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ObjectivesClinical trials evaluating the safety and effectiveness of sedative medication use in critically ill adults undergoing mechanical ventilation differ considerably in their methodological approach. This heterogeneity impedes the ability to compare results across studies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations convened a meeting of multidisciplinary experts to develop recommendations for key methodologic elements of sedation trials in the ICU to help guide academic and industry clinical investigators.DesignA 2-day in-person meeting was held in Washington, DC, on March 28-29, 2019, followed by a three-round, online modified Delphi consensus process.ParticipantsThirty-six participants from academia, industry, and the Food and Drug Administration with expertise in relevant content areas, including two former ICU patients attended the in-person meeting, and the majority completed an online follow-up survey and participated in the modified Delphi process.Measurements and main resultsThe final recommendations were iteratively refined based on the survey results, participants' reactions to those results, summaries written by panel moderators, and a review of the meeting transcripts made from audio recordings. Fifteen recommendations were developed for study design and conduct, subject enrollment, outcomes, and measurement instruments. Consensus recommendations included obtaining input from ICU survivors and/or their families, ensuring adequate training for personnel using validated instruments for assessments of sedation, pain, and delirium in the ICU environment, and the need for methodological standardization.ConclusionsThese recommendations are intended to assist researchers in the design, conduct, selection of endpoints, and reporting of clinical trials involving sedative medications and/or sedation protocols for adult ICU patients who require mechanical ventilation. These recommendations should be viewed as a starting point to improve clinical trials and help reduce methodological heterogeneity in future clinical trials.

Introduction: An association between deep sedation and adverse short-term outcomes has been demonstrated although this evidence has been inconsistent. The A2B (alpha-2 agonists for sedation in critical care) sedation trial is designed to determine whether the alpha-2 agonists clonidine and dexmedetomidine, compared with usual care, are clinically and cost-effective. The A2B intervention is a complex intervention conducted in 39 intensive care units (ICUs) in the UK. Multicentre organisational factors, variable cultures, perceptions and practices and the involvement of multiple members of the healthcare team add to the complexity of the A2B trial. From our pretrial contextual exploration it was apparent that routine practices such as type and frequency of pain, agitation and delirium assessment, as well as the common sedative agents used, varied widely across the UK. Anticipated challenges in implementing A2B focused on the impact of usual practice, perceptions of risk, ICU culture, structure and the presence of equipoise. Given this complexity, a process evaluation has been embedded in the A2B trial to uncover factors that could impact successful delivery and explore their impact on intervention delivery and interpretation of outcomes., Methods and Analysis: This is a mixed-methods process evaluation guided by the A2B intervention logic model. It includes two phases of data collection conducted during and at the end of trial. Data will be collected using a combination of questionnaires, stakeholder interviews and routinely collected trial data. A framework approach will be used to analyse qualitative data with synthesis of data within and across the phases. The nature of the relationship between delivery of the A2B intervention and the trial primary and secondary outcomes will be explored., Ethics and Dissemination: All elements of the A2B trial, including the process evaluation, are approved by Scotland A Research Ethics Committee (Ref. 18/SS/0085). Dissemination will be via publications, presentations and media engagement., Trial Registration Number: NCT03653832., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The sedation needs of critically ill patients have been recognized as a core component of critical care that is vital to assist recovery and ensure humane treatment. Evidence suggests that sedation requirements are not always optimally managed. Suboptimal sedation, both under- and over-sedation, have been linked to short-term (e.g. length of stay) and long-term (e.g. psychological recovery) outcomes. Strategies to improve sedation assessment and management have been proposed. This review was originally published in 2015 and updated in 2018., Objectives: To assess the effects of protocol-directed sedation management compared to usual care on the duration of mechanical ventilation, intensive care unit (ICU) and hospital mortality and other patient outcomes in mechanically ventilated ICU adults and children., Search Methods: We used the standard search strategy of the Cochrane Anaesthesia, Critical and Emergency Care Group (ACE). We searched the Cochrane Central Register of Controlled trials (CENTRAL) (December 2017), MEDLINE (OvidSP) (2013 to December 2017), Embase (OvidSP) (2013 to December 2017), CINAHL (BIREME host) (2013 to December 2017), LILACS (2013 to December 2017), trial registries and reference lists of articles. (The original search was run in November 2013)., Selection Criteria: We included randomized controlled trials (RCTs) and quasi-randomized controlled trials conducted in ICUs comparing management with and without protocol-directed sedation in intensive care adults and children., Data Collection and Analysis: Two authors screened the titles and abstracts and then full-text reports identified from our electronic search. We assessed seven domains of potential risk of bias for the included studies. We examined clinical, methodological and statistical heterogeneity and used the random-effects model for meta-analysis where we considered it appropriate. We calculated the mean difference (MD) for duration of mechanical ventilation and risk ratio (RR) for mortality across studies, with 95% confidence intervals (CIs)., Main Results: We included four studies with a total of 3323 participants (864 adults and 2459 paediatrics) in this update. Three studies were single-centre, patient-level RCTs and one study was a multicentre cluster-RCT. The settings were in metropolitan centres and included general, mixed medical-surgical, medical only and a range of paediatric units. All four included studies compared the use of protocol-directed sedation, specifically protocols delivered by nurses, with usual care. We rated the risk of selection bias due to random sequence generation low for two studies and unclear for two studies. The risk of bias was highly variable across the domains and studies, with the risk of selection and performance bias generally rated high and the risk of detection and attrition bias generally rated low.When comparing protocol-directed sedation with usual care, there was no clear evidence of difference in duration of mechanical ventilation in hours for the entire duration of the first ICU stay for each patient (MD -28.15 hours, 95% CI -69.15 to 12.84; I 2 = 85%; 4 studies; adjusted sample 2210 participants; low-quality evidence). There was no clear evidence of difference in ICU mortality (RR 0.77, 95% CI 0.39 to 1.50; I 2 = 67%; 2 studies; 513 participants; low-quality evidence), or hospital mortality (RR 0.90, 95% CI 0.72 to 1.13; I 2 = 10%; 3 studies; adjusted sample 2088 participants; low-quality evidence). There was no clear evidence of difference in ICU length of stay (MD -1.70 days, 95% CI-3.71 to 0.31; I 2 = 82%; 4 studies; adjusted sample of 2123 participants; low-quality of evidence), however there was evidence of a significant reduction in hospital length of stay (MD -3.09 days, 95% CI -5.08 to -1.10; I 2 = 2%; 3 studies; adjusted sample of 1922 participants; moderate-quality evidence). There was no clear evidence of difference in the incidence of self-extubation (RR 0.88, 95% CI 0.55 to 1.42; I 2 = 0%; 2 studies; adjusted sample of 1687 participants; high-quality evidence), or incidence of tracheostomy (RR 0.67, 95% CI 0.35 to 1.30; I 2 = 66%; 3 studies; adjusted sample of 2008 participants; low-quality evidence). Only one study examined incidence of reintubation, therefore we could not pool data; there was no clear evidence of difference (RR 0.65, 95% CI 0.35 to 1.24; 1 study; 321 participants; low-quality evidence)., Authors' Conclusions: There is currently limited evidence from RCTs evaluating the effectiveness of protocol-directed sedation on patient outcomes. The four included RCTs reported conflicting results and heterogeneity limited the interpretation of results for the primary outcomes of duration of mechanical ventilation and mortality. Further studies, taking into account differing contextual characteristics, are necessary to inform future practice. Methodological strategies to reduce the risk of bias need to be considered in future studies.

Background: High-flow nasal cannulae (HFNC) deliver high flows of blended humidified air and oxygen via wide-bore nasal cannulae and may be useful in providing respiratory support for adult patients experiencing acute respiratory failure in the intensive care unit (ICU)., Objectives: We evaluated studies that included participants 16 years of age and older who were admitted to the ICU and required treatment with HFNC. We assessed the safety and efficacy of HFNC compared with comparator interventions in terms of treatment failure, mortality, adverse events, duration of respiratory support, hospital and ICU length of stay, respiratory effects, patient-reported outcomes, and costs of treatment., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 3), MEDLINE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, Web of Science, proceedings from four conferences, and clinical trials registries; and we handsearched reference lists of relevant studies. We conducted searches from January 2000 to March 2016 and reran the searches in December 2016. We added four new studies of potential interest to a list of 'Studies awaiting classification' and will incorporate them into formal review findings during the review update., Selection Criteria: We included randomized controlled studies with a parallel or cross-over design comparing HFNC use in adult ICU patients versus other forms of non-invasive