Common Rare renal dysfunction are more severe in NKH than in DKA. These
Type II diabetes Rare Common deficits also play a pathogenetic role in the profound hypertonic-
First indication of diabetes Often Often ity characteristic of NKH. The severe hyperglycemia of NKH,
Volume depletion Mild/moderate Severe
often coupled with hypernatremia, increases serum osmolality,
Renal failure (most com- Mild, inconstant Always present
monly of prerenal nature)
thereby causing the characteristic functional abnormalities of the
Severe neurologic Rare Frequent central nervous system. Depression of the sensorium, somno-
abnormalities (coma in 25–50%) lence, obtundation, and coma, are prominent manifestations of
Subsequent therapy with Always Not always NKH. The degree of obtundation correlates with the severity of
insulin serum hypertonicity [17].
Glucose < 800 mg/dL > 800 mg/dL
Ketone bodies ≥ 2 + in 1:1 dilution < 2+ in 1:1 dilution
Effective osmolality < 340 mOsm/kg > 340 mOsm/kg
pH Decreased Normal
[HCO–3] Decreased Normal
[Na+] Normal or low Normal or high
[K+] Variable Variable
MANAGEMENT OF DIABETIC KETOACIDOSIS AND NONKETOTIC HYPERGLYCEMIA
Insulin Fluid Administration Potassium repletion Alkali

1. Give initial IV bolus of 0.2 U/kg actual body weight. Shock absent: Normal saline (0.9% NaCl) Potassium chloride should be Half-normal saline (0.45% NaCl) plus
2. Add 100 U of regular insulin to 1 L of normal saline (0.1 at 7 mL/kg/h for 4 h, and half this added to the third liter of IV 1–2 ampules (44-88 mEq) NaHCO3
U/mL), and follow with continuous IV drip of 0.1 U/kg rate thereafter infusion and subsequently per liter when blood pH < 7.0 or
actual body weight per h until correction of ketosis. Shock present: Normal saline and plasma if urinary output is at least total CO2 < 5 mmol/L; in hyper-
3. Give double rate of infusion if the blood glucose level expanders (ie,albumin, low molecular 30–60 mL/h and plasma [K+] chloremic acidosis, add NaHCO3
does not decrease in a 2-h interval (expected decrease weight dextran) at maximal possible rate < 5 mEq/L. when pH < 7.20; discontinue
is 40–80 mg/dL/h or 10% of the initial value.) Start a glucose-containing solution Add K+ to the initial 2 L of IV NaHCO3 in IV infusion when total
(eg, 5% dextrose in water) when blood fluids if initial plasma [K+] CO2>8–10 mmol/L.
4. Give SQ dose (10–30 U) of regular insulin when ketosis
is corrected and the blood glucose level decreases to glucose level decreases to 250 mg/dL. < 4 mEq/L and adequate
300 mg/dL, and continue with SQ insulin injection diuresis is secured.
every 4 h on a sliding scale (ie, 5 U if below 150, 10 U if
150–200, 15 U if 200–250, and 20 U if 250–300 mg/dL).
CO2—carbon dioxide; IV—intravenous; K+—potassium ion; NaCl—sodium chloride; NaHCO3—sodium bicarbonate; SQ—subcutaneous.
FIGURE 6-24
Diabetic ketoacidosis (DKA) and nonketotic hyperglycemia (NKH) NKH, in which ketoacidosis is generally absent. Because the fluid
management. Administration of insulin is the cornerstone of manage- deficit is generally severe in patients with NKH, many of whom have
ment for both DKA and NKH. Replacement of the prevailing water, preexisting heart disease and are relatively old, safe fluid replacement
sodium, and potassium deficits is also required. Alkali are adminis- may require monitoring of central venous pressure, pulmonary capil-
tered only under certain circumstances in DKA and virtually never in lary wedge pressure, or both [1,17,18].
Renal tubular acidosis

FIGURE 6-25
FEATURES OF THE RENAL TUBULAR ACIDOSIS (RTA) SYNDROMES Renal tubular acidosis (RTA) defines a
group of disorders in which tubular hydro-
gen ion secretion is impaired out of propor-
Feature Proximal RTA Classic Distal RTA Hyperkalemic Distal RTA tion to any reduction in the glomerular fil-
tration rate. These disorders are character-
Plasma bicarbonate 14–18 mEq/L Variable, may be 15–20 mEq/L ized by normal anion gap (hyperchloremic)
ion concentration < 10 mEq/L metabolic acidosis. The defects responsible
Plasma chloride Increased Increased Increased for impaired acidification give rise to three
ion concentration
distinct syndromes known as proximal RTA
Plasma potassium Mildly decreased Mildly to Mildly to severely increased
(type 2), classic distal RTA (type 1), and
ion concentration severely decreased
hyperkalemic distal RTA (type 4).
Plasma anion gap Normal Normal Normal
Glomerular filtration rate Normal or Normal or Normal to
slightly decreased slightly decreased moderately decreased
Urine pH during acidosis ≤5.5 >6.0 ≤5.5
Urine pH after acid loading ≤5.5 >6.0 ≤5.5
U-B PCO2 in alkaline urine Normal Decreased Decreased
Fractional excretion of >15% <5% <5%
- -
HCO3 at normal [HCO3]p
-
Tm HCO3 Decreased Normal Normal
Nephrolithiasis Absent Present Absent
Nephrocalcinosis Absent Present Absent
Osteomalacia Present Present Absent
Fanconi’s syndrome* Usually present Absent Absent
Alkali therapy High dose Low dose Low dose
-
Tm HCO3—maximum reabsorption of bicarbonate; U-B PCO2—difference between partial pressure of carbon
dioxide values in urine and arterial blood.
*This syndrome signifies generalized proximal tubule dysfunction and is characterized by impaired reabsorption of
glucose, amino acids, phosphate, and urate.
Lumen Proximal tubule cell Blood

