Metabolic acidosis can occur because of an increase in endogenous acid production (such as lactate and ketoacids), loss of bicarbonate (as in diarrhea), or accumulation of endogenous acids (as in renal failure). Metabolic acidosis has profound effects on the respiratory, cardiac, and nervous systems. The fall in blood pH is accompanied by a characteristic increase in ventilation, especially the tidal volume (Kussmaul respiration). Intrinsic cardiac contractility may be depressed, but inotropic function can be normal because of catecholamine release. Both peripheral arterial vasodilation and central venoconstriction can be present; the decrease in central and pulmonary vascular compliance predisposes to pulmonary edema with even minimal volume overload. CNS function is depressed, with headache, lethargy, stupor, and, in some cases, even coma. Glucose intolerance may also occur.
Treatment: Metabolic Acidosis
Treatment of metabolic acidosis with alkali should be reserved for severe acidemia except when the patient has no “potential HCO3−” in plasma. Potential [HCO3−] can be estimated from the increment (Δ) in the AG (ΔAG = patient's AG – 10). It must be determined if the acid anion in plasma is metabolizable (i.e., β-hydroxybutyrate, acetoacetate, and lactate) or nonmetabolizable (anions that accumulate in chronic renal failure and after toxin ingestion). The latter requires return of renal function to replenish the [HCO3−] deficit, a slow and often unpredictable process. Consequently, patients with a normal AG acidosis (hyperchloremic acidosis), a slightly elevated AG (mixed hyperchloremic and AG acidosis), or an AG attributable to a nonmetabolizable anion in the face of renal failure should receive alkali therapy, either PO (NaHCO3
or Shohl's solution) or IV (NaHCO3), in an amount necessary to slowly increase the plasma [HCO3−] into the 20–22 mmol/L range.
Controversy exists, however, in regard to the use of alkali in patients with a pure AG acidosis owing to accumulation of a metabolizable organic acid anion (ketoacidosis or lactic acidosis). In general, severe acidosis (pH < 7.10) warrants the IV administration of 50–100 meq of NaHCO3
, over 30–45 min, during the initial 1–2 h of therapy. Provision of such modest quantities of alkali in this situation seems to provide an added measure of safety, but it is essential to monitor plasma electrolytes during the course of therapy, because the [K+] may decline as pH rises. The goal is to increase the [HCO3−] to 10 meq/L and the pH to 7.20, not to increase these values to normal.
Approach to the Patient: High—Anion Gap Acidoses
There are four principal causes of a high-AG acidosis: (1) lactic acidosis, (2) ketoacidosis, (3) ingested toxins, and (4) acute and chronic renal failure (Table 47-4). Initial screening to differentiate the high-AG acidoses should include (1) a probe of the history for evidence of drug and toxin ingestion and measurement of arterial blood gas to detect coexistent respiratory alkalosis (salicylates); (2) determination of whether diabetes mellitus is present (diabetic ketoacidosis); (3) a search for evidence of alcoholism or increased levels of β-hydroxybutyrate (alcoholic ketoacidosis); (4) observation for clinical signs of uremia and determination of the blood urea nitrogen (BUN) and creatinine (uremic acidosis); (5) inspection of the urine for oxalate crystals (ethylene glycol); and (6) recognition of the numerous clinical settings in which lactate levels may be increased (hypotension, shock, cardiac failure, leukemia, cancer, and drug or toxin ingestion).
An increase in plasma l-lactate may be secondary to poor tissue perfusion (type A)—circulatory insufficiency (shock, cardiac failure), severe anemia, mitochondrial enzyme defects, and inhibitors (carbon monoxide, cyanide)—or to aerobic disorders (type B)—malignancies, nucleoside analogue reverse transcriptase inhibitors in HIV, diabetes mellitus, renal or hepatic failure, thiamine deficiency, severe infections (cholera, malaria), seizures, or drugs/toxins (biguanides, ethanol, methanol, propylene glycol, isoniazid, and fructose). Propylene glycol may be used as a vehicle for IV medications including lorazepam, and toxicity has been reported in several settings. Unrecognized bowel ischemia or infarction in a patient with severe atherosclerosis or cardiac decompensation receiving vasopressors is a common cause of lactic acidosis. Pyroglutamic acidemia has been reported in critically ill patients receiving acetaminophen, which is associated with depletion of glutathione. d-Lactic acid acidosis, which may be associated with jejunoileal bypass, short bowel syndrome, or intestinal obstruction, is due to formation of d-lactate by gut bacteria.
