NHLBI ARDS Network

What is ARDS?

Acute Respiratory Distress Syndrome (ARDS) is a severe, often fatal, inflammatory disease of the lung characterized by the sudden onset of pulmonary edema and respiratory failure, usually in the setting of other acute medical conditions resulting from local (e.g. pneumonia) or distant (e.g. multiple trauma) injury.

Acute Lung Injury (ALI) is a term used to describe patients with a milder form of ARDS.

More information on ARDS can be found at http://www.nhlbi.nih.gov/health/dci/Diseases/Ards/Ards_WhatIs.html

Why have an ARDS Network?

At this time, there is no specific treatment for ARDS, and therapy is only supportive, in the hope that the patient will spontaneously recover. Unfortunately, there is disagreement about what constitutes the best support. The development of effective treatments, both supportive and curative, for ARDS is essential. Reaching this goal has been difficult, in part because it requires the study of large numbers of patients in rigorously conducted complex clinical trials.

What is the ARDS Network

The ARDS Network is a clinical research network of approximately 42 hospitals, organized into twelve clinical sites, and a coordinating center. The Principal Investigators from each site together with the NHLBI Project Scientist form the Network Steering Committee, the main governing body of the Network. The Steering Committee is responsible for identification of promising new agents for the treatment of ARDS, setting Network priorities, developing protocols, facilitating the conduct and monitoring of the trials, and reporting study results. A Protocol Review Committee provides an independent scientific evaluation for the NHLBI on each new protocol. The Data and Safety Monitoring Board monitors the conduct of the trial and advises the NHLBI on the quality of the trial and may suggest early termination of the study for either unanticipated large beneficial effects or for safety concerns.

Who can I contact if I have questions about the Network?

You may use the contact form to send an email to the Clinical Coordinating Center.

If you prefer to call, you may reach the Clinical Coordinating Center at (617) 724-3000, or the NHLBI Communications Office at (301) 496-4236.

Who can have access to the ARDSNet.org website?

The ARDS Network's website (http://www.ardsnet.org) has a public section which contains all of our publicly available information, and a password-protected section for network personnel. All of the information released to the public by the network is available without a password. Only personnel funded by the ARDS Network Contract may have access to the restricted section of the website.

What clinical trials has the Network conducted?

• Ketoconazole for ALI/ARDS: The first clinical trial completed by the Network was a randomized, controlled trial of Ketoconazole versus placebo in patients with acute lung injury and ARDS. Ketoconazole was chosen because of its anti-inflammatory actions noted in the laboratory and because previous Phase II clinical trials suggested benefit in patients with or at risk for ARDS. This trial was stopped early by the DSMB in January 1997 after finding Ketoconazole to be ineffective. The clinical trial results were published in JAMA in April 2000 (The ARDS Clinical Trials Network Authors for the ARDS Network. Ketoconazole for early treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome. A randomized controlled trial. JAMA, 2000;283:1995-2002).

• Lysophylline for ALI/ARDS: A second randomized placebo controlled trial compared Lisofylline, an antiinflammatory and antioxidant drug that also showed promising results in phase II trials of immunosuppressed patients. Lisofylline also proved to be ineffective and these clinical trial results were published in the journal Critical Care Medicine (The ARDS clinical Trials Network. Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome. Crit Care Med Vol 30:1-6).

• Lower Tidal Volume Trial: A third trial examined lower tidal volume ventilation versus a traditionally recommended higher tidal volume approach in patients with acute lung injury. This landmark randomized controlled trial, which enrolled 861 subjects, clearly demonstrated that lower tidal volumes result in improved survival, with a similar need for sedatives for patient comfort. This study was published in the New England Journal of Medicine (The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; Vol 342: 1301-1308) If the results are applied to the care of patients across the country, tens of thousands of deaths per year will be prevented.

