Correspondence

Case 7-2006: A Man with Altered Mental Status and Acute Renal Failure

N Engl J Med 2006; 354:2727-2729June 22, 2006

Article

To the Editor:

As clinical toxicologists, we recommend a few additions and corrections to the causes of anion-gap metabolic acidosis that are listed in the case of ethylene glycol poisoning described by Takayesu et al. (March 9 issue).1 Propylene glycol, which is used as a diluent in many medications, including lorazepam, is metabolized to lactate, and patients with propylene glycol toxicity can present with elevated anion gaps as well as osmolal gaps.2 Massive ingestions of analgesics (e.g., acetaminophen and nonsteroidal antiinflammatory drugs) may produce anion-gap acidosis.3,4 Salicylates, mentioned as a cause of anion-gap metabolic acidosis in both Table 2 and the text of the article, are not cytochrome poisons; they uncouple oxidative phosphorylation by inhibiting an ATPase.5 It is noteworthy that the majority of the causes of anion-gap metabolic acidosis discussed were toxins or toxin-related.

Gerald Maloney, Jr., D.O.
Trevonne Thompson, M.D.
Mark Mycyk, M.D.
John Stroger Hospital of Cook County, Chicago, IL 60612
gmaloney@ccbh.org

5 References

1
Case Records of the Massachusetts General Hospital (Case 7-2006). N Engl J Med 2006;354:1065-1072
Full Text | Web of Science | Medline

2
Arbour RB. Propylene glycol toxicity related to high-dose lorazepam infusion: case report and discussion. Am J Crit Care 1999;8:499-506
Medline

3
Koulouris Z, Tierney MG, Jones G. Metabolic acidosis and coma following a severe acetaminophen overdose. Ann Pharmacother 1999;33:1191-1194
CrossRef | Web of Science | Medline

4
Seifert SA, Bronstein AC, McGuire T. Massive ibuprofen ingestion with survival. J Toxicol Clin Toxicol 2000;38:55-57
CrossRef | Medline

5
Miyahara JT, Karler R. The effect of salicylate on oxidative phosphorylation and respiration of mitochondrial fragments. Biochem J 1965;97:194-198
Web of Science | Medline

To the Editor:

We recently treated a case of ethylene glycol poisoning that was similar to the one described in the Case Records. Our patient presented with severe lactic acidosis (serum lactate, 39 mmol per liter), but the presence of a high osmolal gap (38 mOsm per kilogram of body weight) as well as renal failure and hypocalcemia prompted consideration of ethylene glycol poisoning, which was confirmed analytically.

High serum lactate levels in patients with severe ethylene glycol poisoning may be due to the presence of the ethylene glycol metabolite glycolate, which is misread by some serum chemical analyzers because of its structural similarity to lactate.1,2 In addition, there may be a true rise in serum lactate secondary to the inhibition of the citric acid cycle by the condensation products of glyoxylate.3 The diagnosis of ethylene glycol poisoning may be delayed or missed if not considered within the differential diagnosis of an apparent profound lactic acidosis.

James Geoghegan, M.B., Ch.B.
John P. Bleasdale, M.B., Ch.B.
Sandwell and West Birmingham Hospitals, National Health Service Trust, Birmingham B18 7QH, United Kingdom
james.geoghegan@zoom.co.uk

Sally M. Bradberry, M.B.
National Poisons Information Service, Birmingham B18 7QH, United Kingdom

3 References

1
Woo MY, Greenway DC, Nadler SP, Cardinal P. Artifactual elevation of lactate in ethylene glycol poisoning. J Emerg Med 2003;25:289-293
CrossRef | Web of Science | Medline

2
Lindsay S, Akhtar J, Krenzelok EP, Brooks D. Artifactual elevation of plasma L-lactate in the presence of glycolate -- a potential for misdiagnosis. J Toxicol Clin Toxicol 2003;41:476-476

3
Bachmann E, Golberg L. Reappraisal of the toxicology of ethylene glycol. 3. Mitochondrial effects. Food Cosmet Toxicol 1971;9:39-55
CrossRef | Medline

To the Editor:

