Sanjeev Krishna

Lactic acidosis and hypoglycaemia in children with severe malaria: pathophysiological and prognostic significance.

Serial clinical and metabolic changes were monitored in 115 Gambian children (1.5-12 years old) with severe malaria. Fifty-three children (46%) had cerebral malaria (coma score < or = 2) and 21 (18%) died. Admission geometric mean venous blood lactate concentrations were almost twice as high in fatal cases as in survivors (7.1 mmol/L vs. 3.6 mmol/L; P < 0.001) and were correlated with levels of tumour necrosis factor (r = 0.42, n = 79; P < 0.0001) and interleukin 1-alpha (r = 0.6, n = 34; P < 0.0001). Admission blood venous glucose concentrations were lower in fatal cases than survivors (3.2 mmol/L, vs. 5.8 mmol/L; P < 0.0001). Treatment with quinine was associated with significantly more episodes of post-admission hypoglycaemia when compared with artemether or chloroquine. After treatment, lactate concentrations fell rapidly in survivors but fell only slightly, or rose, in fatal cases. Plasma cytokine levels fluctuated widely after admission. Sustained hyperlactataemia (raised lactate concentrations, 4 h after admission) proved to be the best overall prognostic indicator of outcome in this series. Lactic acidosis is an important cause of death in severe malaria.

Treatment of malaria: some considerations and limitations of the current methods of assessment

The currently used methods for assessing the therapeutic response to antimalarial drugs are relatively imprecise and insensitive. These methods are inadequate in severe malaria when the objectives of treatment are to save life and prevent complications. Very large studies are needed to demonstrate significant differences in mortality, but measurement of the rates of clinical, biochemical, and parasitological response may provide useful comparative information. Definitions, assessment criteria, procedures, and data collection forms should be standardized and evaluated prospectively. Antimalarial drug treatment in different clinical situations should be assessed in terms of the balance between the risks of drug toxicity and the benefits of the antimalarial drug action. This balance is considerably different in severe falciparum malaria compared with uncomplicated malaria infections.

Erythrocyte survival in severe falciparum malaria

Erythrocyte survival was studied in 17 Thai patients (10 males, 7 females; aged 13-57 years) with severe falciparum malaria. To ensure radioisotopic labelling of cells before bone marrow recovery and survival analysis under near-steady state conditions, 51Cr labelling of autologous erythrocytes was performed at the time of admission (0 h) and calculation of mean cell lifespan (MCL) was based on semilogarithmic plots of corrected counts from 60 h onwards. Five patients received blood transfusions, all within 48 h of admission. The overall mean (+/- S.D.) MCL was short (44.1 +/- 21.7 days). Nontransfused patients had similar MCL values (43.6 +/- 20.4) to those of transfused patients (45.5 +/- 27.3 days, p greater than 0.8). Patients with and without palpable splenomegaly had MCL values which were not significantly different (54.1 +/- 28.8 vs. 37.2 +/- 12.3 days respectively, p greater than 0.1). There was no association between admission haematocrit or peripheral parasitaemia and MCL (p greater than 0.2 in each case), but there was an inverse correlation between total serum bilirubin and MCL (r = -0.49, p less than 0.025). There is accelerated destruction of non-parasitised erythrocytes in severe malaria resulting in a mean MCL that is half that found previously in healthy Thai volunteers (89.6 +/- 13.1 days, p less than 0.001) and significantly shorter than that reported previously in Thai patients with uncomplicated P. falciparum infections studied after parasite clearance (56.8 +/- 10.2 days, p less than 0.05).

Dichloroacetate for lactic acidosis in severe malaria: A pharmacokinetic and pharmacodynamic assessment☆☆☆

Lactic acidosis and hypoglycemia are potentially lethal complications of falciparum malaria. We have evaluated the pharmacokinetics and pharmacodynamics of dichloroacetate ([DCA], 46 mg/kg infused over 30 minutes), a stimulant of pyruvate dehydrogenase and a potential treatment for lactic acidosis, in 13 patients with severe malaria and compared the physiological and metabolic responses with those of a control group of patients (n = 32) of equivalent disease severity. The mean +/- SD peak postinfusion level of DCA was 78 +/- 23 mg/L, the total apparent volume of distribution was 0.75 +/- 0.35 L/kg, and systemic clearance was 0.32 +/- 0.16 L/kg/h. Geometric mean (range) venous lactate concentrations in control and DCA recipients before treatment were 4.5 (2.1 to 19.5) and 5.5 (2 to 15.4) mmol/L, respectively (P > .1). A single DCA infusion decreased lactate concentrations from baseline by a mean of 27% after 2 hours, 40% after 4 hours, and 41% after 8 hours, compared with decreases of 5%, 6%, and 16%, respectively, in controls (P = .032). These changes were preceded by rapid and marked decreases in pyruvate concentrations. Arterial pH increased from 7.328 to 7.374 (n = 10, P < .02) 2 hours after the infusion. Hypoglycemia was prevented by infusing glucose at 3 mg/kg/min. There was no clinical, electrocardiographic, or laboratory evidence of toxicity. These results suggest that DCA should be investigated further as an adjunctive therapy for severe malaria.

Plasmodium yoelii: blood oxygen and brain function in the infected mouse.

