CASE REPORT chloroquine, ingestion
Chloceauine Pois
in
Chloroquine poisoning in children, although inJrequent, is extremely dangerous because of the narrow margin between therapeutic and toxic doses. Children clinically present with apnea, seizures, and cardiac arrhythmias. We present the case of a 12-month-old infant, the second-youngest patient reported in the US literature to die from chloroquine poisoning. A serum level of 4.4 mg/L (13.64 ~mol/L) was obtained after the infant ingested only one tablet (300 rag). This establishes a n e w minimal lethal dose/ blood level for children. Although some pediatric and adult pharmacokinetic and clinical similarities exist, the outcome is different. Pediatric mortality is 80%, whereas adult mortality is only 10%. Pediatric ingestion cases are primarily unintentional, and most adult cases are suicide attempts. Current treatment in adults includes a protocol of diazepam and epinephrine. Further studies involving children and these medications and other modalities are needed to improve survival. [Kelly JC, Wasserman GS, Bernard WD, Schultz C, Knapp JF: Chloroquine poisoning in a child. Ann Emerg Med January I990; 19:47-50.]
INTRODUCTION Chloroquine (4-amino-quinolone) was first introduced in 1946 for the treatment and prophylaxis of malaria. Today, chloroquine continues to be prescribed widely, not only for malaria but also for at least a dozen other conditions - most notably autoimmune disorders. Beginning with a report of five pediatric deaths in 1961 by Cann and Verhulst, this drug has been cited for its toxic and lethal effects in children by many authors. 1-1o We report the case of an infant who died from a very low dose.
James C Kelly, MD Gary S Wass~rman, DO Walter D Bernard, MD Christopher Schultz, MD Jane F Knapp, MD rXdl Ibctb
~,lty,
IVIIbbUUll
From the Sections of Pediatric Emergency Medicine and Toxicology,Children's Mercy Hospital, and the Department of Pediatrics, University of Missouri at Kansas City School of Medicine. Received for publication September 1, 1989. Accepted for publication September 25, 1989. Address for reprints: James C Kelly, MD, Section of Pediatric Emergency Medicine, The Children's Mercy Hospital, Kansas City, Missouri 64108.
CASE REPORT A 12-month-old infant initially presented to the emergency department at an outlying hospital approximately 30 minutes after she was believed to have sucked on and possibly eaten some chloroquine tablets. Thirteen Aralen ® (300 mg chloroquine base and 45 mg primaquin base) tablets had been in the pill container; 12 intact tablets were retrieved off the floor. The medicine had been issued to the patient's uncle who had received them while performing US National Guard duties in Honduras. No markings or coating were left on the 12 remaining tablets; it appeared that they had been sucked on or licked off by the patient. The patient's medical history was unremarkable. System review included a one-week history of diarrhea and fever for which she had received "baby aspirin" for the previous two to three days. On arrival at the outlying hospital, she was aplleic with occasional gasping respirations. She had a pulse of 20 and no obtainable blood pressure. Resuscitation was initiated with endotracheal intubation and ventilation with 100% oxygen, chest compressions, and IV line access. Initial ECG rhythm strip (Figure) revealed ventricular bradycardia of 33 with wide QRS complexes. An isoproterenol drip was begun that converted the rhythm to a sinus rhythm of 115 with normal QRS complexes. Gastric lavage revealed small blue particles but no definite tablets. She then was given 10 grams of activated charcoal. After initial resuscitation and stabilization, she was transported by ambulance to Children's Mercy Hospital for further evaluation and treatment.
19:1 January 1990
Annals of Emergency Medicine
47/91
CHLOROQUINE Kelly et al
POISONING
FIGURE. A) A d m i t t e d to ED at 2040. ECG recorded at 2042 showing idioventricular rhythm with ventricular bradycardia of 33 after chloroquine. B) Isoproterenol given at 2050. ECG recording at 2055 showing progressive recovery with ventricular rate of 56 and atrial rate of 75. C) ECG recording at 2135 showing normal sinus rhythm with rate of 115.