Approach to the Patient: Lactic Acid Acidosis
The underlying condition that disrupts lactate metabolism must first be corrected; tissue perfusion must be restored when inadequate. Vasoconstrictors should be avoided, if possible, because they may worsen tissue perfusion. Alkali therapy is generally advocated for acute, severe acidemia (pH < 7.15) to improve cardiac function and lactate use. However, NaHCO3
therapy may paradoxically depress cardiac performance and exacerbate acidosis by enhancing lactate production (HCO3− stimulates phosphofructokinase). While the use of alkali in moderate lactic acidosis is controversial, it is generally agreed that attempts to return the pH or [HCO3−] to normal by administration of exogenous NaHCO3 are deleterious. A reasonable approach is to infuse sufficient NaHCO3 to raise the arterial pH to no more than 7.2 over 30–40 min.
therapy can cause fluid overload and hypertension because the amount required can be massive when accumulation of lactic acid is relentless. Fluid administration is poorly tolerated because of central venoconstriction, especially in the oliguric patient. When the underlying cause of the lactic acidosis can be remedied, blood lactate will be converted to HCO3− and may result in an overshoot alkalosis.
Diabetic Ketoacidosis (DKA)
This condition is caused by increased fatty acid metabolism and the accumulation of ketoacids (acetoacetate and β-hydroxybutyrate). DKA usually occurs in insulin-dependent diabetes mellitus in association with cessation of insulin or an intercurrent illness such as an infection, gastroenteritis, pancreatitis, or myocardial infarction, which increases insulin requirements temporarily and acutely. The accumulation of ketoacids accounts for the increment in the AG and is accompanied most often by hyperglycemia [glucose > 17 mmol/L (300 mg/dL)]. The relationship between the ΔAG and ΔHCO3− is typically ∼1:1 in DKA. It should be noted that, because insulin prevents production of ketones, bicarbonate therapy is rarely needed except with extreme acidemia (pH < 7.1), and then in only limited amounts. Patients with DKA are typically volume depleted and require fluid resuscitation with isotonic saline. Volume overexpansion with IV-fluid administration is not uncommon, however, and contributes to the development of a hyperchloremic acidosis during treatment of DKA. The mainstay for treatment of this condition is IV regular insulin and is described in Chap. 344 in more detail.
Alcoholic Ketoacidosis (AKA)
Chronic alcoholics can develop ketoacidosis when alcohol consumption is abruptly curtailed and nutrition is poor. AKA is usually associated with binge drinking, vomiting, abdominal pain, starvation, and volume depletion. The glucose concentration is variable, and acidosis may be severe because of elevated ketones, predominantly β-hydroxybutyrate. Hypoperfusion may enhance lactic acid production, chronic respiratory alkalosis may accompany liver disease, and metabolic alkalosis can result from vomiting (refer to the relationship between ΔAG and ΔHCO3−). Thus, mixed acid-base disorders are common in AKA. As the circulation is restored by administration of isotonic saline, the preferential accumulation of β-hydroxybutyrate is then shifted to acetoacetate. This explains the common clinical observation of an increasingly positive nitroprusside reaction as the patient improves. The nitroprusside ketone reaction (Acetest) can detect acetoacetic acid but not β-hydroxybutyrate, so that the degree of ketosis and ketonuria can not only change with therapy, but can be underestimated initially. Patients with AKA usually present with relatively normal renal function, as opposed to DKA, where renal function is often compromised because of volume depletion (osmotic diuresis) or diabetic nephropathy. The AKA patient with normal renal function may excrete relatively large quantities of ketoacids in the urine, therefore, and may have a relatively normal AG and a discrepancy in the ΔAG/ΔHCO3− relationship.
