Septic Shock
Conditions
Keywords
hydrocortisone, refractory septic shock, sepsis, new/progressive MODS, mortality, health-related quality of life, corticosteroid adverse events, sepsis biomarkers
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.
Interventions
DRUGHydrocortisone, sodium succinate
Patients randomized to the hydrocortisone treatment arm will receive an initial bolus of 2 mg/kg IV hydrocortisone, 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.
DRUGNormal saline
Patients randomized to the placebo treatment arm will receive an equivalent volume of normal saline, with the identical dosing schedule to the intervention (hydrocortisone) arm.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Canadian Institutes of Health Research (CIHR)
Canadian Critical Care Trials Group
Children's Hospital of Eastern Ontario
Jerry Zimmerman
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, 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.
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.
Eligibility
Sex/Gender
ALL
Age
1 Months to 17 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Risk stratification sepsis biomarkers and pediatric sepsis endotype | Enrollment and Day 2 | Risk stratification sepsis biomarkers will be measured in serum obtained at enrollment and on Day 2. The PERSEVERE (PEdiatRic SEpsis biomarkEr Risk modEl) will be used to determine the patient's risk of mortality. mRNA will be isolated from blood samples collected at enrollment and on Day 2 to classify the patient as pediatric septic shock Endotype B or A. A composite outcome of sepsis endotype and PERSEVERE risk of mortality will be used to determine if a biomarker-based prognostic model and predictive enrichment strategies allow identification of children with septic shock more likely to benefit from adjunctive hydrocortisone. We hypothesize that pediatric septic shock endotype B subjects having an intermediate to high Pediatric Sepsis Biomarker Risk Model (PERSEVERE)-based risk of mortality will derive significant benefit from adjunctive corticosteroids, compared to endotype B subjects having a low risk and endotype A subjects at all risk levels. |
| Trichotomous mortality/morbidity outcome | 28 and 90 days following study enrollment | This is a 3-level ordinal endpoint, with levels death, survival with severely impaired HRQL (≥25% decrease from baseline), and survival without severely impaired HRQL, assessed at 28 and 90 days. This approach is similar to that recently reported for assessment of functional status among children encountering critical illness, utilizing the Functional Status Scale. This endpoint is expected to be highly correlated with the primary efficacy endpoint. |
| 90-Day Death or ≥25% decrease in HRQL from baseline | 90 days following study enrollment | Mortality or ≥25% decrease in PedsQL from baseline |
| Mechanical ventilation-free days through day 28 | 28 days following study enrollment | Mechanical ventilation-free days through day 28 is defined as 28 minus duration of mechanical ventilation. Subjects who die, are still receiving mechanical ventilation, or are transferred from the PICU still receiving mechanical ventilation by day 28 will be censored at 28 days and assigned zero mechanical ventilation-free days. |
| Utilization of acute renal replacement therapy (RRT) | Enrollment to PICU discharge, an average of 2 weeks | Proportion of subjects receiving acute RRT. All types of acute RRT will be considered, including hemodialysis, continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), and peritoneal dialysis. RRT in patients on chronic RRT will not be considered. |
| Utilization of extracorporeal membrane oxygenation (ECMO) | Enrollment to PICU discharge, an average of 2 weeks | Proportion of subjects receiving ECMO |
| Functional status - POPC | 28 and 90 days following study enrollment | Gross functional status category staging will be made using the Pediatric Overall Performance Category (POPC) score. |
| Vasoactive-inotropic infusion-free days through day 28 | 28 days following study enrollment | Vasoactive-inotropic infusion-free days through day 28 is defined as 28 minus duration of vasoactive-inotropic infusions. Subjects who die or are still receiving vasoactive-inotropic infusions by day 28 will be censored at 28 days and assigned zero vasoactive-inotropic infusion-free days. |
| PICU-free days through day 28 | 28 days following study enrollment | PICU-free days through day 28 is defined as 28 minus duration of PICU stay. Subjects who die or are still in the PICU by day 28 will be censored at 28 days and assigned zero PICU-free days. |
| Hospital-free days through day 28 | 28 days following study enrollment | Hospital-free days through day 28 is defined as 28 minus duration of hospital stay. Subjects who die or are still in the hospital by day 28 will be censored at 28 days and assigned zero hospital-free days through day 28. |
| Hospital-free days through day 90 | 90 days following study enrollment | Hospital-free days through day 90 is defined as 90 minus duration of hospital stay. Subjects who die or are still in the hospital by day 90 will be censored at 90 days and assigned zero hospital-free days through day 90. |
| Need for new medical devices at hospital discharge | At time of hospital discharge, expected to be an average of 21 days from time of enrollment | New medical devices prescribed at hospital discharge will be collected from the hospital discharge summary. |
| Frequency of primary care, specialty care, and emergency department visits and hospital readmissions | 90 days following study enrollment | Enumeration of additional health care evaluations following the index hospital admission will occur by telephone survey at 90 days. |
| Disruption of family dynamics | Enrollment and 90 days following study enrollment | The PedsQLTM 2.0 Family Impact Module will be used to quantify the impact of septic shock on family dynamics. |
| Cost Analysis - Cost of PICU admission for septic shock | 90 days following study enrollment | The cost of each patients PICU admission will be determined by summing the cost of the following: PICU and hospital length of stay, frequency of primary care, specialty care, emergency department visits, and hospital readmissions up to 90 days following hospital discharge, new medical devices post hospital discharge and hospital costs of the admission for septic shock. |
| Functional status - FSS | 28 and 90 days following study enrollment | Functional Status Scale (FSS) will be employed to provide a more granular determination of changes in functional status. |
| SHIPSS specified adverse events | 28 days following study enrollment | Occurrence of adverse events plausibly associated with corticosteroid administration. SHIPSS specified events include hyperglycemia, gastrointestinal hemorrhage, delirium, and hospital-acquired infection |
Countries
Brazil, Canada, Israel, Japan, Malaysia, Pakistan, Saudi Arabia, Singapore, United States, Vietnam
Contacts
Primary ContactJerry J Zimmerman, MD, PhD
Backup ContactKusum Menon, MD, MSc
Outcome results
None listed