Abstract: Efforts in this study were directed at comparing changes in Packed Cell Volume (PCV) in the cause of treatment of severe malaria patients with artemether and quinine in Ikenne Local Government area of Ogun State, Southwest, Nigeria. Thirty two patients in the study were randomly assigned to receive either artemether or quinine under medical supervision. 16 patients were allocated into two treatment groups. Patients in the quinine group received quinine 10 mg kg-1 in 5% dextrose-saline infusion intravenously at 8 h intervals but changed to oral quinine ( 10 mg kg-1 b.w; 8 h intervals) for 7 days . The patients in the artemether group received 1.6 mg kg-1 artemether twice at day 0 and then 1.6 mg kg-1 daily for the next four days through deep intramuscular route. The patients were then followed up for 14 days. The results this study showed that the PCV of the patients was 25.9% (range of 14-41%) at day 0. The mean PCV of the patients was 26.25% and 25.56% following quinine and artemether treatments, respectively. The mean PCV at day 14 was 34.5 and 38.2%, respectively for quinine and artemether. The results from this study indicate that artemether relative to quinine has a faster and sustained recovery from malaria induced anaemia.
INTRODUCTION
Malaria remains an endemic disease in up to 102 countries, a scourge to which about 40% of the world population is exposed. Malaria due to Plasmodium falciparum is the most dangerous among other human plasmodial infection (i.e., Plasmodium vivax, Plasmodium malariae and Plasmodium ovale). The WHO estimates an incidence of 300 to 500 million cases each year (WHO, 1991).
Ninety percent of the annual mortality of 1.5 – 2.0 million malaria cases occurs in African children under 5 years (WHO, 1996; Peter, 1985). In particularly, young children, pregnant women (worse in those in their first pregnancy) and non-immune individuals visiting the malarious areas are the group of people at greatest risk of severe or fatal illness (WHO, 1991; Steketee et al., 1996). In Nigeria, P. falciparum is responsible for 85-90% of all infections (Salako et al., 1990). The disease if not treated promptly could result in severe malaria, which, include cerebral malaria and severe anaemia (Ademowo, 2000). Cerebral malaria has a mortality rate of up to 25% even with the best of treatment. Malarial attack sometimes results in psychosis, pruritus, chronic anaemia, malnutrition and stunted growth (Warrel et al., 1990; Sowunmi et al., 1992). There is an all year transmission of malaria in Nigeria with a peak rate in wet season (Salako, 1984).
Severe malaria being responsible for up to 40% of cases seen, can be life threatening and intensive care must be required. Appropriate drugs that are sensitive to malaria parasitemia (following clinical suspicion and laboratory confirmation) must therefore be used. Experienced medical personnel and supportive care facilities must be available to reduce already known morbidity and mortality (Gallup and Sach, 2001).
The rapidity by which malarial still devastates children in Africa call for urgent review of malaria therapy and management. This task though enormous (in cost, personnel and facilities), if visionary pursued will revolutionalize our chronic malaria induced anaemia burden. It is on this basis that use of artemether and quinine (being an older drug) needs to be compared. Quinine is an antimalarial drug, which is made from the bark of the Cinchona tree. Moreover, because severe anaemia are usually corrected by blood transfusion which has inherent associated hazards such as HIV, hepatitis and others, prompted us to investigate current antimalarial drugs that may restrict the incidence of malarial associated anaemia. The present study was therefore designed to investigate changes in PCV in the cause of treatment of severe malaria patients with artemether and quinine.
MATERIALS AND METHODS
Patients were recruited in Ikenne Local Government area of Ogun State at Overcomers Specialist Hospital, Ilisan and General Hospital Ikenne between May and November 2003. The hospitals have facilities for resuscitating and handling emergency.
Patients who satisfied inclusion criteria (listed below) were admitted for treatment in the ward. The children were randomly allocated into two treatments groups; treatment A and Q for artemether and quinine respectively. On enrolment, a detailed history was obtained from accompanying adult (the patient or guardian) and a clinical examination was performed. Body weight, oral and rectal temperature were recorded. The following were also documented for the presence or absence of pallor, jaundice, respiratory distress, drowsiness, and organ enlargement for each patient. None of the patients showed signs of anaemic heart failure. Before administration of any drug, laboratory tests were done and blood samples were collected through finger prick for PCV estimation. Determination of packed cell volume was done in a capillary tube using a haematocrit centrifuge and haematocrit reader.
The clinical examination and observations made were recorded daily for 8 days (0-7) and on day 14. At each visit, patients (in case of older children) or parents/guardians were questioned, examined and documented for the presence of any adverse reactions to the administered drugs.
Ethical approval for the study was obtained from the Olabisi Onabanjo University/Olabisi Onabanjo University Teaching Hospital joint ethical review committee and informed consent from the parents/guardians.
Children from either sex with age ranging from 1- 12 years, fever with temperature >37.5°C within the last 24 h; presence of convulsion, vomiting, hypoglycaemia, anaemia and headache, informed consent obtained from the parents or guardians, assurance that patients will be resident within catchments of study for follow-up and absence of concomitant illness such as bronchopneumonia, typhoid, meningitis, urinary tract infection.
History of blood transfusion in the last two months, presence of concomitant illness, history of previous allergy to quinine and artemether and lack of informed consent.
