1. Chicago 2014 TFQO: Peter Meaney #COI 149 EVREV 1: Richard Aickin #COI 153 EVREV 1: Peter Meaney #COI 149 Taskforce: Pediatrics Resuscitation fluids (Peds) (Peds-545)

2. Chicago 2014 COI Disclosure (SPECIFIC to this systematic review) Richard Aickin #COI 3 Commercial/industry None Potential intellectual conflicts None Peter Meaney #COI 105 Commercial/industry None Potential intellectual conflicts None

3. Chicago 2014 2010 Treatment Recommendation Topic not reviewed in 2010 2010 PICO In infants and children with any type of shock (P), does the use of any specific resuscitation fluid or combination of fluids eg: isotonic crystalloid, colloid, hypertonic saline, blood products (I) when compared with standard care (C) improve patient outcome (hemodynamics, survival) (O)?

4. Chicago 2014 C2015 PICO Population: infants and children who are in septic shock in any setting Intervention: restricted volumes of isotonic crystalloid or non-crystalloid Comparison:20cc/kg boluses of isotonic crystalloid Outcomes: 9-CriticalSurvival to hospital discharge 8-CriticalComplications 8-CriticalNeed for mechanical ventilation or vasopressor support 7-CriticalTime to resolution of Shock 5-ImportantHospital length of stay 4-ImportantTotal IV fluids administered 4-ImportantVentilator free days

5. Chicago 2014 Inclusion/Exclusion & Articles Found Inclusions Human, infant/child, controlled trial or case series, septic shock (inc. malaria, dengue shock syndrome) Exclusions Adult only studies, other forms of shock (e.g. burns, trauma), no comparison with isotonic crystalloid bolus Number of Articles initially identified: 2657 Reviewed in full: 27 11 Included in Evidence Profile tables 9 RCTs 2 non-RCTs 16 excluded (no comparison, adherence to protocol only, colloid-colloid, hypotonic, hypertonic, adult only, duplicate)

6. Chicago 2014 2015 Proposed Treatment Recommendations Draft Treatment Recommendations: For infants and children we suggest against restricted fluids in comparison to 20mls/kg who have a Sepsis/Septic Shock (weak recommendation, very low quality of evidence), Malaria with severe anemia or moderate-severe acidosis (weak recommendation, low-moderate quality of evidence). There is no evidence regarding Dengue Shock Syndrome. For infants and children who have a febrile illness and some but not all signs of shock, we recommend for the use of restricted fluids as opposed to 20mls/kg boluses (weak recommendation, moderate quality of evidence).

7. Chicago 2014 2015 Proposed Treatment Recommendations Draft Treatment Recommendations: For infants and children who have Sepsis/Septic Shock, Malaria with severe anemia or moderate-severe acidosis we recommend for the use crystalloid boluses over other fluid (weak recommendation, low to very low quality of evidence). For infants and children who have Dengue Shock Syndrome, we recommend for the use colloid as initial bolus over crytalloid (weak recommendation, moderate to low quality of evidence).

8. Chicago 2014 2015 Proposed Treatment Recommendations Draft Treatment Recommendations: Regardless of etiology of shock, amount of fluid (rapid bolus or restricted fluids), or type of fluid, infants and children with some or all signs of shock should be prioritized for full assessment and treatment and reassessed within one hour.

9. Chicago 2014 Risk of Bias in studies RCT bias assessment StudyYearDesign Total Patients Population Industry Funding Allocation: Generation Allocation: Concealment Blinding: Participants Blinding: Assessors Outcome: Complete Outcome: Selective Other Bias First Author 2002RCT275OHCAPartlyLow HighLow Unclear First Author 2002RCT77OHCAUnclearHigh Low Unclear First Author 2005RCT16OHCAUnclearHigh UnclearLowHigh First Author 2012RCT36OHCANoLow HighLow Unclear First Author 2013RCT950OHCANoLow HighLow Non-RCT bias asssesment StudyYearDesign Total Patients Population Industry Funding Eligibility Criteria Exposure/Outcome Confounding Follow up First Author 2010 Non-RCT 828OHCAUnclearLow HighLow First Author 2011Non-RCT374OHCANoLow HighLow First Author 2011Non-RCT1,145OHCANoLow First Author 2011 Non-RCT 5,317OHCA/IHCANoHigh Low First Author 2012Non-RCT175OHCA/IHCANoUnclear HighLow First Author 2012Non-RCT100OHCA/IHCAUnclearLow HighLow First Author 2012Non-RCT118IHCAUnclearLow HighLow First Author 2013Non-RCT8,316IHCANoUnclearHigh Low Essential slide(s Please paste summary of bias assessments here (estimated time 30 sec). Ideally as one slide for both RCTs and non-RCTs (or two if necessary). Paste from excel spread sheet.

10. Chicago 2014 Evidence profile table(s)

11. Chicago 2014 Evidence profile table(s)

12. Chicago 2014 Evidence summary Colloid vs Crystalloid Fluid Bolus Therapy 3 high quality RCTs (Wills 2005 p877, Nhan 2001 p204, Dung 1999 p787) showed no differences between boluses of colloids and isotonic crystalloids in the treatment of Dengue Shock Syndrome (DSS) for the critical outcomes of complications and time to resolution of shock. None of these studies included a control group who received restricted fluid volumes. Mortality was low at 1.3% providing indirect support for fluid bolus therapy in Dengue SS. 1 retrospective review (very low quality) (Ranjit 2005 p412) of 20mls/kg (1997-1999) vs 30mls/kg (2000-2001) in the first hour for DSS suggested lower mortality for the more recent 30ml/kg bolus cohort.

