Background : The place of blood glucose abnormalities in severe malaria is poorly defined. The objective of the study was to determine the incidence of glycemic abnormalities and to identify the factors associated with their occurrence and death. Patients and Methods: A prospective study was conducted from January to October 2016 at the Teaching Hospital of Brazzaville. The blood glucose levels of all children hospitalized for severe malaria were measured for 3 days. The variables were compared in univariate and multivariate analysis. Results: A total of 158 children with an average age of 69.6 months ± 43.2 (ranges: 5 months and 15 years) were hospitalized for severe malaria. Moderate hyperglycemia was observed in 52.53% of children, severe hyperglycemia: 17.72%, moderate hypoglycemia: 15.19% and severe hypoglycemia: 2.53%. Children aged < 5 years (p = 0.03), females (p = 0.03), with disease duration before admission ≥ 7 days (p = 0.03) and referred from private hospitals (p = 0.04) had an increased risk of hypoglycemia. Age > 5 years was associated with hyperglycemia (p = 0.0006). The presence of hypoglycemia (blood glucose ≤ 3.3 mmol/L) on admission was associated with the risk of death (OR = 9.59, p = 0.02), no death occurred in children with hyperglycemia (p = 0.4) on admission. Conclusion: The incidence of blood glucose abnormalities is high in severe malaria. Hyperglycemia is more common than hypoglycemia, but only hypoglycemia is associated with an increased risk of death.
The World Health Organization (WHO) estimates that around 212 million of persons develop malaria every year and 429,000 die of the infection worldwide. Remarkable progress has been made in malaria control at the global level, but unfortunately this progress is slow in Sub-Saharan Africa and malaria is still responsible for high morbidity and mortality in children [
This morbidity and mortality are mainly related to complications, among which is hypoglycemia; the determining role of hypoglycemia in the outcome of malaria has made it one of the severity criteria as defined by WHO [
It was a prospective and analytical study carried out from January to October 2016 (7 months) in the Pediatric Intensive Care Unit (PICU) of the Teaching Hospital Center (THC) of Brazzaville. Brazzaville is the capital city of the Republic of Congo, its population is estimated to 1,373,382, and where malaria rages in the holo and hyper endemic mode. The THC of Brazzaville is the largest hospital in the country and its Pediatric ICU the only existing PICU department of the city of Brazzaville, which provide cares to seriously ill children. Thus, almost all children with severe malaria in the city are hospitalized there. The capacity of the department is 26 beds.
All children hospitalized in the PICU during the study period and meeting the criteria of severe malaria as defined by WHO in 2015 [
Hospitalized children for severe malaria with a pre-existing known glucose metabolism disorders and those in whom blood glucose levels were not measured on admission were not included.
Children were included in the study systematically and consecutively at the time of their admission in the department.
A standardized questionnaire, which includes sociodemographic, clinical, therapeutic and outcome data, was filled-in for all children.
The sample size was determined using the following formula suggested by Fink et al [
n = ( μ α ) 2 π ( 1 − π ) / i 2 ; where, n = sample size; μ α = 1.96; π = estimated frequency of severe malaria in Brazzaville = 10%, i.e. 0.1 [
Children were examined on admission and regularly until they were discharged by one of the pediatricians of the department. Consciousness was evaluated using the Blantyre coma score [
Immediately after arrival of patients suspected as having malaria, a blood was collected for thick test for malaria (or Malaria Rapid Diagnostic Test) and for complete blood cell count. A lumbar puncture with cerebrospinal fluid study was performed when the child had neurological manifestations. Other laboratory investigations were performed on the basis of symptoms involved. Measurements of lactate and bicarbonate were not performed due to technical difficulties.
Blood glucose concentration was measured via afingerprick measurement (using an AccuChek® Performa glucometers from ROCHE Laboratories), with sensitivity limit of 1 mmol/L on admission and every 8 hours for 3 days, and each time a seizure occurred or after a secondary worsening of the consciousness impairment was observed.
A measurement of venous blood glucose was performed to confirm hypoglycemia cases diagnosed with the glucometer.
The management of patients was done according to the WHO guidelines [
In case of hypoglycemia (blood glucose ≤ 3.3 mmol/L) [
Convulsions were managed with rectal diazepam, followed successively by intravenous midazolam, infusion of Phenobarbital when seizure could not be controlled.
There is no consensus on the definition of different blood glucose abnormalities. The definitions used in this work were as follows [
Mild to moderate hypoglycemia: 2.2 mmol/L ≤ blood glucose ≤ 3.3 mmol/L;
Severe hypoglycemia: blood glucose < 2.2 mmol/L;
Normal blood glucose: blood glucose between 3.3 and 8.3 mmol/L;
Mild to moderate hyperglycemia: 8.3 mmol/L ≤ blood glucose ≤ 11.0 mmol/L;
Severe hyperglycemia: blood glucose > 11 mmol/L.
