ABSTRACT INTRODUCTION: Dengue haemorrhagic fever and dengue shock syndrome are major causes of hospital admission and mortality in children. Up to 5% of people with dengue haemorrhagic fever die of the infection, depending on availability of appropriate supportive care. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of supportive treatments for dengue haemorrhagic fever or dengue shock syndrome in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 13 systematic reviews or RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this system- atic review we present information relating to the effectiveness and safety of the following interventions: adding blood component transfusion to standard intravenous fluids; adding carbazochrome sodium sulfonate, corticosteroids, or intravenous immunoglobulin to standard intravenous fluids; adding recombinant-activated factor VII to blood component transfusion; colloids; crystalloids; and intravenous fluids. QUESTIONS INTERVENTIONS Likely to be beneficial
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To be covered in future updates
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Supportive treatments for dengue fever in adolescents
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Footnote Unknown effectiveness
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Key points • Infection with the dengue virus, transmitted by mosquito, ranges from asymptomatic or undifferentiated febrile illness
to fatal haemorrhagic fever, and affects up to 100 million people a year worldwide.
Dengue haemorrhagic fever is characterised by: a sudden onset of high fever; haemorrhages in the skin, gas-trointestinal tract, and mucosa; and low platelet counts. Plasma leakage results in fluid in the abdomen and lungs. It typically occurs in children under 15 years.
Severe dengue haemorrhagic fever is called dengue shock syndrome.
Dengue haemorrhagic fever and dengue shock syndrome are major causes of hospital admission and mortalityin children. Up to 5% of people with dengue haemorrhagic fever die of the infection, depending on availability ofappropriate supportive care. • are the standard treatment to expand plasma volume and are likely to be beneficial, but studies
to demonstrate their effectiveness would be unethical.
Crystalloids seem as effective as colloids in children with moderately severe dengue shock syndrome, althoughwe don't know whether they are beneficial in severe dengue shock syndrome.
en plasma, packed red blood cells, or platelets)should be added to intravenous fluids in children with coagulopathy or bleeding. The optimal time for beginningtransfusion is unclear. • We don't know whether adding (Aav
avenous fluids reduces the risks of shock, pleural effusion,or mortality. We also don't know whether adding reduces the risk of bleeding episodes, shock, or mortality.
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1 . . . . . . . . . . . . . . . . . . . . . Clinical Evidence 2009;01:917
Dengue haemorrhagic fever or dengue shock syndrome in children ectious diseases DEFINITION
Dengue infection is a mosquito-borne arboviral infection. The spectrum of dengue virus infection ranges from asymptomatic or undifferentiated febrile illness to dengue fever and dengue haemor- rhagic fever or dengue shock syndrome. An important criterion to consider in the diagnosis of dengue infection is history of travel or residence in a dengue-endemic area within 2 weeks of the onset of fever. Dengue fever is an acute febrile illness whose clinical presentation varies with age. Infants and young children may have an undifferentiated febrile disease with a maculopapular rash. Children aged 15 years or older and adults may have either a mild febrile illness, or the classic in- capacitating disease (also called “breakbone fever”), presenting with high fever of sudden onset, and non-specific signs and symptoms of: severe headache; pain behind the eyes; muscle, bone, or joint pains; nausea; vomiting; and rash. Dengue haemorrhagic fever is characterised by four criteria: acute onset of high fever; haemorrhagic manifestations evidenced by a positive , mucosal and gastrointestinal tract bleeding; thrombocytopenia; and evi- dence of plasma leakage manifested by a rise or drop in haematocrit, fluid in the lungs or abdomen, or hypoproteinaemia. Dengue haemorrhagic fever is classified into four grades of sever Presence of thrombocytopenia and haemoconcentration differentiates dengue haemorrhagic fever grades I and II from dengue fever. Grades III and IV dengue haemorrhagic fever are considered dengue shock syndromeview deals with interventions for dengue haemorrhagic fever and dengue shock syndrome in children. INCIDENCE/
Dengue fever and dengue haemorrhagic fever are public health problems worldwide, particularly
in low-lying areas where Aedes aegypti, a domestic mosquito, is present. Cities near to the equatorbut high in the Andes are free from dengue because Aedes mosquitoes do not survive at high alti-tudes. Worldwide, an estimated 50–100 million cases of dengue fever, and hundreds of thousandsof dengue haemorrhagic fever, occur yearly. Endemic regions are the Americas, South EastAsia, the western Pacific, Africa, and the eastern Mediterranean. Major global demographic changesand their consequences (particularly: increases in the density and geographic distribution of thevector with declining vector control; unreliable water supply systems; increasing non-biodegradablecontainer and poor solid waste disposal; increased geographic range of virus transmission due toincreased air travel; and increased population density in urban areas) are responsible for theresurgence of dengue in the past century. The WHO estimates that global temperature risesof 1.0–3.5 °C may increase transmission of dengue fever by shortening the extrinsic incubationperiod of viruses within the mosquito, adding 20,000–30,000 more fatal cases annually.
