954 Ogilvie and others: Canad. Med. Ass. J. Ethchlorvynol Intoxication Nov. 5.1966, vol. 95 Ethchlorvynol (Placidyl) Intoxication and Its Treatment by Hemodialysis RICHARD I. OGILVIE, M.D.,* DONALD E. DOUGLAS, M.Sc, Ph.D., P.Chem.,f JOHN R. LOCHEAD, M.D4 MICHAEL D. MOSCOVICH, M.D.ff and MICHAEL KAYE, M.B., B.S., F.R.C.P. [C], F.A.C.P.,§ Montreal

Twenty hours after ingesting 15-25 g. of ethchlorvynol, Vingt heures apres avoir ingere de 15 a 25 g. d'eth- a 37-year-old woman was admitted comatose and in chlorvynol, une femme de 37 ans etait hospitalisee, shock. The blood level of ethchlorvynol was 21.6 mg. dans un etat de coma et de choc. D'apres la methode % (method of Wallace). Supportive measures were de Wallace, sa concentration sanguine de medicament instituted and hemodialysis, carried out for 10 hours, ^tait de 21.6 mg. %. On prit les mesures de soutien et removed 5.49 g. of the drug. The post-dialysis blood l'hemodialyse, appliqu£e pendant 10 heures, permit level was 9.05 mg. % and the rate of dialysance was d'eliminer 5.49 g. du medicament. La concentration 50.5 ml./min. Only 0.6 g. of the substance was re¬ sanguine apres dialyse &ait de 9.05 mg. % et la vitesse covered from the urine over the same period. de dialysance de 50.5 ml./min. Sur la meme periode, Although dialysis removed significant amounts of on ne put recuperer que 0.6 g. de medicament dans the drug and sustained life, the patient remained Turine. comatose for five days before withdrawal symptoms Malgre la quantite notable de drogue eliminee par and seizures developed. la dialyse, qui permit de soutenir la vie, la patiente resta comateuse pendant cinq jours avant que ne se with sedatives and manifestent les symptomes de sevrage et les con¬ JNTOXICATIONS tranquil- vulsions. .*. lizers have become common clinical problems and the use of dialysis has been the accepted treat¬ ment in many instances.1,2 The present report after intubation, no pulse or blood pressure could be concerns a patient who had ingested a suicidal dose obtained and heart sounds were absent. With ECG of ethchlorvynol (Placidyl) and was treated confirmation of asystole, closed-chest cardiac massage with and was instituted and 0.10 mg. of isoproterenol given successfully hemodialysis supportive Sinus measures. intravenously. rhythm returned almost imme¬ diately and the systolic blood pressure rose to 60 mm. Hg. Because of her A 37-year-old housewife was admitted in a comatose precarious condition, preparations were for a state on December 6, 1965, 20 hours after ingesting made hemodialysis. Over three-hour period from 30 to 50 500-mg. ethchlorvynol capsules. A the following intravenous fluids were given: 2000 ml. admission in 1964 for a duodenal ulcer 5% glucose in saline, 500 ml. 5% glucose in water, 300 previous ml. 20% 900 and pyloric obstruction necessitated a 50% gastrectomy, mannitol, ml. dextran in saline and 500 vagotomy and Billroth I anastomosis. Nine months ml. whole blood. Her jugular venous pressure remained later, post-gastrectomy steatorrhea with fecal fat of normal throughout, but a continuous infusion of iso¬ 16 g./day was diagnosed but further studies were proterenol (30 jug./hr.) was necessary to maintain a not undertaken, as the patient was under treatment systolic blood pressure of 90 mm. Hg. Urine output this was for depression. In May 1965, she took a mild overdose during three-hour period 1300 ml. of tranquillizers and barbiturates and, after treatment Twenty-three hours after ingestion of the drug, the with intravenous fluids, made an uneventful recovery. patient underwent a 10-hour hemodialysis with the Travenol twin-coil catheters in At initial was a dialyzer using placed physical examination, she comatose, the left femoral and vein. She remained thin woman. She was had a artery deeply apneic, systolic blood comatose the entire her reflexes of 40 mm. a of and con- during procedure; pressure Hg, pulse 70/min., were absent and she did not to Bio¬ stricted pupils which reacted sluggishly to light. No respond pain. other of chemical determinations of ethchlorvynol levels were abnormalities the head, neck, chest and the method of Wilson and cardiovascular were was a performed using Wallace, systems noted. There mid- Dahl.3 The blood 20 hours after scar on the abdomen. The extremities were pre-dialysis level, epigastric was 21.6 %. The blood level flaccid and areflexia She did not respond to painful ingestion, mg. post-dialysis stimuli. was 9.05 mg. %; 5.49 g. was recovered in the dialysate. The urine output the was 1750 ml. A cuffed tube was during procedure endotracheal inserted and posi¬ and contained 0.6 