Dengue hemorrhagic fever and shock syndromes*Suchitra Ranjit, MBBS, MD; Niranjan Kissoon, MBBS, FAAP, FCCM, FACPE    Objec...
dengue are complex and include large-                 T-Cell Activation and Apoptosis. In-       antibody levels decline b...
cal parameters (Fig. 2) is crucial for rec-                                                                               ...
blood counts demonstrating the triad of      ficulties in successful treatment of severe      vulsions, and extensor postur...
initial symptoms are often nonspecific,         determine any concurrent central ner-         Table 1. Laboratory findings i...
progresses to the critical phase: knowl-       timely and appropriate. Yet, the seem-            orrhage are repeated, met...
Table 3. Guidelines for reversing dengue shock while minimizing fluid overload                              shock. Wills et...
shock state worsens after initiation. Pres-                                                                               ...
occur (2, 67); prevention of ACS by early                                                                                 ...
from severe dengue shock can be much                    tion and Control. Second Edition. Geneva,               tern, and ...
Dengue hemorragico
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Dengue hemorragico

  1. 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 statementsan emphasis on clinical syndromes, classification, diagnosis, and from the World Health Organization and the Centers for Diseasemanagement, and to outline relevant aspects of epidemiology, Control and Prevention. Dengue viral infections are caused by oneimmunopathogenesis, and prevention strategies. Dengue, a lead- of four single-stranded ribonucleic acid viruses of the familying cause of childhood mortality in Asia and South America, is the Flaviviridae and are transmitted by their mosquito vector, Aedesmost rapidly spreading and important arboviral disease in the aegypti. The clinical syndromes caused by dengue viral infectionsworld 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. ManagementPubMed from 1975 to March 2009 and the Cochrane Database of is predominantly supportive and includes methods to judiciouslySystematic 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 besification,” “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 illnessvant articles that would be important and of interest to the criticalD 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. Indrome 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 anChinese medical encyclopedia in 992 (3). ology, immunopathogenesis, clinical syn- authoritative consensus statement or aThis 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 asquito 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 andtropical 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 ofChildren’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 significantCanada. 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 112flicts of interest. “dengue shock syndrome”; “dengue” and countries; Southeast Asia and the west- For information regarding this article, “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 varyMedicine and the World Federation of Pediatric Inten- agement,” and “prevention.” We also from 1% to 5% (8) but can be 1% withsive 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 of90 Pediatr Crit Care Med 2011 Vol. 12, No. 1
  2. 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 areall 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 beand 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 loadsviruses (DVs), members of the Flavivirus (12, 16). Classification and Clinicalgenus of the Flaviviridae, called DEN-1, Neutralizing Antibodies and Antibody- Course of DengueDEN-2, DEN-3, and DEN-4. Lifetime im- Dependent Enhancement. The severity ofmunity 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 symptomaticshort-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 hasictus and Ae. polynesiensis may act as munopathogenesis of severe dengue (9, been reported, and it is likely that thevectors depending on the geographic lo- 17–19). various categories exist as a continuumcation (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 diseasetransmission 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 dengueDV is introduced into the skin by the bite tomatic infection, mild nonspecific symp- could not be included as having DHFof an infected female Aedes mosquito. toms, or classic dengue (1, 9). The more unless all criteria were present. This hadViremia in susceptible humans begins be- severe manifestations of shock and hem- adverse effects at various levels, includingtween 3 and 6 days after subcutaneous orrhage occur in 5% of DV infections during triage, disposition, and treatmentinjection, 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 denguefrom 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, whichInfections 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 studyDV infections is complex and remains in- Age. Dengue hemorrhagic fever (DHF) across dengue-endemic regions proposedcompletely 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 cliniciansforms by the presence of increased vascu- afflicted with severe disease (21). Infants identify rapidly and treat adequately thelar permeability (1, 2, 9, 12). A few salient can develop features of severe disease most severe, life-threatening forms of thefeatures 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 characterizedFigure 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. 