M R Karim1, M N
Islam2, M I Khan3, A
Kashem4, M M Rahman5 and M A R Chowdhury6.
1Associate Professor of Pediatrics, Faridpur Medical
College, Faridpur, Bangladesh; 2Former
Professor of Pediatrics,
Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh; 3Associate
Professor of Pharmacology, Dhaka Medical College, Dhaka, Bangladesh; 4Assistant
Professor of Nephrology, Chittagong Medical College, Bangladesh, 5Resident
Medical Officer,
Doctors Chamber, Cox's Bazar, Bangladesh, 6Medical
Officer, Pediatrics, District Hospital, Cox's Bazar, Bangladesh.
Key words: Artemether; Quinine; Plasmodium falciparum; severe malaria; Children.
Abstract :
Artemether is a rapidly acting antimalarial drug
derived from a Chinese herb, and ample
of studies proposed its effectiveness
over conventional quinine in the treatment of severe falciparum malaria. In
this prospective study, we compared the effectiveness of intramuscular
artemether with traditional intravenous quinine in 114 Bangladeshi children
with severe falciparum malaria who were admitted into the pediatric ward of a
district hospital, Cox's Bazar.
Fifty-seven patients received intravenous quinine infusion and 57
received intramuscular artemether. The resolution of fever and
the clearance of
parasites from blood were significantly quicker in the artemether group than in
the quinine group.In case of cerebral
malaria, the recovery time from coma was comparatively shorter
with artemether
than with quinine (mean 34 Vs 43 hours respectively). During the treatment
tenure, there were 14 deaths in the quinine group (25%) and 11 in the
artemether group (19%).The
recrudescence rate was 18% in artemether group and 6.0% in quinine group, which
reflect a parasitological cure rate of 82% and 94%, respectively.Quinine treatment was associated with
increased risk of hypoglycemia than with artemether (18% vs. 5%).Therefore, our results further strengthen the
findings that intramuscular artemether has been found superior to or is at
least equally effective as intravenous quinine in the treatment of severe
malaria in children.
Introduction:
Malaria continues to be a major global health problem
and more than 2,000 million
people (40% of the world's population) are exposed
to varying degree of malaria risk in some 100 countries1.
Malaria is the sixth leading cause of
disability in children (0.7 million death/year) in the developing world2.
Severe malaria is one of the leading causes
of death in Bangladesh3 as 1,389
deaths out of 1,52,729 cases of
malaria have been reported in 1995.
There has been a growing
concern about the malaria situation in
Bangladesh
particularly in
Chittagong
area, which is a highly
malaria endemic zone4.
Malaria is one of the frequent presenting illnesses at the pediatric out
patient department and one of the leading causes of indoor admission in our
hospital.It has been observed that
about 200 pediatric cases with severe malaria admitted into the District
Hospital
, Cox's Bazar each year,
and the over all mortality rate is 20-25%5.
Although quinine therapy
has been practiced in the treatment of severe malaria for decades, its efficacy
has been observed to be declining over the last few years6-8, which
is possibly due to the development of drug resistance. Although quinine
resistant falciparum malaria has not been documented yet from
Bangladesh
, a declining quinine
response in some cases of severe malaria has been observed recently.
Therefore, to minimize further development of
drug resistance and to improve the treatment response with minimum side
effects, an alternative new drug or drugs in combination must be sought out.
Artemether has been introduced very recently
in the treatment of falciparum malaria and its efficacy compared to quinine has
been found promising.Since a major
portion of severe malaria cases are pediatric patients and no intervention
study has yet been done with artemether in children with severe malaria in
Bangladesh
, this randomized clinical
trial is designed to evaluate the efficacy and safety of artemether in the
pediatric patients of severe malaria.
Subjects and Methods :
Study :
The study was conducted in the Pediatric unit of DistrictHospital
, Cox's Bazar between the
month of January and December 1995.This study was not a research-funded project, so the information was obtained within
the usual constrains of a routine clinical service.An informed consent about the study was
obtained from the legal guardian of the children.
