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Hong Kong Journal of Emergency Medicine Overdose of Dologesic with a fatal outcome: a case report CY Man Dologesic is a commonly prescribed analgesic in accident and emergency department. Yet report of overdose with this drug is not common. We report a case in which the patient developed cardiac arrest within an hour of ingestion. Dextropropoxyphene, a component of the drug Dologesic, used to be a common cause of fatalities after drug overdose in the seventies. It is highly toxic in overdose and therefore caution should be exercised when prescribing this drug. (Hong Kong j.emerg.med. 2001;8:207-211) Keywords: Arrthmias, cardiac arrest, dextropropoxyphene, naloxone, sodium bicarbonate Case history Our patient was a 41 years lady who had a quarrel with her husband on the day of admission. She rang her relatives subsequently, saying that she had taken many painkillers with alcohol, with the intention to commit suicide. Forty-five minutes after making the phone call, she was discovered unconscious by the relatives. When the ambulance arrived 7 minutes later, she was found to be in cardiac arrest. Basic life support was started immediately. On arrival at the Accident and Emergency department, she was in asystole. Advanced cardiac life support was instituted. A total of 5 mg of adrenaline was given (in 5 shots) and the patient regained pulse. The first blood pressure was 113/72 mmHg with pulse rate of 143 per minute, which gradually dropped to 66/41 mmHg with pulse rate of 110 per minute. Adrenaline infusion was started with good response (BP113/55 mmHg, pulse 106/min). The first ECG after restoration of heart beat showed wide-complex tachycardia. (Figure 1) Naloxone was not given. Correspondence to: Man Chi Yin, MRCP, FRCSEd, FHKAM(Emergency Medicine) Prince of Wales Hospital, Accident & Emergency Department, Shatin, New Territories, Hong Kong Email: [email protected] On physical examination, her general condition was poor. The temperature was 37.6 degrees Celsius (tympanic). She was comatose with the Glasgow Coma Score of 3/15. Her pupils were fixed and dilated. There was no spontaneous respiration. The chest air entry was satisfactory with artificial ventilation and was equal on both sides. Examination of her heart was normal. Gastric lavage was then performed followed by instillation of 50 g activated charcoal. The arterial blood gas (post-cardiac arrest) showed pH 6.9, PCO 2 9.1 kPa, PO 2 26.6 kPa (on 100% oxygen), HCO 3 15.2 mmol/L, Base excess -17.1 mmol/L. Plasma sodium and potassium were 146 mmol/L a n d 5 . 9 m m o l / L r e s p e c t i v e l y. T h e b l o o d glucose was 8.5 mmol/L and the haemoglobin was 13.9 g/dL. The remains of the four drugs suspected to have been taken by the patient were sent to the government forensic laboratory for analysis. They were subsequently confirmed to contain the following: drug 1 contains paracetamol and salicylamide, drug 2 contains paracetamol, chlorpheniramine and diphenhydramine, drug 3 contains oxybutynin, and drug 4 contains paracetamol and propoxyphene. This patient had a mixed drug overdose and the amount of the individual drugs taken unknown. There was also Hong Kong j. emerg. med. 208 Vol. 8(4) Oct 2001 associated alcohol intake. She was admitted to the intensive care unit (ICU) for further management. serum osmolality of 341 mOsm/Kg and urine osmolality of 244 mOsm/Kg which required DDAVP for control. Serum paracetamol level at 4 hours was 1.07 mmol/L. Serum salicylate level was 0.09 mmol/L which was in the therapeutic range (<1.80 mmol/L). The serum urea was 4.5 mmol/L, creatinine 102 umol/L, chloride 108 mmol/L, lactate 4.6 mmol/L, total protein 71 g/L, albumin 36 g/L, total bilirubin 2 umol/L, alkaline phosphatase 60 IU/L, ALT 34 IU/L, albuminadjusted calcium 2.33 mmol/L, amylase 107 U/L, phosphate 0.50 mmol/L, and magnesium 0.66 mmol/L. Plasma ethanol level was <2 mmol/L. Serum and urine propoxyphene levels were not checked. Haemoglobin was 13.8 g/dL, platelet count 205x10E9 /L, and total white cell count was 13.3x10E9/L. Her INR was 1.11 and APTT 28.0 seconds. She remained in metabolic acidosis which required treatment with sodium bicarbonate. Chest X-ray showed left lower zone haziness suggestive with aspiration pneumonitis. CT brain was performed and was normal. While in the ICU she required mechanical ventilation and inotrope infusion. N-acetylcysteine infusion was started and activated charcoal was given through the nasogastric tube at regular intervals. Intravenous cefuroxime and metronidazole were given. She subsequently developed myoclonus requiring sodium valproate for control, as well as diabetes insipidus with Twenty-four hours after admission to the ICU, she suddenly developed ventricular fibrillation which was refractory to treatment and she finally succumbed. Post-mortem report showed bilateral aspiration pneumonia, pulmonary edema and focal myocardial necrosis. Subsequent toxicology analysis confirmed that the patient's blood (taken after admitting to ICU) contained the following drugs: paracetamol (subtherapeutic level), lignocaine (therapeutic level), propoxyphene (therapeutic level) and metronidazole (sub-therapeutic level). Discussion Although the exact cause of her cardiac