13. Chicago 2014 Evidence summary Fluid Bolus Therapy in Severe Malaria Four RCTs investigated fluid bolus therapy for children with severe malaria and acidosis, comparing a variety of fluids (Gelofusine, HES, Albumin, Normal Saline, Ringers Lactate) and bolus volumes (10, 20, 40mls/kg). Outcomes included mortality and time to resolution of acidosis. Other than metabolic acidosis, signs of circulatory compromise were not used as inclusion/exclusion criteria A survival benefit is suggested for albumin vs alternative fluids. No restricted fluid controls were included. Akech 2006 e21, Akech 2010 1630, Maitland 2003 426, Maitland 2005 538

14. Chicago 2014 Evidence summary Fluid Bolus Therapy in Septic Shock (undifferentiated) Two RCTs compared different fluid bolus therapies in undifferentiated septic shock in children Santhanam 2008 647 40mls/kg over 15mins vs 20-60mls/kg over 1 hr Goal directed Ringers lactate No difference in mortality (17.6%) or time to resolution of shock ICU level care

15. Chicago 2014 Evidence summary Fluid Bolus Therapy in Septic Shock (undifferentiated) Two RCTs compared different fluid bolus therapies in undifferentiated septic shock in children Chopra 2009 833 3% saline 15ml/kg over 30 min vs normal saline 20- 40mls/kg over 30min No differences in mortality, time to resolution of shock or duration of ICU stay.

16. Chicago 2014 Evidence summary Fluid Bolus Therapy in children with some but not all signs of shock One large high quality RCT compared boluses of 20- 40mls/kg of 5%albumin vs normal saline vs no bolus in children with severe febrile illness and some but not all signs of shock. Outcome measures 48hr mortality Pulmonary edema, raised ICP 4weekmortality/neurological sequelae

17. Chicago 2014 Evidence summary FEAST Study 3141 children equal groups across 6 study centres in 3 African countries Stratified Stratum A impaired perfusion/fever: assigned to bolus or control Stratum B severe hypotension: assigned to one of 2 bolus groups Initial protocol changed to 40ml/kg in 1 st hr for stratum A and 60ml/kg for stratum B June 2010 No difference between albumin and saline bolus RR mortality bolus therapy 1.45 vs no bolus, absolute excess mortality 3.3%

18. Chicago 2014 Proposed Consensus on Science statements Summary statement: For the critical outcome of “mortality” we have identified high quality evidence from one RCT enrolling 3141 patients showing harm (OR 1.45 95% CI 1.13 – 1.86) from the use of fluid bolus therapy in African children with severe infection. We found weak evidence supporting the use of fluid bolus therapy for children in other settings.

19. Chicago 2014 Proposed Consensus on Science statements Summary statement: We did not identify any evidence to suggest a benefit for alternative types of fluid vs. isotonic crystalloids for fluid bolus therapy for children with septic, malaria or dengue shock in any setting against the following outcome measures. 9-CriticalSurvival to hospital discharge 8-CriticalComplications 8-CriticalNeed for mechanical ventilation or vasopressor support 7-CriticalTime to resolution of Shock 5-ImportantHospital length of stay 4-ImportantTotal IV fluids administered 4-ImportantVentilator free days

20. Chicago 2014 Evidence summary Colloid vs Crystalloid Fluid Bolus Therapy 3 high quality RCTs (Wills 2005 p877, Nhan 2001 p204, Dung 1999 p787) showed no differences between boluses of colloids and isotonic crystalloids in the treatment of Dengue Shock Syndrome (DSS) for the critical outcomes of complications and time to resolution of shock. None of these studies included a control group who received restricted fluid volumes. Mortality was low at 1.3% providing indirect support for fluid bolus therapy in Dengue SS. 1 retrospective review (very low quality) (Ranjit 2005 p412) of 20mls/kg (1997-1999) vs 30mls/kg (2000-2001) in the first hour for DSS suggested lower mortality for the more recent 30ml/kg bolus cohort.

21. Chicago 2014 Evidence summary Fluid Bolus Therapy in Severe Malaria Four RCTs investigated fluid bolus therapy for children with severe malaria and acidosis, comparing a variety of fluids (Gelofusine, HES, Albumin, Normal Saline, Ringers Lactate) and bolus volumes (10, 20, 40mls/kg). Outcomes included mortality and time to resolution of acidosis. Other than metabolic acidosis, signs of circulatory compromise were not used as inclusion/exclusion criteria A survival benefit is suggested for albumin vs alternative fluids. No restricted fluid controls were included. Akech 2006 e21, Akech 2010 1630, Maitland 2003 426, Maitland 2005 538

22. Chicago 2014 Evidence summary Fluid Bolus Therapy in Septic Shock (undifferentiated) Two RCTs compared different fluid bolus therapies in undifferentiated septic shock in children Santhanam 2008 647 40mls/kg over 15mins vs 20-60mls/kg over 1 hr Goal directed Ringers lactate No difference in mortality (17.6%) or time to resolution of shock ICU level care

23. Chicago 2014 Knowledge Gaps *DO NOT USE FOR PLENARY* - BREAKOUT ONLY (eg. ETT vs BVM) Other specific systematic review that would be helpful Relationship with training to ETT success Specific research required Adult ETT vs BVM Slide for Task Force Breakout Presentations Only (one slide only). Estimated time <30 sec