stores. When A.B. is exposed to bicarbonate loading, the reninangiotensin-aldosterone axis is reactivated, and hypokalemia

worsens. In addition, raising the concentration of bicarbonate

in the blood drives potassium intercellularly and contributes to

her hypokalemia.

TREATMENT

CASE 9-1, QUESTION 6: What treatment is indicated for

A.B.?

Although it is rare for patients with type 2 RTA to develop

severe acidosis and potassium depletion chronically, it is not

uncommon in an acute situation such as this. A.B. has a bicarbonate deficit; thus, she should be treated with alkali replacement, and the offending agent, if confirmed to be lead, should be

removed concurrently. Her serum potassium is also dangerously

low, and bicarbonate correction could further decrease it. A.B.

needs potassium supplementation. The clinician should obtain

hourly blood samples for electrolytes until her potassium is

greater than 3.5 mEq/L. In adults such as A.B., chronic treatment

often is not needed because acidosis is self-limited. A.B., however, should be treated with sodium bicarbonate until proximal

RTA resolves. Very large doses of bicarbonate (6–10 mEq/kg/day)

would be required to increase serum bicarbonate to the normal range.10 In adults with proximal RTA, however, the goal is

to increase serum bicarbonate to no more than 18 mEq/L.30

Bicarbonate can be provided as sodium bicarbonate tablets

(8 mEq/600-mg tablet) or Shohl’s solution. Shohl’s solution, USP,

contains 334 mg citric acid and 500 mg sodium citrate per 5 mL.

Sodium citrate is metabolized to sodium bicarbonate in the liver.

Shohl’s solution provides 1 mEq of sodium and 1 mEq of bicarbonate per milliliter of solution. Therapy for A.B. should be

initiated with 1 mEq/kg/day. The clinician should monitor A.B.’s

lithium levels while she is receiving alkali therapy. Sodium ingestion might increase renal lithium excretion and exacerbate her

bipolar disorder. Because of severe hypokalemia resulting from

alkali administration, supplemental potassium as chloride, bicarbonate, acetate, or citrate salts also should be administered.

Metabolic Acidosis With Elevated

Anion Gap

EVALUATION AND OSMOLAL GAP

CASE 9-2

QUESTION 1: G.D., a 34-year-old, 60-kg man, is brought to

the emergency department (ED) by the police in a semicomatose state. He was found lying on the floor of his

hotel room 30 minutes ago. G.D. has a long history of

alcohol abuse. In the ED, supine blood pressure (BP) is

181Acid–Base Disorders Chapter 9

120/60 mm Hg, pulse is 100 beats/minute, and respiratory rate is 40 breaths/minute. G.D.’s pupils are reactive,

and mild papilledema is noted. Laboratory tests reveal the

following:

Serum Na, 140 mEq/L

K, 5.8 mEq/L

Cl, 103 mEq/L

Blood urea nitrogen (BUN), 25 mg/dL

Creatinine, 1.4 mg/dL

Fasting glucose, 150 mg/dL

ABG include pH, 7.16; PaCO2, 23 mm Hg; and HCO−

3 ,

8 mEq/L. His toxicology screen is negative for alcohol, and

his serum osmolality is 332 mOsm/kg. What acid–base disturbance is present in G.D., and what are possible causes of

the disorder?

G.D. has an acidosis (pH, 7.16; HCO−

3 , 8 mEq/L) with a large

AG (29 mEq/L). Subtracting 10 from the anion gap of 29 and

adding this value to his serum bicarbonate concentration (see

Step 5 in the section Evaluation of Acid–Base Disorders) yields a

value of 27, suggesting no other metabolic abnormality is present.

An elevated AG metabolic acidosis often indicates lactic

acidosis resulting from intoxications (e.g., salicylates, acetaminophen, methanol, ethylene glycol, paraldehyde, metformin)

or ketoacidosis induced by diabetes mellitus, starvation, or

alcohol.14,28,32,38,51,55–60 Step 6 in the stepwise approach leads

to the consideration of additional laboratory tests that may be

helpful in the differential diagnosis of an elevated AG. These

include serum ketones, glucose, lactate, BUN, creatinine, and

plasma osmolal gap.32 Osmolal gap is defined as the difference

between measured serum osmolality (SO) and calculated SO

using Eq. 9-7.

Calculated SO (mOsm/kg) = 2 × Na+(mEq/L)

+ Glucose (mg/dL)

18

+ BUN (mg/dL)

2.8

(Eq. 9-7)

When the difference between measured and calculated SO

is greater than 10 mOsm/kg, the presence of an unmeasured

osmotically active substance, such as ethanol, methanol, or ethylene glycol, should be considered.32,61 G.D.’s calculated SO is

297 mOsm/kg, compared with the measured value of 332; therefore, his osmolal gap is 35 mOsm/kg. An increase in the anion

gap and osmolal gap, without diabetic ketoacidosis or chronic

renal failure, suggests the possibility of metabolic acidosis resulting from a toxic ingestion.32 On the basis of G.D.’s presentation

(papilledema, history of alcohol abuse, increased osmolal gap,

increased AG metabolic acidosis), methanol intoxication should

be considered.

