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Metabolic Acidosis and Other Determinants of Hemoglobin-Oxygen Dissociation in Severe Childhood Plasmodium Falciparum Malaria

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Metabolic Acidosis and Other Determinants of Hemoglobin-Oxygen Dissociation in Severe Childhood Plasmodium Falciparum Malaria Am. J. Trop. Med. Hyg., 77(2), 2007, pp. 256–260 Copyright © 2007 by The American Society of Tropical Medicine and Hygiene Metabolic Acidosis and Other Determinants of Hemoglobin-Oxygen Dissociation in Severe Childhood Plasmodium falciparum Malaria Philip Sasi, Shamus P. Burns, Catherine Waruiru, Michael English, Claire L. Hobson, Christopher G. King, Moses Mosobo, John S. Beech, Richard A. Iles, Barbara J. Boucher, and Robert D. Cohen* KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya; Child and Newborn Health Group, Centre for Geographic Medicine Research-Coast, Nairobi, Kenya; Centre for Diabetes and Metabolic Medicine, St Bartholomew’s and The London School of Medicine and Dentistry, London, United Kingdom; School of Applied Sciences, (Biological Sciences), University of Huddersfield, Huddersfield, United Kingdom; Department of Immunology, Royal Victoria Infirmary, Newcastle-upon-Tyne, United Kingdom; Department of Anaesthesia, University of Cambridge, Cambridge, United Kingdom; Department of Clinical Pharmacology, Muhimbili University College of Health Sciences, University of Dar es Salaam, Tanzania Abstract. 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 accumu- lation 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 P50 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 thera- peutic strategy is discussed. INTRODUCTION mize this problem are therefore desirable.10,11 Furthermore, the anemia so common in this group of children is often Lactic acidosis is strongly associated with mortality in se- treated by blood transfusion; however, blood for transfusion, 1,2 vere Plasmodium falciparum malaria in African children. even though collected into citrate-phosphate-dextrose solu- The lactic acidosis of malaria has multiple etiologies; it is tion, tends to have low BPG levels, and may therefore, not likely that poor tissue perfusion related to hypotension, de- have the expected therapeutic effect. The purpose of this hydration, occlusion of the microcirculation by parasites, in- study was to determine the causes of the acidosis in African hibition of gluconeogenesis by circulating tumor necrosis fac- children with severe malaria and to examine the importance 3–5 tor, and decrease in hepatic blood flow play significant of the several factors involved in oxygen release to the tissues. roles. Because severe anemia is commonly present,3 the de- livery of oxygen to the tissues may be further impaired. A MATERIALS AND METHODS major determinant of oxygen release from hemoglobin is the position on the x-axis of the sigmoid curve of the plot of Subjects. There were 62 cases (5 fatal), between 6 and 112 hemoglobin-oxygen saturation against the partial pressure of months of age (mean, 33.9 ± 20.0 [SD] months), and 29 con- oxygen (PO2). Shifts of the curve to the left of the normal trol subjects of similar age range and distribution (range, position result in greater difficulty in oxygen dissociation, i.e., 6–119 months; mean, 33.5 ± 25.26 months). The sex ratio PO2 has to be decreased to a lower level than the fall needed (male:female) was 47:53 in the cases and 40:60 in controls. under normal circumstances before the same amount of oxy- Table 1 shows the distribution of clinical states in the patients. gen is released, whereas right shifts result in the opposite Venous blood samples were collected in two batches: the first situation. The position of the curve is usually denoted by P50, consisting of 23 cases and 8 controls in 1996–1997 and the i.e., the value of PO2 for half-saturation of hemoglobin; second consisting of 39 cases and 21 controls in 2003–2004. higher values than the mean normal (∼27.2 mm of Hg) imply The controls were in apparent good health and were attend- easier dissociation. P50 is affected by several factors; low pH ing planned follow-up, which was 4 weeks after hospitaliza- and high PCO2 lead to an increase. In addition, the unique tion for non-severe malaria. Nevertheless, because of their intra-erythrocytic metabolite 2,3–bisphosphoglycerate (BPG) fairly recent illness, they cannot strictly be regarded as com- interacts with the hemoglobin molecule to raise P50 and thus pletely well children. The criteria for inclusion for the cases facilitate oxygen release. Acidosis of more than a very few were one or more of the following: 1) severe acidosis, defined hours duration impairs the synthesis of BPG,6 and in severe as base deficit > 18 mmol/L; 