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 an emphasis on clinical syndromes, classication, diagnosis, and management, and to outline relevant aspects of epidemiology, immunopathogenesis, and prevention strategies. Dengue, a leading cause of childhood mortality in Asia and South America, is the most rapidly spreading and important arboviral disease in the world and has a geographic distribution of >100 countries. Data Source: Boolean searches were carried out by using PubMed from 1975 to March 2009 and the Cochrane Database of Systematic Reviews from 1993 to March 2009 to identify potentially relevant articles by key search terms such as: dengue; dengue fever; dengue hemorrhagic fever; dengue shock syndrome; severe dengue and immunopathogenesis, pathogenesis, classication, complications, and management. In addition, authoritative seminal and up-to-date reviews by experts were used. Study Selection: Original research and up-to-date reviews and authoritative reviews consensus statements relevant to diagnosis and therapy were selected. Data Extraction and Synthesis: We considered the most relevant articles that would be important and of interest to the critical care practitioner as well as authoritative consensus statements from the World Health Organization and the Centers for Disease Control and Prevention. Dengue viral infections are caused by one of four single-stranded ribonucleic acid viruses of the family Flaviviridae and are transmitted by their mosquito vector, Aedes aegypti. The clinical syndromes caused by dengue viral infections occur along a continuum; most cases are asymptomatic and few present with severe forms characterized by shock. Management is predominantly supportive and includes methods to judiciously resolve shock and control bleeding while at the same time preventing uid overload. Conclusions: Dengue is no longer conned to the tropics and is a global disease. Treatment is supportive. Outcomes can be optimized by early recognition and cautious titrated uid replacement, especially in resource-limited environments. (Pediatr Crit Care Med 2011; 12:90 100) KEY WORDS: dengue hemorrhagic fever; dengue shock syndrome; shock; immunopathogenesis; diagnosis; management; children; critical illness

engue viral infections affect all age groups and produce a spectrum of clinical illness that ranges from asymptomatic to a mild or nonspecic viral syndrome to a severe and occasionally fatal disease characterized by shock and hemorrhage (1, 2). Dengue fever (DF) is an old disease; the rst record of a clinically compatible disease was documented in a Chinese medical encyclopedia in 992 (3). This illness has reemerged in the last 3 4 decades with an expanded geographic distribution of both the viruses and the mosquito vectors (1, 2, 4 6); in 1998, dengue was recognized as the most important tropical infectious disease after malaria
*See also p. 116. From the Pediatric Intensive Care Unit (SR), Apollo Childrens Hospital, Chennai, India; Department of Pediatrics (NK), BC Childrens Hospital, Vancouver, BC, Canada. The authors have not disclosed any potential conicts of interest. For information regarding this article, E-mail: nkissoon@cw.bc.ca Copyright 2011 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0b013e3181e911a7

(1, 2, 4 6). The disease is encountered virtually throughout the tropics, and the 2005 World Health Assembly resolution included dengue as an example of a disease that may constitute a public health emergency of international concern with implications for health security due to rapid epidemic spread beyond national borders (2). In this article we review the epidemiology, immunopathogenesis, clinical syndromes, diagnosis, management, and prevention of dengue.

Method
Boolean searches were carried out by using PubMed from 1975 to March 2009 and the Cochrane Database of Systematic Reviews from 1993 to December 2009 to identify potentially relevant articles by key search terms such as: dengue; dengue fever; dengue hemorrhagic fever; dengue shock syndrome; dengue and immunopathogenesis, pathogenesis, classication, complications, management, and prevention. We also searched the extensive bibliography lists of the relevant articles. Case reports were

considered only if pertinent. Only English-language articles were included. We considered the most relevant articles that would be important and of interest to the critical care practitioner. In particular, we attempted to nd metaanalyses or well-designed randomized, controlled trials to support a recommendation for intervention and treatment. When none was available, we cited an authoritative consensus statement or a clinical guideline such as those from major medical organizations or international health agencies and bodies such as the World Health Organization (WHO) and the Centers for Disease Control and Prevention.

Epidemiology
In the past 50 yrs, the prevalence of DF has increased 30-fold, and signicant outbreaks have occurred in ve of six WHO regions. It is now endemic in 112 countries; Southeast Asia and the western Pacic have the most serious afictions (4, 5, 7). Case fatality rates vary from 1% to 5% (8) but can be 1% with appropriate treatment (2). The reasons for the global resurgence of epidemics of
Pediatr Crit Care Med 2011 Vol. 12, No. 1

90

dengue are complex and include largescale population migration, increased air travel, unprecedented global population growth, and uncontrolled urbanization, all of which facilitate transmission and increase densities of Aedes (Ae.) aegypti borne disease (5, 6, 9). Dengue has also been transmitted via blood transfusion and organ transplantation (10). Dengue Viruses. There are four closely related but serologically distinct dengue viruses (DVs), members of the Flavivirus genus of the Flaviviridae, called DEN-1, DEN-2, DEN-3, and DEN-4. Lifetime immunity follows infection by one serotype, but immunity to the other serotypes is short-lived (11, 12). Mosquito Vectors. Mosquitoes that belong to the genus Aedes play a pivotal role in the transmission of dengue. The principal vector is Ae. aegypti, but Ae. albopictus and Ae. polynesiensis may act as vectors depending on the geographic location (6, 12). Viral Replication and Transmission Cycle of DV. Both epidemic and endemic transmission of DV are maintained through a human-mosquito-human cycle in which humans are the amplifying host. DV is introduced into the skin by the bite of an infected female Aedes mosquito. Viremia in susceptible humans begins between 3 and 6 days after subcutaneous injection, lasts for another 3 6 days, and ends as the fever resolves (6, 13, 14). Dengue can essentially be excluded as the cause of symptoms in a traveler who develops an illness 14 days after returning from a dengue-endemic country (15).

T-Cell Activation and Apoptosis. Intense T-cell activation and massive apoptosis may lead to the sudden onset of vascular permeability and hemorrhage that characterizes severe forms of dengue disease (12). In some patients with secondary dengue infections, however, the T-cell response may cause suboptimal killing of the DV-infected monocytes and serve to augment the severity of the second infection due to higher viral loads (12, 16). Neutralizing Antibodies and AntibodyDependent Enhancement. The severity of secondary infection with a different DV serotype depends on the balance between neutralizing vs. enhancing heterotypic antibodies after the rst infection. This phenomenon has been called antibodydependent enhancement and is one of the best known hypotheses in the immunopathogenesis of severe dengue (9, 1719).

antibody levels decline below the neutralization threshold (12, 22, 23). Nutritional Status. Unlike other infectious diseases, severe forms of dengue are more common in well-nourished children, and grade 2 or 3 protein-calorie malnutrition protects against severe dengue vasculopathy. This negative association may be related to suppression of cellular immunity in malnutrition (11, 24).

