Dengue viral infections are caused by one of four viruses and transmitted by mosquitoes. The disease ranges in severity from asymptomatic to severe and fatal. Most cases are mild, but some develop shock and hemorrhage. Treatment is supportive and focuses on fluid management to resolve shock while preventing fluid overload. Dengue has spread globally and is a major public health problem in over 100 countries.

1. Dengue hemorrhagic fever and shock syndromes*
Suchitra Ranjit, MBBS, MD; Niranjan Kissoon, MBBS, FAAP, FCCM, FACPE
Objectives: To provide a comprehensive review of dengue, with care practitioner as well as authoritative consensus statements
an emphasis on clinical syndromes, classification, diagnosis, and from the World Health Organization and the Centers for Disease
management, and to outline relevant aspects of epidemiology, Control and Prevention. Dengue viral infections are caused by one
immunopathogenesis, and prevention strategies. Dengue, a lead- of four single-stranded ribonucleic acid viruses of the family
ing cause of childhood mortality in Asia and South America, is the Flaviviridae and are transmitted by their mosquito vector, Aedes
most rapidly spreading and important arboviral disease in the aegypti. The clinical syndromes caused by dengue viral infections
world and has a geographic distribution of >100 countries. occur along a continuum; most cases are asymptomatic and few
Data Source: Boolean searches were carried out by using present with severe forms characterized by shock. Management
PubMed from 1975 to March 2009 and the Cochrane Database of is predominantly supportive and includes methods to judiciously
Systematic Reviews from 1993 to March 2009 to identify potentially resolve shock and control bleeding while at the same time pre-
relevant articles by key search terms such as: “dengue”; “dengue venting fluid overload.
fever”; “dengue hemorrhagic fever”; “dengue shock syndrome”; Conclusions: Dengue is no longer confined to the tropics and
“severe dengue” and “immunopathogenesis,” pathogenesis,” “clas- is a global disease. Treatment is supportive. Outcomes can be
sification,” “complications,” and “management.” In addition, au- optimized by early recognition and cautious titrated fluid replace-
thoritative seminal and up-to-date reviews by experts were used. ment, especially in resource-limited environments. (Pediatr Crit
Study Selection: Original research and up-to-date reviews and Care Med 2011; 12:90 –100)
authoritative reviews consensus statements relevant to diagnosis KEY WORDS: dengue hemorrhagic fever; dengue shock syn-
and therapy were selected. drome; shock; immunopathogenesis; diagnosis; management;
Data Extraction and Synthesis: We considered the most rele- children; critical illness
vant articles that would be important and of interest to the critical
D engue viral infections affect (1, 2, 4 – 6). The disease is encountered considered only if pertinent. Only En-
all age groups and produce a virtually throughout the tropics, and the glish-language articles were included.
spectrum of clinical illness 2005 World Health Assembly resolution We considered the most relevant arti-
that ranges from asymptom- included dengue as an example of a dis- cles that would be important and of in-
atic to a mild or nonspecific viral syn- ease that may constitute a public health terest to the critical care practitioner. In
drome to a severe and occasionally fatal emergency of international concern with particular, we attempted to find meta-
disease characterized by shock and hem- implications for health security due to analyses or well-designed randomized,
orrhage (1, 2). Dengue fever (DF) is an rapid epidemic spread beyond national controlled trials to support a recommen-
old disease; the first record of a clinically borders (2). dation for intervention and treatment.
compatible disease was documented in a In this article we review the epidemi- When none was available, we cited an
Chinese medical encyclopedia in 992 (3). ology, immunopathogenesis, clinical syn- authoritative consensus statement or a
This illness has reemerged in the last 3– 4 dromes, diagnosis, management, and clinical guideline such as those from ma-
decades with an expanded geographic dis- prevention of dengue. jor medical organizations or interna-
tribution of both the viruses and the mos- tional health agencies and bodies such as
quito vectors (1, 2, 4 – 6); in 1998, dengue the World Health Organization (WHO)
was recognized as the most important Method and the Centers for Disease Control and
tropical infectious disease after malaria Prevention.
Boolean searches were carried out by
using PubMed from 1975 to March 2009
Epidemiology
*See also p. 116. and the Cochrane Database of Systematic
From the Pediatric Intensive Care Unit (SR), Apollo Reviews from 1993 to December 2009 to In the past 50 yrs, the prevalence of
Children’s Hospital, Chennai, India; Department of Pe-
diatrics (NK), BC Children’s Hospital, Vancouver, BC,
identify potentially relevant articles by DF has increased 30-fold, and significant
Canada. key search terms such as: “dengue”; “den- outbreaks have occurred in five of six
The authors have not disclosed any potential con- gue fever”; “dengue hemorrhagic fever”; WHO regions. It is now endemic in 112
flicts of interest. “dengue shock syndrome”; “dengue” and countries; Southeast Asia and the west-
For information regarding this article, E-mail:
nkissoon@cw.bc.ca
“immunopathogenesis,” pathogenesis,” ern Pacific have the most serious afflic-
Copyright © 2011 by the Society of Critical Care “classification,” “complications,” “man- tions (4, 5, 7). Case fatality rates vary
Medicine and the World Federation of Pediatric Inten- agement,” and “prevention.” We also from 1% to 5% (8) but can be 1% with
sive and Critical Care Societies searched the extensive bibliography lists appropriate treatment (2). The reasons
DOI: 10.1097/PCC.0b013e3181e911a7 of the relevant articles. Case reports were for the global resurgence of epidemics of
90 Pediatr Crit Care Med 2011 Vol. 12, No. 1

2. dengue are complex and include large- T-Cell Activation and Apoptosis. In- antibody levels decline below the neutral-
scale population migration, increased air tense T-cell activation and massive apo- ization threshold (12, 22, 23).
travel, unprecedented global population ptosis may lead to the sudden onset of Nutritional Status. Unlike other infec-
growth, and uncontrolled urbanization, vascular permeability and hemorrhage tious diseases, severe forms of dengue are
all of which facilitate transmission and that characterizes severe forms of dengue more common in well-nourished children,
increase densities of Aedes (Ae.) aegypti– disease (12). In some patients with sec- and grade 2 or 3 protein-calorie malnutri-
borne disease (5, 6, 9). Dengue has also ondary dengue infections, however, the tion protects against severe dengue vascu-
been transmitted via blood transfusion T-cell response may cause suboptimal lopathy. This negative association may be
and organ transplantation (10). killing of the DV-infected monocytes and related to suppression of cellular immunity
Dengue Viruses. There are four closely serve to augment the severity of the sec- in malnutrition (11, 24).
related but serologically distinct dengue ond infection due to higher viral loads
viruses (DVs), members of the Flavivirus (12, 16). Classification and Clinical
genus of the Flaviviridae, called DEN-1, Neutralizing Antibodies and Antibody- Course of Dengue
DEN-2, DEN-3, and DEN-4. Lifetime im- Dependent Enhancement. The severity of
munity follows infection by one serotype, secondary infection with a different DV The widely used 1997 WHO classifica-
but immunity to the other serotypes is serotype depends on the balance between tion grouped patients with symptomatic
short-lived (11, 12). neutralizing vs. enhancing heterotypic dengue infections into three categories: un-
Mosquito Vectors. Mosquitoes that be- antibodies after the first infection. This differentiated fever; DF; and DHF (1) (Fig. 1).