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During transport, she remained neurologically unresponsive and required continuous ventilatory support. Physical examination on arrival, approximately four hours after ingestion, revealed a 7.98-kg infant having continuous seizures with a Glasgow Coma Score of 3. Vital signs were a pulse of 124; blood pressure, 83/53 m m Hg; temperature, 33.4 C reetally~ and ventilator respirations, 24. A previous temperature was not documented in the record. Pupils were approximately 4.0 m m bilaterally and nonreactive. There were no extraocular m o v e m e n t s with lateral m o v e m e n t of the head. The fundoscopic examination was normal. Equal breath sounds were heard bilaterally with ventilation. Cardiac e x a m i n a t i o n revealed a quiet precordium with sinus tachycardia and no murmurs. Abdominal examination was unremarkable. The extremities were pink with capillary refill of two seconds. Pulses were 2/4 in all f o u r e x t r e m i t i e s . N e u r o logically, she was unresponsive with intermittent seizurelike activity. A summary of the patient's laboratory values is presented (Table). During the first hospital day, she remained unresponsive on the ventilator. Blankets and w a r m i n g lights raised her temperature from 33.4 to 37 C over two hours. Seizures were controlled with IV phenytoin. Isoproterenol was discontinued because no further cardiac r h y t h m abnormalities were noted after transport. T h e i n i t i a l h y p e r g l y c e m i a was brought under control with insulin during the first 14 hours. Shortly after admission, her urine output diminished and was associated with a rising BUN, creatinine, and potassium. M a n a g e m e n t consisted of polystyrene sulfonate, restricted fluids, and furosemide. At 16 hours, she developed unequal pupils. Uncal herniation and cerebral edema were suspected and treated w i t h
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mannitol, dexamethasone, and hyperventilation. The first brainstem audio-evoked response showed deterioration of waveforms and lack of waves generated by upper left brainstem. Visualevoked response was interpreted as flat on the left, consistent with a hemianopsia most likely from hypoxia rather than direct effect of chloroquine. Electroretinogram was normal, indicating no toxic effect from chloroquine. On the second hospital day, repeat brainstem audio-evoked response, EEG, and neurologic e x a m i n a t i o n were consistent with brain death. After appropriate consultations, all life support was discontinued. DISCUSSION Our patient exhibited the rapid collapse and triad of findings apnea, seizures, and rhythm disturbances - commonly associated with chloroquine poisoning.ll Cardiac arrest may be the first apparent finding and probably accounts for the high mortality rate. 12 The quinidinelike property of chloroquine and its negative inotropic effect lead to decreased cardiac output and subsequent hypotension. The combination of marked hypotension and bizarre ventricular arrhythmias with wide QRS complexes is very typical of high-dose ingestions of chloroquine in adults, is Annals of Emergency Medicine
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To our knowledge, this is the only report in which typical ECG findings after chloroquine poisoning in children are demonstrated (Figure) and compare closely with the ECG abnormalities that have been reported in adults. 6 Most children, as did this infant, typically become symptomatic within 30 minutes after ingestion. The early symptoms of drowsiness and dizziness are followed by seizures and apnea. Central nervous system symptoms are believed to be due to a direct toxic effect or the result of hypoxic insult. The patients who die will usually do so w i t h i n the f i r s t t h r e e hours. 12,13 The overall mortality of pediatric patients reported in the English-speaking literature since 1961 is 80%, which is much higher than the 30% mortality reported in adults. 12 The majority of the morbidity of survivors in the current pediatric literature is unreported and unclear, but recent survivors have severe neurologic sequelae.4,1° Our case also demonstrates the added complication of hyperkalemia that, in retrospect, probably could have been avoided if the early hypokalemia had been allowed to self-correct. Maintenance IV fluids included potassium acetate 30 mEq/L, and no additional supplemental potassium was g i v e n . r A d m i s s i o n p o t a s s i u m 19:1 January t990
TABLE. Laboratory values
Time After Ingestion (hr) First Hospital .5
Second Hospital 7 12
4
24
Laboratory Values
Sodium (mmol/L) Potassium (mmol/L) BUN (mg/dL) (mmol/L) Creatinine (mg/dL) (l~mol/L) Glucose (mg/dL) (mmol/L) Calcium (mg/dL) (mmol/L) Phosphorous (mg/dL) (mmol/L) Magnesium (mg/dL) (mmol/L) Amylase (IMdL) (U/dL) SGOT (mU/mL) (U/L) AIk. phosphatase (U/L) Chloroquine (mg/L) (i.Lmol/L) Drug screen (urine)
level was 2.5 mEq/L (2.5 mmol/L) and at 24 hours reached a level of 7.3 mEq/L (7.3 mmol/L). A poorly understood observation, hypokalemia, associated with severe chloroquine poisoning, may suddenly rise despite only maintenance levels of IV potassium. 12 Gastrointestinal absorption of this drug is rapid and almost complete. Peak plasma concentration is reached in 1.5 to three hours, and 50% to 60% is protein bound. After ingestion, high concentrations are found in liver, lungs, kidneys, spleen, eyes, and skin. The elimination half-life in children is 75 to 136 hours with 55% excreted in urine and 10% in feces. 12 A review of the literature for serum c h l o r o q u i n e levels showed a wide variation of results that could not be correlated with level of toxicity or outcome. 2,4,s,7A° Until more data are available, serum levels in children c a n n o t be used to guide clinical intervention. In contrast, serum chloroquine levels in adults correlate relatively well with the severity of intoxication. Mild intoxications are a s s o c i a t e d w i t h s e r u m levels of less than 2.5 mg/L (7.75 ~xmol/L). M o d e r a t e t o x i c i t y w i t h ECG abnormalities and occasional neurologic symptoms occur at levels
