====== Ethchlorvynol ======

===== GENERAL =====

The miscellaneous anxiolytics, sedatives and hypnotics are a diverse group of drugs mostly with unknown mechanisms of action that produce central nervous system depression in overdose. Most are older drugs (chloral hydrate was synthesised in 1832) that have been superseded in clinical practice by the [[:wikitox:benzodiazepines|]]. In relatively small doses, the older agents can cause a profound, prolonged and occasionally cyclical coma, respiratory depression and death (especially when [[:wikitox:3.4.3.1_cardiac_arrhythmias_and_cardiac_arrest|cardiac arrhythmias]] accompany the toxic profile). Toxicity is even more severe with sedative coingestants, especially [[:wikitox:3.5.1_alcohol|alcohol]] and opiates, and advanced age is an additional risk factor for severe toxicity. These features have led to a questioning of their therapeutic role (1). Death has been reported after overdose with all the older agents.


===== TOXIC DOSE =====

In any discussion of toxic doses of sedative-hypnotic drugs, there will always be considerable variation due to interindividual differences in tolerance and the contribution or otherwise of active metabolites.

Chronic abusers of ethchlorvynol may ingest up to 4 g/day with only minor symptoms (38), however, death has been seen after acute ingestion of only 2.5 g alone (39) or in combination with alcohol (40). Deep coma occurred after ingestion of 12.5 g of the drug (41). Severe non-cardiogenic pulmonary oedema occurred following the intravenous injection of 25 to 40 mg/kg of ethchlorvynol (42;43).

While death has been reported after ingestion of 5 g (44) and up to 49.5 grams of ethchlorvynol (45), survival of doses from 25 to 45 g has been reported (45).


===== TOXICOKINETICS/TOXICODYNAMICS =====

In most cases, it is the development of tolerance to sedative-hypnotics that determines the recovery of consciousness after overdose rather than the clearance of the drug. In general, because of tolerance and the active metabolites of these drugs, there is a poor correlation between concentration and effect.

Mean peak serum concentration after 500 mg of ethchlorvynol was 6.5 mg/L at 1 h (82). Chronic abusers may ingest up to 4 g/day with steady state serum concentrations of up to 37 mg/L (38). Initial serum concentrations were reported at 70 mg/L in a somnolent yet totally conscious adult with evidence of tolerance (83).

Admission ethchlorvynol blood concentrations in a series of 38 overdose cases ranged from 3 to 46 mg/L in ethchlorvynol alone ingestions and from 3 to 75 mg/L when taken in combination with other agents (84). In pure ingestions, ethchlorvynol concentrations greater than 19 mg/L were usually associated with dysarthria, mydriasis, nystagmus, and tachycardia; when concentrations exceeded 38 mg/L, coma, areflexia, hypotension, and respiratory depression were generally noted as well (84).

Although serial estimations of ethchlorvynol can allow calculation of when the patient will achieve “therapeutic” concentrations (85) there can be a marked lack of correlation between concentrations of the drug and clinical status (86). In a series of nonfatal (51) and fatal (38) ingestions involving ethchlorvynol over a 14-year period (1975 through 1988), the concentrations in the (nonfatal) pure and mixed ingestions were similar (3 – 115 mg/L) and were little different to the concentrations in the fatal cases (5 – 258 mg/L) (87). Concentrations of 8 (45;86), 22 (45) and 85 mg/L (45) have been associated with coma in non-tolerant individuals.

===== PATHOPHYSIOLOGY =====

Intravenous ethchlorvynol interferes with the integrity of endothelial cells in the lung to create gaps between the cells and resultant reversible pulmonary oedema (119;120). The mechanism of the CNS depression is unknown. Tolerance, dependence and a withdrawal syndrome occur (39;121). Like the barbiturates, it can precipitate acute intermittent porphyria in susceptible individuals (122).