g. of The tive ventilation with an ethchlorvynol. dialysance pressure automatically trig- of ethchlorvynol was calculated at 50.5 ml./min. Tests mechanical was One-half hour gered respirator begun. for alcohol and barbiturate in blood and urine were negative. From the Renal Service and Division of Clinical Chemistry, Department of Medicine, The Montreal General Hospital, Following dialysis the patient's neurological state Montreal, Quebec. was Blood pressure was maintained with ?Resident in Medicine, The Montreal General Hospital. unchanged. tSenior Biochemist, Director of the Toxicology Laboratory. the isoproterenol infusion and three units of whole ^Assistant Resident in Medicine, The Montreal General Hos¬ pital. blood were given to correct a low post-dialysis hema¬ flAssistant Resident in Medicine, The Montreal General Hos¬ tocrit. On the second normal and pital. day, systolic pressure SAssociate Physician and Director of the Renal Service, The cardiac output were maintained without this vaso- Montreal General Hospital. pressor infusion. Because the patient remained Reprint requests to: Dr. Richard I. Oefilvie, Department of apneic Medicine, The Montreal General Hospital, Montreal 25, on the third day, a tracheostomy was done so that the Quebec. endotracheal tube could be removed. By the fifth post- Canad. Med. Ass. J. Nov. 5,1966, vol. 95 Ogilvie and others: Ethchlorvynol Intoxication 955

dialysis day, she responded to commands, and the determination. They described venous blood con¬ tracheostomy was closed. centrations in three adults after ingestion of 500 She had weakness in both lower limbs and dimin¬ mg. of the drug after a 12-hour fast. Maximum ished sensation to all modalities in the left leg. A blood levels (0.39-0.44 mg. %) were achieved after convulsion on the seventh generalized occurring day 60 to 180 minutes and significant levels were still was treated with barbiturates and diphenylhydantoin. detectable at six hours. of the These were withdrawn when no further seizures Approximately 10% drugs dose was recovered from the urine within occurred. Her serum calcium was 8.7 mg. % and ingested the first 24 hours. was a serum magnesium 0.75 mEq./l. The electroencephalo¬ There rapidly diminishing gram (EEG) showed considerable slowing and other urinary excretion of the drug thereafter. These find¬ abnormalities in the mid-temporal region. ings are in contrast to those of Algeri, Katsas and Investigations of intestinal absorption showed a Luongo,5 who found no blood level after four fecal fat of 5.76 g./day, normal serum B12 and folate hours and could not detect the drug in the urine levels, and a normal small bowel pattern on barium with their method. Serum iron was 38 % with an unsaturated series. fxg. Reports of intoxications with ethchlorvynol are iron binding capacity (UIBC) of 397 fig. %. Liver func¬ however, clinical with this tion studies were normal except for a serum glutamic infrequent; experience transaminase of 58 units (normal: 15-35). Fast¬ drug is increasing each year. Four such patients pyruvic were described two of them had ataxia ing blood sugar and serum creatinine were normal. by Cahn;6 Because of her mental status it was necessary to with confusion and hallucinations. One had grand transfer the patient to a psychiatric institution before mai seizures after drug withdrawal. Exaggerated further studies could be carried out. At the time of reactions may occur if the drug is taken with al¬ discharge, the neurological deficits had advanced to cohol. Alcoholics taking as little as 0.5-1.0 g. may bilateral weakness of plantar flexion and dorsiflexion of suddenly collapse and remain comatose for hours.7 both legs, and a sensory deficit to all modalities bilater¬ Habituation, tolerance and physical dependence ally to the mid thigh. She is now receiving psychiatric may with 1.5 Persons 10-25 treatment and at another develop g. daily. taking physiotherapy hospital. g. have remained comatose for five to seven days, with depressed respirations and blood pressure; Discussion this has been followed by complete recovery. Al¬ Ethchlorvynol is a tertiary acetylenic alcohol geri, Katsas and Luongo5 reported autopsy findings stated to be a more potent central nervous system in two patients with fatal intoxications. Both had depressant than either primary or secondary al- blood levels of 14 mg. %; in one, this followed the cohols. It is said to produce less initial excitement ingestion of only 10 g. Death has occurred follow¬ than do the barbiturates, and to have muscle-relax- ing the ingestion of 49.5 g. ant and anticonvulsant properties, but its main use