1. Investigators: Kusum Menon, Dayre McNally, Katie O’Hearn, Margaret Lawson, Karen Choong, Lauralyn McIntyre, Hector Wong.

2. STR I PES P ILOT S TUDY A multicentre pilot feasibility randomized controlled trial 7 participating sites across Canada Enrollment: 72 patients over 1.5 years

3. B ACKGROUND Insufficient evidence to support use of corticosteroids to treat pediatric shock Also evidence from other populations suggesting potential harm.

4. O BJECTIVES OF THE FULL RCT Primary To determine the effect of hydrocortisone versus placebo on the time to hemodynamic stability among pediatric patients with fluid and/or vasoactive infusion dependent shock. Secondary To determine the effect of hydrocortisone versus placebo in patients with fluid and/or vasoactive infusion dependent shock on: PICU mortality Duration of mechanical ventilation Organ dysfunction PICU length of stay

5. O BJECTIVES OF THE P ILOT S TUDY STRIPES Pilot Study has these 3 specific feasibility objectives: 1. To estimate the rate of patient recruitment and understand barriers to recruitment; 2. To assess adherence to our specific treatment protocol; 3. To document and understand the reasons for open label steroid use.

6. E LIGIBILITY C RITERIA - I NCLUSION Inclusion Criteria 1. Children newborn to 17 years; and 2. On any dose of any vasoactive infusion for at least one hour but ≤ 6 hours. ** Patients meet the inclusion criteria as soon as any vasoactive infusion is started** Notify on-call research assistant as soon as a patient with shock is started on any vasoactive agent. Research assistant will be on call 24/7.

7. E LIGIBILITY C RITERIA - E XCLUSION Exclusion Criteria 1. Known or suspected HPA axis disease; 2. Received more than one dose of systemic steroids in the last 10 days or any dose of systemic steroids in the last 24 hours; 3. Expected to have treatment withdrawn; 4. Premature infants (<38 weeks corrected GA); 5. Pregnant; 6. Post cardiac surgery; 7. First dose of vasoactive infusion received >24 hours after PICU admission 8. Patient no longer on vasoactive infusion at time of enrollment and/or patient is expected to no longer be on vasoactive infusion at the time the first study drug dose would be administered

8. Exclusion Criteria con’t 9. Primary cardiogenic shock is strongly suspected (e.g. clinical signs of heart failure, large heart on chest radiograph etc.); 10. Spinal shock is strongly suspected (e.g. history and physical findings compatible with spinal injury and/or mass); and 11. Hemorrhagic or hypovolemic shock is strongly suspected (e.g. history suspicious of blood or fluid loss). **Criteria #9 to 11 are based on the clinical judgment of the treating physician. ** Assist study team with verification of eligibility criteria

9. R ECRUITMENT INTRAVENOUS NORMAL SALINE PLACEBO Patient aged newborn to 17 years with shock is started on any vasoactive agent in the PICU or the Emergency Room → Care team notifies study staff Study staff will verify inclusion and exclusion criteria (with assistance from ICU physician) Exclusion criteria present. Patient not eligible. Patient is eligible Enrolled using Deferred Consent Randomize INTRAVENOUS HYDROCORTISONE Patient must be randomized within 6 hours of being started on a vasoactive agent Patient must receive first dose of study drug within 8 hours Blood sample (3ml)

10. D EFERRED C ONSENT Approved by REB Patients will be enrolled using deferred consent, and informed consent will be obtained as soon as possible Study team will provide ICU staff with a pamphlet to give to legal guardian as soon as is appropriate Poster will be hung by patient’s bedside to state that they have been enrolled in the STRIPES study MRP will help study team identify appropriate time to speak to family about continued consent.

11. D EFERRED C ONSENT What if a patient enrolled using deferred consent dies before informed consent is obtained? MRP will notify the legal guardian of child’s enrollment into the STRIPES study and ask if PI can speak to them. PI will fully inform legal guardian of all aspects of the study. Legal guardian will decide what to do with any data collected about their child prior to death.

12. ICU P ROCEDURES : S TUDY D RUG No wean necessary Bolus Dose: 2mg/kg 1 mg/kg q6h until there has been no escalation of therapy* for at least 12 hours 1 mg/kg q8h until the patient is off all vasoactive agents for 12 hours Study drug should be continued for a maximum of 7 days/168 hours If following the initial study drug wean, the patient requires fluid boluses and/or an increase in vasoactive infusion(s), study drug should be increased back to 1 mg/kg q6h until they meet stability criteria again (i.e. no escalation in therapy for at least 12 hours) *Escalation of Therapy defined as an increase in vasoactive infusion(s) OR any fluid bolus(es) including saline, ringer’s lactate, albumin or blood products for low blood pressure, elevated heart rate or signs of poor perfusion No escalation in therapy should be determined together with the resident, fellow or staff physician twice daily during morning and evening rounds

13. ICU P ROCEDURES : CO - INTERVENTIONS The requirement for co-interventions will be left to the discretion of the treating physician. The Surviving Sepsis Guidelines Flowchart will be attached to the study protocol for easy reference by the treating physician but its use will not be mandated.

14. ICU P ROCEDURES : O PEN -L ABEL S TEROIDS We encourage attending physicians to avoid open-label hydrocortisone use. In open-label hydrocortisone is used, the research assistant will speak with the treating physician to determine the reason(s) why.

15. R OLE OF THE ICU/ER M EDICAL T EAM (N URSE AND P HYSICIANS ) Notify study staff as soon as a patient with shock is started on any vasoactive agent Assist RA to identify an appropriate time to approach legal guardian about consent Administer study drug according to protocol (includes determining stability criteria) Blood sampling: o If the patient has lines in place, or is having blood drawn for clinical reasons, draw additional 3 ml blood o Blood sample should be prior to initiation of study drug (or within 24 hours of hospital admission)

16. R ESPONSIBILITIES OF THE S TUDY S TAFF Verify inclusion and exclusion criteria of identified patients Obtain informed consent Randomize patient within 6 hours of being started on any vasoactive agent using web-based randomization system Provide ICU staff with study drug protocol and Surviving Sepsis flowchart Blood sampling: o Provide blood sampling supplies to patient bedside Complete Case Report Form during PICU admission Report Serious Adverse Events

17. QUESTIONS?

18. T HANK YOU ! Participating Sites Alberta Children’s Hospital British Colombia Children’s Hospital Children’s Hospital of Eastern Ontario CHU Sainte Justine IWK Health Centre McMaster Children's Hospital Montreal Children’s Hospital Coordinating Centre Contact Information Study Coordinator: Katie O’Hearn Children’s Hospital of Eastern Ontario Email: kohearn@cheo.on.ca Telephone: 613.737.7600 ext. 4006