19:1 January1990
139 2.4
536 (29.5)
133 2.5 13 (4.6) 1.0 (88.4) 598 (33) 8.7 (2.2) 3.5 (1.1) 2.2 (0.9)
136 3.2 29 (10.4) 1.3 (114.9) 147 (8.1)
139 5.2
134 7.3 46 (16.4) 1.4 (123.8) 127 (7.0)
177 (327.5) 62 (29.8) 2,410 4.4 (13.6) 4-Chloroquine + Phenytoin + Salicylate
between 2.5 and 5 mg/L (15.5 ~mol/ L), whereas levels of more than 5 mg/ L (15.5 ixmol/L) are uniformly associated with severe intoxication resulting in cardiovascular, ECG, and neurologic abnormalities or death. 12 Clinical experience indicates that chloroquine has a very narrow margin of safety. The adult therapeutic dose is 10 mg/kg, whereas the toxic dose is 20 mg/kg, and 30 mg/kg may be lethal. In children, the therapeutic dose is less specific and ranges between 5 and 25 mg/kg, whereas the toxic single dose is 250 mg. 4A2 The lowest lethal dose in children was p r e s e n t e d in a brief report 8 of a 3-year-old child who died after taking two 150-mg base tablets of chloroquine (27 mg/kg). Our patient also died after the ingestion of only 300 mg. It is noteworthy that our patient was not only the second-youngest case reported but also t h e only patient to s u c c u m b from as little as one tablet (300 mg chloroquine base). This represents a dose of 37.60 mg/kg and produced a serum level at seven hours of 4.4 mg/ L (13.64 t~mol/L). These data establish a new minimal lethal dose/blood level for children. Although this infant sucked the coating off 12 tablets, it remains unclear and speculative
Annals of Emergency Medicine
whether this contributed to a lethal level. The occurrence of this infant's illness and death after the ingestion of only one tablet exemplifies children's extreme s e n s i t i v i t y to this drug. Treatment studies in children are unavailable. An early important measure should be prevention of gastrointestinal absorption by administration of activated charcoal at 1 to 2 g/kg mixed with magnesium citrate (4 mL/kg). Ipecac is more readily available, but its potentially delayed effect and associated poor outcome with chloroquine poisonings make it a s e c o n d c h o i c e to charcoal.13A 4 Once the child is admitted to the ED, lavage can be performed through a large orogastric tube (24 F to 34 F) after elective intubation and controlled ventilation. A prehospital protocol of diazepare, epinephrine, and mechanical ventilation has resulted in a 90% success rate in adults after ingesting lethal doses of chloroquine. 1S While the mechanism of action is unclear, a recent study 16 in pigs indicated that diazepam provided a protective effect to the m y o c a r d i u m yet was not a specific antidote. The investigators also p o i n t e d out t h a t d i a z e p a m should be given in high doses and by
49/93
CHLOROQUINE POISONING Kelly et al
c o n s t a n t i n f u s i o n . T h e 1989 P o i s i n d e x ® n o w i n c l u d e s d i a z e p a m as part of the t r e a t m e n t p r o t o c o l for chloroquine intoxication and recomm e n d s one loading dose of 1 mg/kg to be followed by a c o n t i n u o u s infusion at 0.25 to 0.40 mg/kg/hr for 48 hours if cardiac symptoms persist or if the dose ingested exceeds 30 mg/kg body wt.17 F u r t h e r m e a s u r e s i n c l u d e epin e p h r i n e (1:10,000) i n a dose of 0.1 m L / k g IV or per endotracheal tube for c i r c u l a t o r y a r r e s t a n d isoproterenol 0.1 to 1.0 ~ g / k g / m i n as a constant drip for hypotensive shock. O t h e r supportive m e a s u r e s such as d o p a m i n e and e l e c t r i c a l cardioversion m a y be necessary. Peritoneal dialysis a n d charcoal h e m o p e r f u s i o n are of little benefit, z This major difference i n o u t c o m e is unclear but m a y represent n o t only the limited use of diazepam for chloroquine ingestions in children but also the difficulty i n a d m i n i s t r a t i o n of rapid prehospital care to children. Unfortunately, a recent report detailing the use of diazepam i n a child who ingested c h l o r o q u i n e failed to show any improvement in morbidity. 1o T h e u b i q u i t y of c h l o r o q u i n e and the loose control of its d i s t r i b u t i o n make the drug an ever-present danger to children. T h e best approach to c h l o r o q u i n e p o i s o n i n g c o n t i n u e s to be p r e v e n t i o n . O u r case i l l u s t r a t e s the acquisition of chloroquine by an i n f a n t f r o m a n u n a c c e p t a b l e container. Proper and strict instructions, labeling, packaging, and disposal m i g h t decrease p o t e n t i a l disasters. Our patient's death led to the initiation by the Missouri N a t i o n a l Guard and the U n i t e d States A r m y to release n e w guidelines relative to the p r o c u r e m e n t , dispensing, and labeling of chloroquine tablets. It was further r e c o m m e n d e d by the N a t i o n a l Guard that only bitter-tasting generic
94/50
t a b l e t s be m a d e a v a i l a b l e to t h e i r personnel (R Jaeger, personal c o m m u nication, February 26, 1986). A l t h o u g h c h l o r o q u i n e c a n n o t be removed from general distribution or strictly controlled, it might be made available in only its "rugby" generic form. This bitter-tasting form of the drug might at least decrease the dose ingested and possibly would have prevented s u c k i n g on m u l t i p l e tablets as did our patient. Each childproof bottle dispensed by a pharmacy also should include clear and strong warnings as to its danger to children.
