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Hypoglycaemia and lactic acidosis are potentially life-threatening, poorly understood sequelae of Plasmodium falciparum infections. We investigated relationships between clinical status, treatment, and glucose and lactate kinetics during management of falciparum malaria in 14 Vietnamese adults. Nine had severe malaria, of whom 4 were administered quinine (Group 1a) and 5 artesunate (Group 1b). Five uncomplicated cases received artesunate (Group 2). Glucose and lactate turnover were studied on 3 occasions: (i) immediately after initial antimalarial treatment, (ii) at parasite clearance a median of 3 days later, and (iii) at discharge from hospital a median of 9 days post-admission. Steady-state glucose and lactate kinetics were derived from plasma isotopic enrichment during a primed-continuous infusion of D-[6,6-D2]glucose and a parallel infusion of L-[1-13C]lactate. Group 1a patients had the lowest plasma glucose concentrations in the admission study (median [range] 3.9 [3.6-5.1] vs 6.3 [4.9-7.1] and 4.5 [4.3-5.5] mmol/L in Groups 1b and 2 respectively; P < 0.05 vs Group 1b), but glucose production rates and serum insulin concentrations that were similar to those in the other groups (P > 0.17). This was also the case at parasite clearance and suggested an inappropriate beta cell response. Group 1a patients had the highest admission lactate production (60 [36-77] vs 26 [21-47] and 22 [4-31] mumol/kg.min in Group 1b and 2 respectively; P < 0.05 vs Group 2). Amongst the 9 severe cases, there was an inverse association between plasma glucose and lactate production at admission and parasite clearance (P < 0.05), but no correlation between admission lactate production and serum bicarbonate (P = 0.73). The present data confirm previous studies showing that quinine depresses plasma glucose through stimulation of insulin secretion. It is hypothesized that the low plasma glucose activates Na+,K(+)-ATPase through increased plasma catecholamine concentrations, leading to accelerated glycolysis and increased lactate production in well-oxygenated tissues. In some severely ill patients with falciparum malaria, a raised plasma lactate on its own may, therefore, be an unreliable index of a developing acidosis.