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Chapter 58: Acidosis and Alkalosis

Cardinal Manifestations and Presentation of Diseases · Part 2 – Cardinal Manifestations & Presentation

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. Systemic arterial pH is maintained between 7.35 and 7.45 by extracellular and intracellular chemical buffering together with respiratory and renal regulatory mechanisms.
  2. The anion gap (AG) is calculated as AG = Na+ – (Cl− + HCO−); normal value ranges from 6–12 mmol/L with an average of approximately 10 mmol/L.
  3. Winter's equation predicts compensatory Paco in metabolic acidosis: Paco = (1.5 × [HCO−]) + 8 ± 2.
  4. Bicarbonate therapy in diabetic ketoacidosis (DKA) is reserved for adult patients with severe acidemia (pH <7.00) and/or evidence of shock.
  5. Salicylate intoxication usually causes respiratory alkalosis or a mixture of high-AG metabolic acidosis and respiratory alkalosis; urine alkalinization (pH >7.5) increases salicylate clearance fivefold.
  6. A high AG is meaningful even if the [HCO−] or pH is normal; a mixture of high-gap acidosis and metabolic alkalosis is recognized by comparing differences (Δ values) in normal to prevailing patient values.
  7. In DKA, regular insulin is administered IV as an initial bolus of 0.1 U/kg followed by an infusion of 0.1 U/kg/h until the AG returns to normal.
  8. Ethylene glycol ingestion should be suspected if inspection of the urine reveals oxalate crystals.
  9. Pyroglutamic acid (5-oxoproline) acidemia may occur in critically ill patients receiving acetaminophen due to depletion of glutathione.
  10. Osmolar gap is proportional to the concentration of unmeasured solute; calculated and determined osmolality should agree within 10–15 mmol/kg H2O.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure Acid-base nomogram

1. NORMAL ACID-BASE HOMEOSTASIS

Systemic arterial pH is maintained between 7.35 and 7.45 by extracellular and intracellular chemical buffering together with respiratory and renal regulatory mechanisms. The control of arterial CO2 tension (Paco2) by the central nervous system (CNS) and respiratory system and the control of plasma bicarbonate by the kidney stabilize the arterial pH by excretion or retention of acid or alkali. The metabolic and respiratory components that regulate systemic pH are described by the Henderson-Hasselbalch equation and solved for pH when the solubility of CO2 is considered (dissolved CO2 in mmol/L = 0.03 × Paco2 in mmHg), at a pK′ of 6.1: pH = pK′ + log([HCO3−] / (0.03 × PCO2)). Under most circumstances, CO2 production and excretion are matched, and the usual steady-state Paco2 is maintained at ~40 mmHg. Underexcretion of CO2 produces hypercapnia, and overexcretion causes hypocapnia. Nevertheless, production and excretion are again matched at a new steady-state Paco2. Therefore, the Paco2 is regulated primarily by neural respiratory factors and is not subject to regulation by the rate of CO2 production. Hypercapnia is usually the result of hypoventilation rather than of increased CO2 production. Increases or decreases in Paco2 represent derangements of neural respiratory control or are due to compensatory changes in response to a primary alteration in the plasma [HCO3−].

1.1 Henderson-Hasselbalch Equation

The Henderson-Hasselbalch equation describes the relationship between pH, pK′, [HCO3−], and PCO2. The equation is: pH = pK′ + log([HCO3−] / (0.03 × PCO2)). Under most circumstances, CO2 production and excretion are matched, and the usual steady-state Paco2 is maintained at ~40 mmHg.

1.2 Compensatory Responses

Primary respiratory disturbances (primary changes in Paco2) invoke compensatory metabolic responses (secondary changes in [HCO3−]), and primary metabolic disturbances elicit predictable compensatory respiratory responses (secondary changes in Paco2). Physiologic compensation can be predicted from the relationships displayed in Table 58-1. In general, with one exception, compensatory responses return the pH toward, but not to, the normal value. Chronic respiratory alkalosis when prolonged is an exception to this rule and may return the pH to a normal value. Metabolic acidosis due to an increase in endogenous acid production (e.g., ketoacidosis or lactic acidosis) lowers extracellular fluid [HCO3−] and decreases extracellular pH. This change stimulates the medullary chemoreceptors to increase ventilation and to return the ratio of [HCO3−] to Paco2, and, thus, pH, toward, but not typically to, the normal value. The degree of respiratory compensation expected in a metabolic acidosis can be predicted from the relationship: Paco2 = (1.5 × [HCO3−]) + 8 ± 2 (Winter's equation). For example, applying this equation, a patient with metabolic acidosis and [HCO3−] of 12 mmol/L would be expected to have a Paco2 of approximately 26 mmHg. Therefore, if values for Paco2 were <24 mmHg, values that exceed the boundaries for compensation for a simple disorder, a mixed disturbance should be recognized (metabolic acidosis plus respiratory alkalosis or metabolic acidosis plus respiratory acidosis, respectively). Compensatory responses for primary metabolic disorders move the Paco2 in the same direction as the change in [HCO3−], while compensation for primary respiratory disorders moves the [HCO3−] in the same direction as the primary change in Paco2. Therefore, changes in Paco2 and [HCO3−] in opposite directions (i.e., Paco2 or [HCO3−] is increased, but the accompanying value is decreased) indicate a mixed acid-base disturbance. Another way to judge the appropriateness of the response in [HCO3−] or Paco2 is to use an acid-base nomogram (Fig. 58-1). While the shaded areas of the nomogram show the 95% confidence limits for physiologic compensation in simple disturbances, finding acid-base values within the shaded area does not necessarily rule out a mixed disturbance. Imposition of one disorder over another may result in values lying within the area of a third. Thus, the nomogram, while convenient, is not a substitute for the equations in Table 58-1.