SUMMARY Our case represents a classic form of c h l o r o q n i n e p o i s o n i n g t h a t also further defines the minimum a m o u n t (300 mg) of i n g e s t i o n a n d minimum blood level associated w i t h death. O u r patient's serum level and clinical findings correlated well w i t h adult findings; however, the difference was outcome. This case illustrates the futility of supportive treatm e n t i n the b e s t of c i r c u m s t a n c e s and p o i n t s to the n e e d for f u r t h e r studies in children of the possibility of using diazepam and epinephrine to improve quality survival. Clinicians m u s t be aware that c h l o r o q u i n e is e x t r e m e l y dangerous and that children are particularly sensitive to this drug. The authors extend their appreciation and thanks to the ED staff at Nevada City Hospital, Nevada, Missouri, for providing EGG strips and for the rapid stabilization of this patient before transfer to their institution. Also, they thank the Missouri Regional Poison Control Center at Cardinal Glennon Children's Hospital of St Louis for their involvement in this matter.
REFERENCES
1. Cann H, Verhulst H: Fatal acute chloroquine poisoning in children. Pediatrics 1961;27: 95-102.
Annals of Emergency Medicine
2. McCannW, PcrmisohnR, PulmisanoP: Fatal chloroquine poisoning in a child: Experience with peritoneal dialysis. Pediatrics 1975;55: 536-553. 3. Markowitz H, McGinleyJ: Chloroquinepoisoning in a child. JAMA 1964;189:950-951. 4. Centersfor Disease Control: Childhood chloroquine poisonings-Wisconsinand Washington. MMWR 1988;37:437-439. 5. Carson J, BarringerM, Jones R: Fatal chloroquine ingestion: An increasing hazard. Pedi atrics 1967;40:449-450. 6. Don Michael T, AigazzadehS: The effects of acute chloroquinepoisoningwith special reference to the heart. Am Heart J 79:831-842. 7. DiMaio V, Henry L: Chloroquinepoisoning. South Med J 1974;67:1031-1035. 8. ClydeD: Drug resistance of malariaparasites in Tanzania. East African Med J 1966;43: 405~408. 9. LarkworthyW: Acute chloroquinepoisoning. Practitioner 1971;207:212-214. 10. Havens P, SplaingardM, BousounisI3, et al: Survival after chloroquine ingestion in a child. Clin Toxicol 1988;26:381-388. 11. Mack R: 4-Aminoquinolone can be dangerous to your health: Chloroquine(Aralen)intoxication. North Carolina Med J 1984;45: 245-246. 12. Jaeger A, Sander P, Koperschmitt J, et al: Clinical features and managementof poisoning due to antimalarial drugs. Med 7bxicol 1987;2: 249-257. 13. Riou B, Barriot P, Rimailho A, et al: Treatment of severe chloroquinepoisoning.N Engl J Med 1988;319:50. 14. GrensherJ, MofensonH, CaraccioT: Ascendancy of the "black bottle." Pediatrics 1988; 82:522-523. 15. Riou B, Barriot P, Rimaiho A, et al: Treatment of severe chloroquinepoisoning.N Engl J Med 1988;318:1-6. 16. Riou B, Rimailho M, Gulliot M, et al: Protective cardiovasculareffects of diazepam in experimental acute chloroquinepoisoning.Intens Care Med 1988~14:610-616. 17. Poisindex: Chloroquineand Related Drugs. Denver, Micromedex, Inc 1988, voI 58. 18. LobelH, CampbellC, PappaioanouM, et al: Use of prophylaxis for malaria by American travelers to Africa and Haiti. lAMA 1987;257: 2626-2627. 19. RasmussenJ: Antimalarials- Are they safe to use in children? Pediatr Dermatol 1983;1: 89-91.
