Clinical Toxicology Downloaded from informahealthcare.com by University of Adelaide on 11/12/14 For personal use only.
CLINICAL TOXICOLOGY 8(3), pp. 277-282 (1975)
Treatment of Massive Poisoning by the Organophosphate Pesticide Methidathion
U. TEITELMAN, M. ADLER, and I. LEVY Rambam Hospital Haifa, Israel
S. DIKSTEI"* School of Pharmacy Jerusalem, Israel
This case report is interesting, since apart from giving a protocol for treatment of organophosphorus poisoning, it is the first involving methidathion (GS-13005), the active ingredient of Ciba Geigy's insecticide Supracid 40, which contains 40% methidathion, the rest being inactive carrier. CASE R E P O R T On September 4, 1973 at 1600 hr, Y.S., a 25-year-old f a r m e r who weighed 60 kg, was discovered unconscious by his family in the field near his orchard. It was subsequently discovered that at 1400 h r on the same day he had swallowed a number of mouthfuls of the insecticide Supracid 40, the container of which was found in the field next to him.
*Reprint request address: Professor S. Dikstein, P. 0. Box 12065, Jerusalem, Israel. 277 Copyright @ 1975 by Marcel Dekker, Inc. All Rights Reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means. electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher.
Clinical Toxicology Downloaded from informahealthcare.com by University of Adelaide on 11/12/14 For personal use only.
278
TEITELMAN ET AL.
On admission to the recovery room he was semicomatose but arousable and able to answer questions. His blood pressure was 160/100; the pulse rate was 45/min and regular. He was somewhat dyspnic. Marked perspiration was noted, and the mouth was full of saliva and mucus. The pupils were round, equal, and extremely miotic. Coarse crepitations, indicative of hypersecretion, were audible over both lungs. The r e s t of the physical examination, including a detailed neurologic examination, was negative. Over the next few hours, there were distinct fluctuations i n his level of consciousness, Treatment with atropine, Toxogonin, * and cortisol hemisuccinate 1.5 gm i.v./day was commenced. At the time of admission he received 500 mg of Toxogonin i.v. and 6 mg atropine sulfate i.v. His pulse rate decreased to 50/min, but pupils and the hypersecretory state remained unchanged. At 2100 h r he was transferred to the Intensive Care Unit where intubation and gastric lavage were performed. The latter produced fluid with the identical odor to that found in the Supracid 40 container. Over the next seven days he remained in critical condition, with high fever, in deep coma, with transient, changable neurologic findings. On the fourth day, he was clinically slightly icteric. Urine collected during the third day, showed no organic sulfur compounds in the heptane extraction phase when analyzed by gas chromatography. Since sensitivity for the detection of methidathion was 2 ng/pl, we concluded at that time that the patient was free of unmetabolized poison. Laboratory findings showed hemoglobin within normal limits (14-15%). There was a leukocytosis of 11,000-20,000 with a normal differential count. Platelets were normal. The serum bilirubin started rising on the fourth day and remained high for seven days, and varied between 2-4 mg% during this period. The serum amylase r o s e correspondingly and reached a level of 80 units between the fourth and eighth hospital day. The blood glucose was raised to 140 mg/%, and this was attributed to the fact that the patient received continuous intravenous infusions of hypertonic glucose solutions. The blood urea levels increased from 34 mg% on admission to 55 mg%o and the s e r u m creatinine clearance increased to 87 cc/min. Serum electrolytes, phosphorus and calcium, alkaline phosphatase, SGOT, SGPT, uric acid, and serum proteins were within normal limits.' The prothrombin dropped from 100% on admission to 35% on the fifth day. Other coagulation tests were normal. The cholinesterase activity in the serum was found to be zero a few hours after admission [ 11. *Toxogonin [ obidoxime chloride; 1- 1' -0xydimethylenebis- (4 formylpyridinium chloride)-dioxime 1.
Clinical Toxicology Downloaded from informahealthcare.com by University of Adelaide on 11/12/14 For personal use only.