The following are the withdrawal criteria used in the selection of patients in this study, If any concomitant illness developed during the study; if informed consent is withdrawn by parents or guardian, if patients (or patients/guardians) are unwilling to continue in the study and failure to comply with protocol.
The patients in the quinine group received quinine (Evans) 10 mg kg-1 in 5% dextrose/saline infusion; which was administered to the patients through intravenous canula for 4 h. This served as the loading dose. Maintenance dose was given as 10 mg kg-1 dose and then repeated at 8 h intervals. The quinine infusion was later changed to oral medication when patient’s clinical condition allowed for this. An oral dose of 10 mg kg-1 was given 8 hourly. The duration of treatment was 7 days. The patients were monitored for toxic reactions i.e., tinitus, haemolysis, convulsion, restlessness, disturbed vision.
The patients in the artemether group received 1.6 mg kg-1 artemether twice at day 0 and then 1.6 mg kg-1 daily for the next 4 days through deep intramuscular route. The patients were only discharged after their clinical conditions became stable and good response to treatment attained. This happened usually after the third day.
Evaluation of safety parameters: Patients were evaluated for presence of any adverse effects in the cause of treatment. Such adverse events were classified as mild when an adverse experience that can be tolerated by the patient causing minimal discomfort without interfering with everyday activities moderate when an adverse experience that is sufficiently discomforting to interfere with normal everyday activities and Severe when an adverse experience, which prevents normal everyday activities. This therapy was considered safe since adverse event documented were mild.
Statistical analysis: Normally distributed data of body weight and temperature were compared by Student’s t-test. The PCV of the drug treated days were individually compared with day 0 for each drug. Mean value was given in the text and tables as mean±standard deviation and p-value less than 0.05 were taken as statistically significant.
RESULTS
Thirty four patients who met the inclusion criteria out of which thirty two were enrolled into the study. Two patients were withdrawn as a result of default in follow-up within 7 days. The 32 patients studied were randomly allocated to quinine or artemether study group.
| Table 1: | Pattern of clinical presentations of patients at recruitment |
| Table 2: | Changes in PCV of patients in the course of treatment with artemether and quinine |
| *Value for each day was compared to value for day 0 | |
They were made up of 22 (68.7%) male and 12 (31.3%) female. Their age ranged from 1 to 12 years, mean was 7±3.63 and weight ranged from 7 kg to 35 kg, mean 19.83±8.22 kg.
The commonest presenting features were dehydration (100%), poor appetite (96.9%), pallor (96.9%) and fever (84%). This is followed by anaemia (71.9%), convulsion (71.0%) and jaundice (50.0%)(Table 1).
The clinical findings as well as estimated PCV at recruitment were similar in the two groups as shown in Table 1.
Packed Cell Volume (PCV): At recruitment 23 patients (71.4%) were anaemic (i.e., PCV values < 30%) out of which 10 (43.5%) and 13 (56.5%) patients were enrolled under quinine and artemether. Mean PCV at day O was 26.25 and 25.56%, respectively for quinine and artemether. Subsequently, mean PCV for remaining days were as shown in Table 2.
DISCUSSION
A comparative study on PCV changes in the course of treatment of severe malaria patients with artemether and quinine was evaluated in 32 patients that were allocated into two treatment groups. Presenting features such as age, weight, initial PCV values and clinical severity were similar in both groups and were not statistically significant.
The commonest presenting symptoms were poor appetite, fever, vomiting, pallor and dark urine, which are consistent with previous findings (Ademowo, 2000). Vomiting was the commonest gastrointestinal manifestation of severe malaria in children, the reason why this is so is not clearly known, but it has been suggested that it may be due to preferential sequestration of parasites in gastric vascular beds (Sowunmi and Salako, 1992).
Pallor was detected in almost all patients (i.e., 96.99%) whereas 71.9% were confirmed anaemic by PCV estimation. This implies that pallor finding is not a sufficient symptom to diagnose anaemia. Anaemia (i.e., PCV less than 30%) is a common finding in malaria especially in children and the 71.9% found in this study is comparable with result of other workers (Warrel et al., 1990). The cause of anaemia in severe malaria is multifactorial, there is lysis of parasitized erythrocytes, dyseryhroporetic changes, immune mediated haemolysis and reduction in the lifespan of the erythrocytes (Smitten et al., 2002). The lysis of parasitized erythrocytes will inevitably lead to black urine. Artemether despite having more anaemic patients restored anaemia faster than quinine (Table 2). This apparent decrease in number of patients with anaemia after artemether treatment from day 7 is a possible indication that it may possess erythropoetic stimulating factor in addition to its faster malaria parasitaemia clearance (Hien et al., 1996). Warrel et al. (1990) also found that significant changes in the number of children with anaemia after treatment, should not be expected in 1-2 weeks, due to the time required for haemopoiesis, but at the end of 3rd week an increase usually become apparent.
The study demonstrated that artemether relative to quinine give patients faster and sustained recovery from anaemia. The use of artemether can readily reverse or improve malaria induced anaemia hence restricting the incidence or use of blood transfusion in malaria endemic zones especially now that there is need for caution in the use of blood transfusion (due to spread of AIDS, hepatitis etc.) as an important measure for correcting anaemia.