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Beyond Low Tidal Volume Ventilation

Treatment Adjuncts for Severe Respiratory Failure in Acute Respiratory Distress Syndrome

Fielding-Singh, Vikram, MD, JD1; Matthay, Michael A., MD2; Calfee, Carolyn S., MD, MAS2

doi: 10.1097/CCM.0000000000003406
Concise Definitive Review

Objectives: Despite decades of research, the acute respiratory distress syndrome remains associated with significant morbidity and mortality. This Concise Definitive Review provides a practical and evidence-based summary of treatments in addition to low tidal volume ventilation and their role in the management of severe respiratory failure in acute respiratory distress syndrome.

Data Sources: We searched the PubMed database for clinical trials, observational studies, and review articles describing treatment adjuncts in acute respiratory distress syndrome patients, including high positive end-expiratory pressure strategies, recruitment maneuvers, high-frequency oscillatory ventilation, neuromuscular blockade, prone positioning, inhaled pulmonary vasodilators, extracorporeal membrane oxygenation, glucocorticoids, and renal replacement therapy.

Study Selection and Data Extraction: Results were reviewed by the primary author in depth. Disputed findings and conclusions were then reviewed with the other authors until consensus was achieved.

Data Synthesis: Severe respiratory failure in acute respiratory distress syndrome may present with refractory hypoxemia, severe respiratory acidosis, or elevated plateau airway pressures despite lung-protective ventilation according to acute respiratory distress syndrome Network protocol. For severe hypoxemia, first-line treatment adjuncts include high positive end-expiratory pressure strategies, recruitment maneuvers, neuromuscular blockade, and prone positioning. For refractory acidosis, we recommend initial modest liberalization of tidal volumes, followed by neuromuscular blockade and prone positioning. For elevated plateau airway pressures, we suggest first decreasing tidal volumes, followed by neuromuscular blockade, modification of positive end-expiratory pressure, and prone positioning. Therapies such as inhaled pulmonary vasodilators, glucocorticoids, and renal replacement therapy have significantly less evidence in favor of their use and should be considered second line. Extracorporeal membrane oxygenation may be life-saving in selected patients with severe acute respiratory distress syndrome but should be used only when other alternatives have been applied.

Conclusions: Severe respiratory failure in acute respiratory distress syndrome often necessitates the use of treatment adjuncts. Evidence-based application of these therapies in acute respiratory distress syndrome remains a significant challenge. However, a rational stepwise approach with frequent monitoring for improvement or harm can be achieved.

1Department of Anesthesiology and Perioperative Medicine, University of California Los Angeles, Los Angeles, CA.

2Departments of Medicine and Anesthesia, Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, CA.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funding sources had no role in the design or conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the article; or the decision to submit the article for publication.

All authors provided final approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (

Supported, in part, by grants HL51856 (to Dr. Matthay) and HL140026 (to Dr. Calfee).

All authors disclosed off-label product use of therapies listed in the article, as there are no Food and Drug Administration approved therapies for acute respiratory distress syndrome (ARDS). Dr. Matthay’s institution has received funding from Bayer, GlaxoSmithKline, and Amgen. Dr. Matthay has received other support from Roche/Genentech (Chair Data Safety Monitoring Board), Cerus Therapeutics (consultant), CSL Behring (consultant), Boehringer Ingelheim (consultant), and Quark Pharmaceuticals (consultant). Dr. Calfee's institution has received research funding from the National Institutes of Health, GlaxoSmithKline, and Bayer. Dr. Calfee has served on advisory boards or as a consultant for GlaxoSmithKline, Bayer, CSL Behring, Boehringer Ingelheim, Prometic, and Roche/Genentech.

Address requests for reprints to: Carolyn S. Calfee, MD, MAS, Departments of Medicine and Anesthesia, Division of Pulmonary and Critical Care Medicine, University of California San Francisco, 505 Parnassus Avenue, Box 0111, San Francisco, CA. E-mail:

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