Table 1 — Table 58-1 Prediction of Compensatory Responses to Simple Acid-Base Disturbances and Pattern of Changes

DISORDER PREDICTION OF COMPENSATION RANGE OF VALUES PH HCO3− Paco2
Metabolic acidosis Paco2 = (1.5 × HCO3−) + 8 ± 2 or Paco2 will ↓ 1.25 mmHg per mmol/L ↓ in [HCO3−] or Paco2 = [HCO3−] + 15 Low Low Low Paco2 will ↑ 0.75 mmHg per mmol/L ↑ in [HCO3−] or Paco2 will ↑ 6 mmHg per 10 mmol/L ↑ in [HCO3−] or Paco2 = [HCO3−] + 15 High High High
Metabolic alkalosis Paco2 will ↑ 0.75 mmHg per mmol/L ↑ in [HCO3−] or Paco2 will ↑ 6 mmHg per 10 mmol/L ↑ in [HCO3−] or Paco2 = [HCO3−] + 15 High High High
Respiratory alkalosis Acute: [HCO3−] will ↓ 0.2 mmol/L per mmHg ↓ in Paco2 High Low Low Chronic: [HCO3−] will ↓ 0.4 mmol/L per mmHg ↓ in Paco2 Low High High
Respiratory acidosis Acute: [HCO3−] will ↑ 0.1 mmol/L per mmHg ↑ in Paco2 Low High High Chronic: [HCO3−] will ↑ 0.4 mmol/L per mmHg ↑ in Paco2 Low High High

2. DIAGNOSIS OF GENERAL TYPES OF DISTURBANCES

The most common clinical disturbances are simple acid-base disorders; i.e., metabolic acidosis or alkalosis or respiratory acidosis or alkalosis occurring individually. Recognition of simple acid-base disorders requires appreciation of the limits of physiologic compensation for a primary disturbance. An increase in [HCO3−] occurs with either metabolic alkalosis or respiratory acidosis. Conversely, a decrease in [HCO3−] occurs with either metabolic acidosis or respiratory alkalosis. In the determination of arterial blood gases by the clinical laboratory, both pH and Paco2 are measured, and the [HCO3−] is calculated from the Henderson-Hasselbalch equation. This calculated value should be compared with the measured [HCO3−] (or total CO2) on the electrolyte panel. These two values should agree within ±2 mmol/L. If the values do not agree, the blood samples may not have been drawn simultaneously, or a laboratory error may be present. After verifying the blood acid-base values, the precise acid-base disorder can then be classified.

