buffer system is 6.1. Because most of the carbonic acid in plasma is

in the form of carbon dioxide gas, the concentration of acid (acid),

can be estimated as Paco2 multiplied by 0.03 (the solubility constant, k, in Eq. 9-3). The concentration of base (base) is equal

to the serum bicarbonate concentration. Using these values,

Eq. 9-4 can be rewritten as follows:

pH = 6.1 + log (HCO−

3 )

(0.03)(Paco2) (Eq. 9-5)

As shown by Equation 9-5, the arterial pH will be 7.40 when

the ratio of HCO−

3 /H2CO3 is approximately 20:1. Note that it is

the ratio of bicarbonate to the carbon dioxide tension and not the

absolute concentration of these factors that determines the arterial pH. Therefore, if the serum bicarbonate concentration and

the carbon dioxide tension are increased or decreased proportionately, the ratio remains fixed and the pH is not affected.32–35

EVALUATION OF ACID–BASE

DISORDERS

Acid–base disorders should be evaluated using a stepwise

approach.31,32

For a narrated PowerPoint presentation that

works through the following process, see

http://thepoint.lww.com/AT10e.

1. Obtain a detailed patient history and clinical assessment.

2. Check the arterial blood gas, sodium, chloride, and HCO−

3 .

Identify all abnormalities in pH, Paco2, and HCO−

3 .

3. Determine which abnormalities are primary and which are

compensatory based on pH.

a. If the pH is less than 7.40, then a respiratory or metabolic

acidosis is primary.

b. If the pH is greater than 7.40, then a respiratory or

metabolic alkalosis is primary.

c. If the pH is normal (7.40) and there are abnormalities in

Paco2 and HCO−

3 , a mixed disorder is probably present

because metabolic and respiratory compensations rarely

return the pH to normal.

4. Always calculate the anion gap. If it is equal to or greater than

20, a clinically important metabolic acidosis is usually present

even if the pH is within a normal range.36

5. If the anion gap is increased, calculate the excess anion gap

(anion gap – 10). Add this value to the HCO−

3 to obtain corrected value.37

a. If the corrected value is greater than 26, a metabolic alkalosis is also present.

b. If the corrected value is less than 22, a nonanion gap

metabolic acidosis is also present.

6. Consider other laboratory tests to further differentiate the

cause of the disorder.

a. If the anion gap is normal, consider calculating the urine

anion gap.

b. If the anion gap is high and a toxic ingestion is expected,

calculate an osmolal gap.

c. If the anion gap is high, measure serum ketones and lactate.

7. Compare the identified disorders to the patient history and

begin patient-specific therapy.

METABOLIC ACIDOSIS

Metabolic acidosis is characterized by loss of bicarbonate from

the body, decreased acid excretion by the kidney, or increased

endogenous acid production. Two categories of simple metabolic

acidosis (i.e., normal anion gap and increased anion gap) are

listed in Table 9-2. The anion gap (AG) represents the concentration of unmeasured negatively charged substances (anions)

in excess of the concentration of unmeasured positively charged

substances (cations) in the extracellular fluid. The concentrations

of total anions and cations in the body are equal because the body

must remain electrically neutral. Most clinical laboratories, however, measure only a portion of these ions (i.e., sodium, chloride

[Cl−], and bicarbonate). The concentrations of other negatively

and positively charged substances, such as potassium (K+), magnesium (Mg+), calcium (Ca2+), phosphates, and albumin, are

measured less often. The concentration of unmeasured anions

normally exceeds the concentration of unmeasured cations by

6 to 12 mEq/L, and the anion gap can be calculated as follows:

Anion gap = Na+ − (CI− + HCO−

3 ) (Eq. 9-6)

