Six-month and 12-month patient outcomes based on inflammatory subphenotypes in sepsis-associated ARDS: secondary analysis of SAILS-ALTOS trial.

BACKGROUND: Prior acute respiratory distress syndrome (ARDS) trials have identified hypoinflammatory and hyperinflammatory subphenotypes, with distinct differences in short-term outcomes. It is unknown if such differences extend beyond 90 days or are associated with physical, mental health or cognitive outcomes. METHODS: 568 patients in the multicentre Statins for Acutely Injured Lungs from Sepsis trial of rosuvastatin versus placebo were included and assigned a subphenotype. Among 6-month and 12-month survivors (N=232 and 219, respectively, representing 243 unique survivors), subphenotype status was evaluated for association with a range of patient-reported outcomes (eg, mental health symptoms, quality of life). Patient subsets also were evaluated with performance-based tests of physical function (eg, 6 min walk test) and cognition. FINDINGS: The hyperinflammatory versus hypoinflammatory subphenotype had lower overall 12-month cumulative survival (58% vs 72%, p<0.01); however, there was no significant difference in survival beyond 90 days (86% vs 89%, p=0.70). Most survivors had impairment across the range of outcomes, with little difference between subphenotypes at 6-month and 12-month assessments. For instance, at 6 months, in comparing the hypoinflammatory versus hyperinflammatory subphenotypes, respectively, the median (IQR) patient-reported SF-36 mental health domain score was 47 (33-56) vs 44 (35-56) (p=0.99), and the per cent predicted 6 min walk distance was 66% (48%, 80%) vs 66% (49%, 79%) (p=0.76). INTERPRETATION: Comparing the hyperinflammatory versus hypoinflammatory ARDS subphenotype, there was no significant difference in survival beyond 90 days and no consistent findings of important differences in 6-month or 12-month physical, cognitive and mental health outcomes. These findings, when considered with prior results, suggest that inflammatory subphenotypes largely reflect the acute phase of illness and its short-term impact.

Depressive Symptoms After Critical Illness: A Systematic Review and Meta-Analysis.

OBJECTIVES: To synthesize data on prevalence, natural history, risk factors, and post-ICU interventions for depressive symptoms in ICU survivors. DATA SOURCES: PubMed, EMBASE, Cumulative Index of Nursing and Allied Health Literature, PsycINFO, and Cochrane Controlled Trials Registry (1970-2015). STUDY SELECTION: Studies measuring depression after hospital discharge using a validated instrument in more than 20 adults from non-specialty ICUs. DATA EXTRACTION: Duplicate independent review and data abstraction. DATA SYNTHESIS: The search identified 27,334 titles, with 42 eligible articles on 38 unique studies (n = 4,113). The Hospital Anxiety and Depression Scale-Depression subscale was used most commonly (58%). The pooled Hospital Anxiety and Depression Scale-Depression subscale prevalence (95% CI) of depressive symptoms at a threshold score greater than or equal to 8 was 29% (22-36%) at 2-3 months (12 studies; n = 1,078), 34% (24-43%) at 6 months (seven studies; n = 760), and 29% (23-34%) at 12-14 months (six studies; n = 1,041). The prevalence of suprathreshold depressive symptoms (compatible with Hospital Anxiety and Depression Scale-Depression subscale, ≥ 8) across all studies, using all instruments, was between 29% and 30% at all three time points. The pooled change in prevalence (95% CI) from 2-3 to 6 months (four studies; n = 387) was 5% (-1% to +12%), and from 6 to 12 months (three studies; n = 412) was 1% (-6% to +7%). Risk factors included pre-ICU psychologic morbidity and presence of in-ICU psychologic distress symptoms. We did not identify any post-ICU intervention with strong evidence of improvement in depressive symptoms. CONCLUSIONS: Clinically important depressive symptoms occurred in approximately one-third of ICU survivors and were persistent through 12-month follow-up. Greater research into treatment is needed for this common and persistent post-ICU morbidity.

Patient outcomes after critical illness: a systematic review of qualitative studies following hospital discharge.

