Steroid Use in Pediatric Fluid and Vasoactive Infusion Dependent Shock - Pilot Study

Condition(s) targeted: Shock

Intervention: Hydrocortisone (Drug); Placebo (Other)

Phase: Phase 4

Status: Recruiting

Sponsored by: Children's Hospital of Eastern Ontario

Official(s) and/or principal investigator(s):
Kusum Menon, MD, MSc, Principal Investigator, Affiliation: Children's Hospital of Eastern Ontario
Karen Choong, MB, MSc, Study Chair, Affiliation: McMaster Children's Hospital
James D McNally, MD, PhD, Study Chair, Affiliation: Children's Hospital of Eastern Ontario
Lauralyn McIntyre, MD, MSc, Study Chair, Affiliation: The Ottawa Hospital
Margaret Lawson, MD, MSc, Study Chair, Affiliation: Children's Hospital of Eastern Ontario
Hector Wong, MD, Study Chair, Affiliation: Children's Hospital Medical Center, Cincinnati
Tim Ramsay, MSc, PhD, Study Chair, Affiliation: Ottawa Hospital Research Institute

Overall contact:
Kusum Menon, MD, MSc, Phone: 613-737-7600, Ext: 2538, Email: menon@cheo.on.ca

Approximately 20,000 children per year in North America present to the hospital with severe shock. Children who develop this condition have very low blood pressures and as a result may suffer damage to their internal organs and may even die. Some children with this condition may significantly benefit from the use of steroids but steroids in such patients may also have potential side effects. Therefore it is important to study the use of steroids carefully in these children. The STRIPES research program will examine the effectiveness and safety of steroids in children. Before conducting a large, randomized controlled trial (RCT), a pilot study (STRIPES Pilot Study) will be conducted in multiple sites across Canada. The STRIPES Pilot Study will allow testing of the STRIPES study protocol in a smaller group of patients.

Official title: Steroid Use in Pediatric Fluid and Vasoactive Infusion Dependent Shock - Pilot Study (STRIPES)

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Patient accrual rate over one year

Secondary outcome:

1a. Time to administration of the first dose of study drug

1b. Weaning of study drug to q8h when patient is hemodynamically stable

1c. Discontinuation of study drug when off all vasoactive medications

Frequency of open label steroid use

Time to discontinuation of vasoactive infusions

Incidence of adverse events and mortality

Percentage of patients for whom blood samples are sent, and successfully received and analyzed in their respective labs

Detailed description: This study is a multi-centre pilot RCT to determine the feasibility of doing a full trial on the effect of steroids versus placebo in children with fluid and vasoactive infusion dependent shock. The principal investigator and colleagues recently published two articles on this topic which were selected as the Feature Article and Feature Review in the June edition of Pediatric Critical Care Medicine. Both of these publications strongly support the interest in this area and the accompanying editorial strongly supported the need for a well-designed RCT. RATIONALE: Approximately 20,000 children per year present to emergency departments, pediatric wards and intensive care units in North America with fluid and vasoactive infusion dependent shock. This severe type of shock results in significant morbidity and carries a 2-10% mortality rate depending on the setting in which it occurs. This form of shock is thought to arise from dysfunction of the hypothalamic-pituitary-adrenal axis through a variety of mechanisms and has been referred to as relative adrenal insufficiency or critical illness related adrenal insufficiency. Many clinicians believe that corticosteroids improve outcomes in such patients and therefore use them when confronted with a critically ill child with fluid and vasoactive infusion dependent shock. However, the effectiveness and safety of steroid replacement therapy in pediatric shock remain to be demonstrated.

OBJECTIVES - PILOT STUDY: Before embarking on a multi-centre definitive trial to address the

questions listed above, the STRIPES Pilot Study has 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; and 3) To document the frequency of and understand the reasons for open label steroid use.

OBJECTIVES - FULL RCT: Following successful completion of the STRIPES Pilot Study, the next

