Correspondence

Cocaine-Associated Myocardial Ischemia

N Engl J Med 1996; 334:535-537February 22, 1996

Article

To the Editor:

The review article (Nov. 9 issue)1 by Dr. Hollander entitled “The Management of Cocaine-Associated Myocardial Ischemia” needs some clarification. First, it suggests that cocaine blocks the “reuptake of . . . excitatory amino acids” in addition to its well-established inhibitory effect on the reuptake of catecholamines. Are there any published studies demonstrating the inhibitory effect of cocaine on the reuptake of excitatory amino acids? Obviously, this would be an extremely important finding with drastic pathophysiologic and therapeutic implications. Is the suggested inhibitory effect of cocaine on the reuptake of excitatory amino acids the author's personal observation, or is it from some other source?

The author also mentions that alpha-adrenergic–receptor stimulation accounts for the stimulatory effects of cocaine in the periphery. Alpha-adrenergic receptors mediate some of the stimulatory effects of cocaine. However, beta-adrenergic receptors very likely also mediate some of the excitatory effects of cocaine, such as the tachycardic effect.2

Mehmet Sofuoglu, M.D., Ph.D.
University of Minnesota Medical School, Minneapolis, MN 55455

2 References

1
Hollander JE. The management of cocaine-associated myocardial ischemia. N Engl J Med 1995;333:1267-1272
Full Text | Web of Science | Medline

2
Schindler CW, Tella SR, Erzouki HK, Goldberg SR. Pharmacological mechanisms in cocaine's cardiovascular effects. Drug Alcohol Depend 1995;37:183-191
CrossRef | Web of Science | Medline

To the Editor:

Hollander states that “beta-adrenergic antagonists . . . should be avoided in patients who have recently used cocaine.” We disagree strongly. There are no randomized clinical trials that would support such a statement. The use of beta-blockers in cocaine-induced toxicity varies widely among emergency departments. Whether or not it should be avoided is debatable.

The author cites a study by Lange et al.1 in which 10 patients received propranolol during cardiac catheterization after cocaine ingestion. Although coronary vascular resistance increased when intracoronary propranolol was given after cocaine ingestion, it also increased when intracoronary saline was given after cocaine (P = 0.02). Furthermore, the relevance of the study must be questioned, since most patients do not receive intracoronary beta-blockers.

The author states that beta-blockers fail to control the heart rate in cocaine intoxication, but in the study cited (by Sand et al.2) three of the seven patients had reduced heart rates after the infusion of esmolol, and in the one patient with increasing blood pressure, blood pressure was successfully controlled with labetalol. Furthermore, in a 1994 study of five patients with crack-cocaine–induced adrenergic crisis,3 all received beta-blockers as part of the treatment regimen, and all did well.

Finally, Hollander states that beta-blockers increase the likelihood of seizures and decrease survival, but the two studies cited were performed on animals. In fairness, it should be noted that at least three studies in animals have shown that beta-blockers can be used effectively in the treatment of cocaine-induced toxicity.4-6 In our opinion, the assertion that beta-blockers should be avoided in patients with cocaine intoxication is dogmatic and not supported by the literature.

Robert W. Derlet, M.D.
B. Zane Horowitz, M.D.
University of California, Davis, School of Medicine, Sacramento, CA 95817

6 References

1
Lange RA, Cigarroa RG, Flores ED, et al. Potentiation of cocaine-induced coronary vasoconstriction by beta-adrenergic blockade. Ann Intern Med 1990;112:897-903
Web of Science | Medline

2
Sand IC, Brody SL, Wrenn KD, Slovis CM. Experience with esmolol for the treatment of cocaine-associated cardiovascular complications. Am J Emerg Med 1991;9:161-163
CrossRef | Web of Science | Medline

3
Merigian KS, Park LJ, Leeper KV, Browning RG, Giometi R. Adrenergic crisis from crack cocaine ingestion: report of five cases. J Emerg Med 1994;12:485-490
CrossRef | Medline

4
Derlet RW, Albertson TE. Acute cocaine toxicity: antagonism by agents interacting with adrenoceptors. Pharmacol Biochem Behav 1990;36:225-231
CrossRef | Web of Science | Medline

5
Derlet RW, Albertson TE, Rice P. Antagonism of cocaine, amphetamine, and methamphetamine toxicity. Pharmacol Biochem Behav 1990;36:745-749
CrossRef | Web of Science | Medline

6
Robin ED, Wong RJ, Ptashne KA. Increased lung water and ascites after massive cocaine overdosage in mice and improved survival related to beta-adrenergic blockage. Ann Intern Med 1989;110:202-207
Web of Science | Medline

To the Editor:

Hollander advises against the use of beta-adrenergic antagonists in patients who have recently used cocaine. He claims that beta-blockers enhance cocaine-induced coronary vasoconstriction, increase blood pressure, fail to control the heart rate, and decrease survival in the setting of acute myocardial ischemia or infarction.

