A National Institutes of Health trial — stopped early due to futility — settles a long-standing debate in critical care medicine about whether it is better to paralyse and sedate patients in acute respiratory distress (ARD) to aid mechanical ventilation or avoid heavy sedation to improve recovery. The clinical trial conducted at dozens of North American hospitals and led by clinician-scientists at the University of Pittsburgh and University of Colorado schools of medicine.
The results were presented at the American Thoracic Society‘s Annual Meeting.
“It’s been a conundrum – on the one hand, really well-done studies have shown that temporarily paralysing the patient to improve mechanical breathing saves lives. But you can’t paralyse without heavy sedation, and studies also show heavy sedation results in worse recovery. You can’t have both – so what’s a clinician to do?” said senior author Dr Derek Angus, who holds the Mitchell P Fink endowed chair of the Pitt School of Medicine‘s department of critical care medicine. “Our trial finally settles it – light sedation with intermittent, short-term paralysis if necessary is as good as deep sedation with continuous paralysis.”
The Re-evaluation Of Systemic Early neuromuscular blockade (ROSE) trial is the first of the new National Heart, Lung, and Blood Institute’s (NHLBI) Prevention & Early Treatment of Acute Lung Injury (PETAL) Network. PETAL develops and conducts randomised controlled clinical trials to prevent or treat patients who have, or who are at risk for, acute lung injury or acute respiratory distress syndrome.
The trial network places particular emphasis on early detection by requiring every network member institute include both critical care and emergency medicine, acute care or trauma principal investigators to ensure that critical health issues are recognised and triaged as fast as possible to improve patients’ odds of recovery before they are even transferred to the intensive care unit.
From January 2016 through April 2018, 1,006 patients at 48 US and Canadian hospitals were enrolled in ROSE within hours after onset of moderate-to-severe acute respiratory distress syndrome. Half were given a 48-hour continuous neuromuscular blockade – a medication that paralyses them – along with heavy sedation because it is traumatising to be paralysed while conscious. The other half were given light sedation, and the clinician had the option of giving a small dose of neuromuscular blockade that would wear off in under an hour to ease respiratory intubation.
“This is the kind of important question that the PETAL network was designed to answer efficiently,” said Dr James Kiley, director of the division of lung diseases at the NHLBI. “These results will help practicing clinicians make decisions early on in the care of their patients with acute respiratory distress syndrome.”
The trial was needed because a French trial found in 2010 that neuromuscular blockade reduced mortality. However, in that trial all participants were heavily sedated, regardless of whether they received the neuromuscular blockade or not. In recent years, particularly in North America, clinicians have trended away from heavy sedation, which is associated with cardiovascular complications, delirium and increased difficulty weaning patients from mechanical ventilation.
In the ROSE trial, the patients who received the neuromuscular blockade and sedation developed more cardiovascular issues while in the hospital, but there were no significant differences in mortality between the two groups three, six or 12 months later, said Dr David Huang, who oversaw clinical implementation of the trial and is an associate professor of critical care and emergency medicine at Pitt’s School of Medicine.
“Due to the exceptional work of our research coordinators, the study completed enrolment ahead of schedule, a rarity in multicentre clinical trials,” said lead author Dr Marc Moss, the Roger S Mitchell professor of medicine and head of the division of pulmonary sciences and critical care medicine at the University of Colorado’s department of medicine. “Therefore, these important findings are available to health care providers sooner and should result in more rapid implementation of enhanced care for our patients.”
Angus, who also directs Pitt’s Clinical Research, Investigation, and Systems Modelling of Acute Illness (CRISMA) Centre, said the trial results make him confident when he says that avoiding paralysis and deep sedation is the best practice for most patients hospitalised with breathing problems. However, he notes that future trials will be needed to tease out whether there is a sub-population of patients with acute respiratory distress syndrome who still benefit from neuromuscular blockade.
Background: The benefits of early continuous neuromuscular blockade in patients with acute respiratory distress syndrome (ARDS) who are receiving mechanical ventilation remain unclear.
Methods: We randomly assigned patients with moderate-to-severe ARDS (defined by a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of <150 mm Hg with a positive end-expiratory pressure [PEEP] of ≥8 cm of water) to a 48-hour continuous infusion of cisatracurium with concomitant deep sedation (intervention group) or to a usual-care approach without routine neuromuscular blockade and with lighter sedation targets (control group). The same mechanical-ventilation strategies were used in both groups, including a strategy involving a high PEEP. The primary end point was in-hospital death from any cause at 90 days.
Results: The trial was stopped at the second interim analysis for futility. We enrolled 1006 patients early after the onset of moderate-to-severe ARDS (median, 7.6 hours after onset). During the first 48 hours after randomization, 488 of the 501 patients (97.4%) in the intervention group started a continuous infusion of cisatracurium (median duration of infusion, 47.8 hours; median dose, 1807 mg), and 86 of the 505 patients (17.0%) in the control group received a neuromuscular blocking agent (median dose, 38 mg). At 90 days, 213 patients (42.5%) in the intervention group and 216 (42.8%) in the control group had died before hospital discharge (between-group difference, −0.3 percentage points; 95% confidence interval, −6.4 to 5.9; P=0.93). While in the hospital, patients in the intervention group were less physically active and had more adverse cardiovascular events than patients in the control group. There were no consistent between-group differences in end points assessed at 3, 6, and 12 months.
Conclusions: Among patients with moderate-to-severe ARDS who were treated with a strategy involving a high PEEP, there was no significant difference in mortality at 90 days between patients who received an early and continuous cisatracurium infusion and those who were treated with a usual-care approach with lighter sedation targets.
The National Heart, Lung, and Blood Institute Petal Clinical Trials Network