long to the genus Aedes play a pivotal role phenomenon has been called “antibody- However, with dengue being encoun-
in the transmission of dengue. The prin- dependent enhancement” and is one of tered in newer geographical areas, con-
cipal vector is Ae. aegypti, but Ae. albop- the best known hypotheses in the im- siderable overlap between the groups has
ictus and Ae. polynesiensis may act as munopathogenesis of severe dengue (9, been reported, and it is likely that the
vectors depending on the geographic lo- 17–19). various categories exist as a continuum
cation (6, 12). rather than separate entities (2, 9, 25–
Viral Replication and Transmission Factors that Influence Disease 27). Similarly, the classification inher-
Cycle of DV. Both epidemic and endemic Severity ently assumed that DF was a mild disease
transmission of DV are maintained and that only cases of DHF were severe;
through a human-mosquito-human cycle Most DV infections produce, in de- thus, patients even with severe and life-
in which humans are the amplifying host. creasing order of frequency, an asymp- threatening manifestations of dengue
DV is introduced into the skin by the bite tomatic infection, mild nonspecific symp- could not be included as having DHF
of an infected female Aedes mosquito. toms, or classic dengue (1, 9). The more unless all criteria were present. This had
Viremia in susceptible humans begins be- severe manifestations of shock and hem- adverse effects at various levels, including
tween 3 and 6 days after subcutaneous orrhage occur in 5% of DV infections during triage, disposition, and treatment
injection, lasts for another 3– 6 days, and (9, 11). Complex, interlinked mecha- decisions, the urgency of which was dic-
ends as the fever resolves (6, 13, 14). nisms determine whether mild or severe tated by the severity classification of den-
Dengue can essentially be excluded as the disease occurs (9). gue (25). Furthermore, the term “DHF”
cause of symptoms in a traveler who de- Primary vs. Secondary Infection. The puts undue emphasis on hemorrhage;
velops an illness 14 days after returning greatest risk factor for the development however, the hallmark of severe dengue
from a dengue-endemic country (15). of severe dengue is secondary infection (and the manifestation that should be ad-
with a different dengue serotype from the dressed early) is not hemorrhage but in-
Immunopathogenesis of DV original infecting virus (9, 11, 12). Severe creased vascular permeability, which
Infections illness during secondary dengue infec- leads to shock (12). Authors of a WHO/
tions was associated with higher peak Tropical Disease Research–supported,
The immunopathogenesis of severe plasma virus titers (20). prospective, clinical, multicenter study
DV infections is complex and remains in- Age. Dengue hemorrhagic fever (DHF) across dengue-endemic regions proposed
completely understood; however, severe is primarily a disease of infants and chil- a revised and simplified dengue case clas-
dengue is differentiated from its milder dren (1, 9), although adults may also be sification in a move to help clinicians
forms by the presence of increased vascu- afflicted with severe disease (21). Infants identify rapidly and treat adequately the
lar permeability (1, 2, 9, 12). A few salient can develop features of severe disease most severe, life-threatening forms of the
features may explain the dramatic clinical even during a primary DV infection when disease (2, 28).
manifestations. their transplacentally acquired maternal The new system divides dengue cases
into just two major categories of severity: a)
dengue (with or without warning signals);
and b) severe dengue (2, 28) (Fig. 2).
Clinical Manifestations and Phases.
Dengue is a systemic and dynamic disease
with a wide spectrum of clinical presen-
tations that range from mild to severe;
however, the clinical evolution and out-
come may be highly unpredictable.
The course of illness is characterized
Figure 1. The traditional 1997 World Health Organization classification of dengue (1). by three well-demarcated phases: febrile;
Pediatr Crit Care Med 2011 Vol. 12, No. 1 91

3. cal parameters (Fig. 2) is crucial for rec-
ognizing progression to the critical
phase. Although a tender hepatomegaly
and mild hemorrhagic manifestations
(petechiae and mucous membrane bleed-
ing from nasal or oral cavity) may be seen
often, significant bleeding episodes from
the gastrointestinal tract or menorrhagia
are uncommon occurrences in the febrile
phase. The earliest laboratory abnormal-
ity is a progressive leukopenia, which is
another clue to the presence of probable
dengue.
Figure 2. New simplified classification of dengue viral infections, World Health Organization 2009. Phase 2: The critical phase. The criti-
CNS, central nervous system. cal phase begins around the period of
defervescence, when several important
occurrences mark their presence in quick
succession. Leukopenia progresses fur-
ther, and a rapid decrease in platelet
count usually occurs. This precedes the
most specific and life-threatening mani-
festation of this phase: an increase in
capillary permeability that leads to
plasma leakage and an equivalent rise in
hematocrit (Hct).
Plasma leakage begins during the fe-
brile phase, but at a time when the viral
load and body temperature are declining,
and develops rapidly over a period of
hours. The period of plasma leakage is
short-lived, typically lasting 24 – 48 hrs.
However, the extent of plasma loss is
highly variable and is the key that deter-
mines the clinical severity in the critical
phase (i.e., whether the patient recovers
uneventfully, develops dengue with warn-
ing signs, or, in a small proportion with
extensive plasma leak, progresses to have
“severe dengue”).
Some patients with a nonsevere form
of dengue do not develop plasma leak and
steadily improve after defervescence.
Prolonged uncorrected shock, meta-
bolic acidosis, and thrombocytopenia
Figure 3. Phases of dengue in relation to symptoms and laboratory changes. AST, aspartate transam- may worsen disseminated intravascular
inase; ALT, alanine aminotransferase; CNS, central nervous system; IgM, immunoglobulin M; IgG, coagulation, which may, in turn, lead to
immunoglobulin G. Adapted with permission from World Health Organization: Dengue Hemorrhagic massive hemorrhage, thus setting off a
Fever: Diagnosis, Treatment, Prevention and Control. Third Edition. Geneva, WHO/TDR, 2009. progressive downward spiral of worse
shock and hemorrhage (1, 11, 12, 29);
these patients are at high risk of death.
critical; and recovery (2). Although most lasts 2–7 days and is acutely unwell with Apart from shock and hemorrhage,
patients recover after a self-limiting, non- headache, diffuse erythema, generalized other important consequences of in-
severe, clinical course, a small proportion myalgia, and arthralgia; anorexia, nausea, creased capillary permeability are
progress to have severe disease, which is and vomiting are also common. Younger hemoconcentration, hypoalbuminemia,
characterized by plasma leakage with or children may develop febrile seizures. It and serous fluid collections, usually pleu-
without hemorrhage (2). may be difficult to distinguish dengue ral effusions and ascites, the extent of
Clinical Phases of Dengue. After the clinically from other viral fevers, al- which depends both on the magnitude of
incubation period, the illness begins though demonstration of microvascular plasma leak and the volume of fluids con-
abruptly and is followed by the three fragility by a positive tourniquet-test re- sumed or prescribed (1, 2).
phases (Fig. 3). sult increases the likelihood that it is Early confirmation of plasma leakage
Phase 1: The febrile phase. Typically, a dengue (2). Frequent meticulous moni- in the critical phase may be provided by
patient develops a high-grade fever that toring for warning signs and other clini- serial laboratory studies with complete
92 Pediatr Crit Care Med 2011 Vol. 12, No. 1

4. blood counts demonstrating the triad of ficulties in successful treatment of severe vulsions, and extensor posturing; these
progressively increasing Hct, leukopenia, dengue stem from the dynamicity of den- neurologic signs can improve when the
and thrombocytopenia, ultrasound find- gue, which makes it a challenge to detect perfusion normalizes. Other causes of
ings of a thickened gall bladder wall, and and manage, especially for the uniniti- central nervous system symptoms in the
ascitic and pleural fluid and chest radio- ated physician— even experienced clini- patient with severe dengue are coexisting
graph showing pleural effusions (1, 2). cians may be caught unaware. It is this central nervous system infections (bacte-
These findings are useful for triage and dynamicity that may account for delays in rial, viral, or malarial), dengue encepha-
therapy because they may be present recognition of the severity of circulatory lopathy/encephalitis, electrolyte disor-
much earlier than signs of plasma loss compromise, which can be subtle: sys- ders, intracranial hemorrhage, and
are clinically manifest and also indicate tolic BP may be maintained until late, fulminant hepatic failure (38). During re-
progress to the critical phase in patients and patients even in advanced shock of- covery, cerebral edema from FO may lead
who do not defervesce despite the onset ten remain alert (1, 2). to obtundation and seizures. The precise
of plasma leakage (2, 11, 12). Evaluating As shock progresses, the diastolic BPs cause may be difficult to separate and
hemoconcentration in patients with pre- and then the systolic BPs become unre- requires a consideration of the phase of
existing anemia may be difficult, because cordable, and if they are not promptly dengue and thorough clinical examina-
the preillness Hct level may be unavail- reversed, the patient may progress to tion in conjunction with laboratory and
able at the time of admission. Using the have multiorgan failure and a compli- radiologic investigations to rule out sys-
population baseline may be useful (2), cated course. temic causes, electrolyte derangements,
such as a cutoff Hct value (36%) in Indian 2) Bleeding and hemorrhagic manifes- and specific organ insults.
