Indian Pediatrics 2003; 40:939-945 

Objective: To compare the efficacy of artemether and quinine in the treatment of severe malaria in hospitalized children. Study design: Open randomized trial. Setting: Pediatric ward of a tertiary care center. Methods: All children admitted with clinical manifestations of severe malaria (as per WHO criteria) and asexual forms of Plasmodium falciparum demonstrated on peripheral smear were randomized to receive either artemether or quinine. Their clinical status and smears for parasite count were assessed every 12 hours until two successive blood films were negative. The primary end point of the study was death in the hospital and residual damage to the organ involved. The secondary end points were clearance of parasites and fever, length of time of recovery from coma and normal functions of the involved system. Results: Forty-six cases completed the study protocol, 23 assigned to each drug group. Cerebral malaria was the commonest manifestation (76.1%). Mean age in artemether versus quinine group (6.6 ± 3.5 and 5.8 ± 2.4 years) as well as degree of parasitemia at admission (55,800 and 60,300 per microlitre) were comparable. The overall mortality rate was 23.9% with no significant difference between the two groups. Twenty six cases (56.5%) presented with more than one manifestations of severe malaria. The mortality rate was 100% with four coexisting manifestations of severe malaria. Fever clearance time in artemether and quinine group was 44.5 and 45.9 hours respectively (P>0.05). Parasite clearance time was significantly shorter in artemether group (40.9 vs. 51.9 hours; P<0.001). Recovery from coma was shorter in artemether group (34.8 vs. 38.1 hours; P<0.05). Conclusions: Cerebral malaria is the most common manifestation of severe malaria in children. Artemether is a good alternative drug to quinine for P. falciparum malaria. Mortality rate is directly proportional to the number of coexisting manifestations of severe malaria. .

Key words: Artemether, Malaria, Quinine

Malaria is one of the commonest potentially fatal infections in the world with high incidence in South-East Asia region specially India, Bangladesh, Nepal, Sri Lanka, Thailand and Indonesia(1). Plasmodium falciparum is the principal cause of severe disease with most deaths occurring in young children living in areas of intense transmission mainly due to cerebral malaria(2). In absolute terms, malaria kills 3000 children under 5 years old every day(3). Severe and complicated falciparum malaria is defined by the presence of one or more pernicious signs and symptoms in a patient showing asexual parasitemia of P. falciparum in the peripheral blood smear(4). Quinine has been the drug of choice for severe falciparum malaria. Recently RII type resistance to the drug has been reported(5). Moreover, because of its potential toxicity and need for adminis-tration ideally by controlled intravenous infusion-a procedure that is often impractical in rural health clinics specially in young children(6) there is an urgent need to identify new forms of therapy for severe and complicated malaria that are economical, practical and clinically superior to quinine. Among the potential alternatives to quinine, artemesinin (quinghaosu) derivatives have attracted special attention because of their rapid schizonticidal activity against P. falciparum and P. vivax(7)

To the best of our knowledge, there is no published report from India about the comparison of artemether and quinine in the treatment of severe malaria in children. Hence the present open randomized prospective trial was undertaken to compare the efficacy of artemether and quinine in the treatment of severe malaria in children.

Subjects and Methods

The study was conducted between April 2000 and July 2001 in the inpatient unit of Department of Pediatrics, and the Parasito-logy laboratory of the Department of Micro-biology. Total of 99 patients (aged up to 14 years) diagnosed as severe malaria were admitted but only 46 cases that fulfilled all of the following criteria completed the study and were included in the final analysis, 23 being assigned to each of the drug groups.

Inclusion criteria

1. Asexual forms of Plasmodium falciparum demonstrated on peripheral smear.

2. One or more clinical manifestations of severe malaria were present which include – cerebral malaria, severe anemia (hemo-globin <5 g/dL or hematocrit <15%) metabolic abnormalities (hypoglycemia: plasma glucose <40 mg/dL or <2.2 mmol/L), algid malaria (associated with peri-pheral circulatory failure or shock), black-water fever, renal failure, spontaneous bleeding (thrombocytopenia, DIC), pul-monary edema and jaundice(4).

Exclusion criteria

1. History of having received artemether /quinine within 24 hours preceding admission.

2. Severe protein energy malnutrition or clinical/laboratory evidence of other significant illness not attributable to severe malaria.

Among the patients that were excluded, 21 had received artemether/quinine before admission, parents refused consent for the study protocol in 7 cases, 12 had other significant illness, 8 had severe PEM, and 6 cases did not complete the study protocol.

After taking informed consent from the patient’s parents, detailed history and physical examination with relevant investigations of the selected children were recorded on a pre- designed proforma. The patients were admitted in the hospital for duration of at least 7 days for the completion of therapy during which the clinical status was recorded at least twice daily.

Laboratory investigations

The following investigations were carried out in all the patients at the time of admission prior to treatment:

• Thick and thin blood films prepared from finger prick for malarial parasites and repeated every 12 hourly until two successive blood-films were negative.

