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Original Studies |
Department of Physiology, University of Science and Technology, School of Medical Sciences (T.A.), and Departments of Child Health and Medicine, Komfo-Anokye Teaching Hospital (T.A., G.B-A., B.B.-B., S.K.), Kumasi, Ghana; Department of Infectious Diseases, St. George’s Hospital Medical School (B.J.A., S.K.), SW17 ORE London, United Kingdom; Wellcome-Mahidol Oxford Tropical Medicine Research Program, Mahidol University (B.J.A.), Bangkok 10400, Thailand; and Departments of Anesthesiology (T.G.) and Medicine, Biochemistry, and Molecular Biology (P.W.S.), University of Florida College of Medicine, Gainesville, Florida 32610-0226
Address all correspondence and requests for reprints to: Dr. Sanjeev Krishna, Department of Infectious Diseases, St. George’s Hospital Medical School, Cranmer Terrace, SW17 ORE London, United Kingdom. E-mail: s.krishna{at}sghms.ac.uk
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The causes of hypoglycemia in African children with malaria are incompletely understood. Hyperinsulinemia rarely accompanies hypoglycemia in children presenting to hospitals with severe malaria (5, 6, 8), although hyperinsulinemia can complicate the treatment of children who receive quinine (9, 10). The kinetics of glucose have not been investigated in these populations despite the high risk of hypoglycemia, and the metabolic consequences of quinine have not been defined. Although quinine is the preferred treatment for severe malaria in most geographic areas, artemisinin derivatives, such as artesunate, are an increasingly valuable therapeutic option (10, 11). Artesunate is currently being investigated as an alternative to quinine in the management of African children with severe malaria, particularly when it is given by the intrarectal route in primary health care settings. However, artesunate’s effects on intermediary metabolism and insulin dynamics in children with severe malaria have not been investigated.
Sustained lactic acidosis may be the only clinically attributable cause of death in some children (1), but its causes and management are not established. Dichloroacetate (DCA) improves lactic acidosis in children with severe malaria (12) and increases survival in a rodent model of lactic acidosis caused by Plasmodium berghei infection (13). However, the mechanism of action of DCA has not been studied in children with severe malaria.
We used stable isotopes to examine the kinetics of glucose and lactate in African children with malaria-associated lactic acidosis and examined the effects of drugs used in the management of severe malaria. Children received quinine or artesunate as antimalarial therapy, and either DCA or placebo for hyperlactatemia. We hypothesized that quinine would have important effects on glucose metabolism, and that DCA would influence lactate kinetics.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Management
Patients who were referred for study were admitted to the
Department of Child Health at Komfo-Anokye Teaching Hospital (Kumasi,
Ghana) in October-November 1995 with the suspected diagnosis of severe
malaria. The diagnosis of malaria was confirmed by examination of a
blood film. Hypoglycemia (glucose, 
2.2 mmol/L) was excluded by
capillary glucose measurement (BM stix; Roche Diagnostics Ltd., E.
Sussex, UK) at the time of screening, but all glucose
estimations were confirmed as described below. Two iv cannulas were
inserted. One peripheral line was to administer iv fluids and either
DCA or placebo, and a second central line (5Fr 2 lumen or 5.5Fr
multilumen catheter, Arrow-Howest, Kimal Scientific, Uxbridge,
UK) was used to administer 50% glucose to treat hypoglycemia,
to monitor circulating intravascular volume, and to administer fluids
and obtain samples for analyses.
Antimalarial treatment
Antimalarial treatment was begun immediately (15) after venous blood was obtained to measure glucose, lactate, and hematocrit. On the basis of historical evidence, previously untreated patients were randomized to receive quinine (n = 9); 20 mg salt/kg quinine dihydrochloride (BP1980, Martindale Pharmaceuticals Ltd., Romford, UK) were injected im, half into each thigh after dilution 1:1 (vol/vol) with water or normal saline (12). Patients pretreated with quinine (n = 2) received a maintenance dose (10 mg salt/kg diluted as before) thereafter. Subsequent injections of quinine (10 mg salt/kg, diluted) were repeated every 12 h in alternate thighs from the commencement of the first dose until the patient recovered sufficiently to tolerate oral quinine (quinine sulfate suspension, 50 mg/5 mL; Edikay Pharmacy Ltd., Kumasi, Ghana), which was administered as a 10 mg/kg dose every 8 h for a total of 7 days.
