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Quiz Page October 2013
QUIZ PAGE OCTOBER 2013 When Things Are Not as They Seem: A Woman With Anion Gap Metabolic Acidosis After Ingesting Antifreeze CLINICAL PRESENTATION A 34-year-old woman with a history of depression presented to the emergency department after drinking ¾ of a gallon of antifreeze over 2 days in a suicide attempt. She reported feeling as if she were “drunk.” She also noted nausea and vomiting. On physical examination, the patient appeared comfortable, alert, and oriented. Temperature was 36.5°C, heart rate was 110 beats/ min, blood pressure was 100/70 mm Hg, respiratory rate was 20 breaths/min, and pulse oximetry was 99% on room air. There was no papilledema. The remainder of
What is the differential diagnosis of the patient’s anion gap metabolic acidosis? What are the clues to the correct diagnosis? How would you treat this patient?
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Am J Kidney Dis. 2013;62(4):xxv-xxviii
the examination had normal findings. Laboratory analysis showed the following values: sodium, 136 mEq/L; potassium, 4.2 mEq/L; chloride, 104 mEq/L; bicarbonate, 17 mEq/L; serum urea nitrogen (SUN), 17 mg/dL; creatinine, 3.0 mg/dL; glucose, 147 mg/dL; corrected anion gap, 18.5; measured serum osmolality, 342 mOsm/ kg; lactate, 9.9 mmol/L; pH 7.27; and PCO2, 36 mm Hg. Urinalysis showed specific gravity of 1.010 and trace protein and was negative for blood and ketones. Sediment evaluation showed 0-2 red blood cells/ high-power field, 0-2 white blood cells/high-power field, rare granular casts, and no crystals.
QUIZ PAGE OCTOBER 2013 ANSWERS DISCUSSION f What is the differential diagnosis of the patient’s anion gap metabolic acidosis? Although the differential diagnosis of anion gap metabolic acidosis is broad (Box 1),1,2 it is important to rapidly diagnose disorders that require prompt treatment to prevent morbidity and mortality. In individuals who present with altered sensorium or who report ingestions, the clinician must consider consumption of a toxic alcohol.3 These agents are rapidly absorbed from the gastrointestinal tract and initially will increase serum osmolality. Their presence can be ascertained quickly by measuring the osmolar gap: the difference between measured osmolality and calculated osmolality. Calculated osmolality is determined by multiplying the major extracellular cation, sodium (Na) ion, by 2 and converting the predominant extracellular solutes, glucose and SUN, from their traditionally reported units (mg/dL) to mOsm/kg by dividing by 1/10 their molecular weight (2 ⫻ Na ⫹ Glucose/18 ⫹ SUN/2.8). In
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Box 1. Causes of Anion Gap Metabolic Acidosis Glycols Oxoproline L-Lactate D-Lactate Methanol Aspirin Renal failure Ketones Source: Mehta et al.1 xxvi
Figure 1. Metabolism of propylene glycol.
this case, the osmolar gap is 56. A gap greater than 15 suggests the presence of a small-molecularweight substance. Ethanol and isopropyl alcohol ingestions will present with an osmolar gap but do not cause metabolic acidosis. However, because isopropyl alcohol is metabolized to acetone, ketones may be noted if the nitroprusside reaction is used. Three alcohols, methanol, ethylene glycol, and propylene glycol, are associated with both an osmolar gap and an anion gap metabolic acidosis. Ethylene glycol and methanol are highly toxic. As these 2 alcohols are metabolized into glycolic/oxalic acid and formic acid, respectively, the osmolar gap will decrease while the anion gap increases. Propylene glycol, used to solubilize numerous medications, is metabolized to lactic acid and is an increasingly recognized cause of anion gap acidosis (Fig 1).4,5 Medications using this diluent, such as benzodiazepines, if infused rap-
idly enough can cause an osmolar gap and lactic acidosis.4,6 f What are the clues to the correct diagnosis? There are several clues to the correct diagnosis in this case (Table 1). Both ethylene glycol and methanol are extremely toxic, with 1 mL/kg usually resulting in death. Even if exaggerated, the quantity the patient claimed to have ingested should have been rapidly fatal. Methanol ingestion is associated with visual disturbances through inflammation of the optic nerve, which was not noted. The lack of oxalate crystals in the urine makes ethylene glycol toxicity less likely. Finally, although lactic acidosis can be seen in cases of ethylene glycol toxicity, the level present in this case would be very unusual. Although propylene glycol toxicity is most often noted in hospitalized patients receiving intravenous medications, there has been an increase in the use of propylAm J Kidney Dis. 2013;62(4):xxv-xxviii