phase will be a large, multi centre RCT to answer the following questions: 1) What is the effect of hydrocortisone versus placebo on the time to discontinuation of vasoactive agents among pediatric patients with fluid and vasoactive infusion dependent shock?; and 2) In patients with fluid and vasoactive infusion dependent shock, what is the effect of hydrocortisone versus placebo on i) pediatric intensive care unit (PICU) mortality; ii) duration of mechanical ventilation; iii) new onset of organ dysfunction; iv) PICU length of stay; and v) incidence of adverse events? RESEARCH PLAN: The STRIPES Pilot Study is designed as a pragmatic, multi-centre, double blind, RCT of intravenous hydrocortisone versus intravenous placebo in fluid and vasoactive infusion dependent shock. This study aims to enroll 72 patients from 7 pediatric centres across Canada over a one year period. Patients will be recruited from the Emergency Department and the PICU within 6 hours of being stared on a vasoactive agent. Research ethics board approval will be obtained from all participating centres and application for deferred consent will be made at 5 sites. Health Canada approval is not required as hydrocortisone is approved for use in children at the doses and for the indication for which it is being used in this study. As part of the pragmatic design, the prescriptive component of the protocol will be limited to the administration and weaning of the study drug. The requirement for intubation, mechanical ventilation, sedation and analgesia, use of hemodynamic triggers and endpoints, red cell transfusions, antibiotics and fluid boluses 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; however, the use of vasoactive infusions and other therapies will be recorded. The proposed duration of treatment will range from a minimum of 20 hours to a maximum of 7 days of study drug. Outcome data, including survival status and frequency of adverse events, will be collected daily until discharge from hospital. Although the primary focus of this pilot study is to determine the feasibility of conducting a clinical outcome based RCT of steroids versus placebo in shock, this pilot also provides an excellent opportunity to perform some exploratory mechanistic studies. These will include 1) comparison of total and free cortisol levels of patients with shock; 2) measurement of stratification biomarkers; and 3) determination of 25 hydroxyvitamin D and 1,25 hydroxyvitamin D levels on admission. Patients with access for blood sampling and for whom consent has been obtained will have blood samples sent for these mechanistic studies. Patients will be randomized to the hydrocortisone or placebo arm using web-based, centralized permuted block randomization, stratified by centre. All study personnel (the overall study research coordinator, research assistants, site investigators, principal investigator, co-investigators, data management personnel, and statisticians), members of the health care team (treating physicians, bedside nurses, and clinical pharmacists) and patients/families will be blinded to the study group assignment. SIGNIFICANCE: Results of the STRIPES Pilot Study will provide essential feasibility data for planning and conducting a larger, multi-centre trial that will help to establish the role of steroids in children with fluid and vasoactive infusion dependent shock. There are special challenges to patient recruitment in critically ill pediatric populations, adherence to treatment protocols and to the limitation of open label use of steroids, all of which the STRIPES Pilot study will help to address. Success of the STRIPES Pilot Study will be based on the ability to achieve each of the three feasibility objectives listed above. If the pilot study demonstrates feasibility, no major protocol changes are needed, and no safety concerns are raised by the Data Safety Monitoring Board, then the results of the pilot study will be rolled into the full trial. However, if any of the above criteria are not met, then the protocol will be re-evaluated and the feasibility results of the pilot study published independently.

Minimum age: N/A. Maximum age: 17 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Children newborn to 17 years

- On any dose of any vasoactive infusion for between 1 to 6 hours

Exclusion Criteria:

- Patients who have known or suspected hypothalamic, pituitary or adrenal disease

- Patients who are currently receiving steroids for the treatment of shock/suspected

shock prior to randomization

- Patients who are expected to have treatment withdrawn

- Patients who are premature infants (<38 weeks corrected gestational age)

- Patients who are pregnant

- Patients post cardiac surgery

- Patient who received their first dose of vasoactive infusion >24 hours after PICU

admission

- Patient who is no longer on vasoactive infusion at the time of study enrollment,

and/or is expected to no longer be on vasoactive infusion at the time the first dose of study drug will be administered

- Patients for whom primary cardiogenic shock is strongly suspected

- Patients for whom spinal shock is strongly suspected

- Patients for whom hemorrhagic or hypovolemic shock is strongly suspected

- Patients who were previously enrolled in the STRIPES study

- Patients who receive a vasoactive agent for reasons not related to shock

- Physician refusal

Kusum Menon, MD, MSc, Phone: 613-737-7600, Ext: 2538, Email: menon@cheo.on.ca

Alberta Children's Hospital, Calgary, Alberta T3B 6A8, Canada; Not yet recruiting
Elaine Gilfoyle, MD, MSc, Principal Investigator

British Columbia Children's Hospital, Vancouver, British Columbia V6H 3V4, Canada; Recruiting
David Wensley, MB, BS, Principal Investigator

IWK Health Centre, Halifax, Nova Scotia B3K 6R8, Canada; Not yet recruiting
Gavin Morrison, MD, Principal Investigator

McMaster Children's Hospital, Hamilton, Ontario L8N 3Z5, Canada; Recruiting
Karen Choong, MB, MSc, Principal Investigator

Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H8L1, Canada; Recruiting
Katie O'Hearn, MSc, Phone: 613-737-7600, Ext: 4006, Email: kohearn@cheo.on.ca
Kusum Menon, MD, MSc, Principal Investigator
Dayre McNally, MD, PhD, Sub-Investigator

Hospital St. Justine, Montreal, Quebec H3T 1C5, Canada; Recruiting
Marisa Tucci, MD, Principal Investigator

Montreal Children's Hospital of the MUHC, Montreal, Quebec H3H 1P3, Canada; Not yet recruiting
Ronald Gottesman, MD, Principal Investigator

Related publications:

Menon K, McNally JD, Choong K, Ward RE, Lawson ML, Ramsay T, Wong HR. A survey of stated physician practices and beliefs on the use of steroids in pediatric fluid and/or vasoactive infusion-dependent shock. Pediatr Crit Care Med. 2013 Jun;14(5):462-6. doi: 10.1097/PCC.0b013e31828a7287.