19:1 January 1990
Chloceauine Pois
in
Chloroquine poisoning in children, although inJrequent, is extremely dangerous because of the narrow margin between therapeutic and toxic doses. Children clinically present with apnea, seizures, and cardiac arrhythmias. We present the case of a 12-month-old infant, the second-youngest patient reported in the US literature to die from chloroquine poisoning. A serum level of 4.4 mg/L (13.64 ~mol/L) was obtained after the infant ingested only one tablet (300 rag). This establishes a n e w minimal lethal dose/ blood level for children. Although some pediatric and adult pharmacokinetic and clinical similarities exist, the outcome is different. Pediatric mortality is 80%, whereas adult mortality is only 10%. Pediatric ingestion cases are primarily unintentional, and most adult cases are suicide attempts. Current treatment in adults includes a protocol of diazepam and epinephrine. Further studies involving children and these medications and other modalities are needed to improve survival. [Kelly JC, Wasserman GS, Bernard WD, Schultz C, Knapp JF: Chloroquine poisoning in a child. Ann Emerg Med January I990; 19:47-50.]
INTRODUCTION Chloroquine (4-amino-quinolone) was first introduced in 1946 for the treatment and prophylaxis of malaria. Today, chloroquine continues to be prescribed widely, not only for malaria but also for at least a dozen other conditions - most notably autoimmune disorders. Beginning with a report of five pediatric deaths in 1961 by Cann and Verhulst, this drug has been cited for its toxic and lethal effects in children by many authors. 1-1o We report the case of an infant who died from a very low dose.
James C Kelly, MD Gary S Wass~rman, DO Walter D Bernard, MD Christopher Schultz, MD Jane F Knapp, MD rXdl Ibctb
~,lty,
IVIIbbUUll
From the Sections of Pediatric Emergency Medicine and Toxicology,Children's Mercy Hospital, and the Department of Pediatrics, University of Missouri at Kansas City School of Medicine. Received for publication September 1, 1989. Accepted for publication September 25, 1989. Address for reprints: James C Kelly, MD, Section of Pediatric Emergency Medicine, The Children's Mercy Hospital, Kansas City, Missouri 64108.
CASE REPORT A 12-month-old infant initially presented to the emergency department at an outlying hospital approximately 30 minutes after she was believed to have sucked on and possibly eaten some chloroquine tablets. Thirteen Aralen ® (300 mg chloroquine base and 45 mg primaquin base) tablets had been in the pill container; 12 intact tablets were retrieved off the floor. The medicine had been issued to the patient's uncle who had received them while performing US National Guard duties in Honduras. No markings or coating were left on the 12 remaining tablets; it appeared that they had been sucked on or licked off by the patient. The patient's medical history was unremarkable. System review included a one-week history of diarrhea and fever for which she had received "baby aspirin" for the previous two to three days. On arrival at the outlying hospital, she was aplleic with occasional gasping respirations. She had a pulse of 20 and no obtainable blood pressure. Resuscitation was initiated with endotracheal intubation and ventilation with 100% oxygen, chest compressions, and IV line access. Initial ECG rhythm strip (Figure) revealed ventricular bradycardia of 33 with wide QRS complexes. An isoproterenol drip was begun that converted the rhythm to a sinus rhythm of 115 with normal QRS complexes. Gastric lavage revealed small blue particles but no definite tablets. She then was given 10 grams of activated charcoal. After initial resuscitation and stabilization, she was transported by ambulance to Children's Mercy Hospital for further evaluation and treatment.
19:1 January 1990
Annals of Emergency Medicine
47/91
CHLOROQUINE Kelly et al
POISONING
FIGURE. A) A d m i t t e d to ED at 2040. ECG recorded at 2042 showing idioventricular rhythm with ventricular bradycardia of 33 after chloroquine. B) Isoproterenol given at 2050. ECG recording at 2055 showing progressive recovery with ventricular rate of 56 and atrial rate of 75. C) ECG recording at 2135 showing normal sinus rhythm with rate of 115.