Classication and Clinical Course of Dengue

The widely used 1997 WHO classication grouped patients with symptomatic dengue infections into three categories: undifferentiated fever; DF; and DHF (1) (Fig. 1). However, with dengue being encountered in newer geographical areas, considerable overlap between the groups has been reported, and it is likely that the various categories exist as a continuum rather than separate entities (2, 9, 25 27). Similarly, the classication inherently assumed that DF was a mild disease and that only cases of DHF were severe; thus, patients even with severe and lifethreatening manifestations of dengue could not be included as having DHF unless all criteria were present. This had adverse effects at various levels, including during triage, disposition, and treatment decisions, the urgency of which was dictated by the severity classication of dengue (25). Furthermore, the term DHF puts undue emphasis on hemorrhage; however, the hallmark of severe dengue (and the manifestation that should be addressed early) is not hemorrhage but increased vascular permeability, which leads to shock (12). Authors of a WHO/ Tropical Disease Researchsupported, prospective, clinical, multicenter study across dengue-endemic regions proposed a revised and simplied dengue case classication in a move to help clinicians identify rapidly and treat adequately the most severe, life-threatening forms of the disease (2, 28). 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 presentations that range from mild to severe; however, the clinical evolution and outcome may be highly unpredictable. The course of illness is characterized by three well-demarcated phases: febrile;
91

Factors that Inuence Disease Severity

Most DV infections produce, in decreasing order of frequency, an asymptomatic infection, mild nonspecic symptoms, or classic dengue (1, 9). The more severe manifestations of shock and hemorrhage occur in 5% of DV infections (9, 11). Complex, interlinked mechanisms determine whether mild or severe disease occurs (9). Primary vs. Secondary Infection. The greatest risk factor for the development of severe dengue is secondary infection with a different dengue serotype from the original infecting virus (9, 11, 12). Severe illness during secondary dengue infections was associated with higher peak plasma virus titers (20). Age. Dengue hemorrhagic fever (DHF) is primarily a disease of infants and children (1, 9), although adults may also be aficted with severe disease (21). Infants can develop features of severe disease even during a primary DV infection when their transplacentally acquired maternal

Immunopathogenesis of DV Infections
The immunopathogenesis of severe DV infections is complex and remains incompletely understood; however, severe dengue is differentiated from its milder forms by the presence of increased vascular permeability (1, 2, 9, 12). A few salient features may explain the dramatic clinical manifestations.

Figure 1. The traditional 1997 World Health Organization classication of dengue (1).

Pediatr Crit Care Med 2011 Vol. 12, No. 1

Figure 2. New simplied classication of dengue viral infections, World Health Organization 2009. CNS, central nervous system.

Figure 3. Phases of dengue in relation to symptoms and laboratory changes. AST, aspartate transaminase; ALT, alanine aminotransferase; CNS, central nervous system; IgM, immunoglobulin M; IgG, immunoglobulin G. Adapted with permission from World Health Organization: Dengue Hemorrhagic Fever: Diagnosis, Treatment, Prevention and Control. Third Edition. Geneva, WHO/TDR, 2009.

critical; and recovery (2). Although most patients recover after a self-limiting, nonsevere, clinical course, a small proportion progress to have severe disease, which is characterized by plasma leakage with or without hemorrhage (2). Clinical Phases of Dengue. After the incubation period, the illness begins abruptly and is followed by the three phases (Fig. 3). Phase 1: The febrile phase. Typically, a patient develops a high-grade fever that
92

lasts 27 days and is acutely unwell with headache, diffuse erythema, generalized myalgia, and arthralgia; anorexia, nausea, and vomiting are also common. Younger children may develop febrile seizures. It may be difcult to distinguish dengue clinically from other viral fevers, although demonstration of microvascular fragility by a positive tourniquet-test result increases the likelihood that it is dengue (2). Frequent meticulous monitoring for warning signs and other clini-

cal parameters (Fig. 2) is crucial for recognizing progression to the critical phase. Although a tender hepatomegaly and mild hemorrhagic manifestations (petechiae and mucous membrane bleeding from nasal or oral cavity) may be seen often, signicant bleeding episodes from the gastrointestinal tract or menorrhagia are uncommon occurrences in the febrile phase. The earliest laboratory abnormality is a progressive leukopenia, which is another clue to the presence of probable dengue. Phase 2: The critical phase. The critical phase begins around the period of defervescence, when several important occurrences mark their presence in quick succession. Leukopenia progresses further, and a rapid decrease in platelet count usually occurs. This precedes the most specic and life-threatening manifestation 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 febrile 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 determines the clinical severity in the critical phase (i.e., whether the patient recovers uneventfully, develops dengue with warning 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, metabolic acidosis, and thrombocytopenia may worsen disseminated intravascular coagulation, which may, in turn, lead to massive hemorrhage, thus setting off a progressive downward spiral of worse shock and hemorrhage (1, 11, 12, 29); these patients are at high risk of death. Apart from shock and hemorrhage, other important consequences of increased capillary permeability are hemoconcentration, hypoalbuminemia, and serous uid collections, usually pleural effusions and ascites, the extent of which depends both on the magnitude of plasma leak and the volume of uids consumed or prescribed (1, 2). Early conrmation of plasma leakage in the critical phase may be provided by serial laboratory studies with complete
Pediatr Crit Care Med 2011 Vol. 12, No. 1

blood counts demonstrating the triad of progressively increasing Hct, leukopenia, and thrombocytopenia, ultrasound ndings of a thickened gall bladder wall, and ascitic and pleural uid and chest radiograph showing pleural effusions (1, 2). These ndings are useful for triage and therapy because they may be present much earlier than signs of plasma loss are clinically manifest and also indicate progress to the critical phase in patients who do not defervesce despite the onset of plasma leakage (2, 11, 12). Evaluating hemoconcentration in patients with preexisting anemia may be difcult, because the preillness Hct level may be unavailable at the time of admission. Using the population baseline may be useful (2), such as a cutoff Hct value (36%) in Indian children due to the high prevalence of iron-deciency anemia (30). Phase 3: The recovery phase. After the critical 24 48 hrs of plasma leakage, the nal recovery phase is heralded by the gradual resorption of the leaked plasma back into the intravascular compartment over the next 48 72 hrs. The patient may exhibit dramatic improvement with an overall sense of well-being, improved appetite, a stable hemodynamic status, and a brisk diuresis. Pruritis and an asymptomatic bradycardia may be marked (1, 2). The blood picture reects the recovery phase with a lower Hct level on account of the reabsorbed uid and a white cell increment that may precede platelet recovery. Recognition of this phase is important so that intravenous (IV) uids may be promptly ceased. This simple intervention may prevent uid overload (FO), which, along with severe hemorrhage, is an important, preventable cause of death by dengue (Fig. 3). Features of Severe Dengue. Severe dengue occurs in a small proportion of patients and is dened by one or more of the following: 1) shock due to plasma leakage, which is usually associated with uid accumulation and consequent respiratory symptoms; 2) severe bleeding; and 3) severe organ impairment (liver, neurologic symptoms, renal or myocardial dysfunction) (Fig. 2) (2, 28). 1) Shock in severe dengue. The hypovolemic shock in dengue may initially be compensated with a normal systolic blood pressure (BP), elevated diastolic BP, narrow pulse pressure, and features of hypoperfusion, such as cold mottled skin, although in some patients, signicant tachycardia may be absent (31). DifPediatr Crit Care Med 2011 Vol. 12, No. 1