Menon K, McNally D, Choong K, Sampson M. A systematic review and meta-analysis on the effect of steroids in pediatric shock. Pediatr Crit Care Med. 2013 Jun;14(5):474-80. doi: 10.1097/PCC.0b013e31828a8125. Review.

Odetola FO, Gebremariam A, Freed GL. Patient and hospital correlates of clinical outcomes and resource utilization in severe pediatric sepsis. Pediatrics. 2007 Mar;119(3):487-94.

Kissoon N, Carcillo JA, Espinosa V, Argent A, Devictor D, Madden M, Singhi S, van der Voort E, Latour J; Global Sepsis Initiative Vanguard Center Contributors. World Federation of Pediatric Intensive Care and Critical Care Societies: Global Sepsis Initiative. Pediatr Crit Care Med. 2011 Sep;12(5):494-503. doi: 10.1097/PCC.0b013e318207096c.

Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013 Feb;39(2):165-228. doi: 10.1007/s00134-012-2769-8. Epub 2013 Jan 30.

Menon K, Ward RE, Lawson ML, Gaboury I, Hutchison JS, Hébert PC; Canadian Critical Care Trials Group. A prospective multicenter study of adrenal function in critically ill children. Am J Respir Crit Care Med. 2010 Jul 15;182(2):246-51. doi: 10.1164/rccm.200911-1738OC. Epub 2010 Mar 18.

Zimmerman JJ, Barker RM, Jack R. Initial observations regarding free cortisol quantification logistics among critically ill children. Intensive Care Med. 2010 Nov;36(11):1914-22. doi: 10.1007/s00134-010-2007-1. Epub 2010 Aug 19.

Poomthavorn P, Lertbunrian R, Preutthipan A, Sriphrapradang A, Khlairit P, Mahachoklertwattana P. Serum free cortisol index, free cortisol, and total cortisol in critically ill children. Intensive Care Med. 2009 Jul;35(7):1281-5. doi: 10.1007/s00134-009-1480-x. Epub 2009 Apr 8.

Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med. 2004 Apr 15;350(16):1629-38.

Pollack MM, Patel KM, Ruttimann UE. PRISM III: an updated Pediatric Risk of Mortality score. Crit Care Med. 1996 May;24(5):743-52.

Zimmerman JJ, Donaldson A, Barker RM, Meert KL, Harrison R, Carcillo JA, Anand KJ, Newth CJ, Berger J, Willson DF, Jack R, Nicholson C, Dean JM; Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Real-time free cortisol quantification among critically ill children. Pediatr Crit Care Med. 2011 Sep;12(5):525-31. doi: 10.1097/PCC.0b013e3181fe4474.

Boonen E, Vervenne H, Meersseman P, Andrew R, Mortier L, Declercq PE, Vanwijngaerden YM, Spriet I, Wouters PJ, Vander Perre S, Langouche L, Vanhorebeek I, Walker BR, Van den Berghe G. Reduced cortisol metabolism during critical illness. N Engl J Med. 2013 Apr 18;368(16):1477-88. doi: 10.1056/NEJMoa1214969. Epub 2013 Mar 19.

Watson RS, Carcillo JA, Linde-Zwirble WT, Clermont G, Lidicker J, Angus DC. The epidemiology of severe sepsis in children in the United States. Am J Respir Crit Care Med. 2003 Mar 1;167(5):695-701. Epub 2002 Nov 14.

Wong HR, Cvijanovich NZ, Allen GL, Thomas NJ, Freishtat RJ, Anas N, Meyer K, Checchia PA, Lin R, Shanley TP, Bigham MT, Wheeler DS, Doughty LA, Tegtmeyer K, Poynter SE, Kaplan JM, Chima RS, Stalets E, Basu RK, Varisco BM, Barr FE. Validation of a gene expression-based subclassification strategy for pediatric septic shock. Crit Care Med. 2011 Nov;39(11):2511-7. doi: 10.1097/CCM.0b013e3182257675.

McNally JD, Doherty DR, Lawson ML, Al-Dirbashi OY, Chakraborty P, Ramsay T, Menon K. The relationship between vitamin D status and adrenal insufficiency in critically ill children. J Clin Endocrinol Metab. 2013 May;98(5):E877-81. doi: 10.1210/jc.2013-1126. Epub 2013 Apr 1.

Starting date: July 2014
Last updated: May 12, 2015