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Immediate uid managementof children with severe febrile illnessand signs of impaired circulation inlow-income settings: a contextualisedsystematic review

Newton Opiyo,1 Elizabeth Molyneux,2 David Sinclair,3 Paul Garner,3 Mike English1,4

To cite: Opiyo N,Molyneux E, Sinclair D, et al.Immediate fluid managementof children with severe febrileillness and signs of impairedcirculation in low-incomesettings: a contextualisedsystematic review. BMJ Open2014;4:e004934.doi:10.1136/bmjopen-2014-004934

Prepublication history andadditional material isavailable. To view please visitthe journal (http://dx.doi.org/10.1136/bmjopen-2014-004934).

Received 25 January 2014Revised 9 April 2014Accepted 10 April 2014

For numbered affiliations seeend of article.

Correspondence toDr Newton Opiyo; [email protected]

ABSTRACTObjective: To evaluate the effects of intravenous fluidbolus compared to maintenance intravenous fluidsalone as part of immediate emergency care in childrenwith severe febrile illness and signs of impairedcirculation in low-income settings.Design: Systematic review of randomised controlledtrials (RCTs), and observational studies, includingretrospective analyses, that compare fluid bolusregimens with maintenance fluids alone. The primaryoutcome measure was predischarge mortality.Data sources and synthesis: We searched PubMed,The Cochrane Library (to January 2014), withcomplementary earlier searches on, Google Scholarand Clinical Trial Registries (to March 2013). Asstudies used different clinical signs to define impairedcirculation we classified patients into those with signsof severely impaired circulation, or those with anysigns of impaired circulation. The quality of evidencefor each outcome was appraised using the Grading ofRecommendations Assessment, Development andEvaluation (GRADE) approach. Findings are presentedas risk ratios (RRs) with 95% CIs.Results: Six studies were included. Two were RCTs,one large trial (n=3141 children) from a low-incomecountry and a smaller trial from a middle-incomecountry. The remaining studies were from middle-income or high-income settings, observational, andwith few participants (34187 children).Severely impaired circulation: The large RCTincluded a small subgroup with severely impairedcirculation. There were more deaths in those receivingbolus fluids (2040 mL/kg/h, saline or albumin)compared to maintenance fluids (2.54 mL/kg/h; RR2.40, 95% CI 0.84 to 6.88, p=0.054, 65 participants,low quality evidence). Three additional observationalstudies, all at high risk of confounding, found mixedeffects on mortality (very low quality evidence).Any signs of impaired circulation: The large RCTincluded children with signs of both severely and non-severely impaired circulation. Overall, bolus fluidsincreased 48 h mortality compared to maintenancefluids with an additional 3 deaths per 100 childrentreated (RR 1.45, 95% CI 1.13 to 1.86, 3141participants, high quality evidence). In a second small

RCT from India, no difference in 72 h mortality wasdetected between children who received 2040 mL/kgRingers lactate over 15 min and those who received20 mL over 20 min up to a maximum of 60 mL/kg over1 h (147 participants, low quality evidence). In oneadditional observational study, resuscitation consistentwith Advanced Paediatric Life Support (APLS)guidelines, including fluids, was not associated withreduced mortality in the small subgroup with septicshock (very low quality evidence).Signs of impaired circulation, but not severelyimpaired: Only the large RCT allowed an analysis forchildren with some signs of impaired circulation whowould not meet the criteria for severe impairment.Bolus fluids increased 48 h mortality compared tomaintenance alone (RR 1.36, 95% CI 1.05 to 1.76,high quality evidence).Conclusions: Prior to the publication of the largeRCT, the global evidence base for bolus fluid therapyin children with severe febrile illness and signs ofimpaired circulation was of very low quality. This largestudy provides robust evidence that in low-incomesettings fluid boluses increase mortality in childrenwith severe febrile illness and impaired circulation, andthis increased risk is consistent across children withsevere and less severe circulatory impairment.

Strengths and limitations of this study

Timely systematic review given the currentuncertainty on optimal strategy for fluid resusci-tation in children; review incorporates data onthe largest randomised controlled trial (RCT;Fluid Expansion as Supportive Therapy trial) offluid therapy in children.

Review includes all relevant comparative trialsand observational data, and critically appraisesthe research evidence using Grading ofRecommendations Assessment, Developmentand Evaluation (GRADE) methods.

