ORIGINAL

Niger J Paed 2013; 40 (3): 238 –242

Onyiriuka AN

Peters OO

Awaebe PO

Hypoglycaemia at point of hospital

admission of children below five

years of age with falciparum

malaria: prevalence and risk

factors.

DOI:http://dx.doi.org/10.4314/njp.v40i3,7

Accepted: 26th December 2012

Abstract Background: Hypogly-

caemia is a well recognized com-

plication of falciparum malaria in

children but its diagnosis may be

overlooked because all the clinical

features may be mimicked by other

features of severe malaria.

Objective: To determine the preva-

lence of hypoglycaemia at the

point of hospital admission of un-

der-fives with falciparum malaria

and identify its risk factors in pa-

tients seen in a Nigerian secondary

hospital admission. Twenty three

percent, 78 of 339 children below

36 months of age were hypoglycae-

mic compared to 8.6%, 14 of 163

children aged 36 months and above;

p<0.01. Forty (13.1%) of 305

children in whom the time of last

meal was 12 hours and below had

hypoglycaemia compared to 52

(26.4%) of 197 in whom the time of

last meal was greater than 12 hours;

p<0.05. The duration of illness and

the parasite density did not have

significant bearing with the

(

)

Onyiriuka AN

Department of Child Health,

University of Benin Teaching Hospital,

PMB 1111,

Benin City, Nigeria.

E-mail: alpndiony@yahoo.com,

didiruka@gmail.com

Olasimbo OP

Paediatrics Unit,

Awaebe PO

Medical Laboratory Unit,

St Philomena Catholic Hospital,

Benin City, Nigeria.

-healthcare institution.

Methods: At the point of admis-

sion, venous blood sample was

collected into an appropriate sam-

ple bottle (fluoride-oxalate bottle)

from 502 children who were below

prevalence of hypoglycaemia.

Conclusion: Age below 36 months

and a time of last meal greater than

12 hours have significant bearing

with occurrence of hypoglycaemia

in children with falciparum malaria.

Routine monitoring of blood

5

years of age for malaria parasite

examination (Giemsa stain). The

blood sample was analysed using

the glucose-oxidase method.

glucose at point of hospital

admission is suggested.

Results: Ninety two (18.3%) of

5

02 children below five years of

Key words: Hypoglycaemia, falci-

parum malaria, prevalence, risk

factors, under-fives.

age with falciparum malaria had

hypoglycaemia (blood glucose

below 2.6 mmol/L) at the point of

Introduction

of the markers o₆_,f₈_,₁d₀ isease severity in children with falci-

parum malaria. In the light of the above, hypogly-

In the paediatric age group, and particularly among

under-fives, hypoglycaemia is a common metabolic

problem e_-₃ncountered in association with a variety of

caemia should always be considered, assessed and, if

present, treated in severe malaria. Given that hypoglyce-

mia is amenable to inexpensive and readily available

treatment, various clinicians have recommended that

children with falciparum malar₈i_,₁a₀ should be monitored

1

diseases. In countries with limited resources, under-

4

5

nutrition, ₆ infectious diseases, delayed presentation in

hospital,

administration of potentially toxic herbal

and lack of facilities for diagnosis may

frequently for hypoglycaemia

However, regular

10

1

,5,6

concoctions,

monitoring has been ignored by clinicians despite the

fact that hypoglycaemia is associated with serious neu-

rological sequelae₁ when detection is delayed or treat-

increase the frequency of occurrence of hypoglycaemia.

Hypoglycaemia is a well recognized complication of

Plasmodium falciparum malaria with or without treat-

ment with quinine and it is associated with increased

mortality and_-₉neurologic sequelae, particularly among

1

ment inadequate.

Various pathogenetic mechanisms have been postulated

to explain the occurrence of hypoglycaemia in children

with falciparum malaria who have not been treated with

quinine. Firstly, increased glucose consumption.

7

under-fives. In these patients, it is difficult to identify

hypoglycaemia from clinical examination alone, because

all the signs of₇h_,₁y₀_,p₁₁oglycaemia may be mimicked by

those of malaria.

In addition, hypoglycaemia is one

Glucose consumption increases in fever and infection.

2

39

In acute falciparum malaria, there is increased glucose

turnover due to increased₁₂_,g₁₃lucose consumption both by

ries of patients. It has a fairly well equipped laboratory

manned by qualified laboratory scientists and offers a

24-hour laboratory service.

the host and the parasite,

with the host’s requirement

2

1

being considerably greater. Secondly, glycogen deple-

tion and/or impaired gluconeogenesis. Although fasting

reduces glycogen stores rapidly even in well nourished

children, the presence of high substrate levels (lactate

and alanine) and absence of ketosis in many children

with hypoglycaemia sugge₂st that other factors than star-

At the point of admission, all children between the age

of one and 59 months who were suspected to have ma-

laria were recruited into the study after explaining the

relevant details of the study to their parents/caregivers

and obtaining their consent subsequently. The study

design was approved by the hospital authority and con-

sent was obtained from the parents. Following recruit-

ment, pretreatment venous blood sample was obtained

from each of the patients and a thick and a thin blood

film for malaria parasites were performed. Giemsa stain

was used in staining. The full blood count was obtained.

