ORIGINAL ARTICLE
An Open Pilot Study of The Efficacy and Safety of Polygeline
in Adult Subjects with Dengue Haemorrhagic Fever
Herdiman T. Pohan*, Khie Chen Lie*, Suhendro*, Widayat Djoko Santoso*, Eppy**
* Department of Internal Medicine, Faculty of Medicine, University of Indonesia - Dr. Cipto Mangunkusumo Hospital.
Jl. Diponegoro no. 71, Jakarta Pusat 10430.
** Department of Internal Medicine, Persahabatan Hospital, Jakarta, Indonesia.
Correspondence mail to: tropik@indosat.net.id
ABSTRACT
Aim: to observe the efficacy and safety of Polygeline
colloid (Haemaccel®) in adults with stage I – II of dengue
haemorrhagic fever (DHF).
Methods: an open, non-comparative clinical trial. The
subjects were male or female between 17 – 55 years old, who
fulfilled the criteria of stage I or II of DHF according to WHO
and selected with consecutive sampling. Fluid treatments were
given following this protocol: polygeline i.v. infusion: 500 ml
over first 6 hours and continued with 500 ml for the next 18
hours, and maintained to 1000 mL/24 hours from day-2 until
maximum day-5. Ringer’s lactate infusion: 1000 mL/18 hours
from the first day to maximum day-5, as maintenance.
Efficacy and safety of polygeline colloid were evaluated
using initial stabilization of haematocrite level, measured
as percentage of clinical trial subject who has stabilization
of haemodynamic status based on serial haematocrite levels
examinations, total parenteral fluid required and length of
hospitalization. Statisticial analysis was done using ANOVA
test and post hoc analysis using Turkey test.
Results: there were 43 subjects who completely
participated in this study and included in analysis. From
baseline levels, haematocrite decreased in first 6 hours
during fluid treatment. This decrement persisted in 48 hours
of observation. Statistical analysis with ANOVA test showed
the significant differences of haematocrite level during
observation (Sum of square between groups 495 and within
group 4845, p= 0.000). Post hoc analysis with Turkey test
showed significant differences of haematocrite level from
baseline level to 48, 72 and 96 hours during observation
periods.
Conclusion: this pilot study showed that polygeline
colloid was a safe initial fluid treatment and can be used for
maintaining fluid adequacy in adults with stage I-II of DHF.
Key words: efficacy, safety, polygeline, dengue haemorrhagic
fever.
INTRODUCTION
Dengue infection occurs especially in tropical
countries. Indonesia, a tropical country, is classified as a
category “A” country on stratification of dengue/
dengue haemorrhagic fever (DHF) in the South-East Asia
Region by World Health Organization (WHO) 2001
based on the fact that dengue infection/DHF is a major
public health problem and the leading cause of hospital-
ization and death among children In addition, epidemics
have been caused by all four virus serotypes during the
past 20 years and occur in urban centers every 3 to 5
years.1-3 Our national data (2006) showed an increase in
number of patients (which is reflected by an
increment of incidence rate nearly 25% over 2005, to
52,48/ 100.000 citizens), provinces and districts affected.
Despite the decreasing number of deaths of DHF in last
few years, the case fatality rate (CFR) remains
relatively high (1,04% in 2006).4-6
The major pathophysiological abnormality found in
DHF/dengue shock syndrome (DSS) is an acute
increase of vascular permeability leading to loss of plasma
from the vascular compartment. Clinical manifestations
of plasma leakage, presenting as haemoconcentration,
could be found as: an increase of haematocrite levels, a
decrease of haematocrite levels after fluid treatment,
hypoproteinaemia, pleural effusion, pericardial effusion,
ascites, and gallbladder wall oedema. Severe and
uncompensated plasma leakage could lead to shock,
tissue hypoxia, metabolic acidosis and finally death.7-9
Fluid replacement should be given adequately as soon
as possible, based on the severity of plasma leakage and
requirement of fluid maintenance.1,10,11
Dengue fluid treatment protocol based on WHO
recommendation has been adopted and implemented as
national recommendation, using crystalloids (Ringer’s
47
Herdiman T. Pohan
lactate) as first line fluid treatment.2,6,8 Generally,
crystalloid has been proven safe and effective.
However, some adverse events, such as: oedema, lactic
acidosis, instability of hemodynamic and hemoconcen-
tration, still possibly occur.12,13
There has been no research showing the usage of
colloid in the early treatment of stage I – II of DHF.
Previous studies were performed in children with DSS
