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Hong Kong Journal of Emergency Medicine A case of fatal hydroxychloroquine overdose , KK Lam HT Fung , OF Wong , B Lau , CW Kam A 28-year-old woman ingested 20 g of hydroxychloroquine sulphate for suicidal attempt. She developed hypotension, cardiac conduction disturbance, hypokalemia and hypoglycemia. Despite treatment with mechanical ventilation, epinephrine, sodium bicarbonate, diazepam and potassium replacement, she succumbed 10 hours post-overdose. Previous case reports of hydroxychloroquine overdose are summarised and the therapeutic choices are discussed. (Hong Kong j.emerg.med. 2007;14:53-57) 28 20 10 Keywords: Diazepam, hydroxychloroquine, hypoglycemia, hypokalemia, overdose Case A 28-year-old woman having systemic lupus erythematosis and history of attempted suicide, presented to the emergency department in August 2006, about one hour after ingesting 100 tablets of 200 mg hydroxychloroquine sulphate (each tablet containing 155 mg hydroxychloroquine base). At presentation, she had Glasgow Coma Score (GCS) 3/15, blood pressure (BP) 46/21 mmHg, pulse rate 68/min, respiratory rate 22/min, blood glucose 2.6 mmol/L, serum potassium 3.6 mmol/L and ECG of QRS 152 ms and QTc 428 ms (Figure 1). Twenty grams of dextrose given intravenously Correspondence to: Fung Hin Tat, MRCP, FRCSEd, FHKAM(Emergency Medicine) Tuen Mun Hospital, Accident & Emergency Department, Tsing Chung Koon Road, Tuen Mun, N.T., Hong Kong Email: [email protected] Lam Ka Keung, MBBS, MRCSEd, FHKAM(Emergency Medicine) Wong Oi Fung, MBChB, MRCSEd Lau Bun, MBBS, MRCSEd Kam Chak Wah, MRCP, FRCSEd, FHKAM(Emergency Medicine) brought her GCS to 15/15 and blood glucose to 13.4 mmol/L. The BP was improved to 80/50 mmHg after infusion of 1 L of normal saline. Gastrointestinal decontamination was performed with 50 g of oral activated charcoal but gastric lavage was not done. She was later transferred to the Intensive Care Unit. She remained conscious but the BP and central venous pressure were 57/35 mmHg and 26 cmH2O respectively. She was intubated and put on synchronised intermittent mandatory ventilation mode of mechanical ventilation. The medications given included intravenous diazepam 60 mg followed by infusion of 2 mg/h, epinephrine 20 µg/min and sodium bicarbonate 100 mmol. The serum potassium three hours after the overdose was 1.5 mmol/L. Potassium chloride of 20 mmol was given over one hour followed by a maintenance infusion of 1.6 mmol/h. Her BP was sustained well above systolic 100 and diastolic 60 mmHg one hour after starting the epinephrine drip. At six hours post-overdose, the QRS Hong Kong j. emerg. med. Vol. 14(1) Jan 2007 54 Figure 1. The ECG on emergency department arrival. Arm lead reversal was present. and QTc were shortened to 110 ms and 379 ms respectively while the blood results were: pH 7.32, HCO 3 1 9 . 6 m m o l / L , p O 2 2 4 . 3 k Pa , s o d i u m 153 mmol/L and potassium 2.4 mmol/L. There was no more hypoglycemic episode under a 10% dextrose infusion. Echocardiographic imaging revealed poor global ventricular contractility with an ejection fraction of 35%. She developed pulseless ventricular tachycardia 9.5 hours post-ingestion and was certified dead half an hour later. Post-mortem examination was waived. Discussion Hydroxychloroquine is synthesised by adding a hydroxyl group to an N-ethyl group of chloroquine rendering it 2-4 times less toxic.1 As hydroxychloroquine and chloroquine share similar str uctural and pharmacological properties, and there is relatively richer experience with chloroquine toxicity, most of the following discussions are based on studies of chloroquine poisoning. Hydroxychloroquine poisoning is rarely reported. From a literature search, there were 20 cases but a few were in abstract form or non-English languages. Information of doses, clinical presentations and treatments were not always available. The features of all these cases are depicted in Table 1. 