• Blood samples were drawn for blood count, platelet count and biochemistry (blood glucose, renal function test, liver function test, serum electrolyte). Complete blood count and biochemistry were repeated on day 3 or earlier if needed.

• G6PD estimation and urine examination for hemoglobinuria in patients suspected of having intravascular hemolysis.

• Blood culture to rule out septicemia

• Chest X-ray and ECG on admission in each case

• Lumbar puncture in all patients having cerebral malaria (unless clinically contraindicated) to rule out meningitis, encephalitis, etc.

The slides for malarial parasites were transported to the parasitology laboratory where the person examining the slides was unaware of the clinical status of the patient and also the treatment assignment group. The slides were fixed with methyl alcohol, stained by Leishman’s stain and examined under oil immersion lens for parasite species and stage. The degree of parasitemia was calculated by counting the parasites under oil immersion against 200 leukocytes, assuming a standard WBC count of 8000/cumm using the formula: Parasite count per microlitre = Number of parasitesx8000/number of leucocytes. A blood slide was pronounced as negative when the examination of 100 thick-film fields did not show the presence of asexual forms of plasmodium.

Patients were randomized to receive either artemether on even dates [1.6 mg/kg twice a day intramuscular followed by 1.6 mg/kg once a day for the next five days] or quinine dihydrochloride (20 mg/kg by intravenous infusion followed by 10 mg/kg every 8 hourly by intravenous infusion or orally as quinine sulphate once the patient was conscious, for a total period of 7 days. Supportive therapy was given in all patients.

Temperature and vital signs were recorded every 8 hourly during the observation period and Glasgow coma scale was used in grading the level of consciousness of the patients. The primary end-point of the study was death during the hospital stay and residual neurological deficit. The secondary end-points were parasite and fever clearance time, time taken to recover from coma and normalization of function of the involved system.

Each child was examined in detail at the time of discharge and those patients having neurologic sequelae were considered for follow up after one month. A child was considered to have neurological sequelae if he or she had neurological abnormalities like ataxia, paresis, spasticity, floppiness, hearing defect, visual field defect, etc.

Differences between the drug-groups were analyzed using Chi-square test. The therapeutic responses were analyzed statisti-cally using Z-test and Student’s t-test. P value of <0.05 was considered significant.

Results

Most cases were in 5-10 years age group (56.5%) with 32.6% in the 1-5 years age group. Males outnumbered females (67.8%). Almost two-third of the cases were admitted in the months of August to October. Most cases presented within 5 days of illness (78.25%). Cerebral malaria was the commonest manifestation (76.08%). The presenting complaints included fever in 46(100%), unconsciouness in 39 (84.8%), abnormal movements (n = 16, 34.8%), vomiting (n = 8, 17.3%), pallor (n = 7, 15.2%), jaundice (n = 3, 6.5%), cola colored urine (n = 3, 6.5%), and headache, loose stools and irritability in 2 patients (4.3%) each.

The baseline characteristics of the two drug groups were comparable (Table I). The overall mortality was 23.9% (Table II). The difference in the mortality rates in the two drug groups was not significant. More than 45% patients expired within 5 hours of hospital admission. Mortality was seen in 6 out of 7 cases with ³3 coexisting manifestations of severe malaria. Residual sequelae were not detected in any survivors in either of the treatment groups.

TABLE I

Baseline Characteristics of the Treatment Groups

Characteristics	Artemether (n = 23)	Quinine (n = 23)
Male sex (%)	17 (73.39%)	14 (60.86%)
Age (years): mean ± SD*	6.6 ± 3.5	5.8 ± 2.4
Temperature (mean) (ºF)	100	100.5
Presentation: No. (%)
• Cerebral malaria	14 (60.85%)	21 (91.3%)
• Severe anemia	10 (43.47%)	6 (26.08%)
• Hypoglycemia	7 (30.43%)	3 (13.04%)
• Renal failure	4 (17.39%)	0
• Black-water fever	3 (13.04%)	0
• Jaundice	3 (13.04)	4 (17.39%)
• Bleeding manifestation	2 (8.69%)	2 (8.69%)
• Algid malaria	2 (8.69%)	0
Degree of parasitemia per µL: Mean	55,800	60,300
Range	(18,600-272,800)	(20,880-258,400)

 

TABLE II

Mortality Analysis

Characteristics	Number of cases	Mortality
Presentation
• Cerebral malaria	35 (76.08%)	8 (22.85%)
• Severe anemia	16 (34.78%)	9 (56.25%)
• Hypoglycemia	10 (21.73%)	4 (40.0%)
• Jaundice	7 (15.2%)	4 (57.14%)
• Renal failure	4 (8.69%)	3 (75%)
• Blackwater fever	3 (6.52%)	2 (66.67%)
• Algid malaria	2 (4.3%)	1 (50%)
Number of manifestations of severe malaria
• One	20 (43.47%)	1 (50%)
• Two	19 (41.30%)	4 (21.05%)
• Three	5 (10.86%)	4 (80%)
• Four	2 (4.34%)	2 (100%)
Duration of hospital stay
1-5 hours (n = 2 in artemether group & n = 3 in quinine group)		5 (45.45%)
6-10 hours (n = 3 in artemether group & n = 1 in quinine group)		4 (36.36%)
>10 hours (n = 0 in artemether group & n = 2 quinine group)		2 (18.18%)
Total mortality* (N = 46)		11 (23.9%)

*Total of 6 (13.04%) mortalities in quinine group and 5 (10.86%) mortalities in artemether group 
(P >0.05).

