Neuromuscular blockade has been in routine practice in anesthesia and critical care for more than half a century. Claude Bernard, one of the pioneer researchers on neuromuscular blocking agents, conducted groundbreaking animal experiments on the effect of curare in the 19th century. He watched with interest and intrigue as curare administration instantly abolished convulsions arising from strychnine poisoning. By 1857, he had established the neuromuscular junction as the site of action of curare (1). Early preparations of curare were crude extracts from Chondrodendron tomentosum, a woody climbing plant native to the rainforests of South America. The first commercial preparation of curare, branded Intocostrin, was introduced in 1938. On 23rd January 1942, Harold Griffith, an anesthetist, and his resident, Enid Johnson, used curare in a young man who underwent appendicectomy, heralding the modern-day use of neuromuscular blockade. In the early days, they confined curare administration mainly towards the end of the surgery; within a minute, the abdomen turned “soft as dough”, enabling peritoneal closure with effortless ease (2).
The administration of neuromuscular blocking agents in the ICU took it roots from contemporary anesthetic practice. Widespread, often indiscriminate use followed, and by the early 1980s, most ventilated ICU patients routinely received neuromuscular blockade. Although generally considered safe, especially with the introduction of several newer agents with fewer adverse effects, concerns arose from persisting neuromuscular weakness after prolonged administration (3). Thomas Petty, who, along with his colleagues, first reported acute respiratory distress syndrome (ARDS), lamented in an editorial in the Chest journal of August 1998: “What I see these days are paralyzed, sedated patients, lying without motion, appearing to be dead, except for the monitors that tell me otherwise. Why this syndrome of sedation and paralysis has emerged baffles me, because this was not the case in the past”(4).
Background to the ACURASYS trial
Neuromuscular blocking agents had been widely used in mechanically ventilated patients with ARDS to enable patient-ventilator synchrony and improved gas exchange. A four-center randomized controlled trial (RCT) had previously been conducted to evaluate the impact of 48 hours of neuromuscular blockade with cisatracurium on the gas exchange over a 5-day period among patients with ARDS. The control group received conventional care, without neuromuscular blockade. Both groups of patients were ventilated on the assist-control mode with a tidal volume 6–8 m/kg ideal body weight. Patients who received neuromuscular blockade with cisatracurium revealed significantly higher PaO2/FiO2 ratios compared to the conventional arm after 48 hours, 96 hours, and 5 days after randomization. The improved PaO2/FiO2ratio enabled a reduction of the PEEP level among patients who received neuromuscular blockade. A trend towards improved ICU survival was also noted in patients who received continuous neuromuscular blockade for 48 hours. However, this RCT was not powered to evaluate clinical outcomes.
Considering the relative lack of robust evidence regarding the beneficial impact of neuromuscular blockade on clinical outcomes among patients with severe ARDS from available studies, the ARDS et Curarisation Systematique(ACURASYS) trial investigators embarked upon a large RCT using cisatracurium infusion early in the course of the disease (5).
Population and design
The study was conducted during a 2-year period between 2006–2008 across 20 ICUs in France. Patients with severe ARDS, with a PaO2/FiO2 ratio of <150 mm Hg, while being ventilated with a tidal volume of 6–8 ml/kg predicted body weight and a PEEP level ≥5 cm H2O were included within the first 48 hours of meeting the above criteria. Those suspected to have cardiogenic pulmonary edema were excluded. Patients were randomly assigned to receive a continuous infusion of cisatracurium besylate or a matching placebo for 48 hours.
Sample size calculation
The authors calculated the sample size based on a 90-day mortality of 50% based on previous studies of ARDS. They assumed a 15% absolute reduction in mortality with the use of cisatracurium infusion. A sample size of 340 patients was calculated, providing an 80% statistical power with a two-sided alpha value of 0.05.
Intervention and control groups
After administration of sedative agents to attain a target Ramsay sedation score of 6 (no response to glabellar tap), and adjustment of ventilator settings, a rapid infusion of cisatracurium besylate, 15 mg, followed by a continuous infusion of 37.5 mg/hour was commenced and maintained for 48 hours. In the control group, identical volumes of placebo were administered.