===== CLINICAL PRESENTATION =====

==== Acute overdose ====

Ethchlorvynol has a characteristic pungent, aromatic, “vinyl-like” odor (156). Severe poisoning produces a deep, often prolonged (86), coma with hypotension, respiratory depression and hypothermia (45). The coma is deep enough to result in pressure necrosis and [[:wikitox:3.4.15_rhabdomyolysis|rhabdomyolysis]] (168) and may be accompanied by flexor or extensor posturing (169) and acute urinary retention (170). In a series of 11 ethchlorvynol alone overdose cases, the most common physical findings were depressed level of consciousness (10 cases), dysarthria (7), mydriasis (6), nystagmus (6), areflexia (4), tachycardia (4), and hypotension, ataxia and respiratory depression (2 cases each) (84). In a series of 7 patients who ingested the drug, all were severely neurologically depressed; 3 were haemodynamically unstable and 1 developed noncardiogenic pulmonary edema 40 h after admission (43).

Intravenous injection of ethchlorvynol reproducibly causes a severe non-cardiogenic pulmonary oedema (42;43).


==== Acute withdrawal ====

Withdrawal from central nervous system depressants is dealt with in more detail in the [[:wikitox:management_of_alcohol_and_drug_withdrawal|drug withdrawal monograph]]. Suddenly stopping treatment in dependent people may produce withdrawal symptoms and signs including anxiety, dysphoria, irritability, insomnia, nightmares, sweating, memory impairment, hallucinations, hypertension, tachycardia, psychosis, tremors and seizures (227). The withdrawal syndromes associated with the older agents are similar to those associated with barbiturates (228); they are severe and likely to be associated with life-threatening events such as seizures. Acute withdrawal from sedative-hypnotics may present solely as a confusional state due to non-convulsive status epilepticus (toxic ictal delirium) which can easily be missed (229).


==== Adverse reactions ====

Side-effects of ethchlorvynol include gastrointestinal disturbances, dizziness, headache, unwanted sedation and other symptoms of CNS depression such as ataxia, facial numbness, blurred vision, and hypotension. Hypersensitivity reactions include skin rashes, urticaria, and occasionally, thrombocytopenia and cholestatic jaundice. Idiosyncratic reactions include excitement, severe muscular weakness, and syncope without marked hypotension (122).

===== DIAGNOSTIC TESTS =====

Routine quantitative drug estimation is not readily available for any of these agents and not indicated for routine management. Hepatic and renal function tests are indicated. Measurement of creatine kinase in cases of coma will help in the assessment of [[:wikitox:3.4.15_rhabdomyolysis|rhabdomyolysis]]. Core body temperature should be assessed as hypothermia is common. Chest X-ray is helpful to assess for non-cardiogenic pulmonary oedema in a patient with oxygen desaturation. Measurement of partial pressure of carbon dioxide via expired air or arterial blood gases is the best way to assess respiratory compromise from sedation.


==== Postmortem considerations ====

For many drugs, there is a postmortem diffusion of drugs along a concentration gradient, from sites of high concentration in solid organs, into the blood with resultant artifactual elevation of drug concentrations in blood (postmortem redistribution). Highest drug concentrations are found in central vessels such as pulmonary artery and vein, and lowest concentrations are found in peripheral vessels such as subclavian and femoral veins. This creates major difficulties in interpretation and undermines the reference value of data bases where the site of origin of postmortem blood samples is unknown (240). It is widely agreed, however, that the femoral vein site represents the optimum sampling site and this site is now standardised amongst forensic pathologists.

In 13 deaths due to ethchlorvynol, postmortem blood concentrations averaged 199 mg/L (range 14–400) (241). Even after embalming, a high concentration of ethchlorvynol (112 mg/L) was able to be identified in the bile (248).

===== TREATMENT =====

Oral [[:wikitox:3.2.2.2.3_activated_charcoal|activated charcoal]] within 1 hour of ingestion may be of some value in poisoning with the other drugs in this monograph.

