Stress Ulcer Prophylaxis during Invasive Mechanical Ventilation.

BACKGROUND: Whether proton-pump inhibitors are beneficial or harmful for stress ulcer prophylaxis in critically ill patients undergoing invasive ventilation is unclear. METHODS: In this international, randomized trial, we assigned critically ill adults who were undergoing invasive ventilation to receive intravenous pantoprazole (at a dose of 40 mg daily) or matching placebo. The primary efficacy outcome was clinically important upper gastrointestinal bleeding in the intensive care unit (ICU) at 90 days, and the primary safety outcome was death from any cause at 90 days. Multiplicity-adjusted secondary outcomes included ventilator-associated pneumonia, Clostridioides difficile infection, and patient-important bleeding. RESULTS: A total of 4821 patients underwent randomization in 68 ICUs. Clinically important upper gastrointestinal bleeding occurred in 25 of 2385 patients (1.0%) receiving pantoprazole and in 84 of 2377 patients (3.5%) receiving placebo (hazard ratio, 0.30; 95% confidence interval [CI], 0.19 to 0.47; P<0.001). At 90 days, death was reported in 696 of 2390 patients (29.1%) in the pantoprazole group and in 734 of 2379 patients (30.9%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.85 to 1.04; P = 0.25). Patient-important bleeding was reduced with pantoprazole; all other secondary outcomes were similar in the two groups. CONCLUSIONS: Among patients undergoing invasive ventilation, pantoprazole resulted in a significantly lower risk of clinically important upper gastrointestinal bleeding than placebo, with no significant effect on mortality. (Funded by the Canadian Institutes of Health Research and others; REVISE ClinicalTrials.gov number, NCT03374800.).

Intensive care unit interventions to promote sleep and circadian biology in reducing incident delirium: a scoping review.

RATIONALE/OBJECTIVES: Despite plausible pathophysiological mechanisms, research is needed to confirm the relationship between sleep, circadian rhythm and delirium in patients admitted to the intensive care unit (ICU). The objective of this review is to summarise existing studies promoting, in whole or in part, the normalisation of sleep and circadian biology and their impact on the incidence, prevalence, duration and/or severity of delirium in ICU. METHODS: A sensitive search of electronic databases and conference proceedings was completed in March 2023. Inclusion criteria were English-language studies of any design that evaluated in-ICU non-pharmacological, pharmacological or mixed intervention strategies for promoting sleep or circadian biology and their association with delirium, as assessed at least daily. Data were extracted and independently verified. RESULTS: Of 7886 citations, we included 50 articles. Commonly evaluated interventions include care bundles (n=20), regulation or administration of light therapy (n=5), eye masks and/or earplugs (n=5), one nursing care-focused intervention and pharmacological intervention (eg, melatonin and ramelteon; n=19). The association between these interventions and incident delirium or severity of delirium was mixed. As multiple interventions were incorporated in included studies of care bundles and given that there was variable reporting of compliance with individual elements, identifying which components might have an impact on delirium is challenging. CONCLUSIONS: This scoping review summarises the existing literature as it relates to ICU sleep and circadian disruption (SCD) and delirium in ICU. Further studies are needed to better understand the role of ICU SCD promotion interventions in delirium mitigation.

Light, sleep and circadian rhythm in critical illness.

PURPOSE OF REVIEW: Sleep and circadian disruption (SCD) are associated with worse outcomes in the ICU population. We discuss sleep, circadian physiology, the role of light in circadian entrainment and its possible role in treating SCD, with special attention to the use of light therapies and ICU design. RECENT FINDINGS: The American Thoracic Society recently published an official research statement highlighting key areas required to define and treat ICU SCD. Recent literature has been predominantly observational, describing how both critical illness and the ICU environment might impair normal sleep and impact circadian rhythm. Emerging consensus guidance outlines the need for standardized light metrics in clinical trials investigating effects of light therapies. A recent proof-of-concept randomized controlled trial (RCT) showed improvement in delirium incidence and circadian alignment from ICU room redesign that included a dynamic lighting system (DLS). SUMMARY: Further investigation is needed to define the optimal physical properties of light therapy in the ICU environment as well as timing and duration of light treatments. Work in this area will inform future circadian-promoting design, as well as multicomponent nonpharmacological protocols, to mitigate ICU SCD with the objective of improving patient outcomes.