2.1 Anion Gap Evaluation

Evaluations of acid-base disorders should begin with appreciation of the patient's AG. The AG is calculated, either by the clinical laboratory or the clinician, as follows: AG = Na+ – (Cl− + HCO−). The value for plasma [K+] is typically omitted from the calculation of the AG in the United States. The "normal" value for the AG reported by clinical laboratories has declined with improved methodology for measuring plasma electrolytes and ranges from 6–12 mmol/L, with an average of approximately 10 mmol/L. The unmeasured anions normally present in plasma include anionic proteins (e.g., albumin), phosphate, sulfate, and organic anions. When acid anions, such as acetoacetate and lactate, accumulate in extracellular fluid, the AG increases, causing a high-AG acidosis. An increase in the AG is most often due to an increase in unmeasured anions but, less commonly, may be due to a decrease in unmeasured cations (calcium, magnesium, potassium). In addition, the AG may increase with an increase in anionic albumin (e.g., severe dehydration). A decrease in the AG can be due to (1) an increase in unmeasured cations; (2) the addition to the blood of abnormal cations, such as lithium (lithium intoxication) or cationic immunoglobulins (plasma cell dyscrasias); (3) a reduction in the plasma anion albumin concentration (nephrotic syndrome, liver disease, or malabsorption); or (4) hyperviscosity and severe hyperlipidemia, which can lead to an underestimation of sodium and chloride concentrations. Since a normal AG of the normal AG of approximately 10 mmol/L assumes that the serum albumin is normal if hypoalbuminemia is present, the value for the calculated AG must be corrected. For each g/dL of serum albumin below the normal value (4.5 g/dL), 2.5 mmol/L should be added to the reported (uncorrected) AG. Therefore, in a patient with a serum albumin of 2.5 g/dL (2 g/dL below the normal value) and an uncorrected AG of 15, the corrected AG is calculated by adding 5 mmol/L (2.5 × 2 = 5); thus, adding this value to the calculated AG (5 + 15), a corrected AG of 20 mmol/L is appreciated. Since clinical laboratories do not correct the AG for coexisting hypoalbuminemia and typically report the uncorrected value, the attention of the clinician to the prevailing serum albumin concentration is necessary. The clinical disorders that may cause a high-AG acidosis are displayed in Table 58-4. A high AG is usually due to accumulation of non–chloride-containing acids that contain inorganic (phosphate, sulfate), organic (ketoacids, lactate, uremic organic anions), exogenous (salicylate or ingested toxins with organic acid production), or unidentified anions. The high AG is meaningful even if the [HCO3−] or pH is normal. Simultaneous metabolic acidosis of the high-AG variety and either chronic respiratory acidosis or metabolic alkalosis represents a situation in which [HCO3−] may be normal or even high (Table 58-3). In cases of high-AG metabolic acidosis, it is valuable to compare the decline in [HCO3−] from the normal value (ΔHCO3−: 25 – patient's [HCO3−]) with the increase in the AG (ΔAG: patient's AG – 10). Similarly, normal values for [HCO3−], Paco2, and pH do not ensure the absence of an acid-base disturbance. For example, an alcoholic who has been vomiting prior to admission may develop a metabolic alkalosis with a pH of 7.55, Paco2 of 47 mmHg, [HCO3−] of 40 mmol/L, [Na+] of 135, [Cl−] of 80, and [K+] of 2.8. If such a patient were then to develop a superimposed alcoholic ketoacidosis with a β-hydroxybutyrate concentration of 15 mmol/L, the arterial pH would fall to 7.40, the [HCO3−] to 25 mmol/L, and the Paco2 to 40 mmHg. Although these values are normal, the AG is significantly elevated at 30 mmol/L, documenting that a mixed metabolic alkalosis and metabolic acidosis coexist. A mixture of high-gap acidosis and metabolic alkalosis is recognized easily by comparing the differences (Δ values) in the normal to prevailing patient values. In this example, the ΔHCO3− is 0 (25 – 25 mmol/L), but the ΔAG is 20 (30 – 10 mmol/L). Therefore, 20 mmol/L is unaccounted for in the Δ/Δ value (ΔAG to ΔHCO3−).

Table 2 — Table 58-3 Steps in Accurate Diagnosis of Acid-Base Disorders

STEP ACTION
1. Obtain arterial blood gas (ABG) and venous electrolytes simultaneously.
2. Calculated [HCO3−] on ABG and measured value on electrolyte panel should be approximately same; if not, suspect lab error or sampling error.
3. Assess anion gap (AG); correct to albumin concentration of 4.5 g/dL if hypoalbuminemia; high AG present if AG >10 mEq/L.
4. Known causes of high-AG acidosis (Table 58-4; ketoacidosis, lactic acidosis, advanced kidney disease, or toxic alcohol ingestion).
5. Known causes of nongap acidosis (Table 58-5; bicarbonate loss from gastrointestinal tract, renal tubular acidosis).
6. Estimate predicted compensatory response (Table 58-1).
7. Compare delta values (ΔAG and ΔHCO3−).
8. Compare change in [Cl−] with change in [Na+] on the electrolyte panel.