children due to the high prevalence of tations in severe dengue. Common sites Cardiac dysfunction. Plasma leakage
iron-deficiency anemia (30). are from the gastrointestinal tract mani- and/or hemorrhage causing hypovolemia
Phase 3: The recovery phase. After the festing as hematemesis or melena (2, 32, and a compensatory elevated systemic
critical 24 – 48 hrs of plasma leakage, 33). However, even with severe dengue, vascular resistance are the predominant
the final recovery phase is heralded by the in which marked thrombocytopenia and mechanisms of shock in severe dengue
gradual resorption of the leaked plasma coagulation abnormalities are frequent (2, 31). Although primary myocardial in-
back into the intravascular compartment (34, 35), major life-threatening bleeds are sult in dengue is infrequent, there have
over the next 48 –72 hrs. The patient may rare: the most important risk factor for been a few reports of relative bradycardia
exhibit dramatic improvement with an significant hemorrhage is prolonged contributing to low cardiac output (31)
overall sense of well-being, improved ap- shock, especially when complicated by and acute ST-segment and T-wave
petite, a stable hemodynamic status, and acidosis and hypoxia (2, 29, 36). Other changes on electrocardiogram, together
a brisk diuresis. Pruritis and an asymp- risk factors for bleeding are the presence with low ejection fractions and global hy-
tomatic bradycardia may be marked (1, of hepatic and/or renal dysfunction (2); pokinesia on radionuclide ventriculogra-
2). The blood picture reflects the recovery drug (e.g., nonsteroidal anti-inflamma- phy (41, 42). No myocardial necrosis was
phase with a lower Hct level on account tory drug) exposure; and procedures such detected in any of the patients, which
of the reabsorbed fluid and a white cell as nasogastric tube insertion, arterial suggests that myocardial dysfunction
increment that may precede platelet re- puncture, or intramuscular injections. might either be attributable to humoral
covery. 3) Severe organ impairment. Severe factors or coronary hypoperfusion (43).
Recognition of this phase is important organ impairment is the third criteria for Both systolic and diastolic dysfunction
so that intravenous (IV) fluids may be severe dengue (37) and includes acute have been reported to cause refractory
promptly ceased. This simple interven- liver failure, encephalopathy/encephali- shock (38, 44).
tion may prevent fluid overload (FO), tis, renal failure, and myocardial dysfunc- Other complications include hemo-
which, along with severe hemorrhage, is tion. These may also contribute to mor- lytic uremic syndrome (1, 32) and coin-
an important, preventable cause of death tality and may occur even in the absence fections in endemic areas (malaria, lepto-
by dengue (Fig. 3). of severe plasma leakage or shock (2). spirosis, enteric fever) (1, 38). Although
Features of Severe Dengue. Severe Liver failure may be caused by a direct severe abdominal pain presenting as a
dengue occurs in a small proportion of viral effect with hepatitis or focal necrosis surgical emergency had been previously
patients and is defined by one or more of of the liver and is associated with a high classified as an uncommon manifestation
the following: 1) shock due to plasma mortality rate (37, 38). Elevated transam- (32), severe intense abdominal pain is
leakage, which is usually associated with inase levels have been documented to oc- now recognized as one of the most im-
fluid accumulation and consequent respi- cur as part of dengue (1) and also after portant warning signs heralding signifi-
ratory symptoms; 2) severe bleeding; and resuscitation from shock (ischemic hep- cant plasma leakage and imminent
3) severe organ impairment (liver, neu- atitis) (38). shock. Dengue has also been described as
rologic symptoms, renal or myocardial Neurologic complications. Patients an important cause of hemophagocytic
dysfunction) (Fig. 2) (2, 28). with severe dengue may present with a lymphohistiocytosis (45) and pediatric
1) Shock in severe dengue. The hypo- wide variety of neurologic manifestations multiorgan failure (46, 47).
volemic shock in dengue may initially be including encephalopathy, seizures, and
compensated with a normal systolic acute pure motor weakness (11, 32, 38, Diagnosis
blood pressure (BP), elevated diastolic 39). The DV has been isolated from the
BP, narrow pulse pressure, and features cerebrospinal fluid of some patients hav- Although the diagnosis of acute DV
of hypoperfusion, such as cold mottled ing features of encephalitis (40). In the infection is mainly clinical (1), pediatric
skin, although in some patients, signifi- critical phase, cerebral hypoperfusion caregivers frequently find making an
cant tachycardia may be absent (31). Dif- may result in altered mental status, con- early diagnosis challenging, because the
Pediatr Crit Care Med 2011 Vol. 12, No. 1 93

5. initial symptoms are often nonspecific, determine any concurrent central ner- Table 1. Laboratory findings in the critical phase
many common tropical infections can re- vous system infection may be more safely of dengue
sult in a presentation with fever and performed when the patient is stable.
Hematologic investigations
thrombocytopenia with or without shock, Empirical antimicrobials may be deesca- Elevated hematocrit level
viremia may be below detectable levels, lated once the clinical picture emerges Low platelet counts ( 100,000 cells/mm3)
and serological tests confirm dengue only with greater clarity and culture results Progressive leukopenia with atypical
late in the course of illness (2, 48). Per- are available. lymphocytes
forming a tourniquet test at each visit Laboratory Confirmation of Dengue. Abnormal coagulation profile
Biochemical investigations
may help differentiate dengue from other There are three main methods for diag- Hypoalbuminemia
viral infections. Taking note of the tem- nosing DV infections (1, 9, 12, 48): sero- Electrolyte disturbances (hyponatremia)
poral sequence of symptoms is as impor- logical tests; virological diagnosis; and Metabolic acidosis
tant as recording their presence, because molecular methods including the poly- Elevated liver enzyme levels
Imaging features
with dengue, it is at the time of deferves- merase chain reaction. The choice of test
Thickened gall bladder wall
cence that the disease manifests its sever- depends on whether the patient is in the Pleural effusions, right more frequent than
ity, unlike other viral illnesses for which initial stage, in which fever and viremia left
a clinical improvement is to be expected are present (virological and molecular di- Ascites
with a decline in body temperature (2). agnosis most appropriate), or the post-
Ramos et al (49) have attempted to iden- pyrexial period, which lasts a few weeks
tify the clinical features that predict a (serological tests appropriate) (12).
laboratory-positive dengue infection and Viral Isolation and Identification by earliest evidence of plasma leak in the
concluded that the presence of high- Using Mosquito Cell Lines. Serum inoc- critical phase of dengue as alluded to
grade fever, rash, petechiae, or mucosal ulation either into mosquito cell lines or earlier may be obtained by serial blood
bleeds in the absence of cough and other directly into mosquitoes is the most com- counts that demonstrate an increasing
respiratory symptoms has a very high mon method for virus isolation (9). Hct level, progressive leukopenia and
positive predictive value of confirmed Molecular Diagnosis. The sensitivity, thrombocytopenia, and ultrasound find-
dengue infection. specificity, and rapid detection of minute ings of a thickened gall bladder wall, as
Differential Diagnosis. In addition to quantities of dengue viral material in the well as ascitic and pleural fluid (Table 1)
bacterial septic shock, the differential di- patient’s serum makes reverse-tran- (2, 12, 55). If formal laboratory services
agnoses that must be considered in the scriptase polymerase chain reaction use- are unavailable, a microcentrifuge can be
appropriate epidemiologic settings in- ful for the detection of dengue infection used to estimate capillary Hct at the bed-
clude malaria, leptospirosis, typhoid fe- early in the disease (within 48 hrs) when side. Other tests may be dictated by the
ver, and meningococcal septic shock (1, antibodies are not detected (52). A re- clinical status and include measurements
2, 11). Confusion may also arise when a cently available test that can diagnose of glucose, electrolytes, blood gases, and
patient with suspected dengue presents dengue within the first few days of fever is lactate and tests of renal, liver, and coag-
with central nervous system symptoms. the nonstructural protein-1 monoclonal ulation function.
