Steroid Use in Pediatric Fluid and Vasoactive Infusion Dependent Shock - Pilot Study
Condition: Shock
MeSH terms: Shock
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

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.
    

Intervention name(s): Hydrocortisone; Placebo
Intervention type(s): Drug; Other
Intervention description(s): Hydrocortisone will be made up as a 10 mg/ml solution so the volume of added fluid will be very small (2 to 10 mls even for the initial dose of 2 mg/kg).; The placebo (normal saline) will be identical in appearance, volume and smell to the active study drug (hydrocortisone).
Other intervention name(s): SOLU-CORTEF; Placebo (saline solution)
Intervention MeSH terms: Hydrocortisone; Hydrocortisone hemisuccinate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Hydrocortisone; Pediatrics; Adrenal Insufficiency