respiratory support (low-flow oxygen via nasal cannulae or mask, continuous positive airway pressure (CPAP), and bilevel positive airway pressure (BiPAP))., Data Collection and Analysis: Two review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias., Main Results: We included 11 studies with 1972 participants. Participants in six studies had respiratory failure, and in five studies required oxygen therapy after extubation. Ten studies compared HFNC versus low-flow oxygen devices; one of these also compared HFNC versus CPAP, and another compared HFNC versus BiPAP alone. Most studies reported randomization and allocation concealment inadequately and provided inconsistent details of outcome assessor blinding. We did not combine data for CPAP and BiPAP comparisons with data for low-flow oxygen devices; study data were insufficient for separate analysis of CPAP and BiPAP for most outcomes. For the primary outcomes of treatment failure (1066 participants; six studies) and mortality (755 participants; three studies), investigators found no differences between HFNC and low-flow oxygen therapies (risk ratio (RR), Mantel-Haenszel (MH), random-effects 0.79, 95% confidence interval (CI) 0.49 to 1.27; and RR, MH, random-effects 0.63, 95% CI 0.38 to 1.06, respectively). We used the GRADE approach to downgrade the certainty of this evidence to low because of study risks of bias and different participant indications. Reported adverse events included nosocomial pneumonia, oxygen desaturation, visits to general practitioner for respiratory complications, pneumothorax, acute pseudo-obstruction, cardiac dysrhythmia, septic shock, and cardiorespiratory arrest. However, single studies reported adverse events, and we could not combine these findings; one study reported fewer episodes of oxygen desaturation with HFNC but no differences in all other reported adverse events. We downgraded the certainty of evidence for adverse events to low because of limited data. Researchers noted no differences in ICU length of stay (mean difference (MD), inverse variance (IV), random-effects 0.15, 95% CI -0.03 to 0.34; four studies; 770 participants), and we downgraded quality to low because of study risks of bias and different participant indications. We found no differences in oxygenation variables: partial pressure of arterial oxygen (PaO 2 )/fraction of inspired oxygen (FiO 2 ) (MD, IV, random-effects 7.31, 95% CI -23.69 to 41.31; four studies; 510 participants); PaO 2 (MD, IV, random-effects 2.79, 95% CI -5.47 to 11.05; three studies; 355 participants); and oxygen saturation (SpO 2 ) up to 24 hours (MD, IV, random-effects 0.72, 95% CI -0.73 to 2.17; four studies; 512 participants). Data from two studies showed that oxygen saturation measured after 24 hours was improved among those treated with HFNC (MD, IV, random-effects 1.28, 95% CI 0.02 to 2.55; 445 participants), but this difference was small and was not clinically significant. Along with concern about risks of bias and differences in participant indications, review authors noted a high level of unexplained statistical heterogeneity in oxygenation effect estimates, and we downgraded the quality of evidence to very low. Meta-analysis of three comparable studies showed no differences in carbon dioxide clearance among those treated with HFNC (MD, IV, random-effects -0.75, 95% CI -2.04 to 0.55; three studies; 590 participants). Two studies reported no differences in atelectasis; we did not combine these findings. Data from six studies (867 participants) comparing HFNC versus low-flow oxygen showed no differences in respiratory rates up to 24 hours according to type of oxygen delivery device (MD, IV, random-effects -1.51, 95% CI -3.36 to 0.35), and no difference after 24 hours (MD, IV, random-effects -2.71, 95% CI -7.12 to 1.70; two studies; 445 participants). Improvement in respiratory rates when HFNC was compared with CPAP or BiPAP was not clinically important (MD, IV, random-effects -0.89, 95% CI -1.74 to -0.05; two studies; 834 participants). Results showed no differences in patient-reported measures of comfort according to oxygen delivery devices in the short term (MD, IV, random-effects 0.14, 95% CI -0.65 to 0.93; three studies; 462 participants) and in the long term (MD, IV, random-effects -0.36, 95% CI -3.70 to 2.98; two studies; 445 participants); we downgraded the certainty of this evidence to low. Six studies measured dyspnoea on incomparable scales, yielding inconsistent study data. No study in this review provided data on positive end-expiratory pressure measured at the pharyngeal level, work of breathing, or cost comparisons of treatment., Authors' Conclusions: We were unable to demonstrate whether HFNC was a more effective or safe oxygen delivery device compared with other oxygenation devices in adult ICU patients. Meta-analysis could be performed for few studies for each outcome, and data for comparisons with CPAP or BiPAP were very limited. In addition, we identified some risks of bias among included studies, differences in patient groups, and high levels of statistical heterogeneity for some outcomes, leading to uncertainty regarding the results of our analysis. Consequently, evidence is insufficient to show whether HFNC provides safe and efficacious respiratory support for adult ICU patients.