Table 1. Clues to the Diagnosis of a Toxic Alcohol Ingestion
Ethanol
Osmolal gap Anion gap metabolic acidosis Lactate Physical clues
Other laboratory clues Source
Isopropyl Alcohol
Methanol
Ethylene Glycol
Propylene Glycol
⫹⫹⫹ ⫺
⫹⫹⫹ ⫺
⫹⫹⫹ ⫹⫹⫹
⫹⫹⫹ ⫹⫹⫹
⫹⫹⫹ ⫹⫹⫹
⫺ Altered mental status
⫺ Altered mental status ⫹ Acetone
⫺ Altered mental status, visual disturbance, papillitis
⫹ Altered mental status
⫹⫹ Altered mental status
Rubbing alcohol
Wood alcohol
ene glycol as a substitute for ethylene glycol in commercial antifreeze because of its relative lack of toxicity. These agents are advertised as being pet friendly and less toxic. The US Food and Drug Administration considers pharmaceutical-grade propylene glycol as generally safe.7 However, prolonged high-dose infusions of medications containing propylene glycol can produce signifi-
Oxalate crystals in urine sediment Antifreeze
cant lactic acidosis through its metabolism.5 Although no lethal dose has been established in humans, in animals, the LD50 is 18-20 mL/kg. Two days after admission, this patient’s initial ethylene glycol level returned as undetectable and family members brought in the ingested substance, Sierra antifreeze (Safe Brands Corp), containing 94% propylene glycol (Fig 2).
Solvent for numerous medications; antifreeze
f How would you treat this patient? Toxic alcohol ingestions need to be treated rapidly to avoid toxicity. Often treatment must start prior to confirmation of the substance ingested. Because the toxicity of these alcohols is mediated by their metabolites, treatment is aimed at blocking their enzymatic conversion by alcohol dehydrogenase. This is accomplished by the administration of fomepizole, a potent inhibitor of alcohol dehydrogenase. Dialysis then can be considered to remove the alcohol and treat the acidosis. Propylene glycol is far less toxic than ethylene glycol. Toxicity usually manifests as confusion and kidney failure. Although deaths from propylene glycol toxicity are extremely rare, fomepizole has been used in treatment. Although in retrospect ethylene glycol toxicity was unlikely, in view of the morbidity associated with its ingestion, this woman was treated with fomepizole.
FINAL DIAGNOSIS
Am J Kidney Dis. 2013;62(4):xxv-xxviii
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Figure 2. Sierra antifreeze.
Anion gap metabolic acidosis caused by ingestion of a large quantity of propylene glycol.
ACKNOWLEDGEMENTS The authors thank Dr Keith Boesen for assistance in this case.
REFERENCES
QUIZ PAGE
1. Mehta AN, Emmett JB, Emmett M. GOLD MARK: an anion gap mnemonic for the 21st century. Lancet. 2008;372(9642):892. 2. Gabow PA. Disorders associated with an altered anion gap. Kidney Int. 1985;27(2):472-483. 3. Kraut JA, Kurtz I. Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin J Am Soc Nephrol. 2008;3(1):208-225. 4. Miller ON, Bazzano G. Propanediol metabolism and its relation to lactic acid metabolism. Ann N Y Acad Sci. 1965;119(3):957-973.
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5. Zosel A, Egelhoff E, Heard K. Severe lactic acidosis after an iatrogenic propylene glycol overdose. Pharmacotherapy. 2010;30(2): 219. 6. Horinek EL, Kiser TH, Fish DN, MacLaren R. Propylene glycol accumulation in critically ill patients receiving continuous intravenous lorazepam infusions. Ann Pharmacother. 2009;43(12):1964-1971. 7. Food and Drug Adminstration. GRAS status of propylene glycol and propylene glycol monostearate. Fed Regist. 1982;47:27812. CASE PROVIDED AND AUTHORED BY Aswani Alavala, MD,1 Elizabeth Ulliman, MD,1 Mazda Shirazi,
MD,2 and Harold M. Szerlip, MD,1 Departments of 1Internal Medicine and 2Emergency Medicine, University of Arizona College of Medicine, Tucson, AZ. Address correspondence to Harold M. Szerlip, MD, 3950 S Country Club Rd, Ste 200, Tucson, AZ 85714. E-mail: hszerlip@ deptofmed.arizona.edu © 2013 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd. 2013.04.026 SUPPORT: None. FINANCIAL DISCLOSURE: The authors declare that they have no relevant financial interests.
