HYDROcortisone Versus Placebo for Severe HospItal-acquired Pneumonia in Intensive Care Patients: the HYDRO-SHIP Study

Study Overview
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Brief Summary
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The use of corticosteroids in patients with severe community pneumonia, bacterial infection which kills lots of patients around the world, reduces the mortality of this infection. However, there are no studies with this type of drug regarding hospital-acquired pneumonia. This will be the first multicenter randomized trial to test hydrocortisone plus standard therapy in critical care patients with nosocomial pneumonia. This intervention is inexpensive and may improve the outcome of those patients, besides having an acceptable side effects profile.

Detailed Description
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Introduction and Objectives: the use of corticosteroids in patients with severe community pneumonia, bacterial infection which kills lots of patients around the world, reduces morbimortality. However, to our knowledge, there are no studies with steroids for patients in intensive care with nosocomial pneumonia, among which those with ventilator associated pneumonia, infections which carry a high mortality rate. The treatment for those diseases involves intensive care and antibiotics, but there is a need for inexpensive, adjuvant therapies which improve the outcome for those patients. Therefore, the objective of this study is to compare hydrocortisone versus placebo, both with standard therapy, in the outcome of critical care patients diagnosed with nosocomial pneumonia. Methods: multicenter randomized, open-label, controlled trial, with two parallel groups: hydrocortisone or placebo, associated with nosocomial pneumonia's standard treatment. Patients with viral or other etiologies of pneumonia will be excluded, as well as corticosteroids chronical users, or patients with conditions which demand this type of therapy. Intravenous 100mg of hydrocortisone and normal saline (the placebo) will be tested every eight hours for five days or until intensive care unit (ICU) discharge or until the patient dies. The sample will be of 180 patients, 90 in each group, in different ICUs in Brazil. The primary outcome will be early clinical failure between the third and seventh days of the patient's inclusion in the study. The secondary outcomes will be survival and mortality in both groups, need for intubation, mechanical ventilation, vasoactive drugs and dialysis, lengths of stay in the hospital and in the ICU and radiological progression. Moreover, we will analyze adverse events and there will be a safety interim analysis when 25% of the whole sample is recruited, which may interrupt the study in case of a high frequency of such events (> 15% grade 3 or 4 as defined by the FDA). Finally, we will conduct an efficacy interim analysis when 50% of the sample is recruited. The study will be interrupted only if there is a statistical significant difference regarding the primary outcome with p < 0.001 (Haybittle-Peto criteria). Discussion, risks, and benefits: this will be the first multicenter randomized trial to test hydrocortisone plus standard therapy in critical care patients with nosocomial pneumonia. This intervention is inexpensive and may improve the outcome of those patients, besides having an acceptable side effects profile. Weighing the benefits and risks of this study, as well as its strengths and potential weaknesses, it is believed that its realization is justified, in addition to bringing important advances in the field of intensive care.

Official Title
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HYDROcortisone Versus Placebo for Severe HospItal-acquired Pneumonia in Intensive Care Patients: the HYDRO-SHIP Study

Conditions
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Healthcare-Associated Pneumonia, Ventilator Associated Pneumonia

Intervention / Treatment
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* Drug: Hydrocortisone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or older Suspected ou confirmed case of bacterial nosocomial pneumonia (including ventilator-associated pneumonia) Intensive Care Unit stay Signed consent form (by the patient or a legal guardian) Exclusion Criteria: Women who are pregnant, have recently given birth or are breastfeeding Patients who are moribund or do not have a treatment perspective Patients with community acquired pneumonia Patients with other types of pneumonia (viral - including COVID-19, fungal etc.) Those with pulmonary infiltrates in chest image which are not compatible with bacterial pneumonia Patients with adrenal insufficiency Patients who have a condition that demands the use of corticosteroids (acute or chronic) Patients allergic to hydrocortisone Patients with refractory septic shock (those receiving more than 0,5mcg/kg/min of norepinephrine)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This will be a multicenter, randomized, double-blind clinical trial with two parallel groups: hydrocortisone and placebo. Data will be analyzed as intention-to-treat.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Normal saline 100mL every 8 hours for 5 days or until patient dies or is discharged from the intensive care unit | Drug: Placebo<br>* Normal saline only<br>* Other names: NS;|
| Active Comparator: Hydrocortisone<br>Hydrocortisone 100mg + normal saline 100mL every 8 hours for 5 days or until patient dies or is discharged from the intensive care unit | Drug: Hydrocortisone<br>* Corticosteroid<br>* Other names: Solu-CORTEF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early Clinical Failure | Composite outcome: Death OR Respiratory worsening OR Cardiovascular worsening | Between days 3 and 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | In the intensive care unit and in the hospital | Days 7 and 28 | 
| Respiratory failure | Need for mechanical ventilation | 7 days | 
| Septic shock | Need for vasoactive drugs | 7 days | 
| Time of mechanical ventilation | Number of days patients require invasive ventilation support | 7 days | 
| Ventilator parameters | Positive end expiratory pressure (PEEP) | 7 days | 
| Ventilator parameters | Inspired oxygen fraction (FiO2) | 7 days | 
| Arterial blood gas analysis | Partial pressure of oxygen (PaO2) | 7 days | 
| Respiratory condition | Horowitz index for lung function (P/F ratio) - obtained from PaO2/FiO2 | 7 days | 
| Time of vasoactive drugs use | Dosage and types of vasoactive drugs | 7 days | 
| Length of stay | In the Intensive Care Unit and in the hospital | 28 days | 
| Need for renal substitution therapy | Need for dialysis | 7 days | 
| Radiological worsening | Progression of image in the chest X-ray image | 7 days | 
| Adverse effects | psychosis, insomnia, hyperglycemia, hypernatremia, rhabdomyolysis, gastrointestinal bleeding and critical myopathy illness | 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hydrocortisone, Intensive Care Unit, Pneumonia, Steroids, Critical Care