Blood sample for plasma blood glucose estimation were

collected into the appropriate sample containers and

forwarded immediately to the hospital laboratory for

processing. The venous blood glucose samples were

collected into a dry fluoride-oxalate bottles and a₁n₈alysed

using the glucose-oxidase reaction method. Two

medical laboratory scientists (with over 20 years experi-

ence) processed the samples urgently at the request of

the admitting physician and average of the two plasma

glucose values obtained was accepted. Inclusion criteria

included: age below 60 months, Nigerian, positive falci-

parum malaria parasitaemia, absence of overt protein-

energy malnutrition (kwashiorkor/marasmus), negative

history of treatment with quinine and/or herbal concoc-

tions. Patients with a coexisting morbidity were ex-

1

8

vation might be involved. Planche et al has postulated

that hypoglycaemia in children with severe falciparum

malaria is due to a combination of impaired hepatic glu-

coneogenesis and/or increased peripheral utilization of

glucose as a result of increased anaerobic glycolysis.

Obviously, the pathogenesis of hypoglycaemia in chil-

dren with falciparum malaria is multifactorial and debat-

able, but it is generally agreed that it is due to a variable

depletion of hepatic glycogen due to starvation, cytokine

-

to 3-fold increase in glucose turnover.

induced impairment of hepatic glycon₈_,e₁₂o_-₁g₄enesis and a 2

Although various approaches have been applied to de-

fine the cut-off value for hypoglycaemia, an acceptable

cut-off remains debatable. However, a review of the

literature revealed that the most accepted concept is that

of defining hypoglycaemia based on a practical opera-

tional thresholds for glucose₁_,₁v₅_,a₁l₆ues at which interven-

1

tion should be considered.

In this regard, many

experts now define hypoglycaemia in infants and chil-

1

1,15,16

dren as blood glucose level below 2.6 mmol/L.

The relative appropriateness of t₇his cut-off value is sup-

cluded.

Only patients who had positive plasmodium

1

ported by the study of Koh et al which showed

falciparum parasitaemia and no other identifiable cause

for their fever after clinical and laboratory evaluation

had their data analysed in this study. The presence of a

reddish chromatin dot with a purple or blue cytoplasm

of the malaria parasites seen together was accepted as a

definitive diagnosis of malaria. In the present study,

hypoglycaemia was defined as blood glucose value be-

low2.6 mmol/L and this was based on the current, most

acceptable, concept of a practical operational thresholds

for gluco₁s₁e_,₁₅v_,₁a₆lues at which intervention should be con-

evidence of acute neuro-physiological changes in young

infants when blood glucose concentration dropped

below 2.6 mmol/L, indicating the need for intervention.

Between the age of six months and five years, there is

waning of all the malaria-protecting factors resulting

not only in increased frequency of falciparum malaria,

but also, increased occurrence of complications of which

7

hypoglycaemia is one of the most important. The pres-

ence of hypoglycaemia at the point of hospital admis-

sion h₂a_,₈s_,₁₀been shown to be significantly associated with

sidered.

The number of parasites were counted

against 200 white blood cells (WBC) on a thick film and

this was₁₉converted to parasite per microlitre using the

formula:

death₂

and dying within the first 24 hours of admis-

sion. Plasmodium falciparum (the predominant s₉pecies

in Africa) accounts for majority of these deaths. It is

estimated that the fatality rate might be up to 30% in

non-immune in₉fants, if appropriate therapy is not insti-

tuted promptly.

Parasite per µL of blood = Number of parasites counted

X total WBC / Number of WBC counted.

An average WBC count of 8,000/µL was used as the

total WBC. In this way, the parasite density was catego-

rized as follows: < 100,000/µL, 100,000 to < 250,000/

µL and ≥250,000/µL.

The purpose of the present study was to determine the

prevalence hypoglycaemia at the point of hospital ad-

mission among under-fives with falciparum malaria

and identify some of its risk factors.

The data was analyzed using the Computer Package for

Epidemiologist (PEPI). Descriptive statistics such as

frequencies, means, ratios, standard deviations, confi-

dence intervals, percentages were used to describe all

the variables. The chi-square test was used in ascertain-

ing the significance of differences between two propor-

tions with the p-value set at <0.05.

