- Email: [email protected]
Administration of flumazenil
CORRESPONDENCE
vessel occlusion or spasm with resultant infarction but rather from contraction band necrosis or myocardial inflammation. Myocardial necrosis may produce the minor elevations in CK-MB noted in this study. Direct cocaine cardiotoxicity m a y be the pathologic process. The pathologic difference between myocardial infarction and cocaine-associated myocarditis or contraction band necrosis is clear but the clinical s i g n i f i c a n c e of t h e s e d i f f e r e n c e s awaits further description.
Robert D Welch, MD, FACEP Department of Emergency Medicine Wayne State University School of Medicine Detroit, Michigan I. Cregler LL, Mark H: Medical complications of cocaine abuse. N Engl J Med 1986;315:1495-1500. 2. TazeIaar HD, Karch SB, 8tephens BG, et al: Cocaine and the heart. Hum PathoI i987;18:195-199. 3. Peng S, French WJ, PeIikan PCD: Direct cocaine cardiotoxicity demonstrated by endomyocardial biopsy. Arch Pathol Lab ivied 1989;113:842-845. 4. Virmani R, Robinowitz M, Smialek JE, et al: Cardiovascular effects of cocaine: An autopsy study of 40 patients. A m Heart J 1988;115:1068-1076. 5. Karch SB, Billingham ME: The pathology and etiol~ ogy of cocaine-induced heart disease. Arch Patho] Lab Med 1988i112:225-230.
In Reply: Our thanks to Dr Welch for his insightful comments with reference to our article. Although we agree that myocarditis 1 and contraction band necrosis 2 could result in elevation in CK-MB, we urge caution in attributing elevations of this isoenzyme to these pathologic processes, especially when the onset of chest discomfort is related to recent cocaine use. Notable in the study by Peng et al (referred to by Dr Welch}, in which evidence of myocarditis was noted on e n d o m y o c a r d i a l b i o p s y specimens, the time since last cocaine use is not indicated in any patient and only two of the seven patients studied had a clinical complaint of chest pain. The reports by Peng 1 and Tazelaar 2 also report no total CK or CK-ISO v a l u e s in p a t i e n t s w i t h pathologic findings of myocarditis or contraction band necrosis; thus, correlating these pathologic findings with elevated CK-ISO values is im174/592
possible in the absence of this information. In addition, contraction band necrosis is not a specific marker for cocaine toxicity 2 and other autopsy studies have not been able to support this finding to the degree reported by Tazelaar (Virmani et al 3 for example, noted this finding in only 25% of cocaine associated deaths c o m p a r e d with an incidence of 41% among victims of sudden traumatic death). We agree with Dr Welch that the etiology of myocardial necrosis in cocaine users is not entirely clear. However, acute myocardial injury due to coronary artery vasospasm, increased myocardial oxygen demand, or t h r o m b o s i s m u s t be a p r i m a r y consideration w h e n evaluating patients with chest discomfort after recent cocaine use because there is no reliable clinical method of differentiating this process from contraction band necrosis or myocarditis in the emergency department. Accurately d i f f e r e n t i a t i n g b e t w e e n a c u t e ischemic injury, contraction band necrosis, and myocarditis awaits further elucidation.
Glenn F Tokarski, MD Department of Emergency Medicine Henry Ford Hospital Detroit, Michigan 1. Peng SK, French WJ, Pelikan PC: Direct cocaine cardiotoxicity demonstrated by endomyocardial biopsy. Arch Pathol Lab Med 1989;113:842-845. 2. Tazelaar HD, Darch SB, Stephens BG, et ah Cocaine and the heart. H~im Pathol 1987;18:195-199. 3. Virmani R, Robinowitz M, Smialek JE, et al: Cardiovascular effects of cocaine: An autopsy study of 40 patients. A m Heart J i988;115:1068-1076.
