Evaluation of Corticosteroid Therapy in Childhood Severe Sepsis - a Randomised Pilot Study
Condition: Sepsis
MeSH terms: Sepsis; Toxemia
Study type: Interventional
Phase: Phase 2

Summary: 
      Severe bacterial infections affecting multiple body organs, called severe sepsis (including
      meningococcal sepsis), remain an important cause of death and disability among children.
      Although early recognition, powerful antibiotics, and good intensive care have improved
      outcome, we need new ways to further reduce the number of deaths. Research in adults has
      shown that steroid replacement therapy might be useful. However, children are known to
      respond differently to adults and a definitive trial in children is needed because of the
      potentially harmful as well as beneficial effects of steroids.

      This pilot study will provide the necessary information to allow the rational design of a
      large trial conducted at multiple hospitals investigating the role of corticosteroid
      replacement therapy in childhood sepsis. The study will provide information on how to measure
      the effects of steroids, information on length of therapy and a better understanding of how
      steroids work in children. The results emerging from this study will ultimately allow
      paediatric intensive care clinicians to know whether or not steroids are safe and/or useful.

      The primary objective of this open-label study is therefore to gather clinical and laboratory
      data with which to inform the design of a large phase 3 double blind randomised controlled
      trial (RCT). The study will provide basic limited safety data, information on length of
      therapy and an assessment of possible clinical and laboratory endpoints to be used in
      addition to mortality.

      Definition of sepsis:

      Presence of a documented infection (eg clinical evidence of pneumonia, skin or soft tissue
      infection, purpura fulminans, urinary tract infection, abdominal infection) or a diagnostic
      positive blood culture (community or hospital acquired) within the last 72 hours and at least
      two of the following, one of which must be abnormal temperature or leucocyte count[3] core
      temperature of >38.5°C or <36°C; tachycardia (mean heart rate >2 SD above normal for age);
      mean respiratory rate > 2 SD above normal for age; leucocyte count elevated or depressed for
      age.

      Definition of severe sepsis:

      Sepsis plus cardiovascular organ dysfunction (the need for at least 5mcg/kg/min dopamine or
      dobutamine, or any amount of adrenaline or noradrenaline support), acute respiratory distress
      syndrome (ARDS), or 2 or more other organ dysfunctions.
    

Detailed description: 
      1. PURPOSE: The Need for a Paediatric Trial of Steroids in Sepsis - potential benefits and
           risks Numerous targets for new therapies in sepsis have been identified, none of which
           have been shown to have been of benefit in children. The results of adult studies cannot
           therefore be extrapolated directly to childhood disease. Corticosteroids alter the
           inflammatory balance in both beneficial and harmful ways in severe sepsis. Recent adult
           studies have demonstrated transient adrenal insufficiency is associated with adverse
           outcome and that corticosteroids increase survival in specific patient groups, and
           steroid replacement has become a standard of care. There is little uniformity in the
           approach to steroid replacement therapy amongst leading paediatric centres in the UK.
           Expert opinion has emphasised that guidance is interim while awaiting appropriate
           paediatric studies. Steroids are perceived as "safe" and "cheap" but should not be
           introduced into paediatric practice without further research. Sepsis in childhood
           differs in terms of mortality (around 10% overall in children vs in excess of 40% in
           adults), background immunity, co-morbidity, and causative organisms. Given the lower
           overall mortality in childhood sepsis, steroids have the potential to disrupt the
           inflammatory balance in children causing greater harm than benefit. It is not known
           which patients should be targeted for therapeutic intervention; what are the most
           appropriate endpoints; whether the length of steroid therapy can be shorter in children;
           or whether immunological rebound will occur.

        2. DESIGN and METHODOLOGY:

      This is an open randomised prospective pilot exploratory study of corticosteroid replacement
      therapy in three centres. Adrenal function measurements will be assessed on entry to the
      study. To investigate the inflammatory profile and the impact of corticosteroid replacement,
      blood will be taken for cytokine and coagulation protein analysis. This study will provide
      the pilot data necessary for the design of a definitive trial of corticosteroid replacement
      therapy with the identification of variables likely to improve our ability to stratify
      patients for intervention and the mechanistic characterisation of the modulatory effects of
      steroids on inflammation in children with severe sepsis. Enrolment will be undertaken in two
      stages (see flowsheet diagrams in protocol). Forty five eligible children will be randomly
      allocated to steroid replacement therapy for 2 days (n=30) or intensive investigation without
      intervention (n=15) in a 2:1 randomisation (stage 1); 45 subjects (stage 2) will then be
      randomly allocated to steroid replacement therapy for 5 days (n=30) or intensive
      investigation without intervention (n=15). Randomisation will the undertaken in accordance
      with a computer-generated list and will be stratified by age (<1 years; 1 year or more).
      Progression from stage 1 to stage 2 will follow an interim analysis by a Trial Monitoring
      Group to ensure safety. This escalating approach will provide safety data, information on
      length of therapy and an assessment of possible clinical and laboratory endpoints in addition
      to mortality, reducing the potential for adverse events in the pilot phase while providing
      data relevant to this population. A large excess of serious adverse events in stage 1 will
      result in study termination. After careful consideration by the investigators and during the
      peer review process, placebo will not be used in this study, which will inform a future large
      phase 3 randomised controlled trial.

      RESEARCH PARTICIPANTS WILL RECEIVE THE FOLLOWING INTERVENTIONS THAT ARE NOT PART OF ROUTINE
      CLINICAL CARE (Please also refer to figures 1-4 in the protocol that we are unable to
      reproduce here): Children will be screened on admission to PICU. Entry into the study
      following consent involves a clinical test of endocrine function involving 2 blood tests. The
      list of procedures conducted in the study is as follows:

        1. confirm eligibility requirements, assess pre-existing conditions and medical history,
           record weight, height, vital signs, data to inform clinical severity scores, complete
           infection assessment, clinically relevant laboratory investigations

        2. corticotrophin stimulation test

        3. multiple study samples (endocrine, cytokine and coagulation tests)

        4. corticosteroid treatment if randomised to treatment group

        5. follow-up in routine clinic
    

Intervention name(s): hydrocortisone
Intervention type(s): Drug
Intervention description(s): Patients will be assigned to treatment with hydrocortisone at 100mg/m2/24 hours in 4 divided doses (25 mg/m2/q 6 hourly) for 8 doses (48 hours) in phase 1 of study (45 patients, 30 receive IMP) or 20 doses (120 hours) in phase 2 (45 patients, 30 receive IMP).
Other intervention name(s): Solu-Cortef®; Hydrocortisone sodium succinate
Intervention MeSH terms: Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: sepsis; septicaemia; septicemia; paediatric; pediatric; children