Although central nervous system symp- antibody in an enzyme-linked immu-
toms may result from the dengue viral nosorbent assay format that can detect Management of Patients With
infection or complications detailed previ- dengue nonstructural protein-1 antigen Dengue
ously, coinfections are not uncommon, in blood (12, 53).
and if the clinical or laboratory features Serologic Testing. Confirmation of For such a complex, dynamic, and un-
are atypical for dengue, or coexisting in- acute DV infection is most frequently ac- predictable disease, successful outcomes
fections cannot be ruled out, appropriate complished by using serology (1, 2). Se- with mortality rates of 1% can be
empirical antimicrobials (antibiotics, an- rologic tests for the diagnosis of acute DV achieved in the vast majority of patients
tiviral agents, or antimalarial agents) infection include the hemagglutination with surprisingly simple and inexpensive
should be initiated after drawing samples inhibition assay and immunoglobulin G interventions, provided they are early, ap-
for laboratory confirmation and appropri- (IgG) or IgM enzyme immunoassays (52). propriate, and continuously targeted to
ate cultures. The IgM antibody-capture enzyme-linked keep pace with the disease evolution. This
The choice of antimicrobials depends immunosorbent assay is the test most underscores the vital importance of em-
on the patient’s symptoms and signs, widely used, because it is relatively inex- powering the front-line healthcare per-
prevalent infections in the community, pensive, sensitive, and quick and simple sonnel (doctors and nurses) at primary
and their resistance patterns. Early em- to perform; however, it suffers from low and secondary health centers, clinics, and
pirical antibiotics for suspected septic sensitivity compared with the hemag- hospitals to facilitate early recognition
shock or central nervous system infec- glutination-inhibition assay (11, 32). and carefully monitor IV rehydration.
tions are important, because delays in The development of several rapid diag- Priorities during initial patient con-
initiation of appropriate antibiotics have nostic kits, which use immunochro- tact are to establish whether a patient has
been shown to worsen outcomes (50). matographic or immunoblot technolo- dengue, determine the phase of disease
Cranial imaging may be necessary in the gies, has enabled rapid bedside (febrile, critical, or recovery), and recog-
presence of a neurologic presentation. serological testing; however, the diag- nize warning signs and/or the presence of
Performing a lumbar puncture may be nostic accuracy may be low in terms of severe dengue, if present. In addition to a
hazardous in a bleeding, thrombocytope- sensitivity and specificity (9, 54). physical examination, a complete blood
nic patient in whom the hemodynamics Laboratory Studies to Monitor Dis- count in the febrile phase serves seve-
is precarious (51). A lumbar puncture to ease Progression and Complications. The ral useful functions if the patient
94 Pediatr Crit Care Med 2011 Vol. 12, No. 1

6. progresses to the critical phase: knowl- timely and appropriate. Yet, the seem- orrhage are repeated, meticulous, clinical
edge of the patient’s baseline Hct level ingly simple task of getting the pre- evaluation in conjunction with analysis of
can provide early information indicating scribed fluid “just right” is often chal- serial Hct trends by experienced caregiv-
onset of plasma leak, can quantitate the lenging, demands the highest level of ers. Sophisticated invasive monitoring is
extent of plasma loss, is a good guide to clinical judgment, and is ultimately the rarely necessary unless patients arrive
fluid replacement, and, in conjunction key that differentiates a good vs. bad out- late with established shock. The end
with other signs, can indicate occult come in sick children with dengue. In points/targets of fluid administration are
blood loss (2). resource-limited, tropical areas of the normalization of the systolic BP (if low)
Most patients with DF and DHF can be world in which dengue outbreaks are and obtaining a pulse pressure of 30
managed without hospitalization pro- most common, intensive care facilities mm Hg, a urine output of 0.5–1 mL/
vided they are alert, there are no warning for monitoring and treatment of shock kg/hr with stable vital signs, and a grad-
signs or evidence of abnormal bleeding, and respiratory failure may be unavail- ual decrease in the elevated baseline Hct
their oral intake and urine output are able (56). The goals of treatment of den- level (1, 2, 57–59). Monitoring hourly
satisfactory, and the caregiver is educated gue shock are necessarily two-pronged urine output serves two important goals:
regarding fever control and avoiding non- and include both early recognition and an output of 0.5–1.0 mL/kg/hr with stable
steroidal anti-inflammatory agents and is reversal of shock and simultaneously vital signs indicates shock reversal and
familiar with the course of illness. A den- avoiding FO and the consequent need for ensures a minimal acceptable circulating
gue information/home care card that em- ventilation by using simple monitoring volume, whereas an output of 1.5–2
phasizes danger/warning signs is impor- tools (57–59). These goals may be facili- mL/kg/hr may be the earliest indicator of
tant (2). These patients need daily clinical tated by aiming to restore a minimally overhydration/FO with the potential risk
and/or laboratory assessment by trained acceptable circulating volume that is ad- of respiratory insufficiency (59) (Table 3).
doctors or nurses until the danger period equate to establish perfusion to vital or- Similarly, assessing two Hct values at
has passed. For a more detailed guide to gans and avoid hemorrhage and multior- 4-hr intervals in conjunction with the
outpatient assessment and monitoring, gan failure (2, 57–59). In addition, serial circulatory status will provide valuable
the reader may refer to the 2009 WHO/ monitoring and correction of coexisting clues. A high or increasing Hct level in-
Tropical Disease Research document on hypoglycemia, hypocalcemia, and elec- dicates the need for increased volumes of
Dengue (2). trolyte abnormalities are important. crystalloids if the patient has unstable
If dengue is suspected or confirmed, Titrating fluid therapy in dengue. hemodynamics, whereas in a stable pa-
disease notification to public health au- Fluid therapy in a patient with dengue tient, an experienced clinician may elect
thorities is important so that preventive shock has two parts: initial, rapid fluid to monitor the patient closely without
measures may be set into motion. boluses to reverse shock followed by ti- increasing fluid rates. Likewise, a low or
Indications for hospitalization and IV trated fluid volumes to match ongoing “normal” Hct level in conjunction with
fluids include “warning signs” (Fig. 2) of losses (2). However, for a patient who has shock may be an important indicator of
significant plasma leak, of which severe, warning signs of plasma leakage but is occult hemorrhage and the need for ur-
intense abdominal pain is considered the not yet in shock, the initial fluid boluses gent blood transfusion, whereas in a sta-
most important; other warning signs are may not be necessary (Table 2). ble patient in the recovering phase,
persistent vomiting, restlessness or leth- The best methods for titrating fluid prompt cessation of IV fluids is the most
argy, clinical fluid accumulation, muco- therapy and detecting early signs of hem- important action indicated (2).
sal or other significant bleeds, lethargy or The critical phase of plasma loss may
restlessness, and a rise in Hct level, along continue for 24 – 48 hrs, necessitating
with a rapid decrease in platelet count (2, Table 2. Volume-replacement flowchart for pa- constant, careful titration of fluid admin-
28). Infants and patients with comorbid tients with dengue with “warning signs” istration tailored to the clinical status,
conditions such as diabetes, renal failure, Hct level, and urine output for this period
or obesity may also require admission. ● Assess airway and breathing and obtain (2, 56 –58). A detailed flowchart recording
Indications for intensive care unit ad- baseline Hct level hourly vital signs, fluid balance, circula-
● Commence fluid resuscitation with normal
mission include children with severe den- tory status, and Hct level is essential.
saline/Ringer’s lactate at 5–7 mL/kg over 1–2
gue manifesting with shock, respiratory hrs Table 2 and Figures 4 and 5 suggest an
distress, abnormal bleeding, or organ fail- ● If hemodynamics and Hct level are stable, approach for treating dengue with warn-
ure, e.g., neurologic complications or plan a gradually reducing IVF regimen ing signs and dengue with compensated
liver and/or renal dysfunction (1, 2, 38). ● Titrate fluids on the basis of vital signs, shock and hypotensive shock, respec-
The three major priorities of manage- clinical examination, urine output (aim for tively. Figure 6 outlines the approach to
ment of hospitalized patients with den- 0.5–1 mL/kg/hr), and serial Hct level late presenters with established shock,
● IVFs, 5–7 mL/kg/hr for 1–2 hrs, then:
gue in the critical phase are replacement ● Reduce IVFs to 3–5 mL/kg/hr for 2–4 hrs; and Table 3 provides suggestions for con-
of plasma losses, early recognition and ● Reduce IVFs to 2–3 mL/kg/hr for 2–4 hrs trolled fluid resuscitation in dengue
treatment of hemorrhage, and prevention ● Continue serial close clinical monitoring and shock syndrome (DSS) while at the same
of FO. every 6–8 hourly Hct level time attempting to prevent/minimize FO.
