Randomized Comparison of Artesunate and Quinine in the Treatment of Severe Falciparum Malaria Author(s): Paul N. Newton, Brian J.

Angus, Wirongrong Chierakul, Arjen Dondorp, Ronatrai Ruangveerayuth, Kamolrat Silamut, Pramote Teerapong, Yupin Suputtamongkol, Sornchai Looareesuwan and Nicholas J. White Reviewed work(s): Source: Clinical Infectious Diseases, Vol. 37, No. 1 (Jul. 1, 2003), pp. 7-16 Published by: Oxford University Press Stable URL: http://www.jstor.org/stable/4483560 . Accessed: 10/05/2012 12:20
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MAJOR ARTICLE

Randomized Comparison of Artesunate of Severe Treatment in the and Quinine

Falaparum Malaria
RonatraiRuangveerayuth,4 Brian J. Angus,15 Paul N. Newton,1'5 Arjen Dondorp,15 WirongrongChierakul,1 and Nicholas J. White15 Sornchai Looareesuwan,1 KamolratSilamut,' Pramote Teerapong,2 Yupin Suputtamongkol,3 and of Medicine, Mahidol of Pharmacology, University, 3Department of Medicine 2Department and Siriraj Hospital, 'Faculty Tropical of Nuffield for Sot Mae and and Medicine, Medicine, Thailand; 5Centre Tropical DepartmentClinical Bangkok, 4Mae Hospital, Sot,Tak, United JohnRadcliffe Oxford, Kingdom Hospital,

A randomized,open-label comparisonof artesunateand quinine was conductedin 113 adults with clinically severe falciparummalaria in western Thailand. Mortalitywas 12%with artesunateand 22% with quinine treatment(relativerisk, 0.53;95%confidenceinterval,0.23-1.26;P = .22). Multiplelogistic regressionanalysis found admission plasma lactate level, Glasgow Coma Scale score, and total serum bilirubin level to be independent risk factors for death. Coma recoveryand times to normalize plasma lactate levels were similar, but the parasiteclearancetime was much shorteramong artesunate-treated patients (P = .019). Fewerpatients became hypoglycemicduring artesunatetherapy (10%)than during quinine therapy (28%) (P = .03). Artesunate is at least as effectiveas quinine in the treatmentof adultswith severemalaria.Larger trialsarerequired to determinewhether mortality is reducedamong patients treatedwith artesunate.
Although many treatment trials have been conducted, no interventions have been unequivocally shown to reduce the high mortality (12%-22%) associated with severe falciparum malaria. The conventional therapy is parenteral quinine, but this has a narrow therapeutic ratio, is associated with hyperinsulinemic hypoglycemia, and requires either repeated constant-rate infusions or painful intramuscular injections [1-3]. Although there is some evidence that the efficacy of quinine is decreasing in Southeast Asia, in terms of parasite and fever clearance and coma recovery times [4-9], there is no evidence that this has translated into an increase in mortality among treated patients. The artemisinin derivatives artesunate and artemether are used widely in Southeast Asia to treat malaria. In combination with other antimalarial drugs used to treat multidrug-resistant falciparum malaria, they augment efficacy, inhibit the emergence of drug resistance, and reduce transmission [10-19]. There are 3 parenteral forms: water-soluble artesunate, which is rapidly hydrolyzed in vivo to the more active dihydroartemisinin (DHA), and the lipid-soluble, intramuscular artemether and arteether, which are absorbed slowly and also converted to DHA [11, 17, 18]. Most studies of severe malaria have evaluated artemether or
24 Received July 12 2002; 23 2003; accepted February electronically published June2003. Financial Wellcome Trust-Mahidol Oxford Medicine support: University Tropical Research Trust (funded Britain). Programme bytheWellcome of Great or Dr. J. Nicholas White, of Medicine, Reprintscorrespondence: FacultyTropical Mahidol 420/6 Rajvithi Bangkok Rd., 10400,Thailand University, (fnnjw@ diamond.mahidol.ac.th). Clinical Infectious Diseases 2003; 37:7-16 ? 2003bythe Infectious Diseases of All reserved. Society America. rights 1058-4838/2003/3701-0002$15.00

arteether, rather than artesunate [20-29]. An individual patient data meta-analysis of 8 randomized clinical trials involving >1900 patients with severe malaria concluded that parenteral artemether was as effective as quinine in terms of mortality but superior in terms of the number of serious adverse events associated with its use [24, 25]. Artesunate is likely to be superior to artemether in the treatment of
Artesunatevs. Quinine in Severe Malaria * CID 2003:37 (1 July) * 7

