P E D I AT R I C S

V O L U M E 7 5 . No. 1 . F E B R U A R Y 2 0 2 3

PUBBLICAZIONE PERIODICA BIMESTRALE - POSTE ITALIANE S.P.A. - SPED. IN A. P. D.L. 353/2003 (CONV. IN L. 27/02/2004 N° 46) ART. 1, COMMA 1, DCB/CN - ISSN 2724-5276 TAXE PERÇUE
© 2022 EDIZIONI MINERVA MEDICA Minerva Pediatrics 2023 February;75(1):49-61
Online version at https://www.minervamedica.it DOI: 10.23736/S2724-5276.22.06935-X

REVIEW

Fluid management in children

with severe dengue: a narrative review
Mervin V. LOI 1 *, Qi Y. WANG 2, Jan H. LEE 1, 3

1Children’s Intensive Care Unit, KK Women’s and Children’s Hospital, Singapore, Singapore; 2Pediatric Intensive
Care Unit, Department of Pediatrics, University of Malaya, Kuala Lumpur, Malaysia; 3Duke-NUS Medical School,
Singapore, Singapore
*Corresponding author: Mervin Loi, Children’s Intensive Care Unit, KK Women’s and Children’s Hospital, 100 Bukit Timah Road,
229899 Singapore, Singapore. E-mail: mervin.loi.v.t@singhealth.com.sg

A B STRACT
Dengue is a mosquito-borne arboviral infection of increasing public health importance. Globally, children account for a
significant proportion of infections. No pathogen-specific treatment currently exists, and the current approach to reducing
disease burden is focused on preventative strategies such as vector control, epidemiological interventions, and vaccina-
tion in selected populations. Once infected, the mainstay of treatment is supportive, of which appropriate fluid manage-
ment is a cornerstone. The timely provision of fluid boluses has historically been central to the management of septic
shock. However, in patients with dengue shock, particular emphasis is placed on judicious fluid administration. Certain
colloids such as hydroxyethyl starches and dextran, despite no longer being used routinely in intensive care units due
to concerns of acute kidney injury and impairment of coagulation, are still commonly used in dengue shock syndrome.
Current guidelines recommend initial crystalloid therapy, with consideration of colloids for severe or recalcitrant shock
in patients with dengue. In this review, we discuss the pathophysiology of septic shock, and consider whether any differ-
ences in dengue exist that may warrant a separate approach to fluid therapy. We critically review the available evidence
for fluid management in dengue, including the role of colloids. In dengue, there is increasing recognition of the impor-
tance of tailoring fluid therapy to phases of disease, with attention to the need for fluid “deresuscitation” once the critical
phase of vascular leak passes.
(Cite this article as: Loi MV, Wang QY, Lee JH. Fluid management in children with severe dengue: a narrative review. Mi-
nerva Pediatr 2023;75:49-61. DOI: 10.23736/S2724-5276.22.06935-X)
Key words: Severe dengue; Shock, septic; Physiopathology; Endothelium.

D engue is emerging as a disease of increasing

public health importance. Disease models
estimated 96 million clinically apparent infec-
tions globally in 2010, with a further 294 mil-
lion infections that were not picked up by clini-
cal surveillance systems.1 One study found evi-
dence of dengue infection in 128 countries, with
a preponderance for Asia and the Americas2 and
likely under-reporting in Africa.2 The disease has
a predilection for the young, with 95% of infec-
tions involving children under 15 years of age.3
Infants and young children also seem to be more
prone to severe illness.4 Designated a “Neglected
Tropical Disease” by the World Health Organiza-
tion (WHO), there has been recent fresh impetus
to control infection rates and transmission as part
of the sustainable development goals.5
The dengue virus (DENV) is a member of the
Flaviviridae family, genus Flavivirus. Dengue
viruses are single-stranded, positive sense ribo-
nucleic acid (RNA) viruses, with the genome
encoding capsid (C), membrane (M) and enve-
lope (E) structural glycoproteins, as well as non-
structural proteins (NS) designated NS1, NS2A,
NS2B, NS3, NS4A, NS4B and NS5.6 The E gly-
coproteins are involved in receptor binding and
activation of the host immune response, includ-
ing that of neutralising antibodies.6 The four main