culties in successful treatment of severe dengue stem from the dynamicity of dengue, which makes it a challenge to detect and manage, especially for the uninitiated physician even experienced clinicians may be caught unaware. It is this dynamicity that may account for delays in recognition of the severity of circulatory compromise, which can be subtle: systolic BP may be maintained until late, and patients even in advanced shock often remain alert (1, 2). As shock progresses, the diastolic BPs and then the systolic BPs become unrecordable, and if they are not promptly reversed, the patient may progress to have multiorgan failure and a complicated course. 2) Bleeding and hemorrhagic manifestations in severe dengue. Common sites are from the gastrointestinal tract manifesting as hematemesis or melena (2, 32, 33). However, even with severe dengue, in which marked thrombocytopenia and coagulation abnormalities are frequent (34, 35), major life-threatening bleeds are rare: the most important risk factor for signicant hemorrhage is prolonged shock, especially when complicated by acidosis and hypoxia (2, 29, 36). Other risk factors for bleeding are the presence of hepatic and/or renal dysfunction (2); drug (e.g., nonsteroidal anti-inammatory drug) exposure; and procedures such as nasogastric tube insertion, arterial puncture, or intramuscular injections. 3) Severe organ impairment. Severe organ impairment is the third criteria for severe dengue (37) and includes acute liver failure, encephalopathy/encephalitis, renal failure, and myocardial dysfunction. These may also contribute to mortality and may occur even in the absence of severe plasma leakage or shock (2). Liver failure may be caused by a direct viral effect with hepatitis or focal necrosis of the liver and is associated with a high mortality rate (37, 38). Elevated transaminase levels have been documented to occur as part of dengue (1) and also after resuscitation from shock (ischemic hepatitis) (38). Neurologic complications. Patients with severe dengue may present with a wide variety of neurologic manifestations including encephalopathy, seizures, and acute pure motor weakness (11, 32, 38, 39). The DV has been isolated from the cerebrospinal uid of some patients having features of encephalitis (40). In the critical phase, cerebral hypoperfusion may result in altered mental status, con-

vulsions, and extensor posturing; these neurologic signs can improve when the perfusion normalizes. Other causes of central nervous system symptoms in the patient with severe dengue are coexisting central nervous system infections (bacterial, viral, or malarial), dengue encephalopathy/encephalitis, electrolyte disorders, intracranial hemorrhage, and fulminant hepatic failure (38). During recovery, cerebral edema from FO may lead to obtundation and seizures. The precise cause may be difcult to separate and requires a consideration of the phase of dengue and thorough clinical examination in conjunction with laboratory and radiologic investigations to rule out systemic causes, electrolyte derangements, and specic organ insults. Cardiac dysfunction. Plasma leakage and/or hemorrhage causing hypovolemia and a compensatory elevated systemic vascular resistance are the predominant mechanisms of shock in severe dengue (2, 31). Although primary myocardial insult in dengue is infrequent, there have been a few reports of relative bradycardia contributing to low cardiac output (31) and acute ST-segment and T-wave changes on electrocardiogram, together with low ejection fractions and global hypokinesia on radionuclide ventriculography (41, 42). No myocardial necrosis was detected in any of the patients, which suggests that myocardial dysfunction might either be attributable to humoral factors or coronary hypoperfusion (43). Both systolic and diastolic dysfunction have been reported to cause refractory shock (38, 44). Other complications include hemolytic uremic syndrome (1, 32) and coinfections in endemic areas (malaria, leptospirosis, enteric fever) (1, 38). Although severe abdominal pain presenting as a surgical emergency had been previously classied as an uncommon manifestation (32), severe intense abdominal pain is now recognized as one of the most important warning signs heralding signicant plasma leakage and imminent shock. Dengue has also been described as an important cause of hemophagocytic lymphohistiocytosis (45) and pediatric multiorgan failure (46, 47).

Diagnosis
Although the diagnosis of acute DV infection is mainly clinical (1), pediatric caregivers frequently nd making an early diagnosis challenging, because the
93

initial symptoms are often nonspecic, many common tropical infections can result in a presentation with fever and thrombocytopenia with or without shock, viremia may be below detectable levels, and serological tests conrm dengue only late in the course of illness (2, 48). Performing a tourniquet test at each visit may help differentiate dengue from other viral infections. Taking note of the temporal sequence of symptoms is as important as recording their presence, because with dengue, it is at the time of defervescence that the disease manifests its severity, unlike other viral illnesses for which a clinical improvement is to be expected with a decline in body temperature (2). Ramos et al (49) have attempted to identify the clinical features that predict a laboratory-positive dengue infection and concluded that the presence of highgrade fever, rash, petechiae, or mucosal bleeds in the absence of cough and other respiratory symptoms has a very high positive predictive value of conrmed dengue infection. Differential Diagnosis. In addition to bacterial septic shock, the differential diagnoses that must be considered in the appropriate epidemiologic settings include malaria, leptospirosis, typhoid fever, and meningococcal septic shock (1, 2, 11). Confusion may also arise when a patient with suspected dengue presents with central nervous system symptoms. Although central nervous system symptoms may result from the dengue viral infection or complications detailed previously, coinfections are not uncommon, and if the clinical or laboratory features are atypical for dengue, or coexisting infections cannot be ruled out, appropriate empirical antimicrobials (antibiotics, antiviral agents, or antimalarial agents) should be initiated after drawing samples for laboratory conrmation and appropriate cultures. The choice of antimicrobials depends on the patients symptoms and signs, prevalent infections in the community, and their resistance patterns. Early empirical antibiotics for suspected septic shock or central nervous system infections are important, because delays in initiation of appropriate antibiotics have been shown to worsen outcomes (50). Cranial imaging may be necessary in the presence of a neurologic presentation. Performing a lumbar puncture may be hazardous in a bleeding, thrombocytopenic patient in whom the hemodynamics is precarious (51). A lumbar puncture to
94

determine any concurrent central nervous system infection may be more safely performed when the patient is stable. Empirical antimicrobials may be deescalated once the clinical picture emerges with greater clarity and culture results are available. Laboratory Conrmation of Dengue. There are three main methods for diagnosing DV infections (1, 9, 12, 48): serological tests; virological diagnosis; and molecular methods including the polymerase chain reaction. The choice of test depends on whether the patient is in the initial stage, in which fever and viremia are present (virological and molecular diagnosis most appropriate), or the postpyrexial period, which lasts a few weeks (serological tests appropriate) (12). Viral Isolation and Identication by Using Mosquito Cell Lines. Serum inoculation either into mosquito cell lines or directly into mosquitoes is the most common method for virus isolation (9). Molecular Diagnosis. The sensitivity, specicity, and rapid detection of minute quantities of dengue viral material in the patients serum makes reverse-transcriptase polymerase chain reaction useful for the detection of dengue infection early in the disease (within 48 hrs) when antibodies are not detected (52). A recently available test that can diagnose dengue within the rst few days of fever is the nonstructural protein-1 monoclonal antibody in an enzyme-linked immunosorbent assay format that can detect dengue nonstructural protein-1 antigen in blood (12, 53). Serologic Testing. Conrmation of acute DV infection is most frequently accomplished by using serology (1, 2). Serologic tests for the diagnosis of acute DV infection include the hemagglutination inhibition assay and immunoglobulin G (IgG) or IgM enzyme immunoassays (52). The IgM antibody-capture enzyme-linked immunosorbent assay is the test most widely used, because it is relatively inexpensive, sensitive, and quick and simple to perform; however, it suffers from low sensitivity compared with the hemagglutination-inhibition assay (11, 32). The development of several rapid diagnostic kits, which use immunochromatographic or immunoblot technologies, has enabled rapid bedside serological testing; however, the diagnostic accuracy may be low in terms of sensitivity and specicity (9, 54). Laboratory Studies to Monitor Disease Progression and Complications. The