severe malaria,for 3 reasons. First, artesunate,unlike arteand mether,can be administered intravenously, it is absorbed afterintramuscular whereas arintramuscular rapidly injection, temetheris absorbederratically [30, 31]. Delay in deliveryof a lifesaving ill drugin severely patientsis likelyto be deleterious. is and Second,artesunate more potent:artesunate DHA have in vitroantimalarial thatare2.9 and4.0 timesgreater, activities than the activity of artemether[32]. Third, alrespectively, has in though neurotoxicity not been demonstrated humans, in animal models, parenteral artemetheris more neurotoxic than is parenteral artesunate[33]. We thereforeconducted a randomized,open-labeltrial of artesunateversus quinine in adult patientswith severefalciparummalariathat used changesin plasmalactateas the priof maryend point. This studywas a preludeto consideration a large,multicenter mortalitytrial. PATIENTS AND METHODS Study site and patients. The presentstudy was conducted

during May through July 1994 at Sangklaburi Hospital, Kan-

chanaburiProvince,and during 1995-2001 at Mae Sot HosThesehospitalsserve pital, TakProvince,in westernThailand. a predominantly ruralpopulationof Thaifarmers Burmese and and Karenmigrantworkers [15, 19, 29, 34]. Malariatransmission is seasonaland of low intensity[35]. Ethicalclearance the studywas obtainedfrom the Minfor of PublicHealth,Government Thailand. of Patients - 15 istry
years old who had been admitted to the hospital with slideconfirmed, single-species Plasmodium falciparum parasitemia

of >0.1%wererecruited theyor an attending if relative provided writteninformedconsentand if they had severemalaria (table inves1) [20]. Becausethe resultsof some of the laboratory wereenrolled available, tigationswerenot immediately patients in the study on clinical grounds.Pregnantwomen, patients with contraindications takingthe studydrugs,and patients to with artesunate, mefloquine,or significant quinine (>2 g) intake in the previous24 h were excludedfrom the study.To demonstrate reductionfrom 60%to 30%in the proportion a of patientswith plasmalactatelevels :2 mmol/Lat 24 h with 80% power and 95% confidencerequiredthat 96 patientsbe includedin the study. Antimalarialtreatment. Patients wererandomly assigned in blocksof 10 to receiveartesunate quinine.Thefirstgroup or receivedintravenous artesunate (GuilinNo. 2 Pharmaceutical Factory,Guangxi,People'sRepublicof China;2.4 mg/kg on entry,followedby 1.2 mg/kg 12 h later and then 1.2 mg/kg/ day). Each60-mg vial of artesunicacid was dissolvedin 1 mL of 5%sodiumbicarbonate formsodiumartesunate then to and mixedwith 5 mL of 5%dextrose.This was injectedas a bolus into an indwellingintravenous cannula.When the patientwas able to swallowtablets,oral artesunate was administered (12 over the course of 7 days). Beginningin 1995, oral mg/kg artesunate combinedwith mefloquine(either15 mg/kgas was a single dose or 25 mg/kg divided into 1 dose of 15 mg/kg initiallyand 1 dose of 10 mg/kg 12-24 h later).Aftera report indicated increased of neuropsychiatric an risk reactions meto in patientswith severemalaria[36], tetracycline floquine (250 mg q6h for 7 days) or doxycycline(100 mg twice daily for 7 days) was substituted.

Table 1. Distributionof patients enrolled in a study comparingartesunate and quinine for the treatment of malaria in Thailand,by criteria for severe malaria. Treatment group, no. of patients Criterion Glasgow Coma Scale score <11 Hematocrit <20% with asexual parasitemia >100,000 parasites//LL Totalserum bilirubin level >50 ,umol/L with asexual parasitemia >100,000 parasites//uL Serum creatininelevel >264 /mol/L with urineoutput<400 mL/24 h Systolic blood pressure<80 mm Hg with cool extremities Asexual parasitemia >10% Plasma lactate level >4 mmol/L Plasmaglucose level <2.2 mmol/L Plasmavenous bicarbonate level <15 mmol/L Total (n= 113) 35 5 49 6 4 48 57 1 23 Artesunate Quinine (n= 54) (n= 59) 14 4 29 3 4 27 33 1 9 21 1 20 3 0 21 24 0 14 P .1 .4 .3 1.0 .1 .4 .3 1.0 .2

NOTE. AdaptedfromHienet al. [20].Severe malaria definedby the presence of >1 of the criteria was listed. Forall variables, there were no significant differencesbetween the artesunateand quinine groups. 8 ? CID 2003:37 (1 July) - Newton et al.