Treatment: Alcoholic Ketoacidosis
Extracellular fluid deficits almost always accompany AKA and should be repleted by IV administration of saline and glucose (5% dextrose in 0.9% NaCl). Hypophosphatemia, hypokalemia, and hypomagnesemia may coexist and should be corrected. Hypophosphatemia usually emerges 12–24 h after admission, may be exacerbated by glucose infusion, and, if severe, may induce rhabdomyolysis. Upper gastrointestinal hemorrhage, pancreatitis, and pneumonia may accompany this disorder.
Drug- and Toxin-Induced Acidosis
(See also Chap. e49) Salicylate intoxication in adults usually causes respiratory alkalosis or a mixture of high-AG metabolic acidosis and respiratory alkalosis. Only a portion of the AG is due to salicylates. Lactic acid production is also often increased.
Treatment: Salicylate-Induced Acidosis
Vigorous gastric lavage with isotonic saline (not NaHCO3
) should be initiated immediately, followed by administration of activated charcoal per NG tube. In the acidotic patient, to facilitate removal of salicylate, intravenous NaHCO3 is administered in amounts adequate to alkalinize the urine and to maintain urine output (urine pH > 7.5). While this form of therapy is straightforward in acidotic patients, a coexisting respiratory alkalosis may make this approach hazardous. Alkalemic patients should not receive NaHCO3. Acetazolamide may be administered in the face of alkalemia, when an alkaline diuresis cannot be achieved, or to ameliorate volume overload associated with NaHCO3 administration, but this drug can cause systemic metabolic acidosis if HCO3− is not replaced. Hypokalemia should be anticipated with an alkaline diuresis and should be treated promptly and aggressively. Glucose-containing fluids should be administered because of the danger of hypoglycemia. Excessive insensible fluid losses may cause severe volume depletion and hypernatremia. If renal failure prevents rapid clearance of salicylate, hemodialysis can be performed against a bicarbonate dialysate.
Under most physiologic conditions, sodium, urea, and glucose generate the osmotic pressure of blood. Plasma osmolality is calculated according to the following expression: Posm = 2Na+ + Glu + BUN (all in mmol/L), or, using conventional laboratory values in which glucose and BUN are expressed in milligrams per deciliter: Posm = 2Na+ + Glu/18 + BUN/2.8. The calculated and determined osmolality should agree within 10–15 mmol/kg H2O. When the measured osmolality exceeds the calculated osmolality by >15–20 mmol/kg H2O, one of two circumstances prevails. Either the serum sodium is spuriously low, as with hyperlipidemia or hyperproteinemia (pseudohyponatremia), or osmolytes other than sodium salts, glucose, or urea have accumulated in plasma. Examples of such osmolytes include mannitol, radiocontrast media, ethanol, isopropyl alcohol, ethylene glycol, propylene glycol, methanol, and acetone. In this situation, the difference between the calculated osmolality and the measured osmolality (osmolar gap) is proportional to the concentration of the unmeasured solute. With an appropriate clinical history and index of suspicion, identification of an osmolar gap is helpful in identifying the presence of poison-associated AG acidosis. Three alcohols may cause fatal intoxications: ethylene glycol, methanol, and isopropyl alcohol. All cause an elevated osmolal gap, but only the first two cause a high-AG acidosis.
(See also Chap. e49) Ingestion of ethylene glycol (commonly used in antifreeze) leads to a metabolic acidosis and severe damage to the CNS, heart, lungs, and kidneys. The increased AG and osmolar gap are attributable to ethylene glycol and its metabolites, oxalic acid, glycolic acid, and other organic acids. Lactic acid production increases secondary to inhibition of the tricarboxylic acid cycle and altered intracellular redox state. Diagnosis is facilitated by recognizing oxalate crystals in the urine, the presence of an osmolar gap in serum, and a high-AG acidosis. Treatment should not be delayed while awaiting measurement of ethylene glycol levels in this setting.
Treatment: Ethylene Glycol—Induced Acidosis
This includes the prompt institution of a saline or osmotic diuresis, thiamine and pyridoxine supplements, fomepizole or ethanol, and hemodialysis. The IV administration of the alcohol dehydrogenase inhibitor fomepizole (4-methylpyrazole; 15 mg/kg as a loading dose) or ethanol IV to achieve a level of 22 mmol/L (100 mg/dL) serves to lessen toxicity because they compete with ethylene glycol for metabolism by alcohol dehydrogenase. Fomepizole, although expensive, is the agent of choice and offers the advantages of a predictable decline in ethylene glycol levels without excessive obtundation during ethyl alcohol infusion. Hemodialysis is indicated when the arterial pH is <7.3, or the osmolar gap exceeds 20 mOsm/kg.
