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Brief Reports Indian Pediatrics 2002; 39:565-568 |
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Efficacy of a, b - Arteether in Children with Cerebral Malaria in Forested Tribal Belt |
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U.K. Shukla
Malaria continues to be the most important parasitic disease in tropics. The worldwide prevalence of malaria is estimated to be approximately 300-500 million clinical cases each year(1) and it is endemic in 101 countries. In sub Saharan Africa (SSA) alone where transmission is high malaria kills a million people every year. Children below five years of age and pregnant women have the highest mortality. In our country the re-emergence of malaria after reasonable control has been mainly due to development of resistance by the mosquito against insecticides and develop-ment of resistance against chloroquine(2). Plasmodium falciparum is responsible for the most severe, complicated and often fatal forms of the disease, especially cerebral malaria. The problem has further been aggravated by rising trends of infection with P. falciparum (34.5% as against 9.34% in 1972). This modifications of species composition has also been attributed to drug resistance against malaria(3). In Rajasthan during an outbreak in 1994, 95% of the isolated parasites were found to be resistant to chloroquine. In another study from Mumbai, an increase every year in number of cases showing in vivo resistance to chloroquine has been reported(4). This widespread resistance has focussed attention on use of drug combinations and newer anti-malarials. In recent years, outbreasks have been reported in forested villages of tribal blocks in Betul-Hoshangabad districts in Madhya Pradesh. Epidemiological data for the previous 10 years shows a sudden rise in P. falciparum infection and reported R1 and R2 level resistance against chloroquine(5). We, therefore, undertook a trial to evaluate the efficacy of a, b Arteether in children presenting with cerebral malaria in forested tribal belt of Betul, Hoshangabad districts. Subjects and Methods A total of 21 patients in the age-group of 3 to 11 years were brought from tribal villages of Community Health Centre Suktawa and admitted at Government Civil Hospital Itarsi, a referral center during July’98 to February ’99. They were brought in a state of unrousable coma with moderate to high grades of fever. The history of illness was of short duration (2-3 days) with sudden high grade fever, vomiting and convulsions in few cases followed by unconsciousness. There had been no history of previous illness or co-existing ailment. At admission, ‘Parasight-F’ (dipstick test) was performed. The dispstic test is dye conjugated monoclonal antibody of P. falciparum and based on antibody recognition of HRP-2 antigen of P. falciparum. Simulataneously thick and thin films of peripheral smear were prepared and stained with Giemsa. The thin smear was air dried rapidly, fixed in anhydrous methanol and examined under oil immersion microscopy. The thick smear was also dried thoroughly and stained (also with Giemsa) without alcohol fixation. Level of parasitemia was expressed as the number of parasitized erythrocytes per 1000 red blood cells. This figure was then converted to the number per microlitre of blood. A diagnosis of cerebral malaria in highly endemic area was based on brief history of fever, vomiting, convulsions, followed by unrousable coma, near normal cerebrospinal fluid picture, severe and profound anemia and finally demonstration of asexual forms of parasites of Plasmodium falciparum in peripheral smear. All cases were provided with general supportive therapy starting with slow intravenous infusion of Dextrose 10% and 5% Dextrose saline. For convulsions, intravenous Diazepam 0.3 mg/kg of body weight or alternatively paraldehyde 0.1 mg/kg body weight were given by deep intra-muscular injection. For hyper-pyerexia, tepid sponging and intramuscular paracetamol (15 mg/kg of body weight) were used. Parasitic count, hemoglobin estimation, and total and differential counts were repeated every day until day 7 and on day 28. Assessment of recovery from unrousable coma was done every day till full consciousness was regained. In the light of prevailing R1 and R2 resistance against chloroquine in the area, a, b arteether an Ethyl ether or dihydro artemisinin in a dose of 2.5 mg/kg body weight was administrated by deep intra-muscular injection once daily for 3 consecutive days. Patients were evaluated for fever clearance time (FCT), parasitic clearance time (PCT) and recovery from unrousable coma. Fever clearance time was defined as the period from the administration