Dengue virus serotypes 1–4 (DEN 1, 2, 3, 4) belonging to the flavivirus genus are the aetiological
RISK FACTORS agents. These serotypes are closely related, but antigenically distinct. Ae aegypti, the principal
vector, transmits the virus to and between humans. Dengue haemorrhagic fever and dengue shocksyndrome typically occur in children under the age of 15 years, although dengue fever primarilyoccurs in adults and older children. Important risk factors influencing who will develop denguehaemorrhagic fever or severe disease during epidemics include the virus strain and serotype, im-mune status of the host, age, and genetic predisposition. There is evidence that sequential infectionor pre-existing antidengue antibodies increases the risk of dengue haemorrhagic fever throughantibody-dependent enhancement.
Dengue fever is an incapacitating disease, but prognosis is favourable in previously healthyadults — although dengue haemorrhagic fever and dengue shock syndrome are major causes ofhospital admission and mortality in children. Dengue fever is generally self-limiting, with less than1% case fatality. The acute phase of the illness lasts for 2–7 days, but the convalescent phasemay be prolonged for weeks associated with fatigue and depression, especially in adults. Prognosisin dengue haemorrhagic fever and dengue shock syndrome depends on prevention, or earlyrecognition and treatment of shock. Case fatality ranges from 2.5–5.0%. Once shock sets in, fatal-ity may be as high as 12–44%. wever, in centres with appropriate intensive supportive treat-ment, fatality can be less than 1%. There is no specific antiviral treatment. The standard treatmentis to give intravenous fluids to expand plasma volume. People usually recover after prompt andadequate fluid and electrolyte supportive treatment. The optimal fluid regimen, however, remainsthe subject of debate. This is particularly important in dengue, where one of the management diffi-culties is to correct hypovolaemia rapidly without precipitating fluid overload.
To prevent mortality and improve symptoms, with minimal adverse effects. INTERVENTION OUTCOMES
Mortality; recurrence of shock; symptom relief; renal failure; length of hospital stay; time to recovery;time off work; need for blood transfusion; fluid requirements; adverse effects (bleeding, fluid overload,hypersensitivity reactions, and secondary infections). Secondary outcomes include developmentof shock and development of pleural effusion.
BMJ Publishing Group Ltd 2009. All rights reserved. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dengue haemorrhagic fever or dengue shock syndrome in children ectious diseases Clinical Evidence search and appraisal June 2008. The following databases were used to identifystudies for this systematic review: Medline 1966 to June 2008, Embase 1980 to June 2008, andThe Cochrane Database of Systematic Reviews and Cochrane Central Register of ControlledClinical Trials 2008, Issue 2 (1966 to date of issue). An additional search was carried out of theNHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews ofEffects (DARE) and Health Technology Assessment (HTA). We also searched for retractions ofstudies included in the review. Abstracts of the studies retrieved from the initial search were assessedby an information specialist. Selected studies were then sent to the contributor for additional as-sessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusionin this review were: published systematic reviews of RCTs and RCTs in any language and containingmore than 20 individuals of whom more than 80% were followed up. We may use sensitivity anal-ysis that supports the strength of conclusions when losses to follow-up seem to be significant. Length of follow-up required to include studies was at least from admission until discharge fromhospital or occurrence of a main outcome. We did not exclude RCTs described as “open”, “openlabel”, or not blinded. In addition, we use a regular surveillance protocol to capture harms alertsfrom organisations such as the FDA and the UK Medicines and Healthcare products RegulatoryAgency (MHRA), which are added to the reviews as required. The author also retrieved additionalmaterial through hand searches and personal contact with experts in the field. To aid readabilityof the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as RRsand ORs. We have performed a GRADE evaluation of the quality of evidence for interventions in-cluded in this revie
QUESTION What are the effects of supportive treatments for dengue haemorrhagic fever or dengue shock syndrome in children? INTRAVENOUS FLUIDS VERSUS NO TREATMENT*. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . We found no direct information about whether intravenous fluids are better than no active treatment or no treatment. There is consensus that immediate fluid replacement with crystalloids should be undertaken in a child who has dengue haemorrhagic fever or dengue shock syndrome. For GRADE evaluation of interventions for dengue haemorrhagic fever or dengue shock syndrome in children,