Causes, Consequences, and Treatments of Sleep and Circadian Disruption in the ICU: An Official American Thoracic Society Research Statement.

Background: Sleep and circadian disruption (SCD) is common and severe in the ICU. On the basis of rigorous evidence in non-ICU populations and emerging evidence in ICU populations, SCD is likely to have a profound negative impact on patient outcomes. Thus, it is urgent that we establish research priorities to advance understanding of ICU SCD. Methods: We convened a multidisciplinary group with relevant expertise to participate in an American Thoracic Society Workshop. Workshop objectives included identifying ICU SCD subtopics of interest, key knowledge gaps, and research priorities. Members attended remote sessions from March to November 2021. Recorded presentations were prepared and viewed by members before Workshop sessions. Workshop discussion focused on key gaps and related research priorities. The priorities listed herein were selected on the basis of rank as established by a series of anonymous surveys. Results: We identified the following research priorities: establish an ICU SCD definition, further develop rigorous and feasible ICU SCD measures, test associations between ICU SCD domains and outcomes, promote the inclusion of mechanistic and patient-centered outcomes within large clinical studies, leverage implementation science strategies to maximize intervention fidelity and sustainability, and collaborate among investigators to harmonize methods and promote multisite investigation. Conclusions: ICU SCD is a complex and compelling potential target for improving ICU outcomes. Given the influence on all other research priorities, further development of rigorous, feasible ICU SCD measurement is a key next step in advancing the field.

Nonsteroidal anti-inflammatory drugs for analgesia in intensive care units: a survey of Canadian critical care physicians.

PURPOSE: Opioids remain the mainstay of analgesia for critically ill patients, but its exposure is associated with negative effects including persistent use after discharge. Nonsteroidal anti-inflammatory drugs (NSAIDs) may be an effective alternative to opioids with fewer adverse effects. We aimed to describe beliefs and attitudes towards the use of NSAIDs in adult intensive care units (ICUs). METHODS: Our survey of Canadian ICU physicians was conducted using a web-based platform and distributed through the Canadian Critical Care Society (CCCS) email distribution list. We used previously described survey development methodology including question generation and reduction, pretesting, and clinical sensibility and pilot testing. RESULTS: We received 115 completed surveys from 321 CCCS members (36%). Nonsteroidal anti-inflammatory drugs use was most described as "rarely" (59 respondents, 51%) with the primary concern being adverse events (acute kidney injury [108 respondents, 94%] and gastrointestinal bleeding [92 respondents, 80%]). The primary preferred analgesic was acetaminophen (75 respondents, 65%) followed by opioids (40 respondents, 35%). Most respondents (91 respondents, 80%) would be willing to participate in a randomized controlled trial examining NSAID use in critical care. CONCLUSIONS: In our survey, Canadian critical care physicians did not mention commonly using NSAIDs primarily because of concerns about adverse events. Nevertheless, respondents were interested in further studying ketorolac, a commonly used NSAID outside of the ICU, in critically ill patients.