(See also Chap. e49) The ingestion of methanol (wood alcohol) causes metabolic acidosis, and its metabolites formaldehyde and formic acid cause severe optic nerve and CNS damage. Lactic acid, ketoacids, and other unidentified organic acids may contribute to the acidosis. Due to its low molecular mass (32 Da), an osmolar gap is usually present.
Treatment: Methanol-Induced Acidosis
This is similar to that for ethylene glycol intoxication, including general supportive measures, fomepizole, and hemodialysis (as above).
Ingested isopropanol is absorbed rapidly and may be fatal when as little as 150 mL of rubbing alcohol, solvent, or de-icer is consumed. A plasma level >400 mg/dL is life-threatening. Isopropyl alcohol differs from ethylene glycol and methanol in that the parent compound, not the metabolites, causes toxicity, and an AG acidosis is not present because acetone is rapidly excreted.
Treatment: Isopropyl Alcohol Toxicity
Isopropanol alcohol toxicity is treated by watchful waiting and supportive therapy; IV fluids, pressors, ventilatory support if needed, and occasionally hemodialysis for prolonged coma or levels >400 mg/dL.
(See also Chap. 280) The hyperchloremic acidosis of moderate renal insufficiency is eventually converted to the high-AG acidosis of advanced renal failure. Poor filtration and reabsorption of organic anions contribute to the pathogenesis. As renal disease progresses, the number of functioning nephrons eventually becomes insufficient to keep pace with net acid production. Uremic acidosis is characterized, therefore, by a reduced rate of NH4+ production and excretion. The acid retained in chronic renal disease is buffered by alkaline salts from bone. Despite significant retention of acid (up to 20 mmol/d), the serum [HCO3−] does not decrease further, indicating participation of buffers outside the extracellular compartment. Chronic metabolic acidosis results in significant loss of bone mass due to reduction in bone calcium carbonate. Chronic acidosis also increases urinary calcium excretion, proportional to cumulative acid retention.
Because of the association of renal failure acidosis with muscle catabolism and bone disease, both uremic acidosis and the hyperchloremic acidosis of renal failure require oral alkali replacement to maintain the [HCO3−] between 20 and 24 mmol/L. This can be accomplished with relatively modest amounts of alkali (1.0–1.5 mmol/kg body weight per day). Sodium citrate (Shohl's solution) or NaHCO3
tablets (650-mg tablets contain 7.8 meq) are equally effective alkalinizing salts. Citrate enhances the absorption of aluminum from the gastrointestinal tract and should never be given together with aluminum-containing antacids because of the risk of aluminum intoxication. When hyperkalemia is present, furosemide (60–80 mg/d) should be added.
Non–Anion Gap Metabolic Acidoses
Alkali can be lost from the gastrointestinal tract in diarrhea or from the kidneys (renal tubular acidosis, RTA). In these disorders (Table 47-5), reciprocal changes in [Cl−] and [HCO3−] result in a normal AG. In pure non–AG acidosis, therefore, the increase in [Cl−] above the normal value approximates the decrease in [HCO3−]. The absence of such a relationship suggests a mixed disturbance.