Benefits: Intravenous fluids versus placebo or no treatment: We found no RCTs (see comment below). Intravenous fluids versus placebo or no treatment: We found no RCTs. Comment:
It would be considered unethical to compare intravenous fluids against placebo in children withdengue haemorrhagic fever or dengue shock syndrome in a no-treatment trial. There is widespreadconsensus that intravenous fluid replacement with crystalloids should be universally used in childrenwith dengue haemorrhagic fever or dengue shock syndrome because these conditions lead to anacute increase in vascular permeability that leads to plasma leakage, resulting in increasedhaematocrit and decreased blood pressure. CRYSTALLOIDS VERSUS COLLOIDS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Symptom severity Crystalloids compared with colloids Crystalloids and colloids seem equally effective at reducing shock recurrence and the need for rescue colloids in children with dengue shock syndrome ( Ringer's lactate compared with colloids Ringer's lactate is as effective as Dextran 70 (6%), and 6% hydroxyethylstarch, at reducing the proportion of children with moderately severe dengue shock syndrome who need rescuecolloids for initial resucitation (). Dextran compared with starch solutions Dextran 70 (6%) and 6% hydroxyethyl starch are equally effective at reducingthe proportion of children with severe dengue shock syndrome who require rescue fluid (moderate-quality evidence). For GRADE evaluation of interventions for dengue haemorrhagic fever or dengue shock syndrome in children,
We found no systematic review but found three RCTs (see comment below). The firstRCT (50 Vietnamese children aged 5–15 years with dengue shock syndrome) compared four intra-
BMJ Publishing Group Ltd 2009. All rights reserved. . Dengue haemorrhagic fever or dengue shock syndrome in children ectious diseases
venous fluid regimens for acute resuscitation: two crystalloid regimens (sodium chloride or Ringer’slactate solution, 25 children) and two colloid regimens (dextrCrystalloids or colloids were infused at a rate of 20 mL/kg for the first hour followed by 10 mL/kgfor the second hour. All children then received further intravenous infusions on an open basis atthe discretion of the attending physician according to WHO guidelines. All children recovered withfluid resuscitation alone (no deaths in any group). The RCT found no significant difference amonggroups in recurrence of shock (median: 1 episode in each group; P = 0.46), or requirement forfurther infusions of crystalloids (P = 0.16) or colloids (P = 0.70) between the 2-hour infusion andfull recovery from shock. Recovery from shock was defined as a pulse pressure of at least 20 mm Hg. The RCT also found no significant difference among groups in median duration in shock (mean:1.5 hours with sodium chloride v 5.0 hours with Ringer’s v 2.8 hours with dextran 70 v 7.0 hourswith gelafundin; P = 0.36). The second RCT (222 Vietnamese children, aged 1–15 years withdengue shock syndrome) also compared four intravenous fluid regimens for acute resuscitation:two crystalloid regimens (sodium chloride or Ringer’s lactate solution, 111 children) and two colloidregimens (dextr The fluids were infused at a rate of 20 mL/kgfor the first hour. All children then received further infusions of Ringer’s lactate solution accordingto WHO guidelines. However, children who failed to improve or who deteriorated were given addi-tional colloid (dextran 70) infusions at the discretion of the attending physician. All children recoveredwith fluid resuscitation (no deaths in any group). The RCT found no significant difference in theproportion of children who had recurrence of shock between crystalloids and colloids (24/90 [27%]with colloids v 20/81 [25%] with crystalloids; RR 1.02, 95% CI 0.56 to 1.85). It also found no signif-icant difference among groups in the total volume of fluid infused until full recovery from shock(P = 0.95), or in the proportion of children who required further infusions after the first hour (17/56[30%] with sodium chloride v 20/55 [36%] with Ringer’s v 17/55 [31%] with dextran 70 v 15/56[27%] with gelafundin; The third RCT (512 Vietnamese children aged 2–15 yearswith dengue shock syndrome) stratified children into those with moderately severe shock or severeshock according to their pulse pressure at admission (moderate severity: pulse pressure greaterthan 10 mm Hg and up to 20 mm Hg; severe shock: pulse pressure 10 mm Hg or less). TheRCT’s primary outcome measure was the need for supplemental intervention with rescue colloidat any time after the infusion of the study fluid. It compared Ringer’s lactate (a crystalloid) versuseither 6% dextran 70 (a colloid) or 6% hydroxyethyl starch (a colloid) in 383 children with moder-ately severe dengue shock syndrome. Each child received 15 mL/kg body weight of the allocatedfluid within 1 hour, followed by 10 mL/kg over the second hour. The RCT found no significant dif-ference between the groups in the proportion of children who needed rescue fluids (40/128 [31%]with Ringer's lactate v 