2-16 Many of them suffered from hypotension, widened QRS and hypokalemia. The overall mortality was 25%. One case presented with a blood glucose level of 3.4 mmol/L with GCS of 15/15.11 Another presented with slurred speech, drowsiness, blood glucose of 3.2 mmol/L and blood pressure of 63 mmHg by palpation. She was resuscitated with fluid boluses and dopamine. Four hours later, the blood pressure was 100/74 mmHg. She was drowsy but oriented, and she complained of nausea. She was haemodynamically stable over the next three days but further description of her sensorium was not available. Repeat blood glucose measurement was not reported and no dextrose replacement was mentioned. According to the contents of the case report, she remained drowsy over the first four hours after arrival but minor improvement of consciousness might exist as judged Fung et al./Fatal hydroxychloroquine overdose 55 appeared. The drop in the mortality of rats administered LD 50 chloroquine correlated with increasing diazepam doses up to 20 mg/kg. Doses greater than 20 mg/kg increased the mortality as a result of respiratory depression.17 In a prospective study of more than 5 g chloroquine ingestion utilising historical control, 10 of the 11 study patients receiving immediate mechanical ventilation and administration of diazepam (2 mg/kg followed by 1-2 mg/kg/day for 2-4 days) and epinephrine (0.25 µg/kg/min with increments of 0.25 µg/kg/min until systolic BP ≥100 mmHg) survived whereas only 1 of the 11 controls survived.18 However inotropes other than epinephrine were often co-administered and treatment details of the historical controls were not described. A retrospective uncontrolled trial was carried out by other relevant parameters. As no dextrose replacement was given, it was likely that the clinicians did not consider she was suffering from hypoglycemia. From a retrospective view, the BP correction might account for the consciousness improvement, if any, but we cannot rule out that she was under a minor hypoglycemic attack up to four hours post-arrival.13 Our case is one of the two ingesting the second largest dose and the first one with hypoglycemia and precise documentation of the GCS and blood glucose response to intravenous dextrose. In the 1970s, toxic dose chloroquine ingestion was observed in a patient with diazepam co-ingestion, producing no intoxication.17 Since then, studies of the protective effect of diazepam on chloroquine poisoning Table 1. Summary of the case reports of hydroxychloroquine overdose Ref. Age Dose BP QRS QTc Arrhythmia Glucose K+ Diazepam (g) (mmHg) (ms) (ms) (mmol/L) (mmol/L) 2 Adult ? 7.2 40/? 3 16 10.8 4 16 12 5 42 6 29 4 7 2.5 12 8 30 4 9 27 12 104/86 10 30 11 18 20 67/34 105 12 24 12 48/? 160 13 16 76/32 140 14 16 26 41 47 29 16 4 3.9 4 14 3.6 115/45 120/90 104/90 60/? 88/37 110/66 85 90 15 17 22 54/23 16 19 6 Our 28 case Other inotropes Y NaHCO3 Death N Y Y Y 6.4 Y Y N Y N Y 81/45 20 Epinephrine N N 160 >200 100 564 Y 3.4 152 3.2 27.5 mg 140 mg 5-10 µg/min then 4 mg/h 2.1 N Y N N Y N Y N N N N N 1050 mmol Y N 3.4 Y 2.9 2 3.9 180 mg 600 Y 3.1 N Y 120 mmol N 60 mg then 20 µg/min 2 mg/h N 150 mmol Y 428 Y 1.5 2.6 Empty boxes mean clinical data unavailable or unmentioned. N = no; Ref = reference; Y = yes 2.7 1.8 80 mg then 6 mg/h Y 46/21 N 1.5 N 56 evaluating various therapies including the combination of mechanical ventilation, high dose diazepam and epinephrine in acute chloroquine intoxication. Among the 167 patients studied, 87% received at least one of the combination treatment modalities. All the 14 dead were given the full combination treatment regimen. While the 'antidotal' aspect of any particular single or combination therapy was impossible to be confirmed, a <10% mortality rate was achieved with an approach comprising aggressive early use of epinephrine and diazepam, early mechanical ventilation, as well as attention to the fundamental principles of intensive care. 19 Nineteen patients of mild to moderate severity of chloroquine overdose (dose between 2 and 4 g, systolic BP >80 mmHg, QRS width <120 ms and absence of