Review is limited because most studies are smalland unreliable, with only one large RCT provid-ing reliable data to guide policy.

Opiyo N, Molyneux E, Sinclair D, et al. BMJ Open 2014;4:e004934. doi:10.1136/bmjopen-2014-004934 1

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BACKGROUNDHealth staff must rapidly assess, resuscitate and treatseverely ill children to improve survival. Practical, simpleto use protocols have been established to guide care. InNorth America, the most commonly used are thePediatric Advanced Life Support (PALS)1 and inEurope, the European Paediatric Life Support (EPLS)2

guidelines. In low-income settings, the WHO has specicguidelines where there are no intensive care facilities,called the Emergency Triage Assessment and Treatment(ETAT) guidelines. ETAT guidance begins with initialtriage to identify children who need urgent formalassessment such as altered consciousness or severebreathing or circulation problems. Immediate careshould then follow an Airway, Breathing, Circulation,Drugs (ABCD) approach to assessment and actionwhich prioritises care of the airway (A) rst, followed bybreathing (B) and circulation (C).

Septic shockSevere febrile illness in children is often associated withsigns of impaired circulation (also known as septicshock). Current ETAT guidelines dene shock as thepresence of three clinical signs of poor peripheral perfu-sion: weak/absent peripheral pulse, prolonged capillaryrelling >3 s and cold hands and feet (typically with coldskin extending up the limb and termed a temperaturegradient). International guidance, including ETAT, typ-ically recommends a rapid uid bolus of 2040 mL/kgintravenously once shock is diagnosed.3

Why it is important to do this reviewAs early as 1999, authors were arguing that no robustdata existed demonstrating that bolus uid resuscitationimproved clinical outcomes in septic patients.4

Moreover, the results of observational studies suggestedthat large volumes of resuscitation uids may be asso-ciated with increased morbidity in patients with sepsis5

acute respiratory distress syndrome6 or acute kidneyinjury.7

Subsequently, a large, multicentre, randomised con-trolled trial (RCT) published in 2011, and conducted inEast Africa found that bolus uid resuscitation increasedmortality compared to a maintenance uid regimen inchildren with febrile illness and impaired perfusion.8

The results of this trial clashed with the long-standingbelief that uid bolus resuscitation was benecial andcaused considerable international debate.912 To date,no clear guidance has emerged on how to incorporatethese ndings into recommendations for practice inhigh-income or low-income settings.

OBJECTIVETo evaluate the effects of uid bolus (with either col-loids or crystalloids) compared to maintenance uidsalone in children with severe febrile illness and signsof impaired circulation.

METHODSCriteria for considering studies for this reviewTypes of studiesRCTs and observational studies, including retrospectiveanalyses.

Types of participantsChildren (aged 18 years) with clinical features suggest-ing impaired perfusion (including shock) due to pre-sumed acute infectious illnesses or inammatory state(sepsis) and excluding diarrhoeal illness (as dened bythe studies).

Types of interventionsIntravenous uid boluses (crystalloids or colloids) com-pared to no (or lower volume) uid boluses or mainten-ance uids.

Types of outcome measuresThe primary outcome measure was predischarge mortal-ity. Secondary outcomes were: mortality at any time upto 4 weeks and any adverse clinical events reported inthe studies.

Data sources and search strategyWe searched PubMed, The Cochrane Library to January2014, complemented by searches in Google Scholar andClinical Trial Registries (ClinicalTrials.gov, CurrentControlled Trials, WHO International Clinical TrialsRegistry Platform, metaRegister of Controlled Trials) toMarch 2013. We sought eligible published, unpublishedor in-progress articles. No date or language restrictionswere used.The searches were performed iteratively by combining

Medical Subject Headings (MeSH) and free-text termsrelevant to the conditions (sepsis, septicaemia, febrileillness, bacteraemia, infection, meningitis, septic shock,hypovolaemia), treatments (uids, resuscitation, intra-venous uids, uid therapy) and patient groups (neo-nates, infants, children, adolescents) of interest. No dateor language restrictions were used.In addition we searched the websites of relevant orga-

nisations (the International Sepsis Forum, the WorldFederation of Paediatric Intensive Care and Critical CareSocieties) and key emergency/intensive care journals(Critical Care Medicine, Critical Care, PaediatricEmergency Medicine, Shock, Resuscitation, IntensiveCare Medicine). Reference lists of related systematicreviews and primary studies were manually searched. Wealso sought additional papers by contacting authors ofrelated reviews and selected studies.