2) base deficit between 10 and 18 diabetic ketoacidosis, BPG may decrease to < 10% of its mmol/L, but persisting for > 6 hours after admission; 3) coma, previous value6–8; furthermore, a decrease in BPG has been but with base deficit < 10 mmol/L (if postictal or hypoglyce- described in an animal model of severe malaria.9 The simple mic, 1 hour was allowed to elapse after the fit or correction of therapeutic approach would be to treat the acidosis of malaria the hypoglycaemia before collection of the sample for the with bicarbonate infusion; however, this may result in an un- study); 4) blood hemoglobin Յ 5.0 g/dL. The reported dura- desirable left shift of the dissociation curve in a situation in tion of the illness before admission was noted but is of un- which oxygen dissociation has already been impaired by a fall certain reliability. in BPG caused by acidosis. Therapeutic approaches that mini- Methods. The study was approved by the Kenya Medical Research Institute (KEMRI) Scientific Steering Committee (SSC) and the National Ethics Review Committee (ERC). * Address correspondence to Robert D. Cohen, Longmeadow, Venous samples were obtained with informed parental con- East, Chichester, West Sussex PO18 0JB, UK. E-mail: rcohen@ sent on admission and before the start of in-patient treatment doctors.org.uk from children with severe P. falciparum malaria12 and also 256 P50 IN SEVERE MALARIA 257 TABLE 1 600 MHz at room temperature in a Bruker AMX spectrom- Distribution of clinical states in the older and more recent series eter using the following parameters: pre-saturation on H2O, acquisition with a 30° pulse and 10-second recycling time for Clinical category Old series New series Total full relaxation). Cerebral malaria* 8 15 23 6 In vivo P50 was calculated from the following equation. Prostrate† 0 8 8 Respiratory distress‡ 5 1 6 = ͓ + ͑ − ͒ + ͑ − ͔͒ Log10P50 log10 26.6 0.5 MCHC 33 0.69 BPG 14.5 Severe anemia (Hb < 5 g/dL)§ 3 12 15 − 0.0013BD + 0.48͑7.4 − pH͒ + 0.024(T − 37͒ Cerebral malaria and respiratory distress 4 1 5 In this equation, BPG is expressed in ␮mol/g Hb, in contrast Cerebral malaria and anemia 0 1 1 Respiratory distress and anemia 2 1 3 to mol/mol Hb used elsewhere in this paper. BE (base excess) 6 Cerebral malaria, respiratory in the original equation has been replaced by BD (base defi- distress, and anemia 1 0 1 cit), together with the consequent sign change. T is tempera- Totals 23 39 62 ture (°C). Clinical states: (in all states, P. falciparum asexual parasitemia was present). Statistical methods. Because there were no significant dif- * Cerebral malaria—coma (inability to localize a painful stimulus, scoring two or less on the Blantyre coma scale23). ferences between the two batches in respect of mean BPG, † Prostrate—inability to sit upright in a child normally able to do so or inability to drink in the case of children too young to sit. blood lactate, temperature, base deficit, and pH, and only ‡ Respiratory distress—deep breathing (Kussmaul acidotic breathing) or chest in-drawing small significant differences (old series first) for hemoglobin without any finding on auscultation. § Severe anemia—hemoglobin concentration Յ 5 g/dL and the patient needing blood (6.7 versus 5.3 g/dL), MCHC (31.83 versus 30.73 g/dL), and transfusion. packed cell volume (0.22 versus 0.18), the results from the two batches were pooled for analysis; for the same reasons, the from control subjects. All measurements were made at The control results were also pooled. Means are given ±SE, except KEMRI Center for Geographic Medicine Research-Coast, when otherwise stated. Means were compared using one-way with the exception of those for 3-hydroxybutyrate and BPG. analysis of variance (Student t test) or the Kruskal-Wallis test The latter two metabolites were measured on deproteinizates if the variances were non-homogeneous. Correlations were assessed by Pearson test or Spearman rank test if the data of plasma and spun-down erythrocytes shipped on CO2 snow to the United Kingdom, where they were estimated by mag- were not distributed with bivariate normality. Multiple step- netic resonance spectroscopy (31P- or 1H-NMR). wise regression analysis (to P < 0.05) was used to identify independent determinants of variables of interest; this proce- Laboratory methods. Venous blood pH and PCO2 were determined using an IL 1620 blood gas analyser, and hemo- dure adjusts for the influence on the variable under consid- globin (Hb), mean corpuscular volume (MCV), and mean eration of each of the other variables. Two-tailed tests of corpuscular hemoglobin concentration (MCHC) were deter- significance were used. mined by Coulter counter. Whole blood lactate was measured using an Analox lactate analyser.
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