Patients and methods

This cross-sectional study was conducted

between

January and December, 2010 at St Philomena Catholic

Hospital (SPCH), Benin City, Nigeria. SPCH is a large

secondary-healthcare institution that cares for all catego-

2

40

Results

Table 4, shows the higher the parasite density the greater

the prevalence of hypoglycaemia. Two of the eight

(25.0%) cases with hypoglycaemia associated with para-

site density ≥250,000/µL died (Table 4).

During the twelve-month study period, a total of 502

children below five years of age were admitted for

Plasmodium falciparum malaria (irrespective of sever-

ity). Of this number, 270 (53.8%) were males and the

remaining 232 (46.2%) were females, giving a male-to-

female ratio of 1.2:1. Ninety two (18.3%) of the 502

children had hypoglycemia at the point of admission.

Table 1 shows that 23.0%, 78 of 339 children aged

below 36 months were hypoglycaemic compared to

Table 4: Prevalence of hypoglycaemia according to parasite

density

Parasite density

(per µL)

Prevalence of hypoglycaem₂ ia

Number Percent X (p-value)

a

<

1

100,000 (n=270)

00,000_bto < 250,000

(n=198)

43

15.9 a vs b =0.84 (>0.05)

8

.6%, 14 of 163 children aged 36 months and above;

2

38

8

92

19.2 a vs c =1.25 (>0.05)

23.5 b vs c =0.15 (>0.05)

18.3

X = 15.29 p <0.01. Although the prevalence of hypo-

glycemia was slightly higher in girls than boys, it was

not statistically significant [20.7% versus 16.3%, Odd

ratio, OR =0.75 (95% Confidence Interval, CI = 0.48-

c

250,000 (n=34)

≥

Total (n= 502)

The mean blood glucose values for hypoglycaemic and

non-hypoglycaemic children were 1.9+0.2 mmol/L (CI=

1

.18)]; Table 1. Of the 502 children with falciparum

malaria seen during the study period, the duration of

illness before presentation was four days and below in

1

.86-1.94) and 3.4+0.7 mmol/L (CI= 3.1-3.7) respec-

tively; t-statistic=37.16, p-value 0.001. Of the 502 chil-

dren admitted for falciparum malaria, 352(70.1%) had

anaemia (haematocrit below 30%), comprising 236

(67.0%) as mild-to-moderate (haematocrit 20-29%) and

116(33.0%)as severe (haematocit below 20%). Of the

3

1

75 (74.7%) cases and above four days in the remaining

27 (25.3%) cases.

Table 1: Distribution of hypoglycaemia according to age and

gender

1

anaemia (haematorit below 15%).The presenting clinical

features are shown in Table 5.

16 with severe anaemia, 84(72.4%) had very severe

Age (months)

Hypoglycaemia

Number

Percent

<

12 (n=82)

13

65

14

92

15.9

25.3

8.6

Table 5: Presenting clinical features in 502 children below

five years of age admitted for falciparum malaria

1

3

2-35 (n=257)

6-59 (n=163)

Total (n=502)

Gender

Male (n=270)

Female (n=232)

Total (n=502)

18.3

Presenting clinical features

Body temperature: 37.5 – 38.4 C

Body temperature: 38.5 C and above 105

Anaemia (haematocit below 30%)

Convulsion

Vomiting

Hepatosplenomegaly

Splenomegaly

Altered consciousness

Acidotic respiration

Number *

397

Percent

44

48

92

16.3

20.7

18.3

0

79.1

20.9

70.1

41.0

40.1

34.9

31.7

13.9

5.8

0

352

206

201

175

159

70

Table 2, shows the duration of illness before presenta-

tion did not significantly influence the prevalence of

hypoglycemia. The prevalence of hypoglycemia was

significantly higher in patients in whom the time of last

meal was greater than 12 hours compared to those in₂

whom the time of last meal was less than 12 hours; X

29

*Some patients had more than one presenting clinical features

=

14.10 p <0.05 (Table 3).

Table 2: Prevalence of hypoglycaemia according to duration

of illness before presentation

Discussion

2

Duration of illness Prevalence of hypoglycaemia

X

Number

Percent

(p-value)

In the present study, the prevalence of hypoglycaemia at

the point of hospital admission of children less than five

years old with falciparum malaria was 18.3%. This was

lower than the 25₂.5₀_,%₂₁ and 46.9% reported from two

0

-4 days (n=375)

4 days (n=127)

Total (n=502)

70

22

92

18.7

17.3

18.3

0.11

(>0.05)

>

Nigerian studies.