Study selectionTwo reviewers (NO and ME) independently screenedthe titles, abstracts and full texts of retrieved articlesand applied the study eligibility criteria detailedabove to select studies. Disagreements were resolved bydiscussion.

2 Opiyo N, Molyneux E, Sinclair D, et al. BMJ Open 2014;4:e004934. doi:10.1136/bmjopen-2014-004934

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Data extractionData were extracted using a predesigned form by onereviewer (NO) and checked by the other reviewers; dis-agreements were resolved by discussion. We extracteddata on: study designs, settings, sample size, participants(diagnoses, age range), shock denitions, treatmentsand comparisons (types of uids, timing, volumes anduid rates), cointerventions and proportion of patientsexperiencing the events of interest in each treatmentgroup.

Risk of bias in individual studiesTwo reviewers (NO and DS) independently assessed therisk of bias in the included studies according to six cri-teria assessing the risk of selection bias (randomsequence generation, allocation concealment, selectionof two groups), reporting bias (blinding) and confound-ing (baseline characteristics, cointerventions). For eachcriteria, the study was classied as high risk of bias, lowrisk of bias or unclear risk of bias.

Assessment of quality of evidenceThe quality of evidence for each of the efcacy andsafety outcomes was assessed using the Grading ofRecommendations Assessment, Development andEvaluation (GRADE) approach.13 Key quality elementsassessed by GRADE include: risk of bias (study limita-tions), precision of treatment effects, consistency ofresults, directness (applicability) of evidence and publi-cation bias. The GRADE evidence proles were pre-pared by one reviewer (NO) and veried independentlyby two reviewers (ME and DS). Discrepancies in thequality ratings were resolved by discussion.

Synthesis of resultsWe summarised results narratively due to signicant dif-ferences in study designs, uid protocols and patientrisk proles. In order to compare studies with similar

populations we grouped studies by the severity of circula-tory impairment at baseline, after an appraisal of theclinical signs used to dene inclusion. We dened threegroups (table 1):1. Severely impaired circulation (SIC): Studies where inclu-

sion criteria were similar to the ETAT guidance(shock dened as presence of all four signs ofimpaired circulation).

2. Impaired circulation (IC): Studies where inclusion onlyrequired one or two of these signs.

3. IC but without severe impairment: Studies where inclu-sion required one or two signs of IC and moreseverely ill patients were excluded.For consistency all results are presented as risk ratios

(RRs) with 95% CIs (where reported, odds ratios andpercentage point differences were converted into RRs).

RESULTSStudy selection processThe ow of studies through this review is summarised ingure 1. Six studies fullled all our prespecied eligibil-ity criteria: two RCTs,8 14 two prospective cohortstudies15 16 and two retrospective record reviews.17 18

Study characteristicsThe characteristics of the six included studies are sum-marised in online supplementary table S1. Study settingswere varied: USA,1517 Brazil,18 India14 and East Africa(Kenya, Tanzania and Uganda).8 Five studies1418 wereconducted in settings where paediatric intensive careunit facilities including inotropic support, intubationand ventilation were available. The largest study8 wasconducted in typical resource-limited East African hospi-tals without these additional measures being available.The study sample sizes ranged from 34 to 3141 patients.The clinical denitions of severe febrile illness and cir-

culatory impairment or shock varied across studies

Table 1 Severity of circulatory impairment classifications

Clinical group Definition

SIC Children with severe febrile illness who have all four of the following features: AVPU3 s Cold limb extremities (hands and feet) typically with cold skin extending up the limb (referred to as a

temperature gradient)These children typically also have secondary signs such as altered consciousness

IC Children with severe febrile illness who may have AVPU2 s Cold limb extremities with a temperature gradient Severe tachycardia (>180/min if aged 212 m, >160/min if aged 14 years)

IC but withoutSIC

By exclusion a third clinical grouping can be defined, those withimpaired circulation but without severeimpairment

AVPU, Alert, responsive to Verbal, Painful stimuli, or Unresponsive; IC, impaired circulation; SIC, severely impaired circulation.