More aggressive respiratory and cardiovascular support will be required for the older agents. Non-cardiogenic pulmonary oedema should be managed along conventional lines. In the face of continuing hypotension not responding to fluid resuscitation, inotropic agents may be required.

Patients with a significant sedative drug overdose should be advised not to drive until potential interference with psychomotor performance has resolved (260). For overdose of most of these agents this will be at least 48 hours after discharge.


==== Elimination enhancement ====

Principles of [[:wikitox:3.2.3_enhance_elimination_techniques|elimination enhancement]] are discussed in the Treatment monograph.

Although there are numerous case reports of the use of a variety of techniques in ethchlorvynol poisoning (278–281), there is unlikely to be any significant additional elimination of this drug with these techniques. This has been supported by more detailed studies indicating that removal of ethchlorvynol from the overdosed patient by haemoperfusion is limited by extensive distribution into and slow redistribution from body tissues (287). In a separate study, patients intoxicated with ethchlorvynol did not improve with charcoal haemoperfusion (288). Given the quality of supportive care that can be provided in centres capable of performing these techniques, there does not seem to be any indication to use extracorporeal elimination in ethchlorvynol poisoning.


==== Monitoring ====

Routine observation of vital signs, especially GCS airway patency and blood pressure, is indicated. For the older agents, continuous arterial blood pressure monitoring should be considered. Measurement of partial pressure of carbon dioxide via expired air or arterial blood gases is the best way to assess respiratory compromise from sedation.

===== REFERENCES =====

(1) Smith AJ, Whyte IM. New drugs for old: an issue for debate? Med J Aust 1988; 149(11–12):581-582

(39) Flemenbaum A, Gunby B. Ethchlorvynol (Placidyl) abuse and withdrawal (review of clinical picture and report of 2 cases). Dis Nerv Syst 1971; 32(3):188–192

(40) Harenko A. On special traits of acute ethchlorvynol poisoning. Acta Neurol Scand 1967; 43:Suppl. 31:141+

(41) Kathpalia SC, Haslitt JH, Lim VS. Charcoal hemoperfusion for treatment of ethchlorvynol overdose. Artif Organs 1983; 7(2):246-248

(42) Glauser FL, Smith WR, Caldwell A, Hoshiko M, Dolan GS, Baer H et al. Ethchlorvynol (Placidyl)-induced pulmonary edema. Ann Intern Med 1976; 84(1):46–48

(43) Schottstaedt MW, Nicotra MB, Rivera M. Placidyl abuse: a dimorphic picture. Crit Care Med1981; 9(9):677–679

(44) Cravey RH, Baselt RC. Studies of the body distribution of ethchlorvynol. J Forensic Sci 1968; 13(4):532–536

(45) Teehan BP, Maher JF, Carey JJ, Flynn PD, Schreiner GE. Acute ethchlorvynol (Placidyl) intoxication. Ann Intern Med 1970; 72(6):875–882

(51) Noirfalise A. [5 cases of suspected hexapropymate poisoning]. Eur J Toxicol 1971; 4(1):50–52. (52) Ellenhorn MJ, Schonwald S, Ordog G, Wasserberger J. Ellenhorn's Medical Toxicology: Diagnosis and treatment of human poisoning. 2nd ed. Baltimore: Williams & Wilkins, 1997

(82) Cummins LM, Martin YC, Scherfling EE. Serum and urine levels of ethchlorvynol in man. J Pharm Sci 1971; 60(2):261–263

(83) Kolpek JH, Parr MD, Marshall ML, Flueck JA. Ethchlorvynol pharmacokinetics during long-term administration in a patient with hyperlipidemia and hypothyroidism. Pharmacotherapy 1986; 6(6):323–327

(84) Kelner MJ, Bailey DN. Ethchlorvynol ingestion: interpretation of blood concentrations and clinical findings. J Toxicol Clin Toxicol 1983; 21(3):399–408

(85) Pochopien DJ. Rate of decrease in serum ethchlorvynol concentrations after extreme overdosage-a case study. Clin Chem 1975; 21(7):894–895

