Metabolic acidemia is a common laboratory finding, and most cases are caused by conditions such as hypovolemia, systemic infection, and acute diarrhea. The challenge for the physician is to confirm that the acidemia has a presentation, history, and response to treatment that are consistent with one of these common illnesses rather than an alternate heritable or acquired disorder predisposing to acidemia. Specifically, a number of inborn errors of metabolism present with severe metabolic acidemia. This chapter presents a set of principles by which clinicians can recognize signs and symptoms of severe metabolic acidemia, treat severe acidemia if needed, and broaden the differential diagnosis when an acidemia is not adequately explained by the clinical presentation and laboratory workup.

The term acidemia, or “acid in the blood,” is used to denote a state of acidic pH measured by a blood gas analysis or a serum bicarbonate level. The term acidosis is reserved for cases in which a specific acidic substance is suspected or has been identified in the blood (e.g. lactic acidosis, ketoacidosis).

ACID BUFFERING

Buffers in the blood and in the extracellular and intracellular fluid maintain normal body pH. In the blood, both fast-acting mechanisms (buffering by proteins and the bicarbonate–carbonic acid system) and slow-acting mechanisms (modulation of renal bicarbonate reabsorption) contribute to acid–base homeostasis. Quantitatively, proteins such as albumin and hemoglobin form the largest reserve of immediate buffer. The bicarbonate–carbonic acid system has the largest capacity to alter its flux in response to an acid challenge. Impairment of any of these mechanisms can decrease the body’s ability to respond to a perturbation in acid–base status.

ACID PRODUCTION AND EXCRETION

Acidemia of any type represents an imbalance between acid production and acid excretion. Physiologic acid production can generally be categorized into volatile (mostly carbon dioxide) and nonvolatile components. The body generates approximately 15,000 mmol of carbon dioxide per day—an amount equivalent to twenty 2-liter bottles of carbonated beverage.^1,2 Pulmonary ventilation excretes most of this excess carbon dioxide. The majority of nonvolatile acids are generated by dietary acid intake, amino acid catabolism, and fatty acid oxidation (which produces ketones and lactic acid). An adult generates 50 to 70 mEq/day of nonvolatile acid.³ Most nonvolatile acid secretion occurs through renal mechanisms, including bicarbonate reclamation and ammoniagenesis.⁴

ACIDEMIA SECONDARY TO BICARBONATE LOSS

Because the bicarbonate–carbonic acid system is a critical buffering mechanism, metabolic acidemia may be caused solely by excessive loss of bicarbonate rather than by increased acid production. Bicarbonate losses may be either gastrointestinal or renal. Renal tubular acidosis is a relatively common cause of chronic acidemia and is due to renal tubular dysfunction. The anion gap is usually normal, owing to a compensatory increase in the plasma chloride (Cl⁻) concentration (see later). Injury to the proximal renal tubules can result in bicarbonate loss by preventing reabsorption of small molecules, including bicarbonate, glucose, amino acids, phosphate, and urates. This pattern of renal metabolite losses is termed (renal) Fanconi syndrome, not to be confused with Fanconi anemia. Table 87-1 lists exposures and inherited disorders associated with Fanconi syndrome. Metabolic acidemia may be accompanied by other signs of renal dysfunction (e.g. failure to thrive) in these diseases.

Metabolic acidemia causes malaise and a host of end-organ effects. Physiologic effects of acidemia include pulmonary vasoconstriction, decreased myocardial contractility, and a shift of the oxygen–hemoglobin dissociation curve resulting in decreasing oxygen saturation. Air hunger and tachypnea characterize the typical breathing pattern. Patients may be confused, lethargic, or ataxic. Nausea, vomiting, and abdominal pain are useful clues—vomiting is a physiologic mechanism for lowering pH by proton removal. Myocardial suppression and cardiac conduction changes can cause chest pain or palpitations. Muscle weakness and bone pain may be described.

Acute metabolic acidemia may occur from any process that reduces ventilation or perfusion. It is also the hallmark of several inborn errors of metabolism where the course may progress rapidly from anorexia and lethargy to somnolence, coma, and death. Episodes due to inborn errors are usually triggered by an acquired illness, typically a viral infection. Subtle early signs may include worsening of the symptoms associated with the underlying disorder, such as ataxia and a maple syrup odor in children with maple syrup urine disease.