RéSUMé: OBJECTIF: Les opioïdes restent le pilier de l'analgésie pour les patient·es gravement malades, mais l'exposition à ces agents est associée à des effets négatifs, notamment à leur utilisation persistante après le congé de l'hôpital. Les anti-inflammatoires non stéroïdiens (AINS) pourraient constituer une alternative efficace aux opioïdes avec moins d'effets indésirables. Nous avons cherché à décrire les croyances et les attitudes à l'égard de l'utilisation des AINS dans les unités de soins intensifs (USI) pour adultes. MéTHODE: Notre sondage auprès des médecins intensivistes au Canada a été mené à l'aide d'une plateforme Web et distribué aux personnes sur la liste de distribution électronique de la Société canadienne de soins intensifs (SCSI). Nous avons utilisé une méthodologie d'élaboration d'enquêtes décrite précédemment, y compris la génération et la réduction de questions, les tests préalables, la sensibilité clinique et les tests pilotes. RéSULTATS: Nous avons reçu 115 sondages remplis par 321 membres de la SCSI (36 %). L'utilisation d'anti-inflammatoires non stéroïdiens a été décrite comme « rare ¼ (59 répondant·es, 51 %), la principale préoccupation étant les événements indésirables (insuffisance rénale aiguë [108 répondant·es, 94 %] et saignements gastro-intestinaux [92 répondant·es, 80 %]). Le principal analgésique préféré était l'acétaminophène (75 répondant·es, 65 %), suivi des opioïdes (40 répondant·es, 35 %). La plupart des répondant·es (91 répondant·es, 80 %) seraient prêt·es à participer à une étude randomisée contrôlée examinant l'utilisation des AINS en soins intensifs. CONCLUSION: Dans notre sondage, les médecins intensivistes au Canada n'ont pas mentionné l'utilisation courante d'AINS, principalement en raison de préoccupations concernant leurs effets indésirables. Néanmoins, les répondant·es étaient intéressé·es à étudier plus avant le kétorolac, un AINS couramment utilisé en dehors des soins intensifs, chez les patient·es gravement malades.

Does Unprecedented ICU Capacity Strain, As Experienced During the COVID-19 Pandemic, Impact Patient Outcome?

OBJECTIVES: To determine whether patients admitted to an ICU during times of unprecedented ICU capacity strain, during the COVID-19 pandemic in the United Kingdom, experienced a higher risk of death. DESIGN: Multicenter, observational cohort study using routine clinical audit data. SETTING: Adult general ICUs participating the Intensive Care National Audit & Research Centre Case Mix Programme in England, Wales, and Northern Ireland. PATIENTS: One-hundred thirty-thousand six-hundred eighty-nine patients admitted to 210 adult general ICUs in 207 hospitals. INTERVENTIONS: Multilevel, mixed effects, logistic regression models were used to examine the relationship between levels of ICU capacity strain on the day of admission (typical low, typical, typical high, pandemic high, and pandemic extreme) and risk-adjusted hospital mortality. MEASUREMENTS AND MAIN RESULTS: In adjusted analyses, compared with patients admitted during periods of typical ICU capacity strain, we found that COVID-19 patients admitted during periods of pandemic high or pandemic extreme ICU capacity strain during the first wave had no difference in hospital mortality, whereas those admitted during the pandemic high or pandemic extreme ICU capacity strain in the second wave had a 17% (odds ratio [OR], 1.17; 95% CI, 1.05-1.30) and 15% (OR, 1.15; 95% CI, 1.00-1.31) higher odds of hospital mortality, respectively. For non-COVID-19 patients, there was little difference in trend between waves, with those admitted during periods of pandemic high and pandemic extreme ICU capacity strain having 16% (OR, 1.16; 95% CI, 1.08-1.25) and 30% (OR, 1.30; 95% CI, 1.14-1.48) higher overall odds of acute hospital mortality, respectively. CONCLUSIONS: For patients admitted to ICU during the pandemic, unprecedented levels of ICU capacity strain were significantly associated with higher acute hospital mortality, after accounting for differences in baseline characteristics. Further study into possible differences in the provision of care and outcome for COVID-19 and non-COVID-19 patients is needed.

Sleep in the intensive care unit.

PURPOSE OF REVIEW: Sleep is particularly important for critically ill patients. Here, we review the latest evidence on how sleep and circadian disruption in the intensive care unit (ICU) affects physiology and clinical outcomes, as well as the most recent advances in sleep and circadian rhythm promoting interventions including therapeutics. RECENT FINDINGS: On a molecular level, clock genes dysrhythmia and altered immunity are clearly linked, particularly in sepsis. Melatonin may also be associated with insulin sensitivity in ICU patients. Clinically, changes in sleep architecture are associated with delirium, and sleep-promoting interventions in the form of multifaceted care bundles may reduce its incidence. Regarding medications, one recent randomized controlled trial (RCT) on melatonin showed no difference in sleep quality or incidence of delirium. SUMMARY: Further investigation is needed to establish the clinical relevance of sleep and circadian disruption in the ICU. For interventions, standardized protocols of sleep promotion bundles require validation by larger multicenter trials. Administratively, such protocols should be individualized to both organizational and independent patient needs. Incorporating pharmacotherapy such as melatonin and nocturnal dexmedetomidine requires further evaluation in large RCTs.

