Normochloremic metabolic acidosis generally results from addition of organic acids such as lactate, acetoacetate, beta-hydroxybutyrate, and exogenous toxins. Other anions such as isocitrate, alpha-ketoglutarate, malate, and D-lactate may contribute to the anion gap of lactic acidosis, DKA, and acidosis of unknown etiology. Uremia causes an increased anion gap metabolic acidosis from unexcreted organic acids and anions (Table 21–13).
Table 21–13.Common causes and therapy for increased anion gap metabolic acidosis. ||Download (.pdf) Table 21–13. Common causes and therapy for increased anion gap metabolic acidosis.
|Cause ||Treatment |
|Lactic acidosis ||Therapy aimed at correcting the underlying cause. Treatment of type A requires improving perfusion and matching oxygen consumption with fluids, packed red cells, vasopressors, and inotropes as needed. Type B generally requires removal of the offending agent or supplementing key cofactors of anaerobic metabolism. |
|D-Lactic acidosis ||Sodium bicarbonate may be administered in the setting of severe acidemia. Specific antimicrobial agents (metronidazole, neomycin) can be utilized in patients with short gut syndrome. A low carbohydrate diet can be effective by decreasing substrate delivery to the distal colon. Fecal transplant has been utilized successfully in patients unresponsive to conventional therapies. |
|Therapy involves correction of the state of insulin deficiency and glucagon excess. In diabetic ketoacidosis, this requires administration of exogenous insulin, generally with a continuous infusion. In starvation and alcoholic ketoacidosis, dextrose-containing fluids will stimulate endogenous insulin release. In all groups, correction of volume depletion with isotonic fluids as well as judicious repletion of electrolytes (particularly potassium and phosphorous) are imperative. |
|Kidney failure ||Supplemental alkali therapy (sodium bicarbonate or sodium citrate). Hemodialysis when necessary. |
|Ingestions || |
|Initial treatment requires rapid stabilization of the patient’s airway and circulation as needed. Sodium bicarbonate should be given to address systemic acidosis by bolus and subsequently continuous infusion therapy to maintain a pH > 7.35. Fomepizole (or less commonly ethanol) can be given to inhibit alcohol dehydrogenase. Fomepizole is loaded at 15 mg/kg intravenously, followed by 10 mg/kg every 12 hours. Hemodialysis is the most effective method for removing parent alcohols and their toxic metabolites. Hemodialysis should be initiated early in patients with an elevated anion gap metabolic acidosis or end organ damage in the setting of known ingestion. |
|Salicylic acid ||Activated charcoal may be administered to awake or intubated patients within 2 hours of ingestion. Sodium bicarbonate should be initiated by bolus followed by continuous infusion to target a urine pH of 7.5 or higher. Supplemental glucose should be administered to all patients with alteration in mental status. Hemodialysis is effective in removing salicylate and generally reserved for severe cases or marked elevations in salicylate concentration. |
|Pyroglutamic acid (5-Oxoproline) ||Therapy is directed at the underlying cause. Generally requires withdrawal of the offending agent (acetaminophen) and sodium bicarbonate therapy for severe acidemia. N-acetylcysteine may be effective in restoring glutathione stores. |
Lactic acidosis is a common cause of metabolic acidosis, producing an elevated anion gap and decreased serum pH when present without other acid-base disturbances. Lactate is formed from pyruvate in anaerobic glycolysis. Normally, lactate levels remain low (1 mEq/L) because of metabolism of lactate principally by the liver through gluconeogenesis or oxidation via the Krebs cycle.
In lactic acidosis, lactate levels are at least 4–5 mEq/L but commonly 10–30 mEq/L. There are two basic types of lactic acidosis.
Type A (hypoxic) lactic acidosis is more common, resulting from decreased tissue perfusion; cardiogenic, septic, or hemorrhagic shock; and carbon monoxide or cyanide poisoning. These conditions increase peripheral lactic acid production and decrease hepatic metabolism of lactate as liver perfusion declines.