Impaired consciousness was defined by a Blantyre coma score (BCS) < 3; The BCS is a modification of the pediatric Glasgow coma scale, used to assess the level of consciousness in children with malaria. The score is determined by adding the results from three groups: Motor response (range from 0 - 2), verbal response (0 - 2), and eye movement (0 - 1). The minimum score is 0 which indicates poor results while the maximum is 5 indicating good results. All scores under 5 are considered abnormal [
Nutritional status was assessed according to the WHO growth standards [
Normal nutritional status = −2 z-score ≤ weight/size ≤ 2 z-score;
Moderate acute malnutrition: −3 z-score
Severe acute malnutrition = weight/size < −3 z-score;
Overweight = 2 z-score < weight/size < 3 z-score;
Obese = weight/height > 3 z-score.
Data were processed and analyzed using Epi-Info 7.2.1 software. The quantitative variables were expressed as mean ±standard deviation or median and interquartile range (IQR). The qualitative variables were expressed as percentages. The numbers of each variable were also specified. The comparison of percentages was carried out with the independence chi square test or the Fischer test (when at least one of the theoretical numbers was less than 5) and the odds ratio. The comparison of means was carried out using Analysis of Variance (ANOVA) or with the Mann Whitney-Wilcoxon test, the comparison of the continuous quantitative variables between them was carried out by the simple linear regression. The variables for which the p-value was ≤0.05 in univariate analysis were analyzed in multivariate using the logistic regression model. The significance level was set at 5% level and the confidence interval at 95%.
For each child an informed consent of parents or guardians was obtained. The study was carried out in compliance with the Helsinki Declaration [
During the study period, 158 children were hospitalized for severe malaria. The population was divided into 80 males (50.6%) and 78 females (49.4%), sex-ratio of 1.03. The mean age of the overall study population was 69.6 months ± 43.2 (ranges 5 months and 15 years), the one for females was 60.36 months ± 40.65, and for males 79.61 months ± 44.76 (p = 0.006). Children aged 5 years and above represented 82 cases (51.9%). One hundred and twenty-five children (79.11%) were from a health facility and 33 (20.89%) from home. The median duration of symptoms before hospitalization was 4 days (IQR, 3 - 10 days).
The main criteria of severity were: multiple convulsive seizures (n = 108), severe anemia (n = 96), prostration (n = 72), coma (n = 52), hemoglobinuria (n = 43), jaundice (n = 35), respiratory distress (n = 20), hypoglycemia (n = 4), shock (n = 4), abnormal bleeding (n = 2).
Thick for plasmodium was carried out in 108 children, and the malaria rapid diagnostic test in the other 50 children. In all cases the plasmodial species identified was Plasmodium falciparum. The median parasitic density was 10,420.00 (IQR, 640.00 - 19,968.00).
One hundred and thirteen (71.52%) children were treated with quinine, 39 (24.68%) with artesunate and 6 (3.80%) with artemether.
The median duration of in-patient stay was 3.92 days (IQR, 3 - 5 days). One hundred and forty-six children survived, 3 with neurological sequelae (3 cases of hemiparesis, of which one with deafness), and 12 children (7.59%) died, 75% of deaths occurred within 24 hours after admission.
Analysis of blood glucose abnormalities:
The mean blood glucose serum was 6.49 mmol/L ± 2.42 (ranges 1.38 and 22.17 mmol/L), it was 6.71 mmol/L ± 2.48 (ranges, 1.38 and 14.52 mmol/L), 6.27 mmol/L ± 2.14 (ranges, 2.97 and 17.05 mmol/L), 6.38 mmol/L ± 2.70 (ranges, 2.75 and 22.17 mmol/L) and 6.77 mmol/L ± 2.56 (ranges, 2.56 and 12.93 mmol/L) respectively on admission, on the 1st, 2nd and 3rd days.
A total of 105/158 (66.46%) children had at least one episode of glycemic disorder on admission and during 3 days of blood glucose monitoring. Of which, 83 (52.53%) had moderate hyperglycemia, 28 (17.72%) severe hyperglycemia, 24 (15.19%) moderate hypoglycemia and 4 (2.53%) severe hypoglycemia; some children had different blood glucose abnormalities during hospitalization. Sixty (57.14%) of the 105 children had glycemic abnormalities after admission.
The distribution of the blood glucose categories according to the days of hospitalization is shown in
Twenty-three (21.90%) of the 105 children presented the 68 observed recurrences; these recurrences consisted of 48 episodes of moderate hyperglycemia, 12 and 8 episodes of severe hyperglycemia and moderate hypoglycemia respectively. No episode of severe hypoglycemia was observed after admission.
