Acta Anaesthesiol Scand 2000; 44: 1017–1020 Copyright C Acta Anaesthesiol Scand 2000Printed in Denmark. All rights reserved

ACTA ANAESTHESIOLOGICA SCANDINAVICA

ISSN 0001-5172

Case Report

Chloroquine poisoning: report of two cases

V. G. REDDY and S. SINNA

Department of Anaesthesia and ICU, Sultan Qaboos University Hospital, Muscat, Sultanate of Oman

Two patients intentionally took chloroquine in overdose for dif-ferent purposes. The first patient took chloroquine 2.7 g to ter-minate her pregnancy and the second patient took 3.75 g to ter-minate his life. The management of these two patients mainlyconsisted of gastric lavage, activated charcoal, ventilation, di-azepam and inotropic support. The effect of chloroquine on themyocardium is discussed and the role of chloroquine as an abor-tifacient is reviewed. Hypokalemia should be recognized earlyand treated cautiously to avoid hyperkalemia. Refractory seiz-

CHLOROQUINE is prescribed throughout the worldfor the prevention and treatment of malaria,

rheumatoid arthritis, and lupus erythematosis. Chlor-oquine has been used in attempted suicide (1, 2). InAfrica there are reports of pregnant women takingchloroquine as an abortifacient (3). Severe chloroquinepoisoning is usually fatal if the ingested amount ismore than 5 g unless prompt and specific treatment isprovided (1). Death usually occurs within 1–3 h afteringestion and is related to the direct action on themyocardium (1). We present two case reports of chlor-oquine overdose, taken with different intentions.

Case 1

A 25-year-old previously healthy female weighing 45kg was brought to casualty department by a neighborwith a history of sudden onset of dizziness, inabilityto speak, and difficulty in breathing. Just before ar-rival to the casualty she had generalized convulsionslasting for approximately 3 min. On examination, shewas in cardiac arrest. Electrocardiogram monitor re-vealed ventricular fibrillation. External cardiac mass-age was commenced, followed by immediate defibril-lation with 200 J, 300 J and 360 J. Epinephrine 1 mgintravenously (IV) was given and repeated at 1-minintervals followed by 5 mg IV. With the fourth defib-rillation the rhythm reverted to sinus. She was intu-bated and transferred to the intensive care unit (ICU),where she was sedated with midazolam and venti-

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ures not responding to benzodiazepine may require an antiepi-leptic drug.

Received 21 October 1999, accepted for publication 19 April 2000

Key words: Poisoning; chloroquine; abortion; treatment; di-azepam; epinephrine.

c Acta Anaesthesiologica Scandinavica 44 (2000)

lated. She became hypotensive and required dop-amine 10 mg kgª1 minª1. Metabolic acidosis (basedeficit ª12 mmol/L) was corrected with 8.4% sodiumbicarbonate 50 mL IV. A venous sample taken im-mediately after resuscitation revealed marked hypok-alemia (2.6 mmol/L), elevated ASAT 160 U/L andALAT 120 U/L. A 12-lead electrocardiogram (ECG)revealed sinus tachycardia of 124/min, interventricu-lar conduction defect and flattening of the T waves. ACT scan of the brain showed no evidence of cerebraledema. Since the patient presented with ventricularfibrillation and no diagnosis was made it was decidedto correct hypokalemia. An infusion of potassiumchloride 20 mmol in 500 mL of dextrose water at arate of 80 mL hª1 was given.

Six hours after admission, the employer of the pa-tient brought 18 empty shells of chloroquine tablets,250 mg each (base 150 mg, total dose of base 2.7 g),which had been found in her room. Venous blood wasdrawn and sent abroad for determination of chloro-quine levels, as our hospital did not have the facilityto measure the blood levels of chloroquine. Gastriclavage failed to bring out any tablets. Activated char-coal 50 g was instilled through the nasogastric tube.She received a loading dose of diazepam intra-venously 2 mgª1 kgª1 (90 mg) over 30 min, followedby an infusion of diazepam 2 mg kgª1 24 hª1. Despitereceiving large doses of diazepam, the patient had re-peated seizures, which was treated with a loadingdose of phenytoin 1 g IV followed by a maintenance

V. G. Reddy and S. Sinna

dose of 300 mg daily. Urine for human chorionicgonadotropin (hCG) was sent and found to be highlypositive (.50 U/mL). Ultrasound of the pelvis re-vealed a small 2.1 cm gestational sac. The obstetri-cians planned no intervention.