3. METABOLIC ACIDOSIS

Metabolic acidosis can occur because of an increase in endogenous acid production (such as lactate and ketoacids), loss of bicarbonate (as in diarrhea), or accumulation of endogenous acids because of inappropriately low excretion of net acid by the kidney (as in chronic kidney disease). Metabolic acidosis has profound effects on the respiratory, cardiac, and nervous systems. The fall in blood pH is accompanied by a characteristic increase in ventilation. Intrinsic cardiac contractility may be depressed, but inotropic function can be normal because of catecholamine release. Both peripheral arterial vasodilation and central arterial venoconstriction may be present; accordingly, the decrease in central and pulmonary vascular compliance predisposes to pulmonary edema with even minimal volume overload. CNS function is depressed, with headache, lethargy, stupor, and, in some cases, coma. Glucose intolerance may also occur. There are two major categories of clinical metabolic acidosis: high-AG and non-AG acidosis (Tables 58-3 and 58-4). The presence of metabolic acidosis, a normal AG, and hyperchloremia denotes the presence of a non-AG metabolic acidosis. Treatment of metabolic acidosis with alkali should be reserved for severe acidemia except when the patient has no "potential HCO3−" in plasma. The potential [HCO3−] can be estimated from the increment (Δ) in the AG (ΔAG = patient's AG – 10), only if the acid anion that has accumulated in plasma is metabolizable (i.e., β-hydroxybutyrate, acetoacetate, and lactate). Conversely, nonmetabolizable anions that may accumulate in advanced-stage chronic kidney disease or after toxin ingestion are not metabolizable and do not represent "potential" HCO3−. In patients with acute kidney failure or acute-on-chronic kidney failure, improvement in kidney function after volume resuscitation may improve the serum [HCO3−], but this is a slow and unpredictable process. Consequently, patients with a non-AG acidosis (hyperchloremic acidosis) or an AG acidosis attributable to a nonmetabolizable anion due to advanced kidney failure ("uremic" acidosis) should receive alkali therapy, either PO (NaHCO3 tablets or Shohl's solution) or IV (NaHCO3), in an amount necessary to slowly increase the plasma [HCO3−] to a target value of 22 mmol/L. Importantly, overcorrection should be avoided. Bicarbonate therapy in diabetic ketoacidosis (DKA) is reserved for adult patients with severe acidemia (pH <7.00) and/or evidence of shock. In such circumstances, bicarbonate may be administered IV, as a slow infusion of 50 meq of NaHCO3 diluted in 300 mL of a saline solution, over 30–45 min, during the initial 1–2 h of therapy. Bolus administration should be avoided. Administration of NaHCO3 requires careful monitoring of plasma electrolytes during the course of therapy because of the risk for hypokalemia as urine output is reestablished. A reasonable initial goal in DKA is to increase the [HCO3−] to a target of 10–12 mmol/L and the pH to approximately 7.20, but definitely not to increase these values to normal.

3.1 High-Anion Gap Acidoses

There are four principal causes of a high-AG acidosis: (1) lactic acidosis, (2) ketoacidosis, (3) ingested toxins, and (4) acute and chronic kidney failure (Table 58-4). Initial screening to differentiate the high-AG acidoses should include (1) a careful history of whether drug or toxin ingestion is present and measurement of arterial blood gas to detect coexistent respiratory alkalosis (e.g., salicylate intoxication); (2) a history of diabetes mellitus (DKA); (3) evidence of alcohol abuse or increased levels of β-hydroxybutyrate (alcoholic ketoacidosis); (4) a history of progressive chronic kidney disease (CKD) and an increase in the patient's baseline blood urea nitrogen (BUN) and creatinine values (uremic acidosis); (5) inspection of the urine for oxalate crystals (ethylene glycol ingestion); and (6) recognition of the numerous clinical settings in which lactate levels may be increased (hypotension, shock, cardiac failure, leukemia, cancer, and drug or toxin ingestion).

Table 3 — Table 58-4 Causes of High-Anion Gap Metabolic Acidosis

CATEGORY CAUSES
Lactic acidosis Diabetic, Alcoholic, Starvation, Pyroglutamic acid (5-oxoproline), Kidney failure (acute and chronic)
Toxins Ethylene glycol, Methanol, Salicylates, Propylene glycol
Ketoacidosis Diabetic, Alcoholic, Starvation