Patients :
One hundred and fourteen children (66 males and 48
females) with blood film positive for Plasmodium
falciparum with severe malaria were included in this study.The criteria of severe malaria were followed
as described previously7, 8.
All the patients were divided into two groups randomly: quinine group
and artemether group.The quinine group
consisted of 32 (56%) males and 25 (44%) females and the artemether group
consisted of 34 (59.5%) males and 23 (40.5%) females. The mean age was 5.55 ±
2.67 years in the quinine group and 5.39 ± 3.31 years in the artemether group,
and the mean weight was 14.96 ± 4.86 kg in the quinine group and 14.09 ± 5.45
kg in the artemether group. Patients with history of treatment with either
quinine or artemether prior to hospitalization; patients associated with other
concomitant infections e.g. septicemia, meningitis, encephalitis etc.; patients
with mixed infections with other plasmodium; and children below 6 months and
above 12 years were excluded from this study.
The sample size of the patients has been calculated with EPI Info
software version 6 based on a = 0.05, b
= 0.2, randomization 1:1.
Physical examintion and investigations :
All cases were subjected to the following examination
and investigations and data were collected and recorded in a pre-formed coded
sheet designed for
this study.
(i) Identification of the patient including age and
sex. (ii) History and physical examination including
a full neurological
examination and Blantyre coma score were noted
before starting treatment and followed every 6 hourly. Time to sit, stand and
walk was also recorded. (iii) Vital signs e.g. axillary temperature, pulse,
blood pressure and respiratory rate were recorded every 6 hourly during the
period
of coma and thereafter every 12 hourly. (iv) Thick and thin films were
prepared & parasite counts were done daily till day 7 and then on day 14,
21, 28. The number of parasites per µl in the pre-treatment sample was taken as
100% and count on succeeding days were expressed in percentage relative to
the
initial count. A blood film was considered negative when 100 microscopic fields
failed to reveal any asexual form of P.
falciparum. (v) Blood glucose was estimated in all patients immediately after
admission, then 6 hourly for initial 24 hours and thereafter daily. (vi) On
admission complete blood count, serum bilirubin, serum creatinine, and routine
urinalysis were done. (vii) Lumbar puncture was done in all the cases with
coma, convulsion and altered consciousness (20 cases in quinine group and 19
cases in artemether group) and CSF was studied to exclude other possible CNS
diseases.
(viii) X-ray chest and Widal test were done when necessary. (ix) ECG
was done before starting the treatment and then daily for first 3 days and then
on day 7th. (x) Any adverse reactions if developed during the study period were
recorded group-wise with date and time of its appearance and disappearance in a
checklist. (xi) All patients were kept in hospitals at least for 7 days and
followed
up on day of 14, 21 and 28 at the out patient department.
Treatment Schedule :
Patients were selected randomly for either artemether or quinine treatment.
Artemether group: The dose of
artemether was determined from the previous studies2,9 i.e., 3.2
mg/kg body weight IM in 2 divided doses at 12 hour interval was given on day
first, followed by 1.6 mg / Kg IM daily for next 4 days. Quinine group
: A loading dose of quinine dihydrochloride, 20mg/kg dissolved in
5% dextrose in normal saline (5-10 ml / kg) by IV infusion over a period of 4
hours and was followed by
a maintenance dose of 10 mg/kg 8hrly for total 7 days
(similarly prepared as before).In
patients requiring more than 48 hours of intravenous quinine therapy,
maintenance dose was reduced by half to one third i.e. 5-7 mg / kg1.
