Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension.

BACKGROUND: Intravenous fluids and vasopressor agents are commonly used in early resuscitation of patients with sepsis, but comparative data for prioritizing their delivery are limited. METHODS: In an unblinded superiority trial conducted at 60 U.S. centers, we randomly assigned patients to either a restrictive fluid strategy (prioritizing vasopressors and lower intravenous fluid volumes) or a liberal fluid strategy (prioritizing higher volumes of intravenous fluids before vasopressor use) for a 24-hour period. Randomization occurred within 4 hours after a patient met the criteria for sepsis-induced hypotension refractory to initial treatment with 1 to 3 liters of intravenous fluid. We hypothesized that all-cause mortality before discharge home by day 90 (primary outcome) would be lower with a restrictive fluid strategy than with a liberal fluid strategy. Safety was also assessed. RESULTS: A total of 1563 patients were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Resuscitation therapies that were administered during the 24-hour protocol period differed between the two groups; less intravenous fluid was administered in the restrictive fluid group than in the liberal fluid group (difference of medians, -2134 ml; 95% confidence interval [CI], -2318 to -1949), whereas the restrictive fluid group had earlier, more prevalent, and longer duration of vasopressor use. Death from any cause before discharge home by day 90 occurred in 109 patients (14.0%) in the restrictive fluid group and in 116 patients (14.9%) in the liberal fluid group (estimated difference, -0.9 percentage points; 95% CI, -4.4 to 2.6; P = 0.61); 5 patients in the restrictive fluid group and 4 patients in the liberal fluid group had their data censored (lost to follow-up). The number of reported serious adverse events was similar in the two groups. CONCLUSIONS: Among patients with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality before discharge home by day 90 than the liberal fluid strategy. (Funded by the National Heart, Lung, and Blood Institute; CLOVERS ClinicalTrials.gov number, NCT03434028.).

Early Active Mobilization during Mechanical Ventilation in the ICU.

BACKGROUND: Intensive care unit (ICU)-acquired weakness often develops in patients who are undergoing invasive mechanical ventilation. Early active mobilization may mitigate ICU-acquired weakness, increase survival, and reduce disability. METHODS: We randomly assigned 750 adult patients in the ICU who were undergoing invasive mechanical ventilation to receive increased early mobilization (sedation minimization and daily physiotherapy) or usual care (the level of mobilization that was normally provided in each ICU). The primary outcome was the number of days that the patients were alive and out of the hospital at 180 days after randomization. RESULTS: The median number of days that patients were alive and out of the hospital was 143 (interquartile range, 21 to 161) in the early-mobilization group and 145 days (interquartile range, 51 to 164) in the usual-care group (absolute difference, -2.0 days; 95% confidence interval [CI], -10 to 6; P = 0.62). The mean (±SD) daily duration of active mobilization was 20.8±14.6 minutes and 8.8±9.0 minutes in the two groups, respectively (difference, 12.0 minutes per day; 95% CI, 10.4 to 13.6). A total of 77% of the patients in both groups were able to stand by a median interval of 3 days and 5 days, respectively (difference, -2 days; 95% CI, -3.4 to -0.6). By day 180, death had occurred in 22.5% of the patients in the early-mobilization group and in 19.5% of those in the usual-care group (odds ratio, 1.15; 95% CI, 0.81 to 1.65). Among survivors, quality of life, activities of daily living, disability, cognitive function, and psychological function were similar in the two groups. Serious adverse events were reported in 7 patients in the early-mobilization group and in 1 patient in the usual-care group. Adverse events that were potentially due to mobilization (arrhythmias, altered blood pressure, and desaturation) were reported in 34 of 371 patients (9.2%) in the early-mobilization group and in 15 of 370 patients (4.1%) in the usual-care group (P = 0.005). CONCLUSIONS: Among adults undergoing mechanical ventilation in the ICU, an increase in early active mobilization did not result in a significantly greater number of days that patients were alive and out of the hospital than did the usual level of mobilization in the ICU. The intervention was associated with increased adverse events. (Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand; TEAM ClinicalTrials.gov number, NCT03133377.).

Impact of High Dose Early Mobilization on Outcomes for Patients with Diabetes: A Secondary Analysis of the TEAM Trial.