 

Except for fever resolution all secondary outcome variables were better in artemether group (Table III). No significant side effects were noted with the drugs during the study period.

TABLE III

Assessment of Recovery after Treatment with Artemether or Quinine

Variable (hours)	Artemether	Quinine	P value
Time to parasite clearance:
• 50% clearance (mean ± SD*)	16.6 ± 6.0	19.7 ± 6.0	<0.05
• Total clearance (mean ± SD)	40.9 ± 8.4	51.9 ± 1.2	<0.001
Resolution of fever (mean ± SD)	44.5 ± 7.7	45.9 ± 7.2	NS**
Recovery from coma (mean ± SD)	34.8 ± 8.2	40.8 ± 7.0	<0.05

* S.D. = Standard Deviation,     ** NS = Not Significant.

Discussion

The results of this study show that in terms of preventing deaths, artemether is as effective as quinine, which is comparable to findings of other studies (5,6, 8-10). However, Karbwang et al.(7) reported better survival rate (87.20% vs. 63.30% respectively) with artemether com-pared to quinine. Unlike the findings in African children with cerebral malaria where the incidence of neurological sequelae ranged from 8.3%-13.5%(2,6,11), no neurological sequelae were noted in our series. Perhaps the neurological insult before initiation of treatment may have been more substantial in the former.

There is no data to compare the prevalence of various presentations of severe malaria in Indian children because most workers have either worked on patients of cerebral malaria or some other manifestations of complicated malaria(12,13). It is important to appreciate that manifestations of severe malaria can occur in a patient either singly or more commonly in combination as in the present study (43.5% vs 56.5%). The results of our study are in agreement with the observations of other workers who have noted that mortality in severe malaria is directly proportional to the number of pernicious manifestations present in a patient(14-16).

Among the secondary end-points of this study, the time taken for parasite count to fall by 50% and to clear completely was significantly shorter in children treated with artemether than in those treated with quinine (P <0.05 and P <0.001 respectively; Table III). This is confirmed by most other studies(5,10,17) with the exception of some(11). However, despite the convincing rapid parasite clearance, the correspondingly anticipated decline in mortality has not been demonstrated, thus suggesting that rapid parasite clearance may be relatively insignifi-cant determinant of survival. This may partly be explained by the fact that artemether preferentially accelerates the clearance of younger parasites in the circulation over the more mature parasites, which are located deep in the vasculature and mediate most of the organ damage.

Fever clearance time was shorter but did not reach statistical significance in our study unlike observations by other workers(5-7,10,17). Mean recovery time from coma of 34.8 ± 8.2 hours in artemether group was significantly better than 40.8 ± 7 hours seen with quinine (P <0.05). Olumese et al.(8) reported median recovery time of 24 hours [IQ =18-45] and 33 hours [IQ = 19-57] in artemether and quinine groups respectively. Studies have also demonstrated either no significant difference(5,7,11) or even longer recovery time from coma (66 hours 48 hours respectively for artemether and quinine, P = 0.003) in a study by Tran, et al.(9).

No serious side effects of either of the drugs were observed in our study, while most other series have reported higher incidence of side effects with quinine, when compared with artemether. Closer and more frequent monitoring and larger sample size would have probably revealed more subtle adverse drug effects.

Thus, it can be concluded that artemether is as effective as quinine in the management of severe malaria in children. It is simple to administer, almost equivalent in overall cost to quinine and has no serious side effects. In India P. falciparum accounts for 40% of the cases of malaria instead of the usual 15% reported, after the advent of drug resistance(18).

Artemether can be an important alternative to quinine for severe falciparum malaria in rural areas where facilities for controlled intravenous administration of quinine may not yet be optimal. Intramuscular quinine in such a setting is not a very good option because of its need for more frequent dosing besides the higher prevalence of local reactions and risk of potentially fatal tetanus with such injections(19). Whether artemether should be introduced as a first line drug for severe falciparum malaria in children in rural setting is a strategic question that needs further debating and research.

Contributors : SNH and TS collected the data; HMK examined the slides for malaria. SNH, TS, SMA, KA, and HMK were involved in the concept, design, analysis and interpretation of data; KA will act as the guarantor of this article.

Competing interests: None stated.

Funding: None.

 

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