Takayesu et al. report a case of severe ethylene glycol intoxication. The patient ingested ethylene glycol at approximately 8 p.m. and was taken to the emergency room approximately seven hours later, where he was found to have a serum creatinine level of 3.8 mg per deciliter. The discussants state that the patient had no history of renal disease and that the elevated creatinine level was due to acute renal failure. However, the initial elevation in serum creatinine is not likely to have been due to ethylene glycol, since acute renal failure associated with ethylene glycol intoxication needs one to three days to develop. Furthermore, serum creatinine levels lag several days behind actual changes in the glomerular filtration rate because the metabolite creatinine accumulates successively.1,2 Therefore, we suggest that the patient's initial creatinine value was predominantly due to preexisting renal disease. Later in the clinical course, ethylene glycol–related acute renal failure was manifested by the sharp increase in the creatinine level to 12.6 mg per deciliter on day 8. Patients with preexisting renal damage are highly susceptible to pronounced renal impairment after acute insults.

Roland Schmitt, M.D.
Xiaolei Zhu, M.D., Ph.D.
Shuta Ishibe, M.D.
Yale School of Medicine, New Haven, CT 06520
roland.schmitt@yale.edu

2 References

1
Star RA. Treatment of acute renal failure. Kidney Int 1998;54:1817-1831
CrossRef | Web of Science | Medline

2
Schrier RW, Wang W, Poole B, Mitra A. Acute renal failure: definitions, diagnosis, pathogenesis, and therapy. J Clin Invest 2004;114:5-14[Erratum, J Clin Invest 2004;114:598.]
CrossRef | Web of Science | Medline

Author/Editor Response

We thank Maloney and colleagues for their thoughtful comments regarding other potential causes of anion-gap metabolic acidosis, including intravenous propylene glycol and massive ingestion of acetaminophen or nonsteroidal antiinflammatory agents. Our Table 2 was meant to provide the more common causes of anion-gap metabolic acidosis in patients presenting to the emergency department, rather than be an exhaustive list. Thus, we did not include some of the more unusual causes mentioned by Maloney et al.

Regarding the cause of cellular asphyxia in salicylate overdose, we use the term “cytochrome poison” in reference to the poisoning of the cytochromes within the oxidative phosphorylation chain of the mitochondrial membrane. Miyahara and Karler1 found that salicylate poisoning affected mitochondrial membrane fragments in a fashion similar to that of whole mitochondria. Demonstrating decreased uptake of organic phosphate by mitochondrial membrane fragments exposed to salicylate proved that salicylates inhibited a membrane-based enzyme complex.1 In their article, Miyahara and Karler do not specifically mention ATPase but, rather, suggest that the demonstrated increases in free phosphate were “probably a consequence of the hydrolysis of exogenous ATP.”1 Within the oxidative phosphorylation chain, terminal phosphorylation, associated with cytochrome c, is most sensitive to the uncoupling action of salicylates.2 The action of this cytochrome is essential to the action of ATP synthase and the uptake of free phosphate to form ATP; hence, its poisoning leads to the accumulation of organic phosphate within mitochondria, leading in turn to cellular asphyxia. We regret any confusion caused by our lack of specificity in the discussion of these issues.

We thank Geoghegan and colleagues for their commentary on the cross reactivity of glycolate with lactate in certain serum chemical analyzers. On review of the medical record, we found that our patient did not have a lactate measurement during his evaluation, given the clinical impression of ethylene glycol toxicity.

We agree with Schmitt et al. that on arrival, this patient had an elevated serum creatinine level that was out of proportion to the apparent acuteness of his presentation. His primary care physician has told us that the patient's creatinine level is currently normal. The patient's intent to harm himself by ingesting ethylene glycol raises the possibility of either incorrect estimation of the timing of a single ingestion or multiple ingestions of ethylene glycol.

James Kimo Takayesu, M.D.
Hasan Bazari, M.D.
Michael Linshaw, M.D.
Massachusetts General Hospital, Boston, MA 02114

2 References

1
Miyahara JT, Karler R. The effect of salicylate on oxidative phosphorylation and respiration of mitochondrial fragments. Biochem J 1965;97:194-198
Web of Science | Medline