Enrolled 113

--

Quinine 54

Artesunate ____ 59

Alive 42 Excluded 8

Dead | 12 I

Alive | 52

Dead 7 Excluded 5

Severe Malaria 46

Severe Malaria I54

6o

Alive I 34

Dead 12

Alive 48 |

Dead 6l

Figure1.

of for in and in artesunate quinine thetreatment malaria Thailand and Flow chart patient of enrollment outcomes a study comparing Vital signs (pulse, respiratory rate,blood pressure,axillary and Glasgow ComaScale[GCS]score)weremeatemperature, sured every 15 min for the first hour, at 2 h, and then every 2 h until 12 h, every4 h from 12 to 24 h, and every6 h from time 24 h untilparasite clearance. Parasite clearance wasdefined as the intervalbetweenthe startof treatmentand the time of is the first of 2 sequentialnegativethick films. PC50 the time to 50% reductionin parasitedensity,and PC90 the time to is 90% reductionin parasitedensity.These were calculated by log-linearinterpolationof the parasitecount and time data.
Parasite reduction ratios at 24 h (PRR24) and 48 h (PRR48) were

The second group receivedintravenousquinine dihydroPharmaceutical chloride(Government Bangkok, Organisation, 20 Thailand), mg/kgin 666 mL of normalsaline,administered over the courseof 4 h. This was followedby 10 mg in 333 mL of normalsalineover the courseof 2 h, infused3 times daily. When the patientwas ableto swallowtablets,oralquinine(10 for mg/kg q8h) was substituted, a total of 7 daysof treatment, as with additionalmefloquine,tetracycline, doxycycline deor scribedabove. was The randomization open. Supportive treatmentwas in with the 1990 guidelinesof the WorldHealthOraccordance included complete performed ganization[3]. Theinvestigations blood count, serum biochemistry, chest radiography aband dominalultrasound, lumbarpuncturefor comatose diagnostic patients, and hemodynamicmonitoring. Peritonealdialysis wereavailable. Intramuscular and, from 1998on, hemodialysis to (3.5 mg/kg) was administered unconscious phenobarbitone The antibioticsused to treat patients as seizureprophylaxis. complicatinginfectionswere ampicillin,gentamicin,cefotaxime, and ceftazidime,which have no importantantimalarial activity. blood sampleswere obStudyprocedures. At admission, tainedto assess and hematocrit, [37]; parasitemia, parasite staging lactatelevels;glucoselevels;and full biochemistry. Plasplasma ma quinineconcentrations wereestimated dipstick[38].Heby matocritand parasite countswere measured 0, 1, 2, 4, 6, 8, at 10, 12, 16,20, and24 h andthenevery6 h until6 h afterparasite clearance. wereobtained glucoseandlactate for Samples analysis at 0, 4, 8, 12, 16, 20, and 24 h and then every6 h.

definedas the ratio of the parasitecount at admissionto that at 24 or 48 h [39]. Feverclearance times weremeasured from the start of antimalarial treatmentto the time at which the first and temperature droppedbelow37.5?C to the time axillary at which the axillarytemperature first droppedbelow 37.5?C and remained below 37.5?Cfor 24 h. Comarecovery time (for with a GCSscore<11 [of 15] on admission)was meapatients sured from the start of antimalarial treatmentto the time at whichthe GCSscorereached15.Timeto normalplasma lactate level was definedas the interval betweenthe startof treatment and a decreaseto <2 mmol/L. Statisticalanalysis. Analysis performed SPSSsoftwas by ware (version8.0). Normallydistributed data were compared data using Student'st test, and non-normallydistributed were theMann-Whitney UandWilcoxon compared using signedrank tests.The Bonferroni correction used for multiplecomparwas isons. Categorical data were comparedby X2test with Yates' correction and Fisher's exacttest. Kaplan-Meier plots weredeArtesunatevs. Quinine in Severe Malaria * CID 2003:37 (1 July) ? 9

