Clinical Toxicology
ISSN: 0009-9309 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/ictx18
Clonazepam Overdose Resulting in Cyclic Coma R. Welch Thomas, H. Rumack Barry & KEITH HAMMOND To cite this article: R. Welch Thomas, H. Rumack Barry & KEITH HAMMOND (1977) Clonazepam Overdose Resulting in Cyclic Coma, Clinical Toxicology, 10:4, 433-436, DOI: 10.3109/15563657709046280 To link to this article: http://dx.doi.org/10.3109/15563657709046280
Published online: 25 Sep 2008.
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Date: 03 October 2015, At: 09:07
CLINICAL TOXICOLOGY 10(4), pp. 433-436 (1977)
Downloaded by [University of Otago] at 09:07 03 October 2015
Clonazepam Overdose Resulting in Cyclic Coma
THOMAS R WELCH, M.D.; BARRY H. RUMACK, M.D. *; and KEITH HAMMOND, M.S. Departments of Pediatrics and Medicine Division of Clinical Pharmacology and The Rocky Mountain Poison Center Denver General Hospital Denver, Colorado
Clonazepamt is a benzodiazepine recently released as an anticonvulsant. The benzodiazepines in cur r ent use (e. g. , diazepam, chlordiazepoxide) are felt to have a low o r d e r of oral toxicity. T here is, however, no experience with clonazepam toxicity in infants o r children. The following report describes a child in whom a well-documented clonazepam ingestion resulted in an unusual clinical picture. Some suggestions on the recognition and management of this problem are offered in anticipation of m or e widespread use of the drug in the future. *Reprint requests to: B a r r y H. Rumack, M.D., Division of Clinical Pharmacology: C237, University of Colorado Medical Center, 4200 East Ninth Avenue, Denver, Colorado 80220 ?Trade name Clonopin, Hoffman-LaRoche, Inc. Form erl y known as RO-5-4023 This r e s ear ch has been supported in part by the HoffmannLaRoche Foundation. 433 Copyright 0 1977 hy Marcel Dekker. Inc All Rights Reserved Neither this work nor any pdrl may be reproduced or transmitted in any form or by any means. electronic or rneLhanical. including photocopying, microfilming, and recording. or by any information storage and retrieval system without permission in writing from the publisher
434
WELCH, RUMACK, AND HAMMOND
Downloaded by [University of Otago] at 09:07 03 October 2015
CASE REPORT D. M., chart #CGH 362 519, a 4-year-old boy, was admitted to the hospital because of a suspected drug ingestion. The child had been found by his mother on the living room floor. He was unable to be aroused, and several open, spilled bottles of his mother's anticonvulsant medication-clonazepam-were in an adjoining room. He had been behaving normally when the mother last saw him 5 h r before. He was taken to another hospital and easily aroused after which syrup of ipecac produced emesis which contained no pills. He was then transferred to the University of Colorado Medical Center. On admission, he was mildly ill appearing with a temperature of 36"C, pulse rate of 80/min, respiratory r a t e of 18/min, and a B P of 80/56 mm Hg. He responded to voice commands and withdrew from painful stimuli, but made no spontaneous purposeful movements o r verbalizations. His pupils were pinpoint and equal; his deep tendon reflexes were brisk and symmetrical; and his plantar responses were flexor bilaterally. The r e s t of the physical examination was normal. Initial laboratory studies included: s e r u m sodium 138 meq/liter, serum potassium 4.8 meq/liter, serum glucose 125 mg/100 ml, blood urea nitrogen 6 mg/100 ml, serum glutamic oxalacetate transaminase 17 IU/liter, hemoglobin 12.5 gm/100 ml, white blood cell count 7.1 mm, and toxicology studies as summarized below. The child was placed on cardiac monitor in the intensive care unit. An intravenous infusion was begun and 0.4 mg naloxone (Narcan) was given; no change in his condition was noted. A #32 French Edlitch tube was passed orally into the stomach with holes sufficient to pass tablets; gastric lavage produced no tablets. Magnesium sulfate ( 5 gm) and activated charcoal ( 5 gm) were instilled via a nasogastric tube; charcoal was noted in the stool within 3 hr. During the first 24 h r of his hospitalization, his state of consciousn e s s cycled seven times between a l e r t agitation and unresponsive coma with pinpoint pupils. Abdominal x-ray demonstrated no bolus of tablets from which further absorption could occur. His other vital signs, however, remained stable. No lateralizing neurologic signs o r seizure activity were observed, although a bilaterally upgoing plantar response was transiently elicited in one of the deeper cycles of his coma. Bowel sounds became markedly hypoactive 5 h r after admission, but returned a f t e r a second administration of magnesium sulfate. Twenty-four hours after admission (about 36 h r after presumed ingestion), he was alert, active, and was behaving normally. He was transferred to a regular ward where he remained until a social evaluation of his home could be completed. Physical examination a t the time of discharge (7th hospital day) was normal.
