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Design and Rationale of the Reevaluation of Systemic Early Neuromuscular Blockade Trial for Acute Respiratory Distress Syndrome.

ABSTRACT: The Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) trial is a multicenter, randomized trial designed to assess the efficacy and safety of early neuromuscular blockade in patients with moderate to severe acute respiratory distress syndrome. This document provides background for interpretation of the trial results, and highlights unique design approaches that may inform future trials of acute illness. We describe the process by which ROSE was chosen as the inaugural trial of the multidisciplinary Prevention and Early Treatment of Acute Lung Injury Network, provide the trial methodology using the Consolidated Standards of Reporting Trials framework, and discuss key design challenges and their resolution. Four key design issues proved challenging-feasibility, choice of sedation depth in the control group, impact of emphasizing early treatment on enrollment criteria and protocol execution, and choice of positive end-expiratory pressure strategy. We used literature, an iterative consensus model, and internal surveys of current practice to inform design choice. ROSE will provide definitive, Consolidated Standards of Reporting Trials adherent data on early neuromuscular blockade for future patients with acute respiratory distress syndrome. Our multidisciplinary approach to trial design may be of use to other trials of acute illness. Clinical trial registered with www.clinicaltrials.gov (NCT02509078).

SUBMITTER: Huang DT

PROVIDER: S-EPMC5291480 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Design and Rationale of the Reevaluation of Systemic Early Neuromuscular Blockade Trial for Acute Respiratory Distress Syndrome.

Huang David T DT Angus Derek C DC Moss Marc M Thompson B Taylor BT Ferguson Niall D ND Ginde Adit A Gong Michelle Ng MN Gundel Stephanie S Hayden Douglas L DL Hite R Duncan RD Hou Peter C PC Hough Catherine L CL Iwashyna Theodore J TJ Liu Kathleen D KD Talmor Daniel S DS Yealy Donald M DM

Annals of the American Thoracic Society 20170101 1

The Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) trial is a multicenter, randomized trial designed to assess the efficacy and safety of early neuromuscular blockade in patients with moderate to severe acute respiratory distress syndrome. This document provides background for interpretation of the trial results, and highlights unique design approaches that may inform future trials of acute illness. We describe the process by which ROSE was chosen as the inaugural trial of the mult ...[more]

PMID: 27779896

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Project description: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. (Funded by the National Heart, Lung, and Blood Institute; ROSE ClinicalTrials.gov number, NCT02509078.).

Project description:BackgroundPaediatric acute respiratory distress syndrome (PARDS) is a manifestation of severe, life-threatening lung injury necessitating mechanical ventilation with mortality rates ranging up to 40-50%. Neuromuscular blockade agents (NMBAs) may be considered to prevent patient self-inflicted lung injury in PARDS patients, but two trials in adults with severe ARDS yielded conflicting results. To date, randomised controlled trials (RCT) examining the effectiveness and efficacy of NMBAs for PARDS are lacking. We hypothesise that using NMBAs for 48 h in paediatric patients younger than 5 years of age with early moderate-to-severe PARDS will lead to at least a 20% reduction in cumulative respiratory morbidity score 12 months after discharge from the paediatric intensive care unit (PICU).MethodsThis is a phase IV, multicentre, randomised, double-blind, placebo-controlled trial performed in level-3 PICUs in the Netherlands. Eligible for inclusion are children younger than 5 years of age requiring invasive mechanical ventilation with positive end-expiratory pressure (PEEP) ≥ 5 cm H2O for moderate-to-severe PARDS occurring within the first 96 h of PICU admission. Patients are randomised to continuous infusion of rocuronium bromide or placebo for 48 h. The primary endpoint is the cumulative respiratory morbidity score 12 months after PICU discharge, adjusted for confounding by age, gestational age, family history of asthma and/or allergy, season in which questionnaire was filled out, day-care and parental smoking. Secondary outcomes include respiratory mechanics, oxygenation and ventilation metrics, pulmonary and systemic inflammation markers, prevalence of critical illness polyneuropathy and myopathy and metrics for patient outcome including ventilator free days at day 28, length of PICU and hospital stay, and mortality DISCUSSION: This is the first paediatric trial evaluating the effects of muscular paralysis in moderate-to-severe PARDS. The proposed study addresses a huge research gap identified by the Paediatric Acute Lung Injury Consensus Collaborative by evaluating practical needs regarding the treatment of PARDS. Paediatric critical care practitioners are inclined to use interventions such as NMBAs in the most critically ill. This liberal use must be weighed against potential side effects. The proposed study will provide much needed scientific support in the decision-making to start NMBAs in moderate-to-severe PARDS.Trial registrationClinicalTrials.gov NCT02902055 . Registered on September 15, 2016.

