Hydrocortisone for Pediatric Septic Shock

(SHIPSS Trial)

Recruiting at 54 trial locations

Overseen By Kusum Menon, MD, MSc

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Jerry Zimmerman

Must be taking: Vasoactive-inotropic agents

Must not be taking: Systemic corticosteroids, Etomidate, Ketoconazole

Disqualifiers: Pregnancy, Brain death, Dengue, others

Stay on Your Current Meds You can continue your current medications while participating

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 28

Duration: 28 days

500 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are taking systemic corticosteroids or certain other medications like etomidate or ketoconazole, you may not be eligible to participate.

What data supports the effectiveness of the drug hydrocortisone for pediatric septic shock?

Research suggests that hydrocortisone may help children with septic shock who do not respond to other treatments, especially if they have low adrenal function, as it is recommended in guidelines for such cases. ^{1 2 3 4 5}

Is hydrocortisone safe for use in humans?

Hydrocortisone has been used in both adults and children with septic shock, but its safety and effectiveness can vary. In adults, some studies show higher mortality rates in those receiving hydrocortisone, though this may be due to their more severe illness. In children, guidelines recommend its use in specific cases, but more research is needed to fully understand its safety. ^{2 3 4 6 7}

How does hydrocortisone differ from other drugs for pediatric septic shock?

Hydrocortisone is unique in treating pediatric septic shock because it is specifically recommended for children who do not respond to other treatments like fluids and vasopressors (medications that raise blood pressure) and may have adrenal insufficiency (when the adrenal glands don't produce enough hormones). It is used in low doses to help stabilize blood pressure and improve survival in these severe cases. ^{2 3 5 6 8}

What is the purpose of this trial?

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).

Research Team

David Wypij, PhD

Principal Investigator

Boston Children's Hospital, Harvard Medical School

Hector R Wong, MD

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Kusum Menon, MD

Principal Investigator

Children's Hospital of Eastern Ontario

Michael Agus, MD

Principal Investigator

Boston Children's Hospital, Harvard Medical School

Jerry J Zimmerman MD, MD, PhD

Principal Investigator

Seattle Children's Hospital, University of Washington School of Medicine

Eligibility Criteria

This trial is for children aged 1 month to less than 17 years and 8 months with severe septic shock, who have had certain tests done, are on multiple medications to support blood pressure, and show signs of infection. It's not for those treated with specific drugs recently, pregnant, in US protective custody, or with certain diseases like adrenal disorders.

Inclusion Criteria

I am younger than 17 years and 8 months old.

I have been prescribed antibiotics.

I have been given two or more heart medications or high-dose adrenaline infusions for over an hour.

Exclusion Criteria

All inclusion criteria have been present for > 12 hours

Enrolled concurrently in a competing interventional clinical trial (formal assessment to be conducted by SHIPSS Core Committee for each potential competing trial)

I have or might have a condition affecting my hormone glands and may need steroids.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive either hydrocortisone or placebo for septic shock management

28 days

Daily monitoring in PICU

Follow-up

Participants are monitored for safety and effectiveness after treatment

90 days

Assessments at 28 and 90 days post-enrollment

Long-term Follow-up

Evaluation of health-related quality of life and functional status

90 days

Treatment Details

Interventions

• Hydrocortisone

Trial Overview The SHIPSS study is testing if hydrocortisone can help kids with septic shock get better outcomes compared to a normal saline placebo. Kids will be randomly assigned to either the drug or placebo group without knowing which one they're getting.

Participant Groups

Group I: Treatment Active Control 1 Intervention

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.

Group II: Placebo Placebo Group 1 Intervention

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.

Who Is Running the Clinical Trial?

Jerry Zimmerman

Lead Sponsor

Trials

1

Recruited

500+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Canadian Critical Care Trials Group

Collaborator

Trials

32

Recruited

227,000+

Children's Hospital of Eastern Ontario

Collaborator

Trials

134

Recruited

61,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Findings from Research

In a study of 6,693 pediatric patients with severe sepsis, the use of systemic corticosteroids was associated with increased mortality, suggesting that they do not improve outcomes in critically ill infants and children.

Independent predictors of mortality included older age, hematologic-oncologic diagnoses, and the use of steroids, indicating that clinicians should be cautious in using corticosteroids for severe sepsis until further randomized clinical trials are conducted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective cohort study of prognostic factors associated with outcome in pediatric severe sepsis: what is the role of steroids? Markovitz, BP., Goodman, DM., Watson, RS., et al.[2022]

In a study of 70 critically ill children with catecholamine-dependent septic shock, stress dose hydrocortisone therapy was found to correlate more with the severity of illness rather than random serum total cortisol levels, indicating that the therapy may not be beneficial for all patients.