C LONAZE PAM OVERDOSE
43 5
Downloaded by [University of Otago] at 09:07 03 October 2015
TOXICOLOGIC STUDIES Heparinized whole blood samples and random urine specimens w ere obtained for toxicologic analysis. Gas liquid chromatography and thin layer chromatography were used to s c r e e n extracts of the blood and urine for sedatives and tranquilizers (including benzodiazepines). No peaks were found on the assay. Analysis for antidepressants, antihistamines, narcotics, analgesics, and amphetamines was carri ed out but was negative. Aliquots of heparinized blood s am pl es were frozen and shipped t o the laboratories of Hoffmann LaRoche, Inc. (Nutley, N.J. 07110)f o r as s ay for clonazepam by electron capture gas liquid chromatography [ 11. A plasma level on blood drawn shortly after admission w a s 69 ng/ml. A normal adult male ( 7 1-97 kg) receiving a single o r a l 2 mg dose would show a plasma level 8 h r post administration of 4.2-9.6 ng/ml. Although extrapolation between adults and children of therapeutic and overdosage situations are not always valid, the plasma level in this 17 kg patient would be equivalent to 14-32 mg in an adult - o r 7-16 tablets [2]. DISCUSSION The benzodiazepines w er e f i r s t synthesized in 1933. In the last 10 to 15 y e ar s , they have come into widespread use, principally in the management of anxiety. More recently, the effectiveness of these compounds as anticonvulsants has been demonstrated [3]. Diazepam is the benzodiazepine currently in most common use for this purpose. Clonazepam is a benzodiazepine recently introduced as a n anticonvulsant. It has been suggested for use in myoclonic, petit mal, and temporal lobe epilepsy [4]. Most authors discussing the toxicology of the benzodiazepines stress the low o r d er of toxicity of these compounds [5-81. Central nervous system depression and r ar el y cardiorespiratory depression characterize o r a l benzodiazepine overdoses. Death has not been reported after o r a l overdosage. Treatment is supportive and consists primarily of meas u r e s to prevent absorption such as emesis, lavage, charcoal, and cathartics. The present cas e is unusual in that the patient demonstrated shifting neurologic signs for m or e than 24 h r after ingestion. Cyclic coma persisted for 16 h r after charcoal appeared in the stools. This was unusual since the presence of charcoal in the stools would tend to both preclude further cyclic absorption and indicate passage of material through the GI tract. Despite signs of profound neurologic depression, no cardiorespiratory compromise developed. Other than the transient hypoactivity of
WELCH, RUMACK, AND HAMMOND
Downloaded by [University of Otago] at 09:07 03 October 2015
436
bowel sounds, there was no evidence of anticholinergic effect. Also of note is the fact that clonazepam was not detected by the routine assay for benzodiazepines performed in the toxicology laboratory. At the present time, documentation of such an ingestion will be possible only i f the laboratory has access to electron capture gas chromatography since standard GLC systems are not sensitive enough to detect the low plasma levels found either in therapeutic o r overdose amounts. The physician faced with a possible clonazepam ingestion may expect a prolonged course, characterized by shifting levels of consciousn e s s ("cyclic coma?'). Other than such routine measures as gastric lavage