Glucose and Lactate Kinetics in Children with Severe Malaria¹

Abstract

Children with severe malaria often present with lactic acidosis and hypoglycemia. Although both complications independently predict mortality, mechanisms underlying their development are poorly understood. To study these metabolic derangements we sequentially allocated 21 children with falciparum malaria and capillary lactate concentrations of 5 mmol/L or more to receive either quinine or artesunate as antimalarial therapy, and dichloroacetate or saline placebo for lactic acidosis. We then administered a primed infusion (90 min) of L-[3-13C1]sodium lactate and D-[6,6-D2]glucose to determine the kinetics of these substrates. The mean (SD) glucose disposal rate in all patients was 56 (16) micromol/kg x min, and the geometric mean (range) lactate disposal rate was 100 (66-177) micromol/kg x min. Glucose and lactate disposal rates were positively correlated (r = 0.62; P = 0.005). Artesunate was associated with faster parasite clearance, lower insulin/glucose ratios, and higher glucose disposal rates than quinine. Lactate disposal was positively correlated with plasma lactate concentrations (r = 0.66; P = 0.002) and time to recovery from coma (r = 0.82; P < 0.001; n = 15). Basal lactate disposal rates increased with dichloroacetate treatment. Elevated glucose turnover in severe malaria mainly results from enhanced anaerobic glycolysis. Quinine differs from artesunate in its effects on glucose kinetics. Increased lactate production is the most important determinant of lactic acidosis.

Severe Malaria: Metabolic Complications

“…In severe malaria stable L-[3-13 C 1 ]sodium lactate and D-[6,6-2 H 2 ]glucose isotope kinetic studies in Ghanaian children [48] (n=19) and Vietnamese adults [49] (n=14) give similar results. Lactate turnover is increased in severe disease and blood lactate levels correlate positively with lactate turnover, so hyperlactataemia arises primarily from elevated lactate production rather than decreased utilisation.…”

“…severe malaria [48]. In adults there is a negative correlation between admission blood glucose and glucose turnover [116], but this relationship has not been found in children [48,[117][118][119][120].…”

“…It has been used extensively in malaria. DCA lowers lactate more rapidly than placebo in Thai adults [70,104,105] and Ghanaian children [48,68,69] with malaria associated hyperlactataemia. Pharmacokinetic studies have shown reliable disposition of DCA in severe malaria [68-70, 104, 105].…”

“…Pharmacokinetic studies have shown reliable disposition of DCA in severe malaria [68-70, 104, 105]. DCA has been used with both quinine [68-70, 104, 105] and artesunate [48]. A large study of Ghanaian children with malaria associated lactic acidosis (n=124) showed no pharmacokinetic interaction between quinine and DCA [68] and no unexpected adverse events with DCA.…”

“…Admission hypoglycaemia occurs in 5 to 30% of children with severe malaria [5,6,110,113] and in about 5 to 15% of quininetreated children presenting without hypoglycaemia [13,48,113]. Hypoglycaemia often does not result from quinine-induced hyperinsulinaemia [114,115] and children with hypoglycaemia on admission are at highest risk of post-admission hypoglycaemia, despite receiving (in most studies) infusions of glucose (~3 mg/kg/min).…”