Correspondence

Hyperosmolar Metabolic Acidosis and Intravenous Lorazepam

N Engl J Med 2002; 347:857-858September 12, 2002

Article

To the Editor:

In their letter about a patient with severe hyperosmolar metabolic acidosis due to a large dose of intravenous lorazepam (April 18 issue),1 Tayar et al. err in attributing the observed acidosis and osmolarity to polyethylene glycol and overlook the greater contribution of propylene glycol. Each milliliter of Ativan injection (2 mg of lorazepam per milliliter, Wyeth–Ayerst Laboratories) contains 0.8 ml of propylene glycol.2 We calculate that the cumulative lorazepam dose of 1696 mg would include 704 g or 678 ml of propylene glycol (molecular weight, 76) in addition to the 153 ml of polyethylene glycol (mean molecular weight, 400) noted by Tayar et al. In any dose of parenteral lorazepam, propylene glycol contributes nearly 23 times as many osmotically active particles as polyethylene glycol.

Propylene glycol (1,2-propanediol) undergoes oxidation to lactate and pyruvate, which can also contribute to the persistent lactic acidosis described. The association of propylene glycol in lorazepam and other drugs with lactic acidosis, hyperosmolarity, and renal failure has been described in case reports.3-5 Tayar et al. also describe fomepizole as “a polyethylene glycol antagonist.” Fomepizole is a potent inhibitor of alcohol dehydrogenase that is used in treating ethylene glycol poisoning and methanol poisoning. However, there is no clear indication for using fomepizole in a patient with suspected exposure to either polyethylene glycol or propylene glycol. To the extent that the lorazepam infusion contributed to the hyperosmolar metabolic acidosis in this case, propylene glycol had a much greater role than polyethylene glycol.

Michael E. Mullins, M.D.
Washington University School of Medicine, St. Louis, MO 63110
mullinsm@msnotes.wustl.edu

Brian J. Barnes, Pharm.D.
Barnes–Jewish Hospital, St. Louis, MO 63110

5 References

1. 1

   Tayar J, Jabbour G, Saggi SJ. Severe hyperosmolar metabolic acidosis due to a large dose of intravenous lorazepam. N Engl J Med 2002;346:1253-1254
   Full Text | Web of Science | Medline

2. 2

   Toxicity of propylene glycol in Ativan injection. Philadelphia: Wyeth–Ayerst Pharmaceuticals, November 1998 (package insert).
   

3. 3

   Arbour RB. Propylene glycol toxicity related to high-dose lorazepam infusion: case report and discussion. Am J Crit Care 1999;8:499-506
   Medline

4. 4

   Cawley MJ. Short-term lorazepam infusion and concern for propylene glycol toxicity: case report and review. Pharmacotherapy 2001;21:1140-1144
   CrossRef | Web of Science | Medline

5. 5

   Reynolds HN, Teiken P, Regan ME, et al. Hyperlactatemia, increased osmolar gap, and renal dysfunction during continuous lorazepam infusion. Crit Care Med 2000;28:1631-1634
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Although we agree with the calculations of Mullins and Barnes, we did not overlook the role of propylene glycol. Propylene glycol is in fact metabolized to lactic and pyruvic acid, and its association with hyperosmolarity and lactic acidosis has been described in previous reports. In our patient, however, the lactate levels were decreasing while the patient was still receiving a large dose of lorazepam and had a rapidly increasing osmolar gap (up to 165 mOsm per liter). Furthermore, blood tests for propylene glycol and pyruvate were negative. These findings contrast with those of Arbour and Esparis, whose patient had new-onset lactic acidosis after a lorazepam infusion was begun and had high propylene glycol and pyruvate levels.1 Reynolds et al. found that the rise and fall of the serum lactate level and osmolality (which they attributed to propylene glycol) were closely correlated with the lorazepam infusion.2 Although the use of fomepizole seemed reasonable under the circumstances, we agree that there is no clear indication for its use in polyethylene glycol or propylene glycol intoxication.

Jean Tayar, M.D.
Subodh J. Saggi, M.D.
Staten Island University Hospital, Staten Island, NY 10305

2 References

1. 1

   Arbour R, Esparis B. Osmolar gap metabolic acidosis in a 60-year-old man treated for hypoxemic respiratory failure. Chest 2000;118:545-546
   CrossRef | Web of Science | Medline

2. 2

   Reynolds HN, Teiken P, Regan ME, et al. Hyperlactatemia, increased osmolar gap, and renal dysfunction during continuous lorazepam infusion. Crit Care Med 2000;28:1631-1634
   CrossRef | Web of Science | Medline

Citing Articles (6)

Citing Articles

1. 1

   Jean-Sebastien Rachoin, Lawrence S. Weisberg, Christopher B. McFadden. (2010) Treatment of lactic acidosis: Appropriate confusion. Journal of Hospital Medicine 5:4, E1-E7
   CrossRef

2. 2

   Arjunan Ganesh, Paul Audu. (2008) Hyperosmolar, increased-anion-gap metabolic acidosis and hyperglycemia after etomidate infusion. Journal of Clinical Anesthesia 20:4, 290-293
   CrossRef

3. 3

   Genaro Valladolid, Joseph Varon. (2008) Etomidate infusion: a cause of hyperglycemia?. Journal of Clinical Anesthesia 20:4, 245-246
   CrossRef

4. 4

   Tausif Zar, Irfan Yusufzai, Anna Sullivan, Charles Graeber. (2007) Acute kidney injury, hyperosmolality and metabolic acidosis associated with lorazepam. Nature Clinical Practice Nephrology 3:9, 515-520
   CrossRef

5. 5

   Tausif Zar, Charles Graeber, Mark A. Perazella. (2007) Reviews: Recognition, Treatment, and Prevention of Propylene Glycol Toxicity. Seminars in Dialysis 20:3, 217-219
   CrossRef

6. 6

   Ndidi E. Yaucher, Jeffrey T. Fish, Heidi W. Smith, Jeffrey A. Wells. (2003) Propylene Glycol–Associated Renal Toxicity from Lorazepam Infusion. Pharmacotherapy 23:9, 1094-1099
   CrossRef