RATIONALE: Patients with diabetes represent almost 20% of all ICU admissions and might respond differently to high dose early active mobilization. OBJECTIVES: To assess whether diabetes modified the relationship between the dose of early mobilization on clinical outcomes in the TEAM trial. METHODS: All TEAM trial patients were included. The primary outcome was days alive and out of hospital at day 180. Secondary outcomes included 180-day mortality and long-term functional outcomes at day 180. Logistic and median regression models were used to explore the effect of high dose early mobilization on outcomes by diabetes status. MEASUREMENTS AND MAIN RESULTS: All 741 patients from the original trial were included. Of these, 159 patients (21.4%) had diabetes. Patients with diabetes had a lower number of days alive and out of hospital at day 180 (124 [0-153] vs. 147 [82-164], p = 0.013), and higher 180-day mortality (30% vs. 18%, p = 0.044). In patients receiving high dose early mobilization, days alive and out of hospital at day 180 was 73.0 (0.0 - 144.5) in patients with diabetes and 146.5 (95.8 - 163.0) in patients without diabetes (p for interaction = 0.108). However, in patients with diabetes, high dose early mobilization increased the odds of mortality at 180 days (adjusted odds ratio 3.47; 95% confidence interval [CI], 1.67-7.61, p value for interaction, 0.001). CONCLUSIONS: In this secondary analysis of the TEAM trial, in patients with diabetes, a high dose early mobilization strategy did not significantly decrease the number of days alive and out of hospital at day 180 but it increased 180-day mortality.

Tackling Brain and Muscle Dysfunction in Acute Respiratory Distress Syndrome Survivors: NHLBI Workshop Report.

Acute respiratory distress syndrome (ARDS) is associated with long-term impairments in brain and muscle function that significantly impact the quality of life of those who survive the acute illness. The mechanisms underlying these impairments are not yet well understood, and evidence-based interventions to minimize the burden on patients remain unproved. The NHLBI of the NIH assembled a workshop in April 2023 to review the state of the science regarding ARDS-associated brain and muscle dysfunction, to identify gaps in current knowledge, and to determine priorities for future investigation. The workshop included presentations by scientific leaders across the translational science spectrum and was open to the public as well as the scientific community. This report describes the themes discussed at the workshop as well as recommendations to advance the field toward the goal of improving the health and well-being of ARDS survivors.

Impact of SARS-CoV-2 Infection on Long-Term Depression Symptoms among Veterans.

BACKGROUND: Prior research demonstrates that SARS-COV-2 infection can be associated with a broad range of mental health outcomes including depression symptoms. Veterans, in particular, may be at elevated risk of increased depression following SARS-COV-2 infection given their high rates of pre-existing mental and physical health comorbidities. However, few studies have tried to isolate SARS-COV-2 infection associations with long term, patient-reported depression symptoms from other factors (e.g., physical health comorbidities, pandemic-related stress). OBJECTIVE: To evaluate the association between SARS-COV-2 infection and subsequent depression symptoms among United States Military Veterans. DESIGN: Survey-based non-randomized cohort study with matched comparators. PARTICIPANTS: A matched-dyadic sample from a larger, stratified random sample of participants with and without known to SARS-COV-2 infection were invited to participate in a survey evaluating mental health and wellness 18-months after their index infection date. Sampled participants were stratified by infection severity of the participant infected with SARS-COV-2 (hospitalized or not) and by month of index date. A total of 186 participants in each group agreed to participate in the survey and had sufficient data for inclusion in analyses. Those in the uninfected group who were later infected were excluded from analyses. MAIN MEASURES: Participants were administered the Patient Health Questionnaire-9 as part of a phone interview survey. Demographics, physical and mental health comorbidities were extracted from VHA administrative data. KEY RESULTS: Veterans infected with SARS-COV-2 had significantly higher depression symptoms scores compared with those uninfected. In particular, psychological symptoms (e.g., low mood, suicidal ideation) scores were elevated relative to the comparator group (MInfected = 3.16, 95%CI: 2.5, 3.8; MUninfected = 1.96, 95%CI: 1.4, 2.5). Findings were similar regardless of history of depression. CONCLUSION: SARS-COV-2 infection was associated with more depression symptoms among Veterans at 18-months post-infection. Routine evaluation of depression symptoms over time following SARS-COV-2 infection is important to facilitate adequate assessment and treatment.

Risk of Suicide-Related Outcomes After SARS-COV-2 Infection: Results from a Nationwide Observational Matched Cohort of US Veterans.