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(table 2). Fluid therapy protocols (volumes, timing,rates) were similarly varied between comparison studygroups (see online supplementary table S1). In only onecase, the work conducted in East Africa, was a clearlydened no bolus group studied.8

Risk of biasBoth RCTs were considered to be of low risk of bias(table 3). The observational studies were all potentially con-founded (none met all the risk of bias criteria; table 3).The following key criteria were only partially met or wereunclear from the information provided: appropriate par-ticipant selection, study power, appropriate blinding/outcome assessments and association of outcome andtreatment.

OutcomesThe results for the efcacy and safety outcomes,together with quality of evidence, are summarised in thefollowing three distinct population risk groups.A. Children with severe febrile illness and signs of SICFour studies reported outcome data in children rele-

vant to those with SIC: one RCT,8 one prospectivecohort16 and two retrospective studies.17 18 Overall mor-tality in the patients reported in these analyses were:42%, 51%, 29% and 47%, respectively.

Trial data: The RCT8 included children with milderforms of circulatory impairment but provided a sub-group analysis of 65 patients who fullled the ETATcriteria of shock. In this subgroup a uid bolus of2040 mL/kg (saline or albumin) over 1 h was asso-ciated with a considerably higher risk of mortality thanmaintenance uids (24 mL/kg/h) but this was of bor-derline statistical signicance (RR 2.40, 95% CI 0.84 to6.88, p=0.054, low quality evidence; see online supplemen-tary tables S2 and S3).

Observational data: In Brazil a retrospective recordsreview of 90 children admitted to a paediatric intensivecare unit with sepsis and shock assessed the relationshipbetween mortality and uid resuscitation in the rst

hour.18 Administration of 20 mL/kg of bolus resuscita-tion uid (crystalloids, colloids) was associated with a sig-nicantly higher mortality than if 40 mL/kg or morewas given (73% vs 33%, RR 0.45, 95% CI not estimable,p

Table 2 Study inclusion criteria

Study population entrycriteria Shock criteria

Study Age range Severe illness Bloodpressure

Pulse rate Capillaryrefill

Extremities Peripheralpulse

Urineoutput

Mentalstatus

Maitland2011

60 days to12 years

Severe febrileillnesscomplicated byimpairedconsciousness(prostration orcoma),respiratorydistress(increased workof breathing) orboth

and or Severetachycardia*

or 3 s or Lower limbtemperaturegradient

or Weakradialpulsevolume

Oliveira2008

Median age:3647months

Sepsis wasdefined usingthe Society ofCritical CareMedicineConsensusConference22

and

S5). A subgroup analysis suggested that the increasedmortality was only statistically signicant in children withsevere anaemia (haemoglobin 3s

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design aspects which potentially biased the resulttowards favouring high-volume uid resuscitation. Ofparticular note are two of the retrospective studies whichclassied all children who recovered quickly as havingreceived adequate uid therapy irrespective of theuid volume they received. The potential for bias inthese studies resulting from possible exposure misclassi-cation should be noted by paediatricians working inhigh-resource settings.The RCT published in 2011 provides by far the most

direct assessment of uid boluses in children with severefebrile illness in resource poor African settings that donot typically see dengue fever but where malaria may becommon.8 In these settings emergency managementdecisions must typically be made without accurate bloodpressure reading or investigations such as pulse oxim-etry, blood gas analysis, haemoglobin or lactate measure-ment. The robust nding of increased mortality in thelarge group of children with an initial, clinical diagnosisof severe febrile illness and IC but not SIC demonstratesthat the clinical signs linked to this classication are,alone, not sufcient to identify children in whom uidboluses may be benecial. In fact this trial providesrobust evidence that bolus intravenous uids areharmful in such children.Data from the small subgroup of children within the

FEAST study who had all three clinical signs of SIC, arethe only randomised evidence on the risks and benetsof uid boluses for this group. Mortality among thosereceiving bolus uids was higher than those receivingmaintenance uids but the data are compatible with an

effect ranging from a small potential benet of bolus tovery substantial harm, which raises severe doubt aboutthe use of boluses even in this more severely ill group.In an effort to accommodate the highly inuential

observational research on uid use in paediatric emer-gency care we included data from studies traditionallyexcluded from systematic reviews of alternative therapies(such as the recent review by Ford et al21). Although thispresented challenges it is an advantage of the GRADEapproach that the quality of evidence from such studiescan be transparently appraised and, potentially there-fore, contribute to informed decision-making.