BACKGROUND: There is growing interest in patient outcomes following critical illness, with an increasing number and different types of studies conducted, and a need for synthesis of existing findings to help inform the field. For this purpose we conducted a systematic review of qualitative studies evaluating patient outcomes after hospital discharge for survivors of critical illness. METHODS: We searched the PubMed, EMBASE, CINAHL, PsycINFO, and CENTRAL databases from inception to June 2015. Studies were eligible for inclusion if the study population was >50 % adults discharged from the ICU, with qualitative evaluation of patient outcomes. Studies were excluded if they focused on specific ICU patient populations or specialty ICUs. Citations were screened in duplicate, and two reviewers extracted data sequentially for each eligible article. Themes related to patient outcome domains were coded and categorized based on the main domains of the Patient Reported Outcomes Measurement Information System (PROMIS) framework. RESULTS: A total of 2735 citations were screened, and 22 full-text articles were eligible, with year of publication ranging from 1995 to 2015. All of the qualitative themes were extracted from eligible studies and then categorized using PROMIS descriptors: satisfaction with life (16 studies), including positive outlook, acceptance, gratitude, independence, boredom, loneliness, and wishing they had not lived; mental health (15 articles), including symptoms of post-traumatic stress disorder, anxiety, depression, and irritability/anger; physical health (14 articles), including mobility, activities of daily living, fatigue, appetite, sensory changes, muscle weakness, and sleep disturbances; social health (seven articles), including changes in friends/family relationships; and ability to participate in social roles and activities (six articles), including hobbies and disability. CONCLUSION: ICU survivors may experience positive emotions and life satisfaction; however, a wide range of mental, physical, social, and functional sequelae occur after hospital discharge. These findings are important for understanding patient-centered outcomes in critical care and providing focus for future interventional studies aimed at improving outcomes of importance to ICU survivors.

A structured methodology review showed analyses of functional outcomes are frequently limited to "survivors only" in trials enrolling patients at high risk of death.

OBJECTIVE: This structured methodology review evaluated statistical approaches used in randomized controlled trials (RCTs) enrolling patients at high risk of death and makes recommendations for reporting future RCTs. STUDY DESIGN AND SETTING: Using PubMed, we searched for RCTs published in five general medicine journals from January 2014 to August 2019 wherein mortality was ≥10% in at least one randomized group. We abstracted primary and secondary outcomes, statistical analysis methods, and patient samples evaluated (all randomized patients vs. "survivors only"). RESULTS: Of 1947 RCTs identified, 434 met eligibility criteria. Of the eligible RCTs, 91 (21%) and 351 (81%) had a primary or secondary functional outcome, respectively, of which 36 (40%) and 263 (75%) evaluated treatment effects among "survivors only". In RCTs that analyzed all randomized patients, the most common methods included use of ordinal outcomes (e.g., modified Rankin Scale) or creating composite outcomes (primary: 41 of 91 [45%]; secondary: 57 of 351 [16%]). CONCLUSION: In RCTs enrolling patients at high risk of death, statistical analyses of functional outcomes are frequently conducted among "survivors only," for which conclusions might be misleading. Given the growing number of RCTs conducted among patients hospitalized with COVID-19 and other critical illnesses, standards for reporting should be created.

Heterogeneity in design and analysis of ICU delirium randomized trials: a systematic review.

