Chapter 83

Metabolic Acidoses and Alkaloses

Acid-base disturbances are common in patients admitted to the intensive care unit (ICU) and can cause widespread, clinically important physiologic changes. Anticipating and accounting for these changes, and adjusting to the physiologic consequences as these derangements resolve, are essential to the management of critically ill patients. This chapter briefly outlines the terminology, physiology, diagnosis, and management of acid-base disorders commonly encountered in the ICU.

Acidosis and alkalosis refer to the pathophysiologic processes that cause the body to accumulate or lose H⁺ ions, whereas acidemia and alkalemia refer to the actual changes in arterial blood pH. Metabolic acid-base disorders primarily affect serum bicarbonate (HCO₃^–) concentration and relate mainly to renal handling of the bicarbonate ion. Respiratory acid-base disorders primarily affect Paco₂ and relate mainly to respiratory handling of carbon dioxide in the process known as ventilation. The complex interactions of these processes, as well as a complicated system of buffers, are responsible for maintaining body pH within a narrow physiologic range.

Physiology and Pathophysiology

Acid-Base Physiology

Metabolism of food ultimately produces acid (H⁺) and base (HCO₃^–). A typical American diet, heavy in protein, produces slightly more acid than base, equal to approximately 1 mmol H⁺ per kg body weight per day; in contrast, a strict vegetarian diet produces a net base. Basic organic anions—for example, citrate and acetate—should be considered equivalent to HCO₃^– because they produce HCO₃^– when oxidized. Complete oxidation of carbon-containing compounds yields the volatile acid, carbonic acid (H₂CO₃), as shown by Equation 1:

(Equation 1)

The effect of these metabolic events on acid-base homeostasis is influenced by respiration and the exhalation of CO₂. Nonvolatile organic acids (e.g., lactic, beta-hydroxybutyric, and acetoacetic acids) are acids produced by incomplete oxidation and do not yield carbon dioxide. The H⁺ from nonvolatile acids (e.g., sulfuric and lactic acids) must be excreted by the kidneys, as CO₂ is not produced in these reactions.

Buffers minimize pH changes that result from the addition or removal of H⁺. Equation 1 can be rewritten in the Henderson-Hasselbalch format,

(Equation 2)

where pK = 6.1 (equilibrium constant for carbonic acid), [HCO₃^–] = concentration (mmol/L) of bicarbonate ion, and [CO₂] is the concentration (mmol/L) of CO₂ dissolved in blood. [CO₂] is determined by measuring Paco₂ and multiplying it by the solubility coefficient (0.03 mm Hg/mmol/L). Thus, a normal Paco₂ of 40 mm Hg is equal to 1.2 mmol/L of CO₂. When Paco₂ is 40 mm and [HCO₃^–] is also normal (i.e., 24 mmol/L), the ratio of [HCO₃^–]/[CO₂] equals 20:1 (and log 20 = 1.3). This ratio corresponds to the normal pH of 6.1 + 1.3 or 7.40. Remember that it is the ratio of bicarbonate to carbon dioxide in the blood that determines pH—not the absolute value of either.

The [HCO₃^–]/[CO₂] buffer pair is the most important because of the abundance of each part’s components and how the relationship between them can be influenced independently by the kidneys and lungs. For example, by Equation 1, in metabolic acidosis, the addition of H⁺ increases the concentration of hydrogen ion, [H⁺] (which, at equilibrium, proportionately decreases the concentration of bicarbonate ion [HCO₃^–]). By the law of mass action, the increased [H⁺] drives the reaction to the right, increasing the production of CO₂.

Under normal conditions, this increased CO₂ production does not raise [CO₂] or Paco₂ because of a compensatory increase in ventilation. Without this increased ventilation, there would be no attenuation of the fall in pH caused by the metabolic acidosis. In addition to buffering by [HCO₃^–]/[CO₂], inorganic phosphates (especially those in bone), plasma and intracellular proteins (such as albumin), and hemoglobin all help to buffer changes in pH. These secondary buffer systems do contribute some to maintenance of normal extracellular and intracellular pH, but diagnosis and management of acutely ill patients in the ICU depends mainly on the [HCO₃⁻]/[CO₂] system. Therefore, this will be the primary focus of this chapter.