Table 47-5 Causes of Non–Anion Gap Acidosis |Favorite Table|Download (.pdf)
Table 47-5 Causes of Non–Anion Gap Acidosis
I. Gastrointestinal bicarbonate loss
B. External pancreatic or small-bowel drainage
C. Ureterosigmoidostomy, jejunal loop, ileal loop
1. Calcium chloride (acidifying agent)
2. Magnesium sulfate (diarrhea)
3. Cholestyramine (bile acid diarrhea)
II. Renal acidosis
1. Proximal RTA (type 2)
Drug-induced: acetazolamide, topiramate
2. Distal (classic) RTA (type 1)
Drug induced: amphotericin B, ifosfamide
1. Generalized distal nephron dysfunction (type 4 RTA)
a. Mineralocorticoid deficiency
b. Mineralocorticoid resistance (autosomal dominant PHA I)
c. Voltage defect (autosomal dominant PHA I and PHA II)
d. Tubulointerstitial disease
III. Drug-induced hyperkalemia (with renal insufficiency)
A. Potassium-sparing diuretics (amiloride, triamterene, spironolactone)
D. ACE-Is and ARBs
E. Nonsteroidal anti-inflammatory drugs
F. Cyclosporine and tacrolimus
A. Acid loads (ammonium chloride, hyperalimentation)
B. Loss of potential bicarbonate: ketosis with ketone excretion
C. Expansion acidosis (rapid saline administration)
E. Cation exchange resins
Treatment: Non–Anion Gap Metabolic Acidoses
In diarrhea, stools contain a higher [HCO3−] and decomposed HCO3− than plasma so that metabolic acidosis develops along with volume depletion. Instead of an acid urine pH (as anticipated with systemic acidosis), urine pH is usually around 6 because metabolic acidosis and hypokalemia increase renal synthesis and excretion of NH4+, thus providing a urinary buffer that increases urine pH. Metabolic acidosis due to gastrointestinal losses with a high urine pH can be differentiated from RTA because urinary NH4+ excretion is typically low in RTA and high with diarrhea. Urinary NH4+ levels can be estimated by calculating the urine anion gap (UAG): UAG = [Na+ + K+]u – [Cl−]u. When [Cl−]u > [Na+ + K+]u, the UAG is negative by definition. This indicates that the urine ammonium level is appropriately increased, suggesting an extrarenal cause of the acidosis. Conversely, when the UAG is positive, the urine ammonium level is low, suggesting a renal cause of the acidosis.
Loss of functioning renal parenchyma by progressive renal disease leads to hyperchloremic acidosis when the glomerular filtration rate (GFR) is between 20 and 50 mL/min and to uremic acidosis with a high AG when the GFR falls to <20 mL/min. In advanced renal failure, ammoniagenesis is reduced in proportion to the loss of functional renal mass, and ammonium accumulation and trapping in the outer medullary collecting tubule may also be impaired. Because of adaptive increases in K+ secretion by the collecting duct and colon, the acidosis of chronic renal insufficiency is typically normokalemic.
Proximal RTA (type 2 RTA) (Chap. 284) is most often due to generalized proximal tubular dysfunction manifested by glycosuria, generalized aminoaciduria, and phosphaturia (Fanconi syndrome). With a low plasma [HCO3−], the urine pH is acid (pH < 5.5). The fractional excretion of [HCO3−] may exceed 10–15% when the serum HCO3− > 20 mmol/L. Because HCO3− is not reabsorbed normally in the proximal tubule, therapy with NaHCO3
will enhance renal potassium wasting and hypokalemia.
The typical findings in acquired or inherited forms of classic distal RTA (type 1 RTA) include hypokalemia, non-AG metabolic acidosis, low urinary NH4+ excretion (positive UAG, low urine [NH4+]), and inappropriately high urine pH (pH > 5.5). Most patients have hypocitraturia and hypercalciuria, so nephrolithiasis, nephrocalcinosis, and bone disease are common. In generalized distal nephron dysfunction (type 4 RTA), hyperkalemia is disproportionate to the reduction in GFR because of coexisting dysfunction of potassium and acid secretion. Urinary ammonium excretion is invariably depressed, and renal function may be compromised, for example, due to diabetic nephropathy, obstructive uropathy, or chronic tubulointerstitial disease.
Hyporeninemic hypoaldosteronism typically causes non-AG metabolic acidosis, most commonly in older adults with diabetes mellitus or tubulointerstitial disease and renal insufficiency. Patients usually have mild to moderate CKD (GFR, 20–50 mL/min) and acidosis, with elevation in serum [K+] (5.2–6.0 mmol/L), concurrent hypertension, and congestive heart failure. Both the metabolic acidosis and the hyperkalemia are out of proportion to impairment in GFR. Nonsteroidal anti-inflammatory drugs, trimethoprim, pentamidine, and angiotensin-converting enzyme (ACE) inhibitors can also cause non-AG metabolic acidosis in patients with renal insufficiency (Table 47-5).