As the number of children with severe hypoglycemia was low, the items severe and moderate hypoglycemias on admission were grouped as “hypoglycemia on admission” and associated factors to its occurrence were identified.
The factors associated with the risk of hypoglycemia on admission are shown in
We did not identify any factors associated with the risk outbreak of hypoglycemia after admission, or the risk of recurrence.
Age ≥ 5 years was the only factor significantly associated with the risk of outbreak of hyperglycemia [OR = 4.83 (1.85 - 12.60); p = 0.0006].
Factors associated with lethality were the age < 5 years [OR = 6.77 (1.43 - 32.02), p = 0.006], hypoglycemia (moderate and severe) on admission [OR = 17, (4.53 - 65.71), p = 0.0001], Blantyre score < 3 [OR = 4.64 (1.33 - 16.20), p = 0.02],
Characteristics | Glycemic status | p-value | ||||
---|---|---|---|---|---|---|
Normal blood glucose | Severe hypoglycemia | Moderate hypoglycemia | Moderate hyperglycemia | Severe hyperglycemia | ||
Mean age (month) ± SD* (range) | 66.78 ± 40.45 (5 - 168) | 47.00 ± 28.87 (22 - 72) | 24.60 ± 7.04 (15 - 36) | 104.18 ± 49.27 (36 - 180) | 85.75 ± 33.59 (39 - 120) | <0.00001S |
Gender n (%) F M | 56 (49.12) 58 (50.88) | 2 (50.00) 2 (50.00) | 10 (100.00) 0 (0.00) | 10 (45.45) 12 (54.55) | 0 (0.00) 8 (100.00) | 0.001S |
Signs of Severity n (%) Multiple seizures Prostration Coma Severe anemia | 72 (63.16) 50 (43.86) 38 (33.33) 66 (57.89) | 4 (100.00) 2 (50.00) 2 (50.00) 4 (100.00) | 10 (100.00) 6 (60.00) 4 (40.00) 8 (80.00) | 16 (72.73) 10 (45.45) 6 (27.27) 14 (63.64) | 6 (75.00) 4 (50.00) 2 (25.00) 4 (50.00) | 0.08NS 0.8NS 0.8NS 0.3NS |
Nutritional status Normal Moderate acute malnutrition Severe acute malnutrition | 96 (90.57) 10 (9.43) 0 (0.00) | 4 (100.00) 0 (0.00) 0 (0.00) | 8 (80.00) 0 (0.00) 2 (20.00) | 12 (66.67) 6 (33.33) 0 (0.00) | 4 (50.00) 4 (50.00) 0 (0.00) | 0 |
Median parasitic density; (IQR**) | 9080; (440 - 19,968) | 22,5100; (15,200 - 435,000) | 17,200; (10,680 - 48,000) | 4655; (662 - 51,500) | 1000; (600 - 1,0160) | 0.06NS |
Median duration of in-patient stay ± SD* (hour) | 94.57 ± 51.22 (11 - 120) | 72 ± 0 | 128 ± 86.75 (72 - 240) | 100.80 ± 64.02 (24 - 240) | 102 ± 42.06 (72 - 168) | 0.9NS |
Case fatality n (%) | 6/114 (5.26) | 2/4 (50.00) | 4/106 (40.00) | 0/22 (0.00) | 0/8 (0.00) | 0 |
*standard deviation; **interquartile range, Ssignificant difference, NSno significant difference
Variables | Hypoglycemia n (%) | Univariate analysis | Multivariate analysis | |||
---|---|---|---|---|---|---|
no | yes | OR [CI* à 95%] | p-value | OR ajusté [CI* à 95%] | p-value | |
Age (year) < 5 ≥ 5 | 64 (84.21) 80 (97.56) | 12 (15.79) 2 (2.44) | 7.5 (1.6 - 34.7) | 0.03 | 6.5 (1.17 - 35.97) | 0.03S |
Gender M F | 78 (97.50) 66 (84.62) | 2 (2.50) 12 (15.38) | 7.09 (1.53 - 32.83) | 0.004 | 6.5 (1.15 - 37.07) | 0.03S |
Disease duration(day) < 7 ≥ 7 | 118 (93.65) 26 (81.94) | 8 (6.35) 6 (18.75) | 3.40 (1.09 - 10.65) | 0.04 | 4.5 (1.10 - 18.32) | 0.03S |
From private hospitals no yes | 130 (92.86) 14 (77.78) | 10 (7.14) 4 (22.22) | 3.71 (1.02 - 13.41) | 0.03 | 5.2 (1.01 - 26.65) | 0.04S |
Severe acute malnutrition no yes | 114 0 | 12 2 | unknown | 0.007 | 0.9NS | |
Convulsion yes no | 94 (87.04) 50 (100) | 14 (12.96) 0 (0) | unknown | 0.007 | 0.9NS | |
Blantyre < 3 ≥3 | 46 (88.46) 98 (92.45) | 6 (11.54) 8 (7.55) | 1.60 (0.52 - 4.87) | 0.4 |
*CI: confidence interval, Ssignificant difference, NSno significant difference.