Development of a repeated-measures predictive model and clinical risk score for mortality in ventilated COVID-19 patients.

PURPOSE: The COVID-19 pandemic has caused intensive care units (ICUs) to reach capacities requiring triage. A tool to predict mortality risk in ventilated patients with COVID-19 could inform decision-making and resource allocation, and allow population-level comparisons across institutions. METHODS: This retrospective cohort study included all mechanically ventilated adults with COVID-19 admitted to three tertiary care ICUs in Toronto, Ontario, between 1 March 2020 and 15 December 2020. Generalized estimating equations were used to identify variables predictive of mortality. The primary outcome was the probability of death at three-day intervals from the time of ICU admission (day 0), with risk re-calculation every three days to day 15; the final risk calculation estimated the probability of death at day 15 and beyond. A numerical algorithm was developed from the final model coefficients. RESULTS: One hundred twenty-seven patients were eligible for inclusion. Median ICU length of stay was 26.9 (interquartile range, 15.4-52.0) days. Overall mortality was 42%. From day 0 to 15, the variables age, temperature, lactate level, ventilation tidal volume, and vasopressor use significantly predicted mortality. Our final clinical risk score had an area under the receiver-operating characteristics curve of 0.9 (95% confidence interval [CI], 0.8 to 0.9). For every ten-point increase in risk score, the relative increase in the odds of death was approximately 4, with an odds ratio of 4.1 (95% CI, 2.9 to 5.9). CONCLUSION: Our dynamic prediction tool for mortality in ventilated patients with COVID-19 has excellent diagnostic properties. Notwithstanding, external validation is required before widespread implementation.

RéSUMé: OBJECTIF: En raison de la pandémie de COVID-19, les unités de soins intensifs (USI) ont atteint des taux d'occupation nécessitant un triage. Un outil pour prédire le risque de mortalité chez les patients sous ventilation atteints de COVID-19 pourrait éclairer la prise de décision et l'attribution des ressources tout en permettant des comparaisons populationnelles entre les établissements. MéTHODE: Cette étude de cohorte rétrospective a inclus tous les adultes atteints de COVID-19 sous ventilation mécanique admis dans trois USI de centres de soins tertiaires à Toronto, en Ontario, entre le 1er mars 2020 et le 15 décembre 2020. Des équations d'estimation généralisées ont été utilisées pour identifier les variables prédictives de mortalité. Le critère d'évaluation principal était la probabilité de décès à des intervalles de trois jours à partir du moment de l'admission à l'USI (jour 0), avec un nouveau calcul du risque tous les trois jours jusqu'au jour 15; le calcul final du risque a estimé la probabilité de décès au jour 15 et au-delà. Un algorithme numérique a été mis au point à partir des coefficients du modèle final. RéSULTATS: Cent vingt-sept patients étaient éligibles à l'inclusion. La durée médiane de séjour à l'USI était de 26,9 jours (écart interquartile, 15,4 à 52,0). La mortalité globale était de 42 %. Du jour 0 au jour 15, les variables que sont l'âge, la température, les taux de lactate, le volume courant de ventilation et l'utilisation de vasopresseurs ont constitué des prédicteurs significatifs de mortalité. Notre score de risque clinique final avait une aire sous la courbe ROC de 0,9 (intervalle de confiance [IC] à 95 %, 0,8 à 0,9). Pour chaque augmentation de dix points du score de risque, l'augmentation relative des risques de décès était d'environ 4, avec un rapport de cotes de 4,1 (IC 95 %, 2,9 à 5,9). CONCLUSION: Notre outil de prédiction dynamique de la mortalité pour les patients ventilés atteints de COVID-19 possède d'excellentes propriétés diagnostiques. Néanmoins, une validation externe est nécessaire avant sa mise en œuvre généralisée.