and artesunate quininefor the details on admissionfor patientsenrolledin a studycomparing Table2. Clinicaland laboratory in of treatment malaria Thailand.
Treatment group Variable Bodyweight, mean kg (95% CI) No. of male patients/no.of female patients Age, medianyears (range) attacks per patient,median(range) No. of priormalaria No. of days ill, mean (95% CI) No. of patientswith seizuresa mean ?C(95%Cl) temperature, Axillary mean beats/min(95%CI) Pulse, Systolic blood pressure, mean mm Hg (95%Cl) Diastolicblood pressure,mean mm Hg (95% Cl) rate, medianbreaths/min (range) Respiratory mediancm (range) Hepatomegaly, mediancm (range) Splenomegaly, Median Glasgow Coma Scale score (range) No. of patientswith retinalhemorrhagesb Parasitemia, geometric mean parasites/IL (95%CI)c Trophozoites and schizonts, median % (range) Hematocrit, median % (range) WBCcount, mediancells x106/L(range) Peripheral Plasma glucose level, mean mmol/L (95%CI)d Plasma lactate level, median mmol/L (range)e median (range)f Serum creatinine level, jAmol/L, urea level, medianmmol/L(range)9 Serum Total serum bilirubinlevel, median Amol/L (range)h Serum bicarbonate level, median mmol/L (range)' All (n= 113) 50.7 (48.8-52.7) 79/34 25 (15-66) 0 (0-20) 4.0 (3.6-4.5) 12 38.5 (38.3-38.7) 111 (108-114) 107 (104-111) 64 (62-67) 30 (18-54) 1 (0-10) 0 (0-8) 15 (3-15) 8 208,320 (152,693-284,204) 7 (0-99) 33.1 (31.2-35.0) 8.8 (2.2-27.2) 8.5 (7.7-9.3) 4.3 (0.3-27.3) 114 (44-792) 10.2 (1.3-61.3) 51 (9-646) 19.5 (5.0-25.0) Artesunate (n = 59) 50.9 (47.4-54.3) 39/20 25 (15-66) 0.5 (0-5) 4.0 (3.5-4.5) 3 38.3 (38.0-38.7) 112 (109-116) 105 (100-109) 63 (59-67) 28 (20-54) 1 (0-10) 0 (0-10) 15 (3-15) 3 225,092 (139,034-364,427) 7 (0-89) 32.2 (29.4-35.0) 8.9 (2.4-27.2) 8.2 (7.2-9.3) 4.8 (1.0-20.1) 123 (44-792) 11.3 (4.1-61.3) 54 (8-646) 19.0 (5.0-25.0) Quinine (n = 54) 50.4 (48.5-52.3) 40/14 25 (15-59) 0 (0-20) 4.0 (3.3-4.7) 9 38.7 (38.4-39.0) 110 (105-115) 110 (106-115) 66 (63-69) 30 (18-48) 1 (0-8) 0 (0-10) 13 (3-15) 5 194,294 (129,175-292,240) 9 (0-99) 34.2 (31.4-36.9) 8.6 (2.2-26.3) 8.4 (7.4-9.5) 3.8 (0.3-27.3) 110 (53-722) 8.9 (1.3-60.9) 54 (11-453) 20.0 (5.0-25.0) P .8 .4 .6 .8 .9 .07 .1 .4 .07 .2 .6 .5 .4 .04 .5 .6 .6 .1 .9 .8 .4 .5 .06 .9 .9

as NOTE. The variablesin bold are those identified prospectively the mainvariablesto be used in the analysis. a Datawere available from only 58 patientsin the artesunategroup. b Datawere available from only 92 patients,47 in the artesunategroupand 45 in the quininegroup. c No. of asexual parasites/1000erythrocyteson thin filmx hematocrit 125.6. x d Normalrange,3.5-5.5 mmol/L. e Normal, mmol/L. <2 f Normalrange,70-150 Amol/L. g Normal range,2.5-6.7 mmol/L. h Normalrange,3-17 umol/L. Normalrange,21-28 mmol/L.

for and variables. termined primary secondary regression Logistic modelswerecompared usingthe likelihoodratiotest. RESULTS One hundredthirteen patientswere recruitedbetweenApril and 1994 and July2001 (11 at Sangklaburi 102 at Mae Sot); 59 were randomlyassignedto receiveartesunate and 54 were assignedto receivequininetreatment(figure1 and tables1-3). The studylastedlongerthan intended,becausethe majority of admittedwith severemalaria received had antimalarial patients beforeadmissionandweretherefore To therapy ineligible. avoid treatment and before delay,patientswererecruited randomized the resultsof all laboratory wereavailable. Thirinvestigations
10 - CID 2003:37 (1 July)
*

teen patientsrecruitedwere subsequently found not to fulfill the entry criteriafor severemalaria(n = 12) or to have very low levelsof parasitemia = 1; 132 parasites/,uL). Therefore, (n 100 patientswho fulfilledthe criteriafor severemalariawere and studied,54 of whom receivedartesunate 46 of whom receivedquinine.The datawereanalyzed primarily intent-toby treatmethods (n = 113) and secondarily the subsetof pafor tients who met the strict definitionfor severemalaria(n = 100). Some of the patientsrecruitedinto this studywere also included in studies of pathophysiologyreported elsewhere [40-42]. The study population was predominantlyBurmese and Karen(77%),withThai(21%)andHmong(2%)ethnicgroups. Clinical and laboratoryparameterson admission,including

Newton et al.