CAUSES

METHANOL-INDUCED

CASE 9-2, QUESTION 2: How would G.D.’s methanol intake

induce metabolic acidosis with an elevated anion AG?

Methanol intoxication results in the formation of two organic

acids, formic and lactic acids, which consume bicarbonate with

production of an AG metabolic acidosis. Alcohol dehydrogenase

in the liver metabolizes methanol to formaldehyde and then

to formic acid. The formic acid contributes to the metabolic

acidosis and also is responsible for the retinal edema and blindness

associated with methanol intoxication.32,33,60

TABLE 9-5

Classification of Metabolic Alkalosis

Saline-Responsive Saline-Resistant

Diuretic therapy Normotensive

Extracellular volume contraction Potassium depletion

Gastric acid loss Hypercalcemia

Vomiting Hypertensive

Nasogastric suction Mineralocorticoids

Exogenous alkali administration Hyperaldosteronism

Blood transfusions Hyperreninism

Licorice

Serum lactic acid concentrations also are increased in patients

with methanol intoxication.32 Lactic acidosis classically has been

divided into type A, which is associated with inadequate delivery

of oxygen to the tissue, and type B, which is associated with

defective oxygen utilization at the mitochondrial level (Table 9-5).

Although these distinctions often are not clear, the lactic acidosis

caused by methanol intoxication is most consistent with the type

B variety.62

TREATMENT

CASE 9-2, QUESTION 3: How should G.D.’s methanol intoxication be managed acutely?

ANTIDOTES

Because G.D.’s mental status is impaired and his respiratory rate

is 40 breaths/minute, his airway was secured via endotracheal

intubation and he was placed on mechanical ventilatory support. Even though both ethanol and fomepizole compete with

methanol for alcohol dehydrogenase binding sites and could be

used to treat G.D., fomepizole is chosen because it is easier to

dose and does not need serum level monitoring to ensure efficacy like ethanol.33,60–64 Because ethanol and fomepizole have

much greater affinity for alcohol dehydrogenase than methanol,

these agents may reduce the conversion of methanol to its toxic

metabolite, formic acid. The unmetabolized methanol then is

excreted by the lungs and kidneys. Fomepizole can be given IV

as a 15 mg/kg loading dose for 30 minutes, followed by bolus doses

of 10 mg/kg every 12 hours. Because of induction of metabolism

of fomepizole, doses should be increased to 15 mg/kg every

12 hours if therapy is required beyond 2 days.60 Fomepizole

is usually continued until the serum methanol concentration

is less than 20 mg/dL (6.2 mmol/L). Adverse effects of fomepizole are relatively mild; G.D. should be monitored for headache,

nausea, dizziness, agitation, metallic taste, abnormal smell, and

rash. Because of its high cost and infrequent use, some hospitals might not have fomepizole readily available. In such cases,

ethanol is an alternative. Administration of IV ethanol as an antidote can be technically difficult and may produce central nervous

system (CNS) depression.60,63 For G.D., an IV loading dose of

0.6 g/kg ethanol solution should be administered over the course

of 30 minutes, followed by a continuous infusion of about 150 mg/

kg/hour if the patient has been drinking, or 70 mg/kg/hour for

nondrinkers if the patient was not drinking. Serum ethanol concentration should be maintained at more than 100 mg/dL.33,62

Charcoal may be considered to bind other agents that may be

coingested.33,65

When other low-molecular-weight toxins, such as ethanol

or ethylene glycol, are not present, the serum methanol level

can be estimated by multiplying the patient’s osmolal gap by

182 Section 1 General Care

a standardized conversion factor of 2.6. G.D.’s osmolal gap of

35 mOsm/L, therefore, may reflect a methanol level of approximately 91 mg/dL (35 mOsm/L × 2.6). When methanol blood

levels are higher than 50 mg/dL, hemodialysis is indicated to

rapidly reduce concentrations of methanol and its toxic metabolite. The dosage of fomepizole or ethanol should be increased

in patients receiving hemodialysis to account for the increased

elimination of these antidotes.33,62 Ethylene glycol poisoning can

also be treated by using fomepizole or ethanol.