Of the unmeasured anions, albumin is perhaps the most

important. In critically ill patients with hypoalbuminemia, the

calculated AG should be adjusted using the following formula:

adjusted AG=AG+2.5×(normal albumin – measured albumin

in g/dL), where a normal albumin concentration is assumed to be

4.4 g/dL.18–21 For example, a hypoalbuminemic patient (serum

albumin, 2.4 g/dL) with early sepsis and lactic acidosis might have

a calculated AG of 11 mEq/L; however, after the calculation is

corrected for the effect of the abnormal serum albumin concentration, the presence of elevated AG acidosis is more prominent

TABLE 9-2

Common Causes of Metabolic Acidosis

Normal AG Elevated AG

Hypokalemic

Diarrhea

Fistulous disease

Ureteral diversions

Type 1 RTA

Type 2 RTA

Carbonic anhydrase inhibitors

Hyperkalemic

Hypoaldosteronism

Hydrochloric acid or precursor

Type 4 RTA

Potassium-sparing diuretics

Amiloride

Spironolactone

Triamterene

Renal Failure

Lactic Acidosis

(see Table 9-4)

Ketoacidosis

Starvation

Ethanol

Diabetes mellitus

Drug Intoxications

Ethylene glycol

Methanol

Salicylates

AG, anion gap; RTA, renal tubular acidosis.

179Acid–Base Disorders Chapter 9

(the calculated AG is adjusted: AG(adjusted) = 11 mEq/L + 2.5 ×

[normal albumin – measured albumin] = 16 mEq/L).

Metabolic acidosis with a normal AG (e.g., hyperchloremic

metabolic acidosis) usually is caused by loss of bicarbonate and can be further characterized as hypokalemic or

hyperkalemic.5,30,33,38–49 Diarrhea can result in severe bicarbonate loss and a hyperchloremic metabolic acidosis. Elevated AG

metabolic acidosis usually is associated with overproduction of

organic acids or with decreased renal elimination of nonvolatile

acids.33,50–52 Increased production of organic acids (e.g., formic,

lactic acids) is buffered by extracellular bicarbonate with resultant

consumption of bicarbonate and appearance of an unmeasured

anion (e.g., formate, lactate).31,50,51 The decrement in serum

bicarbonate approximates the increment in the AG, the latter

being a good estimate of the circulating anion level. Prolonged

hypoxia results in lactic acidosis. Uncontrolled diabetes mellitus

or excessive alcohol intake with starvation can cause ketoacidosis. In the case of renal failure, the capacity for H+ secretion

diminishes, resulting in metabolic acidosis.38 The accompanying

increased AG results from decreased excretion of unmeasured

anions such as sulfate and phosphate.25

Normal Anion Gap (Hyperchloremic)

Metabolic Acidosis

EVALUATION

CASE 9-1

QUESTION 1: A.B., a 27-year-old, 60-kg woman, is hospitalized for evaluation of weakness. She has a history of bipolar affective disorder and reports recent ingestion of paint

from the walls of her house. A.B.’s only current medication

is lithium carbonate 300 mg three times a day (TID). On

admission, she appears weak and apathetic and complains

of anorexia. Laboratory tests reveal the following:

Serum Na, 143 mEq/L

K, 3.0 mEq/L

Cl, 121 mEq/L

Albumin, 4.4 g/dL

pH, 7.28

PaCO2, 26 mm Hg

HCO−

3 , 12 mEq/L

Urine pH, 5.5

A.B.’s urine pH after an ammonium chloride (NH4Cl)

0.1 g/kg IV load is less than 5.1. A bicarbonate load of

1 mEq/kg infused intravenously (IV) for 1 hour induces bicarbonaturia (urinary pH, 7.0) and lowers the serum potassium

to 2.0 mEq/L. Her blood pH only increased to 7.31. What

type of acid–base disorder is present?

Using a stepwise approach, we see that A.B.’s history gives

a clue to the cause for her acidosis. The low pH is consistent

with a metabolic acidosis because her CO2 and HCO−

3 are both

reduced (Table 9-2). Alterations in pH resulting from a primary

change in serum bicarbonate are metabolic acid–base disorders.