B. CAUSES OF PROXIMAL RENAL
TUBULAR ACIDOSIS
CA
CO2
–
CO2 + OH HCO–3 3HCO–3 Selective defect (isolated bicarbonate wasting) Dysproteinemic states
CA
H2CO3 1Na+ Primary (no obvious associated disease) Multiple myeloma
H 2O
Genetically transmitted Monoclonal gammopathy
HCO–3 + H+ H+ Transient (infants) Drug- or toxin-induced
+ Due to altered carbonic anhydrase activity Outdated tetracycline
Na Na+ 3Na +
Acetazolamide 3-Methylchromone
Na+ Sulfanilamide Streptozotocin
2K+
Glucose Mafenide acetate Lead
Amino acids Genetically transmitted Mercury
Phosphate Idiopathic Arginine
Osteopetrosis with carbonic Valproic acid
Indicates possible cellular mechanisms responsible anhydrase II deficiency
for Type 2 proximal RTA Gentamicin
A York-Yendt syndrome
Ifosfamide
Generalized defect (associated with multiple
dysfunctions of the proximal tubule) Tubulointerstitial diseases
FIGURE 6-26 Renal transplantation
Primary (no obvious associated disease)
A and B, Potential defects and causes of proximal renal tubular Sjögren’s syndrome
acidosis (RTA) (type 2). Excluding the case of carbonic anhydrase Sporadic
Genetically transmitted Medullary cystic disease
inhibitors, the nature of the acidification defect responsible for
bicarbonate (HCO3) wastage remains unknown. It might represent Genetically transmitted systemic disease Other renal diseases
defects in the luminal sodium ion– hydrogen ion (Na+-H+) Tyrosinemia Nephrotic syndrome
- Wilson’s disease Amyloidosis
exchanger, basolateral Na+-3HCO3 cotransporter, or carbonic
anhydrase activity. Most patients with proximal RTA have addi- Lowe syndrome Miscellaneous
tional defects in proximal tubule function (Fanconi’s syndrome); Hereditary fructose intolerance (during Paroxysmal
this generalized proximal tubule dysfunction might reflect a defect administration of fructose) nocturnal hemoglobinuria
in the basolateral Na+-K+ adenosine triphosphatase. K+—potassium Cystinosis Hyperparathyroidism
ion; CA—carbonic anhydrase. Causes of proximal renal tubular Pyruvate carboxylate deficiency
acidosis (RTA) (type 2). An idiopathic form and cystinosis are the Metachromatic leukodystrophy
most common causes of proximal RTA in children. In adults, mul- Methylmalonic acidemia
tiple myeloma and carbonic anhydrase inhibitors (eg, acetazo- Conditions associated with chronic hypocalcemia
lamide) are the major causes. Ifosfamide is an increasingly and secondary hyperparathyroidism
common cause of the disorder in both age groups. Vitamin D deficiency or resistance
Vitamin D dependence
B. CAUSES OF CLASSIC DISTAL RENAL

