Hospital Medicine

Metabolic Acidosis; Gap Positive

Metabolic Acidosis; Gap Positive

I. Problem/Condition.

Metabolic acidosis is defined by low serum pH (less than 7.35-7.45) and low serum bicarbonate. It occurs by one of three major mechanisms:

1. Increased endogenous acid (i.e., lactic acidosis, diabetic ketoacidosis).

2. Decreased renal acid excretion (i.e., renal failure).

3. Loss of bicarbonate (i.e. diarrhea).

In determining the underlying etiology for a metabolic acidosis, the serum anion gap must be calculated by subtracting the major measured anions (chloride and bicarbonate) from the major measured cation (sodium).

Serum AG = Na – (Cl + HCO3)

If the result is greater than 12 meq/L (which is the normal value for most laboratories), the acidosis is said to be an anion gap acidosis. The expected anion gap should is lower in hypoalbuminemia and should be corrected - for each decrease of 1gm/dl in albumin, the normal anion gap should be decreased by approximately 2.5 meq/L.

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

Anion gap acidosis can be the result from:

1. A fall in unmeasured cations (as seen in hypomagnesemia or hypocalcemia).

2. A rise in unmeasured anions.

The most common reasons for a rise in anions are ingestions, lactic acidosis, ketoacidosis and renal failure.

Ingestions of multiple different toxins can result in unmeasured anions causing a metabolic gap acidosis. Most commonly salicylate and the alcohols (methanol and ethylene glycol) can lead to severe acidosis. The inhalant toluene may also be a culprit.

Lactic acidosis is the most common cause of an elevated anion gap acidosis in hospitalized patients, occurring with decreased perfusion causing relative tissue ischemia. This leads to increased lactic acid production and impaired renal excretion with resultant acid accumulation (Type A lactic acidosis). Type B lactic acidosis occurs in patients without overt tissue and can be seen in diabetics on metformin, patients with hematologic and solid malignancies, with toxins and drugs that can impair cellular metabolism, and in HIV patients on certain antiretrovirals. Type D lactic acidosis is a rare form that can be seen in patients with short bowel syndrome and bacterial overgrowth leading to increased lactic acid production.

Ketoacidosis is caused by overproduction of ketones such as acetoacetate and beta-hydroxybutyrate due to lack of available glucose for cells to use as fuel. This occurs with insulin deficiency, insulin resistance, starvation, and low glycogen stores. Clinically this is seen in diabetics (most commonly Type 1), alcoholics, and after a prolonged fast.

As the GFR falls in renal failure, metabolic waste products, sulfate, and phosphate ions are retained as the kidney’s ability to excrete these is overcome. Patients with a GFR between 20 and 50 ml/min are more likely to have a hyperchloremic acidosis, whereas patients with a GFR < 20 ml/min are more likely to have a uremic anion gap acidosis.

A common mnemonic, MUDPILES, can be used to remember causes of anion gap metabolic acidosis:

  • Methanol

  • Uremia

  • Diabetic ketoacidosis (also alcoholic ketoacidosis or starvation ketoacidosis)

  • Propylene glycol, paraldehyde

  • Infection, Iron, Isoniazid, Inborn errors of metabolism

  • Lactic acidosis

  • Ethylene glycol, Ethanol

  • Salicylates

This does not include other ingestions that can lead to anion gap acidosis such as:

  • Cyanide – resulting in uncoupled phosphorylation and lactic acidosis.

  • Ibuprofen – resulting in renal failure.

  • Metformin – rarely resulting in lactic acidosis (and usually only in patients with kidney disease).

Another etiology often over-looked is rhabdomyolysis, which causes increased anions such as phosphate to cause an anion-gap acidosis.

B. Describe a diagnostic approach/method to the patient with this problem.

Once a patient has been diagnosed with an elevated gap acidosis, the underlying etiology must be determined. A chemistry panel including calcium and magnesium as well as an albumin level can confirm that the abnormality is due to a rise in unmeasured anions. The next step is to identify the unmeasured anion.

1. Historical information important in the diagnosis of this problem.

All causes of anion gap metabolic acidosis may present with non-specific symptoms such as fatigue, nausea/vomiting, headache and CNS depression.