a variables considered priorito be key prognosticindicators in did not differ significantly between the quinine and adults, artesunate groupsfor all patientsand for the subsetof patients with severemalaria(P>.1; tables 1 and 2). The median admission GCS score was lower in the quinine group;39% of the patientsin that grouphad cerebral with malaria, compared = .06). The mediannumber 24% in the artesunate group (P of criteriafor severe malariamet per patient was 2 in both groups (range, 1-5 in the quininegroup and 1-6 in the artesunate group;P = .9). Concurrentconditionswere excessive alcohol use (2 patientsin the artesunate group and 2 in the use biquinine group);amphetamine (2 and 1, respectively); lateralcataracts and 1); HIV infection(1 and 1);pulmonary (2 tuberculosis and 1); nephroticsyndrome,treatedwith ster(0 oids (0 and 1); positiveresultsof Coombs'test for hemolytic anemia,treatedwith steroids(1 and 0); and mitralor aortic valvedisease(3 and 0). Urinequinineconcentrations ~2.5 mg/ dL were detectedby dipsticktestingat admissionin 6 patients (4 in the quinine group and 2 in the artesunategroup;P> intravenous lactate solution .05). Fivepatientsreceived Ringer's before recruitment; plasmalactateresultsfrom these pathe tients were excludedfrom the analysis. Lumbar was at for puncture performed admission 33 patients was (29%).The mean openingpressure 14.6cm H2O(95%CI, 8.1-21.0 cm HO2).The mean CSFproteinlevelwas 84 mg/dL (95%CI, 57-110 mg/dL),the mean CSFglucoselevel was 4.9

mmol/L(95%CI,3.7-6.2 mmol/L),andthe median WBCcount was 7 cells/mm3(range,0-200 cells/mm3). The median perof lymphocytes 100%(range, was None of 80%-100%). centage the CSFparameters differed the between 2 treatment significantly bacterial groups.No patienthad coincident meningitis. The frequency mechanical of ventilatory supportwashigher in the quininegroup than in the artesunate group (P = .04). Nineteen patientsreceivedtetracycline, 29 receiveddoxyand with mean total doses of 113 mg/kg (95% CI, 93-33 cycline, mg/kg) and 28.7 mg/kg (95% CI, 26.9-30.5 mg/kg), respecat tively.Twenty-one patientsreceived mefloquine a meantotal dose of 24.9 mg of mefloquinebase/kg(95%CI, 22.4-27.6). Clinical outcome. The overallmortalitywas 17%(19 of 113 patients;tables4 and 5). Sevenpatientsin the artesunate group died (12%),and 12 patientsin the quininegroupdied (22%) (relativerisk [RR],0.53; 95% CI, 0.23-1.26;P = .22). The causesof deathwere usuallymultifactorial (table5). One of the 13 patientsexcludedfrom the final group of 100 also died. This patientpresentedwithout evidenceof previousantimalarial with a GCSscore of 5, and with parasitreatment, temia of only 3 parasites/200 WBCs (120 cells/fL). Despite treatment with artesunate,the patient developed bacterial pneumonia, a spontaneouspneumothorax,and acute respiratorydistresssyndromeand died after 187 h in the hospital. The survivalcurves (for all 113 patients)are illustrated in figure2A (X2= 2.24 and P = .13, by log-ranktest;for the 100

Table 3. Treatmentregimens for patients enrolled in a study comparingartesunate and quinine for the treatment of malaria in Thailand. Treatment group Treatment Intravenous artesunate,mean mg/kg (95% C) Oralartesunate,mean mg/kg (95% CI) Totalartesunate,mean mg/kg (95% CI) Intravenous quinine,mean mg of salt/kg (95% C) Oralquinine,mean mg of salt/kg (95% C) Totalquinine,mean mg/kg (95% CI) No. of intravenous doses, median(range) No. of oraldoses, median (range) Bloodtransfusion,no. of patients Units of bloodtransfusedper patient,median (range) catheter,no. of patients Urinary Furosemideand/ordopamine,no. of patients Centralvenous access, no. of patients Ventilatory support,no. of patients Renaldialysis,no. of patients Antibiotics,no. of patients lonotropes,no. of patients NOTE. Drug doses arein mg/kg body of weight. a Includes loading of twicethe maintenance a dose dose.
Artesunatevs. Quinine in Severe Malaria * CID 2003:37 (1 July)

All (n = 113) -

Artesunate (n = 59) 6.4 (5.6-7.1) 5.9 (4.6-7.0) 11.2 (9.9-12.5) -155 5 (2-9)a 6 (1-12) 22 0 (0-4) 38 19 12 8 2 19 12

Quinine (n = 54)

41 0 (0-8) 72 40 29 24 5 38 25

94 (76-113) (138-172) 209 (179-239) 6 (2-21)a 15 (3-28) 19 0 (0-8) 34 21 17 16 3 19 13

.8 .7 1.0 .6 .2 .04 .7 .8 .7

1]