Chronic metabolic acidosis is associated with growth failure and developmental delay in children. Demineralization of bones can result in osteopenia. Other signs and symptoms are largely determined by the underlying mechanism. Recognition of chronic acidosis should prompt subspecialty referral to a nephrologist, gastroenterologist, or metabolism expert depending on the suspected mechanism.

The differential diagnoses and causes of metabolic acidosis are extensive. These are detailed in Tables 87-1, 87-2, 87-3, 87-4.

The following steps can guide the clinician toward an accurate diagnosis or referral point:

1. 
   

   Confirm metabolic acidemia.

   
   
2. 
   

   Differentiate secondary metabolic acidemia due to common illnesses from cases needing further evaluation.

   
   
3. 
   

   Differentiate acid accumulation from bicarbonate loss.

   
   
4. 
   

   If acidic molecules are accumulating, determine the acid type if possible.

CONFIRM METABOLIC ACIDOSIS

The initial laboratory tests for a child with a suspected unexplained metabolic acidemia include serum electrolytes (sodium, potassium, chloride, bicarbonate), renal function tests (creatinine and BUN), serum osmolality, glucose, blood gas analysis, and urinalysis. If a particular acid is suspected based on the presentation or a preexisting diagnosis, the initial studies should include the measurement of that acid.

DIFFERENTIATE ACIDOSIS DUE TO COMMON ILLNESSES FROM CASES NEEDING FURTHER EVALUATION

An acidemia may not require further evaluation if it presents as the expected consequence of a common illness and is consistent in magnitude and response to treatment. Sepsis, diarrhea, and dehydration are at the root of most cases of acidemia seen in the pediatric setting. Severity, chronicity, history, and context can all be used to decide how comprehensive the workup should be.

DIFFERENTIATE ACID ACCUMULATION FROM BICARBONATE LOSS

As noted earlier, acidosis may result from increased acid production or abnormal loss of bicarbonate from the kidneys or gastrointestinal tract. Distinguishing between these two possibilities is critical, because effective treatment depends on a correct diagnosis. The history, physical examination, and routine laboratory studies allow some acidemias to be sorted into the bicarbonate-losing category. A typical bicarbonate-losing acidemia is associated with hyperchloremia and a normal anion gap. Causes of nongap metabolic acidemia are listed in Table 87-2. Measurement of urine pH and serum potassium can support a diagnosis of renal tubular acidosis, but should be interpreted with caution in the setting of gastrointestinal bicarbonate losses (see below).⁵ Clues to the presence of Fanconi syndrome include hypophosphatemia, alkaline urine in the setting of acidemia, and the presence of urine-reducing substances including glucose.

In contrast, metabolic acidemias caused by the accumulation of acid metabolites generally cause a normochloremic acidosis with an elevated anion gap. Even with an equivocal gap, an unexplained acidemia may warrant additional workup to identify the unknown substance.

DETERMINE WHAT TYPE OF ACID IS BEING ACCUMULATED

Acid accumulation can be caused by normal stress physiology, toxic ingestion, and inborn errors of metabolism. Table 87-3 lists major causes of gap acidoses. Toxins may cause an acidosis by being acidic themselves or by causing secondary, acid-producing metabolic derangements. Methanol is metabolized to formic acid, which, as an unmeasured anion, increases the anion gap. In contrast, cyanide is not a strong acid, but causes lactic acidosis by poisoning mitochondrial energy metabolism. Other important toxins with the potential to cause acidosis include toluene, sulfur, iron, isoniazid, ethylene glycol, and salicylates. Similarly, metabolic disorders can cause acidemia either primarily or secondarily. Methylmalonic acidemia, an organic acidemia (see later), causes a primary acidosis through the accumulation of several organic acids, including propionic acid, methylmalonic acid, lactic acid, and ketone bodies. By contrast, some of the fatty acid oxidation disorders can cause cardiomyopathy, with subsequent decreased tissue perfusion and a secondary lactic acidosis.