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CHAPTER 72  Acid-Base Disorders

has traditionally been separated into three main categories:
(1) proximal RTA, or type 2; (2) distal RTA, or type 1; and
(3) hyperkalemic RTA, or type 4. Sometimes, a fourth kind is
added: combined proximal and distal RTA (mixed RTA), or type
3.127 RTA results in metabolic acidosis due to the lack of urinary
excretion of hydrogen ions or an excessive loss of bicarbonate due
to a variety of tubular disorders.127 Molecular studies have identified genetic or acquired defects in transporters of protons and
bicarbonate in most varieties of RTA.127,128 The underlying defect
in all RTA types is an inability to excrete chloride in proportion
to sodium, although the transporter involved dictates the specific
type of RTA.127,129 In the ICU, the presence of RTA may complicate management of patients, particularly regarding the provision
of resuscitative fluids.129 Undiagnosed RTA must be suspected
whenever a patient’s clinical condition does not improve as expected with the proper therapeutic interventions. Urinary AG
(uGAP 5 [uNa1 1 uK1] 2 [uCl2]) can be used to evaluate for
RTA in a patient with hyperchloremic acidosis. If it is negative
(uCl2 . uNa1 1 uK1), it suggests GI bicarbonate loss, acute
infusion of a high volume of saline isotonic fluid (NaCl 0.9%), or
a proximal RTA. On the other hand, if the uGAP is positive
(uCl2 , uNa1 1 uK1), it suggests the presence of a distal renal
tubular defect.
Type 4 RTA is of special interest in the critical care setting,
as it can triggered by genitourinary disruptions (e.g., urinary
tract infections, bladder obstruction) as well as drugs used in
ICUs, such as heparin, trimethoprim, a-adrenergic agonists,
b-adrenergic antagonists, and digoxin. Other medications can
also cause RTA.130 Topiramate, one of the new anticonvulsant
drugs, causes hyperchloremic metabolic acidosis through inhibition of the enzyme carbonic anhydrase, resulting in a type 3 or
mixed RTA.131 Another rare cause of normal AG metabolic acidosis is acetazolamide, a carbonic anhydrase inhibitor used to
decrease cerebral spinal fluid production or to stimulate renal

bicarbonate wasting in respiratory acidosis. This drug decreases
hydrolysis of H2CO3, resulting in a decrease of renal HCO32
reabsorption.132

Urinary Reconstruction Using Bowel Segments
Children with lower urinary tract dysfunction due to developmental abnormalities may require urologic surgical procedures
for their management that, depending on the clinical situation, may include urinary diversion. Various techniques using
a variety of conduits may be used depending on the clinical
situation. The GI tract, which is occasionally used, is a poor
substitute for urothelium. Its semipermeability often results in
abnormal fluid and electrolyte absorption, leading to metabolic abnormalities.133
Urinary reconstructions often result in hyponatremic and hypochloremic hyperkalemic acidosis, clinically manifested by nausea, vomiting, anorexia, and muscular weakness.133 In less severe
cases, a chronic metabolic acidosis may go undetected, resulting
in growth failure and short stature.

Treating Metabolic Acidosis
Treatment of metabolic acidosis should focus on the underlying
cause. Certain forms of acidosis have specific therapies, such as
insulin and fluids for the patient with DKA, bicarbonate and citrate for patients with distal RTA, and fomepizole for methanol or
ethylene glycol intoxication. The following discussion focuses on
lactic acidosis unless otherwise specified.