The carriage of oxygen by the blood and the in vivo response of the brain were investigated in mice infected with a lethal strain of Plasmodium yoelii. All mice with parasitaemia exceeding 70% were severely anaemic (Hb 3.5 +/- 1.8 g/dl; mean +/- 1 SD), acidotic (blood pH 7.04 +/- 0.06) and hypoglycaemic (blood glucose 0.6 +/- 0.76 mumol/ml). The oxyhaemoglobin dissociation curve (ODC) of blood from heavily infected mice was shifted right as compared to controls, but the increase in p50 was less than expected from the accompanying acidosis. The reduced shift right was due to a decrease in the 2,3-DPG/Hb ratio in infected animals (0.72 +/- 0.12, n = 17 vs 1.10 +/- 0.09, n = 12 in controls). Despite the severity of terminal infection, the cerebral pH and the relative steady-state concentrations of PCr, ATP and Pi measured in vivo by nuclear magnetic resonance (31P NMR) were normal. Alterations in brain energy status and pH cannot account for cerebral signs or death in this proposed mouse model of cerebral malaria.

Plasmodium berghei: Lactic acidosis and hypoglycaemia in a rodent model of severe malaria; effects of glucose, quinine, and dichloroacetate

Fulminant malaria infections are characterised by hypoglycaemia and potentially lethal lactic acidosis. In young adult Wistar rats (n = 26) infected with Plasmodium berghei (ANKA strain), hyperparasitaemia (greater than 50%), anaemia (PCV 19.6 +/- 5.3%; mean +/- SD) hypoglycaemia (1.04 +/- 0.74 mmol/litre), hyperlactataemia (13.2 +/- 2.20 mmol/litre), hyperpyruvicaemia (0.51 +/- 0.12 mmol/litre) and metabolic acidosis (arterial pH 6.96 +/- 0.11) developed after approximately 14 days of infection. Hypoglycaemia was associated with appropriate suppression of plasma insulin concentrations. In a second series of experiments the metabolic effects of treatment with glucose (500 mg/kg/hr), quinine (5 mg/kg bolus followed by 10 mg/kg over 1 hr) and a potent activator of pyruvate dehydrogenase, dichloroacetate (300 mg/kg) were studied over a 1-hr period. In control animals quinine had no measurable effects, but dichloroacetate significantly reduced arterial blood lactate (74%) and pyruvate (80%). In infected animals, glucose infusion attenuated the rise in lactate (38% compared with 82%; P less than 0.01) but quinine had no additional metabolic effects. Dichloroacetate further attenuated the rise in lactate (14%; P less than 0.01).

Fever in uncomplicated Plasmodium falciparum infection: effects of quinine and paracetamol

The effects of quinine and paracetamol on fever were studied in 21 adult patients with acute uncomplicated falciparum malaria. Quinine alone (n = 7) had no significant effect on fever, whereas paracetamol given 2 h after quinine (n = 7) or 2 h before quinine (n = 7) reduced temperature by a mean of 2.1 degrees C (standard deviation [SD] 0.95) and 2.1 degrees C (SD 0.79) respectively. A temperature reduction of 1 degree C was associated with a mean decrement of 9.7 beats/min (SD 3.3) in the pulse rate. Quinine does not possess useful antipyretic activity.

Polymerase chain reaction for the detection of Burkholderia pseudomallei

Melioidosis is a potentially lethal infection of humans and animals in Southeast Asia and northern Australia. Current methods for detection of the causative organism, Burkholderia pseudomallei, lack both speed and sensitivity. We report the development of a highly sensitive polymerase chain reaction-based method that can detect as few as 35 colony-forming units of B. pseudomallei/mL in saline suspensions. This polymerase chain reaction test also detected the presence of B. pseudomallei DNA in culture-negative splenic tissue obtained from mice infected with the organism, but without clinical evidence of disease. Specificity has been confirmed using a variety of pathogenic and nonpathogenic organisms, including B. mallei, B. cepacia, and Pseudomonas species. The clinical usefulness of this test should be assessed prospectively and compared with conventional diagnostic techniques.

The pituitary-thyroid axis in severe falciparum malaria: evidence for depressed thyrotroph and thyroid gland function

Abnormal thyroid function is strongly associated with mortality in severe non-thyroidal illness. We have assessed the pituitary-thyroid axis serially in 18 Thai adults with severe falciparum malaria and in 18 matched controls. The admission total serum thyroxine (T4) concentrations of the patients (median [range]: 64 nmol/litre [less than 30-91]) were significantly lower than those of controls (81 nmol/litre [61-133]; 2P less than 0.01), and remained depressed until after fever and parasite clearance. Two patients who died in hospital had admission serum T4 concentrations less than 35 nmol/litre. The admission basal serum thyrotropin (TSH) levels of the patients (0.9 mU/litre [less than 0.2-3.1]) were similar to those of controls (1.3 mU/litre [less than 0.2-3.7], 2P greater than 0.1) and remained normal throughout fever and parasitaemia. Thirty-minute TSH increments during a thyrotropin-releasing hormone test on admission were reduced in 13 patients with severe malaria (4.1 mU/litre [0.7-8.1]) relative to those in convalescence (7.1 mU/litre [1.7-14.4], n = 10, 2P less than 0.01) and controls (5.6 mU/litre [3.3-12.9], n = 9, 2P less than 0.05). These findings suggest that thyrotroph and thyroid gland function are depressed during acute, severe malaria. As these changes may be an adaptation to accelerated catabolism, the role of thyroid replacement in such patients is uncertain.

Calcium metabolism in malaria-infected erythrocytes

Changes in the concentration of free calcium regulate many intracellular metabolic pathways and other important aspects of cellular function. The erythrocyte maintains intracellular calcium concentrations within a narrow range, but infection by malarial parasites disrupts these homeostatic mechanisms. The observation that infected erythrocytes have supranormal concentrations of calcium raises questions about the storage and functions of calcium ions within parasites. These are addressed in the following review by Sanjeev Krishna and Laura Squire-Pollard.