Table 1. Laboratory ndings in the critical phase of dengue Hematologic investigations Elevated hematocrit level Low platelet counts ( 100,000 cells/mm3) Progressive leukopenia with atypical lymphocytes Abnormal coagulation prole Biochemical investigations Hypoalbuminemia Electrolyte disturbances (hyponatremia) Metabolic acidosis Elevated liver enzyme levels Imaging features Thickened gall bladder wall Pleural effusions, right more frequent than left Ascites

earliest evidence of plasma leak in the critical phase of dengue as alluded to earlier may be obtained by serial blood counts that demonstrate an increasing Hct level, progressive leukopenia and thrombocytopenia, and ultrasound ndings of a thickened gall bladder wall, as well as ascitic and pleural uid (Table 1) (2, 12, 55). If formal laboratory services are unavailable, a microcentrifuge can be used to estimate capillary Hct at the bedside. Other tests may be dictated by the clinical status and include measurements of glucose, electrolytes, blood gases, and lactate and tests of renal, liver, and coagulation function.

Management of Patients With Dengue

For such a complex, dynamic, and unpredictable disease, successful outcomes with mortality rates of 1% can be achieved in the vast majority of patients with surprisingly simple and inexpensive interventions, provided they are early, appropriate, and continuously targeted to keep pace with the disease evolution. This underscores the vital importance of empowering the front-line healthcare personnel (doctors and nurses) at primary and secondary health centers, clinics, and hospitals to facilitate early recognition and carefully monitor IV rehydration. Priorities during initial patient contact are to establish whether a patient has dengue, determine the phase of disease (febrile, critical, or recovery), and recognize warning signs and/or the presence of severe dengue, if present. In addition to a physical examination, a complete blood count in the febrile phase serves several useful functions if the patient
Pediatr Crit Care Med 2011 Vol. 12, No. 1

progresses to the critical phase: knowledge of the patients baseline Hct level can provide early information indicating onset of plasma leak, can quantitate the extent of plasma loss, is a good guide to uid replacement, and, in conjunction with other signs, can indicate occult blood loss (2). Most patients with DF and DHF can be managed without hospitalization provided they are alert, there are no warning signs or evidence of abnormal bleeding, their oral intake and urine output are satisfactory, and the caregiver is educated regarding fever control and avoiding nonsteroidal anti-inammatory agents and is familiar with the course of illness. A dengue information/home care card that emphasizes danger/warning signs is important (2). These patients need daily clinical and/or laboratory assessment by trained doctors or nurses until the danger period has passed. For a more detailed guide to outpatient assessment and monitoring, the reader may refer to the 2009 WHO/ Tropical Disease Research document on Dengue (2). If dengue is suspected or conrmed, disease notication to public health authorities is important so that preventive measures may be set into motion. Indications for hospitalization and IV uids include warning signs (Fig. 2) of signicant plasma leak, of which severe, intense abdominal pain is considered the most important; other warning signs are persistent vomiting, restlessness or lethargy, clinical uid accumulation, mucosal or other signicant bleeds, lethargy or restlessness, and a rise in Hct level, along with a rapid decrease in platelet count (2, 28). Infants and patients with comorbid conditions such as diabetes, renal failure, or obesity may also require admission. Indications for intensive care unit admission include children with severe dengue manifesting with shock, respiratory distress, abnormal bleeding, or organ failure, e.g., neurologic complications or liver and/or renal dysfunction (1, 2, 38). The three major priorities of management of hospitalized patients with dengue in the critical phase are replacement of plasma losses, early recognition and treatment of hemorrhage, and prevention of FO. Replacement of Plasma Losses Goals of Fluid Management in Dengue. IV rehydration is the single most important intervention that can correct shock and save lives in both severe and nonsevere forms of dengue, provided it is
Pediatr Crit Care Med 2011 Vol. 12, No. 1

timely and appropriate. Yet, the seemingly simple task of getting the prescribed uid just right is often challenging, demands the highest level of clinical judgment, and is ultimately the key that differentiates a good vs. bad outcome in sick children with dengue. In resource-limited, tropical areas of the world in which dengue outbreaks are most common, intensive care facilities for monitoring and treatment of shock and respiratory failure may be unavailable (56). The goals of treatment of dengue shock are necessarily two-pronged and include both early recognition and reversal of shock and simultaneously avoiding FO and the consequent need for ventilation by using simple monitoring tools (5759). These goals may be facilitated by aiming to restore a minimally acceptable circulating volume that is adequate to establish perfusion to vital organs and avoid hemorrhage and multiorgan failure (2, 5759). In addition, serial monitoring and correction of coexisting hypoglycemia, hypocalcemia, and electrolyte abnormalities are important. Titrating uid therapy in dengue. Fluid therapy in a patient with dengue shock has two parts: initial, rapid uid boluses to reverse shock followed by titrated uid volumes to match ongoing losses (2). However, for a patient who has warning signs of plasma leakage but is not yet in shock, the initial uid boluses may not be necessary (Table 2). The best methods for titrating uid therapy and detecting early signs of hem-

Table 2. Volume-replacement owchart for patients with dengue with warning signs Assess airway and breathing and obtain baseline Hct level Commence uid resuscitation with normal saline/Ringers lactate at 57 mL/kg over 12 hrs If hemodynamics and Hct level are stable, plan a gradually reducing IVF regimen Titrate uids on the basis of vital signs, clinical examination, urine output (aim for 0.51 mL/kg/hr), and serial Hct level IVFs, 57 mL/kg/hr for 12 hrs, then: Reduce IVFs to 35 mL/kg/hr for 24 hrs; Reduce IVFs to 23 mL/kg/hr for 24 hrs Continue serial close clinical monitoring and every 68 hourly Hct level Oral rehydration solutions may sufce when vomiting subsides and hemodynamics stabilize A monitored uid regimen may be required for 2448 hrs until danger period subsides Hct, hematocrit; IVF, intravenous uid.