TUBULAR ACIDOSIS
Lumen α Intercalated cell (CCT & MCT) Blood

Primary (no obvious associated disease) Disorders associated
Sporadic with nephrocalcinosis
Genetically transmitted Primary or familial hyperparathyroidism
CO2 HCO–3
Vitamin D intoxication
H + CA Autoimmune disorders
Cl– Milk-alkali syndrome
Hypergammaglobulinemia
OH– Hyperthyroidism
Hyperglobulinemic purpura
Idiopathic hypercalciuria
H+ H2 O Cryoglobulinemia
Genetically transmitted
Familial
K+ Cl– Sporadic
Sjögren’s syndrome
Hereditary fructose intolerance
Thyroiditis
(after chronic fructose ingestion)
Cl– Pulmonary fibrosis
Medullary sponge kidney
Chronic active hepatitis
Fabry’s disease
Primary biliary cirrhosis
Wilson’s disease
Indicates possible cellular mechanisms responsible Systemic lupus erythematosus
A for Type 1 distal RTA Vasculitis Drug- or toxin-induced
Amphotericin B
Genetically transmitted systemic disease
Toluene
FIGURE 6-27 Ehlers-Danlos syndrome
Analgesics
A and B, Potential defects and causes of classic distal renal tubular Hereditary elliptocytosis
Lithium
acidosis (RTA) (type 1). Potential cellular defects underlying classic Sickle cell anemia
Cyclamate
distal RTA include a faulty luminal hydrogen ion–adenosine triphos- Marfan syndrome
Balkan nephropathy
phatase (H+ pump failure or secretory defect), an abnormality in the Carbonic anhydrase I deficiency
basolateral bicarbonate ion–chloride ion exchanger, inadequacy of or alteration Tubulointerstitial diseases
carbonic anhydrase activity, or an increase in the luminal membrane Osteopetrosis with carbonic Chronic pyelonephritis
permeability for hydrogen ions (backleak of protons or permeability anhydrase II deficiency Obstructive uropathy
defect). Most of the causes of classic distal RTA likely reflect a secre- Medullary cystic disease Renal transplantation
tory defect, whereas amphotericin B is the only established cause of a Neuroaxonal dystrophy Leprosy
permeability defect. The hereditary form is the most common cause Hyperoxaluria
of this disorder in children. Major causes in adults include autoim-
mune disorders (eg, Sjögren’s syndrome) and hypercalciuria [19].
CA—carbonic anhydrase.
B. CAUSES OF HYPERKALEMIC
Lumen Principal cell Blood DISTAL RENAL TUBULAR ACIDOSIS
Na+
3Na+ Deficiency of aldosterone Resistance to aldosterone action

– Associated with glucocorticoid deficiency Pseudohypoaldosteronism type I
Potential 2K+ Addison’s disease (with salt wasting)
difference Bilateral adrenalectomy Childhood forms with
Enzymatic defects obstructive uropathy
21-Hydroxylase deficiency Adult forms with
Aldosterone renal insufficiency
K+ 3--ol-Dehydrogenase deficiency
receptor Desmolase deficiency Spironolactone
Acquired immunodeficiency syndrome Pseudohypoaldosteronism type II
Cl– Isolated aldosterone deficiency
(without salt wasting)
Combined aldosterone deficiency
α Intercalated cell Genetically transmitted
and resistance
Aldosterone Corticosterone methyl
Deficient renin secretion
oxidase deficiency
receptor Cyclosporine nephrotoxicity
Transient (infants)
CO2 HCO–3 Uncertain renin status
Sporadic
Voltage-mediated defects
CA Heparin
H+ Cl– Obstructive uropathy
Deficient renin secretion
OH– Diabetic nephropathy
Sickle cell anemia
Lithium
Tubulointerstitial renal disease
H+ H2 O Triamterene
Nonsteroidal antiinflammatory drugs
K+ Amiloride
Cl– -adrenergic blockers
Trimethoprim, pentamidine
Acquired immunodeficiency syndrome
Renal transplantation
Renal transplantation
Cl–
Angiotensin I-converting enzyme inhibition
Endogenous
Captopril and related drugs
Indicates possible cellular mechanisms in aldosterone deficiency Angiotensin AT, receptor blockers
Indicates defects related to aldosterone resistance
A
FIGURE 6-28
A and B, Potential defects and causes of hyperkalemic distal renal hyporeninemia, impaired conversion of angiotensin I to angiotensin
tubular acidosis (RTA) (type 4). This syndrome represents the most II, or abnormal aldosterone synthesis. Aldosterone resistance can
common type of RTA encountered in adults. The characteristic reflect the following: blockade of the mineralocorticoid receptor;
hyperchloremic metabolic acidosis in the company of hyperkalemia destruction of the target cells in the collecting tubule (tubulointer-
emerges as a consequence of generalized dysfunction of the collect- stitial nephropathies); interference with the sodium channel of the
ing tubule, including diminished sodium reabsorption and impaired principal cell, thereby decreasing the lumen-negative potential dif-
hydrogen ion and potassium secretion. The resultant hyperkalemia ference and thus the secretion of potassium and hydrogen ions
causes impaired ammonium excretion that is an important contri- (voltage-mediated defect); inhibition of the basolateral sodium ion,
bution to the generation of the metabolic acidosis. The causes of potassium ion–adenosine triphosphatase; and enhanced chloride
this syndrome are broadly classified into disorders resulting in ion permeability in the collecting tubule, with consequent shunting
aldosterone deficiency and those that impose resistance to the of the transepithelial potential difference. Some disorders cause
action of aldosterone. Aldosterone deficiency can arise from combined aldosterone deficiency and resistance [20].
FIGURE 6-29
Management of acute metabolic acidosis Treatment of acute metabolic acidosis. Whenever possible, cause-
specific measures should be at the center of treatment of metabolic
acidosis. In the presence of severe acidemia, such measures should
be supplemented by judicious administration of sodium bicarbon-
Alkali therapy for severe ate. The goal of alkali therapy is to return the blood pH to a safer
Cause-specific measures level of about 7.20. Anticipated benefits and potential risks of
acidemia (blood pH<7.20)
alkali therapy are depicted here [1].
Benefits Risks
• Prevents or reverses acidemia- • Hypernatremia/
related hemodynamic compromise. hyperosmolality
• Reinstates cardiovascular • Volume overload
responsiveness to catecholamines. • "Overshoot" alkalosis
• "Buys time," thus allowing cause- • Hypokalemia
specific measures and endogenous • Decreased plasma ionized
reparatory processes to take effect. calcium concentration
• Provides a measure of safety against • Stimulation of organic
additional acidifying stresses. acid production
• Hypercapnia
Metabolic Alkalosis
Arterial blood [H+], nEq/L
FIGURE 6-30
Ninety-five percent confidence intervals for metabolic alkalosis.
150 125 100 80 70 60 50 40 30 20
Metabolic alkalosis is the acid-base disturbance initiated by an
-
PaCO2 120 100 90 80 70 60 50 increase in plasma bicarbonate concentration ([HCO3]). The
mm Hg resultant alkalemia dampens alveolar ventilation and leads to the
40
50 secondary hypercapnia characteristic of the disorder. Available
observations in humans suggest a roughly linear relationship
between the steady-state increase in bicarbonate concentration
40 and the associated increment in the arterial carbon dioxide ten-