arrest at home was not known, the most likely cause was probably due to dextropropoxyphene (DXP) toxicity, as inferred from the presence of propoxyphene in the patient's blood. It is highly unlikely that paracetamol overdose Figure 1. Electrocardiogram of the patient showing wide-complex tachycardia. Man/Overdose of Dologesic with a fatal outcome: a case report have contributed to her cardiac arrest within an hour of ingestion. The lignocaine and metronidazole from the toxicological studies were probably administered after admission while the paracetamol and propoxyphene were taken by the patient. Furthermore, the fact that the propoxyphene in the blood of the patient was still at therapeutic level after admission suggested that the highest level was actually above the therapeutic level contributing to her cardiac arrest. It is unlikely that the other suspected drugs would cause cardiac arrest within 1 hour after ingestion. This is further supported by their absence in the patient's blood on toxicological analysis. The drug Dologesic, a very commonly prescribed drug for pain relief locally, contains paracetamol 325 mg and dextropropoxyphene 32.5 mg. Dextropropoxyphene (DXP) is an optical isomer of propoxyphene and it is this isomer that contains analgesic properties. Of the constituents of DXPparacetamol preparations, DXP has a far more immediate and dangerous effect than paracetamol. 1 Ever since its launch in the market in the early sixties, reports of death have occurred within a year. But it was not until the late seventies and early eighties that there has been a large increase of DXP poisonings in many countries. 2-7 In Sweden for example, DXP used to be one of the most prescribed analgesic compounds, 8 and the frequency of fatal poisoning by DXP ingestion was constantly high. 9 In UK during that period, it was suggested that many doctors were unaware of the danger of DXP in overdose and the problem of DXP poisoning had not been fully appreciated.10 It was also alleged by some authors that under-reporting of DXP fatalities may increase the risk that knowledge of its toxicity will not reach the population consuming this drug. 8 After reports of deaths from this drug and stricter regulation on the prescription, there was a decline in the incidence of DXP poisonings. 4,11-13 DXP is a highly toxic and lethal drug when taken in overdose. Its toxicity is highly potentiated by alcohol.2,4 The fatal dose may be as small as 15 tablets or possibly less in the DXP 32.5 mg and paracetamol 209 325 mg combination 4 (as in Dologesic). Blood propoxyphene concentrations of 0.2 mg/dl were found to be fatal. 14 Since the two drugs, paracetamol and DXP, have a fixed ratio in the compound preparation of Dologesic, the dose of the DXP (the effective lethal agent) can be inferred from the paracetamol dose calculated by its volume of distribution. 3 Many of the cases of poisoning are fatal at the time of discovery, and if patients survive, serious sequelae are extremely rare. 15 However, optic atrophy after DXP overdose was reported in 1982.16 In comparison with other drug fatalities, death characteristically occurs rapidly, as little as 1 hour after ingestion and usually before hospital treatment can be initiated. 4,14 It was suggested that the rapid death may be due to the predominant narcotic effects of DXP. 10 However, because of the high tissue concentrations and s l ow e l i m i n a t i o n o f a c t i v e D X P m e t a b o l i t e s ( e . g . n o r p r ox y p h e n e ) , s u d d e n u n p re d i c t a b l e deterioration may occur up to 24 hours. 14 This was the case with our patient. Therefore, continued and intensive monitoring after resuscitation is essential. Other patients may be unconscious, in severe respiratory depression, moderate circulatory failure, and quinidine-like changes in the ECG within 1 hour of ingestion. 17 In fact, because of the rapidity of deterioration, 40% of patients sustain irreversible cerebral damage before reaching resuscitation facilities. 18 In another study of 222 consecutive patients with DXP poisoning, 73% had neurological symptoms, 10% had convulsions on admission, 45% were in respiratory failure, and 48% had impaired circulation. The mortality was 8%.19 The cardiotoxic effects of DXP has been widely studied. The cardiovascular failure was found to respond flavourably to dopamine infusion. 20,21 Two cases of improvement of DXP-induced cardiovascular depression after naloxone infusion were reported by Hantson et al in 1995. 22 The occurrence of cardiac complications also appeared to be reduced by mechanical hyperventilation which induces hypocapnia. 23 In 1983, Heaney described the occurrence of left bundle branch block after acute DXP overdosage.24 It was transient and associated with Hong Kong j. emerg. med. 210 no permanent sequelae. Like tricyclic antidepressants, beta-adrenergic antagonists and chlorpromazine, DXP possesses membrane stabilising activity. It was suggested that this property, although regarded as being of little importance in therapeutic use, may be responsible for death in more that 30% of fatal poisonings.25 In 1989, it was found that the marked QRS widening and sodium channel blockage induced by DXP could be reversed with lignocaine. 