CONCLUSIONPrior to the publication of the large multicentre AfricanRCT, the evidence in support of aggressive uid therapyin children with septic shock was only of very low quality.The 2011 RCT provides robust evidence that in low-resource settings uid boluses, even in relatively smallamounts, increase mortality in children with severefebrile illness and signs of IC. For children with signs ofSIC the evidence suggests harm but there is less cer-tainty and further research is warranted.

Author affiliations1Health Services Unit, KEMRI-Wellcome Trust Research Programme, Nairobi,Kenya2Department of Paediatrics, College of Medicine and Queen Elizabeth CentralHospital, Blantyre, Malawi3International Health Group, Liverpool School of Tropical Medicine, Liverpool,UK

Table 3 Quality assessment of included studies

Study design

Selection biasReportingbias Confounding

Study

Randomsequencegeneration

Allocationconcealment

Selectionof twogroups Blinding

Baselinecharacteristics

Co-interventions

Maitland et al8 Randomisedcontrolled trial

Low risk Low risk Low risk Low risk Low risk Low risk

Santhanamet al14

Randomisedcontrolled trial

Low risk Low risk Low risk Low risk Low risk Low risk

Carcillo et al15 Prospectivecohort

NA NA High risk* NA High risk* Unclear risk

Oliveira et al18 Retrospectiverecords review

NA NA High risk NA High risk Unclear risk

Han et al17 Retrospectiverecords review

NA NA High risk NA High risk Unclear risk

Carcillo et al16 Prospectivecohort

NA NA Low risk NA Unclear risk Unclear risk

*Compared those who received recommended APLS/PALS treatment with those who did not. Received recommended APLS/PALS fluidtherapy was defined as those who recovered regardless of fluid therapy plus those who did not recover but received >20 mg/kg of fluids.Children who did not receive recommended APLS/PALS treatment were significantly younger and had significantly longer capillary refill times,lower blood pressure and higher oxygen requirements.Compared survivors and non-survivors. The survivors were more likely to have had higher fluid volumes and were also significantly younger.Compared survivors and non-survivors. Appropriate fluid therapy group includes those where fluid was given in line with ACCM/PALSguidelines AND those who recovered quickly irrespective of how much fluid was given. Non-survivors had significantly higher PRISM scoresat baseline (PRISM assesses the risk of mortality).Compared those who received three different fluid regimens. Adequate baseline characteristics were not presented.APLS, Advanced Paediatric Life Support; NA, not applicable; PALS, Pediatric Advanced Life support.


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4Nuffield Department of Medicine and Department of Paediatrics, University ofOxford, Oxford, UK

Contributors NO conducted the searches. NO, DS and ME screened recordsfor eligibility, extracted data, assessed study quality and analysed data. EMand PG reviewed selected studies. NO wrote the first draft of the manuscript.All the authors participated in the interpretation of results and writing of thefull manuscript. NO and ME are the guarantors.

Funding NO is funded by a post-doctoral training grant from the Consortiumfor National Health Research. ME is supported by a Wellcome Trust SeniorFellowship (#097170). Additional funds from a Wellcome Trust StrategicAward (#084538) and a Wellcome Trust core grant awarded to the KEMRI-Wellcome Trust Research Programme (#092654) made this work possible.The guideline development meeting was supported in part by the EffectiveHealth Care Research Consortium, which is funded by UKaid from the UKGovernment Department for International Development.

Competing interests EM worked with WHO to develop the initial ETATtraining and supports the provision of ETAT training in Malawi and othercountries. ME adapted ETAT when creating ETAT+ and supports the provisionof ETAT+ training in Kenya and has facilitated use of ETAT+ in other countries.

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement No additional data are available.

Open Access This is an Open Access article distributed in accordance withthe terms of the Creative Commons Attribution (CC BY 3.0) license, whichpermits others to distribute, remix, adapt and build upon this work, forcommercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/3.0/

REFERENCES1. American Heart Association. 2005 American Heart Association

(AHA) guidelines for cardiopulmonary resuscitation (CPR) andemergency cardiovascular care (ECC) of pediatric and neonatalpatients: pediatric basic life support. Pediatrics 2006;117:e9891004.

2. Phillips B, Mackway-Jones K, Jewkes F. The EuropeanResuscitation Councils paediatric life support course AdvancedPaediatric Life Support. Resuscitation 2000;47:32934.

