Malaria remains a major scourge in sub-Saharan Africa, killing 1-2 million children each year. Major advances in our understanding of disease pathogenesis have occurred, along with the emergence of drugs which kill the malaria parasite twice as rapidly quinine, the current drug of choice--- but the mortality rate for severe malaria has not changed. Between 15-40% of children with cerebral malaria, malaria-associated acidosis and/or severe anemia will die, and half of those deaths occur within 12 hours of arriving at a hospital. Five clinical centers with much experience of severe malaria in African children have joined together to form a clinical trials network (SMAC). Individually frustrated by our own attempts to demonstrate any impact of promising interventions on malaria mortality, we have decided that our fundamental goal, to lower the death rate associated with severe malaria in African children, would be best realized by conducting mortality-based multi-center studies. This approach is necessary because there are no surrogate markers for outcome deaths in any one site are rare We are proposing to evaluate fluid resuscitation in children with malaria complicated by acidosis, and pentoxifvrnne (PTX) as adjunct therapy in children with cerebral malaria. Both of these require pilot studies (1 year) prior to the larger clinical trials. Our network is also well-positioned to evaluate """"""""disease associations"""""""" which may illuminate pathogenetic processes or reveal potential new targets. Because it is simple to assess and because there are plausible biological and parasitological implications, we would like to determine the predictive value of intraleukocvtic DiQment in children with P. falciparum infections. This study will be part of an ongoing network activity, describing the malaria experience in each site using standardized information collected prospectively and archived in a database. The statistical and administrative """"""""cores"""""""" will facilitate the efforts of the network. Data will be entered at each site and transmitted to a central facility (at one of the five sites) for analysis. There will be an annual SMAC meeting, and the intervals between meetings will be punctuated by frequent visits between sites so that young investigators can standardize their observations and experience other settings. This capacity to conduct multi-center trials in severe pediatric malaria has not existed before. The statistical power of a large group can unearth even a small decrease in mortality associated with a particular intervention. Given the enormous toll of malaria, this could re resent a significant decline in the death rate across sub-Saharan Africa.
