Seven RCTs have been conducted evaluating the benefits, if any, of NMBA use in ARDS patients [20,21,27,34,42,55,56]. The earliest four studies were performed in France [21,34,42,55], two subsequent studies in China [27,56] and the latest, also including the larger number of patients, was performed in USA [20]. The studies have provided conflicting results, so that they have changed the clinical practice in a bidirectional way. Especially when considering the most influential ones (ACURASYS and ROSE study) with the highest recruitment, certain differences have been addressed, although the design of the ROSE study was carefully selected to allow direct comparisons to ACURASYS [20,21].

In the first study in the field, Gainnier et al. randomized 56 patients with moderate and severe ARDS within 36 h of the patients meeting the eligibility criteria. The patients assigned to the NMBAs group received cisatracurium at a dose of 5 μg/kg/min (cumulative dose of 1324 ± 197 mg) after a bolus infusion of 50 mg. The study found that the early use of NMBAs resulted in sustained improvements in oxygenation after 48 h of infusion, persisting during the 120 h of the study period. Hospital mortality on day 28th, 60th and ICU mortality did not differ (Table 1).

Only one patient suffered a pneumothorax in the control group and none of the patients developed any signs of muscle weakness, while there were no differences in the number of patients suffering a ventilator-associated pneumonia (VAP) episode. The second RCT randomized 36 patients with ARDS and PaO₂/FiO₂ < 200 mmHg to receive NMBAs for 48 h or not. The authors reported that the sustained improvement in oxygenation was accompanied with a reduction in pulmonary and systemic cytokines in patients under NMBAs. Ventilator-free days (VFDs) and ICU mortality (27.8% vs. 55.6%) did not differ (Table 1) [42]. The small sample size may have precluded the numerical difference in mortality to reach a statistical significance. The same study group reported that, in 30 ARDS patients with moderate and severe ARDS, the use of NMBAs increased the mean inspiratory and expiratory transpulmonary pressures, as a result of a stable positive end expiratory pressure with the elimination of expiratory efforts [34]. The changes in lung mechanics were associated with improvements in oxygenation in the NMBA group. The authors point that, by abolishing expiratory efforts, a significant amount of derecruitment during expiration can be achieved [34]. There are two Chinese RCTs using vecuronium as the NMBA: Lyu et al. randomized 96 patients with moderate (48 patients) and severe ARDS (48 patients). The patients with PaO₂/FiO₂ < 100 mmHg receiving 24–48 h vecuronium presented significant improvements in oxygenation, perfusion and multiple severity scores, while they had also lower 21-day mortality rates (20.8 vs. 50%, p = 0.04) [27]. Both studies did not report significant adverse effects with the use of aminosteroidal NMBAs.

The most robust evidence concerning the use of NMBAs in ARDS patients comes from the two largest RCTs (ACURASYS and ROSE studies), although reporting conflicting results [20,21]. The ACURASYS study was a multicenter RCT, conducted in France, which randomized 340 patients to receive a 48 h of cisatracurium infusion or placebo, within 48 h of ARDS diagnosis [21]. The primary outcome was 90-day mortality. The study team followed the same NMBA administration protocol as the previous studies [34,42,55]. Using a continuous infusion of 37.5 mg (after a bolus of 15 mg) of cisatracurium, as it had been found adequate to sustain paralysis in the previous studies, no peripheral nerve simulation was performed. The authors found that the hazard ratio for death at 90 days in the cisatracurium group compared to the placebo group was 0.68 (95% confidence interval (CI), 0.48 to 0.98; p = 0.04) after adjustment for the baseline PaO₂/FiO₂, SAPS II and plateau pressures. The crude 90-day mortality was 31.6% (95% CI, 25.2 to 38.8) in the cisatracurium group and 40.7% (95% CI, 33.5 to 48.4) in the placebo group (p = 0.08). Patients in the intervention group had also more VFD in the first 28 days (10.6 ± 9.7 vs. 8.5 ± 9.4, p = 0.04) and an increased hazard ratio for weaning from mechanical ventilation by day 90 (HR 1.41 95% CI 1.08 to 1.83; p = 0.01). Barotrauma was significantly more frequent in the placebo group (4 vs. 11.7%, p = 0.01).

In 2014, the National Heart, Lung and Blood Institute (NHLBI) launched the Prevention and Early Treatment of Acute Lung Injury (PETAL) Network to conduct phase III trials to test treatments with the potential to improve clinical outcomes of patients with or at risk of developing ARDS. PETAL built on a new network (NHLBI ARDS Clinical Trial Network (ARDSNet)) with a focus on early treatment and prevention. Thus, in 2016, PETAL launched the Re-evaluation of Systemic Early Neuromuscular Blockade (ROSE) trial to assess the efficacy and safety of early neuromuscular blockade in reducing mortality and morbidity patients with moderate and severe ARDS [63]. The outcomes were tested on a longer timeframe (up to 12 months). The rational for the conduction of a second trial is summarized below: Firstly, there was a need to re-evaluate the effectiveness of NMBAs in a larger cohort than the one included in ACURASYS study [21]. In view of the change in clinical practice favoring light sedation [39,40], the ROSE protocol intended to compare heavy sedation with additional paralysis with NMBAs to a light sedation protocol adopted in the control group. Thirdly, the patients were randomized if they presented a PaO₂/FiO₂ <150 mmHg with PEEP application of 8 cm H₂O or higher. This is in contrast to the inclusion criterion used in the ACURASYS trial, where hypoxemia was tested with a PEEP of at least 5 cm H₂O [21]. This criterion was selected to exclude patients with transient hypoxemia after intubation [63]. The trial enrolled 1006 patients and was stopped for futility after the second interim analysis; the decision was independently made considering the data analyzed and the safety monitoring results. Treatment with NMBAs was not associated with increases in oxygenation variables, nor were there any effects on in hospital mortality or VFM. The incidence of barotrauma did not differ across the patients in both study arms, while patients receiving muscular relaxants presented serious cardiovascular adverse effects (one death from complete heart block and refractory shock) [20]. There are certain differences that may explain the contradictory results in these two RCTs. Firstly, the approach concerning the ARDS treatment was quite different. The amount of PEEP used in ROSE trial was much higher than the one used in the ACURASYS study (12.6 ± 3.6 vs. 9.2 ± 3.2 cm H₂O), prone positioning was less frequently used (16% vs. 29%), while the patient enrollment in the ROSE study was too quick (actual time of enrollment was 8 h from meeting eligibility criteria). Some patients might have improved in the next few hours only with the application of the ventilator (i.e., PEEP application) and not be eligible for the study.