Specifically, metabolic acidosis is associated with a decrease in

serum HCO−

3 and decreased pH, whereas metabolic alkalosis is

associated with an increase in serum HCO−

3 and increased pH.

In respiratory disorders, the primary change occurs in the Paco2.

If A.B. had a decrease in pH and increase in Paco2, a respiratory

acidosis would be present. Because A.B. has a low Paco2 and

decreased serum HCO−

3 , she has a metabolic acidosis. In most

cases of metabolic acidosis or alkalosis, the lungs compensate for

the primary change in serum HCO−

3 concentration by increasing or decreasing ventilation. Most stepwise approaches would

TABLE 9-3

Normal Compensation in Simple Acid–Base Disorders

Disorder Compensationa

Metabolic acidosis ↓Paco2 (mm Hg) = 1.0 – 1.2 × HCO−

3 (mEq/L)

Metabolic alkalosis ↑Paco2 (mm Hg) = 0.5 – 0.7 × ↑HCO−

3 (mEq/L)

Respiratory acidosis

Acute ↑HCO−

3 (mEq/L) = 0.1 × ↑Paco2 (mm Hg)

Chronic ↑HCO−

3 (mEq/L) = 0.4 × ↑Paco2 (mm Hg)

Respiratory alkalosis

Acute ↓HCO−

3 (mEq/L) = 0.2 × ↓Paco2 (mm Hg)

Chronic ↓HCO−

3 (mEq/L) = 0.4 – 0.5 × ↓Paco2 (mm Hg)

a Based on change from normal HCO−

3 = 24 mEq/L and Paco2 = 40 mm Hg.

next suggest the evaluation of whether the decrease in Paco2 of

14 mm Hg for A.B. is consistent with respiratory compensation

(Table 9-3). A primary decrease in the serum bicarbonate to a

level of 12 mEq/L should result in a compensatory decrease in

the Paco2 concentration by 12 to 17 mm Hg (Table 9-3). A.B.’s

Paco2 has fallen by 14 mm Hg (normal, 40 mm Hg; current,

26 mm Hg), confirming that normal respiratory compensation

has occurred. When values for Paco2 or serum HCO−

3 fall outside of normal compensatory ranges, either a mixed acid–base

disorder, inadequate extent of compensation, or inadequate time

for compensation should be suspected.

Nomograms, especially ones that are different for acute and

chronic disorders, are inherently difficult to memorize, however,

and are often not available to the clinician at the point of care.

Following the stepwise approach advocated herein will enable

clinicians to identify most clinically important disorders without

needing to depend on tables or formulas.

CAUSES

CASE 9-1, QUESTION 2: What are potential causes of

metabolic acidosis in A.B.?

Steps 4 to 7 of the stepwise approach in the evaluation of

acid–base disorders are used to further determine the cause

of the disorder. In patients with metabolic acidosis, calculation

of the AG serves as a first step in classifying the metabolic acidosis

and provides additional information about conditions that might

be responsible. A.B.’s calculated AG is 10 mEq/L (Eq. 9-6). Thus,

A.B. has hyperchloremic metabolic acidosis with a normal AG.

The common causes of metabolic acidosis are presented in

Table 9-2.5,10,50 Normal AG metabolic acidosis usually is caused

by gastrointestinal loss of bicarbonate (diarrhea, fistulous disease, ureteral diversions); exogenous sources of chloride (normal saline infusions); or altered excretion of hydrogen ions (renal

tubular acidosis). A.B. reports a history of both paint ingestion

(perhaps lead-based paint) and chronic use of lithium. Both lead

and lithium have been associated with the development of renal

tubular acidosis.30,53

RENAL TUBULAR ACIDOSIS

CASE 9-1, QUESTION 3: How do the results of NH4Cl and

sodium bicarbonate (NaHCO3) loading help identify the

type of renal tubular acidosis in A.B.?