BICARBONATE

Severe acidosis causes reduced myocardial contractility, impaired

response to catecholamines, and impaired oxygen delivery to

tissues as a result of 2,3-diphosphoglycerate depletion. For this

reason, some clinicians have judiciously administered IV sodium

bicarbonate to patients with metabolic acidosis in an attempt to

raise the arterial pH to about 7.20.66–68 If IV sodium bicarbonate is given, the amount required to correct serum HCO−

3 and

arterial pH can be estimated using Eq. 9-8 as follows:

Bicarbonate dose (mEq) = 0.5 (L/kg) × Body weight (kg)

× Desired increase in serum

HCO−

3 (mEq/L) (Eq. 9-8)

Bicarbonate distributes to approximately 50% of total body

weight (thus, the factor of 0.5 L/kg in Eq. 9-8). To prevent

overtreating, bicarbonate doses should only attempt to increase

the bicarbonate concentration by 4 to 8 mEq/L (see Case 9-2,

Question 4).67 For G.D., the dose required to raise serum bicarbonate from 8 to 12 mEq/L amounts to 120 mEq of bicarbonate

(0.5 L/kg × 60 kg × 4 mEq/L; Eq. 9-8). Clinical assessment of the

effect of bicarbonate can be determined about 30 minutes after

administration.67 Arterial pH and serum bicarbonate concentrations should be obtained before any additional therapy.

RISKS OF BICARBONATE THERAPY

CASE 9-2, QUESTION 4: What are the risks of G.D.’s bicarbonate therapy?

Concerns about the risks of bicarbonate administration and

the failure of studies to demonstrate significant short-term benefits have raised questions about the appropriateness of bicarbonate therapy in metabolic acidosis, particularly in ketoacidosis and lactic acidosis caused by cardiac arrest or other hypoxic

events.68–75 Bicarbonate administration can result in overalkalinization and a paradoxical transient intracellular acidosis. Whereas

arterial pH can increase rapidly after bicarbonate administration,

intracellular pH increases more slowly because of slow penetration of the negatively charged bicarbonate ion across cell membranes. The bicarbonate in plasma, however, is converted rapidly

to carbonic acid, and the carbon dioxide tension increases as a

result (Eq. 9-2). Because CO2 diffuses into cells more rapidly than

HCO−

3 , the intracellular HCO−

3 /CO2 ratio decreases, resulting

in a decrease in intracellular pH. This intracellular acidosis will

persist as long as bicarbonate administration exceeds the CO2

excretion; therefore, adequate tissue perfusion and ventilation

must be provided in patients with diminished CO2 excretion

(e.g., cardiac or pulmonary failure).70

Overalkalinization also will cause a shift to the left in

the oxygen–hemoglobin dissociation curve. This shift increases

hemoglobin affinity for oxygen, decreases oxygen delivery to

tissues, and potentially increases lactic acid production and

accumulation.33 Sodium bicarbonate administration also can

cause hypernatremia, hyperosmolality, and volume overload;

however, the excessive sodium and water retention usually can be

avoided by the administration of loop diuretics.33,61 Hypokalemia

is another potential adverse effect of bicarbonate therapy. Acidosis stimulates movement of potassium from intracellular to extracellular fluid in exchange for hydrogen ions. When acidosis is corrected, potassium ions move intracellularly, and hypokalemia can

occur. This translocation of potassium tends to reduce serum

potassium levels by about 0.4 to 0.6 mEq/L for each 0.1 unit

increase in pH, although wide interpatient variability in this relationship exists.5,8 In G.D. and other patients with organic acid

intoxications, raising extracellular pH helps to provide a gradient

to shift the toxin from the CNS and “trap” it into the blood and

urine, enhancing elimination. To prevent the risks of bicarbonate therapy, G.D.’s mental status, serum sodium and potassium

levels, and ABG should be monitored.

ALTERNATIVE ALKALINIZING THERAPY

Although sodium bicarbonate is the most commonly used agent

to raise arterial pH, alternative therapies are available. Sodium

lactate and acetate have been used in select patients; however,

these agents, which require metabolic conversion to bicarbonate,

are associated with many of the same risks as sodium bicarbonate (i.e., sodium and fluid overload, overalkalinization, carbon

dioxide production).38

Tromethamine acetate (THAM), a sodium-free organic amine

with a pH of 8.6, is available commercially as a 0.3 mol/L

(36 mg/mL) solution for IV administration. THAM can combine with hydrogen ions from carbonic acid and lactic, pyruvic, or other metabolic acids; however, its role in the management of metabolic acidosis needs clarification. THAM may

produce hyperkalemia in patients with renal impairment and

is contraindicated in anuric or uremic patients. Administration of THAM also has been associated with other serious side

effects, including respiratory depression, increased coagulation

times, and hypoglycemia.76–79 Carbicarb and dichloroacetate

have been used investigationally in the treatment of metabolic

acidosis.38,62,81 Carbicarb and THAM are better than bicarbonate

at improving extracellular pH and bicarbonate and intracellular

pH, while not increasing CO2; however, neither has yet resulted

in better patient outcomes.5,24,71 Hemofiltration and continuous

renal replacement therapies have been advocated for patients

with lactic acidosis, especially in Europe; however, their roles

need further study.