and revealed no clear advantage to using either
crystalloid or colloid as initial fluid of choice for
resuscitation purpose, on the outcome from DSS.
However, compared with crystalloid, colloid retains
intravascular longer with less amount of volume, gives
volume effect, and stabilizes the hemodynamic
better. 10,11,14
The clinical usage of colloid in stage I – II of DHF
and its potential benefits compared with crystalloid should
be evaluated in large comparative trial. We performed
this open study as a pilot study of the usage of colloid in
adults DHF. In this study we observed the efficacy and
safety of polygeline colloid (Haemaccel®) in adults with
stage I – II of DHF.
METHODS
An open, non comparative clinical trial was conducted
at Dr. Cipto Mangunkusumo Hospital Jakarta,
Indonesia. The study included 50 subjects in 6 months
period. The study protocol had obtained approval from
the Ethics Committee of Medical Faculty University of
Indonesia and from the National Authority of Drug and
Food Control before its commencement. Informed
consent was obtained from each clinical trial subject or
his/her legal guardian. Eligible clinical trial subjects would
receive study medications and be monitored every day
to evaluate the outcome. The trial population consisted
of adult patients with stage I or II of DHF, who were
referred to Dr. Cipto Mangunkusumo Hospital and
Persahabatan Hospital between August 2007 and
February 2008.
Subjects were recruited based on the following
criteria: male or female between 17 – 55 years old, with
clinical and laboratory findings that supported diagnosis
of DHF based on WHO criteria:2
Clinical Findings
a. high continuous fever with acute onset (2 - 7 days)
b. haemorrhagic manifestations (may or may not be
present) such as:
• a positive tournique test (TT)
• petechiea, echymosis or purpura
• bleeding from the mucosa, GI tract, injection sites
• haematemesis or melena.
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Acta Med Indones-Indones J Intern Med
Laboratory Findings
a. thrombocytopenia (< 100.000 cells/mm3)
b. haemoconcentration (a rise in haematocrite by >
20%)
Subjects with these characteristics were excluded from
the study: pregnant women, women in lactation period,
women in menstrual period during hospitalization, patients
with clinically serious and unstable hemodynamic that were
profound to DSS, elevated ALT level of > 3 times upper
normal limit, elevated serum creatinine level of > 1.5 times
upper normal limit, any disease state which was judged
by the investigator could jeopardize the health of the
patient and/ or interfere with trial participation or trial
evaluation, valvular heart disease, diabetic patients, as
diagnosed by fasting plasma glucose > 126 mg/dl and
known or suspected allergy to the trial product.
Fluid treatments were given following this study
protocol:
• Polygeline (Haemaccel®) i.v. infusion: 500 ml over
first 6 hours and continued with 500 ml for the next
18 hours, maintained to 1000 ml/24 hours from day-
2 until maximum day-5.
• Ringer’s lactate i.v. infusion: 1000 ml/18 hours from
the first day to maximum day-5, as maintenance.
Subjects with unstable hemodynamic were closely
observed and given additional Haemaccel® i.v. infusion
500 ml over first 6 hours. Subject would have been
withdrawn from this study if clinically had worsen or
profound to shock.
Following endpoints observed in this study: Primary
efficacy endpoints. The initial stabilization of
haematocrite level, measured as percentage of clinical
trial subjects who had stable haemodynamic status based
on serial haematocrite level examination.
Secondary efficacy endpoints. Amount of additional
crystalloid infusion was required at any time after
administration of the study fluid, and so were total
parenteral fluid required and length of hospitalization.
Safety endpoints. General clinical observations,
laboratory examinations, adverse events. Laboratory
examinations performed for observing safety endpoints
included prothrombin time (PT), activated partial
thromboplastin time (aPTT), D-dimer, liver and kidney
function test (ALT, AST, blood urea nitrogen and creatinin
level). Severity of adverse events were classified based
on this criteria: (1) Serious adverse events (SAEs),
including death, life threatening conditions, hospitaliza-
tion or prolongation of existing hospitalization, persistent
or significant disability/ incapacity; (2) Non serious
adverse events, further classified into mild, moderate, or
Vol 41 • Number 2 • April 2009 An Open Pilot Study of The Efficacy and Safety of Polygeline in Adult Subjects with DHF

