Correspondence

Case 24-2006: A Woman with Hypotension after an Overdose of Amlodipine

N Engl J Med 2006; 355:1936-1938November 2, 2006

Article

To the Editor:

In the Case Record presented in the August 10 issue,1 which describes the management of an overdose of amlodipine, Harris cites Kline et al.2 and states that “data from studies in animals and humans support the administration of insulin while maintaining normal blood glucose levels (hyperinsulinemia–euglycemia therapy) as first-line therapy in poisoning with calcium-channel blockers.” Kline et al. reported the effects of this therapy in canines only and concluded that, as compared with glucagon, calcium chloride, or epinephrine, hyperinsulinemia–euglycemia therapy prolonged survival. In humans, however, this therapy has been reported to be successful only in single cases and case series, and these reports have recommended that it be used as an adjunct to conventional therapy.3 Furthermore, the guidelines provided in Table 4 of the Case Record are mere proposals.3 In a review of the literature, Shepherd and Klein-Schwartz4 noted that there had been 13 published cases of hyperinsulinemia–euglycemia therapy for overdoses of calcium-channel blockers in humans and that no data from clinical trials were available. We agree that on the basis of animal models and preliminary data, hyperinsulinemia–euglycemia therapy appears to be a promising option in patients with life-threatening calcium-channel blocker overdose, but we think that it is premature to call this investigational and emerging therapy the first line of treatment until data from prospective clinical trials are available.

Charu Aggarwal, M.B., M.P.H.
Sameer Gupta, M.B., M.P.H.
State University of New York at Buffalo, Buffalo, NY 14215
sgupta5@buffalo.edu

4 References

1. 1

   Case Records of the Massachusetts General Hospital (Case 24-2006). N Engl J Med 2006;355:602-611
   Full Text | Web of Science | Medline

2. 2

   Kline JA, Leonova E, Raymond RM. Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine. Crit Care Med 1995;23:1251-1263
   CrossRef | Web of Science | Medline

3. 3

   Boyer EW, Duic PA, Evans A. Hyperinsulinemia/euglycemia therapy for calcium channel blocker poisoning. Pediatr Emerg Care 2002;18:36-37
   CrossRef | Web of Science | Medline

4. 4

   Shepherd G, Klein-Schwartz W. High-dose insulin therapy for calcium-channel blocker overdose. Ann Pharmacother 2005;39:923-930
   CrossRef | Web of Science | Medline

To the Editor:

Harris provides an excellent overview of the toxic effects of calcium-channel blockers. However, he concludes that “suspected cardiac glycoside poisoning is an important contraindication to empirical calcium therapy [for hyperkalemia],” citing a single and controversial reference from 1936.1 In fact, data that provide support for this contraindication are largely theoretical and extrapolated from older studies in animal models. Many of these older studies have design flaws that are unacceptable according to current standards.

Alternatively, recent reports of studies in both animals and humans indicate that intravenous calcium can be administered for hyperkalemia in patients with digoxin toxicity, without adverse events or an increased risk of death.2,3 Since hyperkalemia-associated arrhythmias may need to be treated before the results of testing for serum digoxin levels are known, the risk of causing a “stone heart” should not preclude the judicious, empirical use of intravenous calcium.4 The risk of arrhythmias associated with the use of intravenous calcium in this setting may be decreased with longer infusion times.4,5

Christian P. Erickson, M.D., M.P.H.
University of California, San Francisco, San Francisco, CA 94131
cerickson@medsfgh.ucsf.edu

5 References

1. 1

   Bower JO, Mengle HAK. The additive effects of calcium and digitalis: a warning with a report of two deaths. JAMA 1936;106:1151-1153
   Web of Science

2. 2

   Hack JB, Woody JH, Lewis DE, Brewer K, Meggs WJ. The effect of calcium chloride in treating hyperkalemia due to acute digoxin toxicity in a porcine model. J Toxicol Clin Toxicol 2004;42:337-342
   CrossRef | Medline

3. 3

   Van Deusen SK, Birkhahn RH, Gaeta TJ. Treatment of hyperkalemia in a patient with unrecognized digitalis toxicity. J Toxicol Clin Toxicol 2003;41:373-376
   CrossRef | Medline

4. 4

   Evans KJ, Greenberg A. Hyperkalemia: a review. J Intensive Care Med 2005;20:272-290
   CrossRef | Medline

5. 5

   Olson KR, Anderson IB, Benowitz NL, et al., eds. Poisoning and drug overdose. 5th ed. New York: McGraw-Hill (in press).
   