Anemia (Hb < 6 gm/dl) was corrected by
giving packed cell under frusemide cover
(1 mg/kg IV); hypoglycemia (blood
glucose < 40 mg/dl) was corrected by 25% glucose (2-4 ml/kg) followed by 10%
dextrose infusion.It had been decided
that the patients with ARF lasting > 24 hour would be transferred to a
tertiary center as facilities of dialysis were not available at our center. All
unconscious patients were given a single intramuscular injection of phenobarbitone,
5-7 mg/kg (larger dose up to 20 mg/kg occasionally needed) as a prophylactic
anticonvulsant agent.Convulsions were
controlled with diazepam either per rectally (0.5-1 mg/kg) or intravenously
(0.15 mg/kg) with a maximum dose of 10 mg.
Evaluation criteria of severe malaria were followed as described in
previous studies2, 3.
Data Analysis :
Data entry and analysis were performed using EPI Info
software version 6. Discrete data were compared by the Chi-square test with
Yates correction if necessary or if expected frequency is less than five for
one variable, by Fishers exact test. Means were compared by Students unpaired
't' test. Statistical differences were
tested at 5% level of significance (p < 0.05).Relative risk of 95% confidence interval was
calculated by computer using Epi Info software version-6. To calculate
geometric mean of parasite densities logarithmic transformation of parasite
count was done.
Results:
The clinical and
biochemical characteristics of patients at the time of admission between the
two groups were comparable as shown in Table 1.Patients of both groups had been ill for a period of 1 to 6 days.
In our study, a history of prior convulsion
was found in 95% cases (40% in quinine group and 32% in artemether group).Complications of falciparum malaria at
presentation are shown in Table 2 and severe anemia was the commonest
presentation (25%).
The mean fever clearance
time was 45 hours in quinine group and 29 hours in artemether group, which was
statistically significant (P< 0.001).
The mean parasite clearance time was also statistically shorter in the
artemether group (32 hours) than in the quinine group (58 hours) (P
<0.001).The duration of coma among
the patients of cerebral malaria was 42.5 hours in the quinine group and 34.2
hours in the artemether group, which was statistically not different.
There were 25 (22%) deaths,
14 in the quinine group (25%) and 11 in the artemether group (19%) and most of
them died with in 24 hours of starting specific antimalarial therapy.
The overall mortality was higher in the
younger age group such as 21%, 13% and 12% in 2-5 yr, 5-8 yr and
8-12 yr,
respectively (P < 0.05).Blood
transfusions were required in 16 patients with quinine group
and in 18 patients
of artemether group.
Table 1. Clinical and Laboratory characteristics of the patients on admission
|
Characteristics
|
Quinine Mean±SD
|
Artemether Mean±SD
|
|
Male / Female
|
32/35
|
34/23
|
|
Age(yr)
|
5.55± 2.67
|
5.39± 3.31
|
|
Weight(kg)
|
14.96 ± 4.86
|
14.09 ± 5.45
|
|
Temperature 0 F
|
100.61±2.09
|
100.46±2.21
|
|
Pulse rate/min
|
98.3±17.92
|
99.42±14.76
|
|
BP mm Hg (systolic)
|
85±15
|
82±16
|
|
BP mm Hg (diastolic)
|
52±23
|
54±24
|
|
Respiratory rate/m
|
47.38±14.72
|
52.92±12.96
|
|
History of fit (%)
|
40%
|
32%
|
|
Before admission (hr)
|
6.70±4.8
|
6.37±3.42
|
|
Prior chloroquine treatment (%)
|
46%
|
42%
|
|
Parasite count/µl
|
40,519
|
43,599
|
|
Median (Range)
|
52,200(650-3,12,550)
|
50,640(500-3,10,250)
|
|
WBC /µl
|
6355±2045
|
6218±1984
|
|
Hemoglobin gm/dl
|
7.21±1.84
|
9.7±2.03
|
|
Bl glucose gm/dl
|
80.93±20.54
|
84.35±31.38
|
|
S.creatinine mg/dl
|
1.57±0.42
|
1.65±0.48
|
|
S.bilirubin mg/dl
|
2.84±0.50
|
2.78±0.64
|
|
AST IU/L
|
34.58±9.45
|
36.95±9.51
|
|
ALT IU/L
|
48.83±15.10
|
49.19±16.99
|
|
CSF glucose mg/dl
|
57.60±32.40
|
52.20±27.0
|
|
CSF protein gm/dl
|
37.82±5.65
|
35.30±3.57
|
The mortality rate
was comparatively more among patients with hypoglycemia (11 cases), and it was
50% in quinine group and 40% in artemether group.Among those who presented with severe anemia
(29 cases), the mortality rate was 21% in the quinine group and 13% in the
artemether group.In the patients with
cerebral malaria (21 cases), the mortality was 31% in the quinine group and 25%
in the artemether group.Mortality rate
in patients with hyperparasitemia was 20% in the quinine group and 22% in the
artemether group.Eighteen (20%)
patients dropped out from the follow-up schedule of 28 days (10 from quinine
group and 8 from artemether group).Recrudescence rate and parasitological cure rate were calculated among
the survivors who attended 28 days of follow-up.Recrudescence of parasite was 6% in the quinine
group and 18% in the artemether group.