891

Sodium Bicarbonate
Sodium bicarbonate administration has long been the standard for
management of metabolic acidosis, including lactic acidosis.64,108
In AG acidosis, especially lactic acidosis (in shock and cardiopulmonary resuscitation) and diabetic acidosis, there is a dearth of
evidence regarding the safety and efficacy of bicarbonate. Despite
this, the use of bicarbonate continues to be common in the setting

of critical illness.3,64,108,134,135 Sodium bicarbonate may increase
arterial pH if, and only if, alveolar ventilation is adequate.24,134,136-138
The ultimate effect of sodium bicarbonate on intracellular pH
depends on changes in Pco2, which is influenced by the extracellular nonbicarbonate buffering capacity.136 Additionally, bicarbonate may increase lactic acid production, which may worsen acidosis.136 While the mechanism for this change remains unclear, it
may be due to a combination of factors, including a shift in the
oxyhemoglobin-saturation relationship, enhanced anaerobic glycolysis, or changes in hepatic blood flow or lactate uptake.64,123
Arterial pH can be raised and even normalized with sodium
bicarbonate.64,108,138 However, while sodium bicarbonate reliably
elevates the arterial pH, at the tissue and cellular levels, its effect
can be erratic. In most animal models and in most organs studied
to date, including the brain in healthy human volunteers, intracellular pH decreases with bicarbonate administration.71,137,139
This intracellular acidosis does not appear to damage cells, however.137 Studies that assessed the impact of bicarbonate administration during cardiopulmonary resuscitation showed no benefit
in survival and hemodynamic recovery.64,71,140 Hence, routine use
of sodium bicarbonate during resuscitation is no longer recommended by the American Heart Association. It should be considered only after effective ventilation, chest compressions, and epinephrine administration have occurred or in situations in which
bicarbonate is a specific therapeutic intervention (e.g., hyperkalemia or tricyclic antidepressant poisoning).141
Adverse effects of sodium bicarbonate are related to fluid and
sodium load and include hypervolemia, hyperosmolarity, and
hypernatremia.134 Intravenous bicarbonate administration can
cause sudden shifts of several cations; while this may be used in
the treatment of hyperkalemia, it also must be noted that bicarbonate administration lowers ionized calcium.64 Given as a bolus,
sodium bicarbonate can decrease arterial blood pressure and a
transient rise in intracranial pressure, probably owing to its hypertonicity.138 Overshoot alkalosis can result from overly aggressive
bicarbonate correction.138,141
Dose of sodium bicarbonate is best estimated using either the
SBE or the bicarbonate level derived from Pco2 measured by the
blood gas analyzer:
Total body base deficit  SBE  body weight (kg )  0.3

(Eq. 72.14)
HCO3 deficit (mEq)  0.3  body weight (kg)



 HCO3 expected  HCO3 observed  (Eq. 72.15)

Current consensus recommendations suggest giving bicarbonate
correction using a 0.3 distribution multiplier (“half correction”)
in most cases to avoid unnecessary risks from an excessive load of
solutes and fluid as well as overshoot alkalemia.134,138

Alternative Alkalinizing Agents
Concern about the CO2-producing effect of bicarbonate led to
the development of other agents to provide alkalinization through


892

S E C T I O N V I I   Pediatric Critical Care: Renal

different mechanisms. One of these is carbicarb, which consists of
equimolar concentrations of sodium bicarbonate (NaHCO3) and
sodium carbonate (Na2CO3).142 Carbicarb increases the pH far
more than bicarbonate. While its effect on intracellular pH is
more consistent, studies of its effects on hemodynamics have
yielded conflicting results.135 It is not currently available for clinical use pending further clinical research. Tris(hydroxymethyl)
aminomethane (THAM) is an amino alcohol that behaves as a
weak base (pKa 7.8) and raises both intracellular and central nervous system pH. In addition, THAM’s buffering action occurs
without producing CO2; thus, it is not dependent on pulmonary
function.143 Even though THAM has been commercially available
for several decades, there are few studies establishing its clinical
efficacy. A small adult ICU study showed that THAM had an

equivalent but shorter-lasting alkalinizing effect in comparison
with that of bicarbonate.143 However, minimal clinical utilization
and serious side effects—including hyperkalemia, hypoglycemia,
local extravasation injury, and hepatic necrosis in neonates—have
limited its widespread clinical use.143
Of particular relevance for lactic acidosis is dichloroacetate
(DCA), which stimulates pyruvate dehydrogenase, increasing the
oxidation of pyruvate to acetylcoenzyme A (CoA) and facilitating
its entry into the Krebs cycle. This decreases lactate production
and promotes the clearance of accumulated lactate.144 While initial data from both children and adults were promising, a large
clinical trial in adults with severe lactic acidosis showed that DCA
treatment resulted in statistically significant but clinically unimportant changes in arterial blood lactate concentrations and
pH.144 Renewed interest in DCA has arisen from its potential
applications for attenuating lactic acidosis in certain congenital
errors of metabolism.145