Replacement of Plasma Losses— ● Oral rehydration solutions may suffice when Differences between DSS and septic
vomiting subsides and hemodynamics
Goals of Fluid Management in Dengue. shock. Compared to children with septic
stabilize
IV rehydration is the single most impor- ● A monitored fluid regimen may be required shock, who often require rapid, large-
tant intervention that can correct shock for 24–48 hrs until danger period subsides volume fluid resuscitation (60), there are
and save lives in both severe and nonse- major differences both in the rates and
vere forms of dengue, provided it is Hct, hematocrit; IVF, intravenous fluid. volumes of fluid resuscitation for dengue
Pediatr Crit Care Med 2011 Vol. 12, No. 1 95

7. Table 3. Guidelines for reversing dengue shock while minimizing fluid overload shock. Wills et al (57) have used much
lower fluid resuscitation rates in 500
1. Severe dengue with compensated shock: Stabilize airway and breathing, obtain baseline Hct
patients with DSS, and these restricted
level, initiate fluid resuscitation with NS/RL at 5–10 mL/kg over 1 hr, and insert urine catheter
early.
volumes were successful in not only re-
2. Severe dengue with hypotension: Stabilize airway and breathing, obtain baseline Hct level, versing shock but also minimizing com-
initiate fluid resuscitation with 1–2 boluses of 20 mL/kg NS/RL or synthetic colloid over 15–20 plications of FO, including the need for
mins until pulse is palpable, slow down fluid rates when hemodynamics improve, and repeat assisted ventilation. The authors reported
second bolus of 10 mL/kg colloid if shock persists and Hct level is still high. mortality rates in the range of 0.2% with
3. Synthetic colloids may limit the severity of fluid overload in severe shock.
slow fluid-filling at rates of 25 mL/kg over
4. End points/goals for rapid fluid boluses: Improvement in systolic BP, widening of pulse
pressure, extremity perfusion and the appearance of urine, and normalization of elevated Hct the first 2 hrs. Although there is no evi-
level. dence that colloids are superior to crys-
5. If baseline Hct level is low or “normal” in presence of shock, hemorrhage likely to have talloids for resuscitation, colloids are of-
worsened shock, transfuse fresh WB or fresh PRBCs early. ten used for severe dengue shock (2, 57).
6. After rapid fluid boluses, continue isotonic fluid titration to match ongoing plasma leakage for The significant differences in fluid resus-
24–48 hrs; after shock correction, if patient not vomiting and is alert, oral rehydration fluids
citation volumes for septic vs. dengue
may suffice to match ongoing losses.
7. Check Hct level hourly to twice hourly for first 6 hrs, and decrease frequency as patient shock may probably relate to the fact that
improves. patients with dengue shock are vasocon-
8. Goals for ongoing fluid titration: Stable vital signs, serial Hct measurement showing gradual stricted with a narrow pulse pressure as
normalization (if not bleeding), and low normal hourly urine output are the most objective opposed to the predominantly vasodilated
goals indicating adequate circulating volume; adjust fluid rate downward when this is achieved. states in septic shock (2, 59).
9. Plasma leakage is intermittent even during the first 24 hrs after the onset of shock; hence,
When can IV hydration be discontin-
fluid requirements are dynamic.
10. Targeting a minimally acceptable hourly urine output (0.5–1 mL/kg/hr) is an effective and ued? Cessation of IV fluids is important
inexpensive monitoring modality that can signal shock correction and minimize fluid overload. for preventing FO and can be considered
11. A urine output of 1.5–2 mL/kg/hr should prompt reduction in fluid infusion rates, provided 24 – 48 hrs after defervescence when the
hyperglycemia has been ruled out. hemodynamics, Hct level, and urine out-
12. Separate maintenance fluids are not usually required; glucose and potassium may be
put are stable, despite minimal IV fluids,
administered separately only if low.
13. Hypotonic fluids can cause fluid overload; also, avoid glucose-containing fluids, such as 1/2 especially if the patient is tolerating oral
GNS (GNS or I/2 GNS): the resultant hyperglycemia can cause osmotic diuresis and delay fluids.
correction of hypovolemia. Recognition and Management of
14. Commence early enteral feeds when vital signs are stable, usually 4–8 hrs after admission. Hemorrhage. Early detection of signs of
15. All invasive procedures (intubation, central lines, and arterial cannulation) must be avoided; if
hemorrhage, especially when the losses are
essential, they must be performed by the most experienced person. Orogastric tubes are
preferred to nasogastric tubes.
internal, is important. Failure to recognize
16. Significant hemorrhage mandates early fresh WB or fresh PRBC transfusion; minimize/avoid and treat occult hemorrhage on an emer-
transfusions of other blood products, such as platelets and fresh-frozen plasma unless bleeding gent basis is one of the most important yet
is uncontrolled despite 2–3 aliquots of fresh WB or PRBCs. preventable causes of death (2). Hemor-
rhage should be considered in the critical
NS/RL, normal saline/Ringer’s lactate; Hct, hematocrit; BP, blood pressure; WB, whole blood; phase of dengue when the Hct level is “nor-
PRBC, packed red blood cell; GNS, 5% glucose in normal saline; 1⁄2 GNS, 5% glucose in 1⁄2 normal saline.
mal” or lower than expected for the degree
of shock or the hemodynamics fails to nor-
malize despite the initial 40 – 60 mL/kg of
crystalloids/colloids (2).
Clinical features of significant hemor-
rhage may be subtle and include increase
in tachycardia, abdominal distension
and/or tenderness, stress-induced leuko-
cytosis (instead of the characteristic leu-
kopenia), agitation/lethargy, acidosis, and
evidence of worsening organ function (2).
Frank hypotension with dengue usually
indicates significant hemorrhage but is a
late manifestation, and blood transfusion
should be initiated emergently before this
occurs. The most important intervention
for a patient with dengue shock and life-
threatening bleeding is restoration of ox-
ygen-carrying capacity with fresh whole
blood (WB) or packed red blood cell
(PRBC) transfusions; this must be done
emergently rather than waiting for the Hct
level to decrease significantly. The 2009
Figure 4. Volume-replacement flowchart for patients with severe dengue and compensated shock. IV, WHO dengue guidelines emphasize that,
intravenous. in a bleeding patient with dengue, the
96 Pediatr Crit Care Med 2011 Vol. 12, No. 1

8. shock state worsens after initiation. Pres-
sors may also be indicated before intuba-
tion of a patient with dengue shock, be-
cause some patients may have
catastrophic decompensation during this
period.
Indications for Central Venous Pres-
sure Monitoring. Central venous pressure
monitoring has limited utility for DSS
and is seldom indicated except in late
presenters (Fig. 6). The risks of central
venous catheter insertion are usually
greater than the benefits, but if shock
persists despite 40 – 60 mL/kg fluids and
correction of suspected hemorrhage, an
experienced operator may consider inser-
tion of a central venous catheter. Ultra-
sound-guided placement, if available, will
minimize complications (2).