30
sion (PaCO2). Although data are limited, the slope of the steady-
-
state PaCO2 versus [HCO3] relationship has been estimated as
30 about a 0.7 mm Hg per mEq/L increase in plasma bicarbonate
20 concentration. The value of this slope is virtually identical to
Normal that in dogs that has been derived from rigorously controlled
20 observations [21]. Empiric observations in humans have been
used for construction of 95% confidence intervals for graded
10
degrees of metabolic alkalosis represented by the area in color in
10 the acid-base template. The black ellipse near the center of the
figure indicates the normal range for the acid-base parameters
[3]. Assuming a steady state is present, values falling within the
area in color are consistent with but not diagnostic of simple
6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 metabolic alkalosis. Acid-base values falling outside the area in
Arterial blood pH color denote the presence of a mixed acid-base disturbance [4].
[H+]—hydrogen ion concentration.
FIGURE 6-31
Milk alkali syndrome
Excess alkali Pathogenesis of metabolic alkalosis. Two
Alkali gain Calcium supplements
Enteral crucial questions must be answered when
Absorbable alkali
evaluating the pathogenesis of a case of
Nonabsorbable alkali plus K+
exchange resins metabolic alkalosis. 1) What is the source
of the excess alkali? Answering this ques-
Ringer's solution
Source? Bicarbonate
tion addresses the primary event responsible
Parenteral Blood products for generating the hyperbicarbonatemia. 2)
Nutrition What factors perpetuate the hyperbicarbon-
Dialysis atemia? Answering this question addresses
the pathophysiologic events that maintain
Vomiting the metabolic alkalosis.
Gastric
H+ loss Suction
Villous adenoma
Intestinal
Congenital chloridorrhea
Chloruretic diuretics
Renal Inherited transport defects
Mineralocorticoid excess
Posthypercapnia
H+ shift
K+ depletion
Reduced GFR
Mode of perpetuation?
Increased
renal acidification Cl– responsive defect
Cl– resistant defect
FIGURE 6-32
Baseline Vomiting Maintenance Correction Changes in plasma anionic pattern and body electrolyte balance
Low NaCl and KCl intake High NaCl and KCl intake
45 during development, maintenance, and correction of metabolic
alkalosis induced by vomiting. Loss of hydrochloric acid from the
40
stomach as a result of vomiting (or gastric drainage) generates the
[HCO3– ],
mEq/L
35 hypochloremic hyperbicarbonatemia characteristic of this disorder.

During the generation phase, renal sodium and potassium excre-
30
tion increases, yielding the deficits depicted here. Renal potassium
25 losses continue in the early days of the maintenance phase.
Subsequently, and as long as the low-chloride diet is continued, a
new steady state is achieved in which plasma bicarbonate concen-
105 -
tration ([HCO3]) stabilizes at an elevated level, and renal excretion
of electrolytes matches intake. Addition of sodium chloride (NaCl)
mEq/L
[Cl– ],
100
and potassium chloride (KCl) in the correction phase repairs the
95 electrolyte deficits incurred and normalizes the plasma bicarbonate
and chloride concentration ([Cl-]) levels [22,23].
0
–200
Cl–
–400
Cumulative balance, mEq
0
Na+
–100
–200
K+
–400
–2 0 2 4 6 8 10 12 14 16 18
Days
Baseline Vomiting Maintenance Correction Baseline Diuresis Maintenance Correction