3.2 Lactic Acidosis

An increase in plasma l-lactate may be secondary to poor tissue perfusion ("type A" lactic acidosis)—circulatory insufficiency (shock, cardiac failure), severe anemia, mitochondrial enzyme defects, and inhibitors (carbon monoxide, cyanide)—or to aerobic disorders ("type B" lactic acidosis)—malignancies, nucleoside analogue reverse transcriptase inhibitors in HIV, diabetes mellitus, kidney or hepatic failure, thiamine deficiency, severe infections (cholera, malaria), seizures, or drugs/toxins (biguanides, ethanol, and the toxic alcohols: ethylene glycol, methanol, or propylene glycol). Unrecognized bowel ischemia or infarction in a patient with severe atherosclerosis or cardiac decompensation receiving vasopressors is a relatively common cause of lactic acidosis in elderly patients. Pyroglutamic acid acidemia may occur in critically ill patients receiving acetaminophen, because of depletion of glutathione and accumulation of 5-oxyproline. d-Lactic acid acidosis, which may be associated with jejunoileal bypass, short bowel syndrome, or intestinal obstruction, is due to formation of d-lactate by gut bacteria. The overarching goal of treatment in lactic acidosis is to correct the underlying condition that disrupts lactate metabolism; e.g., tissue perfusion should be restored when inadequate, but vasoconstrictors should be avoided, if possible, or used cautiously, because they may worsen tissue perfusion. Alkali therapy is generally advocated for acute, severe acidemia (pH <7.00) to improve cardiovascular function. However, NaHCO3 therapy may paradoxically depress cardiac performance and exacerbate acidosis by enhancing lactate production (HCO3− stimulates phosphofructokinase). While the use of alkali in moderate lactic acidosis is controversial, it is generally agreed that attempts to return the pH or [HCO3−] to normal by administration of exogenous NaHCO3 are deleterious. A reasonable approach with severe acidemia is to infuse sufficient NaHCO3 to raise arterial pH to no more than 7.2 or the [HCO3−] to no more than 12 mmol/L. NaHCO3 therapy can cause fluid overload, hypercapnia, and hypertension because the amount required can be massive when accumulation of lactic acid is relentless. Fluid administration is poorly tolerated, especially in the oliguric patient, when central venoconstriction coexists. If the underlying cause of the lactic acidosis can be remedied, blood lactate will be converted to HCO3− and may result in an overshoot alkalosis if exogenous NaHCO3 has been administered excessively.

3.3 Ketoacidosis

  • DIABETIC KETOACIDOSIS (DKA) This condition is caused by increased fatty acid metabolism and the accumulation of ketoacids (acetoacetate and β-hydroxybutyrate). DKA usually occurs in insulin-dependent diabetes mellitus in association with cessation of insulin administration or an intercurrent illness such as an infection, gastroenteritis, pancreatitis, or myocardial infarction, which increases insulin requirements temporarily and acutely. DKA is characterized by hyperglycemia, ketonemia, and a high-AG acidosis. Nevertheless, the plasma glucose may be normal or only slightly elevated in the setting of starvation ketoacidosis or in diabetics receiving an agent that inhibits the proximal tubule sodium-glucose co-transporter 2 (SGLT2 inhibitors) (euglycemic DKA [eDKA]). These agents cause glycosuria, an osmotic diuresis, volume depletion, and decreased plasma glucose. Although the accumulation of ketoacids in plasma accounts for the increment in the AG in both classical DKA and eDKA, the plasma glucose is elevated in classical DKA but is typically in the normal range in eDKA. Measurement of urine ketones (by the dipstick nitroprusside reaction) does not detect β-hydroxybutyrate accurately and may underestimate the degree of ketosis (see below). Excretion of ketoacids obligates the excretion of cations, such as Na+ and K+, contributing to volume depletion and Cl− retention. In some circumstances, a mixed non-AG–high-AG acidosis may occur simultaneously and is recognized when the ΔHCO3− exceeds the ΔAG. It should be noted that bicarbonate therapy is rarely necessary in DKA in adults, except with extreme acidemia (pH 7.5) and to maintain urine output. Raising urine pH from 6.5 to 7.5 increases salicylate clearance fivefold. Patients with coexisting respiratory alkalosis may also receive NaHCO3, but if given, it should be administered cautiously to avoid excessive alkalemia. Acetazolamide may be administered with coexisting alkalemia, when an alkaline diuresis cannot be achieved, or to ameliorate volume overload associated with NaHCO3 administration. Caution is needed because acetazolamide may cause systemic metabolic acidosis if the excreted HCO3− is not replaced, a circumstance that can markedly reduce salicylate clearance. Hypokalemia should be anticipated with vigorous bicarbonate therapy and should be treated promptly and aggressively. Glucose-containing fluids should be administered because of the danger of hypoglycemia. Excessive insensible fluid losses may cause severe volume depletion and hypernatremia. If acute kidney injury prevents rapid clearance of salicylate, hemodialysis should be performed against a standard bicarbonate dialysate ([HCO3−] = 30–35 meq/L).