Table 4. Outcome measures for treatment of patients enrolled in a study comparing artesunate and quinine for the treatment of malaria in Thailand. Treatment group Variable All (n = 113) Artesunate (n = 59) 5.1 (4.3-5.9) 0 (0-3) 6 6 3 11 4 13 62.5 (53.4-71.8) 10 9.1 (0.3-37.2) 20.5 (2.8-50.1) 17.5 (0.5-9288) 2394 (10-25,095) 22.4 (21.0-23.8) 26.2 (22.6-29.8) 30 (0-120) 11 (1-83) 41 (3-138) 16 (2-72) 17 (1-125) 7/52 48 (29-408) Quinine (n = 54) 5.0 (3.8-6.2) 0 (0-3) 15 5 2 9 5 13 76.0 (70.2-81.8) 8 8.0 (0.2-46.0) 24.7 (0.9-67.7) 7.0 (0.1-602) 586 (2-15386) 24.2 (22.1-26.3) 28.9 (25.2-32.6) 27 (0-120) 13 (1-184) 65 (12-383) 8 (1-120) 18 (1-188) 12/42 21 (3-144) P .9 .7 .028 1.0 1.0 .8 .7 .8 .019 .8 .3 .08 .02 .03 .2 .4 1.0 .2 .2 .3 .6 .2 .02

Time in hospital, mean days (95%Cl) 5.1 (4.4-5.8) Time in ICU,mediandays (range) 0 (0-3) no. 21 Hypoglycemia, of patients 11 Seizures after admission, no. of patients 5 Bleedingafter admission, no. of patients 20 Sepsis after admission, no. of patients 9 edema, no. of patients Pulmonary no. 26 Oliguria, of patients 68.8 (63.0-74.5) PCT,mean h (95%Cl)a Increasein parasitemia between 0 and 6 h, no. of patients 18 Time to PCo5, median h (range)a 9.0 (0.2-46.0) Time to PCgo, median h (range)a 23.3 (0.9-67.7) median (range)a 10.7 (0.1-9288) PRR24, median (range)a 789 (2-25,095) PRR48, Minimumhematocrit,mean % (95% Cl) 23.3 (22.0-24.5) 27.5 (24.9-30.1) Change in hematocrit,mean % (95% CI) Time to minimumhematocrit,median h (range) 30 (0-120) median h (range)8 11 (1-84) FCTa, median h (range)a 50 (3-383) FCTb, Time to plasma lactate level <2 mmol/L, median h (range)a 14 (1-120) Coma recovery time, median h (range)a 17 (1-188) No. of patients who died/no,who survived 19/94 throughdischarge Time to death, median h (range)a 42 (3-408)

NOTE. Variables boldare those identified in as to fever clearancetime; prospectively the mainvariables be used in the analysis.FCT, intervalbetween the start of antimalarial treatmentand the point at which the axillary FCTa, temperaturefirst droppedbelow 37.5?C; interval between the startof antimalarial treatmentand the pointat which the axillary FCTb, first and temperature droppedbelow 37.5?C remainedbelow 37.5?Cfor 24 h; ICU,intensivecare unit;PCT, in 50% reduction parasitedensity;PCg0, 90% parasiteclearancetime; PCo5, reductionin parasitedensity; PRR,parasitereductionratio;PRR24, ratioof parasitecount at admissionto that at 24 h; PRR48, ratioof parasitecount at admissionto that at 48 h. a Data were available from only 91 patientsfor PCT; from 105, for PCo5; from 102, for PCg0; from 99, for PRR24; from 65, for PRR48; from 84, for FCTa; from 59, for FCTb; from 50, for time to plasmalactate level <2 mmol/L; from 32, for coma recoverytime; and from 19, for time to death.

patients with severe malaria,x2 = 3.71 and P = .05). The overall median time between the initiation of antimalarialtreatment and death was 42 h (range, 3-408 h). This was significantly shorter for quinine-treated patients (21 h; range, 3-144 h) than for artesunate-treated patients (48 h; range, 29-408 h) (P = .02; table 4). Of 9 patients who received a clinical diagnosis of pulmonary edema or acute respiratory distress syndrome, only 1 patient, who had been treated with artesunate, survived. Two patients in each treatment group developed intravenous cannula site infections. The overall median coma recovery time for patients who presented with a GCS score of <15 was 17 h (range, 1-188 h),
12
*

and this was not significantly different between the 2 treatment groups. Coma recovery times in those who presented with a GCS score of <11 were not significantly different (X2 = 0.09 and P = .5, by Kaplan-Meier plot; figure 2B). Fever clearance times (X2 = 0.06 and P = .32, by Kaplan-Meier plot; figure 2C and table 4) and temporal changes in pulse, blood pressure, respiratory rate, and fever did not differ between the 2 treatment groups. Of the 100 patients with strictly defined severe malaria, there were significant differences between the artesunate- and quinine-treated patients in the frequency of hypoglycemia (6 of 54 vs. 15 of 46 patients; RR, 0.34; 95% CI, 0.14-0.81; P =

CID 2003:37 (1 July) * Newton et al.

