INTRODUCTION	Section 2 of 10
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Background: A metabolic acidosis is an acid-base disorder characterized by a decrease in serum pH that results from either a primary decrease in plasma bicarbonate concentration ([HCO₃^-]) or an increase in hydrogen ion concentration ([H⁺]). It is not a disease but rather a biochemical abnormality. The clinical manifestations of a metabolic acidosis are nonspecific, and its differential diagnoses include common and rare diseases.

Pathophysiology: A primary metabolic acidosis is a pathophysiologic state characterized by an arterial pH less than 7.35 in the absence of an elevated PaCO₂. It is created by one of three mechanisms: (1) increased production of acids, (2) decreased excretion of acids, or (3) loss of alkali.

Acutely, medullary chemoreceptors compensate for a metabolic acidosis through increases in alveolar ventilation. The resulting tachypnea and hyperpnea reduces the PaCO₂ in an attempt to increase the pH back toward normal. In a primary metabolic acidosis, the degree of acute respiratory compensation can be predicted by the following relationship:

Expected PaCO₂ = (1.5 X [HCO₃^-]) + 8 ± 2

If the measured PaCO₂ is higher than the expected PaCO₂, a concomitant respiratory acidosis is also present. The development of normocapnia or hypercapnia when a severe metabolic acidosis exists often signals respiratory muscle fatigue, impending respiratory failure, and the possible need for initiating mechanical ventilation.

The kidneys are responsible for reclaiming filtered bicarbonate (HCO₃^-) and eliminating the daily acid load generated from nitrogen (protein) metabolism. Normally, the kidneys excrete hydrogen ions (H⁺) through the formation of titratable acids and ammonium. The ability of the kidney to excrete an increased acid load generally begins 12-24 hours after the compensatory hyperventilation begins and continues for 1-3 days. Over time, the kidneys attempt to increase reabsorption of HCO₃^- to compensate for the acidosis. The severity of the acidosis depends on the rapidity of bicarbonate loss and the ability of the kidney to replenish bicarbonate.

Anion gap

To achieve electrochemical balance, ionic elements in the extracellular fluid must equal a net charge of zero. Therefore, the number of negatively charged ions (anions) should equal the number of positively charged ions (cations). Measured serum anions are chloride and bicarbonate, and the unmeasured anions include phosphates, sulfates, and proteins (eg, albumin). The primary measured serum cation is sodium, but other cations exist, such as calcium, potassium, and magnesium. Under typical conditions, unmeasured anions exceed unmeasured cations; this is referred to as the anion gap and can be represented by the following formulas:

(Chloride + Bicarbonate) + Unmeasured Anions = Sodium + Unmeasured Cations

Unmeasured Anions – Unmeasured Cations = Sodium – (Chloride + Bicarbonate)

Anion Gap = (Sodium) – (Chloride + Bicarbonate)

Practically, a metabolic acidosis is divided into processes that are associated with a normal anion gap (8-12 mEq/L) or an elevated anion gap (>12 mEq/L). A normal anion gap metabolic acidosis involves no gain of unmeasured anions; however, because of the need for electrical neutrality, serum chloride replaces the depleted bicarbonate, and hyperchloremia develops. In contrast, an elevated anion gap metabolic acidosis is caused when extra unmeasured anions are added to the blood.

General physiologic and metabolic effects

The clinical manifestations of a metabolic acidosis are related to the degree of acidemia. Initially, patients with a metabolic acidosis develop a compensatory tachypnea and hyperpnea; if the acidemia is severe, the child can present with significant work of breathing and distress. An increase in serum hydrogen ion concentration results in pulmonary vasoconstriction, which raises pulmonary artery pressure and pulmonary vascular resistance. An increase in right ventricular afterload and, potentially, right ventricular dysfunction can then occur. This is especially problematic in newborn infants with persistent pulmonary hypertension. Tachycardia is the most common cardiovascular effect seen with a mild metabolic acidosis. As the serum pH continues to fall below 7.2, myocardial depression occurs because hydrogen ions act as a negative inotrope and peripheral vasodilation occurs. Also, with acidemia, cardiovascular response to endogenous and exogenous catecholamines can decrease, which can possibly exacerbate hypotension in children with volume depletion or shock.

Central nervous system manifestations can include headache, lethargy, confusion, or any change in mental status secondary to a decrease in intracerebral pH. Cerebral vasodilation occurs as a result of a metabolic acidosis and may contribute to an increase in intracranial pressure.

During a metabolic acidosis, excess hydrogen ions move toward the intracellular compartment and potassium moves out of the cell into the extracellular space (serum). For every decrease in the serum pH by 0.1, a concomitant increase in the serum potassium level by 0.5 mEq occurs. As a result, hyperkalemic arrhythmias (peaked T waves and QRS widening) and ventricular fibrillation may occur. Other acute metabolic effects of acidemia include insulin resistance, increased protein degradation, and reduced adenosine triphosphate (ATP) synthesis. During acidemia, the oxyhemoglobin dissociation curve shifts to the right; oxygen has a lower affinity for hemoglobin, but hemoglobin releases oxygen more readily. Also, nonspecific gastrointestinal complaints, such as abdominal pain, nausea, or vomiting, may be present.

