- Email: [email protected]
Strychnine poisoning successfully treated with diazepam
April, 1971 T h e ]ournal o~ P E D I A T R I C S
697
Strychnine poisoning successfullytreated with diazepam A 15-year-old girl with strychnine-induced convulsions was success[ully treated with diazepam. Diazepam seems to have advantages over barbiturates because o[ its mild central nervous system-depressant effects and may prove to be the drug o[ choice in the therapy o[ strychnine-induced convulsions. The theoretical basis [or using diazepam in strychnine intox~eatlon is discussed.
Barry J. Maron, M.D., Jan R. Krupp, B.S., and Bruce Tune, M.D.* PALO ALTO, CALIF.
R~CENTLY the efficacy and safety of diazepam (Valium, Roche Labs., Nutley, N. J.) has been reported in a variety of conditions, demonstrating its tranquilizing, anticonvulsant, and muscle relaxant properties. 1-5 Intramuscular diazepam was used by Heidrich and associates 6 to treat strychnine poisoning in an 18-year-old girl; her convulsions decreased in frequency and intensity after initiation of therapy. We are not aware of a report in the English literature of the use of diazepam as the only drug for the treatment of strychnine intoxication. This report describes the successful use of diazepam in the treatment of strychnine-induced convulsions in a 15-year-old girl. Because of its mechanism of action and relatively mild depressive effects on the central nervous system, diazepam may be a rational substitute for barbiturates in the treatment of strychnine intoxication. From the Department of Pediatrics, Stan[ord University Medical Center. aReprlnt address: Department of Ped~atrlcs, 300 Pasteur Dr. Palo Alto, Cali]. 94305.
CASE REPORT Patient M. B., a 15-year-old girl, was brought to the Stanford University Hospital emergency room with a history of having ingested an unknown quantity of a rodenticide containing strychnine, 1 to 2 hours previously. Shortly afterward the patient experienced stiffening and cramping in the legs and a feeling of tightness in the chest, followed by a generalized tonic convulsion involving the muscles of the trunk, extremities, and jaw. She remained conscious and experienced severe pain in these muscles, accompanied by a feeling of suffocation. A second similar episode occurred 30 minutes later in the ambulance on the way to the hospital. When initially seen in the emergency room the patient was conscious and alert. Physical examination results revealed an obese, apprehensive, and hyperpneic female without evidence of physical injury. Weight was 94 Kg. Heart rate was 145 beats per minute, respiratory rate was 40 per minute, temperature was 99 ~ F:, and blood pressure was 210//80. Lungs were clear to auscultation. There were symmetrically increased deep tendon reflexes in the lower extremities and bilateral sustained ankle clonus. One ounce of VoI. 78, No. 4, pp. 697-699
6 98
Maron, Krupp, and Tune
syrup of ipecac was administered immediately upon her arrival in the emergency room. A few minutes later she had 2 brief convulsions of the same type as those experienced earlier. An intravenous infusion of 5 per cent dextrose in water was initiated, and oxygen was administered by mask. Shortly afterward she complained of cramps in the calves of the legs and a feeling of tightness in the chest and expressed considerable concern that another convulsion was imminent. These symptoms subsided immediately after intravenous administration of 10 mg. of diazepam over a 30 second period; the patient remained alert. Arterial pH at that time was 7.03, Pco 2 was 20 ram. Hg, Po 2 was 147 ram. Hg, and HCOa was less than 6 mEq. per liter. The patient received 100 mEq. of sodium bicarbonate intravenously to partially correct the acidosis, and the hyperpnea subsided. During the following 90 minutes she experienced 6 episodes of prodromal symptoms similar to those described above. On each occasion she received 10 rag. of diazepam intravenously over 1 to 2 minutes, resulting in prompt relief. A total of 125 rag. of diazepam was administered over a 6 hour period, after which the patient required no further medication. No seizures occurred after diazepam therapy was initiated. The patient was only mildly sedated toward the end of this course of treatment and was conscious enough to complain of nausea and turn to one