BACKGROUND: Negative mental health-related effects of SARS-COV-2 infection are increasingly evident. However, the impact on suicide-related outcomes is poorly understood, especially among populations at elevated risk. OBJECTIVE: To determine risk of suicide attempts and other self-directed violence (SDV) after SARS-COV-2 infection in a high-risk population. DESIGN: We employed an observational design supported by comprehensive electronic health records from the Veterans Health Administration (VHA) to examine the association of SARS-COV-2 infection with suicide attempts and other SDV within one year of infection. Veterans with SARS-COV-2 infections were matched 1:5 with non-infected comparators each month. Three periods after index were evaluated: days 1-30, days 31-365, and days 1-365. PARTICIPANTS: VHA patients infected with SARS-COV-2 between March 1, 2020 and March 31, 2021 and matched non-infected Veteran comparators. MAIN MEASURES: Suicide attempt and other SDV events for the COVID-19 and non-infected comparator groups were analyzed using incidence rates per 100,000 person years and hazard ratios from Cox regressions modeling time from matched index date to first event. Subgroups were also examined. KEY RESULTS: 198,938 veterans with SARS-COV-2 (COVID-19 group) and 992,036 comparators were included. Unadjusted one-year incidence per 100,000 for suicide attempt and other SDV was higher among the COVID-19 group: 355 vs 250 and 327 vs 235, respectively. The COVID-19 group had higher risk than comparators for suicide attempts: days 1-30 hazard ratio (HR) = 2.54 (CI:2.05, 3.15), days 31-365 HR = 1.30 (CI:1.19, 1.43) and days 1-365 HR = 1.41 (CI:1.30, 1.54), and for other SDV: days 1-30 HR = 1.94 (CI:1.51, 2.49), days 31-365 HR = 1.32 (CI:1.20, 1.45) and days 1-365 HR = 1.38 (CI:1.26, 1.51). CONCLUSIONS: COVID-19 patients had higher risks of both suicide attempts and other forms of SDV compared to uninfected comparators, which persisted for at least one year after infection. Results support suicide risk screening of those infected with SARS-COV-2 to identify opportunities to prevent self-harm.

Effectiveness of COVID-19 Treatment With Nirmatrelvir-Ritonavir or Molnupiravir Among U.S. Veterans: Target Trial Emulation Studies With One-Month and Six-Month Outcomes.

BACKGROUND: Information about the effectiveness of oral antivirals in preventing short- and long-term COVID-19-related outcomes in the setting of Omicron variant transmission and COVID-19 vaccination is limited. OBJECTIVE: To measure the effectiveness of nirmatrelvir-ritonavir and molnupiravir for outpatient treatment of COVID-19. DESIGN: Three retrospective target trial emulation studies comparing matched cohorts of nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir. SETTING: Veterans Health Administration (VHA). PARTICIPANTS: Nonhospitalized veterans in VHA care who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 during January through July 2022. INTERVENTION: Nirmatrelvir-ritonavir or molnupiravir pharmacotherapy. MEASUREMENTS: Incidence of any hospitalization or all-cause mortality at 30 days and from 31 to 180 days. RESULTS: Eighty-seven percent of participants were male; the median age was 66 years, and 18% were unvaccinated. Compared with matched untreated control participants, those treated with nirmatrelvir-ritonavir (n = 9607) had lower 30-day risk for hospitalization (22.07 vs. 30.32 per 1000 participants; risk difference [RD], -8.25 [95% CI, -12.27 to -4.23] per 1000 participants) and death (1.25 vs. 5.47 per 1000 participants; RD, -4.22 [CI, -5.45 to -3.00] per 1000 participants). Among persons alive at day 31, reductions were seen in 31- to 180-day incidence of death (hazard ratio, 0.66 [CI, 0.49 to 0.89]) but not hospitalization (subhazard ratio, 0.90 [CI, 0.79 to 1.02]). Molnupiravir-treated participants (n = 3504) had lower 30-day and 31- to 180-day risks for death (3.14 vs. 13.56 per 1000 participants at 30 days; RD, -10.42 [CI, -13.49 to -7.35] per 1000 participants; hazard ratio at 31 to 180 days, 0.67 [CI, 0.48 to 0.95]) but not hospitalization. A difference in 30-day or 31- to 180-day risk for hospitalization or death was not observed between matched nirmatrelvir- or molnupiravir-treated participants. LIMITATION: The date of COVID-19 symptom onset for most veterans was unknown. CONCLUSION: Nirmatrelvir-ritonavir was effective in reducing 30-day hospitalization and death. Molnupiravir was associated with a benefit for 30-day mortality but not hospitalization. Further reductions in mortality from 31 to 180 days were observed with both antivirals. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Effectiveness of Nirmatrelvir-Ritonavir Against the Development of Post-COVID-19 Conditions Among U.S. Veterans : A Target Trial Emulation.

