Should We Paralyze Patients with Severe Acute Respiratory Distress Syndrome?

By Andrew M. Luks, MD, Pulmonary and Critical Care Medicine, University of Washington, Seattle, is Associate Editor for Critical Care Alert.

Dr. Luks reports no financial relationship to this field of study.

Synopsis: The multicenter, randomized trial demonstrated that 48 hours of treatment with cis-atracurium in patients with ARDS and a P/F ratio below 150 mm Hg resulted in improvements in adjusted 90-day mortality and time off the ventilator without increasing the incidence of ICU-acquired paresis.

Source: Papazian L, et al; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med2010;363:1107-1116.

Paralytic agents such as vecuronium and cis-atracurium have been used as "rescue therapies" in patients with ARDS for many years, but, as with other rescue strategies including prone mechanical ventilation or inhaled vasodilators, evidence of a mortality benefit from this intervention has been lacking. Building on a prior study of theirs demonstrating that a 48-hour infusion of cis-atracurium was associated with improved oxygenation and a trend toward improved mortality, Papazian and colleagues conducted an adequately powered randomized trial to investigate if this therapy led to a mortality benefit without increasing the risk of ICU-acquired paresis.

They enrolled patients at 20 ICUs in France that met the consensus definition of ARDS, had a PaO2/FIO2 (P/F ratio) less than 150 mm Hg and had been on mechanical ventilation for < 48 hours. Subjects were randomized to receive a 15 mg bolus of cis-atracurium, followed by an infusion of 37.5 mg/hr for 48 hours, or placebo. Train-of-four monitoring was not performed and all patients in both groups were ventilated with assist-control ventilation with tidal volumes of 6-8 mL/kg. Open-label, 20 mg bolus injections of cis-atracurium were allowed in either patient group when the plateau pressure exceeded 32 cm H2O despite increased sedation, or tidal volume modifications. Prone mechanical ventilation, inhaled nitric oxide, and almitrine mesylate (a vasodilator used in Europe) could be used at the discretion of the attending physician in either group, but no specific protocols governed the use of these therapies. The primary outcomes included death before hospital discharge and 90-day mortality, while secondary outcomes included 28-day mortality, number of days outside the ICU, ventilator-free days, and the incidence of barotrauma and ICU-acquired paresis.

One hundred seventy-eight patients were randomized to treatment with cis-atracurium while 162 received placebo. The groups were well matched except for a lower mean P/F ratio in the intervention group. Crude 90-day mortality was 31.6% in the cis-atracurium group compared to 40.7% in the placebo group (P = 0.08), while the adjusted hazard ratio for death at 90 days in the cis-atracurium group was 0.68 (95% confidence interval, 0.48-0.98; P = 0.04). Of note, improvements in mortality in the cis-atracurium group were limited to those patients with a P/F ratio < 120 mm Hg and the Kaplan-Meier curves only began to diverge after about 18-20 days. With regard to the secondary outcomes, patients in the intervention group had more ventilator-free days and days free of non-pulmonary organ failure. The incidence of pneumothorax was lower in the intervention group (4.0% vs 11.7%; P = 0.01), while the incidence of ICU-acquired paresis was no different between the two groups (~30% in each group). More patients in the placebo group received open-label cis-atracurium in the first 48 hours following enrollment while the daily sedative/analgesic doses and use of alternative rescue strategies were similar between the two groups.

Commentary

This study will likely garner a significant amount of attention, as it is one of the first trials to demonstrate a mortality benefit from use of a rescue strategy in patients with ARDS and severe hypoxemia. In fact, I suspect that with the growing interest in ICU bundles and quality measures, efforts may be made to include it in revised ventilator protocols at many institutions. We need to exercise caution, however, before moving ahead in this regard. Because many problems are difficult to study in the ICU and we lack the volume of large, randomized controlled trials seen in fields like cardiology, there is a tendency in critical care medicine for positive results from single studies to be rapidly adopted into practice before further data are available. This happened with tight glucose control after a single-center study in the surgical ICU alone1 led to widespread use of insulin drip protocols and with the use of corticosteroids in septic shock after a mortality benefit was reported in sub-group analysis in a well-publicized trial.2 In both cases, follow-on studies subsequently questioned the benefit of those interventions or demonstrated a higher incidence of adverse events than earlier reported.

There are several issues that need to be resolved in the case of paralytic agents before we move toward wider adoption of the practice. First, the mechanism for the purported effect is unknown and as a result it falls short with regard to the question: "Does this result make sense?" We are left wondering, for example, why the survival curves do not diverge until more than 18 days from use of the therapy. When lung-protective ventilation was adopted for management of ARDS, there was a large body of animal data and preliminary studies in humans that spoke to the mechanism and demonstrated plausibility of the approach. This body of knowledge is lacking in the case of paralytics.

Second, the investigators only used cis-atracurium, and it would be useful to know whether the benefits extend to other, less expensive paralytic agents such as vecuronium. Finally, and perhaps most important, many studies have demonstrated that use of paralytic agents is associated with an increased risk of ICU paresis, in distinction to one of the main findings in this study. Granted, the data from Papazian and colleagues were collected in a prospective, randomized manner compared to the retrospective nature of much of the other data on this issue. However, given the implications of ICU-acquired paresis for patient outcomes, it is important to validate the findings of this study with regard to the paresis issue, as it would not be in our patients' interests if, similar to the observed rates of hypoglycemia with strict glucose targets, we subsequently discovered higher than anticipated rates of ICU paresis after widespread adoption of paralytic agents. Given these outstanding issues, paralytic use in ARDS is a bandwagon we should let travel a bit further before we look to jump on.

References

  1. Van den Berghe G, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345:1359-1367.
  2. Annane D, et al. Effect of treatment with hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-871.