arrhythmia) received a diazepam loading dose of 0.5 mg/kg with subsequent infusion of 1 mg/kg over 24 hours were enrolled in a prospective doubleblind placebo controlled study. There was no difference in evolution of the systolic BP, QRS duration and QT interval over 24 hours between the two groups.20 The mechanism of action of diazepam in chloroquine intoxication is not well understood. The possible antiarrhythmic properties could be due to a decrease of sympathetic output in the central nervous system and peripheral benzodiazepine receptor mediated regulation of the cardiac calcium channels.21,22 Being a potent vasoconstrictor and inotrope, the therapeutic mechanism of epinephrine is more easily understood and it was demonstrated to enhance the rate and amplitude of the ECG in chloroquine-poisoned dogs.23 In the four reviewed cases (inclusive of our case) of hydroxychloroquine overdose using high dose diazepam therapy, the mortality was 50%. The case ingesting the greatest dose of 22 g survived without utilising any diazepam. Further studies on the benefits of high dose benzodiazepine therapy have yet to be done. The hypokalemia is thought to be secondary to potassium channel blockage causing over-dominant intracellular potassium distribution. Overzealous replacement may cause subsequent hyperkalemia. 24 Tw o c a s e s o f p o s t - p o t a s s i u m r e p l a c e m e n t hyperkalemia, one of 6.7 mmol/L but asymptomatic, Hong Kong j. emerg. med. Vol. 14(1) Jan 2007 another of 5.8 mmol/L associated with ventricular fibrillation, had been reported.11,16 By extrapolating the experience of other membrane stabilising cardiotoxins, sodium bicarbonate should have a role in correcting the cardiac conduction block of hydroxychloroquine or chloroquine poisoning although it has not been formally evaluated in these two particular medications. The possible worsening of hypokalemia warrants close serum potassium monitoring during the use of sodium bicarbonate. Therapeutic dose of hydroxychloroquine causing hypoglycemia in a diabetic patient on insulin was reported. Hydroxychloroquine stimulates insulin release and somatostatin analogue, which suppresses insulin secretion, has been reported to reverse intravenous quinine-induced hypoglycemia. 2 5 However, somatostatin analogues should only be considered in refractory cases of hypoglycemia. The last serum potassium measurement in our case was performed approximately three hours before the cardiac arrest. In light of the strong potassium channel blockade of hydroxychloroquine and the potassium replacement given, life-threatening hypokalemia or hyperkalemia may develop within a short period of time. It was not sure whether more meticulous monitoring and correction of the serum potassium would affect her outcome. Besides the maintenance of normokalemia, the correction of the widened QRS was another difficult issue in clinical management. One had to take great caution in administering agents like sodium bicarbonate and hypertonic saline in the presence of her hypokalemia and hypernatremia. Conclusion Hydroxychloroquine poisoning is rare but may result in hypotension, negative inotropy, cardiac conduction abnormalities, hypoglycemia and marked hypokalemia. Treatment options include early intubation, gastrointestinal decontamination, epinephrine, sodium bicarbonate, careful potassium replacement and correction of hypoglycemia by glucose or somatostatin Fung et al./Fatal hydroxychloroquine overdose analogue. The role of high dose diazepam is not well established but most authors still recommend its use for serious cases. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. McChesney EW. Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate. Am J Med 1983;75(1A): 11-8. Graham JD. An overdose of "plaquenil". BMJ 1960; 1(5181):1256. Anonymous. Overdose of hydroxychloroquine. Pharm J 1963;June:504. Dalley RA, Hainsworth D. Fatal plaquenil poisoning. J Forensic Sci Soc 1965;12:99-101. Bonnichsen R, Maehly AC. 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