https://www.ubccriticalcaremedicine.ca/academic/jc_article/CHEST%202007%20Steroids%20in%20ARDS%20Meduri%20(May-20-2010).pdf

Methylprednisolone Infusion in Early Severe ARDS: Results of a Randomized Controlled Trial

Caring for the Critically Ill Patient

Disclosing individual results of clinical research: implications of respect for participants.

Though well described even in ancient writings, the acute respiratory distress syndrome (ARDS) gained major medical attention with the availability of mechanical ventilation and establishment of intensive care units. In the 50 years since this beginning there have been remarkable advances in the understanding of the etiology, physiology, histology, and epidemiology of this often lethal complication of common human maladies. Until recently, improvements in outcome have mainly followed improvements in intensive care unit operation and their associated life support systems, and have not come through discoveries made in the course of prospective randomized trials. In spite of the remarkable increase in research focused on ARDS, there remain a large number of unanswered clinical questions that are potentially extremely important with regard to short-term morbidity as well as long-term outcome. The ARDS Clinical Trials Network study of tidal volume has proven that randomized trials in ARDS with positive results are possible even when using difficult primary outcome measures such as mortality or ventilator-free days. Therefore, the rich combination of new trial strategies, potential treatments, experienced investigators, and increasingly standardized routine care set the stage for rapid advances to be made in the short- and long-term outcomes of this devastating syndrome.

/pdf/acute-respiratory-distress-syndrome-a-historical-perspective-31isesvxp6.pdf

Acute respiratory distress syndrome: a historical perspective.

Rationale: Intensive care unit (ICU)-based randomized clinical trials (RCTs) among adult critically ill patients commonly fail to detect treatment benefits.

Objectives: Appraise the rates of success, outcomes used, statistical power, and design characteristics of published trials.

Methods: One hundred forty-six ICU-based RCTs of diagnostic, therapeutic, or process/systems interventions published from January 2007 to May 2013 in 16 high-impact general or critical care journals were studied.

Measurement and Main Results: Of 146 RCTs, 54 (37%) were positive (i.e., the a priori hypothesis was found to be statistically significant). The most common primary outcomes were mortality (n = 40 trials), infection-related outcomes (n = 33), and ventilation-related outcomes (n = 30), with positive results found in 10, 58, and 43%, respectively. Statistical power was discussed in 135 RCTs (92%); 92 cited a rationale for their power parameters. Twenty trials failed to achieve at least 95% of their reported target sample size, including 11 that were stopped early due to insufficient accrual/logistical issues. Of 34 superiority RCTs comparing mortality between treatment arms, 13 (38%) accrued a sample size large enough to find an absolute mortality reduction of 10% or less. In 22 of these trials the observed control-arm mortality rate differed from the predicted rate by at least 7.5%.

Conclusions: ICU-based RCTs are commonly negative and powered to identify what appear to be unrealistic treatment effects, particularly when using mortality as the primary outcome. Additional concerns include a lack of standardized methods for assessing common outcomes, unclear justifications for statistical power calculations, insufficient patient accrual, and incorrect predictions of baseline event rates.

/pdf/outcomes-and-statistical-power-in-adult-critical-care-4h3cqg23gh.pdf

Outcomes and Statistical Power in Adult Critical Care Randomized Trials

Clinical research involving critically ill patients is necessary to reduce the extreme morbidity and mortality encountered in the intensive care unit (ICU). Yet such research is ethically challenging because critically ill patients usually are unable to consent for research participation, because conflicts of interest occur among investigators, and because discovering new knowledge while simultaneously protecting research participants from risk may be difficult to achieve. To explore these and other challenges and to elucidate ways of meeting them, the American Thoracic Society (ATS) sponsored a conference on the ethical conduct of clinical research involving critically ill patients on November 21 and 22, 2003 in Washington, DC. The conference was initiated in response to a request for proposals from the Association of American Medical Colleges (AAMC), which hoped professional societies would educate their members about the ethical challenges of clinical research. After the AAMC decided to support the conference, further funding was obtained from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH), and the ATS. At the conference, experts in clinical investigation, patient advocacy, ethics, and research oversight explored various aspects of clinical research with a general audience and a writing committee. The writing committee in turn authored this document. The purpose of the document is to present a series of principles that govern the ethical conduct of clinical research involving critically ill patients and to make specific recommendations based on these principles. Prominent among the recommendations is the use of ethical checklists as tools to assist in clinical trial design, implementation, and monitoring by investigators and independent reviewers of research. Although these recommenda-

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The ethical conduct of clinical research involving critically ill patients in the United States and Canada: principles and recommendations.