Paediatrica Indonesiana

VOLUME 53 November ‡ NUMBER 6

Original Article

Comparison of gelatin and HES 130/0.4 solution

for fluid resuscitation in children
with dengue shock syndrome
Merry Mawardi, Tony Rampengan, Jeanette Manoppo, Novie Homenta Rampengan

D
Abstract HQJXHVKRFNV\QGURPH'66LVDVHYHUH
Background 'HQJXH VKRFN V\QGURPH '66 LV FKDUDFWHUL]HG manifestation of dengue hemorrhagic
by severe vascular leakage and hemostasis disorder, which causes IHYHU'+)$FFRUGLQJWR:RUOG+HDOWK
GHDWKLQRIFDVHV:RUOG+HDOWK2UJDQL]DWLRQPDQDJHPHQW
guidelines for fluid resuscitation in DSS remain empirical, rather
than evidence-based.
Objective To assess the efficacy of gelatin compared to
2UJDQL]DWLRQ:+2UHFRPPHQGDWLRQV
fluid resuscitation in DSS should be with crystalloids,
followed by colloids. The advantage of blood plasma
hydroxyethyl starch (+(6VROXWLRQIRUIOXLGUHVXVFLWDWLRQ
in children with DSS.
Methods We performed a multi-centered, randomized study to
FRPSDUH JHODWLQ DQG +(6  VROXWLRQ IRU UHVXVFLWDWLRQ RI
FKLOGUHQZLWK'66:HUDQGRPO\DVVLJQHGFKLOGUHQZLWK'66
WRUHFHLYHJHODWLQIOXLGDQGFKLOGUHQWRUHFHLYH+(6
Statistical analyses were performed using Chi-square and Mann-
Whitney tests.
Results More rapid increase in pulse pressure was noted in
VXEMHFWV WUHDWHG ZLWK +(6  FRPSDUHG WR WKRVH WUHDWHG
ZLWKJHODWLQDWKRXUVDQGKRXUVRIWKHUDS\3 DQG
is the similarity of its composition with intravascular
body fluid. However, the disadvantages of blood
plasma are disease transmission, allergic reactions,
and the need for the Indonesian Red Cross to provide
it.4 Therefore, replacement fluids must be considered,
such as synthetic colloids.
Synthetic colloid fluid has the desired effect of
fluid resuscitation in children with DSS. Colloids may
replace lost fluid and have oncotic effect, because they
3 7KHGHFUHDVHLQKHPDWRFULWLQVXEMHFWVWUHDWHGZLWK have greater molecular weight than crystalloids. As
+(6ZDVIDVWHUWKDQWKDWRIJHODWLQDWKRXUVRIWKHUDS\ such, colloids may sustain longer intravascular fluid
3 2QHSDWLHQWGLHGGXHWRDQXQXVXDOPDQLIHVWDWLRQRI volume during the period of plasma leakage. Addition-
'665HVSLUDWRU\UDWHGHFUHDVHGIDVWHULQVXEMHFWVWUHDWHGZLWK ally, synthetic colloids are easily obtained at a lower
+(6WKDQWKRVHWUHDWHGZLWKJHODWLQDWKRXUVDQG
KRXUVRIWKHUDS\3%RG\WHPSHUDWXUHUHPDLQHGKLJKHU
price, do not require donors and the supply process
LQVXEMHFWVWUHDWHGZLWKJHODWLQWKDQ+(6DWKRXUVDQG in particular, and do not transmit any disease. How-
KRXUVRIWKHUDS\3+RZHYHUWKHGHFUHDVHLQSODWHOHW
FRXQWVLQVXEMHFWVWUHDWHGZLWK+(6ZDVPRUHWKDQWKDW
RIJHODWLQ3 
Conclusion +(6VROXWLRQPD\EHEHWWHUIRUYROXPHUH-
placement compared to gelatin and is safe for fluid resuscitation
in children with DSS. [Paediatr Indones. 2013;53:328-33.].
Keywords: dengue shock syndrome, resuscitation,
gelatin, HES 130/0.4
328‡Paediatr Indones, Vol. 53, No. 6, November 2013
From the Department of Child Health, Sam Ratulangi University Medical
School, Manado, Indonesia.
Reprint requests to: Merry Mawardi, Department of Child Health, Sam
Ratulangi University Medical School, Prof. Dr. R. D. Kandou Hospital,
-O 5D\D 7DQDZDQJNR 0DQDGR ,QGRQHVLD 7HO  )D[
(PDLONHDQHN\ULH#\DKRRFRLd.
 Merry Mawardi et al: *HODWLQYV+(6VROXWLRQLQGHQJXHVKRFNV\QGURPH