orrhage are repeated, meticulous, clinical evaluation in conjunction with analysis of serial Hct trends by experienced caregivers. Sophisticated invasive monitoring is rarely necessary unless patients arrive late with established shock. The end points/targets of uid administration are normalization of the systolic BP (if low) and obtaining a pulse pressure of 30 mm Hg, a urine output of 0.51 mL/ kg/hr with stable vital signs, and a gradual decrease in the elevated baseline Hct level (1, 2, 5759). Monitoring hourly urine output serves two important goals: an output of 0.51.0 mL/kg/hr with stable vital signs indicates shock reversal and ensures a minimal acceptable circulating volume, whereas an output of 1.52 mL/kg/hr may be the earliest indicator of overhydration/FO with the potential risk of respiratory insufciency (59) (Table 3). Similarly, assessing two Hct values at 4-hr intervals in conjunction with the circulatory status will provide valuable clues. A high or increasing Hct level indicates the need for increased volumes of crystalloids if the patient has unstable hemodynamics, whereas in a stable patient, an experienced clinician may elect to monitor the patient closely without increasing uid rates. Likewise, a low or normal Hct level in conjunction with shock may be an important indicator of occult hemorrhage and the need for urgent blood transfusion, whereas in a stable patient in the recovering phase, prompt cessation of IV uids is the most important action indicated (2). The critical phase of plasma loss may continue for 24 48 hrs, necessitating constant, careful titration of uid administration tailored to the clinical status, Hct level, and urine output for this period (2, 56 58). A detailed owchart recording hourly vital signs, uid balance, circulatory status, and Hct level is essential. Table 2 and Figures 4 and 5 suggest an approach for treating dengue with warning signs and dengue with compensated shock and hypotensive shock, respectively. Figure 6 outlines the approach to late presenters with established shock, and Table 3 provides suggestions for controlled uid resuscitation in dengue shock syndrome (DSS) while at the same time attempting to prevent/minimize FO. Differences between DSS and septic shock. Compared to children with septic shock, who often require rapid, largevolume uid resuscitation (60), there are major differences both in the rates and volumes of uid resuscitation for dengue
95

Table 3. Guidelines for reversing dengue shock while minimizing uid overload 1. Severe dengue with compensated shock: Stabilize airway and breathing, obtain baseline Hct level, initiate uid resuscitation with NS/RL at 510 mL/kg over 1 hr, and insert urine catheter early. 2. Severe dengue with hypotension: Stabilize airway and breathing, obtain baseline Hct level, initiate uid resuscitation with 12 boluses of 20 mL/kg NS/RL or synthetic colloid over 1520 mins until pulse is palpable, slow down uid rates when hemodynamics improve, and repeat second bolus of 10 mL/kg colloid if shock persists and Hct level is still high. 3. Synthetic colloids may limit the severity of uid overload in severe shock. 4. End points/goals for rapid uid boluses: Improvement in systolic BP, widening of pulse pressure, extremity perfusion and the appearance of urine, and normalization of elevated Hct level. 5. If baseline Hct level is low or normal in presence of shock, hemorrhage likely to have worsened shock, transfuse fresh WB or fresh PRBCs early. 6. After rapid uid boluses, continue isotonic uid titration to match ongoing plasma leakage for 2448 hrs; after shock correction, if patient not vomiting and is alert, oral rehydration uids may sufce to match ongoing losses. 7. Check Hct level hourly to twice hourly for rst 6 hrs, and decrease frequency as patient improves. 8. Goals for ongoing uid titration: Stable vital signs, serial Hct measurement showing gradual normalization (if not bleeding), and low normal hourly urine output are the most objective goals indicating adequate circulating volume; adjust uid rate downward when this is achieved. 9. Plasma leakage is intermittent even during the rst 24 hrs after the onset of shock; hence, uid requirements are dynamic. 10. Targeting a minimally acceptable hourly urine output (0.51 mL/kg/hr) is an effective and inexpensive monitoring modality that can signal shock correction and minimize uid overload. 11. A urine output of 1.52 mL/kg/hr should prompt reduction in uid infusion rates, provided hyperglycemia has been ruled out. 12. Separate maintenance uids are not usually required; glucose and potassium may be administered separately only if low. 13. Hypotonic uids can cause uid overload; also, avoid glucose-containing uids, such as 1/2 GNS (GNS or I/2 GNS): the resultant hyperglycemia can cause osmotic diuresis and delay correction of hypovolemia. 14. Commence early enteral feeds when vital signs are stable, usually 48 hrs after admission. 15. All invasive procedures (intubation, central lines, and arterial cannulation) must be avoided; if essential, they must be performed by the most experienced person. Orogastric tubes are preferred to nasogastric tubes. 16. Signicant hemorrhage mandates early fresh WB or fresh PRBC transfusion; minimize/avoid transfusions of other blood products, such as platelets and fresh-frozen plasma unless bleeding is uncontrolled despite 23 aliquots of fresh WB or PRBCs. NS/RL, normal saline/Ringers lactate; Hct, hematocrit; BP, blood pressure; WB, whole blood; PRBC, packed red blood cell; GNS, 5% glucose in normal saline; 12 GNS, 5% glucose in 12 normal saline.

Figure 4. Volume-replacement owchart for patients with severe dengue and compensated shock. IV, intravenous.

shock. Wills et al (57) have used much lower uid resuscitation rates in 500 patients with DSS, and these restricted volumes were successful in not only reversing shock but also minimizing complications of FO, including the need for assisted ventilation. The authors reported mortality rates in the range of 0.2% with slow uid-lling at rates of 25 mL/kg over the rst 2 hrs. Although there is no evidence that colloids are superior to crystalloids for resuscitation, colloids are often used for severe dengue shock (2, 57). The signicant differences in uid resuscitation volumes for septic vs. dengue shock may probably relate to the fact that patients with dengue shock are vasoconstricted with a narrow pulse pressure as opposed to the predominantly vasodilated states in septic shock (2, 59). When can IV hydration be discontinued? Cessation of IV uids is important for preventing FO and can be considered 24 48 hrs after defervescence when the hemodynamics, Hct level, and urine output are stable, despite minimal IV uids, especially if the patient is tolerating oral uids. Recognition and Management of Hemorrhage. Early detection of signs of hemorrhage, especially when the losses are internal, is important. Failure to recognize and treat occult hemorrhage on an emergent basis is one of the most important yet preventable causes of death (2). Hemorrhage should be considered in the critical phase of dengue when the Hct level is normal or lower than expected for the degree of shock or the hemodynamics fails to normalize despite the initial 40 60 mL/kg of crystalloids/colloids (2). Clinical features of signicant hemorrhage may be subtle and include increase in tachycardia, abdominal distension and/or tenderness, stress-induced leukocytosis (instead of the characteristic leukopenia), agitation/lethargy, acidosis, and evidence of worsening organ function (2). Frank hypotension with dengue usually indicates signicant 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 lifethreatening bleeding is restoration of oxygen-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 signicantly. The 2009 WHO dengue guidelines emphasize that, in a bleeding patient with dengue, the
Pediatr Crit Care Med 2011 Vol. 12, No. 1

96

Figure 5. Suggested approach to a patient with severe dengue and hypotension. NS/RL, normal saline/Ringers lactate.