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During transport, she remained neurologically unresponsive and required continuous ventilatory support. Physical examination on arrival, approximately four hours after ingestion, revealed a 7.98-kg infant having continuous seizures with a Glasgow Coma Score of 3. Vital signs were a pulse of 124; blood pressure, 83/53 m m Hg; temperature, 33.4 C reetally~ and ventilator respirations, 24. A previous temperature was not documented in the record. Pupils were approximately 4.0 m m bilaterally and nonreactive. There were no extraocular m o v e m e n t s with lateral m o v e m e n t of the head. The fundoscopic examination was normal. Equal breath sounds were heard bilaterally with ventilation. Cardiac e x a m i n a t i o n revealed a quiet precordium with sinus tachycardia and no murmurs. Abdominal examination was unremarkable. The extremities were pink with capillary refill of two seconds. Pulses were 2/4 in all f o u r e x t r e m i t i e s . N e u r o logically, she was unresponsive with intermittent seizurelike activity. A summary of the patient's laboratory values is presented (Table). During the first hospital day, she remained unresponsive on the ventilator. Blankets and w a r m i n g lights raised her temperature from 33.4 to 37 C over two hours. Seizures were controlled with IV phenytoin. Isoproterenol was discontinued because no further cardiac r h y t h m abnormalities were noted after transport. T h e i n i t i a l h y p e r g l y c e m i a was brought under control with insulin during the first 14 hours. Shortly after admission, her urine output diminished and was associated with a rising BUN, creatinine, and potassium. M a n a g e m e n t consisted of polystyrene sulfonate, restricted fluids, and furosemide. At 16 hours, she developed unequal pupils. Uncal herniation and cerebral edema were suspected and treated w i t h
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mannitol, dexamethasone, and hyperventilation. The first brainstem audio-evoked response showed deterioration of waveforms and lack of waves generated by upper left brainstem. Visualevoked response was interpreted as flat on the left, consistent with a hemianopsia most likely from hypoxia rather than direct effect of chloroquine. Electroretinogram was normal, indicating no toxic effect from chloroquine. On the second hospital day, repeat brainstem audio-evoked response, EEG, and neurologic e x a m i n a t i o n were consistent with brain death. After appropriate consultations, all life support was discontinued. DISCUSSION Our patient exhibited the rapid collapse and triad of findings apnea, seizures, and rhythm disturbances - commonly associated with chloroquine poisoning.ll Cardiac arrest may be the first apparent finding and probably accounts for the high mortality rate. 12 The quinidinelike property of chloroquine and its negative inotropic effect lead to decreased cardiac output and subsequent hypotension. The combination of marked hypotension and bizarre ventricular arrhythmias with wide QRS complexes is very typical of high-dose ingestions of chloroquine in adults, is Annals of Emergency Medicine
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:: :
q i".
To our knowledge, this is the only report in which typical ECG findings after chloroquine poisoning in children are demonstrated (Figure) and compare closely with the ECG abnormalities that have been reported in adults. 6 Most children, as did this infant, typically become symptomatic within 30 minutes after ingestion. The early symptoms of drowsiness and dizziness are followed by seizures and apnea. Central nervous system symptoms are believed to be due to a direct toxic effect or the result of hypoxic insult. The patients who die will usually do so w i t h i n the f i r s t t h r e e hours. 12,13 The overall mortality of pediatric patients reported in the English-speaking literature since 1961 is 80%, which is much higher than the 30% mortality reported in adults. 12 The majority of the morbidity of survivors in the current pediatric literature is unreported and unclear, but recent survivors have severe neurologic sequelae.4,1° Our case also demonstrates the added complication of hyperkalemia that, in retrospect, probably could have been avoided if the early hypokalemia had been allowed to self-correct. Maintenance IV fluids included potassium acetate 30 mEq/L, and no additional supplemental potassium was g i v e n . r A d m i s s i o n p o t a s s i u m 19:1 January t990
TABLE. Laboratory values
Time After Ingestion (hr) First Hospital .5
Second Hospital 7 12
4
24
Laboratory Values
Sodium (mmol/L) Potassium (mmol/L) BUN (mg/dL) (mmol/L) Creatinine (mg/dL) (l~mol/L) Glucose (mg/dL) (mmol/L) Calcium (mg/dL) (mmol/L) Phosphorous (mg/dL) (mmol/L) Magnesium (mg/dL) (mmol/L) Amylase (IMdL) (U/dL) SGOT (mU/mL) (U/L) AIk. phosphatase (U/L) Chloroquine (mg/L) (i.Lmol/L) Drug screen (urine)
level was 2.5 mEq/L (2.5 mmol/L) and at 24 hours reached a level of 7.3 mEq/L (7.3 mmol/L). A poorly understood observation, hypokalemia, associated with severe chloroquine poisoning, may suddenly rise despite only maintenance levels of IV potassium. 12 Gastrointestinal absorption of this drug is rapid and almost complete. Peak plasma concentration is reached in 1.5 to three hours, and 50% to 60% is protein bound. After ingestion, high concentrations are found in liver, lungs, kidneys, spleen, eyes, and skin. The elimination half-life in children is 75 to 136 hours with 55% excreted in urine and 10% in feces. 12 A review of the literature for serum c h l o r o q u i n e levels showed a wide variation of results that could not be correlated with level of toxicity or outcome. 2,4,s,7A° Until more data are available, serum levels in children c a n n o t be used to guide clinical intervention. In contrast, serum chloroquine levels in adults correlate relatively well with the severity of intoxication. Mild intoxications are a s s o c i a t e d w i t h s e r u m levels of less than 2.5 mg/L (7.75 ~xmol/L). M o d e r a t e t o x i c i t y w i t h ECG abnormalities and occasional neurologic symptoms occur at levels