Patients who were randomized to receive artesunate (Guilin No. 2 Pharmaceutical Factory, Guangxi, China) were given an im injection of 2.4 mg/kg (60 mg/mL) that was made up immediately before use in a 5% sodium bicarbonate solution supplied with the drug. This dose was followed by im injections of 1.2 mg/kg artesunate 12 and 24 h after admission and subsequently 1.2 mg/kg daily for a total of 7 days (total dose of artesunate, 10.8 mg/kg). Treatment was changed to oral artesunate (nearest one quarter tablet equivalent; 50 mg/tablet) as soon as patients could swallow oral medication.
Supportive treatment
To minimize the risk of hypoglycemia, all subjects received an
infusion of 5% glucose in water, using a syringe pump (Graseby 3200,
Graseby Medical Ltd., Herts, Watford, UK), at a rate of 1
mg/kg·min for the duration of the stable isotope study. All patients
received a single dose of iv thiamine (100 mg; Northwick Park Hospital,
Harrow, UK) to correct possible subclinical thiamine deficiency (16).
Patients who were comatose or who had seizures received a single im
dose of phenobarbitone (7 mg/kg; Biomedicine SPRI, Brussels, Belgium)
at the start of the study. Seizures after admission were treated with
iv diazepam (0.3 mg/kg; Diazemuls, Dumex Ltd., Princes
Risborough, UK), high temperatures (
38.5° C) were treated with
rectal paracetamol (120 mg paracetamol suppositories, WHA, South West
Thames Pharmacy Services Production Unit, St. George’s Hospital,
London, UK), and severe anemia (hematocrit, 15%) was treated with
transfusions of packed cells screened for human immunodeficiency virus
and hepatitis B virus. Furosemide (1 mg/kg; Antigen Pharmaceuticals
Ltd., Rosivia, Ireland) was also administered during each transfusion.
Patients with secondary bacterial infections received gentamicin (20
mg/2 mL; Roussel 2 Labs Ltd., Uxbridge, UK) and ampicillin (Berk
Pharmaceuticals Ltd., Eastbourne, UK). Intravascular volume depletion
was monitored measuring central venous pressure and was corrected with
iv saline infusions.
Infusion of L-[3-13C1]lactate and D-[6,6-D2]glucose, sampling for stable isotopes, and DCA treatment
Stable isotope solutions were formulated in sterile water (15 mL) by mixing L-[3-13C1]sodium lactate and D-[6,6-D2]glucose to final concentrations of 2.22% and 2.78%, respectively (i.e. 0.333 g sodium lactate and 0.417 g glucose/bottle). Patients were resuscitated and stabilized, and antimalarial and supportive therapies were begun as described above. Baseline venous blood samples were then obtained to determine the natural abundance of stable isotopes and to quantitate glucose, lactate, and insulin concentrations (-10 min, -5 min, and just before DCA or placebo infusion was begun). Sodium dichloroacetate [Tokyo Kasei Kyogo Ltd., Tokyo, Japan; formulated as described previously (17)] was then administered (50 mg/kg) by iv infusion over 10 min. Normal saline instead of DCA was administered to subjects who were randomized to receive placebo.
An iv priming bolus of 0.135 mL/kg stable isotope was injected after the DCA/placebo infusion had stopped, and an infusion of 0.404 mL/kg·h isotope solution was administered by syringe pump immediately after the loading dose of isotope was given. This infusion was continued for 90 min (13.48 mg/kg lactate and 16.8885 mg/kg glucose were infused for the duration of the study). Sixty minutes after the end of the DCA infusion, four samples (2 mL each) were taken at 10-min intervals (i.e. 60, 70, 80, and 90 min after isotope infusion had begun) to measure glucose, lactate, and insulin concentrations, and an aliquot of each sample at the last three time points was used to determine enrichment with stable isotopes.
