Stress Hydrocortisone In Pediatric Septic Shock
- Conditions
- Septic Shock
- Interventions
- Drug: Normal salineDrug: Hydrocortisone, sodium succinate
- Registration Number
- NCT03401398
- Lead Sponsor
- Jerry Zimmerman
- Brief Summary
SHIPSS is a multi-institutional, prospective, controlled, randomized, double-blinded interventional trial that will examine the potential benefits and risks of adjunctive hydrocortisone prescribed for children with fluid and vasoactive-inotropic refractory septic shock.
It is hypothesized that adjunctive hydrocortisone will significantly reduce the incidence of new and progressive organ dysfunction (primary outcome) and proportion of children with poor outcomes, defined as death or severely impaired health-related quality of life (HRQL) (secondary outcome), as assessed at 28 days following study enrollment (randomization).
- Detailed Description
Sepsis represents the most common cause of childhood mortality worldwide. In the United States alone, 200 cases of pediatric sepsis are diagnosed each day, with an associated hospital mortality rate of 5-10% and health care expenditures now approaching $5 billion annually. Moreover, nearly one third of children admitted to pediatric intensive care units (PICUs) for septic shock have not regained their baseline health-related quality of life one year following the sepsis event.
During early resuscitation of the child with septic shock, in addition to antibiotics, volume replacement, and vasoactive-inotropic support, the most recent pediatric treatment guidelines advise the practitioner to consider adjunctive hydrocortisone therapy if the patient "is at risk of absolute adrenal insufficiency or adrenal pituitary axis failure". However, the potential benefits and risks of this recommendation have not been rigorously examined. On the one hand, corticosteroids are inexpensive and have been frequently demonstrated to improve hemodynamic status in children and adults with sepsis. Conversely, this drug class is known to alter transcription of approximately 30% of the human genome. Notably, corticosteroids down regulate most aspects of the immune response, but particularly adaptive immunity. Moreover, recent data suggests that children with particular gene expression profiles in sepsis have increased likelihood of mortality when treated with corticosteroids.
SHIPSS (Stress Hydrocortisone In Pediatric Septic Shock) is a prospective, randomized, double-blinded, placebo-controlled trial examining the potential benefits and risks of adjunctive hydrocortisone prescribed to critically ill children with fluid and vasoactive-inotropic refractory septic shock. Up to 500 children will be enrolled, randomized, and evaluated at baseline, and 28 and 90 days following study enrollment.
The primary hypothesis is that hydrocortisone, compared to placebo, will decrease the the incidence of new or progressive organ dysfunction (primary outcome) and the proportion of subjects with poor outcomes, defined as death or severely impaired (≥25% decrease from baseline) HRQL (secondary outcome). Subjects will be monitored daily while receiving care in the PICU for the occurrence of adverse events, including the following protocol specified events:hyperglycemia treated with any insulin; gastrointestinal hemorrhage treated with blood product transfusion or vasopressin or octreotide infusion; delirium requiring medical treatment; and hospital-acquired infection treated with new antimicrobials. Finally, the investigators will test the hypothesis that biomarker-based prognostic and predictive enrichment strategies can improve our ability to identify which children with septic shock are more likely to benefit from adjunctive hydrocortisone, and which may be harmed. This trial will have a significant impact on public health by providing the heretofore missing evidence to inform guidelines regarding therapy for septic shock in children.
