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Survival after massive hydroxychloroquine overdose.

Hydroxychloroquine poisoning is rarely reported, yet from the limited data available, it is highly lethal when ingested in large doses (1-3). The majority of treatment recommendations and potentially lethal doses are extrapolated from chloroquine poisoning. There is little data on the range of toxicity, serum concentration or the kinetics in overdose. We report two cases of severe hydroxychloroquine poisoning requiring advanced cardiac life support, both of which survived despite severe clinical toxicity.

CASE HISTORIES

Case 1

A previously well 16-year-old female presented to the Emergency Department following deliberate self-poisoning. The patient had ingested alcohol and her mother's rheumatoid arthritis medication: hydroxychloroquine sulfate (20 g), methotrexate (up to 470 mg), prednisolone (up to 30 mg) and folate (up to 500 mg). On arrival 30 minutes later, her vital signs were: heart rate 90 bpm, blood pressure 100/60 mmHg and Glasgow Coma Score 14. Activated charcoal (25 g) was administered orally. Electrocardiograph performed on arrival showed sinus rhythm with a widened QRS (130 ms) and QT interval of 480 ms (Figure 1). Within an hour following ingestion, the patient became obtunded (Glasgow Coma Score 8), cyanosed, hypotensive (systolic blood pressure 60 mmHg) and had short runs of ventricular tachycardia.

Blood gas analysis at this time showed pH 7.34, PC[O.sub.2] 36 mmHg, P[O.sub.2] 252 mmHg, bicarbonate 20.5 mmol/l, lactate 4.5 mmol/l. Other abnormal results were hypokalaemia (2.3 mmol/l) and ethanol 0.14%. Full blood count, blood sugar, liver and renal function tests were within normal limits.

Initial resuscitation involved intravenous fluids (21 Hartmann's solution), sodium bicarbonate (50 mmol bolus), potassium chloride infusion at 20 mmol/hour and boluses of metaraminol (6 mg total). The patient was intubated by rapid sequence induction and she was sedated with a morphine and midazolam infusion. Another dose of activated charcoal (25 g) was administered. Further bicarbonate boluses appeared to narrow QRS complexes and the patient received a total bicarbonate dose of 100 mmol. Hypotension was treated with a high-dose adrenaline infusion (40 [micro]g/min). Potassium replacement was increased to 40 mmol/hour.

[FIGURE 1 OMITTED]

Given the severity of toxicity, the patient was transferred to a tertiary centre for potential extracorporeal membrane oxygenation (ECMO). However, during transfer the patient improved haemodynamically and required less adrenaline. On arrival at the tertiary hospital, her cardiac rhythm was stable and she was deemed to not require ECMO. Over the next six hours the patient improved markedly and adrenaline and potassium were ceased. She received a total potassium replacement of 220 mmol. She had a brief rebound hyperkalaemia (6.2 mmol/l) three hours after cessation of potassium infusion: this was transient and did not require any specific treatment. No treatment for the other ingested substances was required. She was extubated 10 hours following overdose.

Case 2

A 45-year-old female ingested hydroxychloroquine (20 g), paracetamol (12 g), clarithromycin (3.5 g), celecoxib (2 g) and ethanol. Her past medical history included distal pancreatectomy for pseudocyst, bipolar disorder and non-specific arthritis. On arrival of the ambulance at her home, vital signs were: heart rate 78 bpm, pulses impalpable, Glasgow Coma Score of 14/15. On arrival at hospital (45 minutes post-ingestion) the patient was unconscious and in pulseless electrical activity. Pupils were fixed and dilated and the patient was hypothermic (29.9[degrees]C).

Cardiopulmonary resuscitation was immediately commenced and return of circulation was obtained after 20 minutes following ventilation, adrenaline (6 mg), atropine (1 mg), diazepam (200 mg), sodium bicarbonate (100 mmol) and intravenous fluids (5000 ml). Hypokalaemia (serum [K.sup.+] 1.6 mmol/l) was treated with 30 mmol/hour of potassium. The patient's heart rate and blood pressure rapidly improved. Haemodynamic stability was achieved with noradrenaline (25 [micro]g/min) and produced a mean arterial pressure of 60 mmHg, heart rate 98 bpm. The ECG showed sinus rhythm with widened QRS complex (160 ms) at 1.5 hours post-ingestion. Based on a literature search performed at the bedside, it was noted that diazepam in large doses was recommended in treating chloroquine poisoning. Hence, a diazepam infusion at 100 mg/hour was continued for 12 hours--a total dose of 1.4 g was administered. The infusion was ceased following consultation with a toxicologist. The patient was initially acidotic (pH nadir 6.98) with a peak lactate of 10.5 mmol/l, but this corrected over 14 hours. Normothermia occurred at 10 hours. At 36 hours, the patient opened her eyes to voice and was obeying commands.

