A Comparative Study of Glucocorticoids Efficacy in Acute Respiratory Distress Syndrome

The aim of the work is to compare the efficacy of equivalent doses of methylprednisolone, dexamethasone and hydrocortisone in patients with ARDS

Study Overview

• Status: Recruiting
• Conditions: Acute Respiratory Distress Syndrome
• Intervention / Treatment: Drug: Methylprednisolone; Drug: Dexamethasone; Drug: Hydrocortisone

Detailed Description

Acute respiratory distress syndrome (ARDS) is a secondary disease that follows-usually within 6-48 h-a primary disease of multifactorial etiology (most frequently pneumonia and extrapulmonary sepsis) associated with severe systemic inflammation. Inflammatory mediators released into the systemic circulation (systemic inflammation) from the site of infection reach the broad pulmonary capillary surface, producing severe and diffuse inflammatory exudate of the pulmonary lobules and resulting in hypoxemic respiratory failure.

In ARDS, systemic inflammation is activated by the nuclear factor-κB (NF-κB) signaling system and downregulated by activated glucocorticoid receptor α (GRα). In these patients, inadequate (endogenous glucocorticoid-activated) GRα-mediated downregulation of proinflammatory transcription factor NF-κB in circulating and tissue cells leads to higher initial levels and persistent elevation over time of plasma and bronchoalveolar lavage markers of inflammation, hemostasis, and tissue repair. Inadequate intracellular GRα-mediated anti-inflammatory activity for the severity of the patient's illness was recently termed critical illness-related corticosteroid insufficiency (CIRCI). Experimental and clinical research shows that CIRCI can be improved with quantitatively and temporally adequate glucocorticoid administration.

Glucocorticoids are commonly used in patients with acute respiratory distress syndrome (ARDS) or at-risk for ARDS with proposed mechanisms including reduction of local lung inflammation and dampening of systemic immune responses.

Clinical trials of glucocorticoids in patients with ARDS or at-risk from a pulmonary infection have had mixed results with some studies suggesting benefit and others showing no beneficial effects. Notably, the glucocorticoid agent, dose, and duration has varied widely between studies increasing the challenge of interpreting discordant findings.

In animal models of ARDS, glucocorticoids decreased the expression of pro-inflammatory mediators in lung tissue, including TNF-a, IL-1a, IL-1b, IL-6 and IL-12 p40, and reduces lung injury through the reduction of oxygen radicals produced by neutrophils. Beyond their anti-inflammatory effects during the acute phase of inflammation, glucocorticoids also contributed to the resolution of inflammation, trough reprogramming effects on macrophages.

Glucocorticoids have been administered during two distinct phases of ARDS, during the early stage of ARDS when inflammation is expected to be most important and during late phase of ARDS, when lung fibrosis predominates. The biological and pathological characteristics of these two entities differ greatly, explaining the observed conflicting results in the effects of glucocorticoids in these two distinct conditions.

The early phase of ARDS is characterized by major alveolar inflammation. Thus, glucocorticoids, potent anti-inflammatory agents, are theoretically expected to be relevant treatment for ARDS.

Late-stage ARDS is characterized histologically by ongoing inflammation with fibroproliferation, presence of hyaline membranes, and persistent diffuse alveolar damage, leading to prolonged mechanical ventilation and a higher risk of death. The largest multicenter placebo-controlled trial, found no evidence for beneficial effects of glucocorticoids initiated for late-stage ARDS.

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Mahmoud Ezzat Elkmash, Teaching assistant; Phone Number: +201094123841; Email: mam54@fayoum.edu.eg
• Study Contact Backup: Name: Marwa Kamal Tolba, Assistant Professor; Phone Number: +201067789982; Email: mka05@fayoum.edu.eg

Study Locations

• Egypt
  • Fayoum, Egypt
    • Recruiting
    • Fayoum University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

We include patients receiving mechanical ventilation for hypoxemic respiratory failure if they met the diagnostic criteria for ARDS according to the American-European Consensus definition, as later reclassified on the basis of the 2012 Berlin criteria for the diagnosis of ARDS, defined as:

1. Presence of acute hypoxemic respiratory failure (an arterial oxygen partial pressure to fraction of inspired oxygen ratio (PaO2/FiO2) of ≤ 300 mm Hg, requiring supplemental oxygen administrated by simple face mask, nasal cannula, or other similar oxygen-delivery device to maintain oxygen saturation at greater than 93% within the first 48 h of the onset of ARDS)
2. Onset within 7 days of insult, or new (within 7 days) or worsening respiratory symptoms
3. Bilateral opacities on chest x-ray or CT not fully explained by effusions, lobar or lung collapse, or nodules
4. Cardiac failure not the primary cause of acute respiratory failure

Exclusion Criteria:

We exclude patients with acute hypoxemic respiratory failure caused by congestive heart failure

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1; 100 ARDS patients	Drug: Methylprednisolone; Methylprednisolone at a dose of 1 mg/kg/day (an average dose of 70 mg/day based on 70 kg body weight)
Experimental: Group 2; 100 ARDS patients	Drug: Dexamethasone; Dexamethasone at an equivalent dose of 13 mg/day
Experimental: Group 3; 100 ARDS patients	Drug: Hydrocortisone; Hydrocortisone at an equivalent dose of 350 mg/day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
28-day mortality after enrolment	From enrollment to the end of treatment at 28 days

Secondary Outcome Measures

Outcome Measure	Time Frame
The number of patients needing invasive mechanical ventilation	From enrollment to the end of treatment at 28 days
The Number of ventilator-free days	From enrollment to the end of treatment at 28 days
Duration of the ICU stay	From enrollment to the end of treatment at 28 days
Duration of hospitalization	From enrollment to the end of treatment at 28 days
Incidence of serious adverse events, including secondary infections, hyperglycemia, clinically important gastrointestinal bleeding, and hypertension	From enrollment to the end of treatment at 28 days

Collaborators and Investigators

• Sponsor: Fayoum University
• Investigators: Principal Investigator: Mahmoud Ezzat Elkmash, Teaching Assistant, Faculty of Pharmacy - Fayoum University; Study Director: Raghda Roshdy Hussein, Assistant Professor, Faculty of Pharmacy - Beni Suef University; Study Director: Marwa Kamal Tolba, Assistant Professor, Faculty of Pharmacy - Fayoum University; Study Director: Marian Sobhi Saeed, Lecturer, Faculty of Pharmacy - Beni Suef University; Study Director: Mona Ibrahim Ahmed, Lecturer, Faculty of Medicine - Fayoum University

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2024
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): September 1, 2025

Study Registration Dates

• First Submitted: July 4, 2024
• First Submitted That Met QC Criteria: July 4, 2024
• First Posted (Actual): July 11, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 3, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Disease; Lung Diseases; Respiration Disorders; Infant, Premature, Diseases; Infant, Newborn, Diseases; Lung Injury; Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Antineoplastic Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protective Agents; Neuroprotective Agents; Methylprednisolone Acetate; Dexamethasone; Prednisolone; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Hydrocortisone
• Other Study ID Numbers: Steroids Efficacy in ARDS

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No