Metabolic Acidosis

Metabolic acidoses occur when the rate of nonvolatile acid intake (or production), or HCO₃^– loss, exceeds the rate of renal H⁺ excretion and, therefore, HCO₃^– production by the kidney. A conventional distinction exists between processes that cause an increase in the anion gap and processes that do not.

The Anion Gap and Elevated Gap Acidoses

The anion gap (expressed in mEq/L) is the difference between measured serum cations and anions, as in Equation 4,

(Equation 4)

where [HCO₃⁻] is the (total) serum bicarbonate (= dissolved CO₂ and HCO₃⁻) as measured on a venous blood sample as part of the same chemistry panel giving values (mEq/L) for serum [Na⁺] and [Cl^–]. The anion gap consists of net negatively charged proteins (albumin is the major contributor) and small anions like urate and phosphate. The normal anion gap ranges from 8 to 12 and increases when nonvolatile acids accumulate because of increased net production (e.g., lactate, acetoacetate, or beta-hydroxybutyrate) or decreased renal excretion (e.g., phosphate and sulfate in chronic renal failure).

Hypoalbuminemia decreases the anion gap. In general, a decrease in albumin concentration of 1 mg/dL will decrease the normal anion gap by approximately 2.5 mEq/L. Paraproteinemias can increase or decrease the gap depending on the charge of the paraprotein. By increasing the net negative charge of albumin, alkalemia widens the gap; acidemia has the opposite effect, and as a result, the anion gap is an underestimate in significant acidemia. Renal disease causes both an anion gap and a normal gap acidosis (Tables 83.1 and 83.2).

TABLE 83.1

Metabolic Acidoses: Anion Gap Acidoses

Type of Anion	Etiology
Ketones	Diabetic ketoacidosis
	Alcoholic ketoacidosis
Toxins, poisons	Salicylates
	Methanol
	Ethylene glycol Acetaminophen
Lactate	Lactic acidosis
Phosphates and sulfate	Chronic renal failure

TABLE 83.2

Metabolic Acidoses: Hyperchloremic (Nonanion Gap) Acidoses

Mechanism of Disorder	Etiology
Addition of equimolar H⁺ and Cl^–	Ingestion or administration of HCl, NH₄Cl, lysine, or arginine HCl
Loss of HCO₃^– with equimolar gain of Cl^–	Secretory diarrhea (cholera-like) caused by infections or laxatives; other gastrointestinal loss of base (pancreatic fistula)
Inability to excrete daily load of H⁺	Renal tubular acidosis (see Table 83.3)
	Chronic renal failure
Inability to maintain serum [HCO₃^–] because of renal losses of HCO₃^–	Renal tubular acidosis (see Table 83.3) Acetazolamide use
Dilution of serum [HCO₃^–]	Volume expansion with fluid loading with NaCl

Lactic acidosis and diabetic ketoacidosis (DKA) commonly cause an anion gap acidosis in ICU patients (see Table 83.1). In DKA, metabolism of fatty acids produces H⁺ and the anion acetoacetate. Starvation produces ketosis but only minimal acidosis. In contrast, alcoholic ketoacidosis (AKA), which includes aspects of starvation, can produce a severe anion gap acidosis. Binge drinking leads to an altered redox state that generates the anion beta-hydroxybutyrate (which is not detected by the nitroprusside reaction for ketones, unlike acetoacetate).

Several other toxins induce anion gap acidoses. Salicylates induce lactic acid production while also stimulating respiratory centers to produce a second primary disorder, a respiratory alkalosis. Methanol and ethylene glycol are metabolized by hepatic alcohol dehydrogenase to various toxic metabolites, some of which also elevate the anion gap. Particularly, metabolism of methanol produces the toxins formaldehyde and formic acid. Metabolism of ethylene glycol produces glycolic and oxalic acids. In acute acetaminophen toxicity, glutathione depletion can result in elevated concentrations of gamma-glutamyl cysteine, leading to accumulation of pyroglutamic acid. Suspect acetaminophen toxicity in patients with a large anion gap, hepatic or renal dysfunction, and a negative preliminary toxicologic screen for methanol or ethylene glycol. Inhalation of toluene, a component of paint thinners and many glues, produces an anion gap acidosis via metabolism to hippuric acid. Renal failure leads to an accumulation of phosphate and sulfate, elevating the anion gap, most often late in the disease.

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