Dialysis Management of Metabolic Acidosis
Dialysis therapy may be indicated in cases of metabolic acidosis
that are refractory to bicarbonate or in cases in which there are
limitations in the amount of fluid or sodium load that can be
administered to the patient, a common situation in the pediatric
critical care unit. Uncompensated metabolic acidosis (pH ,7.1)
remains one of the acknowledged criteria for the initiation of renal replacement therapy in the pediatric ICU.135 Peritoneal dialysis is often not the best choice, particularly in states of lactic acidosis, shock, and hypoperfusion. In this setting, the peritoneal
membranes may not be efficient to support enough peritoneal
flux, and the increase in intraabdominal pressure may contribute
to a further drop in cardiac output. Acute renal replacement
therapy with continuous hemofiltration and hemodiafiltration are
often better options for critically ill patients with metabolic acidosis that is multifactorial in origin. Once continuous hemofiltration is started, rapid changes in metabolic acid-base status can be
achieved. Hemofiltration techniques replace plasma water, which
is low in bicarbonate concentration, with a solution that contains

an above-normal sodium bicarbonate (or lactate or acetate) concentration. Such weak anions buffer hydrogen ions and then are
transformed into CO2 (lactate and acetate must convert first to
bicarbonate in the liver), which is removed by ventilation.57 The
result is the progressive resolution of acidemia and acidosis, with
lowering concentrations of phosphate and unmeasured anions.

Metabolic Alkalosis
Primary metabolic alkalosis is defined as an elevation of arterial
pH above 7.45 or a reduction in [H1] with an increase in plasma

HCO32 and compensatory hypoventilation, resulting in a rise in
Pco2. However, a high HCO32 concentration alone is not
enough to diagnose metabolic alkalosis, as this can represent compensation by the kidney for respiratory acidosis.
Metabolic alkalosis is generated by net gain of base (primarily
bicarbonate) or loss of nonvolatile acid from the extracellular
fluid.146,147 This excess base may be gained through oral or parenteral bicarbonate administration or by the administration of other
weak anions—such as lactate, acetate, or citrate—with the gain of
strong cations (mainly sodium). The acid deficit may be due to
hydrochloric acid loss by vomiting or enhanced renal acid excretion promoted by diuretics or aldosterone excess and is often accompanied by hypochloremia and hypokalemia.146–148 There can
also be contraction of the extracellular fluid volume (known as
contraction alkalosis) due to chloride loss. Alkalemia can be classified as mild (pH 7.45–7.50), moderate (pH 7.50–7.55), or severe
(pH .7.55).147,148 Metabolic alkalosis involves a generation stage
during which the concentration of alkali within the body increases and a maintenance stage during which the kidneys fail to
compensate for this change.148 In most situations, when volume
and potassium are normalized, metabolic alkalosis self-corrects.
Metabolic alkalosis is common in critically ill pediatric patients. A study of children after cardiac surgery found that 72%
of children younger than 12 months old developed metabolic alkalosis in contrast with 30% of those older than 12 months.148
Studies in adults suggest that metabolic alkalosis may be associated with increased risk of mortality.147 Metabolic alkalosis in
patients with severe sepsis and trauma may be due to a number of
factors—including fluid administration to address shock, hypotension, and acidosis—with large quantities of citrated blood or