3. Brierley J, Carcillo J, Choong K, et al. Clinical practice parametersfor hemodynamic support of pediatric and neonatal septic shock:2007 update from the American College of Critical Care Medicine.Crit Care Med 2009;37:66688. Erratum in: Crit Care Med2009;37:1536.

4. Jardin F, Fourme T, Page B, et al. Persistent preload defect insevere sepsis despite fluid loading: a longitudinal echocardiographicstudy in patients with septic shock. Chest 1999;116:13549.

5. Durairaj L, Schmidt G. Fluid therapy in resuscitated sepsis: less ismore. Chest 2008;133:25263.

6. Wiedemann H. A perspective on the fluids and catheters treatmenttrial (FACTT). Fluid restriction is superior in acute lung injury andARDS. Cleve Clin J Med 2008;75:428.

7. Prowle J, Echeverri J, Ligabo E, et al. Fluid balance and acutekidney injury. Nat Rev Nephrol 2010;6:10715.

8. Maitland K, Kiguli S, Opoka R, et al. Mortality after fluid bolus inAfrican children with severe infection. N Engl J Med2011;364:248395.

9. Brewster D. African fluid bolus study: implications for practice.J Paediatr Child Health 2012;48:54850.

10. Duke T. What the African fluid-bolus trial means. Lancet2011;378:16857.

11. Hilton A, Bellomo R. A critique of fluid bolus resuscitation in severesepsis. Crit Care 2012;16:302.

12. Southall D, Samuels M. Treating the wrong children with fluids willcause harm: response to mortality after fluid bolus in Africanchildren with severe infection. Arch Dis Child 2011;96:9056.

13. GRADE Working Group. http://www.gradeworkinggroup.org/14. Santhanam I, Sangareddi S, Venkataraman S, et al. A prospective

randomized controlled study of two fluid regimens in the initialmanagement of septic shock in the emergency department. PediatrEmerg Care 2008;24:64755.

15. Carcillo J, Kuch B, Han Y, et al. Mortality and functional morbidityafter use of PALS/APLS by community physicians. Pediatrics2009;124:5008.

16. Carcillo J, Davis A, Zaritsky A. Role of early fluid resuscitation inpediatric septic shock. JAMA 1991;266:12425.

17. Han Y, Carcillo J, Dragotta M, et al. Early reversal ofpediatric-neonatal septic shock by community physicians isassociated with improved outcome. Pediatrics 2003;112:7939.

18. Oliveira CF, Nogueira dSF, Oliveira DS, et al. Time- andfluid-sensitive resuscitation for hemodynamic support of children inseptic shock: barriers to the implementation of the American Collegeof Critical Care Medicine/Pediatric Advanced Life SupportGuidelines in a pediatric intensive care unit in a developing world.Pediatr Emerg Care 2008;24:81015.

19. Maitland K, George E, Evans J, et al. Exploring mechanisms ofexcess mortality with early fluid resuscitation: insights from theFEAST trial. BMC Med 2013;11:68.

20. Maitland K, Akech S, Russel E. Mortality after fluid bolus in Africanchildren with sepsis (Authors response). N Engl J Med2011b;365:13513.

21. Ford N, Hargreaves S, Shanks L. Mortality after fluid bolus inchildren with shock due to sepsis or severe infection: a systematicreview and meta-analysis. PLoS ONE 2012;7:e43953.

22. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organfailure and guidelines for the use of innovative therapies in sepsis.The ACCP/SCCM Consensus Conference Committee. AmericanCollege of Chest Physicians/Society of Critical Care Medicine. Chest1992;101:164455.

23. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med2003;31:12506.


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contextualised systematic reviewcirculation in low-income settings: asevere febrile illness and signs of impaired Immediate fluid management of children with

EnglishNewton Opiyo, Elizabeth Molyneux, David Sinclair, Paul Garner and Mike

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Immediate fluid management of children with severe febrile illness and signs of impaired circulation in low-income settings: a contextualised systematic reviewAbstractBackgroundSeptic shockWhy it is important to do this review

ObjectiveMethodsCriteria for considering studies for this reviewTypes of studiesTypes of participantsTypes of interventionsTypes of outcome measures

Data sources and search strategyStudy selectionData extractionRisk of bias in individual studiesAssessment of quality of evidenceSynthesis of results

ResultsStudy selection processStudy characteristicsRisk of biasOutcomes

DiscussionConclusionReferences

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