Vol. 75 - No. 1 Minerva Pediatrics 49

LOI FLUIDS IN SEVERE PEDIATRIC DENGUE
dengue serotypes, DENV-1, DENV-2, DENV-3
and DENV-4, share around 65% of their genome
and result in very similar clinical phenotypes.7
All 4 serotypes are prevalent in the geographi-
cal regions where dengue is endemic, namely the
Americas, Asia and Africa.8 The primary human
vector, the female Aedes aegypti mosquito, is
urban-adapted and contributes to endemicity and
outbreaks in dense, crowded populations.9
Current strategies for managing dengue are
centered on reducing disease burden through
preventative measures such as vector-control,
epidemiological measures and vaccination.10
Once a patient is infected however, treatment
options are limited. Trials evaluating disease-
specific treatment modalities including immu-
nomodulation11, 12 and antiviral therapies13, 14
have not demonstrated clinical efficacy. Clinical
management is therefore focused on support-
ive therapy,15 of which appropriate fluid resus-
citation is key. Robust evidence to inform fluid
management strategies for dengue in children are
lacking, with considerable variation in practice
and recommendations. In particular, some rec-
ommendations emphasise the importance of ju-
dicious fluid therapy, with concerns that dengue
patients may respond to fluid overload more ad-
versely than for other causes of sepsis.16-18 In this
narrative review, we aim to describe and critical-
ly evaluate the available evidence for fluid man-
agement in children with dengue, and consider
whether the approach should be similar to that
for sepsis caused by other pathogens.
We performed Boolean searches on PubMed
and the Cochrane databse of systematic reviews
using the following MeSH headings: “dengue;”
“dengue shock syndrome;” “dengue fever;”
“dengue hemorrhagic fever;” “dengue” ; “fluid
management;” and “pathogenesis”. We did not
limit our search by publication type, and we
hand-searched the bibliography lists of review
papers on dengue for further articles of relevance.
Clinical features of dengue
The majority of children with primary dengue
infections are either asymptomatic, or experi-
ence mild febrile illness. Other differential di-
agnoses need to be considered, including Japa-
50 Minerva Pediatrics February 2023
nese encephalitis, yellow fever, malaria, lepto-
spirosis, typhoid, enteroviruses and measles.9, 19
Whereas adult clinical manifestation of disease
tends towards bleeding diathesis, children tend
to experience dengue shock syndrome (DSS),
with severity being greatest in young children.20
Young children are also at greater risk of adverse
outcomes with secondary heterotypic infections,
probably due to their intrinsic predilection for
vascular fluid leak.21
The 1997 WHO guidelines for dengue classi-
fied the disease into dengue fever (DF), dengue
hemorrhagic fever (DHF) and DSS.22 However,
there were concerns about its utility internation-
ally and across different age groups, as it was
primarily based on clinical characteristics of Thai
children.23 Other criticisms of the 1997 classifi-
cation were that it required repeated clinical tests
over a period of time, thereby precluding it from
use in some resource-poor areas.24 Furthermore,
the emphasis on the presence of hemorrhage for
DHF and DSS failed to adequately account for
the fact that plasma leak leading to shock was of
more clinical importance than hemorrhage.25 The
WHO classification was subsequently updated in
2009, with disease classified based on categories
of severity: dengue with or without warning signs
(abdominal pain, persistent vomiting, volume
overload, mucosal bleeding, lethargy, hepatomeg-
aly, hemoconcentration), and severe dengue.19
Dengue with warning signs corresponded to
DHF, and severe dengue was analogous to DSS.
Following a short period of incubation lasting
3 to 7 days, symptoms begin with three distinct
phases of illness described, namely the febrile,
critical and recovery phases (Figure 1).19
Febrile phase: 3 to 7 days
The febrile phase is marked by a high fever,
which tends to be more pronounced in children
than adults. Other symptoms include headache
with or without retro-orbital pain, vomiting, se-
vere myalgia and arthralgia, as well as a macu-
lopapular to petechial rash. There may also be
hemorrhagic manifestations, such as petechiae
and bruising, particularly around venepuncture
sites. A tourniquet test for capillary fragility may
be positive. Blood tests show leucopenia, throm-
bocytopenia and elevated liver function tests.
FLUIDS IN SEVERE PEDIATRIC DENGUE LOI

Febrile phase Critical phase

Headache Hypotension

Fever Pericardial
effusion

Eye pain Pleural effusion

Mucosal Ascities
bleeding

Swollen Gastrointestinal
lymph bleeding
nodes

Skin rash Recovery phase

Seizure
Nausea
and vomiting

Behavioral
changes
Back pain

Bradycardia
Diarrhea

Muscle,
joint and
bone pain Figure 1.—Signs and symp-
toms commonly seen in den-
gue, based on the three phases
of illness.

Critical phase: 48 to 72 hours
The majority of patients recover at the end of the
febrile phase. However, some patients develop
vascular leak corresponding to the time of defer-
vescence, leading to pleural effusions and ascites.
As intravascular volume depletes, physiological
compensatory mechanisms take effect by vaso-
constriction to preferentially maintain perfusion
to vital organs, resulting in a narrowed pulse pres-
sure. The 1997 WHO criteria for DSS included a
pulse pressure <20 mmHg,22 which if accompa-
nied by clinical signs of hypoperfusion should act
as triggers for more aggressive resuscitation. For
children in particular, hypotension is a late sign of
shock and protends decompensation and deterio-
ration.26 It is therefore critical that clinicians mon-
itor children for signs of significant vascular leak
around the time of defervescence; clinical signs
include severe abdominal pain, hepatomegaly,
persistent vomiting, pleural effusions, ascites as
well as change in mentation. Laboratory investi-
gations often show a rising hematocrit, leucope-
nia, thrombocytopenia that may be profound, with
an increase in partial thromboplastin time and a
fall in fibrinogen levels. Hemorrhage risk is most
prominent during the critical phase, with bleeding
assuming particular significance in children, in
whom it is often associated with profound shock.9
Liver aminotransferases may be elevated, par-
ticularly with DENV-3 and DENV-4 serotypes,27
along with hypoproteinemia. Organ impairment
including encephalopathy, myocarditis and liver
failure are rare complications during this period.