lactated Ringer solution given as well as the administration of
bicarbonate itself (eBox 72.5).147 Other patients may present with
preexisting metabolic alkalosis due to chronic diuretic use, excessive steroids, high-dose antacids, elevated GI fluid losses (emesis,
suction, or chloride-rich diarrhea), and a posthypercapnic state.148
Alkalemia may lead to neuromuscular excitability due to decreased ionized calcium concentration and potassium shifts and
can cause altered mental status, increased seizure activity, cardiac
arrhythmias, decreased oxygen release to tissue from hemoglobin,
and, in some instances, depression of ventilatory drive.
Metabolic alkalosis can be classified by response to therapy
using serum chloride concentration as the variable.3,29 Often, the
loss of Cl2 is temporary and can be treated with replacement;
this type of metabolic alkalosis is known as chloride responsive.
Chloride-responsive metabolic alkalosis is the most frequently
encountered metabolic alkalosis in the pediatric critical care unit
and can also be the most severe.146–148 In other cases, hormonal
mechanisms leading to an excess of mineralocorticoid activity
directly produce ongoing losses of K1 and Cl2, or genetic renal
tubular defects lead to abnormalities in electrolyte transport,
mainly in chloride reabsorption. In this setting, the Cl2 deficit
can be offset only temporarily at best by Cl2 administration.
Therefore, this form of metabolic alkalosis is said to be chloride
resistant (see eBox 72.5).146–148 The hallmark of this group of
disorders is an increased urine Cl2 concentration, more than
20 mEq/L (usually .40 mEq/L).62,146,148
The etiology of metabolic alkalosis can often be ascertained
from the history. If there is no pertinent history, the most likely
diagnoses are surreptitious vomiting or diuretic use, or a cause of
mineralocorticoid excess. Random urine chloride determination
may useful: uCl2 less than 20 mEq/L is consistent with chlorideresponsive metabolic alkalosis; uCl2 greater than 20 mEq/L is

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• eBox 72.5 Causes of Metabolic Alkalosis

in Critically Ill Patients
Chloride-Responsive (Decreased Urine [Cl2])a
Gastrointestinal losses of Cl2
• Gastric drainage or persisting vomiting
• Chloride-wasting acute diarrheas
Renal Losses of Cl2 and K1
• Diuretics (mainly acute use)
• High dose of certain penicillin-derivative antibiotics
• Posthypercapnia

Chloride-Resistant (Increased Urine [Cl2])b
Excess mineralocorticoid activity: ongoing losses of K1 and Cl2
• Primary and secondary hyperaldosteronism
• Congenital adrenal hyperplasia (17a-hydroxylase or 11b-hydroxylase
deficiency)
• Cushing syndrome
• Primary renin-secreting tumors
• Steroid treatment
Genetic renal tubular defects of electrolyte transport
• Problem in chloride reabsorption
• Bartter and Gitelman syndromes
• Defective epithelial sodium channel (decreased sodium elimination)
• Liddle syndrome
Drug-induced hypokalemic alkalosis
• Diuretics administered for prolonged time

• High-dose glucocorticoids
• Fludrocortisone
• Aminoglycosides
• Toxic effects of licorice (Glycyrrhiza glabra)
• Ion exchange resin
Excess cation (alkali) gain
• Massive blood transfusion
• Massive infusion of lactated Ringer solution
• Parenteral hyperalimentation with excessive sodium acetate
• Alkali ingestion/treatment and milk-alkali syndrome
• Magnesium depletion

Miscellaneous Group (Variable Urine [Cl2])b
Hypoproteinemia
Cystic fibrosis
Congenital chloride diarrhea
Salt-losing nephropathy
a

,20 mEq/L, usually ,15 mEq/L.
.20 mEq/L, usually .40 mEq/L.

b


CHAPTER 72  Acid-Base Disorders

consistent with chloride-unresponsive metabolic alkalosis.146,148
Metabolic alkalosis is one of the few clinical settings in which
urine chloride concentration is a more accurate estimate of volume status than urine [Na1].149 The most common clinical situation in the critical care setting is the intravenous administration

of strong cations without strong anions, such as occurs with a
massive blood transfusion. In this case, sodium is administered
predominantly with citrate (a weak anion) instead of chloride. A
similar mechanism of metabolic alkalosis occurs when the parenteral nutrition contains excess sodium acetate (another weak anion) and insufficient chloride to balance the sodium. The excessive
infusion of plasma volume expanders and sodium lactate (such as
in lactated Ringer solution) can also cause metabolic alkalosis.