BACKGROUND: COVID-19 has been linked to the development of many post-COVID-19 conditions (PCCs) after acute infection. Limited information is available on the effectiveness of oral antivirals used to treat acute COVID-19 in preventing the development of PCCs. OBJECTIVE: To measure the effectiveness of outpatient treatment of COVID-19 with nirmatrelvir-ritonavir in preventing PCCs. DESIGN: Retrospective target trial emulation study comparing matched cohorts receiving nirmatrelvir-ritonavir versus no treatment. SETTING: Veterans Health Administration (VHA). PARTICIPANTS: Nonhospitalized veterans in VHA care who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 during January through July 2022. INTERVENTION: Nirmatrelvir-ritonavir treatment for acute COVID-19. MEASUREMENTS: Cumulative incidence of 31 potential PCCs at 31 to 180 days after treatment or a matched index date, including cardiac, pulmonary, renal, thromboembolic, gastrointestinal, neurologic, mental health, musculoskeletal, endocrine, and general conditions and symptoms. RESULTS: Eighty-six percent of the participants were male, with a median age of 66 years, and 17.5% were unvaccinated. Baseline characteristics were well balanced between participants treated with nirmatrelvir-ritonavir and matched untreated comparators. No differences were observed between participants treated with nirmatrelvir-ritonavir (n = 9593) and their matched untreated comparators in the incidence of most PCCs examined individually or grouped by organ system, except for lower combined risk for venous thromboembolism and pulmonary embolism (subhazard ratio, 0.65 [95% CI, 0.44 to 0.97]; cumulative incidence difference, -0.29 percentage points [CI, -0.52 to -0.05 percentage points]). LIMITATIONS: Ascertainment of PCCs using International Classification of Diseases, 10th Revision, codes may be inaccurate. Evaluation of many outcomes could have resulted in spurious associations with combined thromboembolic events by chance. CONCLUSION: Out of 31 potential PCCs, only combined thromboembolic events seemed to be reduced by nirmatrelvir-ritonavir. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

In-person peer support for critical care survivors: The ICU REcovery Solutions cO-Led through surVivor Engagement (ICURESOLVE) pilot randomised controlled trial.

BACKGROUND: Peer support is a promising intervention to mitigate post-ICU disability, however there is a paucity of rigorously designed studies. OBJECTIVES: The objective of this study was to establish feasibility of an in-person, co-designed, peer-support model. METHODS: Prospective, randomised, adaptive, single-centre pilot trial with blinded outcome assessment, conducted at a university-affiliated hospital in Melbourne, Australia. Intensive care unit survivors (and their nominated caregiver, where survivor and caregiver are referred to as a dyad), >18 years of age, able to speak and understand English and participate in phone surveys, were eligible. Participants were randomised to the peer-support model (six sessions, fortnightly) or usual care (no follow-up or targeted information). Two sequential models were piloted: 1. Early (2-3 weeks post hospital discharge) 2. Later (4-6 weeks post hospital discharge). Primary outcome was feasibility of implementation measured by recruitment, intervention attendance, and outcome completion. Secondary outcomes included post-traumatic stress and social support. RESULTS: Of the 231 eligible patients, 80 participants were recruited. In the early model we recruited 38 participants (28 patients, 10 carers; 18 singles, 10 dyads), with an average (standard deviation) age of 60 (18) years; 55 % were female. Twenty-two participants (58 %) were randomised to intervention. Participants in the early intervention model attended a median (interquartile range) of 0 (0-1) sessions (total 24 sessions), with 53% (n = 20) completing the main secondary outcome of interest (Impact of Event Scale) at the baseline and 37 % (n = 14) at the follow-up. For the later model we recruited 42 participants (32 patients, 10 carers; 22 singles, 10 dyads), with an average (standard deviation) age of 60.4 (15.4) years; 50 % were female. Twenty-one participants (50 %) were randomised to intervention. The later intervention model attended a median (interquartile range) of 1 (0-5) sessions (total: 44 sessions), with the main secondary outcome impact of events scale (IES-R) completed by 41 (98 %) participants at baseline and 29 (69 %) at follow-up. CONCLUSIONS: In this pilot trial, a peer-support model that required in-person attendance delivered in a later posthospital phase of recovery appeared more feasible than an early model. Further research should investigate alternative modes of intervention delivery to improve feasibility (ACTRN12621000737831).