Vol. 75 - No. 1 Minerva Pediatrics 51

LOI FLUIDS IN SEVERE PEDIATRIC DENGUE
Recovery phase
The phase of vascular leak spontaneously re-
solves after 48-72 hours, with concomitant im-
provement in symptoms. There is improvement
of appetite, gastrointestinal symptoms, pain and
cardiovascular status.19 A second rash may ap-
pear at this stage, with characteristically macu-
lopapular erythema surrounding areas of normal
skin – so-called ‘islands of white’– which may
then desquamate.9
Pathophysiology of dengue infection
DENV gains entry into humans through bites by
infected mosquitoes, where infected salivary flu-
id is injected. It then proceeds to infect dendritic
cells in the skin, before replicating in regional
lymph nodes.28
Viral presence and dissemination within the re-
ticuloendothelial system leads to activation of the
body’s innate and humoral immune responses.6
Apart from the E glycoproteins of the virus, it
has also been shown that the precursor membrane
(pre-M) and NS1 proteins are central to trigger-
ing the host antibody response.29 NS1 glycopro-
teins are produced in infected host cells, but do
not form part of the replicated viruses; rather they
are present in the circulation and on the plasma
membrane of cells.29 NS1 may have an important
role in pathogenesis of dengue, with animal stud-
ies showing that mice immunised with DENV
anti-NS1 were protected from DENV encephali-
tis.30 The ability of NS1 to trigger the complement
cascade may mediate vascular fluid leakage.31
Primary dengue infections confer lifelong im-
munity to reinfection by the same serological
subtype.9 However, dengue infections also ex-
hibit an intriguing and unusual pathophysiologi-
cal phenomenon, whereby secondary heterotypic
infections caused by viruses of a serotype that
is different from the primary infection results
in higher viral loads and more severe disease.32
Various theories have been put forward to ex-
plain this, but understanding remains incom-
plete, in part due to the dearth of adequate animal
models. Severity of secondary infection has been
observed to be more profound with certain se-
quences of infection.33, 34 The time period sepa-
52 Minerva Pediatrics February 2023
rating primary and secondary infections is also
a factor determining severity of disease, with
longer intervals being associated with more se-
vere disease.33 Secondary heterotypic infections
within 2 years of the primary infection seems to
lead to milder disease,35 whereas a study found
increased disease severity with an interval of 20
years compared to 4 years.33
One of the most widely-held theories behind
this phenomenon is that of antibody-dependent
enhancement (ADE), which has two principal
mechanisms. The first is where viral entry into
phagocytic cells that express Fc gamma receptor
IIa is enhanced by antibodies, and the second is
the augmentation of the inflammatory cascade by
immune complex formation or antibody Fc activa-
tion.36 Other viruses in which ADE has been ob-
served include respiratory syncytial virus (RSV)37
and measles.38 In dengue, sub-neutralising levels
of antibodies form immune complexes with the
virus, leading to increased entry into phagocytic
cells leading to increased viral replication.39 In-
vitro and in-vivo studies have demonstrated in-
creased viral loads in non-human primates follow-
ing prior passive transfer of heterotypic antibod-
ies.40 This phenomenon has also been observed in
human infants, where those who get primary den-
gue infections when maternal dengue-specific an-
tibodies reach sub-neutralising levels experience
more severe disease.41 Primary dengue infection is
marked by a gradual increase in Immunoglobulin
(Ig) M, peaking at approximately 2 weeks follow-
ing the onset of fever, with IgG being detectable
after one week of illness.19 In secondary dengue
infection, high levels of IgG that cross-react with
various flaviviruses are produced during the acute
phase, and continue to increase over 2 weeks.42
This was demonstrated in a study of eight Thai
children with DSS, who all had secondary-type
antibody responses that were most profound to the
initial infecting virus type, a phenomenon termed
“original antigenic sin.”43
Differences in the pathogenesis
of septic shock and severe dengue
As previously elucidated, in dengue, the time of
defervescence often marks the time of entry into
the critical phase. At this phase, patients develop
FLUIDS IN SEVERE PEDIATRIC DENGUE LOI

