By Drayton Hammond, PharmD, MBA, BCPS, BCCCP

Clinical Pharmacy Specialist, Adult Critical Care, Rush University Medical Center, Chicago

Dr. Hammond reports no financial relationships relevant to this field of study.

SYNOPSIS: When the early use of a continuous infusion of cisatracurium was compared to contemporary supportive care for moderate-to-severe ARDS, including a light sedation target, high positive-end expiratory pressure, and conservative fluid strategy, there was no difference in 90-day mortality. Patients in the early neuromuscular blockade group more frequently experienced a severe cardiovascular event and ICU-acquired weakness by day 28.

SOURCE: National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Moss M, Huang DT, et al. Early neuromuscular blockade in the acute respiratory distress syndrome. N Engl J Med 2019;380:1997-2008.

Acute respiratory distress syndrome (ARDS) has a spectrum of severity, with the severe form being least common but associated with the greatest mortality.^1,2 Prior to publication of the Re-evaluation of Systemic Early Neuromuscular Blockade (ROSE) trial,³ the ARDS et Curarisation Systematique (ACURASYS) trial was the largest multicenter study to investigate the safety and efficacy of neuromuscular blockade in moderate-to-severe ARDS.⁴ Authors of the ACURASYS trial found that early administration of neuromuscular blockade improved adjusted 90-day survival and increased ventilator-free days without increasing muscle weakness.⁴ Over the past decade, however, the supportive care provided to patients with ARDS has become exceedingly advanced.² Researchers performed the ROSE trial to evaluate the effects of early neuromuscular blockade in the setting of contemporary supportive management strategies for severe ARDS.³

Investigators conducted a randomized, open-label trial in 49 medical centers in the United States.³ Mechanically ventilated patients with a PaO₂:FiO₂ < 150 and positive end expiratory pressure (PEEP) ≥ 8 cm H₂O who met other criteria for moderate-to-severe ARDS were randomized within a median of 7.6 hours to a 48-hour infusion of cisatracurium 37.5 mg/hour with concomitant deep target sedation or usual care without routine neuromuscular blockade and light target sedation. A high PEEP strategy was employed unless patient clinical status dictated otherwise. Prone positioning and open-label cisatracurium 20 mg bolus injections were allowed per physician discretion in both groups.

Almost all (97.4%) patients in the intervention group received cisatracurium infusions during the 48-hour intervention period, and one-sixth (17.0%) of patients in the usual care group received cisatracurium boluses (median dose, 38 mg). Patients in the intervention group had lower PEEP requirements on day 1 and lower minute ventilation and FiO₂ requirements on days 1 and 2; however, the PaO₂:FiO₂ was similar between days 1 and 7. Patients maintained an approximately net even fluid balance throughout the first 72 hours of interventions. Only 18% of patients received any rescue therapy (i.e., prone positioning, inhaled epoprostenol or nitric oxide, recruitment maneuvers, or extracorporeal membrane oxygenation). The trial enrollment was stopped early because no difference in 90-day in-hospital mortality was observed between the intervention and usual care groups (42.5% vs. 42.8%, 95% confidence interval [CI], -6.4 to 5.9, P = 0.93). The finding of similar mortality remained after treatment-by-subgroup interactions were considered, including ARDS severity, ARDS duration, and previous neuromuscular blockade use. Days free from mechanical ventilation, ICU care, and hospital care were similar between groups. More than 98% of patients who received cisatracurium did not recall paralysis. The Medical Research Council scale for muscle strength scores were similar between the intervention and usual care groups at days 7 and 28, although more patients in the intervention group experienced ICU-acquired weakness on day 28 (46.8% vs. 27.5%, between-group difference 95% CI, -38.2 to -0.6). Serious cardiovascular events (including hypotension and bradycardia) occurred more frequently in the intervention group (14 events vs. 4 events, P = 0.02).

COMMENTARY

When the early use of continuous infusion cisatracurium was compared to contemporary supportive care for moderate-to-severe ARDS, including a light target sedation, more specialized volume-control ventilator modes, higher PEEP, and conservative fluid strategy, there was no difference in 90-day mortality. Compared to patients enrolled in the ACURASYS trial, ROSE trial subjects were more critically ill, could receive intermittent doses of a neuromuscular blocking agent, less frequently developed a pneumothorax, and were randomized to a treatment group approximately 10 hours sooner. These differences may have decreased the likelihood of detecting a mortality benefit with continuous infusion neuromuscular blockade. Notably, only 33-55% of patients in the usual care group received light sedation, and at least 17% received open-label cisatracurium bolus doses, which suggests modifications from the light sedation and no neuromuscular blockade strategy may be warranted in many adult patients with moderate-to-severe ARDS.

For those patients in whom neuro-muscular blockade is provided, the depth of sedation necessary to preclude recall of paralysis appears to increase the risk of severe cardiovascular events (e.g., hypotension, bradycardia), which occurred more frequently in the intervention group. Additionally, ICU-acquired weakness was more common at day 28 in those who received neuromuscular blockade, although the impact of this negative effect on long-term, functional status did not appear to be significant based on similar between-group findings in neuromuscular assessments and activities of daily living at three, six, and 12 months. Early use of continuous infusion neuromuscular blockade is unlikely to provide meaningful benefits in most patients with moderate-to-severe ARDS who can be managed according to high-quality, evidence-based usual care. Its use as salvage therapy still may be considered.

REFERENCES

1. Villar J, Blanco J, Añón JM, et al; ALIEN Network. The ALIEN study: Incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation. Intensive Care Med 2011;37:1932-1941.
2. Bellani G, Laffey JG, Pham T, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA 2016;315:788-800.
3. National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Moss M, Huang DT, et al. Early neuromuscular blockade in the acute respiratory distress syndrome. N Engl J Med 2019;380:1997-2008.
4. Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010;363:1107-1116.