(86) Westerfield BT, Blouin RA. Ethchlorvynol intoxication. South Med J 1977; 70(8):1019–1020. (87) Bailey DN, Shaw RF. Ethchlorvynol ingestion in San Diego County: a 14-year review of cases with blood concentrations and findings. J Anal Toxicol 1990; 14(6):348–352

(119) Fischer P, Glauser FL, Millen JE, Lewis J, Egan P. The effects of ethchlorvynol on pulmonary alveolar membrane permeability. Am Rev Respir Dis 1977; 116(5):901–906

(120) Wysolmerski R, Lagunoff D, Dahms T. Ethchlorvynol-induced pulmonary edema in rats. An ultrastructural study. Am J Pathol 1984; 115(3):447–457

(121) Garza-Perez J, Lal S, Lopez E. Addiction to ethchlorvynol. A report of two cases. Med Serv J Can 1967; 23(5):775–778

(122) Sweetman S. Martindale: The Complete Drug Reference. London: Pharmaceutical Press. Electronic ed. expires 03/2003 Greenwood Village, Colorado: MICROMEDEX, 2003

(156) Goldfrank L, Weisman R, Flomenbaum N. Teaching the recognition of odors. Ann Emerg Med 1982; 11(12):684–686

(168) Chamberlain JM, Klein-Schwartz W, Gorman R. Pressure necrosis following ethchlorvynol overdose. Am J Emerg Med 1990; 8(5):467–468

(169) Greenberg DA, Simon RP. Flexor and extensor postures in sedative drug-induced coma. Neurology 1982; 32(4):448–451

(170) Voto SJ, Drake ME, Jr. Acute urinary retention precipitated by ethchlorvynol overdose. J Natl Med Assoc 1986; 78(9):896–897

(227) Benzodiazepines. In: Rossi S, Vitry A, Hurley E, Abbott F, Goldsworthy S, editors. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd, 2002

(228) Coupey SM. Barbiturates. [Review] [13 refs]. Pediatr Rev 1997; 18(8):260–264

(229) van Sweden B, Mellerio F. Toxic ictal delirium. Biol Psychiatry 1989; 25(4):449–458

(240) Pounder DJ, Jones GR. Post-mortem drug redistribution–a toxicological nightmare. Forensic Sci Int 1990; 45(3):253–263

(241) Rehling CJ. Poison residues in human tissues. Prog Chem Toxicol 1967; 3:363–386

(248) Winek CL, Wahba WW, Rozin L, Winek CL, Jr. Determination of ethchlorvynol in body tissues and fluids after embalmment. Forensic Sci Int 1988; 37(3):161–166

(278) Ogilvie RI, Douglas DE, Lochead JR, Moscovich MD, Kaye M. Ethchlorvynol (Placidyl) intoxication and its treatment by hemodialysis. Can Med Assoc J 1966; 95(19):954–956

(279) Hyde JS, Lawrence AG, Moles JB. Ethchlorvynol intoxication. Successful treatment by exchange transfusion and peritoneal dialysis. Clin Pediatr (Phila) 1968; 7(12):739–741

(280) Welch LT, Bower JD, Ott CE, Hume AS. Oil dialysis for ethchlorvynol intoxication. Clin Pharmacol Ther 1972; 13(5):745–749

(281) Koffler A, Bernstein M, LaSette A, Massry SG. Fixed-bed charcoal hemoperfusion. Treatment of drug overdose. Arch Intern Med 1978; 138(11):1691–1694

(287) Benowitz N, Abolin C, Tozer T, Rosenberg J, Rogers W, Pond S et al. Resin hemoperfusion in ethchlorvynol overdose. Clin Pharmacol Ther 1980; 27(2):236–242

(288) de Torrente A, Rumack BH, Blair DT, Anderson RJ. Fixed-bed uncoated charcoal hemoperfusion in the treatment of intoxications: animal and patient studies. Nephron 1979; 24(2):71–77