A d m i n i s t r a t i o n of Flumazenil To the Editor: In their abstract, entitled "Flumazenil and Seizures" [June 1990;19:631], Dr Seger evaluated the risk to precipitate seizures when flumazenil is administered in pigs intoxicated with nortryptiline and diazepam. The c o n c l u s i o n s suggest that reversal of benzodiazepine activity in this condition is not associated with an increased risk to precipitate convulsive activity. The o c c u r r e n c e of seizures has, Annals of Emergency Medicine
however, been reported in clinical observations 1 when flumazenil was a d m i n i s t e r e d in m i x e d drug overdoses, i n c l u d i n g b e n z o d i a z e p i n e s (BZD) and cyclic a n t i d e p r e s s a n t s (TCA), and seems possible in animals according to our personal data. Six dogs were anesthetized with 5 to 6 mg/kg midazolam and paralyzed with 0.2 mg/kg pancuronium sulfate. A m i t r y p t i l i n e (1 mg/kg.min) t h e n was i n f u s e d u n t i l c a r d i o t o x i c i t y (QRS > 120 ms) was observed. A 0.2 mg/kg bolus of flumazenil was administered at this moment. The EEG was recorded c o n t i n u o u s l y during the experiment. Sustained convulsive activity was observed in three of six dogs shortly (three to four minutes} after flumazenil administration. It persisted during about five minutes in two dogs and had to be interrupted by administration of 1 mg/kg diazepam after ten minutes in one. The discrepancy between our results and Dr Seger's o b s e r v a t i o n s could be related to the high doses (5 mg/kg) of flumazenil she used in her study. Indeed, flumazenil is not an absolute BZD antagonist, and high doses are able to produce an agonistic-like anticonvulsant effect in various animal models.2, 3 Interruption of seizures by IV flumazenil has even been reported in human beings, 4 and high doses are currently under evaluation in the treatment of human epilepsy! Dr Seger's pigs could have been protected against seizures by flumazenil itself. Until more experience is available, we suggest careful and slow injection of flumazenil in patients with mixed TCA-BZD intoxications, especially when ECG signs of conduction disturbances are present.
P Lheureux, MD M Vrankx R Askenasi, MD, PhD Emergency Department Clinical Toxicology Erasme University Hospital Brussels, Belgium 1. Bismuth G, Baud FJ, Fournier PE, et aI: Antagoniste Ro 15-1788 dans l'iutoxication volontaire par benzodiazepines. Valeurs diagnostique et th~rapeutique. A n n Med Int 1986;137:363-364. 2. File SE, Pellow S: Intinsic actions of the benzodiazepine receptor antagonist Ro 15-1788. Psychopharmacology 1986;88:1-11.
20:5 May 1991
CORRESPONDENCE
3. Robertson SA, Rives ML: A benzodiazepine antagonist is an anticonvulsant in an animal model for limbic epilepsy. Brain Research 1983;270:380-382. 4. Scollo-Lavizzari G: The anticonvulsant effect of the benzodiazepine antagonist Ro 15-1788: An EEG study in 4 cases. Eur Neurol 1984;23:1-6.
In Reply: Seizures have occurred in patients with a multiple drug overdose (including cyclic antidepressant agents) when treated with flumazenil. This observation is consistent with the known toxicity of cycle antidepressant agents to cause seizures. What is not clear from clinical reports is what role, if any, flumazenil plays in the generation of seizures. Drs Lheureux et al suggested that flumazenil precipitated convulsions in the dogs in their study because the close given was a relatively low one. They did not provide data, however, on placebo-treated animals to indicate that the convulsions were not simply the result of a significant overdose of amitriptyline. Further, the dogs displayed greater cardiotoxicity than the pigs. The dogs received a m i t r y p t y l i n e until the QRS was greater than 120 ms, whereas the pigs received amitriptyline until the QRS was greater than 100 ms. Therefore, convulsive activity m a y have occurred in three of their six dogs as the animals were more toxic from the tricyclic. In our study, the only animal that seized received placebo. This does not indicate that there was active protection against convulsions in the flumazenil-treated group. It does, however, emphasize the ability of cy-
20:5 May 1991
clic antidepressant agents to produce s p o n t a n e o u s seizures w h e n toxic amounts are present. Without control animals, the difference in epileptogenicity between cyclic antidepressants alone and cyclic antidepressant agents with flumazenil cannot be assessed. The authors suggest that the discrepancy in the results of the two studies was possibly due to the differences in the amount of flumazenil the pigs and dogs received and that flumazenil has anticonvulsant, agonist properties at high doses. Given the premise that flumazenil administered in higher doses than are currently recommended would be protective against cyclic antidepressantmediated seizures, the obviously desirable course of action would be to a d m i n i s t e r h i g h e r doses of flumazenil as rapidly as possible. The dosing recommendation that the authors make indicated that they apparently did not draw this conclusion from their data. Further delineation of the appropriate dose and recommendations for administration in overdosed patients in the US must await the results of US clinical trials.