• ALVEOLI: A fourth trial examined the role of higher positive end-expiratory pressure (PEEP) to keep the lung open between breaths and to further improve lung healing and repair during acute lung injury. The ALVEOLI study tested lower tidal volumes with with higher PEEP and, after enrolling 449 patients, found no further improvement in survival with the addition of higher PEEP. (Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, Ancukiewicz M, Schoenfeld D, Thompson BT; National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Higher vs. lower positive end-expiration pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004 Jul 22;351(4):327-36).

• Late Steroid rescue Study: LaSRS: The use of corticosteroids in the later phases of ARDS showed promise in a small randomized controlled trial. The ARDS Network enrolled 200 patients over 6 years in a placebo controlled trial of methylprednisolone versus placebo for patients with presistend ARDS after 7 to 28 days. Methyplrednisolone improved lung function resulting in earlier liberation from mechanical ventilation. Unfortunately, these promising findings did not result in improved survival. The findings were published in the New England Journal of Medicine in 2007. (The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006;354:1671-168)

• FACTT: This study examined two different strategies for managing intravenous fluids and fluid balance in patients with acute lung injury. A second goal of this trial was to determine if a Pulmonary Artery Catheter (PAC) was superior to a smaller, and less invasive central venous catheter in the management of patients with ARDS. This trial answered these two important questions in a single trial. No benefit was seen with the PAC guided therapy and the strategy of restrictive or conservative fluid administration was superior to the traditional approach by shortening the duration of mechanical ventilation.

What are some of the factors considered in the selection of clinical trials?

• Data suggesting a plausible mechanism of action for an intervention.
• Existence of "Phase II" human data to guide study design and assure patient safety.
• A high perceived likelihood the intervention will benefit ARDS patients.
• Feasibility of conducting the study.
• If the promising clinical trial is unlikely to be conducted in private sector

Does the Network only do clinical studies testing new therapies?

No. Because the Network's investigators are experienced in both clinical trials and more basic research, and because they have collaborative relationships with many other non-Network investigators, there are many opportunities for sub-studies using data or specimens from enrolled patients. We are currently involved in studies of inflammatory blood proteins (cytokines), the protein content and composition of alveolar fluid, and neutrophil function.

If a non-network investigator would like to collaborate with the ARDS Network, they should get in touch with one of the network investigators.

How can I get my patient into some of these clinical studies?

Unfortunately, at this time only patients at participating Clinical centers are eligible for enrollment in these NIH sponsored studies. When feasible, patients may be transferred to participating institutions for care.

What did the OHRP determine in their investigation of ARDSNet studies?

On July 3, 2003 the Office of Human Research Protections (OHRP) published its determinations from an inquiry into the safety and design of completed and ongoing ARDS Network studies. In its most important finding, OHRP said "... almost all of the consultants engaged by OHRP opined that risks to subjects in the ARMA [tidal volume] trial were minimized and reasonable in relation to anticipated benefits to the subjects and the importance of the knowledge that was expected to result." The OHRP consultants expressed the same opinion regarding the ARDS Network fluids and catheters treatment trial (FACTT). The OHRP consultants' findings were consistent with those of the 5 independent consultants engaged by the NHLBI who, on August 30, 2002 concluded unanimously that the ARDS Network trials were safe and appropriately designed. The OHRP determination letter requests that all IRBs review additional background materials pertinent to the FACTT study, examine their practices, and requested changes to the FACTT consent forms. FACTT was resumed without changes to the trial design or procedures after these actions were completed.

For further details, please see:

1. Steinbrook, R. How Best to Ventilate? Trial Design and Patient Safety in Studies of the Acute Respiratory Distress Syndrome. New Eng J Med 2003; 348: 1393-1301.
2. Steinbrook, R. Trial Design and Patient Safety --- The Debate Continues. New Eng J Med 2003; 249: 629-630.
3. Drazen, JM. Controlling Research Trials. New Eng J Med 2003; 248: 1377-1382.