FO in Severe Dengue. Apart from
plasma leak and hemorrhage, the third
major management issue in the critical
Figure 5. Suggested approach to a patient with severe dengue and hypotension. NS/RL, normal
saline/Ringer’s lactate.
phase of dengue relates to FO and pul-
monary edema (PE). IV rehydration is the
sheet anchor of shock therapy; however, a
threshold for PRBCs/WB must be higher are uncorrected hypovolemia due to on- significant proportion of the adminis-
than that suggested for septic shock, for going plasma leakage and hemorrhage, tered fluid will inevitably leak out of the
which an Hct level of 30% is the usual other infrequent causes of persistent vascular compartment with worse edema,
transfusion threshold (2, 60). This is be- shock are myocardial dysfunction and ab- fluid collections, and respiratory insuffi-
cause hemorrhage with dengue is most of- dominal compartment syndrome (ACS), ciency. Overhydration and pathologic
ten preceded by a background of protracted the latter may be encountered in late fluid collections can easily occur if more
shock due to plasma leak, which results in presenters (38, 44). fluid than that sufficient to maintain a
the characteristic elevated Hct level. Myocardial dysfunction in dengue is minimal acceptable circulating volume is
Correction of shock with two or more most often a secondary phenomena due prescribed. Apart from PE, overzealous
aliquots of fresh WB/PRBCs usually to the detrimental adaptive phenomena fluid administration can also cause tense
breaks the vicious cycle of acidosis, hypo- of prolonged uncorrected hypovolemic large-volume ascites, which may lead to
perfusion, and disseminated intravascu- shock (e.g., excessively elevated systemic ACS (1, 38). Strategies for preventing
lar coagulation by restoring circulating vascular resistance causing coronary FO/PE include avoiding prophylactic
volume and improving tissue oxygen de- ischemia) that may be further aggravated blood product transfusions in nonbleed-
livery (2). This should be administered in by high doses of inotropes/pressors. Al- ing patients (even if thrombocytopenia
a controlled fashion to prevent FO. Ad- though primary myocardial dysfunction, and coagulopathy are significant) (2, 6,
ministration of other blood components, including both systolic and diastolic dys- 61). Also important is prompt cessation
such as platelets, fresh-frozen plasma, or function, has been described in children of IV fluids during the recovery phase,
cryoprecipitate, may contribute to vol- with dengue (31, 41– 43), it is an uncom- because resorption of the leaked plasma
ume overload and are not as important as mon entity and is much less frequent in occurs during this period and extraneous
fresh WB or PRBCs (2) unless the bleed- DSS compared to septic shock (58). Care- IV fluid can easily worsen FO, precipitate
ing is ongoing despite 2–3 aliquots of givers must desist from overzealous pre- PE, and large pleural and/or ascitic col-
blood transfusion. It is also important to scriptions of inotropes, because these lections (2).
remember that preventive platelet trans- agents can paradoxically worsen the Despite these strategies, some patients
fusion is unlikely to decrease the inci- shock state, especially if hypovolemia is may develop hypoxemic respiratory failure
dence of significant bleeding (61). Other still uncorrected. Inotrope/pressor sup- with respiratory distress and need positive-
infrequently reported interventions for port may occasionally be indicated in late pressure ventilation, including nasal con-
patients with bleeding and refractory presenters with dengue shock when fea- tinuous positive airway pressure (64).
thrombocytopenia are IV anti-D immu- tures of low cardiac output persist, de- Treatment of Established FO: Diuret-
noglobulin 250 IU/kg (62), IV immuno- spite having received 40 – 60 mL/kg of ics and Peritoneal Dialysis. Postresusci-
globulin (63), and recombinant acti- fluid and correction of blood loss, i.e., tation fluid-removal strategies, such as
vated factor VII (64); all these therapies patients with fluid/blood transfusion re- diuretic infusions, should not be neces-
are expensive, not proven to be of clin- fractory shock in whom myocardial dys- sary at all if fluid resuscitation was done
ical benefit, and not currently recom- function is suspected or confirmed by judiciously; however, on occasion, furo-
mended (2). echocardiography (if resources and ex- semide boluses, continuous infusions,
Although the two most important pertise are available) (Fig. 6). Inotropes and even peritoneal dialysis have been
causes of persistent or recurrent shock must be ceased if tachycardia or the used (44). The decision to administer di-
Pediatr Crit Care Med 2011 Vol. 12, No. 1 97

9. occur (2, 67); prevention of ACS by early
recognition of shock and judicious fluid
administration remains the best policy.
Complications of aggressive invasive
intensive care unit interventions may
lead to significant morbidity and mortal-
ity in sick, bleeding children with den-
gue, although these have been seldom
reported. Catastrophic bleeding may re-
sult from intensive care unit practices,
such as insertion of invasive central and
arterial catheters and intubation. Other
potentially risky invasive care practices
are rapid drainage of large-volume pleu-
ral and ascitic fluid collections during the
critical phase of plasma leakage, which
can often result in sudden worsening of
the hemodynamic status and catastrophic
hemorrhage (67). Judicious IV hydration
will minimize large-volume effusions and
may completely obviate the need for the
thoracic and/or abdominal paracentesis
with its attendant complications (2).
Other Interventions for DHF/DSS. No
drugs are useful for treating shock in
dengue. Serum cortisol levels are high in
children with dengue shock (68), which
supports a Cochrane database review in
which the authors stated that there is no
good-quality evidence that corticoste-
roids are helpful for DSS (69).
Experienced clinicians can minimize
dengue deaths with simple inexpensive
strategies that focus on:
Figure 6. Suggested approach to severe dengue and refractory shock (late presenters). CPAP,
continuous positive airway pressure. ● early recognition of plasma leakage and
shock by an educated front-line work-
force;
● early institution of a tightly controlled
uretics to a patient with dengue and FO orrhage and significant fluid collections;
IV rehydration regimen with isotonic
requires considerable judgment, because a higher prevalence of multiorgan failure;
fluids;
diuretics can easily worsen the circula- and the need for invasive and expensive
● ongoing titration of fluid therapy based
tory status in children who are still in the intensive care unit monitoring and ther-
on serial monitoring of vital signs,
critical phase of plasma leakage (2). If the apy (Fig. 6) (38). It is this group that may
urine output, and Hct level;
critical period has passed as demon- have myocardial dysfunction and pleural
● early recognition of the occult hemor-
strated by a stable Hct level, stable hemo- and ascitic collections, including ACS,
rhage and replacement with fresh WB/
dynamics, and a good urine output de- that may worsen both respiratory and cir-
PRBCs;
spite minimal IV fluids, a patient with culatory status (38, 44). Myocardial dys-
● measures to prevent FO, including
features of FO/PE may be cautiously com- function in this group is usually attribut-
prompt cessation of IV fluid when the
menced on a diuretic infusion at 0.1 mg/ able to prolonged coronary ischemia,
period of plasma leakage has ceased
kg/hr (2). Any hemodynamic deteriora- which may be worsened by cat-
and avoiding preventive transfusion
tion should prompt immediate cessation echolamines; invasive hemodynamic
with platelets, fresh-frozen plasma, and
of the diuretic infusion. monitoring in conjunction with serial
other blood products; and
Peritoneal dialysis has been used for echocardiography may aid in streamlin-
● minimizing iatrogenic interventions
patients with oliguric renal failure or di- ing therapy (Fig. 6). ACS can set off a
that may cause complications (naso-
uretic-resistant FO and for patients with vicious cycle due to a combination of
gastric tubes, central venous pressure
ACS (38, 44) but may provoke bleeding large-volume ascites and ischemic edem-
insertion, pleural and ascitic fluid
and should rarely be necessary. atous gut in conjunction with positive-
drainage).
