Critical Care Alert: Re-evaluation of Systemic Early Neuromuscular Blockade: The ROSE Trial

Article
Moss M, Huang DT, Brower RG, et al. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019;380(21):1997-2008. 

OBJECTIVE
To determine the efficacy and safety of early neuromuscular blockade with concomitant heavy sedation as compared with a strategy of usual care with lighter sedation targets. The investigators hypothesized that early neuromuscular blockade would result in lower all-cause in-hospital mortality at 90 days than usual care.

BACKGROUND
Acute Respiratory Distress Syndrome (ARDS) is a life-threatening disease process invoked by inflammatory pulmonary injury manifesting with hypoxia secondary to poor gas exchange.  Though ARDS has been recognized as a diagnostic entity since the 1960s, with its pathogenesis and therapies being subject to extensive research, there are very few recommended mortality-reducing interventions. The use of neuromuscular blockade as an early intervention in the management of moderate-to-severe ARDS was the basis for the ARDS et Curarisation Systematique (ACURASYS) trial, which concluded from a limited (n=340) patient population that early administration of cisatracurium (a neuromuscular blocking agent) for 48 hours improved the adjusted 90-day survival of patients with moderate-to-severe ARDS. While the promising results of the ACURASYS study have influenced the management of ARDS since 2010, neuromuscular blockade is weakly recommended by current ARDS treatment guidelines and the limited size of the population studied in ACURASYS poses questions regarding the external validity of the study. The ACURASYS trial, which may be considered a pilot study, created an impetus for further investigation of the role of neuromuscular blockade in the management of ARDS. Here, we review the Re-evaluation of Systemic Early Neuromuscular Blockade (ROSE) trial, a study that revisits this question in the setting of updated ARDS management guidelines.

DESIGN

• Multicenter, unblinded, parallel-group, open-label randomized controlled trial
• Intention to treat (ITT) analysis

Inclusion Criterion

• Patients undergoing mechanical ventilation via endotracheal tube were enrolled if the following criteria were present for less than 48 hours:

• • PaO2:FIO2 < 150 mmHg with a PEEP of 8 cm or more of water
  • Bilateral pulmonary opacities on chest radiography or computed tomography that could not be explained by effusions, pulmonary collapse, or nodules
  • Respiratory failure that could not be explained by cardiac failure or fluid overload

Exclusion Criterion

• Continuous neuromuscular blockade at enrollment
• Known pregnancy
• Currently receiving ECMO
• Chronic respiratory failure defined as PaCO2 > 60 mmHg in the outpatient setting
• Actual body weight exceeding 1 kg per centimeter of height
• Severe chronic liver disease defined as a Child-Pugh score of 12-15
• Expected duration of mechanical ventilation < 48 hours
• The decision to withhold life-sustaining treatment, not including those patients committed to full support except cardiopulmonary resuscitation
• Moribund patient not expected to survive 24 hours; if cardiopulmonary resuscitation (CPR) provided, assess for moribund status ≥ 6 hours from CPR conclusion
• Previous hypersensitivity or anaphylactic reaction to cisatracurium
• Neuromuscular conditions that may potentiate NMB or impair spontaneous ventilation
• PaO2/FIO2 (if available) > 200 mmHg after meeting inclusion criteria and before randomization
• The patient receiving mechanical ventilation for greater than 120 hours (5 days)
• The patient has completed lung transplant evaluation and has been officially listed for lung transplant
• Burns > 70% of total body surface

Get a full list of exclusion criteria here.

Randomization

• Between January 2016 and April 2018, 1008 patients in 48 sites in the United States underwent randomization

• 2 (0.199%) were withdrawn due to ineligibility

• 1 from the intervention group

• 1 from the control group

• 1006 patients were included in the final analysis

• 4848 patients screened for trial eligibility

• Eligible patients randomly assigned in 1:1 ratio to receive 48 hours of continuous neuromuscular blockade with concomitant deep sedation (intervention) or receive usual care without routine neuromuscular blockade and with light sedation targets (control)

• The intervention group was given IV bolus 15 mg of cisatracurium followed by continuous infusion of 37.5 mg/hour for 48 hours

• All patients were treated with a strategy of low tidal volume ventilation within 2 hours after randomization and a high PEEP strategy for up to 5 days after randomization.

