Steroids in Patients With Early ARDS

Summary

Scientific background. Dysregulated systemic inflammation is a key pathogenetic mechanism for morbidity and mortality in ALI/ARDS, and is associated with tissue insensitivity and/or resistance to inappropriately elevated endogenous glucocorticoids. In one study, prolonged methylprednisolone treatment of ARDS patients resulted in rapid and sustained reduction in circulating and pulmonary levels of pro-inflammatory cytokines, chemokines, and procollagen.

Preliminary work. Five randomized trials (N = 518) investigating prolonged glucocorticoid treatment in acute lung injury/ARDS reported a significant physiological improvement and a sizable reduction in duration of mechanical ventilation and ICU length of stay. Insufficient data is available on the effects of low dose prolonged methylprednisolone treatment initiated in early ALI/ARDS on mortality.

Hypothesis. We hypothesized that the anti-inflammatory activity associated with prolonged methylprednisolone administration improves pulmonary and extra-pulmonary organ dysfunction in early ALI/ARDS and reduces mortality.

Objective. To investigate the effects of prolonged low-dose methylprednisolone infusion on mortality and morbidity in early ALI/ARDS.

Study design. Multicenter, prospective randomized, placebo-controlled, double-blind clinical trial.

Entry criteria. Patients with ALI/ARDS of less than 72 hours duration.

Stratification. Patients are prospectively stratified prior to randomization as (1) intubated versus NPPV treated, and (2) ARDS versus severe ARDS. The purpose of stratification is to distribute equally in both arms intubated versus NPPV treated, and ARDS versus severe ARDS.

End-points. The primary end-point of trial is 28 days all cause mortality; the secondary end-points are (a) ventilator-free days at 28 days following study entry, (b) organ failure-free days at 28 days following study entry, and (c) duration of ICU stay.

Conditions

• Acute Lung Injury
• ARDS, Human

Interventions

DRUG

Methylprednisolone

Drug: Methylprednisolone Day 0 Loading dose 1 mg/kg IV bolus (30 min) followed by continuous infusion; Days 0 to 14\*† ‡ 1 mg/kg/day mixed in 240cc Normal saline (NS) and infused at 10 cc/hr; Days 15 to 21\*‡ 0.5 mg/kg/day mixed in 240cc NS and infused at 10 cc/hr; Days 22 to 25\*‡ 0.25 mg/kg/day; Days 26 to 28\*‡ 0.125 mg/kg/day \*Five days after the patient is able to ingest medications, methylprednisolone is given per os in one single daily equivalent dose. †If between days 1 to 14 the patient is extubated, he is advanced to day 15 of drug therapy and tapered according to schedule. ‡ When leaving ICU, if the patient is still not tolerating p.o. intake for at least five days, he should receive the specified dosage as IV push every 6 hours until tolerating oral ingestion

OTHER

Normal saline intravenously and vitamin B1 per os

Patients in this group will receive sterile normal saline in an amount that would equal the total diluted dose of study drug (ie. if initial loading dose equals a total of 25 cc \[prednisolone + diluting fluid\], then the patient will receive 25 cc of sterile normal saline). Tapering doses will be equivalent to that of the study arm. Five days after the patient is able to ingest medications, placebo is administered per os in one single daily equivalent dose. The placebo will be a Vitamin B1 (thiamine) 50-mg tablet. We will now designate each placebo tab as a 16-mg equivalent to each tablet of active drug. These tablets are scored and half tabs can be given if needed. Therefore if a patient is receiving 40 mg of study drug: 40/16 = 2.5 tabs x 50 mg = 125 mg actual dose of thiamine.

Sponsors & Collaborators

• Catholic University of the Sacred Heart

  lead OTHER

Principal Investigators

• Massimo Antonelli, MD · Catholic University of Sacred Heart, Rome

• Umberto Meduri, MD · University of Tennessee Health Science Center Memphis, TN, USA

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2008-02-29

Completion

2009-02-28

Countries

• Italy

Study Locations