The study protocol is illustrated in Fig. 1
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Previous treatment with antimalarials was determined in pretreatment plasma samples by dipstick enzyme-linked immunosorbent assays that detect the presence of chloroquine, quinine, mefloquine, and pyrimethamine (18).
Monitoring and sampling
Vital signs (respiratory rate, pulse, and blood pressure) and coma score [Blantyre scale (19)] were monitored every 5 min during the DCA infusion, then at 15, 30, 60, 70, 80, and 90 min during stable isotope infusion, then every 6 h until patients recovered. Other clinical measures, such as time to sit and time to drink, were also noted as end points. Temperature was monitored at 30 and 60 min, then with the other vital signs. Hematocrit and parasitemia were quantified every 6 h until parasites were undetectable by blood smear examination.
Whole blood (400 µL) was collected in chilled, heparinized (20 IU) microcentrifuge tubes each time vital signs were obtained and was transported on ice and centrifuged to isolate plasma. Venous glucose and lactate (50 µL whole blood) were measured immediately after sample collection, using YSI, Inc., 2300 glucose and lactate analyzers (YSI, Inc., Youngtown, OH). For consistency, aliquots of plasma samples collected for isotope analysis were reassayed on a YSI, Inc., 2300 STAT combined glucose/lactate analyzer. These data were used for analyses of glucose and lactate kinetics. Plasma (600 µL) was stored at -20 C and transported on dry ice for stable isotope measurements.
Analysis of stable isotopes
To determinate lactate enrichment of blood, plasma (100 µL) was made acidic by adding 50 µL 0.1 mol/L HCl. The mixture was passed through a Dowex AG-50 x 8 exchange column (Sigma, St. Louis, MO), washed with 0.5 mL distilled water, and collected in a siliconized test tube. The solution was reduced under vacuum until almost dry, and drying was completed under nitrogen. After preparing the t-butyl- demethylsilyl derivative (20), the lactate enrichment was determined using a Hewlett-Packard Co. 5790 gas chromatograph/5790 MSD (Palo Alto, CA) fitted with a 30 mm x 0.25 mm x 0.25 id x 0.25 µm SPB fused silica capillary column (Supelco, Bellefonte, PA). The derivatized lactate had a molecular mass of 318 amu. The electron impact spectrum at 70 eV had a mass spectrum with a weak M-15 peak at 303 amu (without a methyl group) and a strong M-57 peak at 261 (without a t-butyl group). Using selective ion monitoring, we monitored ion channels 261 and 262 for lactate enrichment. Each sample was analyzed in triplicate. The coefficient of variation was less than 1.5%.
To determine glucose enrichment, 50 µL plasma samples were made
acidic by adding 25 µL 0.1 mol/L HCl. The mixture was passed through
a Dowex AG-50 x 8 column, washed with distilled water, collected,
and dried completely under vacuum. The pentaacetate derivative of
glucose was prepared by mixing acetic anhydride (200 µL) and pyridine
(200 µL) and incubating at room temperature overnight. The
derivatized glucose was analyzed using the same gas chromatograph/mass
spectrometer as that used for lactate, under electron impact
conditions. The derivatized glucose produced two peaks in the mass
spectrometry analysis: 
- and ß-D-glucopyranose
pentaacetate. The spectrum of each compound had a fragment of mass 242
amu due to the loss of C-1 carbon of glucose (21). Using selective ion
monitoring of the -D-glucopyranose pentaacetate, three
ion channels, 242, 243, and 244, were monitored for glucose enrichment.
Each sample was analyzed in triplicate. The coefficient of variation
was less than 3%. The results were confirmed by also monitoring
ß-D-glucopyranose pentaacetate.
Calculations
The lactate mole percent excess (MPE) was calculated using the 262/261 ratio for samples obtained after 60 min of infusion (Rs) and at time zero (Ro), as shown in the following equation: MPE = (Rs - Ro)/[1 + (Rs - Ro)].