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 thrombocytopeniaFigure 3. Phases of dengue in relation to symptoms and laboratory changes. AST, aspartate transam- may worsen disseminated intravascularinase; ALT, alanine aminotransferase; CNS, central nervous system; IgM, immunoglobulin M; IgG, coagulation, which may, in turn, lead toimmunoglobulin G. Adapted with permission from World Health Organization: Dengue Hemorrhagic massive hemorrhage, thus setting off aFever: 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 areprogress 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 ofincubation 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 bypatient develops a high-grade fever that toring for warning signs and other clini- serial laboratory studies with complete92 Pediatr Crit Care Med 2011 Vol. 12, No. 1
  4. 4. blood counts demonstrating the triad of ficulties in successful treatment of severe vulsions, and extensor posturing; theseprogressively increasing Hct, leukopenia, dengue stem from the dynamicity of den- neurologic signs can improve when theand thrombocytopenia, ultrasound find- gue, which makes it a challenge to detect perfusion normalizes. Other causes ofings of a thickened gall bladder wall, and and manage, especially for the uniniti- central nervous system symptoms in theascitic and pleural fluid and chest radio- ated physician— even experienced clini- patient with severe dengue are coexistinggraph 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, andare 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 leadwho do not defervesce despite the onset ten remain alert (1, 2). to obtundation and seizures. The preciseof plasma leakage (2, 11, 12). Evaluating As shock progresses, the diastolic BPs cause may be difficult to separate andhemoconcentration in patients with pre- and then the systolic BPs become unre- requires a consideration of the phase ofexisting 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 andable 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 leakageiron-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 systemiccritical 24 – 48 hrs of plasma leakage, 33). However, even with severe dengue, vascular resistance are the predominantthe final recovery phase is heralded by the in which marked thrombocytopenia and mechanisms of shock in severe denguegradual 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 haveover the next 48 –72 hrs. The patient may rare: the most important risk factor for been a few reports of relative bradycardiaexhibit 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-wavepetite, a stable hemodynamic status, and acidosis and hypoxia (2, 29, 36). Other changes on electrocardiogram, togethera 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 wasphase with a lower Hct level on account tory drug) exposure; and procedures such detected in any of the patients, whichof the reabsorbed fluid and a white cell as nasogastric tube insertion, arterial suggests that myocardial dysfunctionincrement that may precede platelet re- puncture, or intramuscular injections. might either be attributable to humoralcovery. 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 dysfunctionso that intravenous (IV) fluids may be severe dengue (37) and includes acute have been reported to cause refractorypromptly 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 adengue occurs in a small proportion of viral effect with hepatitis or focal necrosis surgical emergency had been previouslypatients and is defined by one or more of of the liver and is associated with a high classified as an uncommon manifestationthe following: 1) shock due to plasma mortality rate (37, 38). Elevated transam- (32), severe intense abdominal pain isleakage, 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 imminent3) severe organ impairment (liver, neu- atitis) (38). shock. Dengue has also been described asrologic symptoms, renal or myocardial Neurologic complications. Patients an important cause of hemophagocyticdysfunction) (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, andcompensated with a normal systolic acute pure motor weakness (11, 32, 38, Diagnosisblood pressure (BP), elevated diastolic 39). The DV has been isolated from theBP, narrow pulse pressure, and features cerebrospinal fluid of some patients hav- Although the diagnosis of acute DVof hypoperfusion, such as cold mottled ing features of encephalitis (40). In the infection is mainly clinical (1), pediatricskin, although in some patients, signifi- critical phase, cerebral hypoperfusion caregivers frequently find making ancant tachycardia may be absent (31). Dif- may result in altered mental status, con- early diagnosis challenging, because thePediatr Crit Care Med 2011 Vol. 12, No. 1 93