4. TOXIC ALCOHOL INTOXICATION

Under most physiologic conditions, sodium, urea, and glucose generate the osmotic pressure of blood. Plasma osmolality is calculated according to the following expression: Posm = 2Na+ + Glu + BUN (all in mmol/L), or using conventional laboratory values in which glucose and BUN are expressed in mg/dL: Posm = 2Na+ + Glu/18 + BUN/2.8. The calculated and determined osmolality should agree within 10–15 mmol/kg H2O. When the measured osmolality exceeds the calculated osmolality by >10–15 mmol/kg H2O, one of two circumstances prevails. Either the serum sodium is spuriously low, as with hyperlipidemia or hyperproteinemia (pseudohyponatremia), or osmolytes other than sodium salts, glucose, or urea have accumulated in plasma. Examples of such osmolytes include mannitol, radiocontrast media, ethanol, isopropyl alcohol, ethylene glycol, propylene glycol, methanol, and acetone. In this situation, the difference between the calculated osmolality and the measured osmolality (osmolar gap) is proportional to the concentration of the unmeasured solute. With an appropriate clinical history and index of suspicion, identification of a serum osmolar gap is helpful in identifying the presence of toxic alcohol-associated AG acidosis. Three alcohols may cause fatal intoxications: ethylene glycol, methanol, and isopropyl alcohol. All cause an elevated osmolar gap, but only the first two cause a high-AG acidosis. Isopropyl alcohol ingestion does not typically elevate the AG unless extreme overdose causes hypotension and lactic acid acidosis. This form of high-gap acidosis should be considered in patients with renal failure after volume resuscitation may improve the serum [HCO3−], but this is a slow and unpredictable process. Consequently, patients with a non-AG acidosis (hyperchloremic acidosis) or an AG acidosis attributable to a nonmetabolizable anion due to advanced kidney failure ("uremic" acidosis) should receive alkali therapy, either PO (NaHCO3 tablets or Shohl's solution) or IV (NaHCO3), in an amount necessary to slowly increase the plasma [HCO3−] to a target value of 22 mmol/L. Importantly, overcorrection should be avoided. Treatment of methanol intoxication is similar to that for EG intoxication, including general supportive measures, fomepizole, and hemodialysis. Propylene glycol is the vehicle used in the IV preparation of diazepam, lorazepam, phenobarbital, nitroglycerine, etomidate, enoximone, and phenytoin. Propylene glycol is generally safe for limited use in these IV preparations, but toxicity has been reported in the setting of the intensive care unit in patients receiving frequent or continuous administration, because propylene glycol may accumulate in plasma. This form of high-gap acidosis should be considered in patients with renal failure after volume resuscitation may improve the serum [HCO3−], but this is a slow and unpredictable process. Consequently, patients with a non-AG acidosis (hyperchloremic acidosis) or an AG acidosis attributable to a nonmetabolizable anion due to advanced kidney failure ("uremic" acidosis) should receive alkali therapy, either PO (NaHCO3 tablets or Shohl's solution) or IV (NaHCO3), in an amount necessary to slowly increase the plasma [HCO3−] to a target value of 22 mmol/L. Importantly, overcorrection should be avoided.

4.1 Methanol Intoxication

Treatment of methanol intoxication is similar to that for EG intoxication, including general supportive measures, fomepizole, and hemodialysis.

4.2 Propylene Glycol

Propylene glycol is the vehicle used in the IV preparation of diazepam, lorazepam, phenobarbital, nitroglycerine, etomidate, enoximone, and phenytoin. Propylene glycol is generally safe for limited use in these IV preparations, but toxicity has been reported in the setting of the intensive care unit in patients receiving frequent or continuous administration, because propylene glycol may accumulate in plasma. This form of high-gap acidosis should be considered in patients with renal failure after volume resuscitation may improve the serum [HCO3−], but this is a slow and unpredictable process. Consequently, patients with a non-AG acidosis (hyperchloremic acidosis) or an AG acidosis attributable to a nonmetabolizable anion due to advanced kidney failure ("uremic" acidosis) should receive alkali therapy, either PO (NaHCO3 tablets or Shohl's solution) or IV (NaHCO3), in an amount necessary to slowly increase the plasma [HCO3−] to a target value of 22 mmol/L. Importantly, overcorrection should be avoided.

5. MIXED ACID-BASE DISORDERS

Acid-base disorders in this category are defined as independently coexisting disorders, not merely compensatory responses. These types of disturbances are often seen in critically ill patients and can lead to dangerous extremes of pH (Table 58-2). The diagnosis of mixed acid-base disorders requires consideration of the anion gap (AG). To be accurate, the AG requires the presence of, or correction to, a normal serum albumin of 4.5 g/dL (see below, "Evaluate the Anion Gap"). If a patient with diabetic ketoacidosis (metabolic acidosis) and a high AG has an independent and concomitant respiratory disorder (e.g., pneumonia), the latter may lead to a superimposed respiratory acidosis or alkalosis and the Paco2 will deviate from the predicted value for the response to a pure high-AG metabolic acidosis (Table 58-2). Patients with underlying chronic obstructive pulmonary disease may not respond to metabolic acidosis with an appropriate ventilatory response owing to insufficient respiratory reserve (Table 58-2). The combined presence of respiratory acidosis and metabolic acidosis can lead to severe acidemia. In contrast, when metabolic acidosis and metabolic alkalosis coexist in the same patient, the pH may be in the normal range. In this circumstance, it is the recognition of an elevated AG (see below) that denotes the existence of an accompanying metabolic acidosis. Assuming a normal value for the AG of 10 mmol/L, incongruity in the increase in ΔAG (existing AG minus normal AG) and the ΔHCO3− (normal value of 25 mmol/L minus abnormal HCO3− in the patient) indicates the presence of a mixed high-gap acidosis—metabolic alkalosis (see example below). A diabetic patient with ketoacidosis may have acute or chronic kidney failure resulting in a combination of metabolic acidosis from accumulation of both ketoacids and uremic acids. Patients who have ingested an overdose of drug combinations such as sedatives and salicylates may have mixed disturbances as a result of the acid-base response to the individual drugs (metabolic acidosis mixed with respiratory acidosis or respiratory alkalosis, respectively). Triple acid-base disturbances are more complex. For example, patients with metabolic acidosis due to alcoholic ketoacidosis may develop metabolic alkalosis due to vomiting and superimposed respiratory alkalosis due to the hyperventilation of hepatic dysfunction or alcohol withdrawal.