Table 5. Complications and causes of death among patients enrolled in a study comparingartesunate and quininefor the treatmentof malariain Thailand. No. of patients in treatmentgroup Outcome, syndrome Death edema/ARDS Pulmonary arrest Cardiorespiratory Intractable hypotensionand oliguria tract bleeding Hypotensionand gastrointestinal Survivedthroughdischarge fever Blackwater mediannerve palsy Ulnaror tract infection Klebsiella species urinary Pneumonia Herpes zoster NOTE. ARDS, acuterespiratory distress syndrome.
a Includes2 patientswith spontaneouspneumothoraces 1 with pneumonia. and b Includes1 patientwith severe pneumonia.

Total Artesunate Quinine 6 8 4 1 1 2 1 1 1 3a 3 1 0 1 1 1 1 0 3 5

3b

1 0 1 0 2 1

.017), median PRR48(2920 [range, 9.7-25,095] vs. 408 [range, 2.1-15,386]; P = .027), and frequency of ventilatory support (7 of 54 vs. 16 of 46 patients; P = .016). The applicable subset analysis performed by the ArtemetherQuinine Meta-analysis Study Group [25] was also performed on this data set. There were no significant differences in mortality associated with artesunate treatment among male patients, patients with acute renal failure, patients with hypoglycemia, or patients with jaundice (P>.1). In a multiple logistic regression analysis of factors present at admission that were potentially associated with death, plasma lactate level, GCS score, serum total bilirubin level, serum creatinine level, and the proportion of trophozoites and schizonts in the admission blood film were each independently associated with death (table 6). The likelihood ratio test identified the proportion of trophozoites and schizonts (OR, 1.036; 95% CI, 1.016-1.057; P = .0005) and plasma lactate levels (OR, 1.276; 95% CI, 1.116-1.458; P = .0003) as the best model for prediction of a fatal outcome. The addition of primary drug treatment as a variable did not improve the model.

of 14 mg/kg) and then 7 doses of oral quinine sulphate (14 mg/kg q8h) and 4 doses of oral doxycycline (2.4 mg/kg) cleared parasitemia at 48 h, but P. falciparum parasitemia reappeared on the fifth day after initiation of treatment, representing an RII treatment failure [43]. Glucose and lactate profiles. Fewer patients became hypoglycemic in the artesunate group (10%) than in the quinine group (28%) (RR, 0.37; 95% CI, 0.15-0.88; P = .03). The median time to plasma lactate level -2 mmol/L was 14 h (range, 1-120 h), and this did not differ significantly between the 2 treatment groups (X2 = 0.38 and P = .5, byKaplan-Meierplot; figure 2D and table 4). The proportions of patients with plasma lactate levels -2 mmol/L at 24 h were 32% and 36% in the quinine and artesunate groups, respectively (P>.05). Drug-related adverse events. Patients treated with quinine consistently developed cinchonism and had a significantly higher frequency of hypoglycemia. One patient had a probable adverse reaction to artesunate. This patient presented with parasitemia of 31%, a plasma lactate level of 14.5 mmol/L, and a serum bilirubin level of 23 mg/dL and developed a widespread erythematous urticarial rash 17 h after treatment with intravenous artesunate was initiated. No other drugs had been administered. Intravenous quinine was substituted, but the patient died 52 h later with pulmonary edema, oliguria, hypotension, and electromechanical dissociation. This was attributed to severe malaria.

Parasitologicaland hematologicaloutcome. Hematocrit

profiles did not differ significantly between the 2 treatment groups (table 4). The parasite clearance time for the artesunatetreated patients (mean, 62.5 h; 95% CI, 53.4-71.8 h) was significantly shorter than that for the quinine-treated patients (mean, 76.0 h; 95% CI, 70.2-81.8 h) (P = .019; figure 3). The proportion of patients with a parasite count that had risen at 6 h and the median PC50,PC90,PRR24, and PRR48 not differ did significantly between the 2 groups (P>.05). A 41-kg patient who received a high dose of parenteral quinine (29-mg/kg loading dose, followed by 7 intravenous doses

DISCUSSION
The present study suggests that artesunate is an effective alternative to quinine in the treatment of severe malaria. The
Artesunatevs. Quinine in Severe Malaria * CID 2003:37 (1 July) * 13