severe adverse event. Chest x-ray and electrocardio- Table 1. Demographic and baseline characteristics
graphy were also performed for adverse event of subjects
monitoring. Characteristics n (%)
Gender
Statistical Analysis • Male 38 (88.4)
Statistical analysis with ANOVA test was used to • Female 5 (11.6)
show the differences of haematocrite level during BMI category:
observation. Post hoc with Tukey test was performed to • Underweight 0
show differences of haematocrite level from baseline • Normal 35 (81.4)
level to 6, 12, 18, 24, 48, 72, 96 and 120 hours during • Overweight 4 (9.3)
• Obese 4 (9.3)
observation periods.
Duration of fever before admission (days)
• < 3 days 4 (9.3)
RESULTS • 4 - 6 days 39 (90.7)
From fifty subjects who were screened, 44 subjects • > 6 days 0
Severity of DHF
were eligible to be enrolled in this study. During the study,
• Stage I 20 (46.5)
1 subject (2.3%) was withdrawn due to inadvertent • Stage II 23 (53.5)
enrolment. There were 43 subjects (97.7%) who
completely participated in this study and included in
further analysis.
Demographic and baseline characteristics of patients petechiae, ecchymosis, and purpura. There was no
are shown in Table 1. Mean age of subjects was 25.6 subject experienced severe bleeding (haematemesis,
years, with predominantly male (88,4%). Almost all melena, epistaxis, or gastrointestinal tract bleeding).
subjects had normal body mass index (BMI) category. Table 3 shows changes of haematocrite level from
The mean of fever duration before hospitalization was baseline level during 5 days of fluid treatment. From
4.6 days. There were 20 subjects (46.5%) categorized baseline levels, haematocrite decreased in first 6 hours
in stage I of DHF and 23 subjects (53.3%) categorized during fluid treatment. This decreament persist in 48 hours
in stage II of DHF. of observation. Haematocrite level also decrease during
Most subjects experienced mild haemorrhagic day 3 to day 5 of observation after fluid treatment. Time
manifestations: 21 subjects had positive torniquet test, line of these changes are shown in Figure 1.