Hemodialysis has been used infrequently in the has been as a mild sedative and hypnotic.4 Little treatment of acute ethchlorvynol intoxication. Wes- is known about the fate of this drug in the human tervelt8, 9 reported two such cases. The first was body. Two different methods for determining blood a 22-year-old man who had ingested 6.0 g. of and tissue levels have been described and as yet ethchlorvynol and 1.1 g. of secobarbital. The initial these have not been compared. Studies done with blood level of ethchlorvynol 14 hours after inges¬ these two methods show divergent results with tion was 4.5 mg. % (Algeri phloroglucinol method). respect to the absorption, blood levels and clear¬ Subsequent in vitro determinations showed that ance, and urinary excretion of this drug. ethchlorvynol dialysance ranged from 20 to 98 Algeri, Katsas and Luongo5 described a colouri- ml./min. and was dependent on blood flow. In the metric method based on reaction of phloroglucinol second case the initial blood level was 7.2 mg. %; and concentrated HCI with the allyl group of in vivo dialysance was 48-93 ml./min. and 2130 ethchlorvynol. This method is time-consuming and mg. was recovered in the dialysate after 14 hours. cannot be performed in the presence of many A third such case in which hemodialysis was em¬ substances, including other drugs in concentrations ployed has been reported.10 After the ingestion of over 500 /ig./ml. These authors reported absorp¬ 25 g. of ethchlorvynol, the blood level was 5.0 tion studies in two adult patients without fasting. /xg. % (Algeri method); there was no measurable A single oral dose of 1.0 g. (approximately 12 mg./ fail in blood concentration after 13 hours of dialysis kg. body weight) was given to each. A maximum and only 50 jig. was recovered in the dialysate. blood level of 1.4 mg./lOO ml. was achieved 60 to The use of peritoneal dialysis has been suggested 90 minutes after ingestion; it decreased rapidly by Barry and Schwartz,2 although no clinical in¬ thereafter and the drug was no longer detectable formation was given. A single case of ethchlor¬ in the blood at the fourth hour. Symptoms of cen¬ vynol intoxication has been reported in which blood tral nervous system depression appeared within 30 levels were determined by the method of Wallace, to 60 minutes. Wilson and Dahl:3 that of a 32-year-old woman The method used in our laboratory, that of Wal¬ who had a blood level of 11.1 mg. % seven hours lace, Wilson and Dahl,3 is based on the formation after ingestion of 20-25 g.11 Peritoneal dialysis re¬ of a carbonyl derivative of ethchlorvynol following moved 3.4 g. of the drug in 42 hours. During the reaction of its vinyl chloride group in aqueous same period 3.42 g. of ethchlorvynol was excreted acid solution and subsequent spectrophotometric in the urine. 956 OGILVIE AND OTHERS: ETHCHLORVYNOL Canad. Med. Ass. J. INTOXICATION Nov. 5, 1966, vol. 95

The present patient was admitted to hospital 20 tient underwent a typical withdrawal period char- hours after the ingestion of 15-25 g. of ethchlor- acterized by lethargy, apathy, confusion and dis- vynol, comatose and in shock. Cardiopulmonary orientation; she had hallucinations and a grand arrest responded to external cardiac massage, iso- mal seizure. We have no specific explanation for proterenol and respiratory assistance. The large the development of peripheral neuropathy except volume of fluids that was administered to this pa- that she suffered from malnutrition and pressure tient without increasing the central venous pressure ischemia, and had temporary dialysis catheters in indicates that the primary mechanism of hypoten- the left leg. There are no previous reports of eth- sion and shock was an expansion of intravascular chlorvynol-induced peripheral neuropathy.13 capacity and a deficit of effective circulating blood volume. This is in accordance with the hypothesis SUMMARY of Shubin and Weil,12 who postulate that the ven- A successfully treated case of ethchlorvynol intoxica- ous capacitance bed is the major site of pooling in tion has been described. The patient's course was intoxications with barbiturates, narcotics or tran- complicated by shock, cardiac arrest, withdrawal symp- quillizers. That a myocardial factor was also opera- toms and seizures. Hemodialysis was shown to remove tive is indicated by the response of the blood pres- significant quantities of the drug. sure and cardiac output to isoproterenol intravenous drip. ADDENDUM The initial blood level in this patient 20 hours Since completion of the foregoing manuscript, Wester- after ingestion of the drug, determined by the velt14 