The evolution of mean arterial pressure in critically ill patients on vasopressors before and during a trial comparing a specific mean arterial pressure target to usual care.

BACKGROUND: In randomized clinical controlled trials, the choice of usual care as the comparator may be associated with better clinician uptake of the study protocol and lead to more generalizable results. However, if care processes evolve to resemble the intervention during the course of a trial, differences between the intervention group and usual care control group may narrow. We evaluated the effect on mean arterial pressure of an unblinded trial comparing a lower mean arterial pressure target to reduce vasopressor exposure, vs. a clinician-selected mean arterial pressure target, in critically ill patients at least 65 years old. METHODS: For this multicenter observational study using data collected both prospectively and retrospectively, patients were recruited from five of the seven trial sites. We compared the mean arterial pressure of patients receiving vasopressors, who met or would have met trial eligibility criteria, from two periods: [1] at least 1 month before the trial started, and [2] during the trial period and randomized to usual care, or not enrolled in the trial. RESULTS: We included 200 patients treated before and 229 after trial initiation. There were no differences in age (mean 74.5 vs. 75.2 years; p = 0.28), baseline Acute Physiology and Chronic Health Evaluation II score (median 26 vs. 26; p = 0.47) or history of chronic hypertension (n = 126 [63.0%] vs. n = 153 [66.8%]; p = 0.41). Mean of the mean arterial pressure was similar between the two periods (72.5 vs. 72.4 mmHg; p = 0.76). CONCLUSIONS: The initiation of a trial of a prescribed lower mean arterial pressure target, compared to a usual clinician-selected target, was not associated with a change in mean arterial pressure, reflecting stability in the net effect of usual clinician practices over time. Comparing prior and concurrent control groups may alleviate concerns regarding drift in usual practices over the course of a trial or permit quantification of any change.

Association of Extracorporeal Membrane Oxygenation With New Mental Health Diagnoses in Adult Survivors of Critical Illness.

Importance: Extracorporeal membrane oxygenation (ECMO) is used as temporary cardiorespiratory support in critically ill patients, but little is known regarding long-term psychiatric sequelae among survivors after ECMO. Objective: To investigate the association between ECMO survivorship and postdischarge mental health diagnoses among adult survivors of critical illness. Design, Setting, and Participants: Population-based retrospective cohort study in Ontario, Canada, from April 1, 2010, through March 31, 2020. Adult patients (N=4462; age ≥18 years) admitted to the intensive care unit (ICU), and surviving to hospital discharge were included. Exposures: Receipt of ECMO. Main Outcomes and Measures: The primary outcome was a new mental health diagnosis (a composite of mood disorders, anxiety disorders, posttraumatic stress disorder; schizophrenia, other psychotic disorders; other mental health disorders; and social problems) following discharge. There were 8 secondary outcomes including incidence of substance misuse, deliberate self-harm, death by suicide, and individual components of the composite primary outcome. Patients were compared with ICU survivors not receiving ECMO using overlap propensity score-weighted cause-specific proportional hazard models. Results: Among 642 survivors who received ECMO (mean age, 50.7 years; 40.7% female), median length of follow-up was 730 days; among 3820 matched ICU survivors who did not receive ECMO (mean age, 51.0 years; 40.0% female), median length of follow-up was 1390 days. Incidence of new mental health conditions among survivors who received ECMO was 22.1 per 100-person years (95% confidence interval [CI] 19.5-25.1), and 14.5 per 100-person years (95% CI, 13.8-15.2) among non-ECMO ICU survivors (absolute rate difference of 7.6 per 100-person years [95% CI, 4.7-10.5]). Following propensity weighting, ECMO survivorship was significantly associated with an increased risk of new mental health diagnosis (hazard ratio [HR] 1.24 [95% CI, 1.01-1.52]). There were no significant differences between survivors who received ECMO vs ICU survivors who did not receive ECMO in substance misuse (1.6 [95% CI, 1.1 to 2.4] per 100 person-years vs 1.4 [95% CI, 1.2 to 1.6] per 100 person-years; absolute rate difference, 0.2 per 100 person-years [95% CI, -0.4 to 0.8]; HR, 0.86 [95% CI, 0.48 to 1.53]) or deliberate self-harm (0.4 [95% CI, 0.2 to 0.9] per 100 person-years vs 0.3 [95% CI, 0.2 to 0.3] per 100 person-years; absolute rate difference, 0.1 per 100 person-years [95% CI, -0.2 to 0.4]; HR, 0.68 [95% CI, 0.21 to 2.23]). There were fewer than 5 total cases of death by suicide in the entire cohort. Conclusions and Relevance: Among adult survivors of critical illness, receipt of ECMO, compared with ICU hospitalization without ECMO, was significantly associated with a modestly increased risk of new mental health diagnosis or social problem diagnosis after discharge. Further research is necessary to elucidate the potential mechanisms underlying this relationship.

