Steroid Dosing by bioMARker Guided Titration in Critically Ill Patients With Pneumonia

Phase 2

Completed

Conditions: Pneumonia

Interventions: Other: Usual Care
Drug: Methylprednisolone

Registration Number: NCT03852537

Lead Sponsor: Mayo Clinic

Brief Summary: This research study is being done to determine the appropriate dose of steroids and the appropriate duration for steroid use to reduce inflammation in severe pneumonia needing a form of breathing support. This study seeks to compare usual care to a unique (individualized) dosing strategy. A marker of inflammation in the body will be measured in blood samples. This marker of inflammation is called C- reactive protein. The overall goal is to identify patients that will benefit most from steroid use and decrease use of steroids. The information collected from this study may provide information that may improve management of patients with severe pneumonia requiring a form of breathing support.

Detailed Description: This is a two-arm single-center pilot phase II clinical trial. Patients will be screened at the time of hospital admission and will be required to be enrolled within the clinical trial within 48 hours of hospital admission.

In the individualized, biomarker-concordant arm, all patients will receive steroids once at the time of admission, then a daily morning dose. In order to account for varying turnaround time at different laboratories, C-Reactive Protein (CRP) levels will be drawn with early morning labs, and used to determine the steroid dosing for the day. Patients will receive daily CRP measurements for the first 5 days of the hospitalization, or until hospital discharge. CRP measurements will be discontinued once the CRP is less than 50mmol/L.

Steroid administration will be facilitated using standardized computerized physician order entry. The patients, treating physicians and outcome assessors will be blinded to the group assignment. Steroid order sets will include 6 hourly point of care glucose monitoring, and an insulin sliding scale for glucose levels to facilitate glucose management. The need for insulin drip will be determined by the treating physician. Additional testing including serum and urine ketones will be informed by the glucose level, serum anion gap and bicarbonate levels in routine basic metabolic panels and determined by the treating physician.

In the usual care arm, patients will receive daily CRP measurements for the first 5 days of the hospitalization, or until hospital discharge.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 44

Inclusion Criteria

Patients admitted to hospital with community acquired pneumonia.
Acute respiratory failure SpO2/FiO2 < 315 (SpO2<90% on room air or <97% on 2L NC).

Exclusion Criteria

Contraindications or unwilling to use steroids by patient or provider
Refractory septic shock defined as a requirement of norepinephrine dose or equivalent above >0.1 microgram/kilogram/minute or 2 or more vasopressors
Pre-admission chronic use of steroids or other immunosuppressive medications
Adrenal insufficiency
Comfort care
Leukopenia <1000/mm or neutropenia <500/mm (except if attributable to pneumonia) and HIV positive with a CD4 count <100
Recent or past history of bone marrow or solid organ transplantation
Hospital admission in the previous 30 days
Suspected flare of Interstitial lung disease (infectious and non-infectious)
Positive influenza testing or high suspicion for influenza

For the COVID-19 arm of the study:

Inclusion Criteria:

Patients admitted to hospital with COVID-19 pneumonia (high suspicion or confirmed by positive SARS CoV-2 testing).
Acute respiratory failure SpO2/FiO2 < 315 (SpO2<90% on room air or <97% on 2L NC).

Exclusion Criteria:

Contraindications or unwilling to use steroids by patient or provider
Refractory septic shock defined as a requirement of norepinephrine dose or equivalent above >0.1 microgram/kilogram/minute or 2 or more vasopressors
Pre-admission chronic use of steroids or other immunosuppressive medications
Adrenal insufficiency
Comfort care
Leukopenia <1000/mm or neutropenia <500/mm (except if attributable to pneumonia) and HIV positive with a CD4 count <100
Recent or past history of bone marrow or solid organ transplantation
Suspected flare of Interstitial lung disease (infectious and non-infectious)
Positive influenza testing or high suspicion for influenza