Management of mechanical ventilation
A tidal volume of 6–8 ml/kg of predicted body weight was employed, with titration of the PEEP level based on the ARDSNet table. A plateau pressure of ≤32 cm H2O was targeted, aiming for a SaO2 of 88–95%. A dose of 20 mg of cisatracurium was allowed as a rescue measure to both groups of patients if the plateau pressure remained >32 cm H2O, despite adequate use of sedative agents.
The study included 340 patients – 178 were randomized to receive cisatracurium and 162 to placebo. The time from ARDS onset to study inclusion was 16 (6–29) hours in the study cohort and was similar between the two groups. The duration of mechanical ventilation before inclusion was also similar between groups. However, the mean PaO2/FiO2 ratio was significantly lower in the cisatracurium group at study onset (106 vs. 115 mm Hg).
The primary outcome: 90-day mortality
The unadjusted 90-day mortality was lower in the cisatracurium 31.6% (95% CI, 25.2 to 38.8), compared to the placebo group 40.7% (95% CI, 33.5 to 48.4), but fell short of statistical significance (P=0.08). After adjustment for the baseline PaO2/FiO2 ratio, the SAPS II score, and plateau pressure, the 90-day mortality was lower with cisatracurium infusion (hazard ratio: 0.68; 95% CI, 0.48 to 0.98; P=0.04). Improved 90-day survival among patients who received cisatracurium was confined to those who were severely hypoxic, with a PaO2/FiO2 ratio of <120 mm Hg.
The ICU and hospital mortality were lower with cisatracurium, but the difference was not significantly different between groups. The 28-day mortality was also lower in the cisatracurium group (p=0.05). The cisatracurium group had significantly more ventilator-free days at 28 and 90 days compared to the placebo group. The probability of weaning from mechanical ventilation by 90 days was significantly greater in the cisatracurium group (adjusted hazard ratio: 1.41; 95% CI, 1.08–1.83; p=0.01). Cisatracurium-treated patients also experienced more organ failure-free days at 28 days (15.8±9.9 days, vs. 12.2±11.1 days; p=0.01). ICU-free days at day 90 were also significantly higher in the cisatracurium group. Among the adverse events, pneumothorax occurred more often in the placebo group (11.7 vs. 4%). The incidence of ICU-acquired weakness did not differ between groups on day 28 and at ICU discharge. On day 7, the cisatracurium group experienced a higher PaO2/FiO2 ratio and a lower PaCO2. Rescue interventions, including prone positioning, nitric oxide, or almitrine use either solely or in combination, were similar in both groups.
The ACURASYS trial showed that continuous neuromuscular blockade for 48 hours in early ARDS resulted in improved survival, reduced the duration of mechanical ventilation, and ICU stay.
Strengths of the study
At the time of its publication, the ACURASYS trial was the largest RCT that evaluated the efficacy of continuous neuromuscular blockade among patients with ARDS. The strong points of the study included its double-blinded and multicentric design, although clinicians may have been able to identify patients who received neuromuscular blockade. A protocolized ventilation strategy was followed, and analysis was by intention to treat. Patients were included from 20 ICUs that followed international standard of care, thus enhancing the external validity of the study. Although persisting neuromuscular weakness is considered to be a significant adverse effect with neuromuscular blockade, the ACURASYS trial did not identify this as a significant disadvantage.
The sample size was calculated based on an expected 90-day mortality of 50% based on previous studies. However, the mortality in the placebo group was lower than expected (40.7%), thus rendering the study underpowered. According to the authors themselves, a sample size of 885 patients was required for 80% power and a two-sided alpha level of 0.05 (in contrast to the 339 patients included in the final analysis). The question remained whether neuromuscular blockade would be beneficial to patients with early, less severe, ARDS. This is especially relevant considering that on post-hoc analysis, improved survival was confined to the most severely hypoxic patients with a PaO2/FiO2 ratio of <120 mm Hg. According to the trial protocol published earlier, the primary outcome was “Reduction of the mortality rate of ARDS patients at d-90”; however, the study reported the primary outcome as the 90-day mortality based on adjusted analysis using the Cox regression model. A substantial number of patients were excluded (986/1325), which may limit the generalizability of the study. Whether the beneficial effects observed with cisatracurium would apply to other muscle relaxants also remained unanswered.