ever, colloidal liquids may cause some adverse effects, procedure was repeated once more if the patient was
such as anaphylactic reactions, coagulation disorders, VWLOOLQVKRFN$IWHUSXOVHSUHVVXUHZDV•PP+J
kidney and liver disorders, and accumulation of fluid we performed repeat physical examination (blood
in the tissues.3-5 pressure, pulse pressure, pulse rate, respiratory rate,
Gelatin and HES solutions are frequently used DQGERG\WHPSHUDWXUHDQGODERUDWRU\H[DPLQDWLRQV
for fluid resuscitation in hypovolemic shock. Recent
studies compared dextran and gelatin, as well as HES
DQGGH[WUDQ*RRGHIIHFWVZHUHREVHUYHGLQ
terms of intravascular volume, shorter duration to
overcome shock, and reduced mortality. In Indone-
VLDDVWXG\IRXQGWKDW+(6ZDVHIIHFWLYHDQG
safe. To date, no study has determined the superior
colloid for resuscitation of DSS patients, and no study
KDVFRPSDUHGJHODWLQWR+(6IRUUHVXVFLWDWLRQ
We aimed to compare the effectiveness of gelatin to
+(6VROXWLRQLQ'66
KHPDWRFULW EHIRUH VWDUWLQJ WKH FROORLG VROXWLRQ
7KHQHDFKVXEMHFWZDVJLYHQP/NJ%:KRXURI
JHODWLQRU+(6VROXWLRQIRUDKRXUSHULRG
IROORZHGE\5$VROXWLRQRIP/NJ%:KRXUXQWLO
WKHVXEMHFWZDVVWDEOHIRUDPD[LPXPRIKRXUV
Blood pressure, pulse pressure, pulse rate, respiratory
rate, body temperature, and diuresis were monitored
HYHU\ KRXU IRU D PLQLPXP RI  KRXUV XQWLO WKH
general condition was stable. Capillary hematocrit was
measured every four hours after study entry or in the
event of cardiovascular deterioration. Platelet counts
ZHUHPHDVXUHGHYHU\WRKRXUV
Fluid overload manifestations (palpebral edema,
Methods DVFLWHVRUURQFKLLQERWKOXQJVZHUHDOVRPRQLWRUHG
,IWKHSDWLHQWZDVVWDEOHV\VWROLFEORRGSUHVVXUH•
We conducted a multi-centered, randomized study, to PP+JSXOVHSUHVVXUH•PP+JGLXUHVLV•P/
FRPSDUHJHODWLQZLWK+(6VROXWLRQIRUIOXLG NJ %:KRXU DQG KHPDWRFULW ”  IRU DW OHDVW 
resuscitation in children with DSS, in the pediatric KRXUV 5$ VROXWLRQ ZDV GHFUHDVHG WR  P/NJ %:
LQWHQVLYHFDUHXQLW3,&8IURP'HFHPEHUWR KRXUKRXUVPLQLPXPWKHQWRP/NJ%:KRXU
$SULODWWKH5'.DQGRX+RVSLWDO3DQFDUDQ KRXUVPLQLPXPWKHQWRP/NJ%:KRXUKRXUV
Kasih Hospital, and Robert Wolter Monginsidi PLQLPXPDQGWKHQGHFUHDVHGWRGULSVPLQXWH:KHQ
Hospital in Manado. Inclusion criteria were all patients VXEMHFWVEHFDPHXQVWDEOHJHODWLQRU+(6DW
GLDJQRVHGDV'66EDVHGRQ:+2FULWHULDand P/NJ%:KRXUWRWDOPD[LPXPP/NJ%:ZDV
ZLWKSRVLWLYH16RUDQWLGHQJXHLPPXQRJOREXOLQ,J
0DQGRU,J*6XEMHFWV·SDUHQWVSURYLGHGLQIRUPHG
consent. Patients who had a history of hypersensitivity
WRJHODWLQRU+(6VROXWLRQRUZKRKDGEHHQ
JLYHQ IOXLG UHVXVFLWDWLRQ ZLWK FU\VWDOORLGV DQGRU
colloids before hospital admission were excluded. The
study protocol was approved by the Ethics Committee
of the hospitals.
The patients were randomly assigned to receive
HLWKHUJHODWLQRU+(6VROXWLRQ$WWKHEH-
DGPLQLVWHUHG6XEMHFWVZKRKDGUHSHDWVKRFNV\PSWRPV
ZHUHJLYHQ5$DWP/NJ%:,RQRWURSLFGUXJVEORRG
transfusions, diuretics, and other therapy could also be
given depending on the clinical condition.
All data was processed and analyzed with SPSS
YHUVLRQ  IRU :LQGRZV 7R FRPSDUH WKH JHQHUDO
examination findings (systolic and diastolic blood
pressures, pulse pressure, pulse rate, respiratory rate,
body temperature, hematocrit, diuresis, platelet count,
WRWDO IOXLG YROXPH DQG VXEMHFWV· OHQJWK RI KRVSLWDO
JLQQLQJRIVWXG\ZHUHFRUGHGVXEMHFWV·GHPRJUDSKLF VWD\LQWKHJHODWLQJURXSWRWKH+(6VROXWLRQ
data, history (duration of fever, bleeding manifesta- group of DSS patients, we used T-test or Mann-
WLRQVYRPLWLQJDQGDEGRPLQDOSDLQSK\VLFDOH[- Whitney test. Data normality was initially assessed
amination findings (blood pressure, pulse pressure, using the Kolmogorov-Smirnov test.
SXOVHUDWHUHVSLUDWRU\UDWHDQGERG\WHPSHUDWXUH
laboratory findings (hematocrit, platelet count, IgM
DQG,J*E\5DSLG6WULS7HVWDQGRU16 Results
7KHSDWLHQWZDVJLYHQP/NJ%:5LQJHU·V
DFHWDWH 5$ LPPHGLDWHO\ PD[LPXP  PLQXWHV During WKHVWXG\SHULRGDWRWDORIVXEMHFWVZHUH
DIWHUDUULYDOXQWLOWKHSDWLHQWZDVQRWLQVKRFN7KH recruited, and all received their designated fluid. One

