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.

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

Inclusion Criteria:

• Severe sepsis where enrolment can occur within 20 hours of first contact with paediatric intensive care, or within 20 hours of the diagnosis of severe sepsis when this diagnosis is made on PICU. Randomisation should occur within 24 hours of first contact with paediatric intensive care, or within 24 hours of the diagnosis of severe sepsis when this diagnosis is made on PICU.
• Requiring mechanical ventilation (The subjects must be mechanically ventilated for entry into the study but this is not time limited. It is routine practice at study centres to pre-emptively ventilate children with evolving sepsis)

Exclusion Criteria:

• Concomitant steroid therapy, vasopressor treatment >24 hrs or use of etomidate (not recommended for use in children less than 10 years and selectively inhibits 11 beta-hydroxylase)
• Patients who have a recognised indication for steroids
• Other immunosuppressive/immunomodulatory therapy (not including intravenous immunoglobulin which is considered standard therapy in toxic shock syndrome and may be given for this indication)
• Significant immunocompromise (eg HIV infection)
• Advanced malignancy
• Burns
• Cardiopulmonary resuscitation
• Children not likely to survive the time period of the maximum study intervention (5 days)
• Patients who have undergone organ transplantation (including bone marrow transplantation)
• Patients undergoing plasma exchange or whole blood exchange transfusion
• Treatment with an investigational drug or device within the last 30 days prior to enrolment.
• Patients who have experienced a prior episode of infection or sepsis during the current hospitalisation.
• Patients who are pregnant (a pregnancy test will be carried out for females of 11 years and above as is standard practice for clinical trials).
• Immediate families of investigators or site personnel directly affiliated with the study. Immediate family is defined as child or sibling, whether biological or legally adopted.