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in artesunate lactate level<2 mmol/L among included a study <37.50C andtimeto plasma (dashed to first (D) (C), comparing subjects temperature in in notshown A)died408h of in One and forthetreatment malaria Thailand. patient theartesunate (data lines) quinine (solid lines) group point
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mortality difference in the study was large and in favor of artesunate, but the difference was not statistically significant (this preliminary trial was powered only to detect huge differences in mortality). Among artesunate-treatedpatients, parasite clearance times were shorter, incidence of posttreatment hypoglycemia was lower, and time to death was longer. The 2 groups did not differ in duration of hospitalization, coma recovery time, and time to normalization of plasma lactate levels. The higher incidence of hypoglycemia in the quinine group was expected, because quinine provides a potent stimulus to insulin secretion [1]. The reason for the higher frequency of ventilatory support in the quinine group is unclear; the 2 treatment groups did not differ in the frequency of pulmonary edema and sepsis or of clinical interventions such as placement of central venous access lines, urinary catheters, and antibiotic use. It has recently been suggested that artesunate has a diuretic effect in patients with severe malaria [44], but there were no significant differences between the treatment groups in the proportion of patients who developed oliguria or pulmonary

edema or who required furosemide and/or dopamine, dialysis, urinary catheters, or central venous access (table 3). Shorter parasite clearance time in association with artesunate treatment is a consistent finding in studies comparing the arTable 6. Logistic regression analysis of the association between factors present on admission and death among patients enrolled in a study comparing artesunate and quinine for the treatment of malaria in Thailand.
Variable Glasgow Coma Scale score Total serum bilirubinlevel Percentage of trophozoites and schizonts Plasma lactate level Serum creatinine level OR (95% CI) 0.7 (0.54-0.91) 1.18 (1.03-1.34) 1.03 (1.01-1.06) 1.17 (1.01-1.35) 1.74 (1.02-2.99) P .007 .014 .016 .034 .044

were primary NOTE. Additional factorsenteredintothe modelbutrejected and drugtreatment,hematocrit, parasitemia, systolicbloodpressureat the log time of admission.

14 * CID 2003:37 (1 July) * Newton et al.

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treatment of falciparum malaria [46, 47], but these abnormalities are much more likely to be a consequence of malaria itself than of the treatment [48, 49]. In a larger trial of intramuscularquinine versus artemetherin Vietnamese adults with severe malaria,artemetherwas associated with prolonged fever clearance times, coma recovery times, and duration of hospitalization [20]. This was not found in the present trial. Although our study suggests that artesunate may be superior to quinine in the treatment of adults with severe malaria, clinical malaria research is rife with examples of small studies that provide evidence of a new (lifesaving) treatment for severe malaria that is not supported by subsequent larger trials [2, 50]. A large international multicenter trial is required to test whether artesunate is associated with reduced mortality in comparison to quinine. A power calculation that uses the data presented here suggests that a minimum sample size of-960 patients would be required (80% power and 95% confidence), assuming that a 33% reduction from a 22% mortality would be clinically significant (to detect a 20% reduction in mortality would require an estimated 2600 patients). Until such data are available, the results of this trial suggest that artesunateis equivalent to quinine in the treatment of severe malaria in adults in Thailand and that it is associated with faster parasite clearance and a lower prevalence of hypoglycemia.

mean sub(95% vs. Figure3. Geometric parasitemia Cl) timeamong in included a study artesunate circles)and jects comparing (open quinine Acknowledgments in of for (solid circles) thetreatment malaria Thailand. We are grateful to the directors, doctors, and nurses of Sangtemisinin derivatives with other antimalarial drugs [11, 25, 39]. The single patient who experienced early (RII) failure despite receiving high doses of quinine is of concern. A patient who died as a result of severe malaria with RIII resistance to intravenous quinine has been described [9], but the plasma quinine levels in that patient, despite use of a conventional body-weight dose regimen, were lower than the minimum therapeutic concentration. High-grade resistance of P. falciparum to quinine has been reported elsewhere in Southeast Asia, but the absence of drug measurements makes interpretation in this case difficult [5-8]. There is no evidence of a major decrease in quinine efficacy in treating severe malaria. Reports of serious adverse events attributable to artesunate use are very rare [34]. The development of a rash after receipt of intravenous artesunate, as described in 1 patient in the present study, is consistent with a recent report of 2 patients who developed urticarial rashes after receiving oral artesunate [45]. The patient we described had multiple poor prognostic signs, and the subsequent fatal clinical course was consistent with severe malaria. However, the possibility of an idiosyncratic artesunate reaction cannot be excluded. Case reports have deklaburi and Mae Sot Hospitals, especially Itaporn Thaiaporn and Jantipa Sutham, for their interest and support; Thanongsak Teewarakulpana, for language translation; and Tip Ruechaitrakul, for logistical help. Kenechanh Chanthapadith, Impone Vangkonevilay,Jamie and Sarah Craig, Juanitade Lope, Michele van Vugt, and Mayfong Mayxay helped with patient care. We thank Lizzy Kissinger, Tan Chongsuphajaisiddhi, Kesinee Chotivanich, Sayan Langla, Kongpop Pupae, Nitirat Thima, Nick Day, and Kasia Stepniewska, for their help and advice. References
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16 * CID 2003:37 (1 July) * Newton et al.