Donna Seger, MD Departments of Medicine and Surgery Vanderbilt University Medical Center Nashville, Tennessee Heeton Desar, MD Vancouver, British Columbia, Canada
Annals of Emergency Medicine
The Delta Gap Equation To the Editor: I read with interest Dr Wrenn's article, "The Delta Gap: An Approach to Mixed Acid Based Disorders" [Nov e m b e r 1990;19:1310-1323]. I am looking forward to testing this concept in my practice. It may be easier to apply the formula by combining and rearranging terms, which produces: Delta gap = Na - C 1 - 4 0 .
Andre Raszynski, MD Critical Care Medicine Miami Children's Hospital Miami, Florida
In Reply: Dr Raszynski is correct that the delta gap calculation can be shortened to: Na - C1 - 40. It is important, however, to keep in mind the steps used to shorten the formula and not to omit the calculation of the anion gap (AG) itself. Perhaps a better shortened version is: Delta gap = AG + HCO 3 - 40. For purposes of teaching, I think an unshortened version is best because the principle of comparing the rise in AG with the fall in HCO 3 is important, and the shortened versions tend to hide this comparison.
Keith D Wrenn, MD Emergency Medicine University of Rochester Medical Center Rochester, New York
593/175
vessel occlusion or spasm with resultant infarction but rather from contraction band necrosis or myocardial inflammation. Myocardial necrosis may produce the minor elevations in CK-MB noted in this study. Direct cocaine cardiotoxicity m a y be the pathologic process. The pathologic difference between myocardial infarction and cocaine-associated myocarditis or contraction band necrosis is clear but the clinical s i g n i f i c a n c e of t h e s e d i f f e r e n c e s awaits further description.
Robert D Welch, MD, FACEP Department of Emergency Medicine Wayne State University School of Medicine Detroit, Michigan I. Cregler LL, Mark H: Medical complications of cocaine abuse. N Engl J Med 1986;315:1495-1500. 2. TazeIaar HD, Karch SB, 8tephens BG, et al: Cocaine and the heart. Hum PathoI i987;18:195-199. 3. Peng S, French WJ, PeIikan PCD: Direct cocaine cardiotoxicity demonstrated by endomyocardial biopsy. Arch Pathol Lab ivied 1989;113:842-845. 4. Virmani R, Robinowitz M, Smialek JE, et al: Cardiovascular effects of cocaine: An autopsy study of 40 patients. A m Heart J 1988;115:1068-1076. 5. Karch SB, Billingham ME: The pathology and etiol~ ogy of cocaine-induced heart disease. Arch Patho] Lab Med 1988i112:225-230.
