Neuromuscular blockers and ARDS: Thou shalt not breathe, move, or die!

In patients undergoing mechanical ventilation for Acute Respiratory Distress Syndrome (ARDS), neuromuscular blocking agents (NMBAs) may improve oxygenation and decrease ventilator-induced lung injury but may also cause muscle weakness.


Background
In patients undergoing mechanical ventilation for Acute Respiratory Distress Syndrome (ARDS), neuromuscular blocking agents (NMBAs) may improve oxygenation and decrease ventilator-induced lung injury but may also cause muscle weakness.

Methods
Objective: To identify if 48 hour therapy with the NMBA cisatracurium early in the course of ARDS reduces adjusted 90-day in-hospital mortality rate. Design: Multicenter, double blind, randomized clinical trial. Setting: Twenty multidisciplinary intensive care units in France Subjects: Patients presenting with onset of severe ARDS within the previous 48 hours. Severe ARDS was defi ned as a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of less than 150, with a positive end-expiratory pressure of 5 cm or more of water and a tidal volume of 6 to 8 ml per kilogram of predicted body weight. Intervention: After enrollment, 340 patients were ran domized to receive either cisatracurium besylate (n = 178) or placebo (n = 162). All patients were sedated to a Ramsay sedation score of 6 using sulfentanil and midazolam prior to intervention. A dose of 15 mg cisatracurium besylate or placebo was then administered, followed by a continuous infusion of 37.5 mg/hour for 48 hours. Patients were not monitored for depth of paralysis. Outcomes: Th e primary outcome was the proportion of patients who died either before hospital discharge or within 90 days after study enrollment (i.e., the 90-day inhospital mortality rate), adjusted for predefi ned covariates and baseline diff erences between groups with the use of a Cox model.

Conclusions
In patients with severe ARDS, early administration of a neuromuscular blocking agent improved the adjusted 90-day survival and increased the time off the ventilator without increasing muscle weakness.

Commentary
Th e incidence of ARDS varies between 13.5 to 58.7 cases per 100,000 person years [1], and aff ects 10% to 15% of all patients admitted to the intensive care unit [2,3]. Despite various treatment options, such as high positive endexpiratory pressure, corticosteroids, recruitment maneuvers, conservative fl uid management, and rescue maneuvers, including prone ventilation, nitric oxide, and high frequency oscillation ventilation, severe ARDS has a mortality ranging from 40% to 60% [2,3]. Only low tidal volume ventilation and extracorporeal membrane oxygena tion have been shown to decrease mortality in patients with ARDS [4,5].
Neuromuscular blocking agents are currently used as a salvage maneuver in patients with severe ARDS in whom oxygenation is a challenge. Use of NMBAs has been hypothesized to achieve better synchronization with the ventilator resulting in decreased ventilator-induced lung injury, and improve oxygenation due to lower oxygen consumption [6]. NMBAs are also thought to have an anti-infl ammatory eff ect, including attenuation of interleukin-6 and 8 expression [6]. However, NMBAs preclude the ability to monitor neurological signs clinically and prolonged use has been associated with increased risk of critical illness polyneuropathy [7], and posttraumatic stress disorder symptoms when compared to patients managed with sedatives alone [8]. Th erefore, the current standard of practice in the intensive care unit is to minimize the use of sedation, wake patients early, and avoid use of paralytic medications. Indeed, the Society of Critical Care Medicine guidelines recommend that NMBAs should only be used to manage ventilation and decrease oxygen consumption when all other means have been tried without success (Grade C recommendation) [9].
Papazian and colleagues challenge this existing paradigm and ask a very intriguing question whether short term use of NMBAs is likely to improve outcomes from ARDS. Th e authors in an earlier smaller study found that early and short course of NMBA use were associated with a trend toward lower 28-day mortality [10]. In the current study the authors found that in patients with severe ARDS, early administration of cisatracurium improved the adjusted 90-day survival and increased the time off the ventilator without increasing muscle weakness. Strengths of the trial include a well-defi ned study protocol, multicenter design and early assignment to treatment groups, intention-to-treat analysis, and complete follow-up.
However, there are several important limitations that deserve consideration. First, although the healthcare providers were blinded to the best possible extent, complete blinding would not be possible as physicians can easily identify a paralyzed patient (by a thorough clinical exam). Th is could have introduced a systematic bias in the intervention arm that could have infl uenced the outcomes. Second, it is important to note that the authors used hospital mortality censored at 90 days as a primary outcome measure. However, the abstract as well as the remainder of the manuscript alludes to "90-day" mortality rate as a primary outcome. Th e distinction is important because "90-day mortality" (i.e., assessing whether a patient is alive or dead at 90 days following randomization irrespective of their location) is a more robust outcome measure than hospital mortality censored at 90 days (i.e., assessing mortality only during hospital stay within the fi rst 90 days of randomization) as the latter does not account for patients who might have died following hospital discharge within the fi rst 90 days. Using in-hospital mortality rates can also make it diffi cult to interpret outcome diff erences across institutions if the Figure 1. Forest plot of trials comparing cisatracurium with placebo for 28-day mortality in severe ARDS. Data from studies demonstrate the relative risk (RR) with 95% confi dence intervals (CI) for mortality with cisatracurium vs. placebo in patients with ARDS. The RRs < 1 suggest reduced mortality with cisatracurium compared to placebo, whereas RRs >1 suggest increased mortality with cisatracurium. The size of the data markers corresponds to the weight of the studies. Larger markers imply less uncertainty from the results of the individual study and carry more weight in calculating the fi xed eff ects pooled estimate from the systematic review. discharge policies of these institutions vary. For example, transfer of ICU patients to long term acute care facilities, or earlier hospital discharges, may cause a decrease in the hospital mortality rate.
Th ird, although the authors noted a low risk of barotrauma and organ failure with NMBA use, data related to mechanistic pathways (e.g., decrease in biomarkers) that could have mediated benefi cial outcome is lacking. Fourth, as stated by the authors the study was underpowered to detect diff erences in crude mortality rates and statistical signifi cance was reached only after adjustment for baseline covariates. Finally, the authors used the Medical Research Council scale to evaluate muscle weakness at 28 days, which may be too brief to recognize muscle weakness especially among patients who require prolonged mechanical ventilation. Assessing long term neuromuscular weakness related to NMBA use [11], is likely to provide more robust safety data related to NMBA use.
Th is trial challenges current prevailing practice paradigms of whether a minimalistic approach in the treatment of ARDS, such as use of lighter sedation and no paralytic agents, improves outcomes. Nevertheless, this is the second study showing that short course NMBA may improve outcome among patients with severe ARDS [10,12]. We conducted an analysis from the two studies by pooling crude estimates of treatment eff ects of NMBA on 28-day mortality [10,12] (Figure 1). We found that the use of NMBA cisatracurium lowered mortality rate (Relative Risk = 0.7, 95% CI, 0.53-0.92, P = 0.01) compared to placebo. However, the caveat should be noted that the 28-day mortality is a suboptimal outcome measure for assessing interventions in ARDS [13].

Recommendation
Papazian and colleagues should be commended for showing that early and short term administration of NMBAs is safe, may improve mortality, decrease duration of mechanical ventilation, and complications related to barotrauma. Th e absence of signifi cant short term adverse eff ects and the potential to improve mortality, although needs to be replicated in future studies, suggest that early and short course of NMBAs may be benefi cial in severe ARDS.