vascular leak, leading to hypovolemia and fluid
shifts into the extravascular space (e.g., pleural,
peritoneal and pericardial compartments). Ex-
haustion of compensatory mechanisms in hy-
povolemia would then lead to shock, a state of
inadequate end-organ tissue perfusion resulting
in cellular damage. This phenomenon is not dis-
similar to that observed in septic shock. How-
ever, what is different in dengue shock is the
pathogenesis of endothelial dysfunction within
the microcirculation, which has recently been
described in greater detail (Figure 2).44
Recent human physiological studies into mech-
anisms in vascular leak has shifted attention away
from the oncotic pressure of the interstitium, to
the endothelial glycocalyx layer.45 The integ-
rity of the endothelial glycocalyx layer has been
shown to be critical in preventing albumin efflux
to the tissue spaces, which may rise by more than
300% in septic shock.46 In sepsis, the dysregu-
lated host response leads to direct endothelial
injury with disruption of tight inter-endothelial
junctions through the actions of endotoxins and
myocardial depressant factors.44 Endothelial acti-
vation leads to neutrophil adherence to intercellu-
lar adhesion molecule-1 (ICAM-1) and vascular
adhesion molecule (VCAM), thereby triggering
the inflammatory and complement cascades.44
Microthrombi formation ensues in blood vessels
due to dysregulation of the anticoagulant path-
way, which would impede blood flow. Severe
dengue on the other hand, mediates its effects via
NS1.44 The ability of NS1 to activate heparanases
and sialidases among other enzymes, which de-
grade the glycocalyx, contributes to loss of integ-
rity of the membrane.47 In both cases, activation
of the adaptive immune system by the infective
agent via pathogen-derived molecular patterns
(PAMPs) or damage-associated molecular pattern
(DAMPs),48 would also lead to further inflamma-

Figure 2.—Differences in
Sepsis Dengue the pathogenesis of septic
shock and severe dengue.
In sepsis, bacteria and dys-
regulated host response
leads to direct endothelial in-
jury with disruption of tight
Microthrombi inter-endothelial junctions,
development due to resulting in plasma leak.
impaired anticoagulant
Plasma pathways Microthrombi formation en-
leakage sues in blood vessels due to
Activation of dysregulated anticoagulant
inflammatory pathway. In severe dengue,
mediators
NS1 activates heparanases
Glycocalyx damage and sialidases among other
enzymes, which degrade the
Activation of glycocalyx, resulting in loss
inflammatory Activation of innate of membrane integrity. In
mediators and adaptive both cases, stimulation of
immune system
the innate and adaptive im-
Dengue mune systems lead to further
inflammation and glycocalyx
Activation of innate shedding. Modified from
and adaptive McBride et al.44
immune system
Glycocalyx NS1 activates
shedding ezymes to degrade
glycocalyx