In Reply: Our thanks to Dr Welch for his insightful comments with reference to our article. Although we agree that myocarditis 1 and contraction band necrosis 2 could result in elevation in CK-MB, we urge caution in attributing elevations of this isoenzyme to these pathologic processes, especially when the onset of chest discomfort is related to recent cocaine use. Notable in the study by Peng et al (referred to by Dr Welch}, in which evidence of myocarditis was noted on e n d o m y o c a r d i a l b i o p s y specimens, the time since last cocaine use is not indicated in any patient and only two of the seven patients studied had a clinical complaint of chest pain. The reports by Peng 1 and Tazelaar 2 also report no total CK or CK-ISO v a l u e s in p a t i e n t s w i t h pathologic findings of myocarditis or contraction band necrosis; thus, correlating these pathologic findings with elevated CK-ISO values is im174/592
possible in the absence of this information. In addition, contraction band necrosis is not a specific marker for cocaine toxicity 2 and other autopsy studies have not been able to support this finding to the degree reported by Tazelaar (Virmani et al 3 for example, noted this finding in only 25% of cocaine associated deaths c o m p a r e d with an incidence of 41% among victims of sudden traumatic death). We agree with Dr Welch that the etiology of myocardial necrosis in cocaine users is not entirely clear. However, acute myocardial injury due to coronary artery vasospasm, increased myocardial oxygen demand, or t h r o m b o s i s m u s t be a p r i m a r y consideration w h e n evaluating patients with chest discomfort after recent cocaine use because there is no reliable clinical method of differentiating this process from contraction band necrosis or myocarditis in the emergency department. Accurately d i f f e r e n t i a t i n g b e t w e e n a c u t e ischemic injury, contraction band necrosis, and myocarditis awaits further elucidation.
Glenn F Tokarski, MD Department of Emergency Medicine Henry Ford Hospital Detroit, Michigan 1. Peng SK, French WJ, Pelikan PC: Direct cocaine cardiotoxicity demonstrated by endomyocardial biopsy. Arch Pathol Lab Med 1989;113:842-845. 2. Tazelaar HD, Darch SB, Stephens BG, et ah Cocaine and the heart. H~im Pathol 1987;18:195-199. 3. Virmani R, Robinowitz M, Smialek JE, et al: Cardiovascular effects of cocaine: An autopsy study of 40 patients. A m Heart J i988;115:1068-1076.
A d m i n i s t r a t i o n of Flumazenil To the Editor: In their abstract, entitled "Flumazenil and Seizures" [June 1990;19:631], Dr Seger evaluated the risk to precipitate seizures when flumazenil is administered in pigs intoxicated with nortryptiline and diazepam. The c o n c l u s i o n s suggest that reversal of benzodiazepine activity in this condition is not associated with an increased risk to precipitate convulsive activity. The o c c u r r e n c e of seizures has, Annals of Emergency Medicine
however, been reported in clinical observations 1 when flumazenil was a d m i n i s t e r e d in m i x e d drug overdoses, i n c l u d i n g b e n z o d i a z e p i n e s (BZD) and cyclic a n t i d e p r e s s a n t s (TCA), and seems possible in animals according to our personal data. Six dogs were anesthetized with 5 to 6 mg/kg midazolam and paralyzed with 0.2 mg/kg pancuronium sulfate. A m i t r y p t i l i n e (1 mg/kg.min) t h e n was i n f u s e d u n t i l c a r d i o t o x i c i t y (QRS > 120 ms) was observed. A 0.2 mg/kg bolus of flumazenil was administered at this moment. The EEG was recorded c o n t i n u o u s l y during the experiment. Sustained convulsive activity was observed in three of six dogs shortly (three to four minutes} after flumazenil administration. It persisted during about five minutes in two dogs and had to be interrupted by administration of 1 mg/kg diazepam after ten minutes in one. The discrepancy between our results and Dr Seger's o b s e r v a t i o n s could be related to the high doses (5 mg/kg) of flumazenil she used in her study. Indeed, flumazenil is not an absolute BZD antagonist, and high doses are able to produce an agonistic-like anticonvulsant effect in various animal models.2, 3 Interruption of seizures by IV flumazenil has even been reported in human beings, 4 and high doses are currently under evaluation in the treatment of human epilepsy! Dr Seger's pigs could have been protected against seizures by flumazenil itself. Until more experience is available, we suggest careful and slow injection of flumazenil in patients with mixed TCA-BZD intoxications, especially when ECG signs of conduction disturbances are present.