For D-[6,6-D2]glucose, the 244/242 tracer ratio was corrected for the contribution of singly enriched molecules, as suggested by Rosenblatt and Wolfe (22). Lactate and glucose disposal rates were calculated by a formula (23) that corrects for the change in pool size from the exogenous lactate or glucose, 13C natural abundance, and the enrichment of infusate. The rate of glucose production was obtained by assuming that in fasted children, such as those with severe malaria, the rate of appearance of glucose from glycogenolysis was negligible (8). Hence, glucose production becomes the glucose disposal rate minus the rate of exogenous glucose administration.
Data analysis
SYSTAT (version 5.2, Systat, Evanston, IL) and Stata (version
5, Stata Corporation, College Station, TX) was used for
statistical analysis. Normally distributed data (assessed by
Schapiro-Wilk W test) were analyzed by Student’s t test or
ANOVA and Pearson’s correlation coefficient. Nonnormally distributed
data were analyzed by the Wilcoxon rank sum test, and correlations were
determined by Spearman’s 
. The assumption of steady state was
examined by a test for trend. Repeated measures data were analyzed
using multiple ANOVA with specified linear general hypotheses. Insulin
levels below the level of detection (<10 pmol/L) were coded as 1
pmol/L for purposes of statistical analysis.
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Results |
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During the study period, 86 consecutive children were referred to
the study team, and 54 of these had P. falciparum infection.
The majority did not meet 1 of the study’s entry criteria (screening
lactate, 5 mmol/L), leaving 24 with lactate concentrations of 5
mmol/L or more. Twenty-one of these 24 children were subsequently
entered into this study. Of the remaining 3, 1 child’s parents refused
consent, and 2 children could not be studied because of difficulties
with venous access. The clinical and laboratory characteristics of
children in different treatment categories were comparable (Table 1). For all children, the median (range)
duration of fever before admission was 48 (0.5–96) h, the time after
food was last taken was 8.5 (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24) h, and the time after the last
drink was 6 (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15) h. Fifteen children (71%) presented with cerebral
malaria (unrousable coma for at least 0.5 h after a seizure), 5
children (24%) were hypoglycemic (glucose, 2.2 mmol/L) on admission,
and 5 children (24%) presented with or subsequently developed retinal
hemorrhages. All blood cultures and cerebrospinal fluid samples
obtained on admission to the study were negative for pathogenic
organisms.
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Two patients (1 who received quinine and placebo, and 1 who
received artesunate and DCA) died soon after randomization, so 19
patients were included in metabolic studies. Another patient who
received artesunate and DCA died 120 h after entry into the study
(overall mortality, 14%). Ten patients (48%) required transfusion, 6
patients (29%) had seizures after admission, and 2 boys (10%)
developed hemoglobinuria. At the time of admission, 3 patients had
chloroquine detectable in plasma samples, but no subject had detectable
plasma levels of quinine, mefloquine, or pyrimethamine. Patients
received DCA a mean (range) of 35 min (8 min - 75 min) after
antimalarial treatment began and after correction of hypoglycemia when
appropriate. Table 2 summarizes the
clinical and parasitological measures of recovery for the 2
antimalarial treatments.
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) was significantly more rapid with artesunate
than with quinine. However, more rapid parasite clearance was not
reflected in median times to recover from coma, to eat, to sit unaided,
to be discharged from hospital or to become afebrile. Parasite
clearance times were not related to admission parasitemia,
hepatomegaly, hematocrit, or fever.
The admission geometric mean plasma lactate concentration in patients
who died was higher than that in patients who survived (12.4
vs. 6.0 mmol/L; P < 0.0001) and was also
higher in those who presented with hypoglycemia (geometric mean, 10.7
vs. 5.7 mmol/L; P = 0.013). The parasite
clearance time (Table 2) and the admission plasma lactate concentration
were correlated (r = 0.54; P = 0.017; n =
19), but parasitemia and plasma lactate were not (r = 0.35;
P = 0.12). Admission glucose levels were positively
correlated with parasitemia (r = 0.501; P = 0.02).
There was no relationship between other clinical or parasitological
estimates of recovery (Table 2) and admission lactate concentrations,
and there were no effects of DCA on these variables when DCA was
included as a covariate with either antimalarial drug.