31/126 [25%] with dextran v 43/129 [33%] with starch; P = 0.28). One childin the starch group died (less than 0.2% mortality overall in the RCT). In another 129 Vietnamesechildren with severe dengue shock syndrome, it compared the two colloids (6% dextran 70 and6% hydroxyethyl starch). It did not compare Ringer’s lactate in this group. In children with moder-ately severe shock, the RCT found no significant difference between Ringer’s lactate and either ofthe colloid solutions in the proportion of children who required rescue colloid (RR 1.08, 95% CI0.78 to 1.47; P = 0.65; absolute numbers not reporvere shock, it foundno significant difference between dextran and starch in the proportion of children who requiredrescue colloid (28/67 [42%] with dextran v 23/62 [37%] with starch; RR 1.13, 95% CI 0.74 to 1.74;P = 0.59). In a combined analysis, there was no significant difference in the risk of requiringrescue colloids between children given dextran compared with starch (59/193 [31%] with dextranv 66/191 [35%] with starch; RR 0.88, 95% CI 0.66 to 1.17;
The first RCT found no adverse effects attributable to colloids or crystalloids, but it may have beenunderpowered to detect clinically important adverse effects. , six childrendeveloped fevTwo children receiving colloidshad recurrence of shock, which responded to treatment with crystalloids. One child in the gelafundingroup had severe epistaxis requiring transfusion, and another child in the dextran group developeda large haematoma at a site of minor trauma. A total of 35 children equally distributed among thefour groups required diuretic treatment for 1 or 2 days after recovery from shock. The third RCTfound no significant difference in any adverse effects of the different fluids used, except in the inci-dence of allergic type reactions.  Overall, 15 children receiving dextran had severe reactions(transient high fever and rigors without cardiorespiratory compromise) that occurred within 6 hoursof infusing the study fluid, and one child in the starch group developed an urticarial rash withoutfever at the end of the infusion (in moderately severe shock: 9/126 [7%] with dextran v 1/129 [1%]with starch v 0/128 [0%] with Ringer’s; P less than 0.001; in severe shock: 6/67 [9%] with dextranv 0/62 [0%] with starch; All children responded to symptomatic treatment alone, butone child died. There were no significant differences among the fluid treatment groups in the devel-opment of new bleeding manifestations, clinical fluid overload, depth of right pleural effusion, volumeof ascites, and the use of diuretic treatment.
BMJ Publishing Group Ltd 2009. All rights reserved. . Dengue haemorrhagic fever or dengue shock syndrome in children ectious diseases Drug safety alert: June 2013, hydroxyethyl starch The Medicines and Healthcare products Regulatory Agency (MHRA) has suspended the use of hydroxyethyl starch (HES) products in the UK. This was done after results from large randomised clinical trials reported an increased risk of renal dysfunction and mortality in critically ill or septic patients who received HES rather than crystal- loids.(www.mhra.gov.uk/) Comment:
The first two RCTs comparing crystalloids versus colloids are likely to have been underpoweredto detect a clinically important difference in outcomesThe RCTs measured outcomes at1 or 2 hours after fluid infusion, so a clinically important effect within the first hour of fluid resusci-tation may have been overlooked. Regardless of whether colloid or crystalloid is more effective, ifequal volumes are infused, there is no difference between them with regard to fluid overload. The high-quality, adequately powered third RCT provides strong evidence that Ringer’s lactate orisotonic crystalloid solutions are safe, and are as effective as colloid solutions for the initial resus-citation of children with moderately severe dengue shock syndrome, in terms of the requirementf vere shock, the effectiveness of Ringer’s lactate remainsuntested in a large RCT. ADDING CARBAZOCHROME SODIUM SULFONATE (AC-17) TO STANDARD INTRAVENOUS FLUIDS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Symptom severity Compared with placebo We don't know whether adding carbazochrome sodium sulfonate to standard intravenous fluids is more effective at reducing pleural effusions or the development of shock in children with dengue haemor- rhagic fever or dengue shock syndrome. Adding carbazochrome sodium sulfonate to standard intravenous fluids may be no more effective at reducing the duration of hospital stay in children with dengue haemorrhagic fever or dengue shock syndrome. (). For GRADE evaluation of interventions for dengue haemorrhagic fever or dengue shock syndrome in children,
We found no systematic review but found two RCTsThe first RCT (95 Thai children aged1.8–14.8 years with dengue haemorrhagic fever/dengue shock syndrome confirmed by serologicalexaminations and/or viral cultures, admitted before the onset of shock, receiving standard iv fluids)compared adding carbazochrome sodium sulfonate (AC-17) versus adding B vitamins as placebo.