19:1 January1990
139 2.4
536 (29.5)
133 2.5 13 (4.6) 1.0 (88.4) 598 (33) 8.7 (2.2) 3.5 (1.1) 2.2 (0.9)
136 3.2 29 (10.4) 1.3 (114.9) 147 (8.1)
139 5.2
134 7.3 46 (16.4) 1.4 (123.8) 127 (7.0)
177 (327.5) 62 (29.8) 2,410 4.4 (13.6) 4-Chloroquine + Phenytoin + Salicylate
between 2.5 and 5 mg/L (15.5 ~mol/ L), whereas levels of more than 5 mg/ L (15.5 ixmol/L) are uniformly associated with severe intoxication resulting in cardiovascular, ECG, and neurologic abnormalities or death. 12 Clinical experience indicates that chloroquine has a very narrow margin of safety. The adult therapeutic dose is 10 mg/kg, whereas the toxic dose is 20 mg/kg, and 30 mg/kg may be lethal. In children, the therapeutic dose is less specific and ranges between 5 and 25 mg/kg, whereas the toxic single dose is 250 mg. 4A2 The lowest lethal dose in children was p r e s e n t e d in a brief report 8 of a 3-year-old child who died after taking two 150-mg base tablets of chloroquine (27 mg/kg). Our patient also died after the ingestion of only 300 mg. It is noteworthy that our patient was not only the second-youngest case reported but also t h e only patient to s u c c u m b from as little as one tablet (300 mg chloroquine base). This represents a dose of 37.60 mg/kg and produced a serum level at seven hours of 4.4 mg/ L (13.64 t~mol/L). These data establish a new minimal lethal dose/blood level for children. Although this infant sucked the coating off 12 tablets, it remains unclear and speculative
Annals of Emergency Medicine
whether this contributed to a lethal level. The occurrence of this infant's illness and death after the ingestion of only one tablet exemplifies children's extreme s e n s i t i v i t y to this drug. Treatment studies in children are unavailable. An early important measure should be prevention of gastrointestinal absorption by administration of activated charcoal at 1 to 2 g/kg mixed with magnesium citrate (4 mL/kg). Ipecac is more readily available, but its potentially delayed effect and associated poor outcome with chloroquine poisonings make it a s e c o n d c h o i c e to charcoal.13A 4 Once the child is admitted to the ED, lavage can be performed through a large orogastric tube (24 F to 34 F) after elective intubation and controlled ventilation. A prehospital protocol of diazepare, epinephrine, and mechanical ventilation has resulted in a 90% success rate in adults after ingesting lethal doses of chloroquine. 1S While the mechanism of action is unclear, a recent study 16 in pigs indicated that diazepam provided a protective effect to the m y o c a r d i u m yet was not a specific antidote. The investigators also p o i n t e d out t h a t d i a z e p a m should be given in high doses and by
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CHLOROQUINE POISONING Kelly et al
c o n s t a n t i n f u s i o n . T h e 1989 P o i s i n d e x ® n o w i n c l u d e s d i a z e p a m as part of the t r e a t m e n t p r o t o c o l for chloroquine intoxication and recomm e n d s one loading dose of 1 mg/kg to be followed by a c o n t i n u o u s infusion at 0.25 to 0.40 mg/kg/hr for 48 hours if cardiac symptoms persist or if the dose ingested exceeds 30 mg/kg body wt.17 F u r t h e r m e a s u r e s i n c l u d e epin e p h r i n e (1:10,000) i n a dose of 0.1 m L / k g IV or per endotracheal tube for c i r c u l a t o r y a r r e s t a n d isoproterenol 0.1 to 1.0 ~ g / k g / m i n as a constant drip for hypotensive shock. O t h e r supportive m e a s u r e s such as d o p a m i n e and e l e c t r i c a l cardioversion m a y be necessary. Peritoneal dialysis a n d charcoal h e m o p e r f u s i o n are of little benefit, z This major difference i n o u t c o m e is unclear but m a y represent n o t only the limited use of diazepam for chloroquine ingestions in children but also the difficulty i n a d m i n i s t r a t i o n of rapid prehospital care to children. Unfortunately, a recent report detailing the use of diazepam i n a child who ingested c h l o r o q u i n e failed to show any improvement in morbidity. 1o T h e u b i q u i t y of c h l o r o q u i n e and the loose control of its d i s t r i b u t i o n make the drug an ever-present danger to children. T h e best approach to c h l o r o q u i n e p o i s o n i n g c o n t i n u e s to be p r e v e n t i o n . O u r case i l l u s t r a t e s the acquisition of chloroquine by an i n f a n t f r o m a n u n a c c e p t a b l e container. Proper and strict instructions, labeling, packaging, and disposal m i g h t decrease p o t e n t i a l disasters. Our patient's death led to the initiation by the Missouri N a t i o n a l Guard and the U n i t e d States A r m y to release n e w guidelines relative to the p r o c u r e m e n t , dispensing, and labeling of chloroquine tablets. It was further r e c o m m e n d e d by the N a t i o n a l Guard that only bitter-tasting generic
94/50
t a b l e t s be m a d e a v a i l a b l e to t h e i r personnel (R Jaeger, personal c o m m u nication, February 26, 1986). A l t h o u g h c h l o r o q u i n e c a n n o t be removed from general distribution or strictly controlled, it might be made available in only its "rugby" generic form. This bitter-tasting form of the drug might at least decrease the dose ingested and possibly would have prevented s u c k i n g on m u l t i p l e tablets as did our patient. Each childproof bottle dispensed by a pharmacy also should include clear and strong warnings as to its danger to children.
