ROSE

Published

National Heart, Lung, and Blood Institute PETAL Clinical Trials Network. "Early neuromuscular blockade in the acute respiratory distress syndrome". The New England Journal of Medicine. 2019. 380(21):1997-2008.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

In patients with moderate to severe ARDS, does the early use of continuous neuromuscular blockade with cisatracurium improve mortality when used with current light sedation protocols?

Bottom Line

Not only does early neuromuscular blockade not reduce mortality when using modern light sedation protocols, it was associated with an increase in ICU-acquired weakness and serious adverse cardiovascular events.

Major Points

Acute Respiratory Distress Syndrome (ARDS) has a mortality rate approaching 50%. Numerous therapeutics have been trialed and failed in ARDS, including prostaglandins, statins, pentoxifylline, N-acetylcysteine, ketoconazole, dazoxiben, acyclovir, and indomethacin. Three positive trials in ARDS studied low-tidal ventilation (ARDSNet, 2000), prone ventilation (PROSEVA, 2013), and early neuromuscular (NM) blockade (ACURASYS, 2010). ACURASYS was a multicenter RCT in 20 ICUs in France that enrolled 340 patients with ARDS. It compared early NM blockade with cisatracurium for 48 hours to usual care. Patients received deep sedation. NM blockade was associated with a 9% absolute risk reduction in 28-day mortality. Despite the mortality benefit in ACURASYS, early NM blockade has not been widely adopted in clinical practice given concerns over ICU-acquired weakness, ICU-acquired PTSD, and post-ICU syndrome. Practice guidelines deemed the overall evidence for early NM blockade in ARDS to be weak. Further, ICU practices have shifted since the publication of ACURASYS and now focus on significantly lighter sedation goals. Whether early NM blockade plays a role in modern ARDS management is unknown.

In 2019, the multicenter Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) trial sought to re-test the findings of ACURASYS using modern protocols. It was run by the NHLBI Prevention and Early Treatment of Acute Lung Injury (PETAL) Network. The study aimed to randomize 1,408 adults with moderate-to-severe ARDS to cisatracurium vs. no cisatracurium. The study was stopped early for futility after enrolling 1,006 participants. There was no difference for their primary outcome in 90-day in-hospital mortality (42% cisatracurium vs. 43% control; P=0.93). The secondary outcomes of in-hospital mortality, ventilator free-days, ICU free-days, or out of hospital days all at 28 days were similar between groups. For adverse events there was more ICU acquired weakness in the cisatracurium arm, as well as more serious adverse events and more serious cardiovascular adverse events. However, there was similar rates of barotrauma in both groups. ROSE implicates early NM blockade as a non-beneficial and potentially harmful intervention for moderate-to-severe ARDS.

Guidelines

As of June 2019, no guidelines have been published that reflect the results of this trial.

Design

• Multicenter, unblinded, parallel-group, randomized, controlled trial
• N=1006
  • Early NMB with cisatracurium (n=501)
  • Usual-care (n=505)
• Setting: 48 hospitals in the United States
• Enrollment: 2016-2018
• Follow-up: 12 months
• Analysis: Intention-to-treat
• Primary outcome: 90-day in-hospital death from any cause

Population

Inclusion Criteria

• <48h from onset of moderate to severe ARDS (Pao2:Fio2 <150 mmHg with PEEP ≥8 cm of water)
• Bilateral pulmonary opacities on chest radiography or on computed tomography that could not be explained by other etiologies (e.g., effusions, pulmonary collapse, nodules)
• Respiratory failure that could not be explained by cardiac failure or fluid overload

