Stress Hydrocortisone In Pediatric Septic Shock
Purpose
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).
Condition
- Septic Shock
Eligibility
- Eligible Ages
- Between 1 Month and 17 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
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: 1. Age is at least 1 month (with corrected gestational age ≥42 weeks), but less than 17 years and 8 months of age 2. 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 3. Surveillance cultures (e.g. blood, urine, cerebral spinal fluid, wound) and/or other microbial diagnostic tests have been obtained 4. One or more antimicrobials have been prescribed 5. 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 6. 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 7. 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.
Exclusion Criteria
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: 1. All inclusion criteria have been present for > 12 hours 2. Attending physician expects to prescribe systemic corticosteroids for an indication other than septic shock 3. Patient has received any doses of systemic corticosteroids during treatment for sepsis 4. Enrolled concurrently in a competing interventional clinical trial (formal assessment to be conducted by SHIPSS Core Committee for each potential competing trial) 5. Etomidate or ketoconazole treatment within past 48 hours 6. Patient in whom steroids are contraindicated at time of screening (e.g. treatment for systemic fungal infection, cerebral malaria, strongyloides) 7. 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) 8. Attending physician, PICU care team, or legally recognized guardians not committed to full treatment and resuscitation at the time of screening 9. Patient documented to be pregnant 10. Previous enrollment in the SHIPSS study 11. 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. 12. (U.S. sites only) Patient in the custody of US protective services 13. Patient being evaluated for brain death 14. Vasoactive-inotropic agents prescribed solely for an indication other than septic shock 15. Confirmed dengue fever
Study Design
- Phase
- Phase 3
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Intervention Model Description
- Patients randomized to the hydrocortisone treatment arm will receive an initial bolus of 2 mg/kg IV hydrocortisone (maximum 100 mg), followed by 1 mg/kg (maximum 50 mg) of hydrocortisone dosed every six hours for a maximum of seven days or until all vasoactive infusions have been discontinued for at least 12 hours, whichever comes first. When the hydrocortisone course is completed, the medication will be discontinued. Patients randomized to the placebo treatment arm will receive an equivalent volume of normal saline, with the identical dosing schedule outlined above.
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
- Masking Description
- Subjects, families, critical care providers and investigators will be blinded to study drug administration. Only the local performance site research pharmacist will be un-blinded.
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Active Comparator Treatment |
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. |
|
|
Placebo Comparator Placebo |
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. |
|
Recruiting Locations
Tucson, Arizona 85724
Katri Typpo, MD
Los Angeles, California 90027
Christopher Newth, MD
Oakland, California 94609
Natalie Cvijanovich, MD
Orange, California 92868
Adam Schwarz, MD
San Francisco, California 94143
Wilmington, Delaware 19803
Catherine Madurski, MD
Chicago, Illinois 60637
Grace Chong, MD
Peoria, Illinois 61603
Sandeep Tripath, MD
Louisville, Kentucky 40202
John Berkenbosch, MD
Boston, Massachusetts 02115
Michael Agus, MD
Livingston, New Jersey 07039
Shira J Gertz, MD
Cincinnati, Ohio 45229
Ranjit R Chima, MD
Oklahoma City, Oklahoma 73104
Christine Allen, MD
Hershey, Pennsylvania 17033
Robert Kavanagh, MD
Salt Lake City, Utah 84108
Jennifer Workman, MD
Seattle, Washington 98105
Jerry J Zimmerman, MD, PhD
Madison, Wisconsin 53792
Pelin Cengiz, MD
More Details
- NCT ID
- NCT03401398
- Status
- Recruiting
- Sponsor
- Jerry Zimmerman
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, China, 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.