threshold for PRBCs/WB must be higher than that suggested for septic shock, for which an Hct level of 30% is the usual transfusion threshold (2, 60). This is because hemorrhage with dengue is most often preceded by a background of protracted shock due to plasma leak, which results in the characteristic elevated Hct level. Correction of shock with two or more aliquots of fresh WB/PRBCs usually breaks the vicious cycle of acidosis, hypoperfusion, and disseminated intravascular coagulation by restoring circulating volume and improving tissue oxygen delivery (2). This should be administered in a controlled fashion to prevent FO. Administration of other blood components, such as platelets, fresh-frozen plasma, or cryoprecipitate, may contribute to volume overload and are not as important as fresh WB or PRBCs (2) unless the bleeding is ongoing despite 23 aliquots of blood transfusion. It is also important to remember that preventive platelet transfusion is unlikely to decrease the incidence of signicant bleeding (61). Other infrequently reported interventions for patients with bleeding and refractory thrombocytopenia are IV anti-D immunoglobulin 250 IU/kg (62), IV immunoglobulin (63), and recombinant activated factor VII (64); all these therapies are expensive, not proven to be of clinical benet, and not currently recommended (2). Although the two most important causes of persistent or recurrent shock
Pediatr Crit Care Med 2011 Vol. 12, No. 1

are uncorrected hypovolemia due to ongoing plasma leakage and hemorrhage, other infrequent causes of persistent shock are myocardial dysfunction and abdominal compartment syndrome (ACS), the latter may be encountered in late presenters (38, 44). Myocardial dysfunction in dengue is most often a secondary phenomena due to the detrimental adaptive phenomena of prolonged uncorrected hypovolemic shock (e.g., excessively elevated systemic vascular resistance causing coronary ischemia) that may be further aggravated by high doses of inotropes/pressors. Although primary myocardial dysfunction, including both systolic and diastolic dysfunction, has been described in children with dengue (31, 41 43), it is an uncommon entity and is much less frequent in DSS compared to septic shock (58). Caregivers must desist from overzealous prescriptions of inotropes, because these agents can paradoxically worsen the shock state, especially if hypovolemia is still uncorrected. Inotrope/pressor support may occasionally be indicated in late presenters with dengue shock when features of low cardiac output persist, despite having received 40 60 mL/kg of uid and correction of blood loss, i.e., patients with uid/blood transfusion refractory shock in whom myocardial dysfunction is suspected or conrmed by echocardiography (if resources and expertise are available) (Fig. 6). Inotropes must be ceased if tachycardia or the

shock state worsens after initiation. Pressors may also be indicated before intubation of a patient with dengue shock, because some patients may have catastrophic decompensation during this period. Indications for Central Venous Pressure 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 benets, but if shock persists despite 40 60 mL/kg uids and correction of suspected hemorrhage, an experienced operator may consider insertion of a central venous catheter. Ultrasound-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 phase of dengue relates to FO and pulmonary edema (PE). IV rehydration is the sheet anchor of shock therapy; however, a signicant proportion of the administered uid will inevitably leak out of the vascular compartment with worse edema, uid collections, and respiratory insufciency. Overhydration and pathologic uid collections can easily occur if more uid than that sufcient to maintain a minimal acceptable circulating volume is prescribed. Apart from PE, overzealous uid administration can also cause tense large-volume ascites, which may lead to ACS (1, 38). Strategies for preventing FO/PE include avoiding prophylactic blood product transfusions in nonbleeding patients (even if thrombocytopenia and coagulopathy are signicant) (2, 6, 61). Also important is prompt cessation of IV uids during the recovery phase, because resorption of the leaked plasma occurs during this period and extraneous IV uid can easily worsen FO, precipitate PE, and large pleural and/or ascitic collections (2). Despite these strategies, some patients may develop hypoxemic respiratory failure with respiratory distress and need positivepressure ventilation, including nasal continuous positive airway pressure (64). Treatment of Established FO: Diuretics and Peritoneal Dialysis. Postresuscitation uid-removal strategies, such as diuretic infusions, should not be necessary at all if uid resuscitation was done judiciously; however, on occasion, furosemide boluses, continuous infusions, and even peritoneal dialysis have been used (44). The decision to administer di97

occur (2, 67); prevention of ACS by early recognition of shock and judicious uid administration remains the best policy. Complications of aggressive invasive intensive care unit interventions may lead to signicant morbidity and mortality in sick, bleeding children with dengue, although these have been seldom reported. Catastrophic bleeding may result 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 pleural and ascitic uid 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 corticosteroids 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.

uretics to a patient with dengue and FO requires considerable judgment, because diuretics can easily worsen the circulatory status in children who are still in the critical phase of plasma leakage (2). If the critical period has passed as demonstrated by a stable Hct level, stable hemodynamics, and a good urine output despite minimal IV uids, a patient with features of FO/PE may be cautiously commenced on a diuretic infusion at 0.1 mg/ kg/hr (2). Any hemodynamic deterioration should prompt immediate cessation of the diuretic infusion. Peritoneal dialysis has been used for patients with oliguric renal failure or diuretic-resistant FO and for patients with ACS (38, 44) but may provoke bleeding and should rarely be necessary. Complications and Management Issues in Late Presenters With Established Shock. Late presenters often have a different and difcult course with refractory shock; catastrophic, uncontrollable hem98

orrhage and signicant uid collections; a higher prevalence of multiorgan failure; and the need for invasive and expensive intensive care unit monitoring and therapy (Fig. 6) (38). It is this group that may have myocardial dysfunction and pleural and ascitic collections, including ACS, that may worsen both respiratory and circulatory status (38, 44). Myocardial dysfunction in this group is usually attributable to prolonged coronary ischemia, which may be worsened by catecholamines; invasive hemodynamic monitoring in conjunction with serial echocardiography may aid in streamlining therapy (Fig. 6). ACS can set off a vicious cycle due to a combination of large-volume ascites and ischemic edematous gut in conjunction with positivepressure ventilation (35, 65). Controlled drainage of ascites may result in improved hemodynamics (66, 67) but must be performed with great caution, because hemorrhagic complications can

early recognition of plasma leakage and shock by an educated front-line workforce; early institution of a tightly controlled IV rehydration regimen with isotonic uids; ongoing titration of uid therapy based on serial monitoring of vital signs, urine output, and Hct level; early recognition of the occult hemorrhage and replacement with fresh WB/ PRBCs; measures to prevent FO, including prompt cessation of IV uid when the period of plasma leakage has ceased and avoiding preventive transfusion with platelets, fresh-frozen plasma, and other blood products; and minimizing iatrogenic interventions that may cause complications (nasogastric tubes, central venous pressure insertion, pleural and ascitic uid drainage).

Prognosis
Although mortality from dengue ranges from 1% to 5% (2, 8, 9, 57), mortality
Pediatr Crit Care Med 2011 Vol. 12, No. 1

from severe dengue shock can be much higher, up to 26%, especially in instances of profound shock and hemorrhage and when treatment is delayed (70).

2.

Prevention and Future Directions

Public health measures for curtailing this disease are presently focusing on preventive strategies that include measures for mosquito control and the development of vaccines (9, 71). However, prevention of dengue remains elusive, because control of the Ae. aegypti mosquito is costly and often ineffective and, hence, has not met with much success, similar to vaccine development (72). However, results of clinical eld tests with live attenuated tetravalent vaccines have indicated encouraging preliminary data in Thai adults and children (73).
3.