Eighteen hours after admission the patient had abrief ventricular fibrillation, which reverted to sinusrhythm. Subsequently she had multiple ventricularectopic beats, compromising her hemodynamic sta-bility. Lidocaine bolus 50 mg IV followed by an in-fusion of 2 mg kgª1 hª1 terminated the arrhythmias.On day four the patient had high fever, per vaginalbrownish discharge and bleeding. An emergency re-moval of the product of conception was performedand subsequently she was extubated. In view of ex-cessive drowsiness flumazenil 0.5 mg IV was adminis-tered, which effectively reversed the effect of mida-zolam. She was referred for psychiatric evaluation.She confessed having taken chloroquine tablets fouryears ago to terminate her pregnancy and she wassuccessful. She was satisfactorily discharged fromhospital on the 14th day.

The serum chloroquine level result, which cameafter 10 days, was 0.28 mg/L (therapeutic level up to0.6 mg/L).

Case 2

A 36-year-old male weighing 80 kg, previouslyhealthy but severely depressed, was directly admittedto our ICU from another hospital due to lack of ICUbeds, with history of an attempted suicide three hourspreviously. The patient under the influence of alcoholhad decided to commit suicide by taking 25 tablets ofchloroquine 250 mg each (base 150 mg, total dose ofbase 3.75 g), 20 tabs Proguanil 100 mg each (total dose2 g) and 6 tablets of paracetamol 500 mg each.

On examination he was conscious but drowsy witha Glasgow coma scale score of 12/15. He complainedof difficulty in breathing, headache, weakness andnausea followed by vomiting. No tablets were iden-tified in the vomitus. This was immediately followedby generalized seizures, which responded to di-azepam 10 mg IV. His condition deteriorated withagitation, confusion and violence, followed by respir-atory arrest. He was immediately intubated, afteradministering thiopentone and suxamethonium, andventilated. Gastric lavage did not reveal any tablets.Activated charcoal 50 g was instilled through thenasogastric tube. Blood sample revealed serumpotassium (3.8 mmol/L), normal liver function testsand moderate metabolic acidosis (base deficit ª8.6mmol/L). A 12-lead ECG showed delayed interven-

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tricular conduction defect, with a QRS interval of 0.12s. Paracetamol level was less than 0.01 mmol/L (lowertoxic dose 1 mmol/L). Blood for chloroquine level de-termination abroad for testing in this case was notsent.

In the ICU he received diazepam bolus 190 mg (2mg kgª1) intravenously over 30 min, followed by aninfusion of diazepam 8 mg h (2 mg kgª1 24 hª1) for36 h. Six hours later repeat blood sample showed hy-pokalemia (3 mmol/L). Hypotension required epine-phrine 0.25 mg kgª1 minª1 IV. Diazepam was con-tinued for 48 h and then stopped. He was extubatedwhen he was fully conscious and alert. He was trans-ferred from the ICU to the psychiatric ward. Subse-quently he confessed to taking chloroquine, proguaniland paracetamol to commit suicide. He was dis-charged satisfactorily from the hospital on the 10thday.

Discussion

The overall mortality rate resulting from an overdoseof chloroquine is in the range of 2.5% to 25% (1, 3).Chloroquine has a very narrow margin of safety.Chloroquine is rapidly absorbed from the gastrointes-tinal tract. The interval between ingestion and car-diorespiratory collapse is frequently less than 2 h (4).When cardiac arrest occurs, cardiorespiratory resusci-tation usually fails (1). The cardiovascular toxicity ofchloroquine is related to transient high blood levelspresent early in the distribution phase, resulting fromincomplete distribution of the central compartment(5). Chloroquine exerts its toxicity on the myocardiumby a quinidine-like mechanism (4), negative inotrop-ism, inhibition of spontaneous diastolic depolariza-tion, slowing conduction, increase of effective refrac-tory period, prolongation of QT segment and QRS in-terval, Torsades de pointes, and multiple ventricularectopic beats. Ventricular fibrillation may be the pre-senting sign. The cardiac toxicity may persist beyond24 h and ventricular fibrillation rarely may be seeneven after 24 h (6). Hypotension progressing intocardiogenic shock is frequently seen (6). Other symp-toms of chloroquine toxicity include irritability,drowsiness and seizures. The respiratory depressionprogressing to respiratory arrest is secondary to car-diac depression (6).