Bacterium NS1 destabilizes

inter-endothelial
junctions
Plasma leakage

Direct endothelial
cell injury

Vol. 75 - No. 1 Minerva Pediatrics 53

LOI FLUIDS IN SEVERE PEDIATRIC DENGUE
tion and glycocalyx shedding (Figure 2). Interest-
ingly, plasma leak seems to be more pronounced
in dengue, compared to sepsis,49 suggesting
perhaps a more prominent effect of NS1 on the
disruption of the microcirculation. This hypoth-
esis would require further evaluation. With more
plasma leakage, patients with dengue should the-
oretically be more responsive to fluid resuscita-
tion compared to sepsis. The potentially deleteri-
ous effects of fluid overload remains a concern
in dengue. It is not immediately obvious why pa-
tients with dengue should be any more prone to
fluid overload than patients who are unwell with
other forms of sepsis, but it does suggest the im-
portance of extremely careful clinical evaluation
of the fluid status of patients with dengue. During
the critical phase, fluid resuscitation is required
to maintain cardiac output; however, in the reab-
sorption phase, intravascular fluid overload can
potentially occur, especially in the context of re-
nal failure from prolonged shock.50 Another co-
nundrum in the pathogenesis of plasma leak in
dengue is the timing of the natural history of the
disease. The observation that fluid resorption oc-
curs almost precisely within a timeframe of 48
to 72 hours does make one ponder the exact mo-
lecular mechanism of this temporal occurrence.
Fluid management
Fluid management in septic shock
Fluid management has been a cornerstone of the
care of critically ill septic patients. An early land-
mark study in children with septic shock showed
an association with improved survival in patients
who received in excess of 40 mL/kg fluid bolus in
the first hour (8 of 9 patients survived), compared
to those who received less than 20 mL/kg (6 of
14 patients) and between 20 to 40 mL/kg (4 of
11 patients).51 Adults with severe sepsis or septic
shock enrolled in a randomized controlled trial
(RCT) showed improved in-hospital mortality
and organ dysfunction scores with management
aimed at quantitative restoration of hemodynam-
ics, so-called ‘goal-directed therapy’, of which
fluid management played a central role.52 Col-
lectively, these studies have formed the founda-
tion of approaches to fluid resuscitation in severe
sepsis. This is reflected in the recommendations
54 Minerva Pediatrics February 2023
of the latest Surviving Sepsis guidelines, which
advocate “administering up to 40-60 mL/kg in
bolus fluid (10-20 mL/kg per bolus) over the
first hour, titrated to clinical markers of cardiac
output” in clinical systems where intensive care
support is available.53 Indeed, the early reversal
of shock has been shown to be associated with
lower mortality in pediatric septic shock. A retro-
spective cohort study investigating children with
septic shock requiring critical care transport to
the Children’s Hospital of Pittsburgh, PA, USA,
found that resuscitative efforts by community
physicians consistent with the American College
of Critical Care Medicine Pediatric Advanced
Life Support (ACCM-PALS), which advocated
goal-directed resuscitation of shock using fluids
and inotropes, was associated with a lower mor-
tality (8% vs. 38%).54
In more recent times however, this approach
with an emphasis on more aggressive fluid re-
suscitation has been called into question. One of
the most high-profile studies that has led to this
re-examination has been the Fluid Expansion as
Supportive Therapy (FEAST) Trial.55 This was a
multicenter, RCT in Kenya, Tanzania and Ugan-
da which initially set out to investigate the use
of 5% albumin solution compared to 0.9% saline
solution in children with shock and life-threat-
ening infections. A total of 3141 children were
recruited before the study had to be ended early
because the control group, which were not ran-
domized to receive any fluid boluses, were found
to have the lowest 48-hour mortality of all the
groups (7.3%, vs. 10.5% and 10.6% in the saline
and albumin groups, respectively).55 This pendu-
lum shift has also been observed in adult patients
with septic shock, with 2 large trials published in
2014 (ARISE and ProCESS trials) showing no
benefit to early goal-directed therapy.56, 57 Fur-
ther investigators have highlighted the risks of
harm of fluid resuscitation in sepsis, by exacer-
bating cardiovascular dysfunction and impeding
organ function by fluid overload.58
Fluid overload has long been recognised to
be associated with adverse outcomes in criti-
cally ill patients. Endothelial permeability, and
consequent pulmonary edema are mechanisms
implicated in the development of acute respira-
tory distress syndrome (ARDS); fluid overload
FLUIDS IN SEVERE PEDIATRIC DENGUE LOI
resulting in an increase in pulmonary water may
reduce lung compliance, thereby necessitating
greater mechanical ventilatory pressures lead-
ing to further lung inflammation and impaired
surfactant production.59 In a prospective study
involving 113 patients, there was a correlation
between achieving a negative fluid balance and
improved survival in adults with ARDS.60 A fur-
ther multicenter study involving 1000 patients
showed that a conservative fluid management
strategy was associated with a shorter duration
of mechanical ventilation, although there was no
significant difference in 60-day mortality.61 Sim-
ilarly, fluid overload has been demonstrated to be
associated with poorer outcomes in children with
ARDS, postcardiac surgery,62 and those receiv-
ing continuous renal replacement therapy.63
Fluid management in severe dengue
The latest SEPSIS 3 consensus guidelines from
the Surviving Sepsis Campaign defines sepsis
as a “life-threatening organ dysfunction due to
a dysregulated host response to infection.”64
Dengue is therefore considered a cause of sep-
sis; however, fluid management approaches in