5.1 Clinical Examples of Mixed Acid-Base Disorders

Table 58-2 provides clinical examples of mixed acid-base disorders. Key features include: Metabolic acidosis—respiratory alkalosis (High-AG metabolic acidosis; prevailing Paco2 below predicted value; etiology: lactic acidosis, sepsis in ICU). Metabolic acidosis—respiratory acidosis (High-AG metabolic acidosis; prevailing Paco2 above predicted value; etiology: severe pneumonia or pulmonary edema). Metabolic alkalosis—respiratory alkalosis (Paco2 does not increase as predicted; pH higher than expected; etiology: end-stage liver disease with ascites in patient receiving diuretics). Metabolic alkalosis—respiratory acidosis (Paco2 higher than predicted; pH normal although both Paco2 and HCO3− abnormal; etiology: COPD in patient receiving diuretics). Metabolic acidosis—metabolic alkalosis (Only detectable if in patient with high-AG acidosis; ΔAG (10) >> ΔHCO3− (0); etiology: uremia with vomiting). Metabolic acidosis—metabolic acidosis (Mixed high-AG—normal-AG acidosis; ΔHCO3− accounted for by combined change in ΔAG and ΔCl−; etiology: diarrhea and lactic acidosis, toluene toxicity, treatment of diabetic ketoacidosis).

Table 4 — Table 58-2 Clinical Examples of Mixed Acid-Base Disorders

DISORDER KEY FEATURES EXAMPLE VALUES ETIOLOGY
Metabolic acidosis—respiratory alkalosis High-AG metabolic acidosis; prevailing Paco2 below predicted value (Table 58-1) Na+, 140; K+, 4.0; Cl−, 106; HCO3−, 14; AG, 20; Paco2, 24; pH, 7.39 Lactic acidosis, sepsis in ICU
Metabolic acidosis—respiratory acidosis High-AG metabolic acidosis; prevailing Paco2 above predicted value (Table 58-1) Na+, 140; K+, 4.0; Cl−, 102; HCO3−, 18; AG, 20; Paco2, 42; pH, 7.25 Severe pneumonia or pulmonary edema
Metabolic alkalosis—respiratory alkalosis Paco2 does not increase as predicted; pH higher than expected Na+, 140; K+, 4.0; Cl−, 91; HCO3−, 33; AG, 16; Paco2, 38; pH, 7.56 End-stage liver disease with ascites in patient receiving diuretics
Metabolic alkalosis—respiratory acidosis Paco2 higher than predicted; pH normal although both Paco2 and HCO3− abnormal Na+, 140; K+, 3.5; Cl−, 88; HCO3−, 42; AG, 10; Paco2, 67; pH, 7.42 COPD in patient receiving diuretics
Metabolic acidosis—metabolic alkalosis Only detectable if in patient with high-AG acidosis; ΔAG (10) >> ΔHCO3− (0) Na+, 140; K+, 3.0; Cl−, 95; HCO3−, 25; AG, 20; Paco2, 40; pH, 7.42 Uremia with vomiting
Metabolic acidosis—metabolic acidosis Mixed high-AG—normal-AG acidosis; ΔHCO3− accounted for by combined change in ΔAG and ΔCl− Na+, 135; K+, 3.0; Cl−, 110; HCO3−, 10; AG, 15; Paco2, 25; pH, 7.20 Diarrhea and lactic acidosis, toluene toxicity, treatment of diabetic ketoacidosis