The toxic dose of chloroquine is 20 mg kgª1 and30–50 mg kgª1 may be lethal (4). Our patients hadtaken 60 mg kgª1 and 47 mg kgª1, respectively, whichcould have been lethal if not treated aggressively.Others report 3–4 g in an adult as a lethal dose (1, 2).Riou et al. (1), reported that a dose of 5 g is fatal if no

Chloroquine poisoning

active resuscitation is undertaken immediately. Un-favorable prognostic factors include an ingested doseof more than 5 g, systolic blood pressure less than 80mmHg, QRS duration of more than 12 s, ventricularfibrillation and hypokalemia (1, 2). Blood chloroquinelevels above 25 mmol/L denotes poor prognosis un-less aggressive management is instituted immediately(1), Clemessy et al. (2), in a large series of patientswho had ingested chloroquine, found no correlationbetween the amount ingested and the peak bloodchloroquine concentration. The low blood level thatwas seen with our first patient is probably multifacto-rial. We measured the serum levels rather than thewhole blood. Secondly, we have no idea when the firstpatient took chloroquine since a bystander broughther to the casualty and the time of sampling was morethan 6 h after ingestion, which may give lower levels(7). Lastly, we are unsure whether a delay in measur-ing the sample could lower the values since it wassent abroad.

Chloroquine is wrongly believed to be an aborti-facient in some parts of the world. Vitris and Aubert(3) reported 67 women taking chloroquine, of whichfour were clearly related to abortion. Interestingly, ourfirst patient had taken chloroquine to terminate herfirst pregnancy successfully, which prompted her totake it a second time.

Hypokalemia, frequently noted in severe chloroqui-ne poisoning, is a result of potassium shift from extra-cellular space, to intracellular space, and the severityof hypokalemia closely correlates with toxicity (6, 8).Other factors that lower potassium levels includehyperventilation, use of epinephrine during resusci-tation and subsequently in the management of myo-cardial depression (6). Animal data suggest a possibleprotective effect of hypokalemia, but the survival ofthe animals is not greater (9). We gave potassiumchloride as a slow infusion to correct hypokalemia,since at the time of infusion we did not suspect chlor-oquine toxicity. Severe hypokalemia may be correctedby supplementing 80 mmol of potassium in a 24-hperiod with frequent monitoring. The dose may bedoubled if hypokalemia is ,2 mmol/L and associatedwith ventricular rhythm disturbances (6).

Elevated liver function tests (ASAT, ALAT) as a re-sult of chloroquine toxicity have been reported (10).Metabolic acidosis is common in patients who de-velop seizures or cardiovascular instability (6).

Treatment of chloroquine poisoning includes gastriclavage, activated charcoal, mechanical ventilation, IVdiazepam and IV epinephrine. Riou et al. (1) were thefirst to initiate a combination therapy of early mech-anical ventilation, diazepam bolus 2 mg kgª1 IV fol-

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lowed by an infusion of 2 mg kgª1 24 hª1 and epine-phrine for hypotension. Ten of eleven patients whoingested more than 5 g of chloroquine treated withcombination therapy survived compared to 1 of 11retrospective controls. Clemessy et al. (2) reported amortality rate of 8.4% when the patients received atleast one of the agents: ventilation, diazepam andepinephrine. The efficacy of gastric lavage variesgreatly. In one study gastric lavage removed a meanof 7% (range 0–23%) of the amount ingested (8). Be-cause of the close dependent toxicity of chloroquinegastric lavage may be useful if undertaken in less thanone hour. Activated charcoal effectively prevents (upto 95–99%) absorption of the fraction of ingested chlo-roquine that is in the stomach. Early intubation andmechanical ventilation are recommended in patientswith significant ingestion, seizures, coma, hypoten-sion and QRS widening (1). Chloroquine is known tocause respiratory depression and diaphragmatic dys-function in experimental model (2). Diazepam in highdoses may also contribute to respiratory depression(1). If thiopentone is used to facilitate intubation, itshould be used with great caution as cardiac arrestshave been reported after injecting thiopentone (2).Our case 2 patient had normal blood pressure and hy-dration when he was intubated with thiopentone anda muscle relaxant. He became hypotensive after 7 h ofintubation. We do not believe thiopentone could havecontributed to his hypotension.

Mechanisms that have been proposed to supportthe beneficial effect of diazepam include competitiveinhibition of fixation of chloroquine on the myocar-dium, restoration of inotropism, increase in the uri-nary excretion of chloroquine, central antagonistic ef-fect and antiarrhythmic effect (2).