  5. 5. initial symptoms are often nonspecific, determine any concurrent central ner- Table 1. Laboratory findings in the critical phasemany common tropical infections can re- vous system infection may be more safely of denguesult in a presentation with fever and performed when the patient is stable. Hematologic investigationsthrombocytopenia with or without shock, Empirical antimicrobials may be deesca- Elevated hematocrit levelviremia 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 atypicallate in the course of illness (2, 48). Per- are available. lymphocytesforming a tourniquet test at each visit Laboratory Confirmation of Dengue. Abnormal coagulation profile Biochemical investigationsmay help differentiate dengue from other There are three main methods for diag- Hypoalbuminemiaviral 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 acidosistant as recording their presence, because molecular methods including the poly- Elevated liver enzyme levels Imaging featureswith dengue, it is at the time of deferves- merase chain reaction. The choice of test Thickened gall bladder wallcence that the disease manifests its sever- depends on whether the patient is in the Pleural effusions, right more frequent thanity, unlike other viral illnesses for which initial stage, in which fever and viremia lefta clinical improvement is to be expected are present (virological and molecular di- Asciteswith 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 weekstify 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 theconcluded that the presence of high- Using Mosquito Cell Lines. Serum inoc- critical phase of dengue as alluded tograde fever, rash, petechiae, or mucosal ulation either into mosquito cell lines or earlier may be obtained by serial bloodbleeds in the absence of cough and other directly into mosquitoes is the most com- counts that demonstrate an increasingrespiratory symptoms has a very high mon method for virus isolation (9). Hct level, progressive leukopenia andpositive 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 servicesagnoses that must be considered in the scriptase polymerase chain reaction use- are unavailable, a microcentrifuge can beappropriate 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 thever, and meningococcal septic shock (1, antibodies are not detected (52). A re- clinical status and include measurements2, 11). Confusion may also arise when a cently available test that can diagnose of glucose, electrolytes, blood gases, andpatient 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 Withinfection or complications detailed previ- dengue nonstructural protein-1 antigen Dengueously, 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 outcomesfections cannot be ruled out, appropriate complished by using serology (1, 2). Se- with mortality rates of 1% can beempirical antimicrobials (antibiotics, an- rologic tests for the diagnosis of acute DV achieved in the vast majority of patientstiviral agents, or antimalarial agents) infection include the hemagglutination with surprisingly simple and inexpensiveshould 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 toate 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 primaryand their resistance patterns. Early em- to perform; however, it suffers from low and secondary health centers, clinics, andpirical antibiotics for suspected septic sensitivity compared with the hemag- hospitals to facilitate early recognitionshock 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 hasbeen shown to worsen outcomes (50). matographic or immunoblot technolo- dengue, determine the phase of diseaseCranial 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 ofPerforming a lumbar puncture may be nostic accuracy may be low in terms of severe dengue, if present. In addition to ahazardous in a bleeding, thrombocytope- sensitivity and specificity (9, 54). physical examination, a complete bloodnic 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 patient94 Pediatr Crit Care Med 2011 Vol. 12, No. 1
  6. 6. progresses to the critical phase: knowl- timely and appropriate. Yet, the seem- orrhage are repeated, meticulous, clinicaledge of the patient’s baseline Hct level ingly simple task of getting the pre- evaluation in conjunction with analysis ofcan 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 isextent of plasma loss, is a good guide to clinical judgment, and is ultimately the rarely necessary unless patients arrivefluid replacement, and, in conjunction key that differentiates a good vs. bad out- late with established shock. The endwith other signs, can indicate occult come in sick children with dengue. In points/targets of fluid administration areblood 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 30managed 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 Hcttheir oral intake and urine output are able (56). The goals of treatment of den- level (1, 2, 57–59). Monitoring hourlysatisfactory, 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 stablesteroidal anti-inflammatory agents and is reversal of shock and simultaneously vital signs indicates shock reversal andfamiliar with the course of illness. A den- avoiding FO and the consequent need for ensures a minimal acceptable circulatinggue information/home care card that em- ventilation by using simple monitoring volume, whereas an output of 1.5–2phasizes danger/warning signs is impor- tools (57–59). These goals may be facili- mL/kg/hr may be the earliest indicator oftant (2). These patients need daily clinical tated by aiming to restore a minimally overhydration/FO with the potential riskand/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 athas passed. For a more detailed guide to gans and avoid hemorrhage and multior- 4-hr intervals in conjunction with theoutpatient assessment and monitoring, gan failure (2, 57–59). In addition, serial circulatory status will provide valuablethe 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 ofDengue (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 electthorities is important so that preventive shock has two parts: initial, rapid fluid to monitor the patient closely withoutmeasures 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 withfluids include “warning signs” (Fig. 2) of losses (2). However, for a patient who has shock may be an important indicator ofsignificant 