Background: The sedation needs of critically ill patients have been recognized as a core component of critical care and meeting these is vital to assist recovery and ensure humane treatment. There is growing evidence to suggest that sedation requirements are not always optimally managed. Sub-optimal sedation incorporates both under- and over-sedation and has been linked to both short-term (e.g. length of stay) and long-term (e.g. psychological recovery) outcomes. Various strategies have been proposed to improve sedation management and address aspects of assessment as well as delivery of sedation., Objectives: To assess the effects of protocol-directed sedation management on the duration of mechanical ventilation and other relevant patient outcomes in mechanically ventilated intensive care unit (ICU) patients. We looked at various outcomes and examined the role of bias in order to examine the level of evidence for this intervention., Search Methods: We searched the Cochrane Central Register of Controlled trials (CENTRAL) (2013; Issue 11), MEDLINE (OvidSP) (1990 to November 2013), EMBASE (OvidSP) (1990 to November 2013), CINAHL (BIREME host) (1990 to November 2013), Database of Abstracts of Reviews of Effects (DARE) (1990 to November 2013), LILACS (1990 to November 2013), Current Controlled Trials and US National Institutes of Health Clinical Research Studies (1990 to November 2013), and reference lists of articles. We re-ran the search in October 2014. We will deal with any studies of interest when we update the review., Selection Criteria: We included randomized controlled trials (RCTs) conducted in adult ICUs comparing management with and without protocol-directed sedation., Data Collection and Analysis: Two authors screened the titles and abstracts and then the full-text reports identified from our electronic search. We assessed seven domains of potential risk of bias for the included studies. We examined the clinical, methodological and statistical heterogeneity and used the random-effects model for meta-analysis where we considered it appropriate. We calculated the mean difference (MD) for duration of mechanical ventilation and risk ratio (RR) for mortality across studies, with 95% confidence intervals (CI)., Main Results: We identified two eligible studies with 633 participants. Both included studies compared the use of protocol-directed sedation, specifically protocols delivered by nurses, with usual care. We rated the risk of selection bias due to random sequence generation low for one study and unclear for one study. The risk of selection bias related to allocation concealment was low for both studies. We also assessed detection and attrition bias as low for both studies while we considered performance bias high due to the inability to blind participants and clinicians in both studies. Risk due to other sources of bias, such as potential for contamination between groups and reporting bias, was considered unclear. There was no clear evidence of differences in duration of mechanical ventilation (MD -5.74 hours, 95% CI -62.01 to 50.53, low quality evidence), ICU length of stay (MD -0.62 days, 95% CI -2.97 to 1.73) and hospital length of stay (MD -3.78 days, 95% CI -8.54 to 0.97) between people being managed with protocol-directed sedation versus usual care. Similarly, there was no clear evidence of difference in hospital mortality between the two groups (RR 0.96, 95% CI 0.71 to 1.31, low quality evidence). ICU mortality was only reported in one study preventing pooling of data. There was no clear evidence of difference in the incidence of tracheostomy (RR 0.77, 95% CI 0.31 to 1.89). The studies reported few adverse event outcomes; one study reported self extubation while the other study reported re-intubation; given this difference in outcomes, pooling of data was not possible. There was significant heterogeneity between studies for duration of mechanical ventilation (I(2) = 86%, P value = 0.008), ICU length of stay (I(2) = 82%, P value = 0.02) and incidence of tracheostomy (I(2) = 76%, P value = 0.04), with one study finding a reduction in duration of mechanical ventilation and incidence of tracheostomy and the other study finding no difference., Authors' Conclusions: There is currently insufficient evidence to evaluate the effectiveness of protocol-directed sedation. Results from the two RCTs were conflicting, resulting in the quality of the body of evidence as a whole being assessed as low. Further studies, taking into account contextual and clinician characteristics in different ICU environments, are necessary to inform future practice. Methodological strategies to reduce the risk of bias need to be considered in future studies.