side before vomiting on several occasions; the first of these was about one hour after she received the ipecac. Throughout this time vital signs were stable, with a heart rate of 100 per minute, respiratory rate of 25 per minute, and blood pressure of 14~0. Radiographs of the chest showed no pulmonary infiltrate. The patient was remarkably alert and cooperative considering the amount of medication she had received. A single urine specimen voided 6 hours after the estimated time of ingestion contained 4 rag. of strychnine. From this one can estimate an ingested quantity of at least 20 mg. of strychnine, ~ which is a potentially lethal dose. s The patient was discharged in good health 48 hours after admission. An electroencephalogram performed 7 days after admission was within normal limits. DISCUSSION Strychnine poisoning is now a relatively rare occurrence but nevertheless a difficult
The Journal o} Pediatrics April 197t
problem in management. Control of convulsions is essential and is usually achieved by intravenous administration of central nervous system depressants, most commonly short-acting barbiturates. 8 Care must be taken to avoid cumulative effects of barbiturates resulting in cardiorespiratory depression. 9 Peripheral neuromuscular blocking agents such as d-tubocurarine and succinylcholine have been used with some success as adjuvants in therapy but must be accompanied by prolonged assisted ventilation2 Mephenesin (Tolserol, E. R. Squibb and Sons, New York, N. Y.), a centrally acting muscle relaxant with selective action on spinal cord interneurons, has also been used with some success in strychnine convulsions in combination with barbiturates. 1~ T h e mechanism ot action of strychnine is reasonably well understood: It is a powerful convulsant and produces excitation of many portions of the central nervous system/, 11 Strychnine increases the level of neuronal excitability by selectively blocking postsynaptic inhibition. 1~ This interference with central inhibitory processes, which has its most dramatic effects at the level of the spinal cord, produces the characteristically symmetrical tonic extensor thrusts and convulsions seen in strychnine poisoning/ Diazepam is a 1,4 benzodiazepine analogue of chlordiazepoxide (Librium, Roche Labs., Nutley, N. J.). It has anticonvulsant muscle relaxant properties in addition to its wellknown tranquilizing effect. 1 T h e usefulness of diazepam has recently been demonstrated in status epilepticus, 2 tetanus, a stiff-man syndrome, 4 and musculoskeletal spasticity or spasm. 5 T h e pharmacology of diazepam is not completely understood. It possesses both supraspinal and spinal sites of action. Its tranquilizing effect is due to action on the limbic 12 and hypothalamic ~3 systems. T h e muscle-relaxant property of diazepam is probably related to both its supraspinal and spinal effects24-~5 Ngai and associates ~4 have demonstrated that pharmacologic doses of diazepam cause depression of the brain stem ascending reticular activating system. In ad-
Volume 78 Number 4
Strychnine poisoning treated with diazepam
dition to these supraspinal effects, diazepam also has a direct suppressive action on spinal reflexes by selectively enhancing presynaptic inhibitory mechanisms, as This effect presumably opposes the stimulating action of strychnine on postsynaptic reflexes. Diazepam has been demonstrated to be a potent inhibitor of spinal reflexes in deeerebrate cats and of strychnine-induced convulsions in mice? 2 This theoretical pharmacologic interrelationship between strychnine and diazepam was the basis for using the latter as the only anticonvulsant medication in our patient. Diazepam has the advantage over barbiturates of being weakly hypnotic? 6 This patient remained conscious and was able to alert the staff to recurrent tetanic episodes so that diazepam could be administered before seizures occurred. Also, she remained alert enough to warn the nursing staff of anticipated vomiting so that precautions could be taken to avoid aspiration. Transient apnea, an u n c o m m o n but undesirable side effect of diazepam when used for status epilepticus, 2 did not occur in this patient. I n general the respiratory difficulties encountered with diazepam seem to be neither as frequent nor severe as those which a c c o m p a n y the profound depression which m a y occur following large doses of barbiturates. T h e clinical response of this patient and that of Heidrich and associates * to diazepam is encouraging. Diazepam appears to be very effective and to have a greater margin of safety than barbiturates. If further clinical experience supports its efficacy, diazepam may supplant barbiturates as the treatment of choice for the convulsions accompanying strychnine poisoning. REFERENCES 1. Aivazian, G. I-I.: Clinical evaluation of diazepam~ Dis. Nerv. Syst. 25: 491, 1964,