Table 2. Clinical manifestation of bleeding during observation

Timepoint
Haemorrhagic
Manifestations Day 1 Day 2 Day 3 Day 4 Day 5
n (%) n (%) n (%) n (%) n (%)

Positive tournique test 21 NA NA NA NA

Petechiae, ecchymosis,
22 (50) 28 (65.1) 25 (64.1) 18 (64.3) 9 (64.3)
or purpura
Mucosal bleeding 7 (15.9) 4 (9.3) 4 (10.3) 3 (10.7) 1 (7.1)
Hematemesis or
0 1 (2.3) 1 (2.6) 1 (3.6) 0
melena
Epistaxis 0 0 0 0 0
GIT bleeding 0 0 0 0 0
* Total subjects observed in day 1-5 were 44, 43, 39, 28, 14 subjects respectively

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Herdiman T. Pohan Acta Med Indones-Indones J Intern Med

Table 3. Change of haematocrite level of 43 subjects Statistical analysis with ANOVA test showed the
receiving fluid treatment according to study protocol
significant differences of haematocrite level during
observation (Sum of square between groups 495 and
Parameter n Mean (SD)
within group 4845, p= 0.000). Post hoc with Tukey test
Haematocrite at baseline – % 43 43.91(4.12) showed significant differences of haematocrite level from
Haematocrite at hour 6 – % 42.12 (4.32) baseline level to 48, 72 and 96 hours during observation
Change of haematocrite - % – 1.79 (2.22) periods.
Haematocrite at baseline – % 43 43.91 (4.12) Percentage of change of haematocrite levels during
Haematocrite at hour 12 – % 41.49 (4.46) 48 hours of observation, is shown in Table 4.
Change of haematocrite - % – 2.42 (2.25)
Haematocrite level mostly changed less than 10% from
Haematocrite at baseline – % 43 43.91 (4.12)
Haematocrite at hour 18 – % 42.77 (4.50) baseline haematocrite level. During 36 hours after fluid
Change of haematocrite - % – 1.14 (2.72) treatment, 42% subjects showed change of haematocrite
Haematocrite at baseline – % 42 44.19 (3.72) levels above 10% from baseline level.
Haematocrite at hour 24 – % 42.74 (4.10) During period of observation in this study, all
Change of haematocrite - % – 1.45 (2.74) subjects showed stable haemodynamic condition. There
Haematocrite at baseline – % 42 44.19 (3.72) was no subject who experienced shock during fluid
Haematocrite at hour 36 – % 40.12 (4.09) treatment. All subjects received fluid according to the
Change of haematocrite - % – 4. 07(3.35)
study protocol and no additional fluid was needed during
Haematocrite at baseline – % 38 44.32 (3.74)
Haematocrite at hour 48 – % 41.45 (4.06)
fluid treatment (Table 5). Most subjects were
Change of haematocrite - % – 2.87 (3.45) hospitalized and discharged until 7 to 9 days after first
Haematocrite at day 2 – % 38 42.87 (4.11) onset of fever (5-6 days period of hospitalization).
Haematocrite at day 3 – % 41.45 (4.06) The safety analysis was based on all exposed
Change of haematocrite - % – 1.42 (2.69) subjects who had received at least one dose of trial
Haematocrite at day 3 – % 28 41.32 (4.47) products. Safety parameters were evaluated statistically
Haematocrite at day 4 – % 40.25 (5.26) based on before and after treatment data analysis (Table
Change of haematocrite - % – 1.07(2.90) 7), while the adverse events occurring during the study
Haematocrite at day 4 – % 14 39.71 (6.59) were descriptively evaluated. All subjects tolerated i.v.
Haematocrite at day 5 – % 39.50 (4.9)
fluid treatment according to study protocol. No subject
Change of haematocrite - % – 0.21(2.66)
experienced life threatening side effect or fluid overload

Error Bars show Mean +/- 1.0 SD

Haematocrit Level At Each Time-point Dot/Lines show Means

50
Val ue of h aem atocrite (%)

45
]W
]W ]W
]W
]W ]W ]W
]W ]W ]W
40 ]W
]W
]W

35

30

Haematocrit (%) at baseline Haematocrit (%) at Hour 18 Haematocrit (%) at D3 Haematocrit (%) at D4 H12 Haematocrit (%) at Study End
Haematocrit (%) at Hour 6 Haematocrit (%) at D2 Haematocrit (%) at D3 H12 Haematocrit (%) at D5
Haematocrit (%) at Hour 12 Haematocrit (%) at D2 H12 Haematocrit (%) at D4 Haematocrit (%) at D5 H12

Timepoint

Figure 1. Timeline change of haematocrit level of 43 subjects receiving fluid treatment according to study protocol.