P Lheureux, MD M Vrankx R Askenasi, MD, PhD Emergency Department Clinical Toxicology Erasme University Hospital Brussels, Belgium 1. Bismuth G, Baud FJ, Fournier PE, et aI: Antagoniste Ro 15-1788 dans l'iutoxication volontaire par benzodiazepines. Valeurs diagnostique et th~rapeutique. A n n Med Int 1986;137:363-364. 2. File SE, Pellow S: Intinsic actions of the benzodiazepine receptor antagonist Ro 15-1788. Psychopharmacology 1986;88:1-11.
20:5 May 1991
CORRESPONDENCE
3. Robertson SA, Rives ML: A benzodiazepine antagonist is an anticonvulsant in an animal model for limbic epilepsy. Brain Research 1983;270:380-382. 4. Scollo-Lavizzari G: The anticonvulsant effect of the benzodiazepine antagonist Ro 15-1788: An EEG study in 4 cases. Eur Neurol 1984;23:1-6.
In Reply: Seizures have occurred in patients with a multiple drug overdose (including cyclic antidepressant agents) when treated with flumazenil. This observation is consistent with the known toxicity of cycle antidepressant agents to cause seizures. What is not clear from clinical reports is what role, if any, flumazenil plays in the generation of seizures. Drs Lheureux et al suggested that flumazenil precipitated convulsions in the dogs in their study because the close given was a relatively low one. They did not provide data, however, on placebo-treated animals to indicate that the convulsions were not simply the result of a significant overdose of amitriptyline. Further, the dogs displayed greater cardiotoxicity than the pigs. The dogs received a m i t r y p t y l i n e until the QRS was greater than 120 ms, whereas the pigs received amitriptyline until the QRS was greater than 100 ms. Therefore, convulsive activity m a y have occurred in three of their six dogs as the animals were more toxic from the tricyclic. In our study, the only animal that seized received placebo. This does not indicate that there was active protection against convulsions in the flumazenil-treated group. It does, however, emphasize the ability of cy-
20:5 May 1991
clic antidepressant agents to produce s p o n t a n e o u s seizures w h e n toxic amounts are present. Without control animals, the difference in epileptogenicity between cyclic antidepressants alone and cyclic antidepressant agents with flumazenil cannot be assessed. The authors suggest that the discrepancy in the results of the two studies was possibly due to the differences in the amount of flumazenil the pigs and dogs received and that flumazenil has anticonvulsant, agonist properties at high doses. Given the premise that flumazenil administered in higher doses than are currently recommended would be protective against cyclic antidepressantmediated seizures, the obviously desirable course of action would be to a d m i n i s t e r h i g h e r doses of flumazenil as rapidly as possible. The dosing recommendation that the authors make indicated that they apparently did not draw this conclusion from their data. Further delineation of the appropriate dose and recommendations for administration in overdosed patients in the US must await the results of US clinical trials.
Donna Seger, MD Departments of Medicine and Surgery Vanderbilt University Medical Center Nashville, Tennessee Heeton Desar, MD Vancouver, British Columbia, Canada
Annals of Emergency Medicine
The Delta Gap Equation To the Editor: I read with interest Dr Wrenn's article, "The Delta Gap: An Approach to Mixed Acid Based Disorders" [Nov e m b e r 1990;19:1310-1323]. I am looking forward to testing this concept in my practice. It may be easier to apply the formula by combining and rearranging terms, which produces: Delta gap = Na - C 1 - 4 0 .
Andre Raszynski, MD Critical Care Medicine Miami Children's Hospital Miami, Florida
In Reply: Dr Raszynski is correct that the delta gap calculation can be shortened to: Na - C1 - 40. It is important, however, to keep in mind the steps used to shorten the formula and not to omit the calculation of the anion gap (AG) itself. Perhaps a better shortened version is: Delta gap = AG + HCO 3 - 40. For purposes of teaching, I think an unshortened version is best because the principle of comparing the rise in AG with the fall in HCO 3 is important, and the shortened versions tend to hide this comparison.
Keith D Wrenn, MD Emergency Medicine University of Rochester Medical Center Rochester, New York
593/175