699
2. Bailey, D. W., and Fenichel, G. M.: The treatment of prolonged seizure activity with intravenous diazepam, J. PEDIAT. 73: 923, 1968. 3. Femi-Pearse, D.: Experience with diazepam in tetanus, Brit. Med. J. 2: 862, I966. 4. Howard, F. 32.: A new and effective drug in the treatment of the stiff-man syndrome, Proc. Mayo Clin. 38: 203, 1963. 5. Peirson, G. A., Fowlks, E. W., and King, P. S.: Long term follow-up on tile use of diazepare in the treatment of spasticity, Amer. J. Phys. Med. 47: 143, 1968. 6. Heidrich, H., Ibe, K., and Klinge, D.: Akute vergiftung mit strychnin N-oxydhydrochlorld und ihre behandlung mit diazepam, Arch. Toxik. 24: 188, 1969. 7. Goodman, L. S., and Gilman, A.: The pharmacological basis of therapeutics, New York, 1965, The Macmillan Company, pp. 345-348. 8. Gleason, 32. N., Gosselin, R. E., Hodge, H. C., and Smith, R. P.: Clinical toxicology of commercial products, Baltimore, 1969, The Williams & Wilklns Company, pp. 214-217. 9. Swissman, N., and Jacoby, J.: Strychnine poisoning and its treatment, Clin. Pharmacol. Ther. 5: 136, 1964. 10. Jacoby, J., and Boyle, J.: The treatment of strychnine poisoning with mephenesin, J. Lab. Clin. Med. 48: 270, I956. 1 l. Eccles, J. C.: The physiology of synapses, New York, 1964, Academic Press, Inc. 12. Randall, L. O., Heise, G. A., Schallek, W., Bagdon, R. E., Banziger, R. F., Boris, A., Moe, R. A., and Abrams, W. B.: Pharmacological and clinical studies on Valium, a new psychotherapeutie agent of the benzodiazeplne class, Curr. Ther. Res. 3: 405, 1961. 13. Schallek, W., Zabransky, F., and Kuehn, A.: Effects of benzodlazepines on the central nervous system of the cat, Arch. Int. Pharmacodyn. 149: 467, 1964. 14. Ngai, S. H., Tseng, D. T. C., and Wang, S. C.: Effect of diazepam and other central nervous system depressants on spinal reflexes in cats: A study of site of action, J. Pharmacol. Exp. Ther. 153: 344, 1966. 15. Schmidt, R. F., Vogel, 32. E., and Zimmerman, M.: Die wlrkung yon diazepam auf die pr~isynaptische Hemmung und andere Ruckenmarksreflexe, Arch. Exp. Pharmakol. Path. 258: 69, 1967. 16. Goodman, L. S., and Gilman, A.: The pharmacological basis of therapeutics, New York, 1965, The Macmillan Company, pp. 187-190.
697
Strychnine poisoning successfullytreated with diazepam A 15-year-old girl with strychnine-induced convulsions was success[ully treated with diazepam. Diazepam seems to have advantages over barbiturates because o[ its mild central nervous system-depressant effects and may prove to be the drug o[ choice in the therapy o[ strychnine-induced convulsions. The theoretical basis [or using diazepam in strychnine intox~eatlon is discussed.
Barry J. Maron, M.D., Jan R. Krupp, B.S., and Bruce Tune, M.D.* PALO ALTO, CALIF.
R~CENTLY the efficacy and safety of diazepam (Valium, Roche Labs., Nutley, N. J.) has been reported in a variety of conditions, demonstrating its tranquilizing, anticonvulsant, and muscle relaxant properties. 1-5 Intramuscular diazepam was used by Heidrich and associates 6 to treat strychnine poisoning in an 18-year-old girl; her convulsions decreased in frequency and intensity after initiation of therapy. We are not aware of a report in the English literature of the use of diazepam as the only drug for the treatment of strychnine intoxication. This report describes the successful use of diazepam in the treatment of strychnine-induced convulsions in a 15-year-old girl. Because of its mechanism of action and relatively mild depressive effects on the central nervous system, diazepam may be a rational substitute for barbiturates in the treatment of strychnine intoxication. From the Department of Pediatrics, Stan[ord University Medical Center. aReprlnt address: Department of Ped~atrlcs, 300 Pasteur Dr. Palo Alto, Cali]. 94305.