She had respiratory complications with a chest X-ray showing a diffuse pulmonary infiltrate. Intravenous acetylcysteine was administered at standard doses given an elevated serum paracetamol concentration (1072 [micro]mmol/l at five hours). She had marked myopathy which delayed extubation until day 11. She was discharged home 23 days postingestion with no residual complications of her overdose.

Hydroxychloroquine concentrations

Hydroxychloroquine concentrations were subsequently measured in stored serum using the following in-house high performance liquid chromatography procedure: after addition of chloroquine as internal standard and sodium hydroxide, the compounds were extracted with 1% iso-amyl alcohol in hexane and the organic phase taken to dryness. After reconstitution in the mobile phase (12% acetonitrile in phosphate buffer pH 3), aliquots were injected onto a Merck RP Select B column using a flow rate of 1.3 ml/minute and detection at 330 nm. Serum hydroxychloroquine concentrations in the first case were 13.8 mg/l (one hour post-ingestion) and 6.2 mg/l (four hours post-ingestion). The concentration in the second case (three hours post-ingestion) was 26.0 mg/l.

DISCUSSION

Chloroquine poisoning is a significantly more common problem than hydroxychloroquine poisoning, some of which may relate to chloroquine's widespread use for malaria and its use as a perceived abortifacient in Asia, Africa and the Pacific Islands (4). In developed countries it is most commonly used for the treatment of rheumatoid arthritis. In Australia, a single prescription (200 mgx100 tablets=20 g) presents a supra-lethal dose. There are just 19 published case reports of hydroxychloroquine overdose (1-3,5).

Fatalities reported in the literature indicate that death is due to rapid onset of cardiovascular collapse with refractory hypotension and ventricular arrhythmias. Both of our patients were initially alert with normal haemodynamic parameters, but within an hour of ingestion deteriorated rapidly with obtundation, hypotension and arrhythmias. Urgent resuscitation required airway and ventilatory support followed by agents to increase blood pressure and treat arrhythmias. Commonly recommended therapies are the same as those used for chloroquine poisoning and include inotropes, sodium bicarbonate, potassium and diazepamb (6). Sodium bicarbonate use is simply an extrapolation from the treatment of other weak bases that cause QRS widening and arrhythmias. The concern about giving sodium bicarbonate in hydroxychloroquine poisoning is the potential for further intracellular shift of potassium exacerbating the marked hypokalaemia.

Profound hypokalaemia is a known effect of both chloroquine and hydroxychloroquine poisoning and appears to correlate with toxicity (7). The mechanism is likely to be reduced potassium efflux from blockade of membrane channels. It is unknown whether hydroxychloroquine causes direct cardiotoxicity or whether it is partly due to the hypokalaemia. Aggressive potassium replacement has been advocated by some for profound hypokalaemia (7). Others have raised concerns that over-correction of the low potassium may be potentially adverse. In one case, ventricular fibrillation occurred 36 hours after ingestion due to rebound hyperkalaemia (3). Both our patients presented with initial hypokalaemia. With close monitoring and aggressive treatment with intravenous potassium replacement, neither developed significant hyperkalaemia.

Initial studies in chloroquine poisoning suggested a role for large doses of diazepam in acute poisoning, although this was not shown to be effective in a subsequent prospective controlled trial (8). Despite this, various textbooks and other reviews of the literature continue to recommended high dose diazepam for the treatment of significant hydroxychloroquine poisoning (5-7). High-dose diazepam was administered to Case 2 on the basis of these recommendations: however, it is not known whether this influenced clinical outcomes.

Both our patients ingested 20 g of hydroxychloroquine. These are amongst the highest doses reported and the concentration of Case 2 was higher than that reported in any previous survivor. Although the lethal dose is poorly established, as little as 4 g is thought to be potentially life-threatening (9). Serious toxicity has been reported with concentrations ranging from only 0.64 to 9.87 mg/l (6,7). Thus, survival in our cases with much higher concentrations is notable. It seems likely that the speed of recovery is related to tissue redistribution of hydroxychloroquine and rapidly falling serum concentrations as seen in Case 1. This suggests the use of aggressive and repeated measures to maintain cardiac output, even in the setting of cardiac arrest, may be justifiable.