26 From their animal experiments the authors found that both drugs (DXP and lignocaine) compete for a common receptor during the polarising phase. The more rapid dissociation of lignocaine during the recovery period leads to less blockage when both lignocaine and DXP were present than when exposure was due to DXP alone. In 1995, Stork et al first reported a case of DXPinduced wide complex arrhythmia that was responsive to sodium bicarbonate therapy. 27 In their case, the initial ECG showed a regular rhythm of 84 bpm, no discernable P-waves and a QRS duration 160 msec. The initial arterial pH was 7.16 and the bicarbonate 16 mmol/L. A total of 200 mmol of sodium bicarbonate was given via intravenous push followed by a continuous infusion of sodium bicarbonate (22.5 mmol/h). After the bicarbonate bolus, the QRS complex rapidly narrowed within 1 minute to 110 msec and the rhythm converted to normal sinus. The patient survived and the authors suggested sodium bicarbonate therapy may be a valid option for patients who develop wide complex arrhythmia after DXP overdose. Although the post arrest ECG is difficult to interpret and cannot be confidently attributed to DXP poisoning in our patient, it could serve to remind us of the possibility of DXP-induced ventricular arrhythmia. Our patient's pH remained low and a higher dose of sodium bicarbonate could have been given earlier on and subsequent deterioration of ventricular fibrillation might have been prevented. The importance of early diagnosis and treatment has been stressed by some authors in view of the potentially lethal complications of DXP overdose.28 In fact, it was claimed that half of the patients who arrived at medical facility in asystole could be resuscitated without sequelae.19 This makes early and aggressive treatment of DXP poisoning particularly relevant and mandatory. Vol. 8(4) Oct 2001 Other treatment modalities have also studied. Plasmapheresis, has been reported to be effective in improving the conscious level of the patients, and of six patients heavily intoxicated by DXP treated with this method, 5 survived and only one died.29 On the other hand, there was a case report of DXP poisoning failing to respond to therapeutic doses of naloxone. When 20 times of the manufacturer's recommended dosage was given, the patient responded immediately.30 The authors suggested that if there is no response within two minutes of the initial 0.01 mg/kg dosage of naloxone hydrochloride, a second dose 0.1 mg/kg (ten times the manufacturer's recommended dose) be given. Our patient, however did not received any naloxone. In conclusion, our patient had mixed drug overdose with alcohol which was fatal and the dextropropoxyphene in Dologesic was the mostly likely cause of death. Dologesic is a commonly prescribed analgesic in current medical practice. Death after drug overdose is rare nowadays and the rapid deterioration to cardiac arrest within one hour of ingestion is even rarer. Hopefully this will alert physicians to the potential lethality of this common drug and consequently to exercise due caution when prescribing. References 1. 2. 3. 4. 5. 6. Sengupta A, Peat MA. Propoxyphene overdosage: a study of cases involving analgesic. Arch of Toxicol 1977; 37(2):123-33. Jonasson U, Jonasson B, Saldeen T. Middle-aged mena risk category regarding fatal poisoning due to dextropropoxyphene and alcohol in combination. Prev Med 2000;31(2 Pt 1):103-6. Obafunwa JO, Busuttil A, al-Oqleh AM. Dextropropoxyphene-related deaths-a problem that persists? Int J Legal Med 1994;106(6):315-8. Whittington RM. Dextropropoxyphene deaths: coroner's report. Hum Toxicol 1984;3 Suppl:175S-185S. Whittington RM, Barclay AD. The epidemiology of dextropropoxyphene (Distalgesic) overdose fatalities in Birmingham and the West Midlands. J Clin Hosp Pharm 1981:6(4):251-7. Simonsen J. Accidental fatal drug poisoning with particular reference to dextropropoxyphene. Forensic Sci 1977;10(2):127-32. Man/Overdose of Dologesic with a fatal outcome: a case report 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. Rejent TA, Michalek RW, Lehotay JM. Propoxypheneassociated deaths: methods, post-mortem levels in blood and liver. Clin Toxicol 1977;11(1):43-51. 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Severe, acute propoxyphene overdose treated with dopamine. J Toxicol Clin Toxicol 1985;23(4-6):347-52. 22. Hantson P, Evenepoel M, Ziade D, et al. Adverse cardiac manifestations following dextroporpoxyphene overdose: can naloxone be helpful? Ann Emerg Med 1995;25(2):263-6. 23 Schou J, Angelo H, Dam W, et al. Pharmacokinetics of dextropropoxyphene in acute poisoning. Arch Toxicol Suppl 1978;(1):343-6. 24. Heaney RM. Left bundle branch block associated with propoxyphene hydrochloride poisoning. Ann Emerg Med 1983;12(12):780-2. 25. Henry JA, Cassidy SL. Membrane stabilising activity: a major cause of fatal poisoning. Lancet 1986;1(8495): 1414-7. 26. Whitcomb DC, Gilliam FR, Starmer CF, et al. Marked QRS complex abnormalities and sodium channel blockade by propoxyphene reversed with lidocaine. J Clin Invest 1989;84(5):1629-36. 27. Stork CM, Redd JT, Fine K, et al. Propoxypheneinduced wide QRS complex dysrhythmia responsive to sodium bicarbonate- a case report. 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