CASE REPORT Patient M. B., a 15-year-old girl, was brought to the Stanford University Hospital emergency room with a history of having ingested an unknown quantity of a rodenticide containing strychnine, 1 to 2 hours previously. Shortly afterward the patient experienced stiffening and cramping in the legs and a feeling of tightness in the chest, followed by a generalized tonic convulsion involving the muscles of the trunk, extremities, and jaw. She remained conscious and experienced severe pain in these muscles, accompanied by a feeling of suffocation. A second similar episode occurred 30 minutes later in the ambulance on the way to the hospital. When initially seen in the emergency room the patient was conscious and alert. Physical examination results revealed an obese, apprehensive, and hyperpneic female without evidence of physical injury. Weight was 94 Kg. Heart rate was 145 beats per minute, respiratory rate was 40 per minute, temperature was 99 ~ F:, and blood pressure was 210//80. Lungs were clear to auscultation. There were symmetrically increased deep tendon reflexes in the lower extremities and bilateral sustained ankle clonus. One ounce of VoI. 78, No. 4, pp. 697-699
6 98
Maron, Krupp, and Tune
syrup of ipecac was administered immediately upon her arrival in the emergency room. A few minutes later she had 2 brief convulsions of the same type as those experienced earlier. An intravenous infusion of 5 per cent dextrose in water was initiated, and oxygen was administered by mask. Shortly afterward she complained of cramps in the calves of the legs and a feeling of tightness in the chest and expressed considerable concern that another convulsion was imminent. These symptoms subsided immediately after intravenous administration of 10 mg. of diazepam over a 30 second period; the patient remained alert. Arterial pH at that time was 7.03, Pco 2 was 20 ram. Hg, Po 2 was 147 ram. Hg, and HCOa was less than 6 mEq. per liter. The patient received 100 mEq. of sodium bicarbonate intravenously to partially correct the acidosis, and the hyperpnea subsided. During the following 90 minutes she experienced 6 episodes of prodromal symptoms similar to those described above. On each occasion she received 10 rag. of diazepam intravenously over 1 to 2 minutes, resulting in prompt relief. A total of 125 rag. of diazepam was administered over a 6 hour period, after which the patient required no further medication. No seizures occurred after diazepam therapy was initiated. The patient was only mildly sedated toward the end of this course of treatment and was conscious enough to complain of nausea and turn to one side before vomiting on several occasions; the first of these was about one hour after she received the ipecac. Throughout this time vital signs were stable, with a heart rate of 100 per minute, respiratory rate of 25 per minute, and blood pressure of 14~0. Radiographs of the chest showed no pulmonary infiltrate. The patient was remarkably alert and cooperative considering the amount of medication she had received. A single urine specimen voided 6 hours after the estimated time of ingestion contained 4 rag. of strychnine. From this one can estimate an ingested quantity of at least 20 mg. of strychnine, ~ which is a potentially lethal dose. s The patient was discharged in good health 48 hours after admission. An electroencephalogram performed 7 days after admission was within normal limits. DISCUSSION Strychnine poisoning is now a relatively rare occurrence but nevertheless a difficult
The Journal o} Pediatrics April 197t
problem in management. Control of convulsions is essential and is usually achieved by intravenous administration of central nervous system depressants, most commonly short-acting barbiturates. 8 Care must be taken to avoid cumulative effects of barbiturates resulting in cardiorespiratory depression. 9 Peripheral neuromuscular blocking agents such as d-tubocurarine and succinylcholine have been used with some success as adjuvants in therapy but must be accompanied by prolonged assisted ventilation2 Mephenesin (Tolserol, E. R. Squibb and Sons, New York, N. Y.), a centrally acting muscle relaxant with selective action on spinal cord interneurons, has also been used with some success in strychnine convulsions in combination with barbiturates. 1~ T h e mechanism ot action of strychnine is reasonably well understood: It is a powerful convulsant and produces excitation of many portions of the central nervous system/, 11 Strychnine increases the level of neuronal excitability by selectively blocking postsynaptic inhibition. 1~ This interference with central inhibitory processes, which has its most dramatic effects at the level of the spinal cord, produces the characteristically symmetrical tonic extensor thrusts and convulsions seen in strychnine poisoning/ Diazepam is a 1,4 benzodiazepine analogue of chlordiazepoxide (Librium, Roche Labs., Nutley, N. J.). It has anticonvulsant muscle relaxant properties in addition to its wellknown tranquilizing effect. 