dengue have conventionally been distinct from
that of general sepsis. Traditional approaches
to fluid management in dengue has placed an
emphasis on judicious administration. Recom-
mendations from a medical facility in Thailand
with extensive experience in managing dengue
recommend “just adequate replacement of fluid
loss to achieve the optimal balance of resuscita-
tion from hypovolemia,” and state that “patients
with dengue respond differently than patients
with sepsis to fluid therapy.”16 A single-center
Sri Lankan case series similarly concluded that
large volume fluid resuscitation “is detrimental
in dengue patients with plasma leakage as sub-
sequent fluid overload increases mortality,” and
recommend early vasopressors over fluid resus-
citation.17 WHO guidelines recommend that flu-
id should be given “to maintain a just adequate
intravascular volume and circulation;”18 a 2011
update incorporating recommendations for the
South-East Asian Member States further states
that “fluid resuscitation of DSS is different from
other types of shock such as septic shock.”18
More work is required to elucidate optimal
Vol. 75 - No. 1 Minerva Pediatrics 55
fluid management strategies in dengue and sep-
tic shock. The intriguing findings of the FEAST
study have been re-evaluated, with suggestion
that the lower baseline hemoglobin concentra-
tions, lower bicarbonate and higher chloride
levels and base deficit seen in patients following
fluid bolus, may point to bolus-induced hemodi-
lution, hyperchloremic acidosis and deterioration
in respiratory and neurological function.65 While
the FEAST study did not identify dengue and
analyse outcomes for this specific subset of pa-
tients, given the significant incidence of dengue in
sub-Saharan Africa,2 and the as-yet unanswered
questions about whether coexistent malaria66 or
nutritional deficits may predispose to poorer out-
comes following fluid bolus, it is probably pru-
dent to pursue a judicious fluid replacement strat-
egy in these populations. An Indonesian retro-
spective observational study in 100 children with
dengue shock found no significant differences
in mortality, ventilator dependence or pediatric
intensive care unit stay between children who
received a restrictive versus liberal fluid resusci-
tation.67 Another prospective observational study
of 78 children with severe dengue showed that
positive fluid balance >10% was an independent
predictor of mortality.68 Perhaps, a more tailored
approach taking into account phases of shock,
namely resuscitation, optimization, stabilization
and evacuation, may help provide the appropri-
ate fluid management based on the time course
of the patient’s illness.69 Certainly dengue, with
its well-described phases where plasma leak is
most profound during a 48-72 hour period of the
critical phase,70 with resolution thereafter may
benefit from such a phased approach.
The use of advanced hemodynamic variables,
including information obtained through non-in-
vasive hemodynamic monitoring, has been rec-
ommended in general pediatric sepsis.53 Howev-
er, this has not been assessed in DSS through ad-
equately powered studies. The Indonesian study
comparing restrictive versus liberal fluid resus-
citation in children with DSS discussed above,
also reported hemodynamic parameters obtained
using an ultrasonic cardiac output monitor.67 The
investigators found no difference in preload, in-
otropy, afterload and cardiac index between the
liberal and restrictive fluid resuscitation groups.
LOI FLUIDS IN SEVERE PEDIATRIC DENGUE
However, conclusions on the utility of advanced
hemodynamic monitoring were limited by the
fact that it was a retrospective observational
study. In theory, the use of ultrasonic cardiac out-
put monitoring represents an attractive adjunct
to the standard approach using basic vital signs
and laboratory parameters. Additionally, a case
series of 3 Thai children with DSS found that a
novel computational algorithm using continu-
ous noninvasive photoplethysmographic (PPG)
waveforms may be useful in determining circula-
tory volume to guide replacement volume.71 The
ability to accurately quantify fluid deficit and
requirements in DSS would certainly be help-
ful in reducing organ impairment and morbidity
from fluid overload. Indeed, the utility of these
adjunctive hemodynamic modalities in guiding
fluid therapy need to be formally assessed in pro-
spective controlled trials. It is also important that
any additional monitoring modalities be cost-ef-
fective and easy to operate, so that it may also be
of benefit in reseource-limited settings where a
large proportion of dengue occur. Finally, in line
with the increasing recognition of the importance
of “deresuscitation” in general sepsis, consider-
ation should also be given to removing excess
Table I.—Summary of clinical trials comparing various colloids and crystalloids for fluid management in dengue
shock syndrome.
Study Population
Dung et al. (1999)95 50 Vietnamese children aged 5-15
Single-center RCT years with DSS (DHF with low
pulse pressure or unrecordable
blood pressure, with signs of
circulatory insufficiency)
Ngo et al. (2001)96 230 Vietnamese children aged 1-15 4 fluid arms: 0.9% saline, Ringer’s lactate, dextran 70,
Single-center RCT years with DSS (Clinical DHF
grade III or IV)
Wills et al. (2005)97 512 Vietnamese children aged 2-15 Study fluids: Ringer’s lactate, 6% dextran 70, 6% hydroxyethyl
Single-center RCT years with DSS (WHO criteria)
Kalayanarooj (2008)93 104 Thai patients (mean age
Single-center RCT 8.6±3.9 years) with DHF not
responsive to conventional
crystalloid solution
56 Minerva Pediatrics February 2023
fluid in DSS once the critical phase of vascular
leak has ended, including with the use of diuret-
ics or dialysis as necessary.72
Choice of fluid in general septic shock and spe-
cific considerations for severe dengue
The recognition of DSS and the need for fluid re-