MASSIVE POISONING BY METHIDATHION
279
Chest X-rays were persistently normal, but ECG demonstrated supra and ventricular premature beats when the artificial respirator was temporarily stopped. The treatment during this period follows and is summarized in Fig. 1. 1. Atropine was administered during the first 3 days in isotonic saline in increasing doses until a plateau of 175 mg/day was reached [2, 31. 2. On admission 500 mg i.v. of Toxogonin was administered; on the second and third day, four doses of 250 mg were given. When jaundice appeared on the fourth day, Toxogonin administration was terminated. 3. From the third day he received intravenous hyperalimentation (4liters of glucose 1 H o and 1 liter hydrolyzate of Casein-Amigen (Baxter Lab. Inc., U.S.A.) with supplementation of sodium and potassium according to need) through a catheter placed in the superior vena cava. The latter also allowed for central venous pressure measurements. 4. From the fourth day, to counteract low prothrombin values and possible hepatic damage, 40 mg of Mephyton bhytomenadione; Vitamin K1)was given daily. After four days, the prothrombin value returned to normal and the jaundice recessed. 5. Respiration was maintained on a volume respirator with the patient breathing a mixture of less than 40% oxygen. (The P 0 was a 2 kept constant at a level between 120-140 mm Hg.) 6. Cephalothin, 6 -/day, was given prophylactically. After the first week there was a definite but gradual improvement, and artificial respiration was terminated on the 15th day. At this time the daily dose of atropine was 12 mg/day. The initial abnormal laboratory findings were at this time normal with the exception of cholinesterase activity which remained low. Despite the i.v. hyperalimentation, the patient lost 8 kilos over this period. He continued to complain of severe generalized muscle weakness until the 18th day. Oral alimentation was commenced on the 15th day and the i.v. infusion was stopped a day later. He was then discharged in a satisfactory condition, and at follow-up examinations a t 2, 5, and 10 months, no abnormalities were detected and no delayed neurotoxicity was observed. DISCUSSION The indication for treatment with Toxogonin in these cases is far from clear. Our patient received Toxogonin until the appearance of jaundice, at which point it was stopped due to its known hepatotoxicity.
TEITELMAN ET AL.
280
Atropine
Clinical Toxicology Downloaded from informahealthcare.com by University of Adelaide on 11/12/14 For personal use only.
(mg 1
foxogonin 5oo Img 1
0
L
BIRD;
ENGSTROM
1
SPONTANEOUS
Bilirubin 2.0
:zOj 0
Urinarr outpu (ml/24 hrs )
t
2000
n " 1
2 3 4 5 6 7 8 9 10 ll 121314Kl617 181920
Days o f hospitalization FIG. 1. Summary of treatment.
Clinical Toxicology Downloaded from informahealthcare.com by University of Adelaide on 11/12/14 For personal use only.
MASSIVE POISONING BY METHIDATHION
281
This drug is especially efficient when given prophylactically, but its therapeutic value is as yet undetermined. Usually large doses of atropine proved to be the basic therapeutic measure in this case. This is in line with the accepted practice [2, 31. The best estimation of adequate atropinization can be made on the basis of the amount of salivation and tracheo-bronchial secretions. Pupil size, dryness of the skin, and heart rate were not found to be accurate indicators of adequate atropinization. It is our opinion that controlled volume respiration is indicated in these cases for as long as high doses of atropine a r e prescribed. This should be continued even when the patient is conscious and respiring spontaneously. We found that on each occasion when the artificial respirator was stopped, extra systoles both supra and ventricular made their appearance. It is more than likely that the high death rate in these patients can be attributed to cardiac arrythmias that make their appearance once artificial respiration is stopped. We found that those patients a r e especially sensitive to a drop in oxygen supply to the myocardium and that mechanical ventilation maintains an appropriate oxygen supply. Any precipitation in the kidney is prevented by assuring a urinary output over and above 2500 cc/day a s was achieved in our patient. The raised serum creatinine, despite the normal clearance, can be attributed to the excessive secretion of creatinine due to muscle fasciculations. Finally, we wish to speculate that the gradual deterioration observed in this patient during the first three days is due to the slow metabolism of methidathion to its oxygen analog (Gs-13007), which is far more toxic than the parent compound [ 41. Therefore, we advocate hospitalization and careful observation for at least one week even in cases of mild poisoning. ACKNOWLEDGMENT Our sincere thanks to Mrs. J. Schoenberg from the Ministry of Health, Institute for the Standardization and Control of Pharmaceuticals (Director: Dr. E. Weisenberg) for carrying out the pesticide analysis. REFERENCES
[ 11 G. L. Ellman e t al., A new and rapid colorimetric determination of acetylcholinesterase activity, Biochem. Pharmacol., (1961).
1, 88
Clinical Toxicology Downloaded from informahealthcare.com by University of Adelaide on 11/12/14 For personal use only.
282
TEITELMAN ET AL.
[ 2 ] M. N. Gleason et al., Clinical Toxicology of Commercial Products, Williams and Wilkens, Baltimore, Md., 1969, Sec. III, p. 185. [ 3 ] J. H. Davis et al., Occurrence, diagnosis, and treatment of organophosphoric pesticide poisoning in man, Ann. N.Y. Acad. Sci , . -7160 383 (1969). [4] Y. Dupuis e t al., The metabolic behaviour of the insecticidal phosphorus ester GS-13005, J. Economic Entomol., 64, 588 (1971).