BACKGROUND: There is a growing number of randomized controlled trials (RCTs) evaluating interventions to prevent or treat delirium in the intensive care unit (ICU). Efforts to improve the conduct of delirium RCTs are underway, but none address issues related to statistical analysis. The purpose of this review is to evaluate heterogeneity in the design and analysis of delirium outcomes and advance methodological recommendations for delirium RCTs in the ICU. METHODS: Relevant databases, including PubMed and Embase, were searched with no restrictions on language or publication date; the search was conducted on July 8, 2019. RCTs conducted on adult ICU patients with delirium as the primary outcome were included where trial results were available. Data on frequency and duration of delirium assessments, delirium outcome definitions, and statistical methods were independently extracted in duplicate. The review was registered with PROSPERO (CRD42020141204). RESULTS: Among 65 eligible RCTs, 44 (68%) targeted the prevention of delirium. The duration of follow-up varied, with 31 (48%) RCTs having ≤7 days of follow-up, and only 24 (37%) conducting delirium assessments after ICU discharge. The incidence of delirium was the most common outcome (50 RCTs, 77%) for which 8 unique statistical methods were applied. The most common method, applied to 51 of 56 (91%) delirium incidence outcomes, was the two-sample test comparing the proportion of patients who ever experienced delirium. In the presence of censoring of patients at ICU discharge or death, this test may be misleading. The impact of censoring was also not considered in most analyses of the duration of delirium, as evaluated in 24 RCTs, with 21 (88%) delirium duration outcomes analyzed using a non-parametric test or two-sample t test. Composite outcomes (e.g., rank-based delirium- and coma-free days), used in 11 (17%) RCTs, seldom explicitly defined how ICU discharge, and death were incorporated into the definition and were analyzed using non-parametric tests (11 of 13 (85%) composite outcomes). CONCLUSIONS: To improve delirium RCTs, outcomes should be explicitly defined. To account for censoring due to ICU discharge or death, survival analysis methods should be considered for delirium incidence and duration outcomes; non-parametric tests are recommended for rank-based delirium composite outcomes. TRIAL REGISTRATION: PROSPERO CRD42020141204 . Registration date: 7/3/2019.

Evaluation of a strategy for enrolling the families of critically ill patients in research using limited human resources.

RATIONALE: Clinical trials of interventions aimed at the families of intensive care unit (ICU) patients have proliferated but recruitment for these trials can be challenging. OBJECTIVES: To evaluate a strategy for recruiting families of patients currently being treated in an ICU using limited human resources and time-varying daily screening over 7 consecutive days. METHODS: We screened the Johns Hopkins Hospital medical ICU census 7 days per week to identify eligible family members. We then made daily, in-person attempts to enroll eligible families during a time-varying 2-hour enrollment period until families declined participation, consented, or were no longer eligible. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the proportion of eligible patients for whom ≥1 family member was enrolled. Secondary outcomes included enrollment of legal healthcare proxies, the consent rate among families approached for enrollment, and success rates for recruiting at different times during the day and week. Among 284 eligible patients, 108 (38%, 95% CI 32%-44%) had ≥1 family member enrolled, and 75 (26%, 95% CI 21%-32%) had their legal healthcare proxy enrolled. Among 117 family members asked to participate, 108 (92%, 95% CI 86%-96%) were enrolled. Patients with versus without an enrolled proxy were more likely to be white (44% vs. 30%, P = .02), live in a zip code with a median income of ≥$100,000 (15% vs. 5%, P = .01), be mechanically ventilated (63% vs. 47%, P = .01), die in the ICU (19% vs. 9%, P = .03), and to have longer ICU stays (median 5.0 vs. 1.8 days, P<.001). Day of the week and time of day were not associated with family presence in the ICU or consent rate. CONCLUSIONS: Family members were recruited for more than one third of eligible patients, and >90% of approached consented to participate. There are important demographic differences between patients with vs without an enrolled family member.

Early Mobilization and Rehabilitation in the ICU: Moving Back to the Future.

Despite the historical precedent of mobilizing critically ill patients, bed rest is common practice in ICUs worldwide, especially for mechanically ventilated patients. ICU-acquired weakness is an increasingly recognized problem, with sequelae that may last for months and years following ICU discharge. The combination of critical illness and bed rest results in substantial muscle wasting during an ICU stay. When initiated shortly after the start of mechanical ventilation, mobilization and rehabilitation can play an important role in decreasing the duration of mechanical ventilation and hospital stay and improving patients' return to functional independence. This review summarizes recent evidence supporting the safety, feasibility, and benefits of early mobilization and rehabilitation of mechanically ventilated patients and presents a brief summary of future directions for this field.

Early Mobilization and Rehabilitation of Patients Who Are Critically Ill.