plenishment has resulted in significant improve-
ment in clinical outcomes since the 1960s.73, 74
WHO guidance have remained largely unchanged
since 1975,75 and currently recommend the use
of crystalloids for initial fluid replacement in
DSS, followed by boluses of colloids in refrac-
tory shock.18 However, these recommendations
are not supported by strong clinical evidence,
and are primarily based on limited observational
data and expert opinion.76
There has been considerable interest in the
potential use of colloids for fluid resuscitation
in septic shock, given their greater effect on in-
creasing plasma oncotic pressure and theoretical
benefit in improving intravascular fluid status.77
Colloids in common use include human albumin
solution, as well as synthetic colloids based on
starch, gelatin and dextran. Smaller molecules
tend to have shorter dwell times within the circu-
Intervention; control
4 fluid arms: 2 crystalloids (0.9% saline, Ringer’s lactate) and 2
colloids (dextran 70 and Gelafundin)
20 mL/kg for 1st hour, then 10 mL/kg for subsequent hour
Gelafundin
Study fluids given in 1st hour:
DHF grade III: 20mL/kg
DHF grade IV: 40 mL/kg
starch 200/0.5
Fluid regime: 15 mL/kg in 1st hour, 10 mL/kg in 2nd hour
Moderate severity (pulse pressure >10 mmHg and ≤20 mmHg)
randomized to all fluids; severe shock (pulse pressure ≤10
mmHg) randomized to colloids only (dextran or starch)
Study fluids: 10% dextran 40, 10% Haes-steril (hydroxyethyl
starch)
Fluid regime: 10 mL/kg/hr boluses
FLUIDS IN SEVERE PEDIATRIC DENGUE LOI
lation, but exert a greater osmotic effect.78 How-
ever, there has also been cause for concern with
the use of colloids. Dextrans are naturally oc-
curring glucose polymers produced by bacteria;
there have been concerns about its theoretical ef-
fect on decreasing von Willebrand factor (vWF)
and factor VIII,79 thereby worsening coagulop-
athy. This would be particularly deleterious in
severe dengue where hemorrhage is a particular
risk in the critical phase of illness; however this
interaction has not been found to be of clinical
significance in DSS.19 Other concerns include
the increased risk of anaphylaxis with the use of
dextran.78 Hydroxyethyl starch (HES) is a poly-
disperse solution of ethoxylated amylopectin,
with a wide range of molecular weights. Its use
has been associated with rare allergic reactions,
as well as impairment of coagulation.78 Gelatins
are polydisperse solutions mainly manufactured
from bovine collagen, and have been associated
on rare occasions with allergic reactions. Gela-
tins do not cause coagulopathy apart from its he-
modilutionary effect.78
Several landmark clinical studies have been
conducted in the adult population to explore
the potential role of colloids. Two large RCTs
Outcomes and results
No difference amongst individual study fluids in duration
(P=0.36) and number of episodes of shock (P=0.46).
Dextran 70 associated with greatest relative fall in
hematocrit.
No difference in subsequent recurrence of shock or
requirement of further fluid infusion amongst individual
study fluids.
No clear difference in recovery times (time till pulse
pressure ≥30 mmHg) amongst individual study fluids due
to potential confounder (see Remarks)
Recovery times longest for Ringer’s lactate (P=0.022).
No difference in requirement for rescue colloid amongst
individual study fluids (P=0.38)
No difference between study fluids in volume of fluid
resuscitation required (P=0.138).
No difference between the 2 study fluids in hematocrit drop No allergic reaction to either fluid
after each fluid bolus (P=0.381)
Vol. 75 - No. 1 Minerva Pediatrics 57
in adults showed that hydroxylethyl starch was
associated with higher requirement for renal
replacement therapy80, 81 and increased risk of
death.81 The Colloids versus Crystalloids for the
Resuscitation of the Critically Ill (CRISTAL) tri-
al showed no difference in 90-day mortality be-
tween critically ill adults who received colloids
(gelatins, dextrans, HES or albumin) and crystal-
loids (hypertonic or isotonic saline or Ringer’s
lactate).82 Albumin was not found to be associ-
ated with mortality benefit compared to crystal-
loid in fluid replacement for adults with severe
sepsis or septic shock.83 The Saline versus Albu-
min Fluid Evaluation (SAFE) showed that albu-
min and 0.9% saline were equally effective for
fluid resuscitation in a heterogeneous population
of critically ill adults.84 A meta-analysis found no
mortality benefit of colloid use compared to crys-
talloid in a heterogeneous population of critically
ill adults, although there was an increase in risk
of renal injury with starches. Subgroup analy-
sis found that risks of mortality and renal injury
were primarily observed in critically ill patients
with sepsis.85 Consequently, crystalloids remain
the first-line fluid for the initial resuscitation of
adults with septic shock.86 Similarly for children,
Remarks
Pooled comparison showed greater increases in mean hematocrit,
systolic blood pressure, pulse pressure and cardiac index (using
doppler ultrasound) with colloids than crystalloids
No difference in side effects between study fluids, including
bleeding tendency
Potentially confounded by unequal distribution of illness severity
at baseline amongst the 4 groups by chance.
Subgroup analysis: children with pulse pressure ≤10 mmHg
significantly quicker pulse pressure recovery with colloids than
crystalloids
6 children had allergic-type reactions (5 gelatin, 1 dextran)
Colloid therapy associated with greater reduction in hematocrit
initially, but followed by rebound vascular leak with no
sustained difference in treatment response.
No difference in coagulopathy amongst 3 groups.
More allergic-type responses in patients who received dextran (15
patients), although there was possible contamination of some
batches with nonendotoxin pyrogen.