and the use of charcoal and cathartics, the management of the patient should be supportive. Speculation as to why cyclic coma occurs would tend to implicate a metabolite of the drug with some activity. Enterohepatic circulation, while i t may occur, probably does not enter into consideration since prevention of absorption by charcoal and continued catharsis occurred. SUMMARY Cyclic coma in a 4-year-old boy followed an ingestion of clonazePam, a new benzodiazepine, utilized in treatment of convulsive disorders. Alternation between coma and a hyperalert state occurred even after further gastrointestinal absorption had, presumably, been precluded. Laboratory identification by routine examination for benzodiazepines was unsuccessful. REFERENCES J. A. F. deSilva, C. V. Puglisi, and N. Munno, Determination of clonazepam and flunitrazepam in blood and urine by electron capture GLC, J. Pharm. Sci., 63, 520 (1974). Personal communication, HoffEan-LaRoche Inc., Nutley New Jersey. J. R. Browne and J. R Penry, Benzodiazepines in the treatment of epilepsey, Epilepsia, 14, 277 (1973). M. Lund ed., Symposiumon the Therapeutic U s e of the Anticonvulsant RO 5-4023 (Clonazepam) in Different Forms of Epilepsy, Acta Neurologica, Scandinavica Supplementum 53, Vol. 49,
1973. H. Matthew, A. T. Proudfoot, R. C. B. Aitken, J. A. Roeburn, and N. Wright, Nitrazepam-a safe hypnotic, Brit. Med. J., 1969-3, 23. D. J. Greenblatt and R. I. Shader, Benzodiazepines in Clinical Practice, Raven Press, New York, 1974. D. J. Greenblatt, R L Shader, and J. Koch-Weser, Flurazepam hydrochloride, Clin. Pharm. Therap., 7, 1 (1975). D. J. Greenblatt and R. L Shader, Benzodiazepines, New Engl. J. Med., 291, 1011-1015, 1239-1243 (1974). - _ .
ISSN: 0009-9309 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/ictx18
Clonazepam Overdose Resulting in Cyclic Coma R. Welch Thomas, H. Rumack Barry & KEITH HAMMOND To cite this article: R. Welch Thomas, H. Rumack Barry & KEITH HAMMOND (1977) Clonazepam Overdose Resulting in Cyclic Coma, Clinical Toxicology, 10:4, 433-436, DOI: 10.3109/15563657709046280 To link to this article: http://dx.doi.org/10.3109/15563657709046280
Published online: 25 Sep 2008.
Submit your article to this journal
Article views: 27
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ictx18 Download by: [University of Otago]
Date: 03 October 2015, At: 09:07
CLINICAL TOXICOLOGY 10(4), pp. 433-436 (1977)
Downloaded by [University of Otago] at 09:07 03 October 2015
Clonazepam Overdose Resulting in Cyclic Coma
THOMAS R WELCH, M.D.; BARRY H. RUMACK, M.D. *; and KEITH HAMMOND, M.S. Departments of Pediatrics and Medicine Division of Clinical Pharmacology and The Rocky Mountain Poison Center Denver General Hospital Denver, Colorado
Clonazepamt is a benzodiazepine recently released as an anticonvulsant. The benzodiazepines in cur r ent use (e. g. , diazepam, chlordiazepoxide) are felt to have a low o r d e r of oral toxicity. T here is, however, no experience with clonazepam toxicity in infants o r children. The following report describes a child in whom a well-documented clonazepam ingestion resulted in an unusual clinical picture. Some suggestions on the recognition and management of this problem are offered in anticipation of m or e widespread use of the drug in the future. *Reprint requests to: B a r r y H. Rumack, M.D., Division of Clinical Pharmacology: C237, University of Colorado Medical Center, 4200 East Ninth Avenue, Denver, Colorado 80220 ?Trade name Clonopin, Hoffman-LaRoche, Inc. Form erl y known as RO-5-4023 This r e s ear ch has been supported in part by the HoffmannLaRoche Foundation. 