The use of stress dose hydrocortisone was associated with worse outcomes, including higher PICU mortality and longer hospital stays, particularly in children with higher baseline cortisol levels, suggesting that this treatment may need to be reconsidered in certain cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hydrocortisone Therapy in Catecholamine-Resistant Pediatric Septic Shock: A Pragmatic Analysis of Clinician Practice and Association With Outcomes. Nichols, B., Kubis, S., Hewlett, J., et al.[2019]

In a pilot study involving 38 children with septic shock, low-dose intravenous hydrocortisone showed a trend towards faster shock reversal and reduced need for inotropic support compared to normal saline, although these results were not statistically significant.

The study suggests that while low-dose hydrocortisone may be beneficial in managing pediatric septic shock, further research with a larger sample size is needed to confirm its efficacy, especially considering factors like malnutrition and delayed treatment in developing countries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose hydrocortisone in pediatric septic shock: an exploratory study in a third world setting. Valoor, HT., Singhi, S., Jayashree, M.[2022]

In a study of 3411 patients with septic shock, those treated with hydrocortisone had higher illness severity, indicated by higher lactate levels and APACHE III scores, compared to those who did not receive the treatment.

Although patients receiving hydrocortisone experienced longer vasopressor duration and higher hospital mortality rates, multivariable analysis showed no significant association between hydrocortisone use and increased mortality, suggesting that the observed outcomes may be influenced by the patients' overall severity of illness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Utilization of Stress Dose Hydrocortisone in Adult Patients With Septic Shock: A Retrospective Observational Study at a Large Academic Medical Center. Sacha, GL., Chen, AY., Palm, NM., et al.[2023]

In a study of 499 patients with septic shock, hydrocortisone did not significantly improve survival rates compared to placebo, regardless of the patients' response to corticotropin testing.

While hydrocortisone did lead to a quicker reversal of shock symptoms, it was associated with a higher incidence of superinfections, including new cases of sepsis and septic shock.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hydrocortisone therapy for patients with septic shock. Sprung, CL., Annane, D., Keh, D., et al.[2022]

In a study involving 75 adrenalectomized rats with lethal septic shock, the combination of low-dose hydrocortisone and the antibiotic ertapenem significantly improved survival compared to either treatment alone.

Hydrocortisone treatment reversed sepsis-induced immunosuppression by altering gene expression related to immune response, which included increasing TNF production and decreasing bacterial burden in the kidneys.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose hydrocortisone prolongs survival in a lethal sepsis model in adrenalectomized rats. Doulias, T., Quickert, S., Weis, S., et al.[2019]

In a study of 1,470 patients with vasopressor-dependent septic shock, initiating hydrocortisone treatment within the first 12 hours after shock onset was associated with better outcomes, including more days alive and free from vasopressors.

Delaying hydrocortisone treatment beyond 48 hours was linked to higher ICU mortality, emphasizing the importance of timely intervention in septic shock management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the Initiation Timing of Hydrocortisone in Adult Patients With Septic Shock. Sacha, GL., Chen, AY., Palm, NM., et al.[2023]

In a study of 29 patients with severe burn and septic shock, hydrocortisone treatment significantly increased both systolic and diastolic blood pressure, indicating its efficacy in managing blood pressure in these patients.

Despite the positive response in blood pressure, the mortality rate remained unchanged, suggesting that while hydrocortisone can improve hemodynamics, it may not impact overall survival in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blood pressure alterations in burn patients with septic shock under hydro-cortisone treatment. Alinejad, F., Momeni, M., Fatemi, MJ., et al.[2020]

References

1. United States pubmed.ncbi.nlm.nih.gov

A retrospective cohort study of prognostic factors associated with outcome in pediatric severe sepsis: what is the role of steroids? [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Hydrocortisone Therapy in Catecholamine-Resistant Pediatric Septic Shock: A Pragmatic Analysis of Clinician Practice and Association With Outcomes. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Low-dose hydrocortisone in pediatric septic shock: an exploratory study in a third world setting. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Clinical Utilization of Stress Dose Hydrocortisone in Adult Patients With Septic Shock: A Retrospective Observational Study at a Large Academic Medical Center. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Hydrocortisone therapy for patients with septic shock. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Low-dose hydrocortisone prolongs survival in a lethal sepsis model in adrenalectomized rats. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Evaluation of the Initiation Timing of Hydrocortisone in Adult Patients With Septic Shock. [2023]

8. Iran pubmed.ncbi.nlm.nih.gov

Blood pressure alterations in burn patients with septic shock under hydro-cortisone treatment. [2020]