CLINICAL TOXICOLOGY 8(3), pp. 277-282 (1975)
Treatment of Massive Poisoning by the Organophosphate Pesticide Methidathion
U. TEITELMAN, M. ADLER, and I. LEVY Rambam Hospital Haifa, Israel
S. DIKSTEI"* School of Pharmacy Jerusalem, Israel
This case report is interesting, since apart from giving a protocol for treatment of organophosphorus poisoning, it is the first involving methidathion (GS-13005), the active ingredient of Ciba Geigy's insecticide Supracid 40, which contains 40% methidathion, the rest being inactive carrier. CASE R E P O R T On September 4, 1973 at 1600 hr, Y.S., a 25-year-old f a r m e r who weighed 60 kg, was discovered unconscious by his family in the field near his orchard. It was subsequently discovered that at 1400 h r on the same day he had swallowed a number of mouthfuls of the insecticide Supracid 40, the container of which was found in the field next to him.
*Reprint request address: Professor S. Dikstein, P. 0. Box 12065, Jerusalem, Israel. 277 Copyright @ 1975 by Marcel Dekker, Inc. All Rights Reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means. electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher.
Clinical Toxicology Downloaded from informahealthcare.com by University of Adelaide on 11/12/14 For personal use only.
278
TEITELMAN ET AL.
On admission to the recovery room he was semicomatose but arousable and able to answer questions. His blood pressure was 160/100; the pulse rate was 45/min and regular. He was somewhat dyspnic. Marked perspiration was noted, and the mouth was full of saliva and mucus. The pupils were round, equal, and extremely miotic. Coarse crepitations, indicative of hypersecretion, were audible over both lungs. The r e s t of the physical examination, including a detailed neurologic examination, was negative. Over the next few hours, there were distinct fluctuations i n his level of consciousness, Treatment with atropine, Toxogonin, * and cortisol hemisuccinate 1.5 gm i.v./day was commenced. At the time of admission he received 500 mg of Toxogonin i.v. and 6 mg atropine sulfate i.v. His pulse rate decreased to 50/min, but pupils and the hypersecretory state remained unchanged. At 2100 h r he was transferred to the Intensive Care Unit where intubation and gastric lavage were performed. The latter produced fluid with the identical odor to that found in the Supracid 40 container. Over the next seven days he remained in critical condition, with high fever, in deep coma, with transient, changable neurologic findings. On the fourth day, he was clinically slightly icteric. Urine collected during the third day, showed no organic sulfur compounds in the heptane extraction phase when analyzed by gas chromatography. Since sensitivity for the detection of methidathion was 2 ng/pl, we concluded at that time that the patient was free of unmetabolized poison. Laboratory findings showed hemoglobin within normal limits (14-15%). There was a leukocytosis of 11,000-20,000 with a normal differential count. Platelets were normal. The serum bilirubin started rising on the fourth day and remained high for seven days, and varied between 2-4 mg% during this period. The serum amylase r o s e correspondingly and reached a level of 80 units between the fourth and eighth hospital day. The blood glucose was raised to 140 mg/%, and this was attributed to the fact that the patient received continuous intravenous infusions of hypertonic glucose solutions. The blood urea levels increased from 34 mg% on admission to 55 mg%o and the s e r u m creatinine clearance increased to 87 cc/min. Serum electrolytes, phosphorus and calcium, alkaline phosphatase, SGOT, SGPT, uric acid, and serum proteins were within normal limits.' The prothrombin dropped from 100% on admission to 35% on the fifth day. Other coagulation tests were normal. The cholinesterase activity in the serum was found to be zero a few hours after admission [ 11. *Toxogonin [ obidoxime chloride; 1- 1' -0xydimethylenebis- (4 formylpyridinium chloride)-dioxime 1.
Clinical Toxicology Downloaded from informahealthcare.com by University of Adelaide on 11/12/14 For personal use only.
