The National Heart, Lung, and Blood Institute PETAL Clinical Trials Network published a large randomized controlled trial comparing NMBs(neuromuscular blocker) to placebo in patients with moderate to severe adult respiratory distress syndrome(PEEP of at least >8 with ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of <150 mm Hg).
BACKGROUND
Since its first description by Ashbaugh DG, Bigelow DB et el , ARDS remains a devastating manifestation of heterogeneous disease processes that injure the lung and cause non-hydrostatic pulmonary edema. Mainstay of therapy remains various ventilator strategies and advanced therapy including ECMO.
Neuromuscular blockade is thought to be working by facilitating ventilator synchrony, especially in early ARDS, may reduce VILI by ensuring low delivery of low tidal volume (prevention double triggering), preventing loss of PEEP by active exhalation (prevention of atelectrauma), and controlling the high ventilation demand that is inherent to severely injured lungs and respiratory drive associated with hypercapnia during low tidal volume ventilation as well as through a direct anti-inflammatory effect.
Neuromuscular blockade was found to improve gas exchange in ARDS in 2004 by Gainnier M, Roch A, Forel JM et el. In 2010, ACURASYS Study Investigators found that in severe ARDS, neuromuscular blockade with cisatracurium besylate for 48 hours had a lower 90-day risk of death (hazard ratio 0.68). Furthermore, the rates of ICU acquired weakness did not differ between the two groups. There were more ventilator free days, and less pneumothoraces in cisatracurium group. However, this trial involved 340 patients only, and used a PEEP of 5 as criteria for severe ARDS. One very interesting aspect of this study was that Kaplan–Meier survival curves were virtually superimposable for about 18 days before they separated.
TRIAL
1008 patients with severe ARDS (Pao2:Fio2 of less than 150 mm Hg with a PEEP of 8 cm or more of water; bilateral
pulmonary opacities on chest radiography or on computed tomography that could not be explained by effusions, pulmonary collapse, or nodules; and respiratory failure that could not be explained by cardiac failure or fluid overload.) were randomized to cisatracurium versus usual sedation practices.
METHODS
Treatment group received intravenous bolus of 15 mg of cisatracurium, followed by a continuous infusion of 37.5 mg per hour for 48 hours. No titration was done.
Control group was targeted to have light sedation (Light sedation was defined by a score on the Richmond Agitation–Sedation Scale of 0 or −1 (scores range from 4 [combative] to −5 [unresponsive], with a score of 0 indicating that the patient is alert and calm)).
All patients were treated with a strategy of low tidal volume ventilation within 2 hours after randomization and a high PEEP strategy. Prone therapy was at the discretion of the clinician.
END POINTS
Primary end point was in-hospital death from any cause at 90 days.
Secondary end points were organ dysfunction (as assessed on the basis of the Sequential Organ Failure [SOFA]
score; scores range from 0 to 4 for each of six organ systems, with higher scores indicating more severe organ dysfunction), in-hospital death at day 28, days free of organ dysfunction, days not in the ICU, days free of mechanical ventilation, and days not in the hospital at day 28.
RESULTS
No difference in primary end point between two groups.
At 28 days, there was no between-group difference in hospital mortality, days free of ventilation, days out of the ICU, or days out of the hospital. There were higher number of cardiovascular adverse events in the intervention group. No difference in rate of barotrauma.
No difference between two groups in terms of prone therapy, steroids and other adjunctive therapies.
Trial was stopped early for futility.
POSSIBLE EXPLANATION FOR DIFFERENT RESULTS THAN EARLIER TRIAL
- Use of prone therapy (was not used in earlier trial) may have masked the difference by improving survival anyway.
- Use of higher PEEP strategy may itself reduce mortality among patients with moderate to severe ARDS, thereby blunting the potential treatment effect of early continuous neuromuscular blockade.
- Sedation targets used in the control group were lighter than those used in the ACURASYS trial. There were higher number of cardiovascular adverse events in the intervention group than in the control group could be the result of deep sedation in the intervention group, which could have induced hypotension, bradycardia, and other cardiovascular effects.
BOTTOMLINE
Instead of routine use of NMBs in moderate to severe ARDS, they should be used in patients who despite carefully implemented ventilatory and sedation strategies, has a ventilatory pattern that confers a predisposition to ventilator-induced lung injury (e.g., breath stacking); neuromuscular blocking agents may also be considered in
patients with increased respiratory drive that could generate potentially injurious transpulmonary pressure swings.