Evaluation of a health and social care programme to improve outcomes following critical illness: a multicentre study.

RATIONALE: At present, clinicians aiming to support patients through the challenges after critical care have limited evidence to base interventions. OBJECTIVES: Evaluate a multicentre integrated health and social care intervention for critical care survivors. A process evaluation assessed factors influencing the programme implementation. METHODS: This study evaluated the impact of the Intensive Care Syndrome: Promoting Independence and Return to Employment (InS:PIRE) programme. We compared patients who attended this programme with a usual care cohort from the same time period across nine hospital sites in Scotland. The primary outcome was health-related quality of life (HRQoL) measured via the EuroQol 5-dimension 5-level instrument, at 12 months post hospital discharge. Secondary outcome measures included self-efficacy, depression, anxiety and pain. RESULTS: 137 patients who received the InS:PIRE intervention completed outcome measures at 12 months. In the usual care cohort, 115 patients completed the measures. The two cohorts had similar baseline demographics. After adjustment, there was a significant absolute increase in HRQoL in the intervention cohort in relation to the usual care cohort (0.12, 95% CI 0.04 to 0.20, p=0.01). Patients in the InS:PIRE cohort also reported self-efficacy scores that were 7.7% higher (2.32 points higher, 95% CI 0.32 to 4.31, p=0.02), fewer symptoms of depression (OR 0.38, 95% CI 0.19 to 0.76, p=0.01) and similar symptoms of anxiety (OR 0.58, 95% CI 0.30 to 1.13, p=0.11). There was no significant difference in overall pain experience. Key facilitators for implementation were: integration with inpatient care, organisational engagement, flexibility to service inclusion; key barriers were: funding, staff availability and venue availability. CONCLUSIONS: This multicentre evaluation of a health and social care programme designed for survivors of critical illness appears to show benefit at 12 months following hospital discharge.

Design and analysis of outcomes following SARS-CoV-2 infection in veterans.

BACKGROUND: Understanding how SARS-CoV-2 infection impacts long-term patient outcomes requires identification of comparable persons with and without infection. We report the design and implementation of a matching strategy employed by the Department of Veterans Affairs' (VA) COVID-19 Observational Research Collaboratory (CORC) to develop comparable cohorts of SARS-CoV-2 infected and uninfected persons for the purpose of inferring potential causative long-term adverse effects of SARS-CoV-2 infection in the Veteran population. METHODS: In a retrospective cohort study, we identified VA health care system patients who were and were not infected with SARS-CoV-2 on a rolling monthly basis. We generated matched cohorts within each month utilizing a combination of exact and time-varying propensity score matching based on electronic health record (EHR)-derived covariates that can be confounders or risk factors across a range of outcomes. RESULTS: From an initial pool of 126,689,864 person-months of observation, we generated final matched cohorts of 208,536 Veterans infected between March 2020-April 2021 and 3,014,091 uninfected Veterans. Matched cohorts were well-balanced on all 39 covariates used in matching after excluding patients for: no VA health care utilization; implausible age, weight, or height; living outside of the 50 states or Washington, D.C.; prior SARS-CoV-2 diagnosis per Medicare claims; or lack of a suitable match. Most Veterans in the matched cohort were male (88.3%), non-Hispanic (87.1%), white (67.2%), and living in urban areas (71.5%), with a mean age of 60.6, BMI of 31.3, Gagne comorbidity score of 1.4 and a mean of 2.3 CDC high-risk conditions. The most common diagnoses were hypertension (61.4%), diabetes (34.3%), major depression (32.2%), coronary heart disease (28.5%), PTSD (25.5%), anxiety (22.5%), and chronic kidney disease (22.5%). CONCLUSION: This successful creation of matched SARS-CoV-2 infected and uninfected patient cohorts from the largest integrated health system in the United States will support cohort studies of outcomes derived from EHRs and sample selection for qualitative interviews and patient surveys. These studies will increase our understanding of the long-term outcomes of Veterans who were infected with SARS-CoV-2.

Liberation from Invasive Mechanical Ventilation with Continued Receipt of Vasopressor Infusions.