MASSIVE POISONING BY METHIDATHION
279
Chest X-rays were persistently normal, but ECG demonstrated supra and ventricular premature beats when the artificial respirator was temporarily stopped. The treatment during this period follows and is summarized in Fig. 1. 1. Atropine was administered during the first 3 days in isotonic saline in increasing doses until a plateau of 175 mg/day was reached [2, 31. 2. On admission 500 mg i.v. of Toxogonin was administered; on the second and third day, four doses of 250 mg were given. When jaundice appeared on the fourth day, Toxogonin administration was terminated. 3. From the third day he received intravenous hyperalimentation (4liters of glucose 1 H o and 1 liter hydrolyzate of Casein-Amigen (Baxter Lab. Inc., U.S.A.) with supplementation of sodium and potassium according to need) through a catheter placed in the superior vena cava. The latter also allowed for central venous pressure measurements. 4. From the fourth day, to counteract low prothrombin values and possible hepatic damage, 40 mg of Mephyton bhytomenadione; Vitamin K1)was given daily. After four days, the prothrombin value returned to normal and the jaundice recessed. 5. Respiration was maintained on a volume respirator with the patient breathing a mixture of less than 40% oxygen. (The P 0 was a 2 kept constant at a level between 120-140 mm Hg.) 6. Cephalothin, 6 -/day, was given prophylactically. After the first week there was a definite but gradual improvement, and artificial respiration was terminated on the 15th day. At this time the daily dose of atropine was 12 mg/day. The initial abnormal laboratory findings were at this time normal with the exception of cholinesterase activity which remained low. Despite the i.v. hyperalimentation, the patient lost 8 kilos over this period. He continued to complain of severe generalized muscle weakness until the 18th day. Oral alimentation was commenced on the 15th day and the i.v. infusion was stopped a day later. He was then discharged in a satisfactory condition, and at follow-up examinations a t 2, 5, and 10 months, no abnormalities were detected and no delayed neurotoxicity was observed. DISCUSSION The indication for treatment with Toxogonin in these cases is far from clear. Our patient received Toxogonin until the appearance of jaundice, at which point it was stopped due to its known hepatotoxicity.
TEITELMAN ET AL.
280
Atropine
Clinical Toxicology Downloaded from informahealthcare.com by University of Adelaide on 11/12/14 For personal use only.
(mg 1
foxogonin 5oo Img 1
0
L
BIRD;
ENGSTROM
1
SPONTANEOUS
Bilirubin 2.0
:zOj 0
Urinarr outpu (ml/24 hrs )
t
2000
n " 1
2 3 4 5 6 7 8 9 10 ll 121314Kl617 181920
Days o f hospitalization FIG. 1. Summary of treatment.
Clinical Toxicology Downloaded from informahealthcare.com by University of Adelaide on 11/12/14 For personal use only.
MASSIVE POISONING BY METHIDATHION
281
This drug is especially efficient when given prophylactically, but its therapeutic value is as yet undetermined. Usually large doses of atropine proved to be the basic therapeutic measure in this case. This is in line with the accepted practice [2, 31. The best estimation of adequate atropinization can be made on the basis of the amount of salivation and tracheo-bronchial secretions. Pupil size, dryness of the skin, and heart rate were not found to be accurate indicators of adequate atropinization. It is our opinion that controlled volume respiration is indicated in these cases for as long as high doses of atropine a r e prescribed. This should be continued even when the patient is conscious and respiring spontaneously. We found that on each occasion when the artificial respirator was stopped, extra systoles both supra and ventricular made their appearance. It is more than likely that the high death rate in these patients can be attributed to cardiac arrythmias that make their appearance once artificial respiration is stopped. We found that those patients a r e especially sensitive to a drop in oxygen supply to the myocardium and that mechanical ventilation maintains an appropriate oxygen supply. Any precipitation in the kidney is prevented by assuring a urinary output over and above 2500 cc/day a s was achieved in our patient. The raised serum creatinine, despite the normal clearance, can be attributed to the excessive secretion of creatinine due to muscle fasciculations. Finally, we wish to speculate that the gradual deterioration observed in this patient during the first three days is due to the slow metabolism of methidathion to its oxygen analog (Gs-13007), which is far more toxic than the parent compound [ 41. Therefore, we advocate hospitalization and careful observation for at least one week even in cases of mild poisoning. ACKNOWLEDGMENT Our sincere thanks to Mrs. J. Schoenberg from the Ministry of Health, Institute for the Standardization and Control of Pharmaceuticals (Director: Dr. E. Weisenberg) for carrying out the pesticide analysis. REFERENCES
[ 11 G. L. Ellman e t al., A new and rapid colorimetric determination of acetylcholinesterase activity, Biochem. Pharmacol., (1961).
1, 88
Clinical Toxicology Downloaded from informahealthcare.com by University of Adelaide on 11/12/14 For personal use only.
282
TEITELMAN ET AL.
[ 2 ] M. N. Gleason et al., Clinical Toxicology of Commercial Products, Williams and Wilkens, Baltimore, Md., 1969, Sec. III, p. 185. [ 3 ] J. H. Davis et al., Occurrence, diagnosis, and treatment of organophosphoric pesticide poisoning in man, Ann. N.Y. Acad. Sci , . -7160 383 (1969). [4] Y. Dupuis e t al., The metabolic behaviour of the insecticidal phosphorus ester GS-13005, J. Economic Entomol., 64, 588 (1971).