Project description:Background:Neuromuscular blocking agent (NMBA) has been proposed by medical guidelines for early severe acute respiratory distress syndrome (ARDS) because of its survival benefits. However, new studies have provided evidence contradicting these results. Method:A search was performed of the Pubmed, Scopus, Clinicaltrials.gov, and Virtual Health Library databases for randomized controlled trials (RCT) evaluating 28-day mortality in ARDS patients treated with NMBA within 48?h. An English language restriction was applied. Relevant data were extracted and pooled into risk ratios (RR), mean differences (MD), and corresponding 95% confidence intervals (CI) using random-effect model. Sensitivity and meta-regression analysis were performed. Results:From 2675 studies, we included five RCTs in the analysis, for a total of 1461 patients with a mean PaO2/FIO2 of 104?±?35?mmHg. The cisatracurium group had the same risk of death at 28?days (RR, 0.90; 95% CI, 0.78-1.03; I 2 =?50%, p =?0.12) and 90?days (RR, 0.81; 95% CI, 0.62-1.06; I 2 =?56%, p =?0.06) as the control group (no cisatracurium). The secondary outcomes of mechanical ventilation duration and ventilator-free days were not different between the two groups. Cisatracurium had a significantly lower risk of barotrauma than the control group with no difference in intensive care unit (ICU)-induced weakness. The PaO2/FIO2 ratio was higher in the cisatracurium group but not until 48?h. Meta-regression analysis of the baseline PaO2/FIO2 ratio, positive end-expiratory pressure (PEEP) revealed no heterogeneity. Subgroup analysis excluding the trial using high PEEP and light sedation strategy yielded an improvement in all mortality outcomes. Conclusion:NMBA improves oxygenation only after 48?h in moderate, severe ARDS patients and has a lower barotrauma risk without affecting ICU weakness. However, NMBA does not reduce ventilator-free days, duration of mechanical ventilation or, most importantly, the mortality risk regardless of the severity of ARDS.

Project description:BACKGROUND:The effects of neuromuscular blocking agents (NMBAs) on adult patients with acute respiratory distress syndrome (ARDS) remain unclear. We performed a meta-analysis of randomized controlled trials (RCTs) to evaluate its effect on mortality. METHODS:We searched the Cochrane (Central) database, Medline, Embase, the Chinese Biomedical Literature Database (SinoMed), WanFang data and ClinicalTrials from inception to June 2019, with language restriction to English and Chinese. We included published RCTs and eligible clinical trials from ClinicalTrials.gov that compared NMBAs with placebo or usual treatment in adults with ARDS. We pooled data using random-effects models. The primary outcome was mortality. The secondary outcomes were the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2/FIO2), total positive end expiratory pressure (PEEP), plateau pressure (Pplat), days free of ventilator at day 28, barotrauma and ICU-acquired weakness. RESULTS:We included 6 RCTs (n = 1557). Compared with placebo or usual treatment, NMBAs were associated with lower 21 to 28-day mortality (RR 0.72, 95% CI 0.53-0.97, I2 = 59%). NMBAs significantly improved oxygenation (Pao2:Fio2 ratios) at 48 hours (MD 27.26 mm Hg, 95% CI 1.67, 52.84, I2 = 92%) and reduced the incidence of barotrauma (RR 0.55, 95% CI 0.35, 0.85, I2 = 0). However, NMBAs had no effect on oxygenation (Pao2:Fio2 ratios) (MD 18.41 mm Hg, 95% CI -0.33, 37.14, I2 = 72%) at 24 hours. We also found NMBAs did not affect total PEEP, plateau pressure, days free of ventilation at day 28 and ICU-acquired weakness. CONCLUSIONS:In patients with moderate-to-severe ARDS, the administration of NMBAs could reduce 21 to 28-day mortality and barotrauma, and improve oxygenation at 48 hours, but have no significant effects on 90-day/ICU mortality, days free of ventilation at day 28 and the risk of ICU-acquired weakness. Further large-scale, high-quality RCTs are needed to confirm our findings. Registration: PROSPERO (ID: CRD 42019139656).