Metabolic changes
To establish that kinetic measurements were carried out under steady state conditions, linear regression analysis of data points obtained at sampling times after 60 min was used to estimate slopes for lactate and glucose disposal for each patient. The mean [95% confidence interval (CI)] values of slopes for lactate and glucose disposal were -0.12 (-0.62 to 0.38) and -0.08 (-0.65 to 0.50), respectively, and were not significantly different (P > 0.1) from zero. Admission plasma glucose and lactate levels were not correlated with each other (r = 0.15; P = 0.52), but glucose and lactate disposal rates were positively correlated (r = 0.62; P = 0.005). The mean (SD) Ra for glucose was 56 (17) µmol/kg·min, and the geometric mean (range) Ra for lactate was 100 (66–177) µmol/kg·min.
In all patients, glucose disposal was not related to admission glucose values (r = 0.35; P = 0.15), admission insulin concentrations (r = 0.04; P = 0.86), or age of the patient (r = 0.025; P = 0.92). By contrast, lactate disposal was positively correlated with admission lactate concentrations (r = 0.66; P = 0.002). Lactate disposal was also positively correlated with the time to recovery from coma in patients with cerebral malaria (r = 0.84; P < 0.001; n = 15). There was no relationship between admission parasitemia or temperature and measures of glucose or lactate kinetics (data not shown).
Thirteen patients had sustained hyperlactatemia (lactate
concentrations, 5 mmol/L), both at screening and at the time of
admission to the study (6 in the quinine or DCA treatment categories
and 7 in the artesunate or placebo categories) and represented children
with the most severe metabolic derangement. The following results are
therefore presented for 19 patients who were studied and separately for
the subgroup of 13 more severely ill patients. Because the subgroup
analysis was not specified prospectively, the results are
exploratory.
Effects of antimalarials
Glucose. The plasma glucose and lactate concentrations
obtained at the time of admission and during kinetic investigations
were similar in patients who received quinine and those who received
artesunate (Table 3). Insulin levels at
the start of the kinetic study were slightly higher in quinine-treated
compared with artesunate-treated patients (P = 0.14)
and were correlated with insulin levels measured after 60 min in the
quinine group (r = 0.99; P < 0.001), but not the
artesunate group (r = 0.30; P = 0.41).
Insulin/glucose ratios were significantly higher in quinine-treated
patients than in subjects treated with artesunate during the study
(F = 4.45; P = 0.05, by repeated measures
analysis; Fig. 1).
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; P =
0.04). This difference was more obvious in the subgroup of patients who
remained hyperlactatemic from the time of screening to the start of the
study. In these individuals the mean ± SD
glucose disposal was 49.2 ± 6.6 for subjects treated with quinine
and 70 ± 15 µmol/kg·min for subjects administered artesunate
(P = 0.011; Fig. 2).
Glucose production, calculated from glucose disposal, was also
significantly lower after treatment with quinine, compared with that
after treatment with artesunate (Table 3) and accounted for a median
(range) of 89.9% (83.7–93.6%) of the Ra values for glucose.
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)
or in the more severely ill
patients with sustained acidosis. Effects of dichloroacetate
Glucose. Glucose disposal was not significantly influenced by DCA, either in the group as a whole or in those patients with sustained hyperlactatemia.
Lactate. The mean (95% CI) change in venous plasma lactate
concentrations after DCA was -39% (-55 to -22%) at the end of the
study period (90 min) and was -15% (-55 to 50%) after placebo
administration (P > 0.1). Lactate disposal was
positively correlated with admission lactate levels (r = 0.66; see
above) and was not significantly different between patients who
received DCA and those who did not (Table 3; P = 0.6).
However, in the 13 more severely ill patients with sustained
hyperlactatemia, there was a highly significant difference in mean
(95% CI) lactate disposal between DCA-treated patients [134
(109–160) µmol/kg·min] and placebo-treated patients [97
(80–114) µmol/kg·min; t = -3.2; P
< 0.01; Fig. 3].