433 Copyright 0 1977 hy Marcel Dekker. Inc All Rights Reserved Neither this work nor any pdrl may be reproduced or transmitted in any form or by any means. electronic or rneLhanical. including photocopying, microfilming, and recording. or by any information storage and retrieval system without permission in writing from the publisher
434
WELCH, RUMACK, AND HAMMOND
Downloaded by [University of Otago] at 09:07 03 October 2015
CASE REPORT D. M., chart #CGH 362 519, a 4-year-old boy, was admitted to the hospital because of a suspected drug ingestion. The child had been found by his mother on the living room floor. He was unable to be aroused, and several open, spilled bottles of his mother's anticonvulsant medication-clonazepam-were in an adjoining room. He had been behaving normally when the mother last saw him 5 h r before. He was taken to another hospital and easily aroused after which syrup of ipecac produced emesis which contained no pills. He was then transferred to the University of Colorado Medical Center. On admission, he was mildly ill appearing with a temperature of 36"C, pulse rate of 80/min, respiratory r a t e of 18/min, and a B P of 80/56 mm Hg. He responded to voice commands and withdrew from painful stimuli, but made no spontaneous purposeful movements o r verbalizations. His pupils were pinpoint and equal; his deep tendon reflexes were brisk and symmetrical; and his plantar responses were flexor bilaterally. The r e s t of the physical examination was normal. Initial laboratory studies included: s e r u m sodium 138 meq/liter, serum potassium 4.8 meq/liter, serum glucose 125 mg/100 ml, blood urea nitrogen 6 mg/100 ml, serum glutamic oxalacetate transaminase 17 IU/liter, hemoglobin 12.5 gm/100 ml, white blood cell count 7.1 mm, and toxicology studies as summarized below. The child was placed on cardiac monitor in the intensive care unit. An intravenous infusion was begun and 0.4 mg naloxone (Narcan) was given; no change in his condition was noted. A #32 French Edlitch tube was passed orally into the stomach with holes sufficient to pass tablets; gastric lavage produced no tablets. Magnesium sulfate ( 5 gm) and activated charcoal ( 5 gm) were instilled via a nasogastric tube; charcoal was noted in the stool within 3 hr. During the first 24 h r of his hospitalization, his state of consciousn e s s cycled seven times between a l e r t agitation and unresponsive coma with pinpoint pupils. Abdominal x-ray demonstrated no bolus of tablets from which further absorption could occur. His other vital signs, however, remained stable. No lateralizing neurologic signs o r seizure activity were observed, although a bilaterally upgoing plantar response was transiently elicited in one of the deeper cycles of his coma. Bowel sounds became markedly hypoactive 5 h r after admission, but returned a f t e r a second administration of magnesium sulfate. Twenty-four hours after admission (about 36 h r after presumed ingestion), he was alert, active, and was behaving normally. He was transferred to a regular ward where he remained until a social evaluation of his home could be completed. Physical examination a t the time of discharge (7th hospital day) was normal.