A decade later ‐ the ROSE trial
Although the results of the ACURASYS trial supported the use of early neuromuscular blockade in mechanically ventilated patients with severe ARDS, it did not result in a widespread change of practice, with many guidelines continuing to proffer a weak recommendation (6). The ROSE trial followed nearly a decade later, conducted by The National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, and was published in 2019 (7). The study aimed to compare the safety and efficacy of neuromuscular blockade combined with deep sedation with usual care, using lighter levels of sedation among patients with moderate to severe ARDS. The study included patients with moderate to severe ARDS with a PaO2/FiO2 ratio of <150 mm Hg and a PEEP level of ≥8 cm H2O, across 48 ICUs in the US. They randomized patients to receive a 48-hour continuous infusion of cisatracurium with deep sedation or a usual care strategy with lighter levels of sedation. Light sedation was titrated based on pre-defined targets. Patients in both groups were treated with a low-tidal volume, high-PEEP strategy. Open label cisatracurium in 20 mg boluses was allowed in both groups based on pre-defined criteria.
The trial was stopped for futility after enrolment of 1006 patients. During the 48-hour period after randomization, 97.4% of patients (488/501) in the cisatracurium group received the infusion, while 17% (86/505) of patients in the light sedation group received a neuromuscular blocking agent. Hospital mortality at 90 days, the primary endpoint, was similar in both groups (cisatracurium infusion vs. control, 42.5% vs. 42.8%, p=0.93). The secondary endpoints, including hospital mortality at 28 days, ventilation-free days, and the number of days of ICU and hospital stay were not significantly different between the two groups. ICU-acquired weakness was marginally higher with cisatracurium infusion, although the difference was not statistically significant.
These results contrasted with the findings of the ACURASYS trial which had revealed improved survival at 90 days with atracurium infusion compared with placebo. However, there were differences between the two trials that may have led to the disparate findings. Unlike ACURASYS, the ROSE trial was unblinded, which may have led to bias and confounded the findings. The ACURASYS trial employed deep sedation in both groups, unlike the ROSE trial which used light sedation in the control group. The PEEP levels used were higher in the ROSE trial. In the ROSE trial, a large number of patients were excluded (3840/4848) during the initial screening; 655 among them were already on a cisatracurium infusion. The ROSE trial was stopped prematurely and hence, resulted in an underpowered trial. No pre-defined criteria were set for prone ventilation in both trials; however, far fewer patients were ventilated in the prone position in the ROSE trial (16% vs. 50%).
Neuromuscular blockade permeated into the ICU following its introduction and experience in anesthetic practice. By the 1980s, it was employed fairly routinely among critically ill patients on mechanical ventilation. However, there was growing concern regarding adverse effects from long-term use of muscle relaxants, including persisting neuromuscular weakness, deep vein thrombosis, and pressure ulcers. In patients with severe ARDS, the putative benefits of neuromuscular blockade were recognized from early studies, including improved patient-ventilator synchrony, optimization of PEEP, and improved gas exchange. A previous underpowered RCT had also revealed a trend towards improved survival with the short-term use of neuromuscular blockade in ARDS. Against this background, the ACURASYS trial investigators evaluated the impact of a 48-hour infusion of cisatracurium in patients with severe ARDS with a PaO2/FiO2 ratio of <150 mm Hg. The authors noted a reduction in the 90-day mortality with the use of cisatracurium infusion for the first 48 hours after randomization. The survival benefit was confined to patients with a PaO2/FiO2 ratio of <120 mm Hg, suggesting that patients with severe hypoxia are the most likely to benefit with neuromuscular blockade. Besides, cisatracurium use was associated with reduced organ failure, a higher likelihood of weaning, less time on mechanical ventilation and in the ICU. The incidence of neuromuscular weakness was no higher compared to the placebo group. Thus, the ACURASYS trial strongly suggested benefits with a 48-hour duration of neuromuscular blockade in severe ARDS. Although the subsequent ROSE trial did not corroborate these findings, the ACURASYS trial triggered a change of practice in mechanically ventilated patients with severe ARDS.
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