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The Ra for glucose in our patients is approximately 5 times the value
estimated in adults with severe malaria treated with quinine (Ra
glucose, 
10 µmol/kg·min) (28). Glucose turnover is also much
higher in children with severe malaria (Ra in this study, 56
µmol/kg·min) compared to that in children suffering from
uncomplicated infections with P. falciparum (Ra glucose,
26 µmol/kg·min) (27). Normal children have approximately 3-fold
higher rates of glucose production (35 µmol/kg·min) than do
adults, and age influences these estimates significantly (29). We were
unable to detect any influence of age on our glucose turnover
estimates, as in our patients, the range of ages was relatively
limited. To assess the metabolic effects of antimalarials, we allocated
children to receive quinine or artesunate and evaluated their effects
on glucose and lactate metabolism.
Quinine use is associated with higher mean insulin/glucose ratios and
lower glucose turnover rates (by 30%) compared to artesunate. In
adults with severe malaria, there is a similar decrease (by 40%) in
glucose turnover after treatment with quinine (28). Although insulin
increases glucose utilization by peripheral tissues and decreases
gluconeogenesis by the liver, adults with severe malaria demonstrate
peripheral resistance to insulin’s action (30). Plasma levels of
glucose did not fall to hypoglycemic levels (2.2 mmol/L) partly
because a constant infusion of glucose supplied approximately 10% of
the total glucose requirements in these closely monitored
individuals.
Our findings provide the first evidence that there are important differences in the effects of quinine and artesunate on glucose metabolism. Taken together with results from two large prospective studies (7, 10) that found artemether to be associated with fewer episodes of postadmission hypoglycemia compared to quinine, our data indicate that wherever monitoring of plasma glucose is difficult, an artemisinin derivative may offer important advantages over quinine for children who are severely ill with malaria. This may be particularly important when glucose supplementation is not reliably achievable in practice.
The fact that glucose and lactate kinetics are positively correlated in our subjects suggests that glucose is consumed predominantly through anaerobic pathways. This interpretation is consistent with our current understanding of the pathophysiology of lactic acidosis in severe malaria (2) and with the positive correlation we observed between Ra for lactate and plasma lactate concentrations. These results also suggest that increased production of lactate (rather than decreased disposal) is the most important determinant of hyperlactatemia in severe malaria in African children.
Increased anaerobic glycolysis in severe malaria may be due to tissue hypoxia, severe anemia, enhanced skeletal muscle activity during seizures, the metabolic demands of parasitized erythrocytes, inhibition of mitochondrial glucose oxidation by host cells due to thiamine deficiency (17), fever and associated increased cytokine production (1), and diminished clearance of lactate by the liver due to decreased hepatic blood flow (31, 32).
The positive correlation between duration of coma and the lactate disposal rates is consistent with the hypothesis that microvascular obstruction, due to sequestration of infected erythrocytes, is an underlying mechanism that is common to the development of both cerebral malaria and lactic acidosis.
Overall, there was an elevated turnover of lactate in our study group compared with similar measurements in other patient populations (e.g. 36 µmol/kg·min in healthy adults) (33). Values for lactate kinetics in our children were comparable to those obtained in nonacidotic adults with severe malaria who were treated with quinine (85 µmol/kg·min) (34).
DCA rapidly lowers plasma lactate concentrations in both adults and children with severe malaria (6, 12, 35). DCA treatment in patients who had sustained hyperlactatemia was also associated with a higher Ra for lactate. This suggests that basal lactate disposal is still capable of being augmented in these patients.
DCA stimulates pyruvate dehydrogenase and thus accelerates the oxidative removal of glucose, pyruvate, and lactate (36). It improved survival in an animal model of lactic acidosis due to malaria when it was administered together with quinine (13). DCA did not affect glucose concentrations or kinetics in our patients. This suggests that it is unlikely to cause hypoglycemia in children with severe malaria who receive glucose supplementation. These effects together with DCA’s stability and ease of use make it a potentially important intervention to improve mortality in patients with severe malaria complicated by lactic acidosis.
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Acknowledgments |
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Footnotes |
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2 Wellcome Trust Senior Research Fellow in Clinical Science.
Received August 31, 1999.
Revised December 15, 1999.
Accepted December 29, 1999.
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