Paediatr Indones, Vol. 53, No. 6, November 2013‡329

 Merry Mawardi et al: *HODWLQYV+(6VROXWLRQLQGHQJXHVKRFNV\QGURPH

VXEMHFWGURSSHGRXWEHFDXVHRIFRPSOLFDWLRQVGHQJXH ,QDGGLWLRQVXEMHFWVLQWKH+(6JURXSKDGD

encephalopathy, pulmonary edema, and massive significantly lower respiratory rate compared to that of
EOHHGLQJ2IWKHUHPDLQLQJVXEMHFWVUHFHLYHG WKHJHODWLQJURXSDWKRXUVDQGKRXUV3EXW
JHODWLQ DQG  UHFHLYHG +(6  VROXWLRQ $OO respiratory rates were not significantly different at the
VXEMHFWV UHFRYHUHG IXOO\ Baseline characteristics of RWKHUWLPHVRIHYDOXDWLRQ3•%RG\WHPSHUDWXUH
VXEMHFWVE\JURXSDUHVKRZQLQTable 1. ZDVVLJQLILFDQWO\ORZHULQWKH+(6JURXSWKDQ
The mean total fluid used by the gelatin group was LQWKHJHODWLQJURXSDWKRXUVDQGKRXUV3
P/NJ%:DQGWKDWXVHGE\WKH+(6 but not significantly different at the other times of the
JURXSZDVP/NJ%:(Table 2). Administration HYDOXDWLRQ3•
of fluids resulted in significantly improved hemodynamic Mann-Whitney test also revealed a significantly
variables, such as systolic blood pressure, diastolic more rapid decrease in hematocrit at 4 hours in
blood pressure, pulse pressure, respiratory rate, body WKH +(6  JURXS WKDQ LQ WKH JHODWLQ JURXS
temperature, and hematocrit for both groups. Mann- 3 Figure 2
Whitney test revealed a significantly higher increase in Nevertheless, there were no significant differ-
SXOVHSUHVVXUHLQWKH+(6JURXSWKDQLQWKHJH HQFHVEHWZHHQWKH+(6DQGJHODWLQVROXWLRQ
ODWLQJURXSDWKRXUVDQGKRXUVRIWKHUDS\3  groups for systolic blood pressure, diastolic blood
DQG3  (Figure 1), DQGUHPDLQHGVWDEOHXQWLO pressure, pulse rate and diuresis using Mann-Whitney
hours treatment with no significant difference afterwards. WHVWDQG7WHVW3!

Table 1. Baseline characteristics of study subjects

Characteristics Gelatin group *'5ITQWR
(n=25) (n=25)
Gender, n
Male 15 15
Female 10 10
Mean age (SD), years 6.76 (3.19) 7.72 (2.45)
Mean body weight (SD), kg 22.88 (9.87) 24.82 (8.62)
Mean length of fever before shock (SD), days 4.40 (0.86) 4.52 (0.71)
Clinical manifestations on admission, n
Abdominal pain 15 22
Vomiting 8 22
Epistaxis 2 1
Primary infection, n 5 2
Secondary infection, n 20 23
Mean platelet count (SD), x103/mm3 60,320 (24,304) 67,520 (24,634)
Mean hematocrit, % 48.00 46.00
/GCPU[UVQNKEDNQQFRTGUUWTGOO*I 90.00 100.00
/GCPFKCUVQNKEDNQQFRTGUUWTGOO*I 70.00 80.00

Table 2. Main outcomes measurements

Gelatin group *'5ITQWR P value
Outcomes
(n=25) (n=25)
/GCPVQVCNXQNWOGƀWKFO. 152.84 153.12 0.323
Mean platelet count, x103/mm3
Before treatment 60,320 67,520 0.670
After treatment 52,080 47,800 0.048
Recurrent shock, n 2 1 0.466
Allergic reactions, n 0 0
Bleeding manifestations, n 0 1 0.156
Mean length of hospital stay, days 4.52 4.48 0.405
'ZEGUUKXGƀWKF 2 0

330‡Paediatr Indones, Vol. 53, No. 6, November 2013

 Merry Mawardi et al: *HODWLQYV+(6VROXWLRQLQGHQJXHVKRFNV\QGURPH

/GCPRWNUGRTGUUWTGOO*I

Gelatin
*'5

^ŚŽĐŬ
Shock
Time of evaluation, hours

Figure 1%WTXGQHOGCPRWNUGRTGUUWTGKPVJGIGNCVKPCPF*'5
ITQWRUFWTKPIƀWKFVTGCVOGPV
Mean hematocrit, %

Gelatin
*'5

/ŶŝƚŝĂůDZ^
Initial admission
Time of evaluation, hours
Figure 2%WTXGQHOGCPJGOCVQETKVKPVJGIGNCVKPCPF*'5
ITQWRUFWTKPIƀWKFVTGCVOGPV

