Correspondence

Severe Hyperosmolar Metabolic Acidosis Due to a Large Dose of Intravenous Lorazepam

N Engl J Med 2002; 346:1253-1254April 18, 2002

Article

To the Editor:

In a 34-year-old woman with a history of alcohol abuse, cardiomyopathy, and AIDS, acute respiratory failure developed as a result of Escherichia coli sepsis and pneumonia. Initial laboratory studies revealed a pH of 7.2, a bicarbonate level of 8.8 mmol per liter, a partial pressure of carbon dioxide of 26 mm Hg, an anion gap of 15.4 mmol per liter, a lactate level of 6.9 mmol per liter, and a creatinine level of 1.8 mg per deciliter, with a normal blood sugar level and no ketones.

After four days of treatment, the patient's acidosis was worse (pH, 6.9; bicarbonate level, 6.2 mmol per liter; anion gap, 17.8 mmol per liter), despite a slow improvement in the lactate level (to 4.5 mmol per liter). The serum osmolality was 462 mOsm per liter with an osmolal gap of 165 mOsm per liter. Standard blood tests for methanol, ethylene glycol, and isopropyl alcohol were negative. It was noted that the woman was being sedated with increasing doses of intravenous lorazepam (up to 30 mg per hour), which contained 0.18 ml of polyethylene glycol–400 (PEG-400) in propylene glycol with 2 percent benzyl alcohol per 2-mg vial. She had received 1696 mg of lorazepam in 78 hours, for a cumulative PEG-400 dose of 153 ml. Despite treatment with fomepizole, a polyethylene glycol antagonist that is administered intravenously, she required hemodialysis. After three hemodialysis sessions, the patient's pH and bicarbonate level had improved (7.37 and 26 mmol per liter, respectively), and her osmolal gap had decreased to 40 mOsm per liter. She was discharged after 26 days in the hospital. Her renal function was stable; the creatinine level was 1.7 mg per deciliter. It should be noted that our laboratory was unable to quantify the levels of PEG-400, its metabolites, or benzyl alcohol.

Polyethylene glycol is oxidized by alcohol dehydrogenase to hydroxy acid and diacid metabolites, possibly contributing to the development of metabolic acidosis.1 In previous reports polyethylene glycol has been implicated in hyperosmolar states,2,3 acute renal failure,3-5 and mild metabolic acidosis3,4 due to the topical or intravenous use of various drugs, including lorazepam.5 Although our patient had preexisting metabolic anion-gap acidosis, we believe that the large dose of intravenous lorazepam that she received contributed to the development of severe, hyperosmolar metabolic acidosis.

Jean Tayar, M.D.
George Jabbour, M.D.
Subodh J. Saggi, M.D.
Staten Island University Hospital, Staten Island, NY 10305
jtayar@yahoo.com

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   Jason A Yahwak, Richard R Riker, Gilles L Fraser, Sarah Subak-Sharpe. (2008) Determination of a Lorazepam Dose Threshold for Using the Osmol Gap to Monitor for Propylene Glycol Toxicity. Pharmacotherapy 28:8, 984-991
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   Tausif Zar, Charles Graeber, Mark A. Perazella. (2007) Reviews: Recognition, Treatment, and Prevention of Propylene Glycol Toxicity. Seminars in Dialysis 20:3, 217-219
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   Douglas D DeCarolis, Kathryn L Rice, Libin Ho, Mark L Willenbring, Susan Cassaro. (2007) Symptom-Driven Lorazepam Protocol for Treatment of Severe Alcohol Withdrawal Delirium in the Intensive Care Unit. Pharmacotherapy 27:4, 510-518
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