In fact, studies by Lange et al.1 demonstrate that intracoronary propranolol enhances cocaine-induced coronary vasoconstriction but does not alter blood pressure. In the study by Sand et al.,2 intravenous esmolol caused a 23 percent decrease in the mean heart rate in patients with cocaine-associated cardiovascular complications. There are no data showing that treatment with beta-blockers increased mortality after acute myocardial infarction associated with cocaine use.

Beta-blockers have become state-of-the-art therapy in acute myocardial ischemia or infarction. Large clinical trials have shown that these agents reduce both long-term and short-term mortality, although the mechanism of this cardioprotective action is unclear.

We find it difficult to accept Dr. Hollander's recommendation not to use beta-blockers on the basis of the small studies cited. Treatment with either sublingual nitroglycerin or the alpha-blocker phentolamine has been shown to reduce cocaine-induced coronary vasoconstriction and elevated blood pressure.3,4 We suggest that patients with acute myocardial ischemia or infarction associated with cocaine use should be treated with nitrates (and possibly an alpha-blocker) along with a beta-blocker.

Vijay Rajput, M.D.
Kenneth P. Sunnergren, Ph.D., M.D.
University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Camden, NJ 08103

4 References

1
Lange RA, Cigarroa RG, Flores ED, et al. Potentiation of cocaine-induced coronary vasoconstriction by beta-adrenergic blockade. Ann Intern Med 1990;112:897-903
Web of Science | Medline

2
Sand IC, Brody SL, Wrenn KD, Slovis CM. Experience with esmolol for the treatment of cocaine-associated cardiovascular complications. Am J Emerg Med 1991;9:161-163
CrossRef | Web of Science | Medline

3
Lange RA, Cigarroa RG, Yancy CW Jr, et al. Cocaine-induced coronary-artery vasoconstriction. N Engl J Med 1989;321:1557-1562
Full Text | Web of Science | Medline

4
Brogan WC III, Lange RA, Kim AS, Moliterno DJ, Hillis LD. Alleviation of cocaine-induced coronary vasoconstriction by nitroglycerin. J Am Coll Cardiol 1991;18:581-586
CrossRef | Web of Science | Medline

To the Editor:

. . . We have successfully used beta-adrenergic antagonists to treat the cardiotoxic effects of cocaine.1 These drugs are a standard part of the treatment of myocardial infarction, a flow-restrictive event that occurs with documented increases in circulating catecholamines. Their use is based on sound pharmacologic and physiologic principles. Beta-adrenergic antagonists decrease myocardial work and oxygen consumption and protect myocardial muscle in times of decreased flow and increased demand. The use of beta-adrenergic antagonists, especially a short-acting, selective drug such as esmolol, has been shown to be both safe and effective in treating the cardiovascular toxicity associated with cocaine.2,3

Kari Blaho, Ph.D.
Kevin Merigian, M.D.
Stephen Winbery, Ph.D., M.D.
University of Tennessee, Memphis, Memphis, TN 38163

3 References

1
Merigian KS, Park LJ, Leeper KV, Browning RG, Giometi R. Adrenergic crisis from crack cocaine ingestion: report of five cases. J Emerg Med 1994;12:485-490
CrossRef | Medline

2
Rappolt RT, Gay GR, Inaba DS. Propranolol: a specific antagonist to cocaine. Clin Toxicol 1977;10:265-271
CrossRef | Web of Science | Medline

3
Robin ED, Wong RJ, Ptashne KA. Increased lung water and ascites after massive cocaine overdosage in mice and improved survival related to beta-adrenergic blockage. Ann Intern Med 1989;110:202-207
Web of Science | Medline

Author/Editor Response

Dr. Hollander replies:

To the Editor: As I noted, the mechanism of action of cocaine in the central nervous system is not clearly understood. In mice, antagonists of excitatory amino acid receptors prevent cocaine-induced seizures and death.1 It is not clear whether the inhibition of reuptake, increased release, or a direct effect of cocaine on the excitatory amino acid receptors accounts for this observation.

