Neuromuscular blockade in patients with ARDS: a rapid practice guideline.

The aim of this Intensive Care Medicine Rapid Practice Guideline (ICM-RPG) is to formulate an evidence-based guidance for the use of neuromuscular blocking agents (NMBA) in adults with acute respiratory distress syndrome (ARDS). The panel comprised 20 international clinical experts from 12 countries, and 2 patient representatives. We adhered to the methodology for trustworthy clinical practice guidelines and followed a strict conflict of interest policy. We convened panelists through teleconferences and web-based discussions. Guideline experts from the guidelines in intensive care, development, and evaluation Group provided methodological support. Two content experts provided input and shared their expertise with the panel but did not participate in drafting the final recommendations. We followed the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the certainty of evidence and grade recommendations and suggestions. We used the evidence to decision framework to generate recommendations. The panel provided input on guideline implementation and monitoring, and suggested future research priorities. The overall certainty in the evidence was low. The ICM-RPG panel issued one recommendation and two suggestions regarding the use of NMBAs in adults with ARDS. Current evidence does not support the early routine use of an NMBA infusion in adults with ARDS of any severity. It favours avoiding a continuous infusion of NMBA for patients who are ventilated using a lighter sedation strategy. However, for patients who require deep sedation to facilitate lung protective ventilation or prone positioning, and require neuromuscular blockade, an infusion of an NMBA for 48 h is a reasonable option.

Frequency of Screening and SBT Technique Trial - North American Weaning Collaboration (FAST-NAWC): a protocol for a multicenter, factorial randomized trial.

RATIONALE: In critically ill patients receiving invasive mechanical ventilation (MV), research supports the use of daily screening to identify patients who are ready to undergo a spontaneous breathing trial (SBT) followed by conduct of an SBT. However, once daily (OD) screening is poorly aligned with the continuous care provided in most intensive care units (ICUs) and the best SBT technique for clinicians to use remains controversial. OBJECTIVES: To identify the optimal screening frequency and SBT technique to wean critically ill adults in the ICU. METHODS: We aim to conduct a multicenter, factorial design randomized controlled trial with concealed allocation, comparing the effect of both screening frequency (once versus at least twice daily [ALTD]) and SBT technique (Pressure Support [PS] + Positive End-Expiratory Pressure [PEEP] vs T-piece) on the time to successful extubation (primary outcome) in 760 critically ill adults who are invasively ventilated for at least 24 h in 20 North American ICUs. In the OD arm, respiratory therapists (RTs) will screen study patients between 06:00 and 08:00 h. In the ALTD arm, patients will be screened at least twice daily between 06:00 and 08:00 h and between 13:00 and 15:00 h with additional screens permitted at the clinician's discretion. When the SBT screen is passed, an SBT will be conducted using the assigned technique (PS + PEEP or T-piece). We will follow patients until successful extubation, death, ICU discharge, or until day 60 after randomization. We will contact patients or their surrogates six months after randomization to assess health-related quality of life and functional status. RELEVANCE: The around-the-clock availability of RTs in North American ICUs presents an important opportunity to identify the optimal SBT screening frequency and SBT technique to minimize patients' exposure to invasive ventilation and ventilator-related complications. TRIAL REGISTRATION: Clinical Trials.gov, NCT02399267 . Registered on Nov 21, 2016 first registered.

Protocol adherence for continuously titrated interventions in randomized trials: an overview of the current methodology and case study.