Low NaCl and KCl intake High NaCl and KCl intake Low NaCl intake
8.0 Low KCl intake High KCl intake
Urine pH
7.0 40
[HCO3– ],
mEq/L
6.0 35
5.0 30
25
Urine HCO–3 excretion,
75
105
50
mEq/d
mEq/L
[Cl– ],
100
25
95
0
125
excretion, mEq/d
Urine net acid
100 100
75 75
Urine net acid excretion,
50 50
mEq/d
25
0 0
–200
Cl–
–25
–50 –400
Cumulative balance, mEq
–2 0 2 4 6 8 10 12 14 16 18 0
Na+
Days –100
FIGURE 6-33 0
K+
Changes in urine acid-base composition during development, main- –100

tenance, and correction of vomiting-induced metabolic alkalosis.
During acid removal from the stomach as well as early in the phase –2 0 2 4 6 8 10 12
after vomiting (maintenance), an alkaline urine is excreted as acid
Days
excretion is suppressed, and bicarbonate excretion (in the company
of sodium and, especially potassium; see Fig. 6-32) is increased,
with the net acid excretion being negative (net alkali excretion). FIGURE 6-34
This acid-base profile moderates the steady-state level of the result-
Changes in plasma anionic pattern, net acid excretion, and body
ing alkalosis. In the steady state (late maintenance phase), as all fil-
electrolyte balance during development, maintenance, and correc-
tered bicarbonate is reclaimed the pH of urine becomes acidic, and
tion of diuretic-induced metabolic alkalosis. Administration of a
the net acid excretion returns to baseline. Provision of sodium
loop diuretic, such as furosemide, increases urine net acid excretion
chloride (NaCl) and potassium chloride (KCl) in the correction
(largely in the form of ammonium) as well as the renal losses of
phase alkalinizes the urine and suppresses the net acid excretion, as
chloride (Cl-), sodium (Na+), and potassium (K+). The resulting
bicarbonaturia in the company of exogenous cations (sodium and
- hyperbicarbonatemia reflects both loss of excess ammonium chlo-
potassium) supervenes [22,23]. HCO3—bicarbonate ion.
ride in the urine and an element of contraction (consequent to
diuretic-induced sodium chloride [NaCl] losses) that limits the
space of distribution of bicarbonate. During the phase after diure-
sis (maintenance), and as long as the low-chloride diet is continued,
a new steady state is attained in which the plasma bicarbonate con-
-
centration ([HCO3]) remains elevated, urine net acid excretion
returns to baseline, and renal excretion of electrolytes matches
intake. Addition of potassium chloride (KCl) in the correction
phase repairs the chloride and potassium deficits, suppresses net
acid excretion, and normalizes the plasma bicarbonate and chloride
concentration ([Cl-]) levels [23,24]. If extracellular fluid volume
has become subnormal folllowing diuresis, administration of NaCl
is also required for repair of the metabolic alkalosis.
Maintenance of Cl–-responsive metabolic alkalosis
Basic mechanisms ↓GFR ↑HCO3– reabsorption
Mediating factors Cl– depletion ECF volume depletion K+ depletion Hypercapnia

HCO–3
Na+
3HCO–3
Cl–
P-cell +
+ K
Na+ K
Na
K
+
↑Na+ reabsorption and consequent ↑H+ and K+ secretion
Na+
Cl–
H+, NH+4
Na+
–
↓GFR K+ Cl
α-cell
HCO3
NH4
+ H+ Cl ↑H+ secretion ↑H+ secretion coupled to K+ reabsorption
↑HCO3 reabsorption
–
K+ + H+
H K+
+ +
NH4 , K Na+ Cl–
Na+ HCO–3 ß-cell
2Cl– + H+
K Cl– Cl
NH4+ Cl HCO3– secretion
↑NH4+ synthesis and HCO3
luminal entry
NH3 NH3
H 2O NH3
NH3
↑NH4+ entry in medulla and secretion
in medullary collecting duct
NH4+
Net acid excretion maintained at control
FIGURE 6-35
Maintenance of chloride-responsive metabolic alkalosis. each of these factors is a vexing task. Notwithstanding, here
Increased renal bicarbonate reabsorption frequently coupled depicted is our current understanding of the participation of
with a reduced glomerular filtration rate are the basic mecha- each of these factors in the nephronal processes that maintain
nisms that maintain chloride-responsive metabolic alkalosis. chloride-responsive metabolic alkalosis [22–24]. In addition to
These mechanisms have been ascribed to three mediating fac- these factors, the secondary hypercapnia of metabolic alkalosis
tors: chloride depletion itself, extracellular fluid (ECF) volume contributes importantly to the maintenance of the prevailing
depletion, and potassium depletion. Assigning particular roles to hyperbicarbonatemia [25].
Maintenance of Cl–-resistant metabolic alkalosis
Basic mechanism ↑HCO3– reabsorption
Mediating factors Mineralocorticoid excess K+ depletion