Rationale: Weaning protocols for discontinuation of invasive mechanical ventilation often mandate resolution of shock. Whether extubation while receiving vasopressors is associated with harm is uncertain. Objectives: To examine whether extubation while still receiving vasopressors is associated with worse outcomes. Methods: We performed a retrospective cohort study of adults in Calgary ICUs who received vasopressors with invasive mechanical ventilation and an extubation attempt. The primary exposure was continued vasopressor use at extubation. The primary outcome was reintubation within 96 hours. Secondary outcomes included in-hospital mortality and ICU/hospital length of stay (LOS). We assessed associations of vasopressor use at extubation with outcomes using multivariable competing-risk (reintubation/LOS) and Cox proportional-hazards (mortality) models. Measurements and Main Results: Of 6,140 patients who received invasive mechanical ventilation while on vasopressors, 721 (11.7%) were extubated while receiving vasopressors, and 5,419 (88.3%) after discontinuation. Extubation on vasopressors was not, in aggregate, significantly associated with an increased hazard of reintubation (subhazard ratio [SHR], 1.81 [95% confidence interval, 0.91-3.61]; P = 0.09). Both mortality (hazard ratio, 1.22 [1.02-1.47]; P = 0.03) and time to hospital discharge (SHR for remaining hospitalized, 0.78 [0.68-0.91]; P < 0.01) were increased. Extubation on high-dose vasopressors (>0.1 µg/kg/min) was associated with a greater hazard of reintubation (SHR, 2.25 [1.01-4.98]; P = 0.046) compared with extubation after vasopressor discontinuation. Meanwhile, extubation on low-dose vasopressors (⩽0.1 µg/kg/min) was associated with a lower mortality (hazard ratio, 0.69 [0.51-0.91]; P = 0.01) and a shorter ICU LOS (SHR, 1.34 [1.09-1.65]; P = 0.01), but no difference in reintubation or hospital LOS as compared with those weaned off vasopressors. Conclusions: Extubation while receiving high-dose but not low-dose vasopressors was associated with an increased risk of reintubation.

Effectiveness of mRNA COVID-19 Vaccine Boosters Against Infection, Hospitalization, and Death: A Target Trial Emulation in the Omicron (B.1.1.529) Variant Era.

BACKGROUND: The effectiveness of a third mRNA COVID-19 vaccine dose (booster dose) against the Omicron (B.1.1.529) variant is uncertain, especially in older, high-risk populations. OBJECTIVE: To determine mRNA booster vaccine effectiveness (VE) against SARS-CoV-2 infection, hospitalization, and death in the Omicron era by booster type, primary vaccine type, time since primary vaccination, age, and comorbidity burden. DESIGN: Retrospective matched cohort study designed to emulate a target trial of booster vaccination versus no booster, conducted from 1 December 2021 to 31 March 2022. SETTING: U.S. Department of Veterans Affairs health care system. PARTICIPANTS: Persons who had received 2 mRNA COVID-19 vaccine doses at least 5 months earlier. INTERVENTION: Booster monovalent mRNA vaccination (Pfizer-BioNTech's BNT162b2 or Moderna's mRNA-1273) versus no booster. MEASUREMENTS: Booster VE. RESULTS: Each group included 490 838 well-matched persons, who were predominantly male (88%), had a mean age of 63.0 years (SD, 14.0), and were followed for up to 121 days (mean, 79.8 days). Booster VE more than 10 days after a booster dose was 42.3% (95% CI, 40.6% to 43.9%) against SARS-CoV-2 infection, 53.3% (CI, 48.1% to 58.0%) against SARS-CoV-2-related hospitalization, and 79.1% (CI, 71.2% to 84.9%) against SARS-CoV-2-related death. Booster VE was similar for different booster types (BNT162b2 or mRNA-1273), age groups, and primary vaccination regimens but was significantly higher with longer time since primary vaccination and higher comorbidity burden. LIMITATION: Predominantly male population. CONCLUSION: Booster mRNA vaccination was highly effective in preventing death and moderately effective in preventing infection and hospitalization for up to 4 months after administration in the Omicron era. Increased uptake of booster vaccination, which is currently suboptimal, should be pursued to limit the morbidity and mortality of SARS-CoV-2 infection, especially in persons with high comorbidity burden. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Extracorporeal membrane oxygenation for COVID-19: evolving outcomes from the international Extracorporeal Life Support Organization Registry.