To the Editor:

In his case report of an overdose of amlodipine, Harris states that whole-bowel irrigation is “a reasonable intervention” in the management of an overdose of a calcium-channel blocker. The references cited in support of that statement are troublesome. The first reference is to a case series in which whole-bowel irrigation was recommended regardless of the patient's cardiovascular status.1 The second reference is to a position statement on cathartics that does not address the use of whole-bowel irrigation.2 The actual position statement regarding whole-bowel irrigation clearly states that hemodynamic instability is a contraindication to this method.3 Our group's experience as clinical toxicologists has shown that whole-bowel irrigation is detrimental in cases in which hemodynamic instability is present or impending.4 We caution readers on the use of whole-bowel irrigation in settings in which gastrointestinal perfusion may become compromised.

Trevonne M. Thompson, M.D.
Sean M. Bryant, M.D.
Jenny J. Lu, M.D.
Toxikon Consortium, Chicago, IL 60612
tthomps@uic.edu

4 References

1. 1

   Buckley N, Dawson AH, Howarth D, Whyte IM. Slow-release verapamil poisoning: use of polyethylene glycol whole-bowel lavage and high-dose calcium. Med J Aust 1993;158:202-204
   Web of Science | Medline

2. 2

   Position paper: cathartics. J Toxicol Clin Toxicol 2004;42:243-253[Erratum, J Toxicol Clin Toxicol 2004;42:1000.]
   CrossRef | Medline

3. 3

   Position paper: whole bowel irrigation. J Toxicol Clin Toxicol 2004;42:843-854[Erratum, J Toxicol Clin Toxicol 2004;42:1000.]
   CrossRef | Medline

4. 4

   Cumpston K, Manzanares M, Pallasch E, Sigg T, Aks S. Hypotension complicating whole bowel irrigation in diltiazem overdose. J Toxicol Clin Toxicol 2002;40:616-617
   

Author/Editor Response

Aggarwal and Gupta state, “it is premature to call this investigational and emerging therapy [hyperinsulinemia–euglycemia] the first line of treatment until data from prospective clinical trials are available.” New therapies should not be adopted lightly. However, a review of the data from studies in animals and humans to date, when placed in the context of the potential lethality of an overdose of calcium-channel blockers and the dearth of other effective therapies, provides support for early and active consideration of hyperinsulinemia–euglycemia until definitive studies are completed.

Erickson expresses concern about the role of empirical calcium therapy. The 1936 article by Bower and Mengle is not a model of empirical rectitude, but rather is cited as the seminal report that called attention to what remains prudent clinical practice. Erickson cites the isolated data from a study in pigs and the single case report of a patient who received intravenous calcium therapy for the toxic effects of digoxin. These reports are interesting, but ultimately they are not fully persuasive.1 Given the limited data available and the potentially devastating side effects, the longstanding hesitancy about administering calcium in patients with a potential digoxin overdose should not be cast aside lightly.2

Thompson et al. “caution readers on the use of whole-bowel irrigation in settings in which gastrointestinal perfusion may become compromised” and cite a single abstract from a study on the use of this method in humans.3 One can certainly agree that whole-bowel irrigation is unlikely to prove effective in patients with major hemodynamic compromise. However, in patients who have taken a large overdose of calcium-channel blockers, especially of extended-release preparations, minimizing absorption as early as possible is critical for avoiding hemodynamic compromise. Overly broad cautions against the use of whole-bowel irrigation in patients in whom hemodynamic instability is even impending could paradoxically limit the use of this method to those in whom a clinically significant overdose is not suspected.

Although clinical practice may vary when data are sparse, a reasonable rendering of expert clinical opinion on this topic can be found in the 2006 edition of Goldfrank's Toxicologic Emergencies: “Because of the significant lethality of large ingestions of sustained-release calcium channel blockers, it is imperative to make gastrointestinal decontamination with whole-bowel irrigation a high priority.”4

Clinical toxicologists are given the difficult charge of managing acute clinical cases for which the scope of and prospects for carefully controlled prospective trials are limited. This ongoing discussion honors these physicians and their work.

N. Stuart Harris, M.D., M.F.A.
Peter J. Fagenholz, M.D.
Massachusetts General Hospital, Boston, MA 02114
nsharris@partners.org

4 References

1. 1

   Van Deusen SK, Birkhahn RH, Gaeta TJ. Treatment of hyperkalemia in a patient with unrecognized digitalis toxicity. J Toxicol Clin Toxicol 2003;41:373-376
   CrossRef | Medline

2. 2

   Hoffman RS. What to do with case reports: is folly that succeeds folly nonetheless? J Toxicol Clin Toxicol 2003;41:377-379
   CrossRef | Medline

3. 3

   Cumpston K, Manzanares M, Pallasch E, Sigg T, Aks S. Hypotension complicating whole bowel irrigation in diltiazem overdose. J Toxicol Clin Toxicol 2002;40:616-617
   

4. 4

   DeRoos F. Calcium channel blockers. In: Flomenbaum NE, Goldfrank LE, Hoffman RS, Howland MA, Lewin NA, Nelson LS, eds. Goldfrank's toxicologic emergencies. 8th ed. New York: McGraw-Hill, 2006:920.