Neuromuscular Blockers Improves Outcome in Severe and Early Adult Respiratory Distress Syndrome

Adult Respiratory Distress Syndrome (ARDS) is an inflammatory lung disease characterized by pulmonary edema, stiff lungs, and hypoxemia. It has a very high mortality rate of more than 40% and affects approximately 140,000 patients annually in the United States. Despite the fact that this disease causes such a high morbidity and mortality and a huge economic burden on the society, there has been no pharmacologic therapy that has been associated with improved survival in ARDS. The only strategy that has been found beneficial in ARDS until now is the lungprotective ventilation strategy using low tidal volumes compared with conventional tidal volumes. In that study conducted by the ARDS Network, patients with acute lung injury and ARDS were randomized to mechanical ventilation at a tidal volume of 12 mL/kg of predicted body weight and an inspiratory pressure of 50 cm H2O or less versus a tidal volume of 6 mL/kg and an inspiratory pressure of 30 cm H2O or less. The study was stopped early after interim analysis of 861 patients showed that patients in the low tidal volume group had a significantly lower mortality rate, 31% versus 39.8%. Although a quarter of the patients who develop ARDS receive a neuromuscular blocker in the intensive care unit (ICU), most intensivists are reluctant to use it secondary to concerns of long term development of critical care neuropathy and critical care polyneuropathy, in particular if the patient is also on aminoglycosides and glucocorticoids. Neuromuscular-blocking agents (NMBAs) paralyze skeletal muscles by blocking the transmission of nerve impulses at the myoneural junction. These drugs may be useful in the ICU to improve patient-ventilator synchrony, enhance gas exchange, and diminish the risk of barotrauma. This study supports the use of NMBAS but only at the beginning of ARDS, only for short duration, and most importantly, only for patients with severe ARDS. In this multicenter (conducted at 20 ICUs in France) double-blinded study, 340 patients presenting with severe ARDS within the previous 48 hours were randomly assigned to receive either cisatracurium besylate or placebo for 48 hours [178 were randomized to receive cisatracurium (150 mg) and 162 to receive placebo 6 times daily for 2 days]. They enrolled patients with significant acute lung injury with pulmonary function ratios (PaO2/FiO2) of less than 150. Most of the patients actually had the ratio below 120. The primary outcome was the proportion of patients who died either before hospital discharge or within 90 days after study enrollment. NMBA showed a protective effect with regard to the study’s primary outcome of 90-day inhospital mortality. This outcome was experienced by 31.6% of the NMBA group, compared with 40.7% of the placebo group, leading to a hazard ratio of 0.68 for the NMBA group. The between-group difference was greatest among patients with a Pao2/Fio2 scores less than 120. In addition, 28-day mortality was 23.7% in the NMBA group compared with 33.3% in the placebo group. A brief period of paralysis early in the course of ARDS may facilitate lung-protective mechanical ventilation by improving patient-ventilator synchrony and allowing accurate adjustment of tidal volume and pressure levels, thereby limiting asynchrony-related alveolar collapse and regional alveolar pressure increase with alveolar distension. NBMA’s also may decrease lung and systemic inflammation. The method used in this study (blinded and randomized study with well defined protocol, complete follow-up, and intention to treat analyses) is the strength of this study. In addition, the fact that this was a multicenter trial suggests that the study can be generalized to other populations. The sample size of this study was not enough to achieve statistical power, besides this protocol did not assess the use of NMBA in late or less severe ARDS. Finally, cisatracurium was the agent chosen for the study, and the results may not apply to other NMBA. Although this study is thought provoking and encourages the use of NMBAs in the early phase of severe ARDS, future studies including more patients, are needed which can replicate the results before this can be accepted as the standard of care.