BACKGROUND: Over the course of the COVID-19 pandemic, the care of patients with COVID-19 has changed and the use of extracorporeal membrane oxygenation (ECMO) has increased. We aimed to examine patient selection, treatments, outcomes, and ECMO centre characteristics over the course of the pandemic to date. METHODS: We retrospectively analysed the Extracorporeal Life Support Organization Registry and COVID-19 Addendum to compare three groups of ECMO-supported patients with COVID-19 (aged ≥16 years). At early-adopting centres-ie, those using ECMO support for COVID-19 throughout 2020-we compared patients who started ECMO on or before May 1, 2020 (group A1), and between May 2 and Dec 31, 2020 (group A2). Late-adopting centres were those that provided ECMO for COVID-19 only after May 1, 2020 (group B). The primary outcome was in-hospital mortality in a time-to-event analysis assessed 90 days after ECMO initiation. A Cox proportional hazards model was fit to compare the patient and centre-level adjusted relative risk of mortality among the groups. FINDINGS: In 2020, 4812 patients with COVID-19 received ECMO across 349 centres within 41 countries. For early-adopting centres, the cumulative incidence of in-hospital mortality 90 days after ECMO initiation was 36·9% (95% CI 34·1-39·7) in patients who started ECMO on or before May 1 (group A1) versus 51·9% (50·0-53·8) after May 1 (group A2); at late-adopting centres (group B), it was 58·9% (55·4-62·3). Relative to patients in group A2, group A1 patients had a lower adjusted relative risk of in-hospital mortality 90 days after ECMO (hazard ratio 0·82 [0·70-0·96]), whereas group B patients had a higher adjusted relative risk (1·42 [1·17-1·73]). INTERPRETATION: Mortality after ECMO for patients with COVID-19 worsened during 2020. These findings inform the role of ECMO in COVID-19 for patients, clinicians, and policy makers. FUNDING: None.

Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome.

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.).

Patient and Caregiver-Derived Health Service Improvements for Better Critical Care Recovery.

OBJECTIVES: To engage critical care end-users (survivors and caregivers) to describe their emotions and experiences across their recovery trajectory, and elicit their ideas and solutions for health service improvements to improve the ICU recovery experience. DESIGN: End-user engagement as part of a qualitative design using the Framework Analysis method. SETTING: The Society of Critical Care Medicine's THRIVE international collaborative sites (follow-up clinics and peer support groups). SUBJECTS: Patients and caregivers following critical illness and identified through the collaboratives. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty-six interviews were conducted. The following themes were identified: 1) Emotions and experiences of patients-"Loss of former self; Experiences of disability and adaptation"; 2) Emotions and experiences of caregivers-"Emotional impacts, adopting new roles, and caregiver burden; Influence of gender roles; Adaptation, adjustment, recalibration"; and 3) Patient and caregiver-generated solutions to improve recovery across the arc of care-"Family-targeted education; Expectation management; Rehabilitation for patients and caregivers; Peer support groups; Reconnecting with ICU post-discharge; Access to community-based supports post-discharge; Psychological support; Education of issues of ICU survivorship for health professionals; Support across recovery trajectory." Themes were mapped to a previously published recovery framework (Timing It Right) that captures patient and caregiver experiences and their support needs across the phases of care from the event/diagnosis to adaptation post-discharge home. CONCLUSIONS: Patients and caregivers reported a range of emotions and experiences across the recovery trajectory from ICU to home. Through end-user engagement strategies many potential solutions were identified that could be implemented by health services and tested to support the delivery of higher-quality care for ICU survivors and their caregivers that extend from tertiary to primary care settings.

Interviews with primary care physicians identify unmet transition needs after ICU.

AIM: We sought to explore unmet needs in transitions of care for critical illness survivors that concern primary care physicians. FINDINGS: Semi-structured interviews with primary care physicians identified three categories of concerns about unmet transition needs after patients' ICU stays: patients' understanding of their ICU stay and potential complications, treatments or support needs not covered by insurance, and starting and maintaining needed rehabilitation and assistance across transitions of care. CONCLUSION: Given current constraints of access to coordinated post-ICU care, efforts to identify and address the post-hospitalization needs of critical illness survivors may be improved through coordinated work across the health system.

A multicentre evaluation exploring the impact of an integrated health and social care intervention for the caregivers of ICU survivors.