Ingestions

A thorough history including any substance abuse and possible underlying depression or suicidal ideation should be conducted to help determine the likelihood of ingestion. A history of alcohol abuse increases the probability of ethanol, methanol or ethylene glycol ingestion. Patient report of vision changes can suggest methanol toxicity. Flank pain can suggest ethylene glycol intoxication due to calcium oxalate crystal deposition in the kidneys. Cyanide poisoning can be seen in fire victims, in industrial settings and with prolonged nitroprusside administration. Additional dietary and alternative medication histories should be obtained for unusual exposures.

Lactic Acidosis

Lactic acidosis is suggested by acute illness with concern for organ hypoperfusion, often seen in settings of shock, such as sepsis or heart failure. A history of severe abdominal pain or GI complaints raises concern for gut ischemia leading to lactic acidosis. Other history to consider is metformin ingestion (Type B lactic acidosis) or past medical history to suggest short gut syndrome (Type D lactic acidosis).

Ketoacidosis

A history of diabetes, starvation or alcoholism can suggest ketoacidosis. In the hospitalized setting, prolonged NPO status can lead to a gradual elevation of the anion gap from ketones.

Renal failure

Known chronic kidney disease can suggest renal failure as a possible etiology. Additional history regarding urine output, obstructive uropathy, or history suggestive of decreased renal perfusion should be explored.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

All causes of anion gap metabolic acidosis may present with CNS depression and altered mental status due to the acid base disturbance. Acidosis will lead to increased tidal volume due to respiratory compensation (hyperventilation).

Ingestions

In evaluating a patient for possible ingestions leading to an increased anion gap metabolic acidosis, additional toxidromes should be considered due to the potential for co-ingestions. Specific toxins may lead to additional physical exam findings.

In salicylate toxicity the medullary center is stimulated causing tachypnea. Signs of liver disease (jaundice, spider angiomas, palmar erythema, caput medusa) increase the likelihood of ethanol, methanol or polyethylene glycol ingestions. An eye examination should be performed in suspected toxic alcohol poisoning. An afferent pupillary defect is a sign of advanced methanol toxicity. Other findings include mydriasis, a retinal sheen due to retinal edema, and hyperemia of the optic disk. Ethylene glycol metabolism can lead to cranial nerve palsies and tetany from oxalate induced hypocalcemia. Flushing (classically described as ‘cherry-red’) may be prominent in cyanide toxicity.

Lactic Acidosis

Lactic acidosis will be suggested by evidence of poor systemic perfusion or evidence of infection. In shock, patients will have hypotension along with weak peripheral pulses. In addition, they can have poor urine output, impaired mental status, and either cool, clammy skin (cardiogenic or late septic shock) or flushed and hyperemic skin in early septic shock. Evidence of abdominal tenderness should prompt thorough evaluation for gut ischemia.

Ketoacidosis

In diabetic ketoacidosis, patients acutely present with altered mental status, abdominal pain, and signs of volume depletion. Cachexia or wasting may be evidence of starvation or decreased glycogen stores putting a patient at higher risk for ketoacidosis.

Renal failure

Patients with acidosis due to decreased GFR may demonstrate exam findings of uremia (altered mental status, asterixis, pleural effusions, pericardial friction rubs) or volume overload.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

All patients with a suspected metabolic acidosis should have electrolytes, albumin and an arterial blood gas drawn in the initial diagnosis. A complete metabolic panel including BUN, Cr, calcium, magnesium and glucose should be obtained. Additional laboratory data to identify the underlying cause include a serum lactic acid, beta-hydroxybutyrate (for ketoacids) and a comprehensive toxicology screen. Acetaminophen, salicylate, and ethanol levels should be drawn to evaluate for common ingestants. Creatinine kinase is useful to confirm suspected rhabdomyolysis. An alcohol panel including ethylene glycol and isopropyl alcohol may be sent but generally results will not be available to guide initial treatment decisions.

If infection is suspected, standard infectious work-up including blood and urine cultures should be obtained. Those presenting with abdominal pain should have an abdominal x-ray to evaluate for free air as a consequence of gut ischemia. Additional abdominal imaging may also be indicated.