Although statistically was not significant, a greater
tendency of hypoglycemia was observed in quinine group (18%) than in artemether
(5%) during the treatment period.In the
quinine group, minor side effects like vomiting, vertigo and dizziness were
noticed in some children (16%) including bradycardia in one patient and
prolongation of QT-interval in two patients which disappeared subsequently
without any treatment.Another patient
of quinine group developed generalized motor weakness on day 21st of
follow up but improved completely later whereas, no such symptoms were observed
in the artemether group except mild transient (10-15 min) pain at the
intramuscular injection site and an erythematous lesion in the left arm of a
patient which appeared on day 2nd and disappeared on day 6th
without any intervention.
Table 2. Complications of the patients on presentation
|
|
Quinine
|
Artemether
|
Total no. (%)
|
|
Severe anemia
|
14
|
15
|
29(25.43)
|
|
Cerebral malaria
|
13
|
8
|
21(18.42)
|
|
Hyperparasitemia
|
10
|
9
|
19(16.66)
|
|
Convulsions
|
5
|
7
|
12(10.52)
|
|
Hypoglycemia
|
6
|
5
|
11(6.65)
|
|
Hyperpyrexia
|
3
|
2
|
5(4.38)
|
|
Impaired consciousness
|
2
|
4
|
6(5.26)
|
|
Extreme weakness
|
2
|
4
|
6(5.26)
|
|
Hemoglobinuria
|
1
|
2
|
3(2.63)
|
|
Clinical jaundice
|
1
|
0
|
1(0.87)
|
|
Shock
|
0
|
1
|
1(0.87)
|
Discussion :
The clinical management of severe malaria, especially
in children is a continuous challenge to physicians in the malaria endemic
areas of Bangladesh.In this study, we observed a difference in
fever clearance time between the two treatment groups, which was significantly
shorter with Artemether treatment than with quinine treatment (P <
0.001).This result is compatible
with
the previous studies10, 11, although some authors reported an equal
fever clearance time in the groups9, 12, 13.
The parasite clearance time
was also significantly faster in patients receiving artemether than in patients
receiving intravenous quinine (P < 0.001). These findings are in agreement
with other recent studies9, 11, 12. However, some studies10, 14
reported equal parasite clearance time between the two groups.
The speed of coma recovery
among the survivors of cerebral malaria patients although shorter
with
artemether than with quinine treatment (34 hours versus 43 hours),
statistically was not different.Our
findings are in consistent with the previous reports14,15.In contrast, Hien et al10 and Hensbroek et al12 showed that coma resolution time in quinine
group was significantly faster than
in artemether group.These conflicting results might be due to the
difference of individual response
to the drugs, which may be resolved by
multi-center based larger clinical trials.