Carbazochrome sodium sulfonate was given as an initial bolus injection followed by a continuousdrip infusion for 3 days. The RCT found no significant difference in the development of shock duringthe course of treatment between adding carbazochrome sodium sulfonate to intravenous fluidsand adding placebo to intravenous fluids (4/45 [9%] with carbazochrome sodium sulfonate v 3/50[6%] with placebo; P = 0.44). It also found no significant difference between groups in the meanduration of hospital stay (mean: 4 days with carbazochrome sodium sulfonate v 4 days withplacebo; reported as not significant, P value not reported) and in the overall development of pleuraleffusion (15/45 [33%] with carbazochrome sodium sulfonate v 15/50 [30%] with placebo; P = 0.89).
The RCT found no significant difference between groups in pleural effusion occurring on day1, 2, or 3 after admission (day 1: 20% with carbazochrome sodium sulfonate v 14% with placebo;day 2: 31% with carbazochrome sodium sulfonate v 28% with placebo; day 3: 20% with car-bazochrome sodium sulfonatev 14% with placebo; reported as not significant, P values not repor
The second RCT (77 Indonesian children aged 6 months to 12 years with serologically confirmedgrade II dengue haemorrhagic fever, receiving standard iv fluids; see comment below) comparedadding carbazochrome sodium sulfonate versus adding 0.9% sodium chloride as placebo.  TheRCT found no significant difference between groups in the development of pleural effusion on thefirst day after admission (13/37 [35%] with carbazochrome sodium sulfonate v 21/39 [54%] withplacebo; P less than 0.20), but found that adding carbazochrome sodium sulfonate significantlydecreased the development of pleural effusion compared with intravenous fluids alone on thesecond day after admission (8/38 [21%] with carbazochrome sodium sulfonate v 19/36 [53%] withplacebo; P less than 0.005) and on the third day after admission (5/37 [14%] with carbazochromesodium sulfonate v 16/38 [42%] with placebo;The analysis was not by intentionto treat.
In the first RCT the occurrence of bleeding during treatment was similar between the carbazochromesodium sulfonate and placebo groups (2/45 [2%] children with carbazochrome sodium sulfonatev 3/50 [6%] children with placebo). leeding manifestations were mild; four children hadepistaxis that needed local packing and one child had blood-stained vomitus. None of the childrenneeded a blood transfusion. The second RCT did not report on adverse effects
Neither RCT reported mortality as a primary outcome Only intermediate outcomes, suchas the development of shock and pleural effusion as a marker of plasma leakage, were reported.