respiratory distress on admission [OR = 4.06 (1.1 - 15.02), p = 0.04] and convulsion in the history (p = 0.01) in univariate analysis, and the age < 5 years [OR = 24.09 (2.55 - 227.83), p = 0.005], hypoglycemia (moderate and severe) on admission [OR = 9.59 (1.43 - 63.93); p = 0.02], Blantyre score < 3 [OR = 21.04 (2.95 - 149.86), p = 0.002] and respiratory distress [OR = 10.75 (27 - 91.21), p = 0.02] on admission in a multivariate analysis.
Moderate hypoglycemia after admission was not associated with lethality.
No death had been recorded among children with hyperglycemia on admission. However, there was no significant association between hyperglycemia and death (p = 0.4).
The recurrence of any of the glycemic abnormalities did not expose the patient to excess mortality.
This study, which is the first in Congo and one of the few in Africa devoted to glycemic disorders during severe malaria, showed that the incidence (66.46%) of these disorders was high in children in Brazzaville. The majority of these disorders were observed after admission. Overall, hyperglycemia (70.25%) was the most observed glycemic anomaly. These data are similar to those reported by Wilcox et al. in Mali [
Hypoglycemia on overall was observed in 17.72% of children. This frequency is much higher than that would have been noted if blood glucose had been measured only on arrival and if the WHO definition was used [
In the present study, no case of relapse of severe hypoglycemia was observed after admission, unlike some authors who reported a relatively large number of cases [
The factors involved in the genesis of hypoglycemia during malaria are multiple and varied depending on regions, countries and age [
Parasite density was higher in hypoglycemic children than in non-hypoglycemic, but without significant difference, unlike authors who reported a causal relationship between parasitic density and hypoglycemia [
The small number of severely malnourished children did not allow to establish the link with hypoglycemia.
In this study, the only factor significantly associated with hyperglycemia was age > 5 years. The factors (convulsions, respiratory distress, shock) usually incriminated in the genesis of hyperglycemia [
The case fatality rate observed in our series is as high as those reported by the majority of African authors [
In this work, factors associated with risk of death were age < 5 years, the existence of respiratory distress, impaired of consciousness (score Blantyre < 3), hypoglycemia on admission. Hypoglycemia on admission was the only glycemic abnormality significantly associated with an increased risk of death [OR = 17.25 (4.53 - 65.71)]. Our results corroborate those reported by most authors [
Hyperglycemia, which yet is recognized by several authors as risk factors for poor prognosis in severely ill children [
This study presents some limitations; the blood glucose assessment was performed mainly using handheld glucometer, this method not only allows a limited number of blood glucose assessments, but it’s also known to underestimate hypoglycemic events, particularly in patients with anemia [
These findings confirm the need to regularly monitoring of blood glucose in any child hospitalized for severe malaria on and after admission at least until the clinical condition is stabilized. Severe and moderate hypoglycaemia is associated with a poor prognosis child with severe malaria. Moderate hypoglycemia as well as severe hypoglycemia is associated with a poor prognosis and should be the subject of prevention and management.
Hypoglycemia, the only glycemic disorder associated with risk of death in children with malaria, is much more common than would suggest the only blood glucose measurement on admission. The revision of the threshold defining its severity, the implementation of simple and effective control measures against it other factors of severity are necessary to hope to reduce the lethality related to malaria.
Hyperglycemia, which is the most common glycemic disorder, appears to have a protective effect in children severely affected by malaria.
We are indebted to children and mothers who participated in the study.
We acknowledge all our colleagues, especially the nursing staff of the Pediatric Intensive Care Unit and the laboratory workers of the Teaching Hospital Center of Brazzaville.
The authors declare that they have no competing interests.
Gildas, O.A.P., Gaston, E.B., Laetitia, L., Vassili, M.M.S., Judicaël, K., Yoleine, P.J.P., Nelly, P.G., Cyriaque, N.M.I., Engombo, M. and Marius, M.G. (2017) Blood Glucose Concentration Abnormalities in Children with Severe Malaria: Risk Factors and Outcome. Open Journal of Pediatrics, 7, 222-235. https://doi.org/10.4236/ojped.2017.74026