HCO–3
Na+
3HCO–3
Cl–
P-cell +
K
Na+ Na
K ↑Na+ reabsorption and consequent ↑H+ and K+ secretion
Na+
Cl–
H+, NH+4
Na+
K+ Cl
α-cell
HCO–3
NH+4 H +
Cl– ↑H+ secretion coupled to K+ reabsorption ↑H+ secretion
↑HCO3 reabsorption
–
K+ + H+
H K+
+
NH+4, K Na+ Cl–
Na+ HCO–3 ß-cell
2Cl– H+
+
K Cl– Cl–
NH+4 –Cl
–
↑NH4+ synthesis and HCO 3
luminal entry
NH3 NH3
H 2O NH3
NH3
↑NH4+entry in medulla and secretion
in medullary collecting duct
NH+4
FIGURE 6-36
Maintenance of chloride-resistant metabolic alkalosis. Increased ened bicarbonate reabsorption and include mineralocorticoid
renal bicarbonate reabsorption is the sole basic mechanism that excess and potassium depletion. The participation of these factors
maintains chloride-resistant metabolic alkalosis. As its name in the nephronal processes that maintain chloride-resistant meta-
implies, factors independent of chloride intake mediate the height- bolic alkalosis is depicted [22–24, 26].
FIGURE 6-37
Virtually absent
(< 10 mEq/L)
Urinary composition in the diagnostic evaluation of metabolic alka-
Urinary [Cl–] • Vomiting, gastric suction losis. Assessing the urinary composition can be an important aid in
• Postdiuretic phase of loop the diagnostic evaluation of metabolic alkalosis. Measurement of uri-
and distal agents
• Posthypercapnic state nary chloride ion concentration ([Cl-]) can help distinguish between
Abundant chloride-responsive and chloride-resistant metabolic alkalosis. The
• Villous adenoma of the colon
(> 20 mEq/L)
• Congenital chloridorrhea virtual absence of chloride (urine [Cl-] < 10 mEq/L) indicates signifi-
• Post alkali loading cant chloride depletion. Note, however, that this test loses its diag-
nostic significance if performed within several hours of administra-
Urinary [K+]
tion of chloruretic diuretics, because these agents promote urinary
chloride excretion. Measurement of urinary potassium ion concen-
Low (< 20 mEq/L) • Laxative abuse tration ([K+]) provides further diagnostic differentiation. With the
• Other causes of profound K+ depletion
exception of the diuretic phase of chloruretic agents, abundance of
Abundant both urinary chloride and potassium signifies a state of mineralocor-
(> 30 mEq/L) • Diuretic phase of loop and distal agents ticoid excess [22].
• Bartter's and Gitelman's syndromes
• Primary aldosteronism
• Cushing's syndrome
• Exogenous mineralocorticoid agents
• Secondary aldosteronism
malignant hypertension
renovascular hypertension
primary reninism
• Liddle's syndrome
SIGNS AND SYMPTOMS OF METABOLIC ALKALOSIS
Central Renal (Associated

Nervous System Cardiovascular System Respiratory System Neuromuscular System Metabolic Effects Potassium Depletion)
Headache Supraventricular and Hypoventilation with Chvostek’s sign Increased organic acid and Polyuria
Lethargy ventricular arrhythmias attendant hypercapnia Trousseau’s sign ammonia production Polydipsia
Stupor Potentiation of and hypoxemia Weakness (severity Hypokalemia Urinary concentration defect
Delirium digitalis toxicity depends on degree of Hypocalcemia Cortical and medullary
Tetany Positive inotropic potassium depletion) Hypomagnesemia renal cysts
ventricular effect Hypophosphatemia
Seizures
Potentiation of hepatic
encephalopathy
FIGURE 6-38
Signs and symptoms of metabolic alkalosis. Mild to moderate these clinical manifestations. The arrhythmogenic potential of alka-
metabolic alkalosis usually is accompanied by few if any symp- lemia is more pronounced in patients with underlying heart disease
toms, unless potassium depletion is substantial. In contrast, severe and is heightened by the almost constant presence of hypokalemia,
-
metabolic alkalosis ([HCO3] > 40 mEq/L) is usually a symptomatic especially in those patients taking digitalis. Even mild alkalemia
disorder. Alkalemia, hypokalemia, hypoxemia, hypercapnia, and can frustrate efforts to wean patients from mechanical ventilation
decreased plasma ionized calcium concentration all contribute to [23,24].
of hypercalcemia after primary hyper-

