Inter-relationships of cardinal features and outcomes of symptomatic pediatric Plasmodium falciparum MALARIA in 1,933 children in Kampala, Uganda.

Malaria remains a challenging diagnosis with variable clinical presentation and a wide spectrum of disease severity. Using a structured case report form, we prospectively assessed 1,933 children at Mulago Hospital in Kampala, Uganda with acute Plasmodium falciparum malaria. Children with uncomplicated malaria significantly differed from those with severe disease for 17 features. Among 855 children with severe disease, the case-fatality rate increased as the number of severity features increased. Logistic regression identified five factors independently associated with death: cerebral malaria, hypoxia, severe thrombocytopenia, leukocytosis, and lactic acidosis. Cluster analysis identified two groups: one combining anemia, splenomegaly, and leukocytosis; and a second group centered on death, severe thrombocytopenia, and lactic acidosis, which included cerebral malaria, hypoxia, hypoglycemia, and hyper-parasitemia. Our report updates previous clinical descriptions of severe malaria, quantifies significant clinical and laboratory inter-relationships, and will assist clinicians treating malaria and those planning or assessing future research (NCT00707200) (www.clinicaltrials.gov).

Metabolic acidosis and other determinants of hemoglobin-oxygen dissociation in severe childhood Plasmodium falciparum malaria.

Metabolic acidosis is a common complication of severe malaria caused by Plasmodium falciparum. The factors contributing to the acidosis were assessed in 62 children with severe falciparum malaria (cases) and in 29 control children who had recently recovered from mild or moderate malaria. The acidosis was largely caused by the accumulation of both lactic and 3-hydroxybutyric acids. The determinants of oxygen release to the tissues were also examined; although there was no difference between cases and controls in respect of 2,3-bisphosphoglycerate and mean corpuscular hemoglobin concentration, there was a marked increase in P(50) in the cases, caused by pyrexia, low pH, and base deficit. There was substantial relative or actual hypoglycemia in many cases. The relationship of these observations to therapeutic strategy is discussed.

Severe malaria: metabolic complications.

Metabolic complications of severe malaria are some of the most important and potentially treatable manifestations of this deadly disease. The commonest metabolic complications (lactic acidosis and hypoglycaemia) arise from increased host anaerobic metabolism probably due to a mismatch between tissue oxygen supply and requirement. Optimising treatments for these complications should be guided by detailed understanding of their underlying pathophysiology, and may help to reduce the intolerably high case fatality rate of severe malaria.

The relevance of malaria pathophysiology to strategies of clinical management.

PURPOSE OF REVIEW: Malaria claims 1-2 million lives a year, mostly children in sub-Saharan Africa. The majority of hospital deaths occur within 24 h of admission despite adequate treatment with antimalarial chemotherapy. Understanding the pathophysiological disturbances of malaria should allow the development of supportive therapy to "buy time" for antimalarial chemotherapy to clear the infection. It is sobering, however, that despite many trials over the last quarter of a century all large trials of adjunctive therapy so far have resulted in either increased morbidity or mortality, or both. RECENT FINDINGS: Severe malaria may be divided broadly into neurological and metabolic complications. We review recent findings about the pathophysiology of these complications and the implications for future adjunctive therapy of malaria, including the proposed importance of fluid volume depletion and sequestration of parasitized red cells in severe malaria. We also consider other anaemia, hyperparasitaemia and renal failure, which also require urgent treatment in severe malaria. SUMMARY: We review the important pathophysiological features of severe malaria and promising adjunctive therapies such as dichloroacetate that warrant further larger trials to determine whether they improve the so-far intractable death rate of severe malaria.

Lactic acidosis and oxygen debt in African children with severe anaemia.

A syndrome of severe anaemia (Hb < or = 5 g/dl), particularly severe malarial anaemia (SMA), remains a major cause of childhood mortality in sub-Saharan Africa. We hypothesized that the lactic acidosis which identifies those at the greatest risk of death often represents an oxygen debt incurred as a result of inadequate tissue perfusion. To examine this hypothesis, we measured oxygen consumption (VO2) using a portable metabolic monitor. Blood lactate and acid-base status were also determined. Pre-transfusion data on 44 children (28 with mild symptoms, 7 with respiratory distress and 9 controls) demonstrated very close dependence of VO2 on body surface area (BSA, R2 = 0.86, p < 0.001). After correcting for BSA, no significant differences were observed in mean VO2 values of the three clinical groups, indicating that a critical reduction in oxygen delivery is not the sole explanation for the development of a lactic acidosis and severe symptoms. Nine children (including five of the original 44) were monitored during transfusion. In four of the five with SMA, severe symptoms and severe lactic acidosis, transfusion produced a marked, transient increase in VO2 (maximum 30-41%), with a marked fall in blood lactate and clinical improvement. These data suggest that some children with SMA and respiratory distress accumulate an oxygen debt when a relatively high oxygen demand outstrips supply, this debt being repaid when supply is increased during transfusion. However, in the remaining one of these five children, an increase in VO2 (maximum 20%), was accompanied by a rise in blood lactate and clinical deterioration, suggesting that more pathophysiologically complex mechanisms, which may predominate in some children.

PIP: A syndrome of severe anaemia (Hb or= 5 g/dl), particularly severe malarial anaemia (SMA), remains a major cause of childhood mortality in sub-Saharan Africa. The authors hypothesized that the lactic acidosis which identifies those at the greatest risk of death often represents an oxygen debt incurred as a result of inadequate tissue perfusion. To examine this hypothesis, the authors measured oxygen consumption (VO2) using a portable metabolic monitor. Blood lactate and acid-base status were also determined. Pre-transfusion data on 44 children (28 with mild symptoms, 7 with respiratory distress, and 9 controls) demonstrated very close dependence of VO2 on body surface area (BSA, R2 = 0.86, p 0.001). After correcting for BSA, no significant differences were observed in mean VO2 values of the three clinical groups, indicating that a critical reduction in oxygen delivery is not the sole explanation for the development of a lactic acidosis and severe symptoms. 9 children (including 5 of the original 44) were monitored during transfusion. In 4 of the 5 children with SMA, severe symptoms, and severe lactic acidosis, transfusion produced a marked, transient increase in VO2 (maximum 30-41%), with a marked fall in blood lactate and clinical improvement. These data suggest that some children with SMA and respiratory distress accumulate an oxygen debt when a relatively high oxygen demand outstrips supply, this debt being repaid when supply is increased during transfusion. However, in the remaining one of these 5 children, an increase in VO2 (maximum 20%) was accompanied by a rise in blood lactate and clinical deterioration, suggesting more pathophysiologically complex mechanisms, which may predominate in some children.