Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome
Papazian L, Forel JM, Gacouin A, et al; ACURASYS Study Investigators
N Engl J Med. 2010;363:1107-1116
Acute respiratory distress syndrome (ARDS) requires mechanical ventilation in the intensive care unit (ICU) and has a high rate of mortality. Because of the need for intubation as an integral part of management, with consequent restlessness on the part of the patient, sedation is usually required. When sedation alone is inadequate, neuromuscular blockade is instituted. However, there has always been concern that the latter will compromise muscle activity and interfere with weaning if and when mechanical ventilation can be discontinued. An early trial of neuromuscular blockade unexpectedly showed that neuromuscular blockade for 48 hours was associated with a trend toward improved survival, but the trial was small. The present study was conducted to examine this issue with adequate power and statistical rigor.
The multicenter, double-blind trial enrolled 340 patients with severe ARDS (partial pressure of arterial oxygen [PaO2]/fraction of inspired oxygen [FiO2] ratio < 150) with a positive end-expiratory pressure of 5 cm water or more and a tidal volume of 6-8 mL/kg of predicted body weight. Patients received all usual therapy and were randomly assigned to receive either the neuromuscular blocking agent cisatracurium besylate (Nimbex®) or placebo for the first 48 hours of treatment. The primary outcome was mortality over the next 90 days adjusted for predefined covariates and baseline differences.
At 90 days, the hazard ratio for mortality was 0.68 (95% confidence interval [CI], 0.48-0.98; P < .04) in favor of the cisatracurium group. Crude mortality was 31.6% in the cisatracurium group vs 40.7% in the placebo group. Secondary outcomes included increases in the number of ventilator-free days, the number of ventilator-free days outside the ICU, and a reduction in the incidence of barotrauma, all in favor of the cisatracurium group. The rate of paresis (using a measure of muscle strength on day 28) did not differ between groups.
This study is important because ARDS remains one of the most common indications for mechanical ventilation in the ICU and because the results run counter to our present understanding of the optimal management of this condition. Indeed, the trend over the last decade has been to minimize interventions by, for example, using less sedation, less intubation, lower tidal volumes, and earlier mobilization.[3,4] The mechanism of the effect of neuromuscular blockade is unknown. Is it associated with a reduction in oxygen consumption? Or improved patient-ventilator synchrony? Less ventilator-induced lung injury? Or another mechanism? However, if the results of this study are confirmed (and confirmation by others is necessary), there could be a substantial reduction in mortality using a relatively simple treatment. This could represent the first pharmacologic intervention to improve the outlook of ARDS and would signify a breakthrough in the management of this condition.
The latest figures indicate an incidence of ARDS in the United States of 190,600 cases per year, with a mortality of 74,500 or 40%. Thus, although mortality has declined since the syndrome was first recognized in the 1960s, it remains substantial. Since the institution of mechanical ventilation, positive end-expiratory pressure, and modest reduction in tidal volumes, no major therapeutic advances or dramatic reductions in mortality have occurred for many years.
The strengths of this study are the well designed, prospective protocol and the intention-to-treat analysis. The involvement of several study sites suggests that the results can be generalized to other ICUs. Because the trial's enrollment was limited to patients with severe ARDS, however, it is not certain that patients with milder ARDS would benefit. In fact, post hoc analysis of the present results suggested that the benefit of neuromuscular blockade was almost entirely confined to patients with the worst gas exchange, namely those with a PaO2/FiO2 ratio of < 120. Thus the results cannot be extrapolated to all patients with ARDS. Nor can it be assumed that other neuromuscular blocking agents or other administration protocols (eg, 24 hours of administration or use with other modes of ventilation) would be similarly beneficial. Such details will need to be determined by further studies. The editorial by Dr. Slutsky that accompanies this article is well worth reading.
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