Treatment of Torsades de Pointes should be directedat removing the precipitating factors. Drug therapyincludes magnesium, isoproterenol, phenytoin or at-rial overdrive pacing to electrical cardioversion in apatient with hemodynamic instability. Plasma alkali-nization may be effective in the treatment of conduc-tion disturbances (widening of QRS complex) due tochloroquine. Hypertonic sodium bicarbonate partiallyreversed sodium channel blockade and resultant QRSinterval prolongation by chloroquine in rats (11).Studies have failed to identify whether it is the so-dium load or the alkaline pH that is effective in thetreatment of conduction disturbances (12–14).

We administered flumazenil on the 5th day to re-verse the sedative effect of diazepam since the toxiceffect of chloroquine on the myocardium usually doesnot persist beyond 24 h after ingestion (1).

Proguanil is considered one of the safest antima-

V. G. Reddy and S. Sinna

larial treatments used in prophylaxis. Reviewing theliterature, we were unable to find any previous reportof proguanil poisoning. Toxicity is usually manifestedin the form of epigastric discomfort, vomiting, hema-turia and renal irritation.

Conclusion

These two case reports highlight the severity of chlor-oquine toxicity and the belief that it could be used asan abortifacient. Early aggressive management withthe triple regime using ventilation, diazepam andepinephrine could save life. The drug should neverbe prescribed in bulk for patients who have provenpsychiatric problems. A warning on the package‘‘Chloroquine is not an abortifacient and taken in ex-cess can kill you’’ should appear in countries wheremalaria is frequent.

References

1. Riou B, Barriot P, Rimailho A, Baud FJ. Treatment of severechloroquine poisoning. New Engl J Med 1988: 318: 1–6.

2. Clemessy JL, Taboulet P, Hoffman JR, Hantson P, Barriot P,Bismuth C et al. Treatment of acute chloroquine poisoning:A 5-year experience. Crit Care Med 1996: 24: 1189–1195.

3. Vitris M, Aubert M. Intoxications a la chloroquine: notre ex-perience a propos de 80 cas. Dakar Medical 1983: 28: 593–602.

4. Weninger H. Review of the side effects and toxicity of chlor-oquine. Bull World Health Organ 1979: 79: A906.

5. Loareesuwan S, White NJ, Chanthavanich P, Edwards G,Nicholl DD, Bunch C et al. Cardiovascular toxicity and dis-tribution kinetics of intravenous chloroquine. Br J Clin Phar-macol 1986: 22: 31–36.

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6. Clemessy JL, Favier C, Borron SW, Hantson PE, Vicaut E,Baud FJ. Hypokalemia related to acute chloroquine inges-tion. Lancet 1995: 346: 877–880.

7. White NJ. Antimalarial pharmacokinetics and treatmentregimens. Br J Clin Pharmacol 1992: 34: 1–10.

8. Jaeger A, Sauder P, Kopferschmitt J, Flesch F. Clinical fea-tures and management of poisoning due to antimalarialdrugs. Med Toxicol Adverse Drug Exp 1987: 2: 242–273.

9. Brandfenbrener M, Kronholm J, Jones HR. The effect ofserum potassium concentration and quinidine toxicity. JPharmacol Exp Ther 1966: 154: 250–254.

10. Makin AJ, Wendon J, Fitt S, Portmann BC, William R. Ful-minant hepatic failure secondary to hydroxychloroquine.Gut 1994: 35: 569–570.

11. Curry SC, Connor DA, Clark RF, Holland D, Carrol L,Raschke R. The effect of hypertonic sodium bicarbonate onQRS duration in rats poisoned with chloroquine. J ToxicolClin Toxicol 1996: 34: 73–76.

12. Goldman MJ, Mowry JB, Kirk MA. Sodium bicarbonate tocorrect widened QRS complex in a case of flecainide over-dose. J Emerg Med 1997: 15: 183–186.

13. McCabe JL, Cobaugh DJ, Menegazzi JJ, Fanta J. Experimen-tal tri cyclic anti-depressant toxicity: a randomized con-trolled comparison of hypertonic saline, sodium bicarbonateand hyperventilation. Ann Emerg Med 1998: 32: 329–333.

14. Stone CK, Kraemer H, Carroll R, Low R. Does a sodiumfree buffer affect QRS width in experimental amitriptylineoverdose. Ann Emerg Med 1995: 26: 58–64.

Address:Dr. Venu Gopal Reddy MD, EDICDepartment of Anaesthesia and ICUCollege of MedicinePO Box 35, PC 123-SQUMuscatSultanate of Omane-mail: gowri/omantel.net.om