Health-Related Quality-of-Life and Cost Utility Analyses in Critical Care: A Systematic Review.

OBJECTIVES: Cost utility analyses compare the costs and health outcome of interventions, with a denominator of quality-adjusted life year, a generic health utility measure combining both quality and quantity of life. Cost utility analyses are difficult to compare when methods are not standardized. It is unclear how cost utility analyses are measured/reported in critical care and what methodologic challenges cost utility analyses pose in this setting. This may lead to differences precluding cost utility analyses comparisons. Therefore, we performed a systematic review of cost utility analyses conducted in critical care. Our objectives were to understand: 1) methodologic characteristics, 2) how health-related quality-of-life was measured/reported, and 3) what costs were reported/measured. DESIGN: Systematic review. DATA SOURCES: We systematically searched for cost utility analyses in critical care in MEDLINE, Embase, American College of Physicians Journal Club, CENTRAL, Evidence-Based Medicine Reviews' selected subset of archived versions of UK National Health Service Economic Evaluation Database, Database of Abstracts of Reviews of Effects, and American Economic Association electronic databases from inception to April 30, 2020. SETTING: Adult ICUs. PATIENTS: Adult critically ill patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 8,926 citations, 80 cost utility analyse studies were eligible. The time horizon most commonly reported was lifetime (59%). For health utility reporting, health-related quality-of-life was infrequently measured (29% reported), with only 5% of studies reporting baseline health-related quality-of-life. Indirect utility measures (generic, preference-based health utility measurement tools) were reported in 85% of studies (majority Euro-quality-of-life-5 Domains, 52%). Methods of estimating health-related quality-of-life were seldom used when the patient was incapacitated: imputation (19%), assigning fixed utilities for incapacitation (19%), and surrogates reporting on behalf of incapacitated patients (5%). For cost utility reporting transparency, separate incremental costs and quality-adjusted life years were both reported in only 76% of studies. Disaggregated quality-adjusted life years (reporting separate health utility and life years) were described in only 34% of studies. CONCLUSIONS: We identified deficiencies which warrant recommendations (standardized measurement/reporting of resource use/unit costs/health-related quality-of-life/methodological preferences) for improved design, conduct, and reporting of future cost utility analyses in critical care.

Mechanical Ventilation for Acute Respiratory Distress Syndrome during Extracorporeal Life Support. Research and Practice.

Ventilator-induced lung injury remains a key contributor to the morbidity and mortality of acute respiratory distress syndrome (ARDS). Efforts to minimize this injury are typically limited by the need to preserve adequate gas exchange. In the most severe forms of the syndrome, extracorporeal life support is increasingly being deployed for severe hypoxemia or hypercapnic acidosis refractory to conventional ventilator management strategies. Data from a recent randomized controlled trial, a post hoc analysis of that trial, a meta-analysis, and a large international multicenter observational study suggest that extracorporeal life support, when combined with lower Vt and airway pressures than the current standard of care, may improve outcomes compared with conventional management in patients with the most severe forms of ARDS. These findings raise important questions not only about the optimal ventilation strategies for patients receiving extracorporeal support but also regarding how various mechanisms of lung injury in ARDS may potentially be mitigated by ultra-lung-protective ventilation strategies when gas exchange is sufficiently managed with the extracorporeal circuit. Additional studies are needed to more precisely delineate the best strategies for optimizing invasive mechanical ventilation in this patient population.