Project description:ObjectiveTo determine whether neuromuscular blocking agents (NMBAs) can decrease the mortality of patients with acute respiratory distress syndrome (ARDS) and improve their clinical outcomes.DesignSystematic review, meta-analysis and meta-regression.Data sourcesPubMed, Embase, Cochrane Library, Web of Science and ClinicalTrials.gov.MethodsRandomised controlled trials (RCTs) comparing the treatment effect of NMBAs with that of placebo (or traditional treatment) in patients with ARDS were carefully selected. The primary outcome was 90-day mortality. The secondary outcomes were 21-28 days mortality, NMBA-related complications (barotrauma, pneumothorax and intensive care unit (ICU)-acquired muscle weakness), days free of ventilation and days not in the ICU by day 28, Medical Research Council score, Acute Physiology and Chronic Health Evaluation II score and arterial oxygen tension (PaO2)/fractional inspired oxygen (FiO2) (at 48 hours and 72 hours). Random-effects meta-regression was used to explore models involving potential moderators. Trial sequential analysis was performed to estimate the cumulative effect on mortality across RCTs.ResultsNMBAs were not associated with reduced 90-day mortality (risk ratio (RR) 0.85; 95% CI 0.66 to 1.09; p=0.20). However, they decreased the 21-28 days mortality (RR 0.71; 95% CI 0.53 to 0.96; p=0.02) and the rates of pneumothorax (RR 0.46; 95% CI 0.28 to 0.77; p=0.003) and barotrauma (RR 0.56; 95% CI 0.37 to 0.86; p=0.008). In addition, NMBAs increased PaO2/FiO2 at 48 hours (mean difference (MD) 18.91; 95% CI 4.29 to 33.53; p=0.01) and 72 hours (MD 12.27; 95% CI 4.65 to 19.89; p=0.002). Meta-regression revealed an association between sample size (p=0.042) and short-term mortality. Publication year (p=0.050), sedation strategy (p=0.047) and sample size (p=0.046) were independently associated with PaO2/FiO2 at 48 hours.ConclusionsIn summary, the results suggested that use of NMBAs might reduce 21-28 days mortality, NMBA-related complications and oxygenation. However, NMBAs did not reduce the 90-day mortality of patients with ARDS, which contradicts a previous meta-analysis.Prospero registration numberCRD42019139440.

Project description:ObjectivesSystemic endothelial activation may contribute to sepsis-associated organ injury, including acute respiratory distress syndrome. We hypothesized that children with extrapulmonary sepsis with versus without acute respiratory distress syndrome would have plasma biomarkers indicative of increased endothelial activation and that persistent biomarker changes would be associated with poor outcome.DesignObservational cohort.SettingAcademic PICU.PatientsPatients less than 18 years old with sepsis from extrapulmonary infection with (n = 46) or without (n = 54) acute respiratory distress syndrome and noninfected controls (n = 19).InterventionsNone.Measurements and main resultsEndothelial (angiopoietin-1, angiopoietin-2, tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, vascular endothelial growth factor, soluble fms-like tyrosine kinase, von Willebrand factor, E-selectin, intercellular adhesion molecule, vascular cell adhesion molecule, thrombomodulin) and inflammatory biomarkers (C-reactive protein, interleukin-6, and interleukin-8) were measured from peripheral plasma collected within 3 days (time 1) of sepsis recognition and at 3-6 days (time 2) and 7-14 days (time 3). Time 1 biomarkers and longitudinal measurements were compared for sepsis patients with versus without acute respiratory distress syndrome and in relation to complicated course, defined as greater than or equal to two organ dysfunctions at day 7 or death by day 28. Angiopoietin-2, angiopoietin-2/angiopoietin-1 ratio, tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, vascular endothelial growth factor, von Willebrand factor, E-selectin, intercellular adhesion molecule, vascular cell adhesion molecule, thrombomodulin, endocan, C-reactive protein, interleukin-6, and interleukin-8 were different between sepsis and noninfected control patients at time 1. Among patients with sepsis, those with acute respiratory distress syndrome had higher angiopoietin-2/angiopoietin-1 ratio, vascular endothelial growth factor, vascular cell adhesion molecule, thrombomodulin, endocan, interleukin-6, and interleukin-8 than those without acute respiratory distress syndrome (all p < 0.003). Angiopoietin-2 and angiopoietin-2/angiopoietin-1 ratio remained higher in sepsis with versus without acute respiratory distress syndrome after multivariable analyses. Time 1 measures of angiopoietin-2, angiopoietin-2/-1 ratio, von Willebrand factor, and endocan were indicative of complicated course in all sepsis patients (all area under the receiver operating curve ≥ 0.80). In sepsis without acute respiratory distress syndrome, soluble fms-like tyrosine kinase decreased more quickly and von Willebrand factor and thrombomodulin decreased more slowly in those with complicated course.ConclusionsChildren with extrapulmonary sepsis with acute respiratory distress syndrome had plasma biomarkers indicative of greater systemic endothelial activation than those without acute respiratory distress syndrome. Several endothelial biomarkers measured near sepsis recognition were associated with complicated course, whereas longitudinal biomarker changes yielded prognostic information only in those without sepsis-associated acute respiratory distress syndrome.

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Design and Rationale of the Reevaluation of Systemic Early Neuromuscular Blockade Trial for Acute Respiratory Distress Syndrome.

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Design and Rationale of the Reevaluation of Systemic Early Neuromuscular Blockade Trial for Acute Respiratory Distress Syndrome.

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