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
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