Treating Metabolic Alkalosis
Regardless of the type of metabolic alkalosis, the first step is to
attenuate or stop the process that generated the imbalance in the
first place.147 As mortality is especially high when a pH in excess
of 7.6 develops, intervention at a pH of 7.55 and greater is recommended.136,147 Up to 10% of the total bicarbonate filtered is reabsorbed or lost to urine in the distal renal tubule. In most patients
with metabolic alkalosis, extracellular fluid—together with chloride, potassium, and magnesium concentrations—is decreased. As
potassium, chloride, and magnesium concentrations limit bicarbonate excretion, their low concentrations will make metabolic
alkalosis refractory to correction. Treatment of metabolic alkalosis
should focus on the restoration of circulating volume and electrolyte composition to allow renal excretion of bicarbonate and the
correction of alkalosis.147

Respiratory Acid-Base Derangements
Although the pathology that results in respiratory acid-base abnormalities depends on the clinical situation, respiratory acidbase derangements always have the same mechanism: alveolar
ventilation is altered (either increased or decreased) out of proportion to CO2 production. Normal CO2 production by the body is
robust: about 220 mL/min or about 317 L/day in a 70-kg adult,
which is equivalent to 15,000 mmol of carbonic acid per day,
30 times that handled by the kidneys and GI tract.29 CO2 is
produced through cellular metabolism or HCO32 is produced
through metabolic acids. Paco2 levels of 35 to 45 mm Hg at sea
level are maintained by a match of alveolar minute ventilation to
CO2 production. This central control creates a responsive system
that allows adjustment of Pao2 to compensate for metabolic
alterations in pH in predictable patterns (see eTable 72.1 and

eBox 72.2).29 Pulmonary ventilation is adjusted by the brainstem’s
respiratory center in response to changes in Paco2 and pH. Respiratory drive can also be influenced by other neural (anxiety, wakefulness) and nonneural factors (e.g., exercise, muscle strength)
and can be altered in pathologic situations (cystic fibrosis, asthma,
and congenital central hypoventilation syndrome).150
When this normal respiratory balance is disrupted, Paco2 deviates from normal and respiratory acid-base disturbances can occur. Respiratory acidosis is caused by CO2 retention and hypercapnia (Paco2 elevation), while respiratory alkalosis results from
hyperventilation, leading to a drop in Paco2. Buffers in the body
result in a metabolic response to alterations in CO2, with the response depending on the degree and chronicity of the alteration in
CO2. The initial response to Paco2 change is almost instantaneous,

893

leading to adequate compensation within 30 minutes. If the alteration in Paco2 is sustained for more than 6 hours, mechanisms
within the kidney induce changes in bicarbonate concentration,
reaching maximal impact within 3 to 5 days. These renal effects
lead to a new steady state for the pH.22,51

Respiratory Acidosis
Respiratory acidosis results when CO2 elimination by the
lungs is not sufficient to match CO2 production by the tissues,
with an increase in Paco2 to a new equilibrium.29,151 The increase in Paco2 immediately increases both the hydrogen ion
and bicarbonate concentrations in blood (see Eq. 72.6).15,18,21
If the Paco2 remains increased, compensatory mechanisms are
activated to restore [H1] toward normal. When Pco2 acutely
rises above 70 mmHg, loss of consciousness and seizures can
be seen due to the decrease of intracellular pH.152 However, in
patients with ARDS, hypercapnic acidosis may provide beneficial effects on pulmonary function through complex interactions with reactive oxygen species, alveolar-capillary barrier,
and the immune system.68
Primarily, compensation is accomplished by removal of Cl2
from the plasma space. Because movement of Cl2 into the tissues
or red blood cells results in a drop of intracellular pH, Cl2 must