C LONAZE PAM OVERDOSE
43 5
Downloaded by [University of Otago] at 09:07 03 October 2015
TOXICOLOGIC STUDIES Heparinized whole blood samples and random urine specimens w ere obtained for toxicologic analysis. Gas liquid chromatography and thin layer chromatography were used to s c r e e n extracts of the blood and urine for sedatives and tranquilizers (including benzodiazepines). No peaks were found on the assay. Analysis for antidepressants, antihistamines, narcotics, analgesics, and amphetamines was carri ed out but was negative. Aliquots of heparinized blood s am pl es were frozen and shipped t o the laboratories of Hoffmann LaRoche, Inc. (Nutley, N.J. 07110)f o r as s ay for clonazepam by electron capture gas liquid chromatography [ 11. A plasma level on blood drawn shortly after admission w a s 69 ng/ml. A normal adult male ( 7 1-97 kg) receiving a single o r a l 2 mg dose would show a plasma level 8 h r post administration of 4.2-9.6 ng/ml. Although extrapolation between adults and children of therapeutic and overdosage situations are not always valid, the plasma level in this 17 kg patient would be equivalent to 14-32 mg in an adult - o r 7-16 tablets [2]. DISCUSSION The benzodiazepines w er e f i r s t synthesized in 1933. In the last 10 to 15 y e ar s , they have come into widespread use, principally in the management of anxiety. More recently, the effectiveness of these compounds as anticonvulsants has been demonstrated [3]. Diazepam is the benzodiazepine currently in most common use for this purpose. Clonazepam is a benzodiazepine recently introduced as a n anticonvulsant. It has been suggested for use in myoclonic, petit mal, and temporal lobe epilepsy [4]. Most authors discussing the toxicology of the benzodiazepines stress the low o r d er of toxicity of these compounds [5-81. Central nervous system depression and r ar el y cardiorespiratory depression characterize o r a l benzodiazepine overdoses. Death has not been reported after o r a l overdosage. Treatment is supportive and consists primarily of meas u r e s to prevent absorption such as emesis, lavage, charcoal, and cathartics. The present cas e is unusual in that the patient demonstrated shifting neurologic signs for m or e than 24 h r after ingestion. Cyclic coma persisted for 16 h r after charcoal appeared in the stools. This was unusual since the presence of charcoal in the stools would tend to both preclude further cyclic absorption and indicate passage of material through the GI tract. Despite signs of profound neurologic depression, no cardiorespiratory compromise developed. Other than the transient hypoactivity of
WELCH, RUMACK, AND HAMMOND
Downloaded by [University of Otago] at 09:07 03 October 2015
436
bowel sounds, there was no evidence of anticholinergic effect. Also of note is the fact that clonazepam was not detected by the routine assay for benzodiazepines performed in the toxicology laboratory. At the present time, documentation of such an ingestion will be possible only i f the laboratory has access to electron capture gas chromatography since standard GLC systems are not sensitive enough to detect the low plasma levels found either in therapeutic o r overdose amounts. The physician faced with a possible clonazepam ingestion may expect a prolonged course, characterized by shifting levels of consciousn e s s ("cyclic coma?'). Other than such routine measures as gastric lavage and the use of charcoal and cathartics, the management of the patient should be supportive. Speculation as to why cyclic coma occurs would tend to implicate a metabolite of the drug with some activity. Enterohepatic circulation, while i t may occur, probably does not enter into consideration since prevention of absorption by charcoal and continued catharsis occurred. SUMMARY Cyclic coma in a 4-year-old boy followed an ingestion of clonazePam, a new benzodiazepine, utilized in treatment of convulsive disorders. Alternation between coma and a hyperalert state occurred even after further gastrointestinal absorption had, presumably, been precluded. Laboratory identification by routine examination for benzodiazepines was unsuccessful. REFERENCES J. A. F. deSilva, C. V. Puglisi, and N. Munno, Determination of clonazepam and flunitrazepam in blood and urine by electron capture GLC, J. Pharm. Sci., 63, 520 (1974). Personal communication, HoffEan-LaRoche Inc., Nutley New Jersey. J. R. Browne and J. R Penry, Benzodiazepines in the treatment of epilepsey, Epilepsia, 14, 277 (1973). M. Lund ed., Symposiumon the Therapeutic U s e of the Anticonvulsant RO 5-4023 (Clonazepam) in Different Forms of Epilepsy, Acta Neurologica, Scandinavica Supplementum 53, Vol. 49,
1973. H. Matthew, A. T. Proudfoot, R. C. B. Aitken, J. A. Roeburn, and N. Wright, Nitrazepam-a safe hypnotic, Brit. Med. J., 1969-3, 23. D. J. Greenblatt and R. I. Shader, Benzodiazepines in Clinical Practice, Raven Press, New York, 1974. D. J. Greenblatt, R L Shader, and J. Koch-Weser, Flurazepam hydrochloride, Clin. Pharm. Therap., 7, 1 (1975). D. J. Greenblatt and R. L Shader, Benzodiazepines, New Engl. J. Med., 291, 1011-1015, 1239-1243 (1974). - _ .