Frequency:

• In the US: Metabolic acidosis is a biochemical derangement occurring as part of certain disease states and conditions. No statistics are available on its frequency.

Mortality/Morbidity: The underlying disorder usually produces most of the signs and symptoms in children with a mild or moderate metabolic acidosis. Untreated severe metabolic acidosis may be associated with life-threatening arrhythmias, myocardial depression, and respiratory muscle fatigue but is not the ultimate cause of morbidity and mortality.

Race: No racial predilection exists.

Sex: The prevalence rates of metabolic acidosis are equal for males and females.

Age: Metabolic acidosis can occur in any age group.

	CLINICAL	Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

History: The etiology of a metabolic acidosis is often apparent from the history and physical examination. The following questions are included in a complete investigation of the patient's history:

• Is there a prodrome of anorexia, nausea, vomiting, or diarrhea? In pediatric patients, diarrhea is the most common cause of a metabolic acidosis.

• Is the metabolic acidosis associated with seizures, a depressed sensorium, or both in a neonate? This warrants consideration of an inborn error of metabolism.

• Is there a history of depressed mental status, lethargy, and poor feeding in an infant? Left-sided obstructive cardiac lesions should be considered (eg, aortic coarctation or hypoplastic left heart syndrome).

• Is there failure to thrive to suggest a chronic metabolic acidosis? This can be seen with renal insufficiency or renal tubular acidosis (RTA).

• Is there new onset of polyuria, polydipsia, and weight loss? This could signify undiagnosed diabetes mellitus and diabetic ketoacidosis in a child.

• Is there a possible ingestion of a toxin or other form of intoxication? What medications are in the home? Suspect a poisoning in a healthy child who quickly develops a metabolic acidosis; possible agents are ethanol, ethylene glycol, salicylates, and methanol.

• Is there a history of trauma, hives, or fever? Consider states associated with a lactic acidosis secondary to shock from hypovolemia, sepsis, cardiac failure, anaphylaxis, or spinal shock.

• Is there a chronic medical or surgical issue? Examples to be concerned with are chronic renal failure, presence of a ureterosigmoidostomy, or diabetes mellitus.

Physical: Clinical findings generally depend on the etiology and severity of the metabolic acidosis.

• Hyperventilation or Kussmaul breathing may often be the first sign of a metabolic acidosis in a child.

• CNS manifestations may include lethargy, coma, and seizures.

• Signs of dehydration may be tachycardia, dry mucous membranes, and delayed capillary refill.

• Signs of a low cardiac output state may be weak pulses or cardiac gallop; an associated cardiovascular abnormality (eg, cardiomyopathy or left-sided cardiac lesion) may exist.

Causes: The causes of a metabolic acidosis can be classified on the basis of a normal or elevated anion gap.

• An elevated anion gap is created by inorganic (eg, phosphate or sulfate), organic (eg, ketoacids or lactate), or exogenous (eg, salicylate) acids incompletely neutralized by bicarbonate. Frequent causes of an elevated anion gap metabolic acidosis is represented by the mnemonic MUDPILES:

• Methanol

• Uremia

• Diabetic ketoacidosis

• Paraldehyde

• Iron, isoniazid (INH)

• Lactic acid

• Ethanol, ethylene glycol

• Salicylates

• A normal anion gap metabolic acidosis occurs when loss of bicarbonate from the GI tract or kidneys is excessive or when hydrogen ions cannot be secreted because of renal failure. The causes can be represented by the mnemonic USEDCARP:

• Ureterostomy

• Small bowel fistula

• Extra chloride

• Diarrhea

• Carbonic anhydrase inhibitors (eg, acetazolamide)

• Adrenal insufficiency

• Renal tubular acidosis

• Pancreatic fistula

• Infants are more likely to develop a normal anion gap metabolic acidosis secondary to significant losses of bicarbonate in diarrheal stools. The stool output can contain as much as 70-80 mEq/L of bicarbonate.

• Patients with a ureterosigmoidostomy may lose bicarbonate in exchange for the reabsorption of chloride and ammonium as urine accumulates in the sigmoid colon.

• Children with congenital or acquired renal tubular acidosis can lose large amounts of bicarbonate, with or without concomitant potassium loss.

• Inborn errors of metabolism may result in a metabolic acidosis, with or without hypoglycemia or hyperammonemia.

• In children, metabolic acidosis is frequently caused by lactate. Lactate is the end product of anaerobic glycolysis, which can be represented by the following equation:
  Glucose + 2 ATP + 2 H₂PO₄ ® 2 Lactate + 2 ADP + 2 H₂O

• Hydrogen ions generated by the hydrolysis of ATP converts lactate to lactic acid.
  • Under normal conditions, the liver rapidly converts these small amounts of lactic acid to pyruvic acid, which is then metabolized to carbon dioxide and water.

  • Under conditions of oxygen deprivation and decreased oxygen delivery to the tissues, anaerobic metabolism produces excessive amounts of lactic acid. Most disease processes that result in decreased oxygen delivery also frequently lead to diminished hepatic function, further compounding lactic acid accumulation.

  • Conditions that frequently lead to lactic acidosis include shock, sepsis, thiamine deficiency, diabetic ketoacidosis, and cellular poisoning (eg, cyanide toxicity).