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Vol 41 • Number 2 • April 2009 An Open Pilot Study of The Efficacy and Safety of Polygeline in Adult Subjects with DHF

Table 4. Percentage of change of haematocrite level

Percentage of Timepoints*
changes of
haemocrite level* In 6 hrs In 12 hrs In 18 hrs In 24 hrs In 36 hrs In 48 hrs
n (%) n (%) n (%) n (%) N (%) n (%)
< 10% 37 (86) 30 (69.8) 38 (88.4) 37 (88.1) 24 (57.1) 28 (73.7)
> 10% 6 (14) 13 (40.2) 5 (11.6) 5 (11.9) 18 (42.9) 10 (22.3)

n= 43 43 43 42 42 38
* Value compared to baseline

Table 5. Mean of total iv fluid required during treatment used to replace the plasma leakage from intravascular
Type of fluid required Mean (SD) (ml/day) compartment. The amount of fluid given is based on body
Haemaccel 769.77 (207.63)
weight and is aimed at replacing the volume deficit from
plasma loss and fulfil daily fluid requirement. In normal
Ringer's lactate solution 772.09 (208.54)
adults (approximate body weight 50-60 kg), crystalloids
are usually given as much as 3000-5000 ml/24 hours. In
Table 6. Length of hospitalization
this study protocol, polygeline colloid was given as single
fluid in first 6 hours and its efficacy in overcoming
Length of hospitalization* n (%)
haemoconcentration was monitored. After 6 hours, the
< 7 days 4 (9.3)
combination of colloids and crystalloids was given as fluid
7 days 10 (23.3)
8 days 13 (30.2)
replacement therapy until 5 days of treatment.
9 days 12 (27.9) Some parameters are used to monitor
> 9 days 4 (9.3) haemoconcentration, including the serial haematocrite
* days counted from first onset of fever level changes, hemodynamic stabilization and total fluid
requirement and length of hospitalization. Serial
haematocrite level has been used as the clinical
(needed diuretics treatment) during observation. Based parameter of haemoconcentration degree and as tool for
on electrocardiography examination at end of the study, monitoring fluid treatment. The decrease of haematocrite
there were 5 subjects (10%) who experienced sinus level after fluid treatment reflects the dilution effect of
bradycardia and 2 subjects (4%) experiencing sinus plasma concentration. 7-9
tachycardia. All these subjects were asymptomatic and In our study, the decrease of haematocrite levels
stable, and didn’t need any special treatment. Some after fluid treatment occured in the first 6 hours of
laboratory changes observed during this study included polygeline treatment. Haemodilution was also noted
the increase of AST and D-dimer. D-dimer was until 48 hours and persisted in 5 days of fluid treatment.
significantly increased, but there were no clinical All subjects showed stable haemodynamic condition. No
symptoms observed. shock events occured. These results support the
efficacy of polygeline as alternative replacement fluid in
DISCUSSION DHF. Compared with crystalloids, polygeline colloid
According to the WHO treatment guideline, retains relatively longer intravascular, is excreted easily
crystalloids have been used as standard fluid in treating in the kidney, and has less effect on haemostatic
DHF. This is a pilot study that observes the efficacy and disturbance; makes it suitable as an alternative choice
safety of polygeline colloids (Haemaccel®) in to crystalloids.13-15 Other potential benefit of colloids, i.e.
overcoming haemoconcentration in adults with stage I- less fluid accumulation in third space (such as edema,
II of DHF. This study was designed as open non pleural effusion or ascites), should be proven in larger
comparative study, as there were no previous study that comparative study.
can be used as preliminary data about efficacy of this The amount of fluid replacement required by each
colloid in adults with DHF. subject in this study was less than total crystalloids amount
Based on WHO treatment guideline, crystalloids recommended in WHO guideline: approximately 3000 to
(Ringer’s lactate, Ringer’s acetate or normal saline) are 5000 ml fluid per day.2,5,6 Mean total polygeline and

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Herdiman T. Pohan Acta Med Indones-Indones J Intern Med