parathyroidism and malignancy. Another
Ingestion of Ingestion of
large amounts large amounts of common presentation of the syndrome origi-
of calcium absorbable alkali nates from the current use of calcium car-
bonate in preference to aluminum as a phos-
phate binder in patients with chronic renal
Augmented body Increased urine calcium Urine Augmented body insufficiency. The critical element in the
content of calcium excretion (early phase) alkalinization bicarbonate stores pathogenesis of the syndrome is the devel-
opment of hypercalcemia that, in turn,
results in renal dysfunction. Generation and
maintenance of metabolic alkalosis reflect
Nephrocalcinosis the combined effects of the large bicarbon-
ate load, renal insufficiency, and hypercal-
Reduced renal cemia. Metabolic alkalosis contributes to
Renal Renal Metabolic
Hypercalcemia
vasoconstriction insufficiency bicarbonate alkalosis the maintenance of hypercalcemia by
excretion increasing tubular calcium reabsorption.
Superimposition of an element of volume
Decreased urine Increased renal contraction caused by vomiting, diuretics, or
calcium excretion reabsorption of calcium hypercalcemia-induced natriuresis can wors-
en each one of the three main components
of the syndrome. Discontinuation of calcium
Increased renal H+ secretion
carbonate coupled with a diet high in sodi-
um chloride or the use of normal saline and
furosemide therapy (depending on the sever-
FIGURE 6-39 ity of the syndrome) results in rapid resolu-
Pathophysiology of the milk-alkali syndrome. The milk-alkali syndrome comprises the triad tion of hypercalcemia and metabolic alkalo-
of hypercalcemia, renal insufficiency, and metabolic alkalosis and is caused by the ingestion sis. Although renal function also improves,
of large amounts of calcium and absorbable alkali. Although large amounts of milk and in a considerable fraction of patients with
absorbable alkali were the culprits in the classic form of the syndrome, its modern version the chronic form of the syndrome serum
is usually the result of large doses of calcium carbonate alone. Because of recent emphasis creatinine fails to return to baseline as a
on prevention and treatment of osteoporosis with calcium carbonate and the availability of result of irreversible structural changes in
this preparation over the counter, milk-alkali syndrome is currently the third leading cause the kidneys [27].
and hypercalciuria and nephrocalcinosis

Clinical syndrome Affected gene Affected chromosome Localization of tubular defect are present. In contrast, Gitelman’s syn-
drome is a milder disease presenting later
Bartter's syndrome TAL in life. Patients often are asymptomatic,
or they might have intermittent muscle
Type 1 NKCC2 15q15-q21
spasms, cramps, or tetany. Urinary con-
centrating ability is maintained; hypocal-
TAL
ciuria, renal magnesium wasting, and
CCD
hypomagnesemia are almost constant fea-
Type 2 ROMK 11q24 tures. On the basis of certain of these clin-
ical features, it had been hypothesized
Gitelman's syndrome that the primary tubular defects in
DCT
Bartter’s and Gitelman’s syndromes reflect
TSC 16q13 impairment in sodium reabsorption in the
thick ascending limb (TAL) of the loop of
Henle and the distal tubule, respectively.
Tubular Peritubular Tubular Peritubular Tubular Peritubular This hypothesis has been validated by
lumen Cell space lumen Cell space lumen Cell space recent genetic studies [28-31]. As illustrat-
2K+ 2K+ Na+ ed here, Bartter’s syndrome now has been
Na+ ATPase ATPase Cl–
3Na +
Na +
3Na+ shown to be caused by loss-of-function
K+,NH+4 + 3Na +
Cl– K ATPase + mutations in the loop diuretic–sensitive

Cl– Cl– K+ 2K sodium-potassium-2chloride cotransporter
Loop diuretics
K + Thiazides K +
(NKCC2) of the TAL (type 1 Bartter’s
K+
H+ 3HCO–3 Cl– syndrome) [28] or the apical potassium
Na+ 3Na+ channel ROMK of the TAL (where it recy-
Ca2+
Ca 2+ cles reabsorbed potassium into the lumen
for continued operation of the NKCC2
Ca2+
Mg2+ cotransporter) and the cortical collecting
Thick ascending limb (TAL) Distal convoluted tuble (DCT) Cortical collecting duct (CCD) duct (where it mediates secretion of potas-
sium by the principal cell) (type 2
Bartter’s syndrome) [29,30]. On the other
FIGURE 6-40 hand, Gitelman’s syndrome is caused by
Clinical features and molecular basis of tubular defects of Bartter’s and Gitelman’s syn- mutations in the thiazide-sensitive Na-Cl
dromes. These rare disorders are characterized by chloride-resistant metabolic alkalosis, cotransporter (TSC) of the distal tubule
renal potassium wasting and hypokalemia, hyperreninemia and hyperplasia of the jux- [31]. Note that the distal tubule is the
taglomerular apparatus, hyperaldosteronism, and normotension. Regarding differentiat- major site of active calcium reabsorption.
ing features, Bartter’s syndrome presents early in life, frequently in association with Stimulation of calcium reabsorption at
growth and mental retardation. In this syndrome, urinary concentrating ability is usual- this site is responsible for the hypocalci-
ly decreased, polyuria and polydipsia are present, the serum magnesium level is normal, uric effect of thiazide diuretics.
FIGURE 6-41
Management of Metabolic alkalosis management. Effective
For alkali gain
metabolic alkalosis Discontinue administrationof management of metabolic alkalosis requires
bicarbonate or its precursors. sound understanding of the underlying
via gastric route pathophysiology. Therapeutic efforts should
Administer antiemetics;
discontinue gastric suction; focus on eliminating or moderating the
For H+ loss administer H2 blockers or processes that generate the alkali excess and
Eliminate source H+-K+ ATPase inhibitors. on interrupting the mechanisms that perpet-
of excess alkali via renal route
Discontinue or decrease loop uate the hyperbicarbonatemia. Rarely, when
and distal diuretics; substitute the pace of correction of metabolic alkalo-
with amiloride, triamterene, or
spironolactone; discontinue
sis must be accelerated, acetazolamide or an
or limit drugs with mineralo- infusion of hydrochloric acid can be used.
For H+ shift corticoid activity. Treatment of severe metabolic alkalosis can
Potassium repletion be particularly challenging in patients with
For decreased GFR advanced cardiac or renal dysfunction. In
ECF volume repletion; such patients, hemodialysis or continuous
renal replacement therapy hemofiltration might be required [1].
For Cl– responsive
Interrupt perpetuating acidification defect
Administer NaCl and KCl
mechanisms
For Cl– resistant