In the gelatin group, there were two patients who Discussion

KDGUHFXUUHQWVKRFNDWDQGKRXUVUHVSHFWLYHO\
ZKLOHLQ+(6JURXSWKHUHZDVRQHSDWLHQW The general introduction of intensive intravenous
ZKR KDG UHFXUUHQW VKRFN DW  KRXUV 3 •
(Table 2).
)RUWKHILUVWKRXUVRIWUHDWPHQWZHREVHUYHG
QR DOOHUJLF UHDFWLRQV LQ DQ\ RI RXU  VXEMHFWV
+RZHYHU H[FHVV IOXLG ZDV IRXQG LQ WZR VXEMHFWV
of the gelatin group and gastrointestinal bleeding
ZDVIRXQGRQHLQVXEMHFWLQWKH+(6JURXS
(Table 2). The mean lengths of hospital stay were
not significantly different between the two groups
(Table 2).
IOXLG WUHDWPHQW IRU '66 PRUH WKDQ  \HDUV DJR
led to a marked reduction in mortality rates in the
EHVW SHGLDWULF FHQWHUV IURP DSSUR[LPDWHO\  WR
 +RZHYHU WKHUH LV VWLOO QR FRQVHQVXV RQ ZKLFK
intravenous fluid should be used.
Colloid solutions are usually given to prevent
plasma leakage and to normalize the hemodynamics
in patients with DSS.3-5 Repeat state of shock that
occurs before six hours from the onset of the disease
has the worst prognosis.3-5 From this study, we found
Paediatr Indones, Vol. 53, No. 6, November 2013‡331
 Merry Mawardi et al: *HODWLQYV+(6VROXWLRQLQGHQJXHVKRFNV\QGURPH