Complications and Management Is- pressure ventilation (35, 65).
sues in Late Presenters With Established Controlled drainage of ascites may re-
Prognosis
Shock. Late presenters often have a dif- sult in improved hemodynamics (66, 67)
ferent and difficult course with refractory but must be performed with great caution, Although mortality from dengue ranges
shock; catastrophic, uncontrollable hem- because hemorrhagic complications can from 1% to 5% (2, 8, 9, 57), mortality
98 Pediatr Crit Care Med 2011 Vol. 12, No. 1

10. from severe dengue shock can be much tion and Control. Second Edition. Geneva, tern, and virus serotype correlate with dis-
higher, up to 26%, especially in instances of World Health Organization, 1997 ease severity. J Infect Dis 2000; 181:2–9
profound shock and hemorrhage and when 2. Dengue Hemorrhagic Fever: Diagnosis, 21. Binh PT, Matheus S, Huong VT, et al: Early
treatment is delayed (70). Treatment, Prevention and Control. Third clinical and biological features of severe clin-
Edition. A joint publication of the World ical manifestations of dengue in Vietnamese
Health Organization (WHO) and the Special adults. J Clin Virol 2009; 45:276 –280
Prevention and Future Programme for Research and Training in 22. Nguyen TH, Lei HY, Nguyen TL, et al: Den-
Directions Tropical Diseases (TDR), Geneva, 2009 gue hemorrhagic fever in infants: A study of
3. Gubler DJ: Dengue/dengue hemorrhagic fe- clinical and cytokine profiles. J Infect Dis
Public health measures for curtailing ver: History and current status. Novartis 2004; 189:221–232
this disease are presently focusing on pre- Found Symp 2006; 277:3–16 23. Kliks SC, Nimmanitya S, Nisalak A, et al:
ventive strategies that include measures 4. Centers for Disease Control and Prevention: Evidence that maternal dengue antibodies
for mosquito control and the develop- Dengue. Available at http://www.cdc.gov/ are important in the development of dengue
ment of vaccines (9, 71). However, pre- NCIDOD/DVBID/DENGUE. Accessed Sep- hemorrhagic fever in infants. Am J Trop Med
vention of dengue remains elusive, be- tember 2008 Hyg 1988; 38:411– 419
cause control of the Ae. aegypti mosquito 5. Pinheiro FP, Corber SJ: Global situation of 24. Thisyakorn U, Nimmannitya S: Nutritional
is costly and often ineffective and, hence, dengue and dengue hemorrhagic fever and status of children with dengue hemorrhagic
its emergence in the Americas. World Health fever. Clin Infect Dis 1993; 16:295–297
has not met with much success, similar
Stat Q 1997; 50:161–168 25. Bandyopadhyay S, Lum LC, Kroeger A: Clas-
to vaccine development (72). However, sifying dengue: A review of the difficulties in
results of clinical field tests with live at- 6. Gubler DJ: Dengue and dengue hemorrhagic
fever. Clin Microbiol Rev 1998; 11:480 – 496 using the WHO case classification for dengue
tenuated tetravalent vaccines have indi- haemorrhagic fever. Trop Med Int Health
7. World Health Organization: Scientific work-
cated encouraging preliminary data in ing group on dengue, Geneva, 2006. Available 2006; 11:1238 –1255
Thai adults and children (73). at http://www.who.int/tdr/svc/publications/tdr- 26. Rigau-Perez JG: Severe dengue: The need for
´
research-publications/swg-report-dengue. Ac- new case definitions. Lancet Infect Dis 2006;
Summary and Conclusion cessed March 2009 6:297–302
8. Halstead SB: Is there an inapparent dengue 27. Deen JL, Harris E, Wills B, et al: The WHO
Infections with DVs result in a spec- explosion? Lancet 1999; 353:1100 –1101
dengue classification and case definitions:
trum of responses, from a mild, undiffer- Time for a reassessment. Lancet 2006; 368:
9. Guzman MG, Kourí G: Dengue: An update.
´
entiated, self-limited febrile illness to se- 170 –173
Lancet Infect Dis 2002; 2:33– 42
vere dengue, which can have a high 28. TDR: World Health Organization issues new
10. Teo D, Ng LC, Lam S: Is dengue a threat to
dengue guidelines. Available at http://
mortality rate if detected late or treated the blood supply? Transfus Med 2009; 19:
apps.who.int/tdr/svc/publications/tdrnews/
inappropriately. The diagnosis of acute 66 –77
issue-85/tdr-briefly. Accessed July 1, 2010
DV infection is based mainly on clinical 11. Malavige GN, Fernando S, Fernando DJ:
29. Wills BA, Oragui EE, Stephens AC, et al:
signs and symptoms in endemic coun- Dengue viral infections. Postgrad Med J
Coagulation abnormalities in dengue hemor-
tries. 2004; 80:588 – 601
rhagic fever: Serial investigations in 167
12. Halstead SB: Dengue. Lancet 2007; 370:
In dengue-epidemic regions, mortality Vietnamese children with dengue shock syn-
1644 –1652
rates of 1% are achievable when highly drome. Clin Infect Dis 2002; 35:277–285
13. Vaughn DW, Green S, Kalayanarooj S, et al:
trained caregivers at all levels are tuned 30. Gomber S, Ramachandran VG, Satish Kumar
Dengue in the early febrile phase: Viremia
to three aspects of management: a thor- KN, et al: Hematological observations as di-
and antibody responses. J Infect Dis 1997; agnostic markers in dengue hemorrhagic fe-
ough understanding of the unpredictable 176:322–330 ver: A reappraisal. Indian Pediatr 2001; 38:
and dynamic nature of the disease; early 14. Rothman AL: Pathogenesis of dengue virus 477– 481
recognition of warning signs and occult infection, UpToDate 2008. Available at http:// 31. Khongphatthanayothin A, Suesaowalak M,
hemorrhage; and continuously monitor- www.Uptodate.com. Accessed September Muangmingsook S, et al: Hemodynamic pro-
ing the patient and titrating interven- 2008 files of patients with dengue hemorrhagic
tions to match the rapidly evolving clin- 15. Shirtcliffe P, Cameron E, Nicholson KG, et fever during toxic stage: An echocardio-
ical status. al: Don’t forget dengue! Clinical features of graphic study. Intensive Care Med 2003; 29:
dengue fever in returning travellers. J R Coll 570 –574
Physicians Lond 1998; 32:235–237 32. Rothman AL: Clinical presentation and diag-
ACKNOWLEDGMENTS 16. Mongkolsapaya J, Dejnirattisai W, Xu XN, et nosis of dengue virus infections UpToDate
We are grateful for the detailed anal- al: Original antigenic sin and apoptosis in the 2008. Available at http://www.Uptodate.com.