of the first dose of Arteether until the axillary temperature remained at or below 37º C for 72 hours. Parasitic clearance time was defined as the time from the administration of the first dose until parasites were undetectable in peripheral blood film and remained so for 7 days. Recovery from coma was considered when the patient had become fully conscious and responded to verbal commands. Total duration of stay in the hospital was 7 to 10 days. Before discharge, each patient was given tablet Mefloquine 15 m/kg in two divided doses and requested to report back on 14th and 28th days for evaluation. Cure was recorded if patients had fully recovered and did not have a recrudescence during and beyond 28 days. Results On clinical examination at admission, all cases were brought in comatose condition, the depth of consciousness being variable (<2 on Blantyre scale or modified Glasgow coma scale). A variety of transient abnormalities of eye movements like conjugate deviations were seen in 7 out of 21 cases. No neck rigidity was found in any case. Abdominal and plantar reflexes were either slow or absent. Motor abnormalities like decerebrate rigidity or decortical rigidity were not observed. Splenic enlargement was not detected in these patients. Respiration was deep, rapid and acidotic in some of cases. Mild to moderate dehydration was present in all the cases but urinary output and renal functions were within normal limits. Lumbar puncture was done routinely in each case with pressure normal or moderately raised and CSF protein levels were either normal or elevated (<100 mg/dl). No bacteria were demonstrated in any case. Cells were few and mostly lymphocytes. Anemia was severe in all the 21 cases, (8 cases had Hb <6 g/dl and the remaining had Hb <4 g/dl), requiring urgent blood transfusion. Leukocytic counts were low or normal with high parasitemia (more than 25,000/dl) and scizontocemia. Twenty one subjects with cerebral complication of P. falciparum malaria were evaluated. After initiating therapy, the level of consciousness started improving after 24 hours with return of full consciousness in 72 hours. The clinical and hematological indices with time are summarized in Table I. Table I- Clinical and Hematological Parameters with Time
Only 17 patients could be followed up for 28 days. Recrudescence was not found in these patients. There were no neurological deficits or sequalae. No adverse effect or side-effect of therapy was documented. Cure rate was thus 100% among the follow-up cases. a-b arteether, a newer anti-malarial, is a derivative of Artemisinin which is obtained from the Chinese plant Artemisia annua ‘Quinghao’. The drug is recommended specifically for chloroquine resistant falciparum malaria and severe cerebral malaria(6). The first clinical efficacy study in patients with Plasmodium falciparum malaria was done in Orissa in 51 patients who received 150 mg arteether for 3 days. Complete parasite clearance was reported in 80% of the patients at 8 hours and 98% at 72 hours with a mean fever clearance time of 52.04 + 27.09 hours(7). In another multicentric study for complicated falciparum malaria (Bhilai, Guwahati, Jamshedpur and Rourkela) a cure rate of 97% to 100% was documented with a fixed dose schedule of a-b arteether given intramuscularly, 150 mg as a single daily dose for 3 consecutive days(8). The efficacy and safety of intra-muscular arteether was found to be comparable to intravenous quinine in 92 African children with cerebral malaria in a prospective randomized open-label study in Zambia; 48 received Arteether and 44 received quinine. Rates for negative malaria smears one month after therapy were similar in both groups. Arteether was well tolerated and appeared to be therapeutically equivalent to quinine for the treatment of pediatric cerebral malaria(9). The results of this descriptive trial also confirm the utility and safety of arteether in treating cerebral malaria in children in under-resourced district settings. However, currently it may be appropriate to reserve the drug for serious and life threatening infections and make it available only for hospitals and institutions. Acknowledgement The authors are grateful to Dr. R.P. Tikrya, Medical Superintendent Government Civil Hospital, J.S.R. Itarsi (District Hoshangabad) for permission to conduct the study and provide necessary assistance. Contributors: UK co-ordinated the study and drafted the paper; he will act as the guarantor for the study. RK helped in laboratory testing, analysis and also helped in drafting of the paper. MM and NS helped in designing and analysis. Funding: None. Competing interests: None stated.
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