BACKGROUND: The standard definition for protocol adherence is the proportion of all scheduled doses that are delivered. In clinical research, this definition has several limitations when evaluating protocol adherence in trials that study interventions requiring continuous titration. DISCUSSION: Building upon a specific case study, we analyzed a recent trial of a continuously titrated intervention to assess the impact of different definitions of protocol deviations on the interpretation of protocol adherence. The OVATION pilot trial was an open-label randomized controlled trial of higher (75-80 mmHg) versus lower (60-65 mmHg) mean arterial pressure (MAP) targets for vasopressor therapy in shock. In this trial, potential protocol deviations were defined as MAP values outside the targeted range for >4 consecutive hours during vasopressor therapy without synchronous and consistent adjustments of vasopressor doses. An adjudication committee reviewed each potential deviation to determine if it was clinically-justified or not. There are four reasons for this contextual measurement and reporting of protocol adherence. First, between-arm separation is a robust measure of adherence to complex protocols. Second, adherence assessed by protocol deviations varies in function of the definition of deviations and the frequency of measurements. Third, distinguishing clinically-justified vs. not clinically-justified protocol deviations acknowledges clinically sensible bedside decision-making and offers a clear terminology before the trial begins. Finally, multiple metrics exist to report protocol deviations, which provides different information but complementary information on protocol adherence. CONCLUSIONS: In trials of interventions requiring continuous titration, metrics used for defining protocol deviations have a considerable impact on the interpretation of protocol adherence. Definitions for protocol deviations should be prespecified and correlated with between-arm separation, if it can be measured.

Is there a role for physician involvement in introducing research to surrogate decision makers in the intensive care unit? (The Approach trial: a pilot mixed methods study).

PURPOSE: To assess the feasibility of conducting a randomized trial comparing two strategies [physician (MD) vs. non-physician (non-MD)] for approaching substitute decision makers (SDMs) for research and to evaluate SDMs' experiences in being approached for consent. METHODS: A pilot mixed methods study of first encounters with SDMs. RESULTS: Of 137 SDMs (162 eligibility events), 67 and 70 were randomized to MD and non-MD introductions, respectively. Eighty SDMs (98 events) provided consent and 21 SDMs (24 events) declined consent for studies, including 2 SDMs who provided and declined consent. We identified few missed introductions [4/52 (7.7 %)] and protocol violations [6/117 (5.1 %)], high comfort, satisfaction and acceptance scores and similar consent rates in both arms. SDMs provided consent significantly more often when a patient update was provided in the MD arm. Most SDMs (85.7 %) felt that physician involvement was inconsequential and preferred physician time to be dedicated to patient care; however, SDM experiences were closely related to their recall of being approached and recall was poor. SDMs highlighted 7 themes of importance to them in research surrogate decision-making. CONCLUSION: SDMs prioritized the personal attributes of the person approaching them over professional designation and preferred physician time to be dedicated to patient care. A mixed methods design evaluated intervention fidelity and provided the rationale for not proceeding to a larger trial, despite achieving all feasibility metrics in the pilot trial. TRIAL REGISTRATION NUMBER: NCT01232621.

Attitudes and views of the general public towards research participation.

BACKGROUND: While the challenges of recruitment into clinical trials are well described, little is known about the public's perceptions towards research. AIMS: We sought to describe the attitudes, beliefs and knowledge of the public towards research and research participation, focusing on clinical trials, contrast these attributes among individuals with different relationships with the healthcare system and to identify predictors of willingness to participate. METHODS: We conducted a self-administered cross-sectional survey of patients and their significant others in two clinics and two intensive care unit waiting rooms and in three public venues. RESULTS: We analysed responses from 417 respondents (102 and 105 in dialysis and oncology clinics, and 106 in intensive care unit (ICU) waiting rooms, 104 in public locations). While most (68.3%) respondents favoured the use of humans in clinical trials, 53% felt that trial participants always or almost always receive the best quality of care, only 30.4% had participated in clinical research. Approximately 70% felt that subjects are always advised of the risks and benefits of participation, and 30% expressed ambiguity regarding whether participants are informed of their involvement. Oncology and dialysis respondents were the most and least informed regarding research methods and ethics. The perceived risks and benefits associated with clinical circumstances influence research participation decisions and vary with healthcare experiences. We identified six predictors of willingness to participate. CONCLUSION: Attitudes of the public towards research participation are beleaguered by misconceptions. Stakeholders in clinical research must educate the general public regarding research methods and ethics.

Pharmacologic therapies for adults with acute lung injury and acute respiratory distress syndrome.