On the other hand, the prevalence

observed in the present study was 2.5 times higher than

10

that reported from a district hospital in Kenyan. The

lower prevalence observed in the present study com-

pared to the study in Katsina may be due to differences

in timing of collection of blood sample from the pa-

tients. The blood sampling was performed at the point

admission in the present study whereas it was collected

any time in the first 24 hours of admission in the Katsina

study. Besides, the investigators included patients on

quinine before presentation in the hospital. Quinine is

Table 3: Prevalence of hypoglycaemia according to time of

last meal

2

Time of last meal

Prevalence of hypoglycaemia

X

Number

Percent

(p-value)

<

>

Total (n=502)

12 hours (n=305)

12 hours (n=197)

40

52

92

13.1

26.4

18.3

14.10

(<0.05)

2

41

hours or less. T₂h_,₁i₀s_,₂f₅inding is in keeping with the report

of other studies. The increased risk of development

of hypoglycaemia in patients in whom the time of last

meal was greater than 12 hours might be explained by

depletion of glycogen store during fasting; more than

eight hours after the last meal being indicative of

fasting.

1

2

known to induce hypoglycaemia in children. The

implication is that inclusion of some patients on quinine

might have resulted in the comparatively higher preva-

lence reported by the authors. This view is supported by

the even higher prevalence (30.0%) reported among

patients on therapy for severe malari₂a₂ admitted into an

Intensive Care Unit (ICU) in India.

The higher

prevalence observed in the present study compared to

the Kenyan study may be due to differences in definition

of hypoglycaemia used and the age range of study

populations. In the present study, a higher cut-off

Although the frequency of hypoglycaemia increased

with increasing parasite density, it was not statistically

significant. However, two out of the eight (25.0%)

cases with hypoglycaemia co-existing with hyperparasi-

taemia ≥250,000/µL died, suggesting that there might be

a link between hyperparasitaemia and hypoglycaemia in

relation to mortality. This discrepant finding between

parasite density and occurrence of hypoglycaemia may

be explained by the report of Silamut and White in

which they stated that some patients may have most of

their parasite biomass sequestered,₆and others may have

(

<2.6 mmol/L, based on the concept of operational

threshold blood glucose values) was used in defining

hypoglycaemia whereas 2.2 mmol/L was used as cut-off

in the Kenyan study, partly accounting for the higher

prevalence observed in the present study. Definition of

hypoglycaem₃ia used in a study is known to influence its

2

prevalence. The study population in the present study

were children less than five years of age whereas some

of the subjects in Kenyan study were older than five

years. Studies have shown that the risk of hypoglycae-

mia is higher in younger childre_,₂n₄, particularly among

2

most of their parasites circulating. In addition, the den-

sity of parasitaemia as measured in the peripheral circu-

lation may wax and wane, emphasizing the importance

of exa₂m₇ ining serial blood films at intervals of 6 to 12

hours. However, the present study was not designed to

address that issue as it focused on hypoglycaemia at

point of hospital admission.

1

those below three years of age. This view is further

supported by the observation in the present study that

the prevalence of hypoglycaemia was 2.7 times higher

among children whose ages were below three years

compared to their counterparts who were three years

and above.

Numerically, more males than females were admitted,

the prevalence of hypoglycemia was slightly higher in

girls than boys but it was not statistically significant. A

similar finding wa₈s reported from Ghana but with differ-

1

1,25

data from the pre-

In consonance with other studies,

sent study revealed that children with falciparum malaria

who were less than three years old had a significantly

higher risk of developing hypoglycaemia than their

counterparts whose ages were 3 years and above. A

partial explanati₄on might be found in the report of

2

ent percentages. There is no readily available explana-

tion for this female preponderance. However, the au-

thors in the Ghanaian study attributed it to gender₂-₈

related health-seeking behaviour and/or genetic factor.

The present study was not designed to address this issue,

making it impossible to draw such a conclusion from it.

The duration of illness before presentation did not sig-

nificantly influence the prevalence of hypoglycemia in

the present stu₀dy. This is in consonance to the finding

2

Zijlmans et al, which stated that older children are

better able to reduce peripheral glucose utilization

during fasting, resulting in lower prevalence of hypogly-

caemia among them. In that study, they reached this

conclusion after showing that endogenous glucose pro-

duction was not influenced by age in children with falci-

1

by Osier et al, in Kenyan.

8

parum malaria. Planche et al, proposed that the

increased peripheral uptake of glucose was due to

increased anaerobic glycolysis. It is also possible that

children below three years of age have a comparatively

lower glycogen reserve than children above three years

of age, resulting in higher risk of hypoglycaemia in the

former.

Conclusion

Age below three years and a time of last meal greater

than 12 hours were the significant risk factors for the

occurrence of hypoglycaemia in children with

falciparum malaria.

Data from the present study showed that among

children with falciparum malaria, those in whom the

time of last meal was greater than 12 hours were at

higher risk of developing hypoglycaemia compared with

their counterparts in whom the time of last meal was 12

Conflict of interest: None

Funding: None

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