The use of beta-adrenergic antagonists in the treatment of cocaine-associated myocardial ischemia is not supported by the literature. Although studies by Derlet and colleagues in animals pretreated with beta-adrenergic antagonists support their use, most laboratory investigations have shown they have a harmful effect in the setting of cocaine-induced toxicity.2,3 In humans, the data are more clear. Lange et al. performed a randomized, double-blind, placebo-controlled trial of propranolol administered to patients after cocaine-induced coronary vasoconstriction.4 They found that cocaine decreased coronary-sinus blood flow from 139 to 120 ml per minute. The addition of propranolol further decreased coronary-sinus blood flow to 100 ml per minute. Similarly, coronary vascular resistance rose from a base-line value of 0.87 mm Hg per milliliter per minute to 1.05 mm Hg per milliliter per minute after cocaine and 1.20 mm Hg per milliliter per minute after propranolol. With propranolol one subject had complete coronary-artery occlusion, symptoms of myocardial ischemia, and electrocardiographic changes.

Merigian et al. described five patients who received beta-adrenergic antagonists after crack-cocaine ingestion.5 Two patients had seizures, and two patients had electrocardiographic evidence of ischemia after beta-adrenergic antagonists were given, even though they were treated with benzodiazepines, the treatment of choice for cocaine-induced toxicity. Twenty percent of the patients who received beta-adrenergic antagonists died. It is unclear how Blaho et al. can claim this represents a safe therapy. In the study by Sand et al.,6 more patients did not respond favorably to treatment with esmolol than responded to it. Serious adverse effects occurred in three of seven patients, leading the authors to recommend against the use of esmolol for the treatment of cocaine-associated cardiovascular complications.

Drs. Rajput and Sunnergren note that no clinical trials have shown an increased mortality when beta-adrenergic antagonists are used in patients with cocaine-associated myocardial infarction. Fortunately, in the published studies, very few patients received beta-adrenergic antagonists. Unpublished data from the Cocaine Associated Myocardial Infarction Study Group suggest that the use of beta-adrenergic antagonists increases the occurrence of delayed complications. The early administration of such drugs to patients with cocaine-associated myocardial infarction was associated with an increased likelihood of delayed complications, even after adjustment for the severity of illness (as measured by an initial electrocardiogram, early elevations in creatine kinase MB, and the presence of earlier complications).

On the basis of the available laboratory and clinical studies, beta-adrenergic antagonists should not be used in patients with cocaine-associated myocardial ischemia. Benzodiazepines, nitroglycerin, and phentolamine are better choices.

Judd E. Hollander, M.D.
University Medical Center, Stony Brook, NY 11794-7400

6 References

1
Rockhold RW, Oden G, Ho IK, Andrew M, Farley JM. Glutamate receptor antagonists block cocaine-induced convulsions and death. Brain Res Bull 1991;27:721-723
CrossRef | Web of Science | Medline

2
Spivey WH, Schoffstall JM, Kirkpatrick R, Fuhs L. Comparison of labetalol, diazepam, and haloperidol for the treatment of cocaine toxicity in a swine model. Ann Emerg Med 1990;19:467-468 abstract.

3
Vargas R, Gillis RA, Ramwell PW. Propranolol promotes cocaine-induced spasm of porcine coronary artery. J Pharmacol Exp Ther 1991;257:644-646
Web of Science | Medline

4
Lange RA, Cigarroa RG, Flores ED, et al. Potentiation of cocaine-induced coronary vasoconstriction by beta-adrenergic blockade. Ann Intern Med 1990;112:897-903
Web of Science | Medline

5
Merigian KS, Park LJ, Leeper KV, Browning RG, Giometi R. Adrenergic crisis from crack cocaine ingestion: report of five cases. J Emerg Med 1994;12:485-490
CrossRef | Medline

6
Sand IC, Brody SL, Wrenn KD, Slovis CM. Experience with esmolol for the treatment of cocaine-associated cardiovascular complications. Am J Emerg Med 1991;9:161-163
CrossRef | Web of Science | Medline