more rapid increase of pulse pressure in the HES  Like all other colloids, HES-associated
JURXSFRPSDUHGWRWKDWRIWKHJHODWLQJURXS anaphylactic reactions are mild, with a frequency of
Pulse pressure variables were significantly different DSSUR[LPDWHO\+\GUR[\HWK\OVWDUFKGRHVQRW
EHWZHHQ WKH JURXSV DW  KRXUV DQG  KRXUV RI cause histamine release, as is the case of gelatin, but
WUHDWPHQW3+(6LVNQRZQWRVWD\ it may still cause anaphylactic reactions, as well as
LQ WKH LQWUDYDVFXODU VSDFH ORQJHU  KRXUV HYHQ
though the second half of this colloid as the 3-4 hours
WR DFKLHYH  YROXPH H[SDQVLRQ &RPSDUHG WR
RWKHU FROORLGDO VROXWLRQV +(6  KDV ORQJHU
O transport effects. A previous study reported
DQ LQFUHDVH LQ SXOVH SUHVVXUH DW  PLQXWHV DIWHU
DGPLQLVWUDWLRQ RI +(6  although it was
not statistically significant. In contrast, we gave HES
VROXWLRQHDUOLHULQWKHUHVXVFLWDWLRQSURFHVV
and rapid pulse pressure observations were made
LQ WKH  PLQXWHV DQG  PLQXWHV DIWHU WUHDWPHQW
6HYHUDOVWXGLHVKDYHUHSRUWHGWKDW+(6KDVD
good effect on the microcirculation during shock, by
increasing organ perfusion pressure and intravascular
volume.
Results showed a decrease in hematocrit values
for both treatment groups, particularly after 4 hours of
observation, after which the hematocrit values were
relatively stable. This observation may be due to the
effect of the second half of the colloidal fluid in the
intravascular space, that is at 3-4 hours.7 Decreased
KHPDWRFULWYDOXHVLQGLFDWHWKDW+(6LVPRUH
dextran.In our study, we found no allergic reactions
LQHLWKHUJURXSRIVXEMHFWV
In our study, we observed no bleeding in the
JHODWLQ JURXS EXW RQH SDWLHQW LQ WKH +(6 
group experienced bleeding in form of melena.
Bleeding occurs as a manifestation of DSS, not
as an effect of HES. However, HES may dilute
coagulation factors and large volumes may decrease
levels of factor VIII. Although studies have reported
increased bleeding tendency after the use of HES
DWP/NJ%:KHPRVWDVLVLVQRWXVXDOO\DIIHFWHG
Nonetheless, the use of repeated small doses may
cause coagulation disorders, hence, HES should be
limited in dose and duration. Adverse effects of HES,
especially with regards to the molecular weight and
degree of substitution, are high. HES solution has a
GDOWRQPROHFXODUZHLJKWDQGGHJUHHRI
substitution, but was reported to not cause coagulation
GLVRUGHUVDWDPD[LPXPGRVHRIP/NJ%:
Hematologic variables, namely mean platelet
counts, were not significantly different between the
JHODWLQ DQG +(6  JURXSV PP3 and
durable in the intravascular space compared to liquid
gelatin, and has the effect of hemodilution which
may increase plasma volume, lower blood viscosity
and improve microcirculation in the network so as to
prevent recurrent shock in DSS patients.7
Differences in the total fluid required between
groups is related to the oncotic pressure difference in