BACKGROUND: Multiple pharmacologic treatments have been studied for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). OBJECTIVES: Our objective was to determine the effects of pharmacologic treatments on clinical outcomes in adults with ALI or ARDS. SEARCH STRATEGY: We searched OVID versions of CENTRAL (The Cochrane Library Issue 3, 2003), MEDLINE (1966 to week 2, January 2004), EMBASE (1980 to week 4, 2004), CINAHL (1982 to week 2, January 2004), and HEALTHSTAR (1995 to December 2003); proceedings from four conferences (1994 to 2003); and bibliographies of review articles and included studies. SELECTION CRITERIA: Randomized controlled trials of pharmacologic treatments compared to no therapy or placebo for established ALI or ARDS in adults admitted to an intensive care unit, with measurement of early mortality (primary outcome), late mortality, duration of mechanical ventilation, ventilator-free days to day 28, or adverse events. We excluded trials of nitric oxide, partial liquid ventilation, fluid and nutritional interventions, oxygen, and trials in other populations reporting outcomes in subgroups of patients with ALI or ARDS. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened titles and abstracts, rated studies for inclusion, extracted data and assessed methodologic quality of included studies. Disagreements were resolved by consensus in consultation with a third reviewer. For each pharmacologic therapy, we quantitatively pooled the results of studies using random effects models where permitted by the available data. We contacted study authors when clarification of the primary outcome was required. MAIN RESULTS: Thirty three trials randomizing 3272 patients met our inclusion criteria. Pooling of results showed no effect on early mortality of prostaglandin E1 (seven trials randomizing 697 patients; relative risk [RR] 0.95, 95% confidence interval [CI] 0.77 to 1.17), N-acetylcysteine (five trials randomizing 239 patients; RR 0.89, 95% CI 0.65 to 1.21), early high-dose corticosteroids (two trials randomizing 187 patients; RR 1.12, 95% CI 0.72 to 1.74), or surfactant (nine trials randomizing 1441 patients; RR 0.93, 95% CI 0.77 to 1.12). Two interventions were beneficial in single small trials; corticosteroids given for late phase ARDS reduced hospital mortality (24 patients; RR 0.20, 95% CI 0.05 to 0.81), and pentoxifylline reduced one-month mortality (RR 0.67, 95% CI 0.47 to 0.95) in 30 patients with metastatic cancer and ARDS. Individual trials of nine additional interventions failed to show a beneficial effect on prespecified outcomes. REVIEWERS' CONCLUSIONS: Effective pharmacotherapy for ALI and ARDS is extremely limited, with insufficient evidence to support any specific intervention.

Noninvasive positive pressure ventilation as a weaning strategy for intubated adults with respiratory failure.

BACKGROUND: Noninvasive positive pressure ventilation (NPPV) provides ventilatory support without the need for an invasive airway. Interest has emerged in using NPPV to facilitate earlier removal of the endotracheal tube and decrease complications associated with prolonged intubation. OBJECTIVES: To summarize the evidence comparing NPPV and invasive positive pressure ventilation (IPPV) weaning on clinical outcomes in intubated adults with respiratory failure. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, issue 2, 2003), MEDLINE (January 1966 to July 2003) and EMBASE (January 1980 to July 2003) for randomized controlled trials comparing NPPV and IPPV weaning. Additional data sources included personal files, conference proceedings and author contact. SELECTION CRITERIA: Randomized and quasi-randomized studies comparing early extubation with immediate application of NPPV to IPPV weaning in intubated adults with respiratory failure. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and abstracted data according to prespecified criteria. Sensitivity and subgroup analyses were planned to assess the impact of (i) excluding quasi-randomized trials and (ii) the etiology of respiratory failure on outcomes. MAIN RESULTS: We identified eleven trials, of which five were included, involving 171 participants with predominantly chronic obstructive pulmonary disease. Overall, the included studies were of moderate to good quality. Compared to the IPPV strategy, the NPPV strategy decreased mortality (RR 0.41, 95% CI 0.22 to 0.76), the incidence of ventilator associated pneumonia (RR 0.28, 95% CI 0.09 to 0.85), intensive care unit length of stay (WMD -6.88 days, 95% CI -12.60 to -1.15), hospital length of stay (WMD -7.33 days, 95%CI -14.05 to -0.61), total duration of mechanical support (WMD -7.33 days, 95% CI -11.45 to -3.22) and the duration of endotracheal mechanical ventilation (WMD -6.79 days, 95% CI -11.70 to -1.87). There was no effect of NPPV on weaning failures or the duration of mechanical support related to weaning and insufficient data to pool adverse events or quality of life. Excluding a single quasi-randomized trial maintained the significant reduction in mortality and ventilator associated pneumonia. Subgroup analyses suggested that the mortality benefit of the NPPV approach is greater in patients with chronic obstructive pulmonary disease. REVIEWER'S CONCLUSIONS: Summary estimates from five studies of moderate to good quality demonstrated a consistent positive effect on overall mortality. At present, use of NPPV to facilitate weaning in mechanically ventilated patients, with predominantly chronic obstructive lung disease, is associated with promising, although insufficient, evidence of net clinical benefit.