BACKGROUND: Caregivers and family members of Intensive Care Unit (ICU) survivors can face emotional problems following patient discharge from hospital. We aimed to evaluate the impact of a multi-centre integrated health and social care intervention, on caregiver and family member outcomes. METHODS: This study evaluated the impact of the Intensive Care Syndrome: Promoting Independence and Return to Employment (InS:PIRE) programme across 9 sites in Scotland. InS:PIRE is an integrated health and social care intervention. We compared caregivers who attended this programme with a contemporary control group of ICU caregivers (usual care cohort), who did not attend. RESULTS: The primary outcome was anxiety measured via the Hospital Anxiety and Depression Scale at 12 months post-hospital discharge. Secondary outcome measures included depression, carer strain and clinical insomnia. A total of 170 caregivers had data available at 12 months for inclusion in this study; 81 caregivers attended the InS:PIRE intervention and completed outcome measures at 12 months post-hospital discharge. In the usual care cohort of caregivers, 89 completed measures. The two cohorts had similar baseline demographics. After adjustment, those caregivers who attended InS:PIRE demonstrated a significant improvement in symptoms of anxiety (OR: 0.42, 95% CI: 0.20-0.89, p = 0.02), carer strain (OR: 0.39; 95% CI: 0.16-0.98 p = 0.04) and clinical insomnia (OR: 0.40; 95% CI: 0.17-0.77 p < 0.001). There was no significant difference in symptoms of depression at 12 months. CONCLUSIONS: This multicentre evaluation has shown that caregivers who attended an integrated health and social care intervention reported improved emotional health and less symptoms of insomnia, 12 months after the delivery of the intervention.

Caregiving in the COVID-19 pandemic: Family adaptations following an intensive care unit hospitalisation.

AIM AND OBJECTIVE: To identify how family caregivers adapt to the caregiving role following a relative's COVID-19-related intensive care unit (ICU) hospitalisation. BACKGROUND: Family caregiving is often associated with poor health amongst caregivers which may limit their capacity to effectively support patients. Though severe COVID-19 infection has necessitated increasing numbers of persons who require caregiver support, little is known about these caregivers, the persons they are caring for, or the strategies used to effectively adjust to the caregiving role. DESIGN: A qualitative descriptive study design was adopted, and findings are reported using COREQ. METHODS: A secondary analysis of transcripts from semi-structured interviews conducted with recently discharged ICU patients who had COVID-19 (n = 16) and their family caregivers (n = 16) was completed using thematic analysis. MAXQDA 2020 and Miro were used to organise data and complete coding. Analysis involved a structured process of open and closed coding to identify and confirm themes that elucidated adaptation to family caregiving. RESULTS: Six themes highlight how family caregivers adapt to the caregiving role following an ICU COVID-19-related hospitalisation including (1) engaging the support of family and friends, (2) increased responsibilities to accommodate caregiving, (3) managing emotions, (4) managing infection control, (5) addressing patient independence and (6) engaging support services. These themes were found to be congruent with the Roy adaptation model. CONCLUSIONS: Family caregiving is a stressful transition following a patient's acute hospitalisation. Effective adaptation requires flexibility and sufficient support, beginning with the care team who can adequately prepare the family for the anticipated challenges of recovery. RELEVANCE TO CLINICAL PRACTICE: Clinical teams may improve post-hospitalisation care outcomes of patients by preparing families to effectively adjust to the caregiver role-particularly in identifying sufficient support resources. PATIENT OR PUBLIC CONTRIBUTION: Participation of patients/caregivers in this study was limited to the data provided through participant interviews.

Exploring the process of information sharing in an adult intensive care unit: an ethnographic study.

Information sharing, a component of patient and family engagement (PFE), is an important process that may contribute to intensive care unit (ICU) quality of care. Yet, virtually no studies explore how the process of information sharing unfolds in the ICU from the interprofessional team and family member perspectives. To better understand the process of information sharing, we conducted ethnographic fieldwork in a 20-bed medical ICU, focusing on behaviors and interactions of the interprofessional team and family members (May 2016 - October 2016). We completed 17.5 observation hours, 6 shadowing sessions, and 12 semi-structured interviews with 17 total participants. We used thematic content analysis and iterative inductive coding to identify three themes about the information sharing process: 1) family factors (health literacy and past experience with the ICU environment) influence information sharing; 2) clinicians strategies can support engagement in the process of information sharing (assessing families' need for information, understanding a families' hope, using rounds as an opportunity for information sharing); 3) the process of information sharing allows for trust building between families and the ICU team. Our findings suggest that information sharing is a crucial process that may serve as a catalyst for effective patient and family engagement in the ICU.