the two types of fluids in maintaining hemodynamics
in DSS patients. A study reported that differences in
the hemodynamic variables for four types of fluids,
GH[WUDQ JHODWLQ 5LQJHU·V ODFWDWH DQG  1D&O
PP3UHVSHFWLYHO\DWEDVHOLQH+RZHYHUDIWHU
treatment there were significant differences in mean
SODWHOHWFRXQWVEHWZHHQWKHWZRJURXSVPP3
96 PP3 LQ WKH JHODWLQ DQG +(6
JURXSVUHVSHFWLYHO\7KH+(6JURXSPD\KDYH
increased consumption of platelets compared to that
of the gelatin group, in order to overcome capillary
endothelial leakage. One cause of thrombocytopenia
on DSS due to increased platelet consumption occurs
in the closed capillary endothelial vascular leakage.5
A limitation of our study was the experimental
were directly proportional to the total amount of
fluid used.6
Allergic reactions may occur in patients who
UHFHLYHJHODWLQRU+(6VROXWLRQV+RZHYHU
gelatin more frequently causes allergic reactions
than other colloidal fluids, ranging from skin redness
and pyrexia to life-threatening anaphylaxis. Those
reactions are associated with histamine release as
a possible direct effect of gelatin on the mast cells.
However, the frequency of any type of reaction is low
332‡Paediatr Indones, Vol. 53, No. 6, November 2013
RSHQODEHOGHVLJQRSHQWULDOZLWK WUHDWPHQWGRQH
in parallel. Diagnosis of patients was made by DSS
:+2FULWHULDDQGSRVLWLYH16RUDQWLGHQJXH
,J0DQGRU,J* VHURORJ\ $OVRZH GLGQRW SHUIRUP
viral isolations to determine the dengue serotypes in
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to differ in virulence, we were not able to compare the
HIIHFWVRIWKHFROORLGVLQRXUVXEMHFWVEDVHGRQVHURW\SH
In addition, synthetic colloid fluid administration
may affect coagulation factors causing bleeding in
 Merry Mawardi et al: *HODWLQYV+(6VROXWLRQLQGHQJXHVKRFNV\QGURPH
DSS patients. We only examined the coagulation
factor if there was a bleeding manifestation. However,
Wills et al. found no evidence of colloidal adverse
side effects on the intrinsic coagulopathy or bleeding
manifestations. et al. Comparison of three fluid solutions for resuscitation in
,QFRQFOXVLRQHIILFDF\RI+(6IOXLGLV
better than liquid gelatin in the treatment of DSS
in children, especially in terms of improving towards
a normovolume intravascular state and lower
KHPDWRFULW +(6  IOXLG GR QRW FDXVH DQ\
DGYHUVHVLGHHIIHFWVLQRXUVXEMHFWVVXFKDVDOOHUJLF
reactions, bleeding, or excess fluid.
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 :+2'HQJXHKDHPRUUKDJLFIHYHUWUHDWPHQWSUHYHQWLRQ
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UHJLPHQVLQWKHILUVWKRXU&OLQ,QIHFW'LV
REVHUYDWLRQDOSRVWDXWKRUL]DWLRQVDIHW\VWXG\3$663DHGLDWU
$QDHVWK
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 0RO\QHX[(00DLWODQG.,QWUDYHQRXVIOXLGVJHWWLQJWKH
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Paediatr Indones, Vol. 53, No. 6, November 2013‡333