Background: During intensive care unit (ICU) admission, patients experience extreme physical and psychological stressors, including the abnormal ICU environment. These experiences impact on a patient's recovery from critical illness and may result in both physical and psychological disorders. One strategy that has been developed and implemented by clinical staff to treat the psychological distress prevalent in ICU survivors is the use of patient diaries. These provide a background to the cause of the patient's ICU admission and an ongoing narrative outlining day-to-day activities., Objectives: To assess the effect of a diary versus no diary on patients, and their caregivers or families, during the patient's recovery from admission to an ICU., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 1), Ovid MEDLINE (1950 to January 2014), EBSCOhost CINAHL (1982 to January 2014), Ovid EMBASE (1980 to January 2014), PsycINFO (1950 to January 2014), Published International Literature on Traumatic Stress (PILOTS) database (1971 to January 2014); Web of Science Conference Proceedings Citation Index - Science and Social Science and Humanities (1990 to January 2014); seven clinical trial registries and reference lists of identified trials. We applied no language restriction., Selection Criteria: We included randomized controlled trials (RCTs) or clinical controlled trials (CCTs) that evaluated the effectiveness of patient diaries, when compared to no ICU diary, for patients or family members to promote recovery after admission to ICU. Outcome measures for describing recovery from ICU included the risk of post-traumatic stress disorder (PTSD), anxiety, depression and post-traumatic stress symptomatology, health-related quality of life and costs., Data Collection and Analysis: We used standard methodological approaches as expected by The Cochrane Collaboration. Two review authors independently reviewed titles for inclusion, extracted data and undertook risk of bias according to prespecified criteria., Main Results: We identified three eligible studies; two describing ICU patients (N = 358), and one describing relatives of ICU patients (N = 30). The study involving relatives of ICU patients was a substudy of family members from one of the ICU patient studies. There was a mixed risk of bias within the included studies. Blinding of participants to allocation was not possible and blinding of the outcome assessment was not adequately achieved or reported. Overall the quality of the evidence was low to very low. The patient diary intervention was not identical between studies. However, each provided a prospectively prepared, day-to-day description of the participants' ICU admission.No study adequately reported on risk of PTSD as described using a clinical interview, family or caregiver anxiety or depression, health-related quality of life or costs. Within a single study there was no clear evidence of a difference in risk for developing anxiety (risk ratio (RR) 0.29, 95% confidence interval (CI) 0.07 to 1.19) or depression (RR 0.38, 95% CI 0.12 to 1.19) in participants who received ICU diaries, in comparison to those that did not receive a patient diary. However, the results were imprecise and consistent with benefit in either group, or no difference. Within a single study there was no evidence of difference in median post-traumatic stress symptomatology scores (diaries 24, SD 11.6; no diary 24, SD 11.6) and delusional ICU memory recall (RR 1.04, 95% CI 0.84 to 1.28) between the patients recovering from ICU admission who received patient diaries, and those who did not. One study reported reduced post-traumatic stress symptomatology in family members of patients recovering from admission to ICU who received patient diaries (median 19; range 14 to 28), in comparison to no diary (median 28; range 14 to 38)., Authors' Conclusions: Currently there is minimal evidence from RCTs of the benefits or harms of patient diaries for patients and their caregivers or family members. A small study has described their potential to reduce post-traumatic stress symptomatology in family members. However, there is currently inadequate evidence to support their effectiveness in improving psychological recovery after critical illness for patients and their family members.

Introduction: Numerous primary studies and several review papers have highlighted delayed physical and psychological recovery for survivors of critical illness, often beyond 6 months after discharge. This randomized controlled trial with blinded assessment aims to test the effects of an 8-week, home-based, individually tailored physical rehabilitation programme on physical and psychological recovery for survivors of a critical illness after discharge from hospital., Method: Participants are survivors of a critical illness discharged from nine intensive care units (ICUs) in Australia, who are aged 18 years or older, in an ICU longer than 48 hours, discharged home to self-care or carer (non-institutional care), able to participate in physical rehabilitation, and within the hospitals' local geographical areas for home visits. The study is based in participants' home environments. Blinded assessments at weeks 1, 8 and 26 after hospital discharge examine physical functioning, exercise capacity, health-related quality of life and psychological well being. The intervention is graded, individualized endurance and strength training prescribed by a pulmonary rehabilitation physiotherapist over an 8-week period, with three home visits, five follow-up phone calls, and a printed exercise manual supporting the training. Initial focus is on lower limb exercises and walking, with warm-up stretches, and progresses to the addition of core stabilization and upper limb exercises., Results: The burden of a critical illness is well documented. This novel study will determine whether a home-based physical rehabilitation programme improves the recovery trajectory for survivors of critical illness. The projected sample size of 200 patients aims to detect a clinically important 10% improvement in physical functioning. The study will also examine whether other important physical and psychological measures are improved., Conclusion: This multicentre, randomized controlled trial will examine outcomes that are meaningful to patients, their family and society, namely functional ability and well being. The study will also target a health problem that is likely to increase as the population ages. If the programme is effective, it will provide a model that can be easily adapted and adopted by existing primary care or community services to improve the recovery of individuals following critical illness.