Type B lactic acidosis may be due to metabolic causes (eg, diabetes mellitus, ketoacidosis, liver disease, kidney disease, infection, leukemia, or lymphoma) or toxins (eg, ethanol, methanol, salicylates, isoniazid, or metformin). Propylene glycol can cause lactic acidosis from decreased liver metabolism; it is used as a vehicle for intravenous drugs, such as nitroglycerin, etomidate, and diazepam. Parenteral nutrition without thiamine causes severe refractory lactic acidosis from deranged pyruvate metabolism. Patients with short bowel syndrome may develop D-lactic acidosis with encephalopathy due to carbohydrate malabsorption and subsequent fermentation by colonic bacteria. Nucleoside analog reverse transcriptase inhibitors can cause type B lactic acidosis due to mitochondrial toxicity.
(For treatment of lactic acidosis, see below and Chapter 27.)
B. Diabetic Ketoacidosis (DKA)
DKA is characterized by hyperglycemia and metabolic acidosis with an increased anion gap:
H+ + B− + NaHCO3 ↔ CO2 + NaB + H2O
where B– is beta-hydroxybutyrate or acetoacetate, the ketones responsible for the increased anion gap. Diabetics with ketoacidosis may have an additional lactic acidosis from tissue hypoperfusion and increased anaerobic metabolism.
During the recovery phase of DKA, a hyperchloremic non–anion gap acidosis can develop because saline resuscitation results in chloride retention, restoration of GFR, and ketoaciduria.
Patients with DKA and normal kidney function may have marked ketonuria and severe metabolic acidosis but only a mildly increased anion gap. Thus, the size of the anion gap correlates poorly with the severity of the DKA; the urinary loss of Na+ or K+ salts of beta-hydroxybutyrate will lower the anion gap without altering the H+ excretion or the severity of the acidosis. Urine dipsticks for ketones test primarily for acetoacetate and, to a lesser degree, acetone but not the predominant ketoacid, beta-hydroxybutyrate. Dipstick tests for ketones may become more positive even as the patient improves due to the metabolism of beta-hydroxybutyrate. Thus, the patient’s clinical status and pH are better markers of improvement than the anion gap or ketone levels.
C. Alcoholic Ketoacidosis
Chronically malnourished patients who consume large quantities of alcohol daily may develop alcoholic ketoacidosis. Most of these patients have mixed acid-base disorders. Although decreased HCO3– is usual, 50% of the patients may have normal or alkalemic pH. Three types of metabolic acidosis are seen in alcoholic ketoacidosis: (1) Ketoacidosis is due to beta-hydroxybutyratic acid and acetoacetic acid excess. (2) Lactic acidosis: Alcohol metabolism increases the NADH:NAD ratio, causing increased production and decreased utilization of lactate. Accompanying thiamine deficiency, which inhibits pyruvate carboxylase, further enhances lactic acid production in many cases. Moderate to severe elevations of lactate (greater than 6 mmol/L) are seen with concomitant disorders such as sepsis, pancreatitis, or hypoglycemia. (3) Hyperchloremic acidosis from bicarbonate loss in the urine is associated with ketonuria. A concomitant metabolic alkalosis may occur from volume contraction and vomiting. Respiratory alkalosis resulting from alcohol withdrawal, pain, or associated disorders such as sepsis or liver disease may lead to a triple acid-base disorder in these patients.
(See also Chapter 38.) Multiple toxins and drugs increase the anion gap by increasing endogenous acid production. Common examples include methanol (metabolized to formic acid), ethylene glycol (glycolic and oxalic acid), and salicylates (salicylic acid and lactic acid). The latter can cause a mixed disorder of metabolic acidosis with respiratory alkalosis. In toluene poisoning, the metabolite hippurate is rapidly excreted by the kidney and may present as a normal anion gap acidosis. Isopropanol, which is metabolized to acetone, increases the osmolar gap, but not the anion gap.
As the GFR drops below 15–30 mL/min/m2, the kidneys are increasingly unable to synthesize NH3. The reduced excretion of H+ (as NH4Cl) and accumulation organic anions (eg, phosphate and sulfate) results in an increased anion gap metabolic acidosis.