ysis and insightful comments of Dr. In- pathogenesis of dengue hemorrhagic fever. Accessed September 2008
Nat Med 2003; 9:921–927 33. Kabra SK, Jain Y, Pandey RM, et al: Dengue
dumathy Santhanam and Dr. Shanthi
17. Rothman AL: Dengue: Defining protective hemorrhagic fever in children in the 1996
Sangaredddy, assistant professors of
versus pathologic immunity. J Clin Invest Delhi epidemic. Trans R Soc Trop Med Hyg
emergency medicine and intensive care 2004; 113:946 –951 1999; 93:294 –298
from the Institute of Child Health 18. Guzman MG, Alvarez M, Rodriguez-Roche R, 34. Srichaikul T, Nimmanitaya S, Artchararit N,
(Chennai, India), and Dr. Shrishu Ka- et al: Neutralizing antibodies after infection et al: Fibrinogen metabolism and dissemi-
math and Dr. Gayathri Subramaniam, with dengue 1 virus. Emerg Infect Dis 2007; nated intravascular coagulation in dengue
junior consultants from Apollo Chil- 13:282–286 hemorrhagic fever. Am J Trop Med Hyg
dren’s Hospital (Chennai). 19. Morens DM: Antibody-dependent enhance- 1977; 26:525–532
ment of infection and the pathogenesis of 35. Mitrakul C, Poshyachinda M, Futrakul P, et
REFERENCES viral disease. Clin Infect Dis 1994; 19: al: Hemostatic and platelet kinetic studies in
500 –512 dengue hemorrhagic fever. Am J Trop Med
1. World Health Organization: Dengue Hemor- 20. Vaughn DW, Green S, Kalayanarooj S, et al: Hyg 1977; 26:975–984
rhagic Fever: Diagnosis, Treatment, Preven- Dengue viremia titer, antibody response pat- 36. Lum LCS, Goh AYT, Chan PWK, et al: Risk
Pediatr Crit Care Med 2011 Vol. 12, No. 1 99

11. factors for hemorrhage in severe dengue in- tion of hypotension before initiation of effec- drome: Is it necessary? J Pediatr 2003; 143:
fections. J Pediatr 2002; 140:629 – 631 tive antimicrobial therapy is the critical de- 682– 684
37. Nimmannitya S, Thisyakorn U, Hemsrichart terminant of survival in human septic shock. 62. de Castro RA, de Castro JA, Barez MY, et al:
V: Dengue haemorrhagic fever with unusual Crit Care Med 2006; 34:1589 –1596 Thrombocytopenia associated with dengue
manifestations. Southeast Asian J Trop Med 51. Mellor DH: The place of computed tomogra- hemorrhagic fever responds to intravenous
Public Health 1987; 18:398 – 406 phy and lumbar puncture in suspected bac- administration of anti-D (Rh(0)-D) immune
38. Kamath SR, Ranjit S: Clinical features, com- terial meningitis. Arch Dis Child 1992; 67: globulin. Am J Trop Med Hyg 2007; 76:
plications and atypical manifestations of chil- 1417–1419 737–742
dren with severe forms of dengue hemor- 52. De Paula SO, Pires Neto RJ, Correa JA, et al: 63. Rajapakse S: Intravenous immunoglobulins
rhagic fever in South India. Indian J Pediatr The use of reverse transcription-polymerase in the treatment of dengue illness. Trans R
2006; 73:889 – 895 chain reaction (RT-PCR) for the rapid detec- Soc Trop Med Hyg 2009; 103:867– 870
39. Solomon T, Dung NM, Vaughn DW, et al: tion and identification of dengue virus in an 64. Chuansumrit A, Wangruangsatid S, Lektr-
Neurological manifestations of dengue infec- endemic region: A validation study. Trans R akul Y, et al: Control of bleeding in children
tion. Lancet 2000; 355:1053–1059 Soc Trop Med Hyg 2002; 96:266 –269 with dengue hemorrhagic fever using recom-
40. Lum LC, Lam SK, Choy YS, et al: Dengue 53. Dussart P, Labeau B, Lagathu G, et al: Eval- binant activated factor VII: A randomized,
encephalitis: A true entity? Am J Trop Med uation of an enzyme immunoassay for detec- double-blind, placebo-controlled study.
Hyg 1996; 54:256 –259 tion of dengue virus NS1 antigen in human Blood Coagul Fibrinolysis 2005; 16:549 –555
41. Wali JP, Biswas A, Chandra S, et al: Cardiac serum. Clin Vaccine Immunol 2006; 13: 65. Cam BV, Tuan DT, Fonsmark L, et al: Ran-
involvement in dengue haemorrhagic fever. 1185–1189 domized comparison of oxygen mask treat-
Int J Cardiol 1998; 64:31–36 54. Chakravarti A, Gur R, Berry N, et al: Evalu- ment vs. nasal continuous positive airway
42. Kabra SK, Juneja R, Madhulika, et al: Myo- ation of three commercially available kits for pressure in dengue shock syndrome with
cardial dysfunction in children with dengue serological diagnosis of dengue haemor- acute respiratory failure. J Trop Pediatr
haemorrhagic fever. Natl Med J India 1998;
rhagic fever. Diagn Microbiol Infect Dis 2002; 48:335–339
11:59 – 61
2000; 36:273–274 66. Carlotti AP, Carvalho WB: Abdominal com-
43. Khongphatthanayothin A, Lertsapcharoen P,
55. Colbert JA, Gordon A, Roxelin R, et al: Ultra- partment syndrome: A review. Pediatr Crit
Supachokchaiwattana P, et al: Myocardial de-
sound measurement of gallbladder wall Care Med 2009; 10:115–120
pression in dengue hemorrhagic fever: Prev-
thickening as a diagnostic test and prognos- 67. Clinical Practice Guideline on Management
alence and clinical description. Pediatr Crit
tic indicator for severe dengue in pediatric of Dengue in Adults. Second Edition. 2008.
Care Med 2007; 8:524 –529
patients. Pediatr Infect Dis J 2007; 26: Available at http://www.moh.gov.my. Ac-
44. Ranjit S, Kissoon N, Jayakumar I: Aggressive
850 – 852 cessed October 25, 2009
management of dengue shock syndrome may
56. Singhi S, Khilnani P, Lodha R, et al: Guide- 68. Myo-Khin, Soe-Thein, Thein-Thein-Myint, et
decrease mortality rate: A suggested proto-
lines for treatment of septic shock in re- al: Serum cortisol levels in children with
col. Pediatr Crit Care Med 2005; 6:412– 419
45. Srichaikul T, Punyagupta S, Kanchanapoom source limited environments. J Pediatr In- dengue haemorrhagic fever. J Trop Pediatr
T: Hemophagocytic syndrome in dengue fect Dis 2009; 4:173–192 1995; 41:295–297
hemorrhagic fever with severe multiorgan 57. Wills BA, Nguyen MD, Ha TL, et al: Compar- 69. Panpanich R, Sornchai P, Kanjanaratana-
complications. J Med Assoc Thai 2008; 91: ison of three fluid solutions for resuscitation korn K: Corticosteroids for treating dengue
104 –109 in dengue shock syndrome. N Engl J Med shock syndrome. Cochrane Database Syst
46. Khilnani P, Sarma D, Zimmerman J, et al: 2005; 353:877– 889 Rev. 2006; 3:CD003488
Epidemiology and peculiarities of pediatric 58. Moxon C, Wills B: Management of severe 70. Cherian T, Ponnuraj E, Kuruvilla T, et al: An
multiple organ dysfunction syndrome in New dengue in children. Adv Exp Med Biol 2008; epidemic of dengue haemorrhagic fever &
Delhi. India Intensive Care Med 2006; 32: 609:131–144 dengue shock syndrome in & around Vellore.
1856 –1862 59. Ranjit S, Kissoon N, Gandhi D, et al: Early Indian J Med Res 1994; 100:51–56
47. Khilnani P, Sarma D, Singh R, et al: Demo- differentiation between dengue and septic 71. Rothman AL: UpToDate May 2008. Preven-
graphic profile and outcome analysis of a shock by comparison of admission hemody- tion and treatment of dengue virus infection
tertiary level pediatric intensive care unit. namic, clinical, and laboratory variables: A UpToDate 2008. Available at http://www.
Indian J Pediatr 2004; 71:587–591 pilot study. Pediatr Emerg Care 2007; 23: Uptodate.com. Accessed September 2008
48. De Paula SO, da Fonseca BAL: Dengue: A 368 –375 72. Monath TP: Dengue and yellow fever: Chal-
review of the laboratory tests a clinician 60. Brierley J, Carcillo JA, Choong K, et al: Clin- lenges for the development and use of vac-
must know to achieve a correct diagnosis. ical practice parameters for hemodynamic cines. N Engl J Med 2007; 357:2222–2225
Braz J Infect Dis 2004; 8:390 –398 support of pediatric and neonatal septic 73. Sabchareon A, Lang J, Chanthavanich P, et
49. Ramos M, Tomashek K, Arguello D, et al: shock: 2007 update from the American Col- al: Safety and immunogenicity of a three
Early clinical features of dengue infection in lege of Critical Care Medicine. Crit Care Med dose regimen of two tetravalent live-attenu-
Puerto Rico. Trans R Soc Trop Med Hyg 2009; 37:666 – 688 ated dengue vaccines in five- to twelve-year-
2009; 103:878 – 884 61. Lum LC, Abdel-Latif Mel-A, Goh AY, et al: old Thai children. Pediatr Infect Dis J 2004;
50. Kumar A, Roberts D, Wood KE, et al: Dura- Preventive transfusion in dengue shock syn- 23:99 –109
100 Pediatr Crit Care Med 2011 Vol. 12, No. 1