1 T h e usefulness of diazepam has recently been demonstrated in status epilepticus, 2 tetanus, a stiff-man syndrome, 4 and musculoskeletal spasticity or spasm. 5 T h e pharmacology of diazepam is not completely understood. It possesses both supraspinal and spinal sites of action. Its tranquilizing effect is due to action on the limbic 12 and hypothalamic ~3 systems. T h e muscle-relaxant property of diazepam is probably related to both its supraspinal and spinal effects24-~5 Ngai and associates ~4 have demonstrated that pharmacologic doses of diazepam cause depression of the brain stem ascending reticular activating system. In ad-
Volume 78 Number 4
Strychnine poisoning treated with diazepam
dition to these supraspinal effects, diazepam also has a direct suppressive action on spinal reflexes by selectively enhancing presynaptic inhibitory mechanisms, as This effect presumably opposes the stimulating action of strychnine on postsynaptic reflexes. Diazepam has been demonstrated to be a potent inhibitor of spinal reflexes in deeerebrate cats and of strychnine-induced convulsions in mice? 2 This theoretical pharmacologic interrelationship between strychnine and diazepam was the basis for using the latter as the only anticonvulsant medication in our patient. Diazepam has the advantage over barbiturates of being weakly hypnotic? 6 This patient remained conscious and was able to alert the staff to recurrent tetanic episodes so that diazepam could be administered before seizures occurred. Also, she remained alert enough to warn the nursing staff of anticipated vomiting so that precautions could be taken to avoid aspiration. Transient apnea, an u n c o m m o n but undesirable side effect of diazepam when used for status epilepticus, 2 did not occur in this patient. I n general the respiratory difficulties encountered with diazepam seem to be neither as frequent nor severe as those which a c c o m p a n y the profound depression which m a y occur following large doses of barbiturates. T h e clinical response of this patient and that of Heidrich and associates * to diazepam is encouraging. Diazepam appears to be very effective and to have a greater margin of safety than barbiturates. If further clinical experience supports its efficacy, diazepam may supplant barbiturates as the treatment of choice for the convulsions accompanying strychnine poisoning. REFERENCES 1. Aivazian, G. I-I.: Clinical evaluation of diazepam~ Dis. Nerv. Syst. 25: 491, 1964,
699
2. Bailey, D. W., and Fenichel, G. M.: The treatment of prolonged seizure activity with intravenous diazepam, J. PEDIAT. 73: 923, 1968. 3. Femi-Pearse, D.: Experience with diazepam in tetanus, Brit. Med. J. 2: 862, I966. 4. Howard, F. 32.: A new and effective drug in the treatment of the stiff-man syndrome, Proc. Mayo Clin. 38: 203, 1963. 5. Peirson, G. A., Fowlks, E. W., and King, P. S.: Long term follow-up on tile use of diazepare in the treatment of spasticity, Amer. J. Phys. Med. 47: 143, 1968. 6. Heidrich, H., Ibe, K., and Klinge, D.: Akute vergiftung mit strychnin N-oxydhydrochlorld und ihre behandlung mit diazepam, Arch. Toxik. 24: 188, 1969. 7. Goodman, L. S., and Gilman, A.: The pharmacological basis of therapeutics, New York, 1965, The Macmillan Company, pp. 345-348. 8. Gleason, 32. N., Gosselin, R. E., Hodge, H. C., and Smith, R. P.: Clinical toxicology of commercial products, Baltimore, 1969, The Williams & Wilklns Company, pp. 214-217. 9. Swissman, N., and Jacoby, J.: Strychnine poisoning and its treatment, Clin. Pharmacol. Ther. 5: 136, 1964. 10. Jacoby, J., and Boyle, J.: The treatment of strychnine poisoning with mephenesin, J. Lab. Clin. Med. 48: 270, I956. 1 l. Eccles, J. C.: The physiology of synapses, New York, 1964, Academic Press, Inc. 12. Randall, L. O., Heise, G. A., Schallek, W., Bagdon, R. E., Banziger, R. F., Boris, A., Moe, R. A., and Abrams, W. B.: Pharmacological and clinical studies on Valium, a new psychotherapeutie agent of the benzodiazeplne class, Curr. Ther. Res. 3: 405, 1961. 13. Schallek, W., Zabransky, F., and Kuehn, A.: Effects of benzodlazepines on the central nervous system of the cat, Arch. Int. Pharmacodyn. 149: 467, 1964. 14. Ngai, S. H., Tseng, D. T. C., and Wang, S. C.: Effect of diazepam and other central nervous system depressants on spinal reflexes in cats: A study of site of action, J. Pharmacol. Exp. Ther. 153: 344, 1966. 15. Schmidt, R. F., Vogel, 32. E., and Zimmerman, M.: Die wlrkung yon diazepam auf die pr~isynaptische Hemmung und andere Ruckenmarksreflexe, Arch. Exp. Pharmakol. Path. 258: 69, 1967. 16. Goodman, L. S., and Gilman, A.: The pharmacological basis of therapeutics, New York, 1965, The Macmillan Company, pp. 187-190.