be removed from the body to achieve a lasting effect on pH. The
kidneys play a key role in Cl2 removal by using ammonium as a
cation for the excretion of Cl2 without losing Na1 or K.21,61 Thus,
when kidney function is intact, Cl2 is eliminated in the urine.
After a few days, blood pH returns to near 7.35. Compensation
results in an increased pH for any degree of hypercarbia. According to the Henderson-Hasselbalch equation (see Eqs. 72.7 and
72.8), the increased pH will result in an increased HCO32 concentration for a given Pco2.24
Acute respiratory acidosis develops as a consequence of the
impaired function of one or more of the respiratory “compartments” that are essential to ventilatory function: central nervous
system; neuronal, muscular (skeletal, including the diaphragm);
and lung parenchyma (airway and alveoli; eTable 72.3). Conditions that cause the failure of the lungs to eliminate CO2 can also
be grouped by anatomic area in which the abnormality occurs.71,151,153 The most common causes of acute CO2 retention
in critical illness are airway and parenchymal lung disease. It is
important to note that acute CO2 retention can also produce
primary hypoxemia, which poses the principal threat to life.
While there are numerous pathophysiologic mechanisms and
many clinical examples, two account for the majority of cases
of respiratory acidosis in critical illness. The first is “pure” hypoventilation due to brainstem, neuromuscular dysfunction, or
restrictive lung disease. In this situation, the lungs fail to exchange CO2 and oxygen, resulting in a fall in Pao2 and a proportional rise in Paco2. In the second and more common situation, alveolar hypoventilation results from an imbalance
between perfusion and hypoventilation in damaged lung (i.e.,
ventilation-perfusion [V/Q] mismatch). In this case, a fall in
Pao2 often precedes hypercapnia. When hypercapnia finally
develops, the reduction in Pao2 is proportionally greater than
the rise in Paco2.29
Chronic respiratory acidosis occurs typically in the setting of
chronic pulmonary disease, whether it be from parenchymal abnormalities (e.g., bronchopulmonary dysplasia), altered chest wall
mechanics (chest congenital deformities, kyphoscoliosis), upper


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eTABLE Etiology of Respiratory Acid-Base
72.3
Derangements

Respiratory Acidosis
(Increased Paco)2
Central Nervous System
Depression
Severe head trauma
Cerebral edema
Metabolic diseases
Infectious diseases, sedation
Pharmacologic effect of drugs

Neural (Peripheral), Muscular,
and Skeletal Structures
Electrolyte Disturbances

Hypophosphatemia
Hypokalemia

Specific Diseases

Myasthenia gravis
Guillain-Barré syndrome
Spinal cord injury
Muscular dystrophy
Other

Ventilatory Restriction

Skeletal dysplasias
Rib fractures and flail chest
Intraabdominal hypertension from
ascites, closure of congenital
abdominal wall defects, etc.

Lungs (Airway and Alveoli)
Respiratory Obstructive
Disease, Either Acute or
Chronic

Croup
Asthma
Bronchiolitis
Bronchopulmonary dysplasia

Alveolar Injury

Pneumonia
Acute lung injury
Acute respiratory distress
syndrome
Cardiogenic pulmonary edema

Respiratory Alkalosis
(Decreased Paco)2
Hypoxemia
High altitudes

Pulmonary disease

Pulmonary Disorders

Pneumonia,
Interstitial pneumonitis
Fibrosis
Edema
Pulmonary embolism
Vascular disease
Bronchial asthma
Pneumothorax

Cardiovascular Disorders

Congestive heart failure
Hypotension

Metabolic Disorders

Acidosis (diabetic, renal, or lactic)
Hepatic failure

Central Nervous System
Disorders

Psychogenic or anxiety-induced
hyperventilation
Central nervous system infection
Central nervous system tumors

Drugs

Salicylates
Methylxanthines
b-Adrenergic agonists
Progesterone

Miscellaneous

Fever
Sepsis
Pain
Pregnancy