4.

5.

6. 7.

Summary and Conclusion

Infections with DVs result in a spectrum of responses, from a mild, undifferentiated, self-limited febrile illness to severe dengue, which can have a high mortality rate if detected late or treated inappropriately. The diagnosis of acute DV infection is based mainly on clinical signs and symptoms in endemic countries. In dengue-epidemic regions, mortality rates of 1% are achievable when highly trained caregivers at all levels are tuned to three aspects of management: a thorough understanding of the unpredictable and dynamic nature of the disease; early recognition of warning signs and occult hemorrhage; and continuously monitoring the patient and titrating interventions to match the rapidly evolving clinical status.
8. 9. 10.

11.

12. 13.

14.

15.

ACKNOWLEDGMENTS
We are grateful for the detailed analysis and insightful comments of Dr. Indumathy Santhanam and Dr. Shanthi Sangaredddy, assistant professors of emergency medicine and intensive care from the Institute of Child Health (Chennai, India), and Dr. Shrishu Kamath and Dr. Gayathri Subramaniam, junior consultants from Apollo Childrens Hospital (Chennai).

16.

17.

18.

19.

REFERENCES
1. World Health Organization: Dengue Hemorrhagic Fever: Diagnosis, Treatment, Preven20.

tion and Control. Second Edition. Geneva, World Health Organization, 1997 Dengue Hemorrhagic Fever: Diagnosis, Treatment, Prevention and Control. Third Edition. A joint publication of the World Health Organization (WHO) and the Special Programme for Research and Training in Tropical Diseases (TDR), Geneva, 2009 Gubler DJ: Dengue/dengue hemorrhagic fever: History and current status. Novartis Found Symp 2006; 277:316 Centers for Disease Control and Prevention: Dengue. Available at http://www.cdc.gov/ NCIDOD/DVBID/DENGUE. Accessed September 2008 Pinheiro FP, Corber SJ: Global situation of dengue and dengue hemorrhagic fever and its emergence in the Americas. World Health Stat Q 1997; 50:161168 Gubler DJ: Dengue and dengue hemorrhagic fever. Clin Microbiol Rev 1998; 11:480 496 World Health Organization: Scientic working group on dengue, Geneva, 2006. Available at http://www.who.int/tdr/svc/publications/tdrresearch-publications/swg-report-dengue. Accessed March 2009 Halstead SB: Is there an inapparent dengue explosion? Lancet 1999; 353:1100 1101 Guzman MG, Kour G: Dengue: An update. Lancet Infect Dis 2002; 2:33 42 Teo D, Ng LC, Lam S: Is dengue a threat to the blood supply? Transfus Med 2009; 19: 66 77 Malavige GN, Fernando S, Fernando DJ: Dengue viral infections. Postgrad Med J 2004; 80:588 601 Halstead SB: Dengue. Lancet 2007; 370: 1644 1652 Vaughn DW, Green S, Kalayanarooj S, et al: Dengue in the early febrile phase: Viremia and antibody responses. J Infect Dis 1997; 176:322330 Rothman AL: Pathogenesis of dengue virus infection, UpToDate 2008. Available at http:// www.Uptodate.com. Accessed September 2008 Shirtcliffe P, Cameron E, Nicholson KG, et al: Dont forget dengue! Clinical features of dengue fever in returning travellers. J R Coll Physicians Lond 1998; 32:235237 Mongkolsapaya J, Dejnirattisai W, Xu XN, et al: Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nat Med 2003; 9:921927 Rothman AL: Dengue: Dening protective versus pathologic immunity. J Clin Invest 2004; 113:946 951 Guzman MG, Alvarez M, Rodriguez-Roche R, et al: Neutralizing antibodies after infection with dengue 1 virus. Emerg Infect Dis 2007; 13:282286 Morens DM: Antibody-dependent enhancement of infection and the pathogenesis of viral disease. Clin Infect Dis 1994; 19: 500 512 Vaughn DW, Green S, Kalayanarooj S, et al: Dengue viremia titer, antibody response pat-

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

tern, and virus serotype correlate with disease severity. J Infect Dis 2000; 181:29 Binh PT, Matheus S, Huong VT, et al: Early clinical and biological features of severe clinical manifestations of dengue in Vietnamese adults. J Clin Virol 2009; 45:276 280 Nguyen TH, Lei HY, Nguyen TL, et al: Dengue hemorrhagic fever in infants: A study of clinical and cytokine proles. J Infect Dis 2004; 189:221232 Kliks SC, Nimmanitya S, Nisalak A, et al: Evidence that maternal dengue antibodies are important in the development of dengue hemorrhagic fever in infants. Am J Trop Med Hyg 1988; 38:411 419 Thisyakorn U, Nimmannitya S: Nutritional status of children with dengue hemorrhagic fever. Clin Infect Dis 1993; 16:295297 Bandyopadhyay S, Lum LC, Kroeger A: Classifying dengue: A review of the difculties in using the WHO case classication for dengue haemorrhagic fever. Trop Med Int Health 2006; 11:1238 1255 Rigau-Perez JG: Severe dengue: The need for new case denitions. Lancet Infect Dis 2006; 6:297302 Deen JL, Harris E, Wills B, et al: The WHO dengue classication and case denitions: Time for a reassessment. Lancet 2006; 368: 170 173 TDR: World Health Organization issues new dengue guidelines. Available at http:// apps.who.int/tdr/svc/publications/tdrnews/ issue-85/tdr-briey. Accessed July 1, 2010 Wills BA, Oragui EE, Stephens AC, et al: Coagulation abnormalities in dengue hemorrhagic fever: Serial investigations in 167 Vietnamese children with dengue shock syndrome. Clin Infect Dis 2002; 35:277285 Gomber S, Ramachandran VG, Satish Kumar KN, et al: Hematological observations as diagnostic markers in dengue hemorrhagic fever: A reappraisal. Indian Pediatr 2001; 38: 477 481 Khongphatthanayothin A, Suesaowalak M, Muangmingsook S, et al: Hemodynamic proles of patients with dengue hemorrhagic fever during toxic stage: An echocardiographic study. Intensive Care Med 2003; 29: 570 574 Rothman AL: Clinical presentation and diagnosis of dengue virus infections UpToDate 2008. Available at http://www.Uptodate.com. Accessed September 2008 Kabra SK, Jain Y, Pandey RM, et al: Dengue hemorrhagic fever in children in the 1996 Delhi epidemic. Trans R Soc Trop Med Hyg 1999; 93:294 298 Srichaikul T, Nimmanitaya S, Artchararit N, et al: Fibrinogen metabolism and disseminated intravascular coagulation in dengue hemorrhagic fever. Am J Trop Med Hyg 1977; 26:525532 Mitrakul C, Poshyachinda M, Futrakul P, et al: Hemostatic and platelet kinetic studies in dengue hemorrhagic fever. Am J Trop Med Hyg 1977; 26:975984 Lum LCS, Goh AYT, Chan PWK, et al: Risk