Renal tubular acidosis (RTA) is characterized by defective

secretion of hydrogen ion in the renal tubule with essentially

normal GFR. Many medical conditions and chemical substances

have been associated with RTA (Table 9-4).30,33 The recognized

forms are type 1 (distal), type 2 (proximal), and type 4 (distal,

180 Section 1 General Care

TABLE 9-4

Common Causes of Lactic Acidosis

Type A Type B

Anemia Diabetes mellitus

Carbon monoxide poisoning Liver failure

Congestive heart failure Renal failure

Shock Seizure disorder

Sepsis Leukemia

Drugs

Didanosine

Ethanol

Isoniazid

Metformin

Methanol

Salicylates

Zidovudine

hypoaldosterone). Type 1 RTA is caused by a defect in the distal tubule’s ability to acidify the urine, type 2 by altered urinary

bicarbonate reabsorption in the proximal tubule, and type 4 by

hypoaldosteronism and impaired ammoniagenesis.30,47

Evaluation of bicarbonate reabsorption during bicarbonate

loading and of response to acid loading by infusion of ammonium chloride is useful in distinguishing among the various types

of RTA. In healthy subjects, approximately 10% to 15% of the

filtered bicarbonate escapes reabsorption in the proximal tubule

but is reabsorbed in more distal segments of the nephron. Urine

bicarbonate excretion is therefore negligibly small, and urine pH

is maintained between 5.5 and 6.5.

Type 2 RTA is associated with a decrease in proximal tubular

bicarbonate reabsorption. The distal tubular cells partially compensate for this defect by increasing bicarbonate reabsorption,

but urinary bicarbonate excretion still is increased. As occurred

with A.B., serum HCO−

3 concentration in patients with type 2

RTA may acutely fall below a threshold of 15 but then stabilize

around 15 mEq/L.10,30 At this point, distal bicarbonate delivery

no longer is excessive, allowing the distal nephron to acidify the

urine appropriately and excrete acid in the form of titratable

ammonia and phosphate.

In type 1 RTA, a defect in net hydrogen ion secretion results

from a back-diffusion of H+ from the tubule lumen to the tubule

cell. Patients with type 1 RTA cannot reduce their urine pH below

5.5 even when systemic acidosis is severe.47

A.B.’s response to the acid (NH4Cl) load demonstrates an

ability to acidify the urine (i.e., pH <5.1), which helps rule out

type 1 RTA. During bicarbonate loading in patients with type 2

RTA, serum bicarbonate concentration is increased, and abnormally large amounts of bicarbonate are again delivered to the

distal tubule. Its hydrogen secretory processes are overwhelmed,

resulting in bicarbonaturia. Administration of bicarbonate to A.B.

produced bicarbonaturia and an elevation in urine pH (7.0), with

low blood pH (7.31). These findings indicate that the reabsorption of bicarbonate in the proximal tubule is impaired, which is

characteristic of type 2 RTA. Type 4 RTA is unlikely given her

initial serum potassium of 3.0 mEq/L.

LEAD-INDUCED

CASE 9-1, QUESTION 4: What is the cause of A.B.’s proximal

RTA?

The most likely cause of A.B.’s proximal RTA is her exposure to

presumably lead-based paint. The pathogenesis of lead-induced

type 2 RTA is unclear. Some studies suggest that carbonic anhydrase deficiency in the proximal tubule is the major factor, but

these data are inconclusive.

CASE 9-1, QUESTION 5: Why is A.B. hypokalemic?

Bicarbonate wasting in proximal RTA is associated with

sodium loss, extracellular fluid reduction, and activation of the

renin-angiotensin-aldosterone axis. Aldosterone increases distal

tubular sodium reabsorption and greatly augments potassium

and hydrogen ion secretion. This results in potassium wasting,

which explains A.B.’s hypokalemia.54 When plasma bicarbonate

achieves steady state, less bicarbonate reaches the distal tubule,

and the stimulus for aldosterone release is removed. Therefore, A.B. experiences only a mild depletion of potassium body