BMJ Publishing Group Ltd 2009. All rights reserved. . Dengue haemorrhagic fever or dengue shock syndrome in children ectious diseases
The second RCT may have had methodological flaws, which could have overestimated the treatmentefft the randomisation scheme and allocation concealment, how the identityof the experimental drug and the placebo were masked from the healthcare providers, or thebaseline comparability of the two groups in terms of age and duration of illness prior to treatment. ADDING CORTICOSTEROIDS TO STANDARD INTRAVENOUS FLUIDS. . . . . . . . . . . . . . . . . . Symptom severity Compared with placebo Adding corticosteroids to standard intravenous fluids may be no more effective at reducing serious complications, such as pulmonary haemorrhage, convulsions, or the need for blood transfusions or mean hospital stay, in childen with serologically confirmed dengue shock syndrome ( Mortality Compared with placebo Adding corticosteroids to standard intravenous fluids may be no more effective at reducing mortality in childen with serologically confirmed dengue shock syndrome (very low-quality evidence). For GRADE evaluation of interventions for dengue haemorrhagic fever or dengue shock syndrome in children,
We found one systematic review (search date 2006, 4 RCTs, 284 children) comparing corticosteroidsversus no treatment in children with serologically confirmed dengue shock syndrome receiving in-travenous fluidswo of the trials identified by the review were conducted in Thailand, one inIndonesia, and one in Burma. The review found that corticosteroids did not significantly reducemortality or the need for blood transfusions (4 RCTs, 284 children, mortality: 21/134 [16%] withcorticosteroids v 32/150 [21%] with no corticosteroids; RR 0.68, 95% CI 0.42 to 1.11; blood trans-fusions: 2 RCTs, 89 children, 11/39 [28%] with corticosteroids v 12/50 [24%] with no corticosteroids;RR 1.08, 95% CI 0.52 to 2.24). In one RCT identified by the review (63 children) corticosteroidsdid not significantly decrease the number of serious complications (pulmonary haemorrhage: 1/32[3%] with corticosteroids v 1/31[3%] with no corticosteroids; RR 0.97 95% CI 0.06 to 14.82; convul-sions: 3/32 with corticosteroids v 0/31 with placebo, RR 6.79, 95% CI 0.36 to 126.24; proportionof children who needed blood transfusion: 11/32 [34%] with methylprednisolone v 8/31 [26%] withplacebo; RR 1.33, 95% CI 0.62 to 2.86; mean hospital stay: 7.3 days with methylprednisolone v6.2 days with placebo; RR +1.10, 95% CI –1.83 to +4.03; P greater than 0.2).
The systematic review did not assess adverse effects.  y the review,the frequency of episodes of infection (pneumonia, bacteraemia) and pulmonary haemorrhagewere similar with methylprednisolone compared with placeboThree children taking methylpred-nisolone had convulsions. All surviving children were followed up 2 weeks after treatment, andsequelae rates (including haematomas, stiff joints, otitis media, abscesses, and gingivitis) weresimilar between the two groups The other two RCTs gave no information on adverse effects.
ourth clinical trial found that, in people receiving hydrocortisone, there were higher
rates of infection of the cutdown site (2/7 [28%] with hydrocortisone v 0/19 [0%] with intravenousfluids alone), gastrointestinal bleeding (6/7 [86%] with hydrocortisone v 7/19 [37%] with intravenousfluids alone), and bleeding from the cutdown site (4/7 [57%] with hydrocortisone v 8/19 [42%] withintravenous fluids alone (significance not assessed for an
One of the RCTs included in the systematic review was an open trial with unclear randomisationscheme and allocation concealment, which could have overestimated the effect of adding hydro-cortisone. Baseline characteristics of the two groups in the RCT were not comparable, with agreater proportion of children aged under 2 years and longer duration of shock in the children whodid not receive corticosteroids, which could have contributed to the higher mor
There was also a slight discrepancy between what was reported in the text of the article andwhat was reported in the table about the number of children receiving intravenous fluids alone whodied; the figure reported in the table was 19/50, which gives a slightly different result (9/48 [19%]with hydrocortisone plus intravenous fluids v 19/50 [38%] with iv fluids alone; RR 0.49, 95% CI0.25 to 0.98). The other RCTs   did not find the mortality reduction found in the first RCT
ial had gross imbalance in the number of children in the 2 groups (7 in the hy-drocortisone plus intravenous fluid group v 19 in the intravenous fluids alone group). Differencesin quality of methods of the trials and improvements in supportive care in the 1990s may accountfor the inconsistent results. ADDING INTRAVENOUS IMMUNOGLOBULIN TO STANDARD INTRAVENOUS FLUIDS. . . . . Symptom severity
BMJ Publishing Group Ltd 2009. All rights reserved. . Dengue haemorrhagic fever or dengue shock syndrome in children ectious diseases Intravanous immunoglubulin (IVIG) compared with no IVIG Adding IVIG to standard intravenous fluids is no moreeffective at reducing the duration of thrombocytopenia, or at increasing platelet counts from the day IVIG treatmentis initiated to day 7 of hospitalisation, in children with secondary dengue infection who are at risk of developingdengue haemorrhagic fev
Mortality Compared with adding placebo Adding IVIG to standard intravenous fluids is more effective at reducing mortality in children with serologically confirmed dengue shoc Note We found no direct information about the effects of IVIG in people with dengue haemorrhagic fever or dengue shock syndrome. For GRADE evaluation of interventions for dengue haemorrhagic fever or dengue shock syndrome in children,
We found no systematic review but found one RCT (31 Filipino children with secondary dengueinfection) comparing high doses (0.4 g/kg/day for 3 days) of intravenous immunoglobulin (IVIG)versus no immunoglobulin.  Children in both groups (15 in IVIG group and 16 in control) receivedstandard intravenous fluids according to WHO guidelines. The RCT found no significant differencein the duration of severe thrombocytopenia (mean days of severe thrombocytopenia: 3.1 days withIVIG v 2.5 days with no IVIG; P = 0.11) or in an increase in platelet counts from the day of initiationof IVIG treatment until day 7 of hospitalisation (mean platelet counts x 10³/microlitres: 54.9 withIVIG v 48.0 with no IVIG; P = 0.147). The RCT is likely to have been underpowered to detect aclinically important difference. The RCT did not report on mortality but only reported surrogateoutcomes.
