Sepsis Clinical Trial
Official title:
Evaluation of Corticosteroid Therapy in Childhood Severe Sepsis (Steroids in Paediatric Sepsis, StePS) - a Randomised Pilot Study
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
;
Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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