Early Paralytic Agents for ARDS? Yes, No, and Sometimes

Arthur S. Slutsky, Jesús Villar

N Engl J Med May 19, 2019
DOI: 10.1056/NEJMe1905627

Lung-protective ventilation, which includes low tidal volumes and limitation of plateau pressures, is the standard approach in patients with acute respiratory distress syndrome (ARDS).1 Almost a decade ago, the ARDS et Curarisation Systematique (ACURASYS) trial2 showed that in patients with moderate-to-severe ARDS, a strategy of 48 hours of deep sedation with muscle paralysis induced by an intravenous infusion of cisatracurium resulted in a lower incidence of barotrauma and higher adjusted overall survival at 90 days than deep sedation alone. These results were unexpected, since the intervention was performed only for the first 2 days, yet the Kaplan–Meier survival curves were virtually superimposable for about 18 days before they separated. The reason for the lower mortality in the intervention group was uncertain, but it was thought to be because the use of cisatracurium led to decreased ventilator-induced lung injury and biotrauma (i.e., the release of mediators in the lung and translocation of these mediators into the systemic circulation).3,4 Perhaps because of this uncertainty, along with concerns about long-term neuromuscular function after treatment with cisatracurium, the addition of a paralytic agent to a lung-protection strategy was not widely adopted by the critical care community.

For these reasons, and because current clinical practice has changed since the ACURASYS trial was conducted, the Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) trial was performed to reexamine the benefits of cisatracurium-induced paralysis in patients early after the onset of ARDS. Patients with moderate-to-severe ARDS were assigned either to a 48-hour continuous infusion of cisatracurium with deep sedation or to a usual-care approach with light sedation and without routine neuromuscular blockade. The trial, the results of which are now reported in the Journal,5 was stopped early for futility. The results were markedly different from those of the ACURASYS trial. In the ROSE trial, there was no between-group difference in the number of patients with barotrauma, and mortality at 90 days was virtually identical in the two groups (42.5% of patients in the intervention group and 42.8% in the control group died).

Why should the results of two well-performed trials differ so greatly? As shown in Table 1, there were a number of differences between the trials that could plausibly explain the different results. However, we postulate that one of these factors — the difference in sedation levels — is the major reason. Many patients who are admitted to an intensive care unit receive some sedation to treat anxiety or agitation and to facilitate care. Deeper sedation is also often used when the patient is “fighting the ventilator” (so-called patient–ventilator dyssynchrony). Dyssynchrony is common during mechanical ventilation and is associated with prolonged duration of mechanical ventilation and increased mortality.6

In 2013, Akoumianaki et al.7 identified a previously unrecognized form of dyssynchrony in patients with ARDS. They called this dyssynchrony reverse triggering, because a breath delivered by the ventilator triggered a contraction of the diaphragm, which initiated a spontaneous breath — the reverse of what happens during assisted ventilation. Because the second breath can occur before a complete exhalation, the patient can receive a much larger tidal volume (called breath stacking) than with the initial ventilator breath. This can worsen ventilator-induced lung injury because of pulmonary overdistention, and it can potentially cause diaphragmatic muscle-fiber damage and increased work of breathing — all of which lead to poorer outcomes.7

There are a number of important attributes of reverse triggering. First, it is very difficult to recognize at the bedside without measurement of esophageal pressure or diaphragmatic electrical activity, and these techniques are not routinely performed in a clinical setting.7 Second, although the prevalence of reverse triggering is unknown, it is thought to be relatively common (it occurred in 30% of patients with ARDS in one study8). Third, contrary to expectations, the incidence of reverse triggering increases with deeper sedation levels. We postulate that in the ACURASYS trial, deep sedation in the control group led to breath stacking, increased ventilator-induced lung injury, and higher mortality. The intervention group was protected from this effect because cisatracurium prevented the diaphragmatic contraction that would have occurred in response to the reverse triggering mechanism.8 What, then, are the implications of the results of these trials? First, we recommend that neuromuscular blocking agents not be used routinely in patients with moderate-to-severe ARDS. We would draw this conclusion regardless of whether the hypothesis of reverse triggering is correct. The ROSE trial is more current than the ACURASYS trial, is much larger, and shows some acute, serious cardiovascular events with cisatracurium use. Second, from a physiological perspective, there is a rationale to consider neuromuscular blocking agents in any patient with ARDS (or, indeed, in any patient) who, despite carefully implemented ventilatory and sedation strategies, has a ventilatory pattern that confers a predisposition to ventilator-induced lung injury (e.g., breath stacking); neuromuscular blocking agents may also be considered in patients with increased respiratory drive that could generate potentially injurious transpulmonary pressure swings.9 Third, we suggest that patient–ventilator dyssynchronies may have a greater effect on clinical outcomes than generally recognized. A recent trial that examined the effects of lung-recruitment maneuvers and high positive end-expiratory pressure in patients with moderate-to-severe ARDS unexpectedly showed that this strategy resulted in higher mortality than a strategy of low positive end-expiratory pressure.10 It is likely that dyssynchrony in the form of breath stacking, albeit not necessarily reverse triggering, contributed to this higher mortality.10

Therapeutic strategies in ARDS should ideally be tailored to the specific underlying disease or injury mechanism at any given point in time, rather than being applied uniformly to all patients. Early paralytic agents for ARDS? Given their long-term neuromuscular safety profile in the ROSE trial, we suggest that paralytic agents can sometimes be used, when physiologically and clinically indicated.