• The final analysis includes 501 patients randomized to the intervention group and 505 patients randomized to the control group

Population Characteristics

• Baseline population characteristics were reviewed, with the following differences reported as statistically significant:

• Median time to randomization (p = 0.047)

• Shock at baseline (p = 0.05)

• Intervention Group

• Median age: 56.6 +/- 14.7 years

• % Female: 41.9

• Median time to randomization: 8.2 (IQR = 4.0-16.4)

• Shock at baseline = 276 (55.1%)

• Control Group

• Median age = 55.1 +/- 15.9

• % Female = 46.7

• Median time to randomization: 6.8 (IQR = 3.3-14.5)

• Shock at baseline = 309 (68.1%)

Outcomes Measured

• Primary

• In-hospital death from any cause at 90 days 

• Secondary

• Organ dysfunction, assessed with Sequential Organ Failure (SOFA) score

• In-hospital death at day 28

• Days free of organ dysfunction

• Days not in the ICU

• Days free from mechanical ventilation

• Days not spent in the hospital at day 28

• Endpoints at 3, 6, and 12 months:

• Survival

• Disability

• Health-related quality of life

• Patient-reported health

• Pain interference

• Symptoms resembling post-traumatic stress

• Cognitive function

• Return to work

• Safety Outcomes

• Recall of paralysis

• ICU-acquired weakness up to day 28

• Limitations on physical activity

• New-onset atrial fibrillation or supraventricular tachycardia

• Barotrauma

KEY RESULTS

• Primary

• In-hospital death from any cause at 90 days for intervention v. control group was, respectively, 42.5% v. 42.8%, (95% confidence interval [CI] -6.4 to 5.0; p = 0.93)

• Secondary

• Amongst the secondary end-points specified by the investigators, only the following were determined to have between-group differences that were statistically significant.

• Day 1 Cardiovascular SOFA Score: 0.2 between-group difference (95% CI, 0.1 to 0.4)

• Day 2 Cardiovascular SOFA Score: 0.3 between-group difference (95% CI, 0.1 to 0.5)

Study Strengths

• Randomized, controlled, multicenter trial

• Intent to treat (ITT) analysis

• Survival is a patient-centered outcome

• The primary outcome of 90-day mortality is a robust endpoint

• Neuromuscular blocking agent and dosing regimen replicated ACURASYS trial

• Sedation and ventilation protocols for the control group were consistent with current ARDS guidelines

• Good adherence to PEEP, FiO2 recommendations days 1 through 7

• Adherence to low tidal volume ventilation ranged from 80.1 to 87.5%

• Adherence to low plateau pressures ranged from 85.6 to 90.8% 

Study Limitations

• The trial was stopped at the second interim analysis due to futility
• Limitations to blinding
• Effect of neuromuscular blockade on ventilator dyssynchrony was not measured
  

Authors' Conclusions
The use of cisatracurium (continuous infusion for 48 hours) early in the setting of moderate-to-severe ARDS does not confer a significant difference in mortality at 90 days compared to patients treated with light sedation targets without neuromuscular blockade.

Discussion
The early use of neuromuscular blocking agents in the setting of moderate-to-severe ARDS was previously understood to confer a survival advantage at 90 days, based on the outcomes of the 2010 ACURASYS trial. The ROSE trial – the largest randomized controlled trial of neuromuscular blockade in ARDS - re-examines this in the setting of a much larger patient population with high adherence to newer ARDS management guidelines, providing an updated and more validated insight to the role of neuromuscular blockade in ARDS. Though the early use of neuromuscular blockade has been recommended following the ACURASYS trial, the study suggested that neuromuscular blockade conferred a mortality benefit compared to a strategy of deep sedation targets. The current guidelines for ARDS management recommend lighter sedation targets, and thus the continued use of neuromuscular blockade has been conflated for a mortality benefit over outdated sedation guidelines. The ROSE trial demonstrates that early neuromuscular blockade yielded no significant difference in 90-day mortality compared to light sedation targets in adherence with updated guidelines. Of note, the study demonstrated a higher rate of cardiovascular adverse events in the interventional study arm (14 v. 4, p = 0.02), which is purported to be related to deeper sedation requirements in the setting of neuromuscular blockade. The findings of this study are relevant to the scope of practice for emergency medicine physicians, as it provides high-quality evidence that early and continuous neuromuscular blockade does in the setting of moderate-to-severe ARDS not improve in-hospital mortality at 90 days. In the emergency department setting, physicians should remain primarily concerned with adequate airway control and initiation of mechanical ventilation with low tidal volumes and low inspiratory pressures while maintaining adequate sedation throughout. Consideration of cisatracurium infusion for ventilator-patient dyssynchrony should follow patient stabilization and may remain an appropriate comfort measure for ventilated patients in the setting of ARDS when neuromuscular blockade is not contraindicated. Further studies should quantitate the effect of neuromuscular blockade on ventilator-patient dyssynchrony.

References
1. Moss M, Huang DT, Brower RG, et al. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019;380(21):1997-2008.
2. Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107-1116. 
3. Fan E, Del Sorbo L, et al. American Thoracic Society, European Society of Intensive Care Medicine, and Society of Critical Care Medicine. An official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2017;195(9):1253–1263.