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To evaluate the effects of neuromuscular blocking agents (NMBAs) on pulmonary and systemic inflammation in patients with acute respiratory distress syndrome ventilated with a lung-protective strategy.Multiple-center, prospective, controlled, and randomized trial.One medical and two medical–surgical intensive care units.A total of 36 patients with acute respiratory distress syndrome (Pao2/Fio2 ratio of ≤200 at a positive end-expiratory pressure of ≥5 cm H2O) were included within 48 hrs of acute respiratory distress syndrome onset.Patients were randomized to receive conventional therapy plus placebo (n = 18) or conventional therapy plus NMBAs (n = 18) for 48 hrs. Both groups were ventilated with a lung-protective strategy (tidal volume between 4 and 8 mL/kg ideal body weight, plateau pressure of ≤30 cm H2O).Bronchoalveolar lavages and blood samples were performed, before randomization and at 48 hrs, to determine the concentrations of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-8. Pao2/Fio2 ratio was evaluated before randomization and at 24, 48, 72, 96, and 120 hrs. A decrease over time in IL-8 concentrations (p = .034) was observed in the pulmonary compartment of the NMBA group. At 48 hrs after randomization, pulmonary concentrations of IL-1β (p = .005), IL-6 (p = .038), and IL-8 (p = .017) were lower in the NMBA group as compared with the control group. A decrease over time in IL-6 (p = .05) and IL-8 (p = .003) serum concentrations was observed in the NMBA group. At 48 hrs after randomization, serum concentrations of IL-1β (p = .037) and IL-6 (p = .041) were lower in the NMBA group as compared with the control group. A sustained improvement in Pao2/Fio2 ratio was observed and was reinforced in the NMBA group (p < .001).Early use of NMBAs decrease the proinflammatory response associated with acute respiratory distress syndrome and mechanical ventilation.