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 mostargy, 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 mayrestlessness, and a rise in Hct level, along continue for 24 – 48 hrs, necessitatingwith 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 periodor 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 normalmission include children with severe den- tory status, and Hct level is essential. saline/Ringer’s lactate at 5–7 mL/kg over 1–2gue manifesting with shock, respiratory hrs Table 2 and Figures 4 and 5 suggest andistress, 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 compensatedliver 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 toment 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 denguetreatment of hemorrhage, and prevention ● Continue serial close clinical monitoring and shock syndrome (DSS) while at the sameof 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 hemodynamicsGoals of Fluid Management in Dengue. shock. Compared to children with septic stabilizeIV 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 areand save lives in both severe and nonse- major differences both in the rates andvere forms of dengue, provided it is Hct, hematocrit; IVF, intravenous fluid. volumes of fluid resuscitation for denguePediatr Crit Care Med 2011 Vol. 12, No. 1 95
  7. 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 considered11. 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 of14. Commence early enteral feeds when vital signs are stable, usually 4–8 hrs after admission. Hemorrhage. Early detection of signs of15. 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 recognize16. 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 2009Figure 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, the96 Pediatr Crit Care Med 2011 Vol. 12, No. 1
  8. 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 criticalFigure 5. Suggested approach to a patient with severe dengue and hypotension. NS/RL, normalsaline/Ringer’s lactate. phase of dengue relates to FO and pul- monary edema (PE). IV rehydration is the sheet anchor of shock therapy; however, athreshold 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 thewhich 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 pathologicten preceded by a background of protracted the latter may be encountered in late fluid collections can easily occur if moreshock due to plasma leak, which results in presenters (38, 44). fluid than that sufficient to maintain athe 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, overzealousaliquots of fresh WB/PRBCs usually to the detrimental adaptive phenomena fluid administration can also cause tensebreaks the vicious cycle of acidosis, hypo- of prolonged uncorrected hypovolemic large-volume ascites, which may lead toperfusion, and disseminated intravascu- shock (e.g., excessively elevated systemic ACS (1, 38). Strategies for preventinglar coagulation by restoring circulating vascular resistance causing coronary FO/PE include avoiding prophylacticvolume 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 thrombocytopeniaa 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 cessationsuch 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 plasmaume overload and are not as important as mon entity and is much less frequent in occurs during this period and extraneousfresh WB or PRBCs (2) unless the bleed- DSS compared to septic shock (58). Care- IV fluid can easily worsen FO, precipitateing 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 patientsfusion is unlikely to decrease the inci- shock state, especially if hypovolemia is may develop hypoxemic respiratory failuredence 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 asvated 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 doneical 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 beencauses 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. 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 controlleduretics to a patient with dengue and FO orrhage and significant fluid collections; IV rehydration regimen with isotonicrequires 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 basedtory 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, includingfeatures of FO/PE may be cautiously com- function in this group is usually attribut- prompt cessation of IV fluid when themenced on a diuretic infusion at 0.1 mg/ able to prolonged coronary ischemia, period of plasma leakage has ceasedkg/hr (2). Any hemodynamic deteriora- which may be worsened by cat- and avoiding preventive transfusiontion should prompt immediate cessation echolamines; invasive hemodynamic with platelets, fresh-frozen plasma, andof 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 interventionspatients 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 pressureACS (38, 44) but may provoke bleeding large-volume ascites and ischemic edem- insertion, pleural and ascitic fluidand 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- PrognosisShock. 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 rangesshock; catastrophic, uncontrollable hem- because hemorrhagic complications can from 1% to 5% (2, 8, 9, 57), mortality98 Pediatr Crit Care Med 2011 Vol. 12, No. 1
  10. 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; 181:2–9profound shock and hemorrhage and when 2. Dengue Hemorrhagic Fever: Diagnosis, 21. Binh PT, Matheus S, Huong VT, et al: Earlytreatment 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 –280Prevention 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. 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