Incidence of clinically unsuspected pulmonary embolism in mechanically ventilated lung transplant recipients.

BACKGROUND: The incidence of pulmonary embolism (PE) in lung transplant recipients has not been well established. The purpose of this study was to describe the incidence of clinically unsuspected PE in a cohort of lung transplant recipients requiring mechanical ventilatory support. These patients underwent surgical lung biopsy (SLBx) for progressive deterioration in the absence of a specific diagnosis. METHODS: We retrospectively reviewed all SLBx pathology reports for mechanically ventilated lung transplant recipients with clinical deterioration, progressive radiographic abnormalities, or both at any time after transplantation. Our objective was to determine the incidence of clinically unsuspected PE in this patient population during an 11-year period. RESULTS: Clinically unsuspected PE was identified in 8 (19.5%) of 41 mechanically ventilated lung transplant recipients after a median of 20 days (interquartile range: 16.3, 148.8 days) after transplantation. There was a tendency for clinically unsuspected PE to occur in the early postoperative period, with the majority of events (75%) occurring within 14 weeks of transplantation. Pulmonary infarction occurred in 37.5% of cases and occurred uniformly during the postoperative period. The finding of pulmonary emboli on SLBx lead to confirmatory investigations in five (62.5%) of eight patients and changed management in seven (87.5%) of eight patients. CONCLUSIONS: A high index of suspicion and reliance on ancillary diagnostic testing may be insufficient to establish the diagnosis of postoperative pulmonary emboli. PE is an underappreciated complication contributing to respiratory failure in the early postoperative period in lung transplant recipients, warranting identification of putative risk factors and consideration for prophylaxis.

Diagnostic properties of transbronchial biopsy in lung transplant recipients who require mechanical ventilation.

INTRODUCTION: Bronchoscopy with transbronchial biopsy (TBBx) and bronchoalveolar lavage is useful and safe for diagnosing acute rejection and infection in lung transplant recipients. However, its role is less well defined in determining the etiology of allograft dysfunction in the setting of respiratory failure necessitating mechanical ventilation. METHODS: We retrospectively identified 41 mechanically ventilated patients with respiratory failure in whom 42 TBBx were followed within a 10 day period by surgical lung biopsy (SLBx) to determine the sensitivity, specificity, and positive and negative predictive values of TBBx compared with SLBx. RESULTS: The sensitivity, specificity, and positive and negative predictive values of TBBx for all episodes of acute rejection and for significant episodes of acute cellular rejection were 53.3% and 36.0%; 91.7% and 94.1%; 94.1% and 90.0%; 44.0% and 50.0%, respectively. A significantly higher histologic grade was noted on SLBx compared with TBBx specimens obtained within a 10-day period (2.39 +/- 1.02 vs 0.97 +/- 0.11, p