Extracorporeal methods for sustaining oxygenation have been increasingly utilised in poisoning. Only one case of hydroxychloroquine poisoning (ingested dose 12 g) has been reported to have been treated with ECMO (2). It was considered in both our cases; however their rapid improvement obviated the need for ECMO. All the same, this rapid improvement provides support for short-term use of ECMO being justified in any institution where it is promptly available.

REFERENCES

(1.) Yanturali S, Aksay E, Demir OF, Atilla R. Massive hydroxychloroquine overdose. Acta Anaesthesiol Scand 2004; 48:379-381.

(2.) Mongenot F, Gonthier YT, Derderian F, Durand M, Blin D. [Treatment of hydroxychloroquine poisoning with extracorporeal circulation]. Ann Fr Anesth Reanim 2007; 26:164-167.

(3.) Megarbane B, Resiere D, Sonneville R, Guerrier G, Deye N, Baud F [Acute hydroxychloroquine poisoning. The danger of rapid or excessive correction of initial hypokalemia]. Presse Med 2005; 34:933-934.

(4.) Ball DE, Tagwireyi D, Nhachi CFB. Chloroquine poisoning in Zimbabwe: a toxicoepidemiological study. J Appl Toxicol 2002; 22:311-315.

(5.) Wong AIN, Chung ITF, Graham CA. Hydroxychloroquine overdose: case report and recommendations for management. Eur J Emerg Med 2008; 15:16-18.

(6.) Marquardt K, Albertson TE. Treatment of hydroxychloroquine overdose. Am J Emerg Med 2001; 19:420-424.

(7.) Jordan P, Brookes JG, Nikolic G, Le Couteur DG. Hydroxychloroquine overdose: toxicokinetics and management. Clin Toxicol 1999; 37:861-864.

(8.) Clemessy J-L, Angel G, Borron SW, Ndiaye M, Le Brun F, Julien H et a]. Therapeutic trial of diazepam versus placebo in acute chloroquine intoxications of moderate gravity. Intensive Care Med 1996; 22:1400-1405.

(9.) Isbister GK, Dawson A, Whyte IM. Hydroxychloroquine overdose: a prospective case series. Am J Emerg Med 2002; 20:377-378.

N. GUNJA *, D. ROBERTS ([dagger]), D. MCCOUBRIE ([double dagger]), P. LAMBERTH ([section]), A. JAN **, D. C. SIMES ([dagger][dagger]), P. HACKETT ([double dagger][double dagger]), N. A. BUCKLEY ([section][section])

New South Wales Poisons Information Centre, The Children's Hospital at Westmead, Sydney, New South Wales, Australia

* M.B., B.S., F.A.C.E.M., Deputy Medical Director and Toxicologist.

([dagger]) B.Pharm., M.B., B.S., Medical Registrar, Department of Medicine, The Canberra Hospital, Canberra, Australian Capital Territory.

([double dagger]) M.B., B.S., F.A.C.E.M., Clinical Toxicologist, Emergency Department, Royal Perth Hospital, Perth, Western Australia.

([section]) M.B., B.S., F.A.C.E.M., M.Astron., Intensive Care Physician, Intensive Care Unit, Calvary Health Care, Canberra, Australian Capital Territory.

** M.B., B.S., F.A.C.E.M., B.A., F.A.M.A.C., Director, Emergency Department, St John of God Hospital, Murdoch, Western Australia.

([dagger][dagger]) M.B., B.S., F.A.N.Z.C.A., F.J.F.I.C.M., Intensive Care Physician, Intensive Care Unit, St John of God Hospital, Murdoch, Western Australia.

([double dagger][double dagger]) M.R.S.C., Research Scientist, PathWest Laboratory Medicine, Western Australia.

([section][section]) M.B., B.S., M.D., F.R.A.C.P, Clinical Toxicologist, Department of Medicine, The Canberra Hospital, Canberra, Australian Capital Territory.

Address for reprints: Dr N. Gunja, NSW Poisons Information Centre, The Children's Hospital at Westmead, Westmead, NSW 2145.

Accepted for publication on July 23, 2008.
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Article Details
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Author:Gunja, N.; Roberts, D.; McCoubrie, D.; Lamberth, P.; Jan, A.; Simes, D.C.; Hackett, P.; Buckley, N.A
Publication:Anaesthesia and Intensive Care
Article Type:Clinical report
Geographic Code:8AUST
Date:Jan 1, 2009
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