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Usual Care	Usual Care	Usual care as determined by the patient's primary team.
Biomarker-adjusted Steroid Dosing	Methylprednisolone	Individualized, biomarker concordant steroid use: dosing, titration and duration according to CRP level. This is a predetermined dosing table that adjusts dose of steroid by CRP level. Specifically: if CRP \< 50 mmol/L: discontinue steroid; if CRP is between 51-100 mmol/L: 0.5 mg methylprednisolone (or dose equivalent of oral prednisone); if CRP is between 101-150 mmol/L: 0.75 mg/kg methylprednisolone (or dose equivalent of oral prednisone); if CRP level is between 151-200 mmol/L: 1 mg/kg methylprednisolone (or dose equivalent of oral prednisone); if CRP level \> 200 mmol/L: 1.5 mg/kg methylprednisolone (or dose equivalent of oral prednisone).

Primary Outcome Measures

Name	Time	Method
Timely Initiation of Corticosteroids and Implementation of Biomarker-titrated Corticosteroid Dosing	Within 30 days of enrollment in study.	Number of eligible subjects to adhered to the timely initiation and daily corticosteroid treatment according to ESICM/Society of Critical Care Medicine SCCM clinical practice guideline (control group) or biomarker concordance (intervention group)

Secondary Outcome Measures

Name	Time	Method
Mortality	90 days	Number of subject deaths
Need for High Flow Nasal Cannula Oxygen	Within hospitalization or 30 days of study enrollment (whichever is sooner)	Number of subjects to need high flow nasal cannula oxygen
Need for Noninvasive Mechanical Ventilation	Within hospitalization or 30 days of study enrollment (whichever is sooner)	Assessed by the number of participants that required noninvasive mechanical ventilation.
Need for Invasive Mechanical Ventilation	Within hospitalization or 30 days of study enrollment (whichever is sooner)	Assessed by the number of participants that required invasive mechanical ventilation.
Organ Failure	Measured daily for approximately 5 days	Organ failures measured by Sequential Organ Failure Assessment (SOFA). The overall score is based on 6 sub-scores respiratory system, neurologic system, cardiovascular system, hepatic system, coagulation, and renal system using an overall scale of 0-24, which 0=no organ failure, 24=complete organ failure.
New Onset Cardiac Arrhythmias	Within hospitalization or 30 days of study enrollment (whichever is sooner)	Number of participants who develop arrhythmias identified by electrocardiogram or echocardiogram.
Occurrence of Delirium	Up to day +5 following study enrollment.	Number of participants who develop delirium while receiving corticosteroids. Delirium will be assessed by Confusion Assessment Method for the ICU (CAM-ICU) measurement tool. The CAM-ICU is a binary (yes/no) scale for assessing the presence of delirium.
Occurrence of Secondary Infection	Up to day +14 following study enrollment.	Number of participants who develop secondary infections during and after steroid therapy. A secondary infection is defined as a new infection that develops after initiation of corticosteroid therapy, until 5 days after steroids are discontinued.
Myocardial Injury	Up to day +14 following study enrollment.	Number of participants with evidence of myocardial injury determined by daily troponin peak and /or new diagnosis of Left Ventricular (LV) dysfunction (LVEF \<40%) or new diagnosis of cor pulmonale
Cardiovascular Dysfunction	Within hospitalization or 30 days of study enrollment (whichever is sooner)	Number of subjects with new and/or worsening right ventricle (RV)/left ventricle (LV) dysfunction
Occurrence of Hyperglycemia	Up to day +5 following study enrollment.	Number of participants who have hyperglycemia while receiving corticosteroids. Hyperglycemia is defined as a consistently elevated blood sugar level requiring insulin administration.
ICU Admission	Within hospitalization or 30 days of study enrollment (whichever is sooner)	Number of subjects admitted to the ICU
Oxygen-free Days	Within hospitalization or 30 days of study enrollment (whichever is sooner)	Number of days subjects did not require oxygen assistance.