Pediatr Crit Care Med 2011 Vol. 12, No. 1

99

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

factors for hemorrhage in severe dengue infections. J Pediatr 2002; 140:629 631 Nimmannitya S, Thisyakorn U, Hemsrichart V: Dengue haemorrhagic fever with unusual manifestations. Southeast Asian J Trop Med Public Health 1987; 18:398 406 Kamath SR, Ranjit S: Clinical features, complications and atypical manifestations of children with severe forms of dengue hemorrhagic fever in South India. Indian J Pediatr 2006; 73:889 895 Solomon T, Dung NM, Vaughn DW, et al: Neurological manifestations of dengue infection. Lancet 2000; 355:10531059 Lum LC, Lam SK, Choy YS, et al: Dengue encephalitis: A true entity? Am J Trop Med Hyg 1996; 54:256 259 Wali JP, Biswas A, Chandra S, et al: Cardiac involvement in dengue haemorrhagic fever. Int J Cardiol 1998; 64:3136 Kabra SK, Juneja R, Madhulika, et al: Myocardial dysfunction in children with dengue haemorrhagic fever. Natl Med J India 1998; 11:59 61 Khongphatthanayothin A, Lertsapcharoen P, Supachokchaiwattana P, et al: Myocardial depression in dengue hemorrhagic fever: Prevalence and clinical description. Pediatr Crit Care Med 2007; 8:524 529 Ranjit S, Kissoon N, Jayakumar I: Aggressive management of dengue shock syndrome may decrease mortality rate: A suggested protocol. Pediatr Crit Care Med 2005; 6:412 419 Srichaikul T, Punyagupta S, Kanchanapoom T: Hemophagocytic syndrome in dengue hemorrhagic fever with severe multiorgan complications. J Med Assoc Thai 2008; 91: 104 109 Khilnani P, Sarma D, Zimmerman J, et al: Epidemiology and peculiarities of pediatric multiple organ dysfunction syndrome in New Delhi. India Intensive Care Med 2006; 32: 1856 1862 Khilnani P, Sarma D, Singh R, et al: Demographic prole and outcome analysis of a tertiary level pediatric intensive care unit. Indian J Pediatr 2004; 71:587591 De Paula SO, da Fonseca BAL: Dengue: A review of the laboratory tests a clinician must know to achieve a correct diagnosis. Braz J Infect Dis 2004; 8:390 398 Ramos M, Tomashek K, Arguello D, et al: Early clinical features of dengue infection in Puerto Rico. Trans R Soc Trop Med Hyg 2009; 103:878 884 Kumar A, Roberts D, Wood KE, et al: Dura-

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

tion of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34:1589 1596 Mellor DH: The place of computed tomography and lumbar puncture in suspected bacterial meningitis. Arch Dis Child 1992; 67: 14171419 De Paula SO, Pires Neto RJ, Correa JA, et al: The use of reverse transcription-polymerase chain reaction (RT-PCR) for the rapid detection and identication of dengue virus in an endemic region: A validation study. Trans R Soc Trop Med Hyg 2002; 96:266 269 Dussart P, Labeau B, Lagathu G, et al: Evaluation of an enzyme immunoassay for detection of dengue virus NS1 antigen in human serum. Clin Vaccine Immunol 2006; 13: 11851189 Chakravarti A, Gur R, Berry N, et al: Evaluation of three commercially available kits for serological diagnosis of dengue haemorrhagic fever. Diagn Microbiol Infect Dis 2000; 36:273274 Colbert JA, Gordon A, Roxelin R, et al: Ultrasound measurement of gallbladder wall thickening as a diagnostic test and prognostic indicator for severe dengue in pediatric patients. Pediatr Infect Dis J 2007; 26: 850 852 Singhi S, Khilnani P, Lodha R, et al: Guidelines for treatment of septic shock in resource limited environments. J Pediatr Infect Dis 2009; 4:173192 Wills BA, Nguyen MD, Ha TL, et al: Comparison of three uid solutions for resuscitation in dengue shock syndrome. N Engl J Med 2005; 353:877 889 Moxon C, Wills B: Management of severe dengue in children. Adv Exp Med Biol 2008; 609:131144 Ranjit S, Kissoon N, Gandhi D, et al: Early differentiation between dengue and septic shock by comparison of admission hemodynamic, clinical, and laboratory variables: A pilot study. Pediatr Emerg Care 2007; 23: 368 375 Brierley J, Carcillo JA, Choong K, et al: Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med 2009; 37:666 688 Lum LC, Abdel-Latif Mel-A, Goh AY, et al: Preventive transfusion in dengue shock syn-

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

drome: Is it necessary? J Pediatr 2003; 143: 682 684 de Castro RA, de Castro JA, Barez MY, et al: Thrombocytopenia associated with dengue hemorrhagic fever responds to intravenous administration of anti-D (Rh(0)-D) immune globulin. Am J Trop Med Hyg 2007; 76: 737742 Rajapakse S: Intravenous immunoglobulins in the treatment of dengue illness. Trans R Soc Trop Med Hyg 2009; 103:867 870 Chuansumrit A, Wangruangsatid S, Lektrakul Y, et al: Control of bleeding in children with dengue hemorrhagic fever using recombinant activated factor VII: A randomized, double-blind, placebo-controlled study. Blood Coagul Fibrinolysis 2005; 16:549 555 Cam BV, Tuan DT, Fonsmark L, et al: Randomized comparison of oxygen mask treatment vs. nasal continuous positive airway pressure in dengue shock syndrome with acute respiratory failure. J Trop Pediatr 2002; 48:335339 Carlotti AP, Carvalho WB: Abdominal compartment syndrome: A review. Pediatr Crit Care Med 2009; 10:115120 Clinical Practice Guideline on Management of Dengue in Adults. Second Edition. 2008. Available at http://www.moh.gov.my. Accessed October 25, 2009 Myo-Khin, Soe-Thein, Thein-Thein-Myint, et al: Serum cortisol levels in children with dengue haemorrhagic fever. J Trop Pediatr 1995; 41:295297 Panpanich R, Sornchai P, Kanjanaratanakorn K: Corticosteroids for treating dengue shock syndrome. Cochrane Database Syst Rev. 2006; 3:CD003488 Cherian T, Ponnuraj E, Kuruvilla T, et al: An epidemic of dengue haemorrhagic fever & dengue shock syndrome in & around Vellore. Indian J Med Res 1994; 100:5156 Rothman AL: UpToDate May 2008. Prevention and treatment of dengue virus infection UpToDate 2008. Available at http://www. Uptodate.com. Accessed September 2008 Monath TP: Dengue and yellow fever: Challenges for the development and use of vaccines. N Engl J Med 2007; 357:22222225 Sabchareon A, Lang J, Chanthavanich P, et al: Safety and immunogenicity of a three dose regimen of two tetravalent live-attenuated dengue vaccines in ve- to twelve-yearold Thai children. Pediatr Infect Dis J 2004; 23:99 109

100

Pediatr Crit Care Med 2011 Vol. 12, No. 1