has reviewed his experience with ethchlorvynol in- toxication, and reports two cases in which hemodialysis method of Wallace, Wilson and Dahl,3 was over removed significant quantities of the drug. 50 times the maximum blood level achieved one The analyses were performed by Miss I. Dobuschak, hour after ingestion of 0.5 g. A total of 5.49 g. was whose help is gratefully acknowledged. recovered in the 10-hour dialysate, while only 0.6 g. was recovered in the urine over the same period. REFERENCES This confirms that the renal clearance is low, as 1. CLARK, J. E. AND SORICELLI, R. R.: Med. Olin. N. Amer., 49: 1213, 1965. reported previously.3 The dialysance, calculated at 2. BARRY, K G. AND SCHWARTZ, F. D.: Pediat. Clin. N. Amer., 11: 593, 1964. 50.5 ml./min., cannot be compared to the figures 3. WALLACE, J. E., WILSON, W. J., JR. AND DAHL, E. V.: J. Forensic Sci., 9: 342, 1964. given by Westervelt,9 who used Algeri, Katsas and 4. P'AN, S. Y. et al.: J. Pharmacol. Exp. Ther., 114: 326, 1955. Luongo's method. 5. ALGERI, E. J., KATSAS, G. G. AND LUONGO, M. A.: Amer. J. Olin. Path., 38: 125, 1962. Although dialysis of the present patient was 6. CAHN, C. H.: Canad. Med. Ass. J., 81: 733, 1959. 7. KUENSSBERG, E. V.: Brit. Med. J., 2: 1610, 1962. undoubtedly successful in lowering blood levels, 8. WESTERVELT, F. B., JR.: Olin. Res., 13: 55 1965. 9. Idem: Quoted by Maher, J. F. and Schreiner. G. E.: removing significant amounts of the drug from the Trans. Amer. Soc. Artif. Intern. Organs, 11: 394, 1965. body, and sustaining she remained 10. MAHER, J. F. AND SCHREINER, G. E.: Ibid 11 s349, 1965. life, comatose 11. SCHULTZ, J. C., CROWDER, D. G. AND MEDART W. S.: for five days. This experience resembles that in Arch. Intern. Med. (Chicago), 117: 409 1966. 12. SHUBIN, H. AND WEIL, M. H.: Amer. J. Med., 38: 853, patients previously reported who survived without 1965. 13. NASH, P. H.: Personal communication. dialysis. After recovery of consciousness, this pa- 14. WESTERVELT, F. B., JR.: Ann. Intern. Med., 64: 1229, 1966.

PAGES OUT OF THE PAST: FROM THE JOURNAL OF FIFTY YEARS AGO THIS DIRE DISEASE of the past, physicians noted any indications of a convey- ance of the infection from one child to others in the same Epidemic poliomyelitis is a comparatively new disease. family, the possibility of such transmission must now be Scarcely half a century has elapsed since Heine published regarded as definitely proven. Not only may the disease the first known description of the disease under the name germs be conveyed from the sick to the well, but un- of spinal infantile paralysis. Sporadic cases have doubtless doubtedly may be carried by those who have come in occurred in the past. Sir Walter Scott is said to have suf- contact with the sick and thus infect others at a distance. fered from it in early infancy. Sir William Osler suggests It becomes imperative, therefore, that in such a disease that this disease was the cause of Mephibosheth's lameness. the physician should insist on the strictest quarantine mea- In Canada slight epidemics have occurred both in Nova sures in the affected household, and exercise most careful Scotia and Ontario, bt up to the present no extensive precautions in his own person while attending the sick. epidemic has developed, but sporadic cases have not been An important fact which has doubtless contributed greatly infrequent. It is evident, however, that unless great care to the spread of the disease in the past is the nunber of is exercised this dire disease with its crippling results may so called "abortive" cases in which the disease is not recog- develop suddenly in epidemic form. Careful investigation nized, and yet in which the organisms are present which shows that the disease spreads along the ordinary routes may transmit the disease to others in a virulent form. In of travel. The virus of this disease, to a greater degree than these atypical forms in which paralysis does not occur, and is the case with other infectious diseases, apjears to be recovery from transient initial sym-ptoms leaves the motor subject to variations in which its virulence becomes in- centres uninjured, diagnosis is always very difficult, espe- creased or lessened, and at the same time 'also its powers cially as at the present all laboratory methods for the iden,ti- of transmission, but the exact conditions under which these fication of the organism are extremely difficult and for the mutations of virulence occur have not yet been accurately ordinary bacteriologist impossible.-Editorial, Canad. Med. determined. While it was seldom that in the sporadic cases Ass. J., 6: 916, 1916.