No significant associated impairment of renal function or
coagulation
LOI FLUIDS IN SEVERE PEDIATRIC DENGUE
the Surviving Sepsis Campaign has recommend-
ed the use of crystalloids in the initial resuscita-
tion of septic shock in children, with a preference
for balanced/buffered solutions where avail-
able.53 The committee recommended against the
use of starches on the basis of adult data showing
an increased risk of acute kidney injury (AKI),
coagulopathy and mortality with HES,80, 81, 87 as
there were no pediatric studies available.
In dengue shock however, the prominent role of
capillary leak in its pathophysiology makes col-
loids a particularly attractive option due to their
oncotic effect on improving intravascular fluid
status.73, 77, 88 This may allow effective hemody-
namic resuscitation with lower volumes of fluid,
thereby reducing the risk of complications from
fluid overload.89 In addition, there is evidence that
certain colloids such as fresh frozen plasma (FFP)
and albumin, may interact with the dysfunctional
glycocalyx layers to restore barrier function and
restrict ultrafiltration.90 Studies in burns patients,
who also exhibit capillary leak, showed possible
benefit in the use of albumin solutions in reducing
replacement fluid volumes, the so-called ‘fluid
creep’91. There is however the alternate argument
that colloid molecules may themselves leak out
of the intravascular compartment, and exert an
osmotic effect in the interstitium thereby wors-
ening tissue oedema.92 In practice some centers,
particularly those in limited-resource areas, use
synthetic colloids in their management of DSS
(commonly hydroxyethyl starch and dextran so-
lutions) due to the high cost of albumin.93, 94
Several RCTs have been carried out to inves-
tigate the effects of colloids and crystalloids for
fluid resuscitation in DSS.93, 95-97 Taken together
(Table I), these clinical trials point to better hemo-
dynamic effects of colloids compared to crystal-
loids, although these benefits do not translate into
sustained improved clinical outcomes. Dextran
was shown to be associated with an increase in
allergic-type reactions in one of the studies, but
synthetic colloids on the whole seem to be safe to
use in children with DSS. There might be more
benefit for colloid use in children at the severe end
of the DSS spectrum, although the available stud-
ies were unable to definitively demonstrate this.
Other novel fluids have also been evaluated
in DSS. An Indonesian prospective single-blind
58 Minerva Pediatrics February 2023
clinical trial randomized 50 children with DSS
to fluid resuscitation either with Ringer’s lactate,
or a smaller volume of hypertonic sodium lactate
(HSL) solution. The results showed no signifi-
cant difference in plasma expansion, hemody-
namic recovery and in-hospital survival despite
the HSL group receiving a smaller volume of flu-
id.98 HSL use was also associated with a signifi-
cant decrease in soluble vascular cell adhesion
molecule-1 (sVCAM-1, a marker of endothelial
cell inflammation. The use of HSL shows prom-
ise for DSS, but needs to be further evaluated in
an adequately powered clinical trial. However,
there have not been any controlled trials evaluat-
ing the use of albumin in DSS.99
In summary, whereas colloids have fallen out
of favour in the general adult intensive care popu-
lation, they may still have a role in fluid resuscita-
tion for DSS. Part of the reason why clinical tri-
als have shown different outcomes for colloids in
DSS, may be due to the fact that the main trials of
fluids for general septic shock tend to have been
conducted principally in Western, well-resourced
settings where DSS is rarely encountered. Chil-
dren form a significant proportion of patients with
DSS, and they frequently have healthy renal func-
tion and coagulation profiles compared to the gen-
eral adult intensive care population. In addition,
capillary leak from DSS tends to resolve soon af-
ter the critical phase of dengue passes, and fluid
is required for a shorter and more defined time
period.73 Further well-designed studies need to
be carried out in children with DSS, particularly
in those with severe disease and preferably in the
settings where they are most commonly managed.
Conclusions
Current evidence supports the use of crystalloids as
first-line fluids for replenishment in most children
with severe dengue, with colloids being reserved
for the children with severe DSS, or in whom ini-
tial fluid resuscitation with crystalloids remains
suboptimally effective. Perils exist in the event of
both under- and over-resuscitation. Colloids have a
superior profile in improving hemodynamics com-
pared to crystalloids, but this effect is transient and
its impact on clinically relevant outcomes have yet
to be demonstrated. There are potential adverse
FLUIDS IN SEVERE PEDIATRIC DENGUE LOI
effects with colloids, including allergic reactions
and coagulopathy. There is no single colloid that
is clearly superior amongst those that are com-
mercially available. A phased approach to fluid
resuscitation and “deresuscitation” is important to
reduce the risk of fluid overload. Large scale trials
in locations where dengue is most prevalent, par-
ticularly resource-poor settings, are urgently need-
ed to provide evidence to guide decisions regard-
ing choice and volume of fluid in DSS patients.
Further research into mechanisms of vascular leak
could potentially uncover novel interventions for
stabilising the dysfunctional glycocalyx.
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Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material
discussed in the manuscript.
Authors’ contributions.—All authors read and approved the final version of the manuscript.
History.—Article first published online: October 25, 2022. - Manuscript accepted: October 11, 2022. - Manuscript received: April
26, 2022.
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