METABOLIC ALKALOSIS

Metabolic alkalosis is associated with an increase in serum

bicarbonate concentration and a compensatory increase in

Paco2 (caused by hypoventilation). The two general classifications of metabolic alkalosis, saline-responsive and saline-resistant

(Table 9-6), are usually distinguishable based on an assessment

of the patient’s volume status, BP, and urinary chloride concentration.

Saline-responsive metabolic alkalosis is associated with disorders that result in the loss of chloride-rich, bicarbonate-poor

fluid from the body (e.g., vomiting, nasogastric suction, diuretic

therapy, cystic fibrosis). Physical examination may reveal volume

depletion (e.g., orthostatic hypotension, tachycardia, poor skin

turgor), and the urinary chloride concentration often will be

less than 10 to 20 mEq/L (although urine chloride levels may be

>20 mEq/L in patients with recent diuretic use).10,34,81

Severe hypokalemia or excessive mineralocorticoid activity

can result in a saline-resistant metabolic alkalosis, but this disorder is rare in comparison with saline-responsive metabolic

alkalosis. Saline-resistant metabolic alkalosis should be suspected

in alkalemic patients with evidence of increased ECF volume,

183Acid–Base Disorders Chapter 9

TABLE 9-6

Common Causes of Respiratory Acidosis

Airway Obstruction Cardiopulmonary

Foreign body aspiration Cardiac arrest

Asthma Pulmonary edema or infiltration

COPD Pulmonary embolism

Adrenergic blockers Pulmonary fibrosis

CNS Disturbances Neuromuscular

Cerebral vascular accident Amyotrophic lateral sclerosis

Sleep apnea Guillain-Barre syndrome ´

Tumor Myasthenia gravis

CNS depressant drugs Hypokalemia

Barbiturates Hypophosphatemia

Benzodiazepines Drugs

Opioids Aminoglycosides

Antiarrhythmics

Lithium

Phenytoin

CNS, central nervous system; COPD, chronic obstructive pulmonary disease.

hypertension, or high urinary chloride values (>20 mEq/L) without recent diuretic use.10,81

Evaluation

CASE 9-3

QUESTION 1: K.E., a 60-year-old, 50-kg woman, was admitted to the hospital 4 days ago with peripheral edema and

pulmonary congestion consistent with a congestive heart

failure exacerbation. Since admission, she has been treated

aggressively with furosemide 80 to 120 mg IV daily, which

has generated approximately 3 L of urine output each day.

Her chest radiograph findings and peripheral edema now

show considerable improvement with diuresis; however, she

now complains of dizziness when she gets out of bed to go

to the bathroom. Physical examination reveals a tachycardic

(heart rate [HR], 100 beats/minute), thin elderly woman with

poor skin turgor and slight muscle weakness. K.E.’s electrocardiogram shows flattened T waves and U waves. Laboratory tests reveal the following:

Serum Na, 138 mEq/L

K, 2.5 mEq/L

Cl, 92 mEq/L

Creatinine, 0.9 mg/dL

BUN, 28 mg/dL

pH, 7.49

PaCO2, 46 mm Hg

HCO−

3 , 34 mEq/L

Urine Cl concentration is 60 mEq/L. What acid–base disorder is present in K.E.?

Using the stepwise approach to the evaluation of acid–base

disorders as previously described, K.E.’s elevated pH is consistent

with alkalosis.

For a case that demonstrates how these steps

would be worked through, see the narrated

PowerPoint presentation at http://thepoint.

lww.com/AT10e.

Furosemide-induced diuresis may be a clue to her acid–base

disorder. The increased serum HCO−

3 and increased Paco2 suggest primary metabolic alkalosis with respiratory compensation.

K.E.’s anion gap is 12, suggesting no additional metabolic acid–

base abnormalities are present. A Paco2 of 46 mm Hg suggests

normal respiratory compensation for metabolic alkalosis. Appropriate treatment of the metabolic alkalosis should return her

Paco2 to normal if there is no underlying pulmonary disease.

Causes

DIURETIC-INDUCED

CASE 9-3, QUESTION 2: What is the most likely cause of

K.E.’s acid–base imbalance?

Common causes of metabolic alkalosis are listed in Table 9-5.

The hypokalemic, hypochloremic, metabolic alkalosis in K.E.

most likely is the result of diuretic-induced volume contraction.

The incidence of this adverse effect is influenced by the type,