Table 7. Laboratory examinations (baseline and end

of study)
Baseline End of study
Laboratory examinations
(n=44) (n=44)
SGOT/AST* (U/L)
Mean (SD) 105.3 (55.46) 98.8 (122.41)
Male with SGOT > 165 – n (%) 7 (15.9%) 2 (4.5%)
Female with SGOT > 135 – n (%) 4 (9%) -
SGPT/ALT** (U/L)
Mean (SD) 64.4 (39.04) 93.6 (115.29)
Male with SGPT > 250 – n (%) - 2 (4.5%)
Female with SGPT > 170 – n (%) - -
apTT*** (second)
Mean (SD) 40.8 (6.67) 32.1 (4.60)#
APTT > 39.5 second – n (%) 27 (61.4%) 3 (6.8%)
PT**** (second)
Mean (SD) 13.5 (1.79) 13.3 (1.67)
PT > 14.4 second – n (%) 5 (11.4%) 5 (11.4%)
D-Dimer (mg/dL)
Median 0.200 0.300#
D-Dimer > 0.3 mg/L – n (%) 11 (25%) 26 (59%)
BUN***** (mg/dL)
Mean (SD) 9.3 (2.63) 8.3 (3.26)
BUN > 20 mg/L – n (%) - -
Creatinine (mg/dL)
Median 0.8 0.8
Male with Cr > 1.2 – n (%) 1 (2.3%) -
Female with Cr > 0.9 – n (%) - -
*SGPT, serum glutamic-piruvic transferase; **SGOT, serum
glutamic-oxaloacetic transferase; ***aPTT, activated partial
thromboplastin time; ****PT, prothrombin time; ***** BUN, blood
urea nitrogen; # Paired Student t test p<0.05

Ringer’s lactate perfomed in the study was 769.77+207.63
and 772.09+208.54 ml/day, respectively. Length of
hospitalization was also no longer than our previous
experience; the platelet count usually increases after 7
days of disease counted from first course of fever.
Elevation of ALT and AST levels compared to
baseline level were noted at the end of the study. At the
end of the study, two (4.5%) male subjects had an
elevation of AST level by 5 times upper limit of normal
(ULN). Elevation of ALT and AST levels have been
reported as associated with the injury of liver cell caused
by the progression of dengue viral infection, rather than
with adverse drug reaction of the given colloid. Safety
of usage of polygeline colloid to kidney was also
monitored by measurement of blood urea nitrogen and
plasma creatinine. Both parameters were within normal
ranges both at baseline and at the end of the study.
Coagulation factors such as aPTT and PT were
declined at the end of study but not clinically significant
and still within normal ranges. D-Dimer level was
increased beyond ULN, but regarded not clinically
significant. Increasing of D-Dimer might have also
occurred as part of disease course of DHF.16 There was
no sign of deep vein thrombosis (DVT), disseminated
intravascular coagulation (DIC) and other significant
pathological signs observed, related to the D-dimer
elevation at the end of the study.
Serious adverse event, such as shock or volume
overload was not found during the study. There were
about 10% of the subjects experienced bradycardia and
4% of the subjects experiencing tachycardia. Even
though polygeline colloid has also been reported to be
associated with some events of bradycardia, bradycardia
has also been reported to occur in DHF because of edema
and SA node dysfunction.17 Despite the occurrance of
bradycardia in some subjects, all subjects were in stable
haemodynamic condition and completed the study
protocol.

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Vol 41 • Number 2 • April 2009 An Open Pilot Study of The Efficacy and Safety of Polygeline in Adult Subjects with DHF
CONCLUSION
This pilot study showed that polygeline colloid is a
safe initial fluid treatment and can be used for
maintaining fluid adequacy in adults with stage I-II of
DHF. Further larger comparative studies are needed to
prove its efficacy and safety in DHF treatment.
ACKNOWLEDGEMENT
Many thanks to PT Dexa Medica, which supported
this study. We appreciate Prof. Arini Setiawati, PhD,
Samuel Halim, MD, Steven David Panggabean, MD, and
Wagner Tulus, MD for their assistance in our study.
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