Neuromuscular disorders are increasingly recognized as a cause of both short- and long-term physical morbidity in survivors of critical illness. This recognition has given rise to research aimed at better understanding the risk factors and mechanisms associated with neuromuscular dysfunction and physical impairment associated with critical illness, as well as possible interventions to prevent or treat these issues. Among potential risk factors, bed rest is an important modifiable risk factor. Early mobilization and rehabilitation of patients who are critically ill may help prevent or mitigate the sequelae of bed rest and improve patient outcomes. Research studies and quality improvement projects have demonstrated that early mobilization and rehabilitation are safe and feasible in patients who are critically ill, with potential benefits including improved physical functioning and decreased duration of mechanical ventilation, intensive care, and hospital stay. Despite these findings, early mobilization and rehabilitation are still uncommon in routine clinical practice, with many perceived barriers. This review summarizes potential risk factors for neuromuscular dysfunction and physical impairment associated with critical illness, highlights the potential role of early mobilization and rehabilitation in improving patient outcomes, and discusses some of the commonly perceived barriers to early mobilization and strategies for overcoming them.

Interactive Online Module Failed to Improve Sustained Knowledge of the Maryland Medical Orders for Life-Sustaining Treatment Form.

RATIONALE: Legal documents similar to the Maryland Medical Orders for Life-Sustaining Treatment (MOLST) form requiring physician endorsement are increasingly used by critically ill patients. OBJECTIVES: To evaluate whether an interactive, online training module on completion and interpretation of the MOLST form leads to a sustained increase in knowledge among house staff. METHODS: Pre/post survey of 329 house staff at Johns Hopkins Hospital who admit and discharge patients between June 2014 and July 2015. House staff were encouraged to complete a voluntary, interactive, online educational module on completing and interpreting MOLST forms. Participants received $25 for accessing the module and $10 for completing each survey. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the change in the number of questions answered correctly on the post- versus presurvey comparing house staff who viewed the module for at least 20 minutes with house staff who never viewed or never completed the module. Overall, 329 (69%) house staff completed the knowledge assessment survey both before and after the module was available, and 201 (61%) of these house staff completed the voluntary module. The median score on the presurvey conducted in July and August of 2014 was 14 out of 21 (interquartile range [IQR] 12, 16). The median (IQR) score on the postsurvey conducted in May and June of 2015 was 15 out of 21 (13, 17). The median (IQR) change in score among those who spent at least 20 minutes completing the module was 1 question (-1, 3), and among those who never viewed or never completed the module it was also 1 (IQR -1, 2). The postsurvey was completed a median (IQR) of 59 (52, 62) days after viewing the module. After adjusting for years of postgraduate clinical training, self-reported baseline experience completing MOLST forms, and self-reported responsibility for discharging patients, viewing the module for at least 20 minutes was associated with a nonsignificant increase in score of 0.41 questions (95% confidence interval, -0.25, 1.06; P = 0.23). CONCLUSIONS: An interactive, online educational module had no effect on trainee knowledge of completing and interpreting MOLST forms approximately 2 months after completion. Information conveyed via online modules alone may have minimal sustained impact on house staff knowledge.

Anxiety symptoms in survivors of critical illness: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the epidemiology of and postintensive care unit (ICU) interventions for anxiety symptoms after critical illness. METHODS: We searched five databases (1970-2015) to identify studies assessing anxiety symptoms in adult ICU survivors. Data from studies using the most common assessment instrument were meta-analyzed. RESULTS: We identified 27 studies (2880 patients) among 27,334 citations. The Hospital Anxiety and Depression Scale-Anxiety (HADS-A) subscale was the most common instrument (81% of studies). We pooled data at 2-3, 6 and 12-14month time-points, with anxiety symptom prevalences [HADS-A≥8, 95% confidence interval (CI)] of 32%(27-38%), 40%(33-46%) and 34%(25-42%), respectively. In a subset of studies with repeated assessments in the exact same patients, there was no significant change in anxiety score or prevalence over time. Age, gender, severity of illness, diagnosis and length of stay were not associated with anxiety symptoms. Psychiatric symptoms during admission and memories of in-ICU delusional experiences were potential risk factors. Physical rehabilitation and ICU diaries had potential benefit. CONCLUSIONS: One third of ICU survivors experience anxiety symptoms that are persistent during their first year of recovery. Psychiatric symptoms during admission and memories of in-ICU delusional experiences were associated with post-ICU anxiety. Physical rehabilitation and ICU diaries merit further investigation as possible interventions.