From Pages to Practice
A few weeks ago, I cared for a patient with acute respiratory distress syndrome (ARDS) secondary to community acquired pneumonia. She arrived to the medical ICU on broad-spectrum antibiotics and was intubated for acute hypoxemic respiratory failure with a PaO2:FIO2 (P:F) ratio of 100. We placed her on low-tidal volume ventilation and despite increasing propofol infusion and fentanyl boluses, she kept “bucking the vent” (patient-ventilator dyssynchrony). The patient also had hypoxemia refractory to positive end-expiratory pressure (PEEP) and Fio2 titration. The decision was made to add an infusion of cisatracurium, a neuromuscular blocking (NMB) agent, to maximize her oxygenation by decreasing metabolic demand and patient-ventilator dyssynchrony, and in turn, reduce the risk of ventilator-associated lung injury.
Cisatracurium is one of the few pharmacologic agents (other than agents used to treat the underlying cause) that was thought to improve mortality in ARDS, based on the ACURASYS trial conducted about 10 years ago. The results indicated that early NMB use was associated with significantly improved 90-day survival, when compared with placebo, in patients with moderate-to-severe ARDS (albeit only after adjusting for three baseline covariates). However, early NBM blockade was never widely adopted because it requires deep sedation and the effect on neuromuscular function and other long-term outcomes is uncertain.
In the Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) trial, investigators reexamined the benefits of cisatracurium-induced paralysis in patients with moderate-to-severe ARDS. In this larger trial, patients were randomized to receive cisatracurium (requiring deep sedation) or no NMB (with lighter sedation targets). Mortality at 90 days did not differ significantly between the two groups. Although these results may prove to be an epitaph for routine early NMB use in ARDS, editorialists argue that NMB agents can sometimes be used when physiologically indicated (e.g., dyssynchrony), as in the patient described above.
The following NEJM Journal Watch summary explains the study and results in more detail:
Patricia Kritek, MD reviewing The National Heart, Lung, and Blood Institute PETAL Clinical Trials Network. N Engl J Med 2019 May 19 Slutsky AS and Villar J. N Engl J Med 2019 May 19
Ten years ago, a large randomized trial demonstrated lower mortality when patients with severe acute respiratory distress syndrome (ARDS) were treated with neuromuscular blockade (NMB; NEJM JW Hosp Med Oct 2010 and N Engl J Med 2010; 363:1107). Concerns about the deep sedation required for NMB, as well as the neuromuscular weakness associated with its use, led investigators to reexamine this benefit.
More than 1000 patients with moderate-to-severe ARDS (partial pressure of oxygen: fraction of inspired oxygen [PaO2:FIO2], <150) were randomized to 48 hours of either cisatracurium with deep sedation or light sedation without NMB. More than half of patients had pneumonia; prone positioning was used rarely. The trial included a high positive end-expiratory pressure (PEEP) strategy.
The trial was stopped early for futility. Mortality was quite high (43%) but was not different between groups. Lengths of stay (hospital and intensive care unit) and days free from mechanical ventilation were similar between groups; neuromuscular weakness and patient-reported quality of life at 3, 6, and 12 months also did not differ between groups.
Comment: The high mortality seen in this study is perplexing. Some people have proposed that higher PEEP was not helpful (as the authors suggest) but potentially harmful. Despite this, the results mean that patients with moderate-to-severe ARDS should not be treated uniformly with early NMB. However, I agree with the editorialists' position that NMB still should be considered on an individual basis, particularly for patients with ventilator dyssynchrony. In other patients, early, “moderate-to-severe” ARDS might resolve relatively quickly, mitigating the need for NMB and the downsides of deep sedation.
Tenzing T. Lama, MD, MScRes, is a resident physician in the department of Anesthesiology and Pain Medicine at the University of Washington and a Fellow at the Ethics and Transformative Values Center at the Massachusetts Institute of Technology. He graduated from Harvard Medical School and Oxford. He is ultimately interested in an academic career in cardiac critical care with a research interest in mechanical circulatory support devices and nitric oxide.