In suspected ingestions or when severe acidosis is present, plasma osmolarity should be measured to calculate the osmolar gap, which is the difference between measured plasma osmolarity and calculated osmolarity (normally less than 10).

Calculated Posm = (2 x plasma sodium) + (glucose/18) + (BUN/2.8)

A urinalysis should be obtained if renal failure is the underlying diagnosis or if ethylene glycol toxicity (which an lead to hematuria) is suspected. An EKG should be conducted to evaluate for QTc prolongation which can be caused by hypocalcemia from ethylene glycol.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Lactic acidosis, ketoacidosis and renal failure can be confirmed with appropriate laboratory measurement of these anions as well as BUN, creatinine and glucose.

Ingestions

Ingestions represent the most complicated diagnostic group and history is the most important guiding factor. In the presence of known intake of a toxin the diagnosis is clear. For most other causes of anion gap metabolic acidosis the unmeasured anion can be identified. Ethanol and salicylates can easily be confirmed with laboratory testing. However, other alcohols require inference.

Although not specific, a large osmolar gap in the absence of a significant ethanol levels suggests methanol, ethylene glycol, or isopropyl alcohol ingestion. This, in combination with severe acidosis without suggestion of other causes, should be treated as methanol or ethylene glycol ingestion as laboratory alcohol panels will not be available acutely. Supportive eye exam findings can help confirm methanol toxicity and urinary findings can help confirm ethylene glycol toxicity. Similarly, cyanide toxicity must be suspected clinically as laboratory evaluation of cyanide levels will generally not assist with patient care initially. A history of exposure with a severely elevated lactate will suggest the diagnosis.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Alcohol panels and cyanide levels may be drawn but do not contribute to the acute management of the patient with these suspected ingestions. Urinary evaluation for oxalate crystals and fluorescence can be performed in patients with possible ethylene glycol poisoning but these are non-specific tests which add little to the diagnosis.

III. Management while the Diagnostic Process is Proceeding.

A. Management of Clinical Problem Metabolic Acidosis; Gap Positive.

Ingestions

Toxicology assistance should be sought for all serious ingestions. In the United States, Poison Control is available by calling 1-800-222-1222. Supportive therapy, including ensuring adequate airway, breathing, and circulation, must be initiated in any poisoned patient. Gastric decontamination with activated charcoal (AC) should be considered. Salicylates readily bind AC and this should be administered in aspirin toxicity. Alcohols are rapidly absorbed from the GI tract and thus AC is not typically used in their ingestion. Similarly, cyanide is absorbed quickly and thus AC may have limited utility. For all ingestions, the majority of benefit is seen when AC is given within one hour of consumption. AC should not be given to obtunded patients unless an airway is secured.

Alcohols

Patients with severe acidosis, elevated osmolar gap and no obvious unmeasured anion (such as ethanol) should be treated presumptively for methanol and ethylene glycol poisoning. The tenants of therapy include correction of acidosis to prevent the effects of toxic metabolites, alcohol dehydrogenase inhibition (ADH), treatment with enzymatic co-factors, and consideration of hemodialysis in patients with severe acidosis or end-organ damage.

Acidosis correction is accomplished with sodium bicarbonate, given intravenously to maintain a normal serum pH. This can be given as an initial IV bolus followed by a continuous infusion. ADH can be inhibited using either ethanol or fomepezole. If available, fomipezole is the preferred antidote. A loading dose of 15 mg/kg should be administered, followed by doses of 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours thereafter until toxic alcohol levels have been reduced <20 mg/dL, symptoms have resolved, and pH has normalized. If hemodialysis has been initiated the dosing of fomipezole will need to be adjusted. Treatment should also be started with folic acid, thiamine and pyridoxine. This will maximize the non-toxic metabolic pathways for methanol and ethylene glycol. In patients with known ingestions and severe acidemia or end-organ damage, hemodialysis is indicated. Consultation with a nephrologist and toxicologist should be considered with any serious toxic alcohol consumption.