Am J Kidney Dis. 2013;62(4):xxv-xxviii
What is the differential diagnosis of the patient’s anion gap metabolic acidosis? What are the clues to the correct diagnosis? How would you treat this patient?
xxv
QUIZ PAGE
Am J Kidney Dis. 2013;62(4):xxv-xxviii
the examination had normal findings. Laboratory analysis showed the following values: sodium, 136 mEq/L; potassium, 4.2 mEq/L; chloride, 104 mEq/L; bicarbonate, 17 mEq/L; serum urea nitrogen (SUN), 17 mg/dL; creatinine, 3.0 mg/dL; glucose, 147 mg/dL; corrected anion gap, 18.5; measured serum osmolality, 342 mOsm/ kg; lactate, 9.9 mmol/L; pH 7.27; and PCO2, 36 mm Hg. Urinalysis showed specific gravity of 1.010 and trace protein and was negative for blood and ketones. Sediment evaluation showed 0-2 red blood cells/ high-power field, 0-2 white blood cells/high-power field, rare granular casts, and no crystals.
QUIZ PAGE OCTOBER 2013 ANSWERS DISCUSSION f What is the differential diagnosis of the patient’s anion gap metabolic acidosis? Although the differential diagnosis of anion gap metabolic acidosis is broad (Box 1),1,2 it is important to rapidly diagnose disorders that require prompt treatment to prevent morbidity and mortality. In individuals who present with altered sensorium or who report ingestions, the clinician must consider consumption of a toxic alcohol.3 These agents are rapidly absorbed from the gastrointestinal tract and initially will increase serum osmolality. Their presence can be ascertained quickly by measuring the osmolar gap: the difference between measured osmolality and calculated osmolality. Calculated osmolality is determined by multiplying the major extracellular cation, sodium (Na) ion, by 2 and converting the predominant extracellular solutes, glucose and SUN, from their traditionally reported units (mg/dL) to mOsm/kg by dividing by 1/10 their molecular weight (2 ⫻ Na ⫹ Glucose/18 ⫹ SUN/2.8). In
QUIZ PAGE
Box 1. Causes of Anion Gap Metabolic Acidosis Glycols Oxoproline L-Lactate D-Lactate Methanol Aspirin Renal failure Ketones Source: Mehta et al.1 xxvi
Figure 1. Metabolism of propylene glycol.
this case, the osmolar gap is 56. A gap greater than 15 suggests the presence of a small-molecularweight substance. Ethanol and isopropyl alcohol ingestions will present with an osmolar gap but do not cause metabolic acidosis. However, because isopropyl alcohol is metabolized to acetone, ketones may be noted if the nitroprusside reaction is used. Three alcohols, methanol, ethylene glycol, and propylene glycol, are associated with both an osmolar gap and an anion gap metabolic acidosis. Ethylene glycol and methanol are highly toxic. As these 2 alcohols are metabolized into glycolic/oxalic acid and formic acid, respectively, the osmolar gap will decrease while the anion gap increases. Propylene glycol, used to solubilize numerous medications, is metabolized to lactic acid and is an increasingly recognized cause of anion gap acidosis (Fig 1).4,5 Medications using this diluent, such as benzodiazepines, if infused rap-
idly enough can cause an osmolar gap and lactic acidosis.4,6 f What are the clues to the correct diagnosis? There are several clues to the correct diagnosis in this case (Table 1). Both ethylene glycol and methanol are extremely toxic, with 1 mL/kg usually resulting in death. Even if exaggerated, the quantity the patient claimed to have ingested should have been rapidly fatal. Methanol ingestion is associated with visual disturbances through inflammation of the optic nerve, which was not noted. The lack of oxalate crystals in the urine makes ethylene glycol toxicity less likely. Finally, although lactic acidosis can be seen in cases of ethylene glycol toxicity, the level present in this case would be very unusual. Although propylene glycol toxicity is most often noted in hospitalized patients receiving intravenous medications, there has been an increase in the use of propylAm J Kidney Dis. 2013;62(4):xxv-xxviii
Table 1. Clues to the Diagnosis of a Toxic Alcohol Ingestion