The RCT reported no adverse effects during or after IVIG treatment. The time for platelet countsto return to normal was not shortened with IVIG.
One unpublished, double blind RCT, conducted in a tertiary university teaching hospital in thePhilippines (216 Filipino children, age 6 months to 14 years, 205 with serologically confirmeddengue shock syndrome) compared intravenous immunoglobulin (0.4 g/kg once daily for 3 days)versus placebo (personal communication, Frias MV All children received standard in-travenous crystalloids as prescribed by WHO guidelines. The RCT found that immunoglobulinsignificantly reduced mortality compared with placebo (18/108 [17%] with iv immunoglobulin v31/108 [29%] with placebo; RR 0.58, 95% CI 0.35 to 0.97; NNT 8, 95% CI 4 to 102). It founda similar duration of hospital stay between intravenous immunoglobulin and placebo. More childrenhad a rash with intravenous immunoglobulin than with placebo, but the difference was not significant(RR 1.6, 95% CI 0.95 to 2.68).
ADDING BLOOD COMPONENT TRANSFUSION TO STANDARD INTRAVENOUS FLUIDS. . . We found no direct information about blood component transfusion in children with dengue haemorrhagic fever or dengue shock syndrome. Current consensus is that children with active bleeding should receive blood component transfusion — either packed red blood cells, fresh frozen plasma, or platelet concentrates. The optimal time for commencing transfusion is unclear, and there is much variation in clinical practice. For GRADE evaluation of interventions for dengue haemorrhagic fever or dengue shock syndrome in children,
We found no systematic review or RCTs assessing platelet transfusions in children with denguehaemorrhagic fever or dengue shock syndrome. Comment: Clinical guide: It is widely accepted that children with dengue haemorrhagic fever or dengue shock syndrome with active bleeding should receive blood component transfusion (packed red blood cells, fresh frozen plasma, or platelet concentrates) depending on the degree of bleeding, and volume status of the child. Transfusion is associated with serious adverse effects, such as fluid overload, if used injudiciously. The optimal time for commencing transfusion is unclear, and there is much variation in clinical practice. It would be considered unethical to assess blood component transfusion in a placebo-controlled RCT. ADDING RECOMBINANT-ACTIVATED FACTOR VII TO BLOOD COMPONENT TRANSFUSION. Symptom severity
BMJ Publishing Group Ltd 2009. All rights reserved. . Dengue haemorrhagic fever or dengue shock syndrome in children ectious diseases Compared with placebo Adding recombinant-activated factor VII to blood component transfusion is no more effectiveat reducing the incidence of partially controlled or uncontrolled bleeding or at reducing the need for platelets, packedred blood cells, and frozen fresh plasma infusions in children with serologically confirmed dengue haemorrhagicfev
For GRADE evaluaton of interventions for dengue haemorrhagic fever or dengue shock syndrome in children,
We found one RCT (25 Thai and Filipino children aged less than 18 years with serologically con-firmed dengue haemorrhagic fever) comparing recombinant activated factor VII (rFVIIa) given byintravenous injection at 100 microgram/kg body weight versus placebo in children with activebleeding receiving blood component transfusion.  leeding was not effectively controlled,a second dose (100 microgram/kg) of recombinant factor VII was given 30 minutes after the firstdose. Blood components were transfused any time after the first dose of trial medication, dependingon the clinical status of the child as assessed by the investigators. The children also receivedsupportive treatment, airway management, fluid and electrolyte infusions, and appropriate antibioticsas deemed necessary. At two hours and at 24 hours after blood infusion, the addition of rFVIIa didnot significantly reduce the incidence of partially controlled or uncontrolled bleeding compared withplacebo (bleeding at 2 hours after infusion 4/16 [25%] with rFVIIa v 5/9 [56%] with placebo; RR0.45, 95% CI 0.16 to 1.26; bleeding at 24 hours after infusion 5/16 [31%] with rFVIIa v 3/9 [33%]with placebo, RR 0.94, 95% CI 0.29 to 3.04). At 24 hours after blood transfusion, the addition ofrFVIIa did not significantly reduce the need for platelets, red blood cells, or fresh frozen plasmainfusions compared with placebo (platelet infusion: 1/16 [6%] with rFVIIa v 3/9 [33%] with placebo;RR 0.19, 95% CI 0.02 to 1.55; packed red blood cells infusions 5/16 [31%] with rFVIIa v 3/9 [33%]with placebo; RR 0.94, 95% CI 0.29 to 3.04; fresh frozen plasma infusions 4/16 [25%] with rFVIIav 2/9 [22%] with placebo; RR 1.13, 95% CI 0.25 to 4.98).