Salicylate

Alkalization of the serum and urine is the mainstay of therapy for salicylate poisoning. Elevated serum pH inhibits salicylates from crossing the blood brain barrier, thus decreasing CNS toxicity. Elevated urine pH enhances salicylate excretion. Sodium bicarbonate should be administered as an IV bolus of 1-2 meq/kg followed by an IV infusion to maintain a urine pH of 7.5-8.0. The respiratory alkalosis seen in patients with salicylate toxicity from the stimulation of the medullary cortex can be protective and is not a contraindication to bicarbonate therapy. Frequent blood gases should be obtained to monitor for severe alkalosis (pH > 7.6).

Cyanide

Cyanide poisoning is rare and can cause a life-threatening acidosis. Antidotes are available and work by three different mechanisms. The first mechanism is direct binding by hydroxycobalamin, which converts cyanide to relatively inert cyanocobalamin. The second mechanism is induction of methemoglobinemia, which can be accomplished by amyl nitrite, sodium nitrite, or dimethylaminophenol. When cyanide binds methemoglobin, cyanomethemoglobin is formed which is less toxic. Induction of methemoglobinemia is contraindicated in patients with carbon monoxide poisoning and thus this should be ruled out prior to therapy. The third type of antidote, sodium thiosulfate, donates sulfur to the enzyme rhodanese which detoxifies cyanide to thiocyanate.

Antidotes are usually administered in combination and the regimen depends on the level of suspicion for cyanide poisoning, the severity of illness, and any concurrent disorder (i.e. carbon monoxide poisoning after a fire). Treatment should be done in consultation with an experienced toxicologist.

Lactic acidosis

Since lactic acidosis most commonly results from impaired tissue perfusion, treatment should be focused on re-establishing adequate organ perfusion. Etiologies of the underperfusion such as sepsis, hypovolemia, or cardiac shock should be investigated and treated appropriately. In Type B lactic acidosis, the culprit toxin should be removed. Type D lactic acidosis involves treating the gut bacterial overgrowth. The use of bicarbonate therapy in lactic acidosis is controversial. Most authors recommend reserving its use for severe lactic acidosis (pH < 7.1), as this degree of acidemia can cause hemodynamic instability by negatively affecting left ventricular contractility, arterial vasodilation, and responsiveness to catecholamines. Exogenous bicarbonate therapy in less severe lactic acidosis has not been shown to be beneficial, and has the potential for harm by increasing pCO2, lactate generation, hypernatremia, extracellular fluid, and decreasing ionized calcium. In less severe lactic acidosis, the underlying etiology should be addressed instead.

Ketoacidosis - See Endocrine.

Renal Failure - See Nephrology.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

If history is unclear or unobtainable, patients with anion gap metabolic acidosis should be managed presumptively based on the suspected cause or causes. Ingestions may be difficult to identify diagnostically due to laboratory delays in obtaining toxic alcohol or cyanide levels. Additionally, they may be masked due to elevated lactate levels which can be seen in ethylene glycol toxicity and are always seen in cyanide toxicity. It is important not to exclude toxic ingestion due to the presence of lactic acidosis.

Plasma osmolar gap is a useful tool to help identify possible methanol or ethylene glycol ingestions. However, this only estimates the parent alcohol levels. Patients presenting late will have metabolized the alcohols and may not have an osmolar gap. Additionally, the osmolar gap is insensitive for identifying small ingestions which may still be clinically significant. Finally, large quantities of ethanol may increase the osmolar gap more than would be predicted making it less accurate.

IV. What’s the evidence?

Dubose, TD, Longo, DL, Fauci, AS, Kasper, DL, Hauser, SL, Jameson, L, Loscalzo, J. "Acidosis and Alkalosis". Harrison’s Online. McGraw-Hill.

Seifter, JL, Goldman, L, Schafer, AI. "Acid-Base Disorders". Goldman’s Cecil Medicine. Saunders. 2012. pp. 741-753.

Boyd, JH, Walley, KR. "Is there a role for sodium bicarbonate in treating lactic acidosis from shock?". Curr Opin Crit Care.. vol. 14. 2008 Aug. pp. 379-83.

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