The recrudescence rate of parasite was 18% in the
artemether group and 6% in the quinine group. Although this rate was three
times higher with artemether treatment than in quinine group, statistically was
not significant.Previous studies 11,13,16,17
also showed a higher recrudescence rate in-patient treated with artemisin
derivatives compared to the standard intravenous quinine treatment. This
recurrence of parasites could result from either recrudescence of survivors
from the original parasite
or a re-infection, which could not be differentiated
in an area of continuous malaria transmission as
there are no facilities to
prevent the patients from continuous exposure to malaria. Besides these,
the
higher recrudescence rate might be due to a shorter duration of drug
administration used in this study as reported by Karbwang et al18.However,
any possible relationship between the length of treatment and / or the dose of
drug with recrudescence needs further investigation.It is worth to be mentioned that, in order to
prevent rapid development of resistance to artemether a 100% parasitological
cure rate should be achieved, which had been achieved with artemether followed
by mefloquine treatment in a previous study19. So, further trial
with artemether versus artemether plus mefloquine
may be considered to reduce
the recrudescence rate.
The mortality rate in the
artemether group was comparatively lower (19%) than in the quinine
group (25%),
but the difference was not statistically significant.A number of studies have been done previously
to find out the effectiveness of artemether compared to quinine in reduction of
the mortality from severe malaria.Some
authors showed similar mortality rate in two groups9, 10, 12,
whereas a lower mortality rate with artemether than with quinine was observed
by others20, 21, 22.Part of
this variation might be due to differences in the definition of severe and
cerebral malaria, and the severity of illness.Recently, a 2 years clinical trial in
Myanmar and Cambodia
showed that intramuscular
artemether has saved the lives of 87% of patients with severe malaria compared
with intravenous quinine, which saved only 64%22.
In this study, we did not investigate the prognostic
indicators in severe malaria patients, but a higher mortality rate was observed
in patients of younger age groups, delayed treatment, hypoglycemia and cerebral
malaria.Mortality rate was widely varied
in patients with different presentations such as 45% in hypoglycemic cases, 29%
in cerebral malaria, 21% in hyperparasitemia and 17% in case of severe
anemia.A higher mortality rate (61%) in
cerebral malaria presented with hypoglycemia was reported by Molyneux et al23.We observed that most of the deaths (88%)
occurred within 24 hours of treatment, whereas Molyneux et al23 found 67% but Marsh et al24 noted 84% deaths within 24 hours
of
admission.As it was not possible to
perform autopsies, the cause of death could not be ascertained on the basis of
clinical findings alone.
Although a greater tendency
(3.33 times more) to develop hypoglycemia was observed with quinine treatment
than with artemether (17 vs. 5 percent), the data was not statistically
significant.Previous studies also documented
a higher occurrence of hypoglycemia with quinine treatment than with artemether
in severe malaria25, 26.
Although, the recrudescence
rate was higher in artemether group the present study further supports the
efficacy of artemether against severe falciparum malaria as documented
previously12, 17, 20. The drug artemether may be considered superior
to quinine, because of faster fever remission and parasite clearance time with
a higher survival rate.Artemether saved
about 1.27 times more lives than did quinine.In our health system, district hospitals serve as an intermediate level
of health care unit between the rural health centers and the tertiary care
hospitals; which receive patients from rural health centers as referral or
directly from neighboring households.Therefore for the best outcome and to reduce the mortality, district
hospitals have a vital role for early diagnosis and early initiation of
treatment for severe malaria.
Conclusion :
The results of the present study suggest that artemether
is safe and effective in the treatment of severe malaria, which is either
superior to or is at least equally effective as quinine.Although, intravenous quinine is still
therapeutically useful in severe malaria, the principal advantage of artemether
may be its easy route of administration.Therefore, use of intramuscular artemether could be a satisfactory and
convenient alternative to intravenous quinine infusion in the treatment of
severe malaria in children in rural health centers as well as in district
hospitals which
are far away from tertiary care hospitals and resources for
carefully controlled intravenous infusion of
quinine are largely lacking.
However, a larger study may be needed to
determine the efficacy of intramuscular artemether over intravenous quinine
therapy.
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Last Updated on 1-10-2004
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