The SHIPSS trial will enroll patients from PICUs in Canada, the United States, Saudi Arabia, Israel, Brazil, Vietnam, Pakistan, Japan, Malaysia, and Singapore. Health Canada approval is not required as hydrocortisone is approved for use in septic shock in children, and this trial meets the criteria of a Phase IV study. In the United States, this trial is considered a Phase III trial as hydrocortisone is not approved for use in pediatric septic shock.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 500
A child receiving treatment in a pediatric intensive care unit is eligible for recruitment into SHIPSS if she/he meets all of the following inclusion criteria:
- Age is at least 1 month (with corrected gestational age ≥42 weeks), but less than 17 years and 8 months of age
- A documented focus of infection or a strong suspicion of infection at PICU admission, or for patients who develop septic shock during PICU stay, at the onset of the septic shock event
- Surveillance cultures (e.g. blood, urine, cerebral spinal fluid, wound) and/or other microbial diagnostic tests have been obtained
- One or more antimicrobials have been prescribed
- Core temperature >38.5 C or <36.0 C or leukocytosis or leukopenia (as defined by the local laboratory) or a left-shifted leukocyte differential (>10% immature granulocyte forms) or a neutrophil count of <0.5 x 109 cells per litre documented at least once within the 24 hours preceding screening
- Treatment with a continuous infusion of vasoactive-inotropic agent(s) to maintain mean or systolic arterial blood pressure above the age-appropriate target set by the treating clinician
- Administration of two or more vasoactive-inotropic agents at any dose or epinephrine or norepinephrine infusion(s) alone at greater than or equal to 0.10 mcg/kg/min for >1 hour.
A child receiving treatment in a pediatric intensive care unit for sepsis is ineligible for enrollment into SHIPSS if she/he meets any of the following exclusion criteria:
- All inclusion criteria have been present for > 12 hours
- Attending physician expects to prescribe systemic corticosteroids for an indication other than septic shock
- Patient has received any doses of systemic corticosteroids during treatment for sepsis
- Enrolled concurrently in a competing interventional clinical trial (formal assessment to be conducted by SHIPSS Core Committee for each potential competing trial)
- Etomidate or ketoconazole treatment within past 48 hours
- Patient in whom steroids are contraindicated at time of screening (e.g. treatment for systemic fungal infection, cerebral malaria, strongyloides)
- Known or suspected hypothalamic, pituitary or adrenal disease (including patient has received acute or chronic corticosteroid administration and the physician intends to provide corticosteroid for suspected adrenal suppression)
- Attending physician, PICU care team, or legally recognized guardians not committed to full treatment and resuscitation at the time of screening
- Patient documented to be pregnant
- Previous enrollment in the SHIPSS study
- Patient admitted directly to the PICU with a thermal burn who has been in the PICU for <72 hours prior to meeting SHIPSS inclusion criteria.
- (U.S. sites only) Patient in the custody of US protective services
- Patient being evaluated for brain death
- Vasoactive-inotropic agents prescribed solely for an indication other than septic shock
- Confirmed dengue fever
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Normal saline Approximately half of the subjects randomized into SHIPSS will be randomized into the Placebo Group and will receive equivalent study drug volumes of normal saline. Treatment Hydrocortisone, sodium succinate Approximately half of the subjects randomized into SHIPSS will be randomized into the Treatment Group and will receive hydrocortisone sodium succinate according to a predetermined dosing schedule.
- Primary Outcome Measures
Name Time Method New or progressive multiple organ dysfunction syndrome as assessed utilizing the Pediatric Logistic Organ Dysfunction (PELOD-2) instrument. 28 days following study enrollment Appearance of new or progression of existing organ dysfunctions according to PELOD-2 definitions. PELOD-2 considers 5 organ dysfunctions (neurological, cardiovascular, renal, respiratory, and hematological) with 10 total variables, with dysfunction scored 0 up to 6 for each organ category. Total minimum/maximal scores are 0/33, with increasing score indicating increasing risk of mortality. Logit (mortality) = -6.61 + 0.47 × PELOD-2 score. Probability of death = 1/(1 + exp \[-logit(mortality)\]). A new organ dysfunction or progression of organ dysfunction is defined as an increase score in any organ category from baseline.