SUMMARY Our case represents a classic form of c h l o r o q n i n e p o i s o n i n g t h a t also further defines the minimum a m o u n t (300 mg) of i n g e s t i o n a n d minimum blood level associated w i t h death. O u r patient's serum level and clinical findings correlated well w i t h adult findings; however, the difference was outcome. This case illustrates the futility of supportive treatm e n t i n the b e s t of c i r c u m s t a n c e s and p o i n t s to the n e e d for f u r t h e r studies in children of the possibility of using diazepam and epinephrine to improve quality survival. Clinicians m u s t be aware that c h l o r o q u i n e is e x t r e m e l y dangerous and that children are particularly sensitive to this drug. The authors extend their appreciation and thanks to the ED staff at Nevada City Hospital, Nevada, Missouri, for providing EGG strips and for the rapid stabilization of this patient before transfer to their institution. Also, they thank the Missouri Regional Poison Control Center at Cardinal Glennon Children's Hospital of St Louis for their involvement in this matter.
REFERENCES
1. Cann H, Verhulst H: Fatal acute chloroquine poisoning in children. Pediatrics 1961;27: 95-102.
Annals of Emergency Medicine
2. McCannW, PcrmisohnR, PulmisanoP: Fatal chloroquine poisoning in a child: Experience with peritoneal dialysis. Pediatrics 1975;55: 536-553. 3. Markowitz H, McGinleyJ: Chloroquinepoisoning in a child. JAMA 1964;189:950-951. 4. Centersfor Disease Control: Childhood chloroquine poisonings-Wisconsinand Washington. MMWR 1988;37:437-439. 5. Carson J, BarringerM, Jones R: Fatal chloroquine ingestion: An increasing hazard. Pedi atrics 1967;40:449-450. 6. Don Michael T, AigazzadehS: The effects of acute chloroquinepoisoningwith special reference to the heart. Am Heart J 79:831-842. 7. DiMaio V, Henry L: Chloroquinepoisoning. South Med J 1974;67:1031-1035. 8. ClydeD: Drug resistance of malariaparasites in Tanzania. East African Med J 1966;43: 405~408. 9. LarkworthyW: Acute chloroquinepoisoning. Practitioner 1971;207:212-214. 10. Havens P, SplaingardM, BousounisI3, et al: Survival after chloroquine ingestion in a child. Clin Toxicol 1988;26:381-388. 11. Mack R: 4-Aminoquinolone can be dangerous to your health: Chloroquine(Aralen)intoxication. North Carolina Med J 1984;45: 245-246. 12. Jaeger A, Sander P, Koperschmitt J, et al: Clinical features and managementof poisoning due to antimalarial drugs. Med 7bxicol 1987;2: 249-257. 13. Riou B, Barriot P, Rimailho A, et al: Treatment of severe chloroquinepoisoning.N Engl J Med 1988;319:50. 14. GrensherJ, MofensonH, CaraccioT: Ascendancy of the "black bottle." Pediatrics 1988; 82:522-523. 15. Riou B, Barriot P, Rimaiho A, et al: Treatment of severe chloroquinepoisoning.N Engl J Med 1988;318:1-6. 16. Riou B, Rimailho M, Gulliot M, et al: Protective cardiovasculareffects of diazepam in experimental acute chloroquinepoisoning.Intens Care Med 1988~14:610-616. 17. Poisindex: Chloroquineand Related Drugs. Denver, Micromedex, Inc 1988, voI 58. 18. LobelH, CampbellC, PappaioanouM, et al: Use of prophylaxis for malaria by American travelers to Africa and Haiti. lAMA 1987;257: 2626-2627. 19. RasmussenJ: Antimalarials- Are they safe to use in children? Pediatr Dermatol 1983;1: 89-91.
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