acidification defect
Adrenalectomy or other surgery,
potassiuim repletion, administration
of amiloride, triamterene, or
spironolactone.
References
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disorders. N Engl J Med, 1998, 338:26–34, 107–111. disparity in circulatory failure: studies on mechanism. Am J Physiol
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Disorders of

hypercapnia. This acute adaptation is complete within 5 to 10 min-

30 utes from the onset of hypercapnia and originates exclusively from

globin, intracellular proteins and phosphates, and to a lesser extent

acid production, leading to generation of new bicarbonate ions

ions is ensured by the gradual augmentation in the rate of renal bicar-

net acid excretion is accompanied by a transient increase in chloride

hypercapnia are under active investigation. Available evidence sup-

its development include the magnitude and

Cerebrum Ventilatory requirement

Controller Brain stem

DETERMINANTS AND CAUSES OF CARBON DIOXIDE RETENTION

Respiratory Pump Load

has chronic obstructive pulmonary disease and chronic hypercapnia.

20 Cl–- rich diet

• Consider intubation and initiation of mechanical

Mental status deteriorates

CO2 retention worsens

these patients from ventilators. As a rule,

acute adaptation is complete within 5 to 10 minutes from the onset

20 sis requires 2 to 3 days for completion and reflects retention of hydro-

gen ions by the kidneys as a result of downregulation of renal acid-

ification [2,10]. Shown are the average decreases in plasma bicar-

10 bonate and hydrogen ion concentrations per mm Hg decrease in

hypocapnia entails a persistent decrease in the renal tubular secretory

balance and a reduction in the bicarbonate stores of the body.

bonate is precisely balanced by the dampened rate of bicarbonate

(Na+-H+) exchanger and the basolateral sodium ion–3 bicarbonate

decrease reflects a decrease in the maximum velocity (Vmax) of each

CAUSES OF RESPIRATORY ALKALOSIS

Consider measures to correct blood pH ≤ 7.50 by:

state decrease in plasma bicarbonate concentration and the associ-

Normal Metabolic acidosis

reduces the availability of adenosine triphosphate (ATP) and NAD+

Diabetic ketoacidosis and nonketotic hyperglycemia

Decreased amino acid uptake

MANAGEMENT OF DIABETIC KETOACIDOSIS AND NONKETOTIC HYPERGLYCEMIA

Insulin Fluid Administration Potassium repletion Alkali

Renal tubular acidosis

Lumen Proximal tubule cell Blood

B. CAUSES OF CLASSIC DISTAL RENAL

Lumen α Intercalated cell (CCT & MCT) Blood

3Na+ Deficiency of aldosterone Resistance to aldosterone action

40 and the associated increment in the arterial carbon dioxide ten-

35 hypochloremic hyperbicarbonatemia characteristic of this disorder.

Baseline Vomiting Maintenance Correction Baseline Diuresis Maintenance Correction

Changes in urine acid-base composition during development, main- –100

Maintenance of Cl–-responsive metabolic alkalosis

Basic mechanisms ↓GFR ↑HCO3– reabsorption

Mediating factors Cl– depletion ECF volume depletion K+ depletion Hypercapnia

Net acid excretion maintained at control

Maintenance of Cl–-resistant metabolic alkalosis

Basic mechanism ↑HCO3– reabsorption

Mediating factors Mineralocorticoid excess K+ depletion

SIGNS AND SYMPTOMS OF METABOLIC ALKALOSIS

Central Renal (Associated

of hypercalcemia after primary hyper-

and hypercalciuria and nephrocalcinosis

Cl– K ATPase + mutations in the loop diuretic–sensitive

For Cl– resistant

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