6. RESPIRATORY ACIDOSIS AND ALKALOSIS

Primary respiratory disturbances (primary changes in Paco2) invoke compensatory metabolic responses (secondary changes in [HCO3−]), and primary metabolic disturbances elicit predictable compensatory respiratory responses (secondary changes in Paco2). Physiologic compensation can be predicted from the relationships displayed in Table 58-1. In general, with one exception, compensatory responses return the pH toward, but not to, the normal value. Chronic respiratory alkalosis when prolonged is an exception to this rule and may return the pH to a normal value. Metabolic acidosis due to an increase in endogenous acid production (e.g., ketoacidosis or lactic acidosis) lowers extracellular fluid [HCO3−] and decreases extracellular pH. This change stimulates the medullary chemoreceptors to increase ventilation and to return the ratio of [HCO3−] to Paco2, and, thus, pH, toward, but not typically to, the normal value. The degree of respiratory compensation expected in a metabolic acidosis can be predicted from the relationship: Paco2 = (1.5 × [HCO3−]) + 8 ± 2 (Winter's equation). For example, applying this equation, a patient with metabolic acidosis and [HCO3−] of 12 mmol/L would be expected to have a Paco2 of approximately 26 mmHg. Therefore, if values for Paco2 were <24 mmHg, values that exceed the boundaries for compensation for a simple disorder, a mixed disturbance should be recognized (metabolic acidosis plus respiratory alkalosis or metabolic acidosis plus respiratory acidosis, respectively). Compensatory responses for primary metabolic disorders move the Paco2 in the same direction as the change in [HCO3−], while compensation for primary respiratory disorders moves the [HCO3−] in the same direction as the primary change in Paco2. Therefore, changes in Paco2 and [HCO3−] in opposite directions (i.e., Paco2 or [HCO3−] is increased, but the accompanying value is decreased) indicate a mixed acid-base disturbance. Another way to judge the appropriateness of the response in [HCO3−] or Paco2 is to use an acid-base nomogram (Fig. 58-1). While the shaded areas of the nomogram show the 95% confidence limits for physiologic compensation in simple disturbances, finding acid-base values within the shaded area does not necessarily rule out a mixed disturbance. Imposition of one disorder over another may result in values lying within the area of a third. Thus, the nomogram, while convenient, is not a substitute for the equations in Table 58-1.

7. KEY PEARLS & CLINICAL TRAPS

  • Systemic arterial pH is maintained between 7.35 and 7.45 by extracellular and intracellular chemical buffering together with respiratory and renal regulatory mechanisms. • The anion gap (AG) is calculated as AG = Na+ – (Cl− + HCO−); normal value ranges from 6–12 mmol/L with an average of approximately 10 mmol/L. • Winter's equation predicts compensatory Paco2 in metabolic acidosis: Paco2 = (1.5 × [HCO3−]) + 8 ± 2. • Bicarbonate therapy in diabetic ketoacidosis (DKA) is reserved for adult patients with severe acidemia (pH 7.5) increases salicylate clearance fivefold. • A high AG is meaningful even if the [HCO3−] or pH is normal; a mixture of high-gap acidosis and metabolic alkalosis is recognized by comparing differences (Δ values) in normal to prevailing patient values. • In DKA, regular insulin is administered IV as an initial bolus of 0.1 U/kg followed by an infusion of 0.1 U/kg/h until the AG returns to normal. • Ethylene glycol ingestion should be suspected if inspection of the urine reveals oxalate crystals. • Osmolar gap is proportional to the concentration of unmeasured solute; calculated and determined osmolality should agree within 10–15 mmol/kg H2O. • Pyroglutamic acid (5-oxoproline) acidemia may occur in critically ill patients receiving acetaminophen due to depletion of glutathione. • Normal values for [HCO3−], Paco2, and pH do not ensure the absence of an acid-base disturbance. For example, an alcoholic who has been vomiting prior to admission may develop a metabolic alkalosis with a pH of 7.55, Paco2 of 47 mmHg, [HCO3−] of 40 mmol/L, [Na+] of 135, [Cl−] of 80, and [K+] of 2.8. If such a patient were then to develop a superimposed alcoholic ketoacidosis with a β-hydroxybutyrate concentration of 15 mmol/L, the arterial pH would fall to 7.40, the [HCO3−] to 25 mmol/L, and the Paco2 to 40 mmHg. Although these values are normal, the AG is significantly elevated at 30 mmol/L, documenting that a mixed metabolic alkalosis and metabolic acidosis coexist.

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Acid-base nomogram

Caption: FIGURE 58-1 Acid-base nomogram. Shown are the 90% confidence limits (range of values) of the normal respiratory and metabolic compensations for primary acid- base disturbances. (Reproduced with permission from LL Hamm and TD DuBose Jr, in Alan S.L. Yu, et al (eds): Brenner and Rector’s The Kidney, 11th ed. Philadelphia, Elsevier, 2020.) — Figure 58-1 Acid-base nomogram showing the 90% confidence limits (range of values) of the normal respiratory and metabolic compensations for primary acid-base disturbances. The shaded areas represent the 95% confidence limits for physiologic compensation in simple disturbances.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.