Ethanol
Osmolal gap Anion gap metabolic acidosis Lactate Physical clues
Other laboratory clues Source
Isopropyl Alcohol
Methanol
Ethylene Glycol
Propylene Glycol
⫹⫹⫹ ⫺
⫹⫹⫹ ⫺
⫹⫹⫹ ⫹⫹⫹
⫹⫹⫹ ⫹⫹⫹
⫹⫹⫹ ⫹⫹⫹
⫺ Altered mental status
⫺ Altered mental status ⫹ Acetone
⫺ Altered mental status, visual disturbance, papillitis
⫹ Altered mental status
⫹⫹ Altered mental status
Rubbing alcohol
Wood alcohol
ene glycol as a substitute for ethylene glycol in commercial antifreeze because of its relative lack of toxicity. These agents are advertised as being pet friendly and less toxic. The US Food and Drug Administration considers pharmaceutical-grade propylene glycol as generally safe.7 However, prolonged high-dose infusions of medications containing propylene glycol can produce signifi-
Oxalate crystals in urine sediment Antifreeze
cant lactic acidosis through its metabolism.5 Although no lethal dose has been established in humans, in animals, the LD50 is 18-20 mL/kg. Two days after admission, this patient’s initial ethylene glycol level returned as undetectable and family members brought in the ingested substance, Sierra antifreeze (Safe Brands Corp), containing 94% propylene glycol (Fig 2).
Solvent for numerous medications; antifreeze
f How would you treat this patient? Toxic alcohol ingestions need to be treated rapidly to avoid toxicity. Often treatment must start prior to confirmation of the substance ingested. Because the toxicity of these alcohols is mediated by their metabolites, treatment is aimed at blocking their enzymatic conversion by alcohol dehydrogenase. This is accomplished by the administration of fomepizole, a potent inhibitor of alcohol dehydrogenase. Dialysis then can be considered to remove the alcohol and treat the acidosis. Propylene glycol is far less toxic than ethylene glycol. Toxicity usually manifests as confusion and kidney failure. Although deaths from propylene glycol toxicity are extremely rare, fomepizole has been used in treatment. Although in retrospect ethylene glycol toxicity was unlikely, in view of the morbidity associated with its ingestion, this woman was treated with fomepizole.
FINAL DIAGNOSIS
Am J Kidney Dis. 2013;62(4):xxv-xxviii
xxvii
QUIZ PAGE
Figure 2. Sierra antifreeze.
Anion gap metabolic acidosis caused by ingestion of a large quantity of propylene glycol.
ACKNOWLEDGEMENTS The authors thank Dr Keith Boesen for assistance in this case.
REFERENCES
QUIZ PAGE
1. Mehta AN, Emmett JB, Emmett M. GOLD MARK: an anion gap mnemonic for the 21st century. Lancet. 2008;372(9642):892. 2. Gabow PA. Disorders associated with an altered anion gap. Kidney Int. 1985;27(2):472-483. 3. Kraut JA, Kurtz I. Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin J Am Soc Nephrol. 2008;3(1):208-225. 4. Miller ON, Bazzano G. Propanediol metabolism and its relation to lactic acid metabolism. Ann N Y Acad Sci. 1965;119(3):957-973.
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5. Zosel A, Egelhoff E, Heard K. Severe lactic acidosis after an iatrogenic propylene glycol overdose. Pharmacotherapy. 2010;30(2): 219. 6. Horinek EL, Kiser TH, Fish DN, MacLaren R. Propylene glycol accumulation in critically ill patients receiving continuous intravenous lorazepam infusions. Ann Pharmacother. 2009;43(12):1964-1971. 7. Food and Drug Adminstration. GRAS status of propylene glycol and propylene glycol monostearate. Fed Regist. 1982;47:27812. CASE PROVIDED AND AUTHORED BY Aswani Alavala, MD,1 Elizabeth Ulliman, MD,1 Mazda Shirazi,
MD,2 and Harold M. Szerlip, MD,1 Departments of 1Internal Medicine and 2Emergency Medicine, University of Arizona College of Medicine, Tucson, AZ. Address correspondence to Harold M. Szerlip, MD, 3950 S Country Club Rd, Ste 200, Tucson, AZ 85714. E-mail: hszerlip@ deptofmed.arizona.edu © 2013 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd. 2013.04.026 SUPPORT: None. FINANCIAL DISCLOSURE: The authors declare that they have no relevant financial interests.
Am J Kidney Dis. 2013;62(4):xxv-xxviii