Exclusion Criteria

• Lack of informed consent
• Continuous NM blockade at enrollment
• Pregnancy
• ECMO therapy
• Chronic respiratory failure with an outpatient PaCO2 >60 mmHg
• Home mechanical ventilation (non-invasive ventilation or via tracheotomy); CPAP/BiPAP for OSA or similar conditions was allowed
• Body weight >1 kg/cm height
• Liver disease with Child-Pugh score of 12-15
• Bone marrow transplantation within the last 1 year
• Expected duration of mechanical ventilation <48 hours
• Withholding of life-sustaining treatment other than CPR
• Expected survival <24 hours
• Diffuse alveolar hemorrhage from vasculitis
• Burns >70% total BSA
• Unwillingness to utilize low tidal ventilation
• Previous hypersensitivity or anaphylactic reaction to cisatracurium
• NM conditions preventing safe use of a NM blockade agent
• Treatment for intracranial hypertension
• Other ARDS trial enrollment

Baseline Characteristics

Cisatracurium group shown

• Demographics: Mean age 56 years, 42% female, 72% white race
• Physiologic parameters: Shock 55%, tidal volume 6.3±0.9 mL/kg, Fio2 0.8±0.2, inspiratory plateau pressure 26 cm H2O, PEEP 13 cm H2O, Pao2:Fio2 99 cm H2O
• Median time to randomization: 8.2 h
• Primary cause of lung injury (ARDS):
  • Pneumonia: 58%
  • Aspiration: 18%
  • Non-pulmonary sepsis: 14%
  • Other: 10%
• Illness severity: APACHE III score 104, SOFA score 9

Interventions

• Randomized to a group:
  • Early NM blockade - Treated with 48-hrs continuous cisatracurium with deep sedation
  • Usual care - Routine NM blockade with light sedation
• Cisatracurium: 15mg bolus of cisatracurium once, and then a continuous infusion of 37.5mg/hr
  • deeply sedated (RASS -5) within 4hrs of randomization
• Usual care: lightly sedated (RASS 0 to -1)
• All patients were ventilated using low-tidal volume ventilation with a high PEEP strategy unless medically contraindicated

Outcomes

Comparisons are early NM blockade vs. usual care. SD are excluded for brevity but appear in Table 2 on page 2005.

Primary Outcomes

In-hospital death fromany cause by day 90

42.5% vs. 42.8% (Difference -0.3, 95% CI -6.4 to 5.9; P=0.93)

Secondary Outcomes

In-hospital death by day 28

36.7% vs. 37.0% (Difference -0.3, 95% CI -6.3 to 5.7)

Days free of ventilation at day 28

9.6 vs. 9.9 days (Difference -0.3, 95% CI -1.7 to 1.0)

Days not in ICU at day 28

9.0 vs. 9.4 days (Difference -0.4, 95% CI -1.6 to 0.8)

Days not in hospital at day 28

5.7 vs. 5.9 days (Difference -0.2, 95% CI -1.1 to 0.8)

Subgroup Analysis

No subgroup interactions were significant for ARDS severity, ARDS duration, or previous NMBD.

Adverse Events

In-hospital recall of paralysis

1.8% vs. 2.0% (Difference −0.2, 95% CI −1.9 to 1.5)

ICU-acquired weakness

At Day 7: 41.0% vs. 31.3% (Difference -9.7, 95% CI -21.5 to 2.1)

At Day 28: 46.8% vs. 27.5% (Difference -19.4, 95% CI -38.2 to -0.6)

Serious adverse events

35 events vs. 22 events (P=0.09)

Barotrauma: 4.0% vs. 6.3% (P=0.12)

Serious adverse cardiovascular events: 14 events vs. 4 events (P = 0.02)

AF or SVT in ICU: 20.2% vs. 19.6% (P=0.88)

Criticisms

• A large portion of patients were excluded due to prior to exposure to NM blockade
• Prone position was by the discretion of the treating physician
• This trial was unblinded but given the intervention blinding would have been impossible
• Cross-over exposure may have led to confounding the results
  • 14% of cisatracurium patients stopped early
  • 17% of control arm received cisatracurium

Funding

Funded by the National Heart, Lung, and Blood Institute