- Secondary Outcome Measures
Name Time Method 28-day hospital mortality or ≥25% decrease from baseline in health-related quality of life (HRQL) assessed utilizing the Pediatric Quality of Life Inventory, (PedsQL) 28 days following study enrollment Mortality or ≥25% decrease in PedsQL from baseline
Trial Locations
- Locations (51)
HOSPITAL SINO BRASILEIRO - Hospital São Luiz Osasco
🇧🇷São Paulo, Brazil
Real e Benemérita Associação Portuguesa de Beneficência/SP
🇧🇷São Paulo, Brazil
REDE D'OR SAO LUIZ S.A. - Hospital São Luiz Anália Franco
🇧🇷São Paulo, Brazil
REDE D'OR SAO LUIZ S.A. - Hospital São Luiz Vila Lobos
🇧🇷São Paulo, Brazil
Alberta Children's Hospital
🇨🇦Calgary, Alberta, Canada
Hadassah University Medical Center, Ein Kerem
🇮🇱Jerusalem, Israel
Schneider Children's Medical Center of Israel
🇮🇱Petah Tikva, Israel
Kobe Children's Hospital
🇯🇵Kobe, Japan
BC Children's Hospital
🇨🇦Vancouver, British Columbia, Canada
IWK Health Centre
🇨🇦Halifax, Nova Scotia, Canada
Sarawak General Hospital
🇲🇾Kuching, Malaysia
Shifa International Hospital
🇵🇰Islamabad, Pakistan
Aga Khan University Hospital
🇵🇰Karachi, Pakistan
King Abdullah Specialist Children's Hospital
🇸🇦Riyadh, Saudi Arabia
KK Women's and Children's Hospital
🇸🇬Singapore, Singapore
Vietnam National Children's Hospital
🇻🇳Hanoi, Vietnam
City Children's Hospital
🇻🇳Ho Chi Minh City, Vietnam
McMaster Children's Hospital
🇨🇦Hamilton, Ontario, Canada
Aichi Children's Health and Medical Center
🇯🇵Nagoya, Japan
Tokyo Metropolitan Children's Medical Center
🇯🇵Tokyo, Japan
UKM Specialist Children's Hospital
🇲🇾Kuala Lumpur, Malaysia
University Malaya Medical Centre
🇲🇾Kuala Lumpur, Malaysia
University of Arizona Medical Centre
🇺🇸Tucson, Arizona, United States
Children's Hospital of Los Angeles
🇺🇸Los Angeles, California, United States
UCSF Benioff Children's Hospital - Oakland
🇺🇸Oakland, California, United States
Children's Hospital of Orange County
🇺🇸Orange, California, United States
UCSF Benioff Children's Hospital - San Francisco
🇺🇸San Francisco, California, United States
Nemours Children's Health
🇺🇸Wilmington, Delaware, United States
University of Chicago, Comer Children's Hospital
🇺🇸Chicago, Illinois, United States
The University of Illinois at Chicago/OSF Children's Hospital of Illinois
🇺🇸Peoria, Illinois, United States
University of Louisville, Norton Children's Hospital
🇺🇸Louisville, Kentucky, United States
Boston Children's Hospital
🇺🇸Boston, Massachusetts, United States
Saint Barnabas Medical Center
🇺🇸Livingston, New Jersey, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Penn State Milton S. Hershey Children's Hospital
🇺🇸Hershey, Pennsylvania, United States
Primary Children's Hospital
🇺🇸Salt Lake City, Utah, United States
The Children's Hospital at Oklahoma University Medical Center
🇺🇸Oklahoma City, Oklahoma, United States
London Health Sciences Centre
🇨🇦London, Ontario, Canada
Children's Hospital of Eastern Ontario
🇨🇦Ottawa, Ontario, Canada
Centre hospitalier universitaire Sainte-Justine
🇨🇦Montréal, Quebec, Canada
Montreal Children's Hospital
🇨🇦Montréal, Quebec, Canada
Centre hospitalier de l'Université Laval
🇨🇦Québec, Quebec, Canada
Royal University Hospital
🇨🇦Saskatoon, Saskatchewan, Canada
Rambam Health Care Campus
🇮🇱Haifa, Israel
Le Bonheur Children's Hospital
🇺🇸Memphis, Tennessee, United States
Santa Casa de Misericordia Da Bahia
🇧🇷Bahia, Brazil
University of Wisconsin Health/American Family Children's Hospital
🇺🇸Madison, Wisconsin, United States
Hospital Jutta Batista - Rio de Janeiro
🇧🇷Rio de Janeiro, Brazil
Hospital Jutta Batista
🇧🇷Rio de Janeiro, Brazil
Hospital Alvorada Taguatinga LTDA
🇧🇷São Paulo, Brazil