Organic Acidoses

This chapter describes two clinical disorders that involve excessive production of organic (carbon-based) acids by intermediary metabolism. Both of these disorders, lactic acidosis and ketoacidosis, can be adaptive processes in the right setting, but are pathological processes in the ICU setting.

I. Lactic Acidosis

Lactic acidosis is probably the most concerning of all metabolic acidoses, but the source of the concern is not the acidosis, but the condition that is responsible for the acidosis.

A. Responsible Conditions

(Note: Because the pertinent issues in lactic acidosis are often related to the lactate level rather than the acidosis, the term hyperlactatemia will be used interchangeably with lactic acidosis.) Several conditions can be responsible for hyperlactatemia, as shown in Table 24.1. The most prevalent of these conditions are sepsis and the clinical shock syndromes (i.e., hypovolemic, cardiogenic, and septic shock).

1. Clinical Shock Syndromes

Hyperlactatemia is universal in the clinical shock syndromes (since it is required for the diagnosis) and the prognosis in these conditions is related to the severity of the lactate elevation, and the time required for the lactate levels to normalize (lactate clearance). These relationships are demonstrated in Figure 6.2 (Chapter 6).

Table 24.1 Sources of Hyperlactatemia in the ICU

Inflammatory:	sepsis
Shock syndrome:	hypovolemic, cardiogenic, septic
Drugs:	antiretroviral agents, β₂ agonists, epinephrine, linezolid, metformin, nitroprusside, propofol, salicylates
Toxins:	carbon monoxide, cyanide, propylene glycol
Nutritional:	thiamine deficiency
Others:	alkalosis (severe), fulminant hepatic failure, seizure

2. Sepsis

Serum lactate levels have the same diagnostic and prognostic significance in sepsis as they do in in the shock syndromes. The lactic acidosis in sepsis is not the result of inadequate tissue oxygenation (see Chapter 6, Section III-F), which has important implications for the traditional emphasis on promoting tissue oxygenation in patients with lactic acidosis.

3. Thiamine Deficiency

Thiamine deficiency is often overlooked as a cause of elevated blood lactate levels. Thiamine is a cofactor for pyruvate dehydrogenase (the enzyme that converts pyruvate to acetyl coenzyme A, and limits conversion to lactate), and thiamine deficiency can result in severe lactic acidosis (2). (See Chapter 36, Section III-A for more information on thiamine deficiency.)

4. Drugs

A variety of drugs can produce hyperlactatemia, as indicated in Table 24.1. Most cases are due to an impaired oxidative metabolism, but epinephrine and high-dose β₂
agonists promote hyperlactatemia by increasing the production of pyruvate (1).

METFORMIN: Metformin is an oral hypoglycemic agent that produces lactic acidosis during therapeutic dosing. The mechanism is unclear, and it occurs primarily in patients with renal insufficiency (3). The lactic acidosis can be severe, with a mortality rate that exceeds 45% if untreated (3,4). Plasma metformin levels are not routinely available, and the diagnosis is based on excluding other causes of lactic acidosis. The preferred treatment is hemodialysis (3,4).

5. Propylene Glycol

Propylene glycol is used as a solvent in intravenous preparations of lorazepam, diazepam, esmolol, nitroglycerin, and phenytoin. It is metabolized primarily in the liver, and the principal metabolites are lactate and pyruvate (5).

Propylene glycol toxicity (i.e., agitation, coma, seizures, hypotension, and lactic acidosis) has been reported in 19–66% of patients receiving high-dose IV lorazepam infusions for more than 48 hours (5,6).
The diagnosis can be elusive. There is an assay for propylene glycol in blood, but the acceptable range has not been determined.
Prolonged infusions of lorazepam should be avoided. (In fact, prolonged infusions of any benzodiazepine should be avoided because these drugs accumulate in the brain and produce excessive and prolonged sedation.)

6. Other Notable Conditions

Generalized seizures can produce marked increases in serum lactate levels, but this is a hypermetabolic effect, and it resolves quickly after the seizures subside (7).
The liver is responsible for 70% of lactate clearance. Hyperlactatemia is common in acute, fulminant liver failure (1), but is not a frequent finding in chronic liver failure unless there is a coexisting condition that increases lactate production (e.g., sepsis) (1).

B. Diagnostic Considerations

Serum lactate levels are readily available, and screening tests for lactic acidosis, such as the anion gap, are not necessary (and can be unreliable, as described in Chapter 23, Section III-C).
Lactate levels can be measured in venous or arterial blood, with equivalent results (1).
The upper limit of normal for serum lactate varies from 1.0 to 2.2 mmol/L in individual laboratories (1), but 2 mmol/L seems to be a common cutoff point. However, lactate levels must rise above 4 mmol/L to show an association with increased mortality (8), so a cutoff of 4 mmol/L may be more appropriate for clinically significant hyperlactatemia.

C. Alkali Therapy

Therapy aimed at correcting the acidosis does not have a major role in the management of patients with lactic acidosis. The following is a brief summary of the relevant issues in alkali therapy for lactic acidosis.

1. The Bicarbonate Experience

Clinical studies have consistently shown that sodium bicarbonate infusions are without hemodynamic benefit or survival benefit in lactic acidosis (9,10,11). Furthermore, bicarbonate infusions are accompanied by several undesirable effects (see Table 24.2), including an increase in arterial PCO₂ and a paradoxical decrease in
intracellular pH (attributed to transcellular movement of the generated CO₂) (9,12).

Table 24.2 Bicarbonate Replacement

7.5% NaHCO₃	Undesirable Effects^†
Na: 0.9 mEq/L	↑ Arterial PCO₂
HCO₃: 0.9 mEq/L	↓ Intracellular pH
PCO₂: >200 mm Hg	↓ Ionized calcium
pH: 8.0	↑ Serum lactate
Osmolality: 1,461 mosm/kg
^† From References 9,10,11,12.