In the RCT no clinical evidence of thromboembolic complications was observed in either group
The RCT is likely to have been underpowered to detect a clinically important difference betweengroups. GLOSSARY High-quality evidence Further research is very unlikely to change our confidence in the estimate of effect. Moderate-quality evidence Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Tourniquet test A test performed by inflating the blood pressure cuff to a point midway between systolic and diastolic pressures for 5 minutes. It involves then deflating the cuff, waiting for the skin to return to its normal colour, and then counting the number of petechiae visible in a 2.5 cm square in the ventral surface of the forearm. Twenty or more petechiae in square patch (6.25 cm2) constitutes a positive tourniquet test. Very low-quality evidence Any estimate of effect is very uncertain. SUBSTANTIVE CHANGES Adding intravenous immunoglobulin to standard intravenous fluids: One RCT added. The RCT found in- sufficient evidence in assessing the addition of intravenous immunoglobulin to standard intravenous fluids in children with secondary dengue infection. Categorisation unchanged (Unknown effectiveness). REFERENCES 1.
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Departments of Medicine and Clinical Epidemiology College of Medicine, University of the Philippines
Competing interests: MA declares that she has no competing interests. Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate ajudgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit andharms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical researchwe strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, thecategories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimatelyit is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullestextent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to anyperson or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, inci-dental or consequential, resulting from the application of the information in this publication.
BMJ Publishing Group Ltd 2009. All rights reserved. . Dengue haemorrhagic fever or dengue shock syndrome in children ectious diseases WHO grading of severity of dengue haemorrhagic fever. Description
Fever accompanied by non-specific constitutional symptoms; the only haemorrhagic manifestation is a positive tourniquet test, easy bruising, orboth
Spontaneous bleeding in addition to the manifestations of Grade I, usually in the form of skin and other haemorrhages
Circulatory failure manifested by a rapid, weak pulse and narrowing of pulse pressure or hypotension, with the presence of cold, clammy skin, andrestlessness
Profound shock with undetectable blood pressure or pulse
Reproduced with permission of WHO. Dengue haemorrhagic fever: diagnosis, treatment, prevention and control. Geneva: WHO 1997
BMJ Publishing Group Ltd 2009. All rights reserved. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dengue haemorrhagic fever or dengue shock syndrome in children ectious diseases GRADE evaluation of interventions for dengue fever or dengue shock sydrome in children Important outcomes Symptom severity, mortality, adverse effects Number of studies (participants) Comparison evidence
What are the effects of supportive treatments for dengue haemorrhagic fever or dengue shock syndrome in children?
Directness point deducted for delayed measurementof outcome
Quality points deducted for sparse data, incompletereporting of results, no intention-to-treat analysis, andmethodological flaws. Consistency point deductedfor conflicting results. Directness point deducted forbaseline differences of population (uncertainty aboutduration of illness or age of participants)
Quality points deducted for sparse data and
methodological weaknesses (open label trial withunclear randomisation and allocation concealment). Directness points deducted for baseline differencesbetween groups and disparity in numbers of partici-pants in comparator groups
Quality points deducted for methodological weakness-
es (open label trial with unclear randomisation andallocation concealment, and disparities in reportingof results in text article and table of results). Consis-tency point deducted for conflicting results. Directnesspoints deducted for baseline differences betweengroups and disparity in numbers of participants incomparator groups
Type of evidence: 4 = RCT; 2 = ObservationalConsistency: similarity of results across studiesDirectness: generalisability of population or outcomesEffect size: based on relative risk or odds ratio
BMJ Publishing Group Ltd 2009. All rights reserved. .
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