Effect of Probiotics on Incident Ventilator-Associated Pneumonia in Critically Ill Patients: A Randomized Clinical Trial.

Importance: Growing interest in microbial dysbiosis during critical illness has raised questions about the therapeutic potential of microbiome modification with probiotics. Prior randomized trials in this population suggest that probiotics reduce infection, particularly ventilator-associated pneumonia (VAP), although probiotic-associated infections have also been reported. Objective: To evaluate the effect of Lactobacillus rhamnosus GG on preventing VAP, additional infections, and other clinically important outcomes in the intensive care unit (ICU). Design, Setting, and Participants: Randomized placebo-controlled trial in 44 ICUs in Canada, the United States, and Saudi Arabia enrolling adults predicted to require mechanical ventilation for at least 72 hours. A total of 2653 patients were enrolled from October 2013 to March 2019 (final follow-up, October 2020). Interventions: Enteral L rhamnosus GG (1 × 1010 colony-forming units) (n = 1321) or placebo (n = 1332) twice daily in the ICU. Main Outcomes and Measures: The primary outcome was VAP determined by duplicate blinded central adjudication. Secondary outcomes were other ICU-acquired infections including Clostridioides difficile infection, diarrhea, antimicrobial use, ICU and hospital length of stay, and mortality. Results: Among 2653 randomized patients (mean age, 59.8 years [SD], 16.5 years), 2650 (99.9%) completed the trial (mean age, 59.8 years [SD], 16.5 years; 1063 women [40.1%.] with a mean Acute Physiology and Chronic Health Evaluation II score of 22.0 (SD, 7.8) and received the study product for a median of 9 days (IQR, 5-15 days). VAP developed among 289 of 1318 patients (21.9%) receiving probiotics vs 284 of 1332 controls (21.3%; hazard ratio [HR], 1.03 (95% CI, 0.87-1.22; P = .73, absolute difference, 0.6%, 95% CI, -2.5% to 3.7%). None of the 20 prespecified secondary outcomes, including other ICU-acquired infections, diarrhea, antimicrobial use, mortality, or length of stay showed a significant difference. Fifteen patients (1.1%) receiving probiotics vs 1 (0.1%) in the control group experienced the adverse event of L rhamnosus in a sterile site or the sole or predominant organism in a nonsterile site (odds ratio, 14.02; 95% CI, 1.79-109.58; P < .001). Conclusions and Relevance: Among critically ill patients requiring mechanical ventilation, administration of the probiotic L rhamnosus GG compared with placebo, resulted in no significant difference in the development of ventilator-associated pneumonia. These findings do not support the use of L rhamnosus GG in critically ill patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02462590.

Higher ICU Capacity Strain Is Associated With Increased Acute Mortality in Closed ICUs.

OBJECTIVES: To determine whether patients admitted to an ICU during times of strain, when compared with its own norm (i.e. accommodating a greater number of patients, higher acuity of illness, or frequent turnover), is associated with a higher risk of death in ICUs with closed models of intensivist staffing. DESIGN: We conducted a large, multicenter, observational cohort study. Multilevel mixed effects logistic regression was used to examine relationships for three measures of ICU strain (bed census, severity-weighted bed census, and activity-weighted bed census) on the day of admission with risk-adjusted acute hospital mortality. SETTING: Pooled case mix and outcome database of adult general ICUs participating in the Intensive Care National Audit and Research Centre Case Mix Programme. MEASUREMENTS AND MAIN RESULTS: The analysis included 149,310 patients admitted to 215 adult general ICUs in 213 hospitals in United Kingdom, Wales, and Northern Ireland. A relative lower strain in ICU capacity as measured by bed census on the calendar day (daytime hours) of admission was associated with decreased risk-adjusted acute hospital mortality (odds ratio, 0.94; 95% CI, 0.90-0.99; p = 0.01), whereas a nonsignificant association was seen between higher strain and increased acute hospital mortality (odds ratio, 1.04; 95% CI, 1.00-1.10; p = 0.07). The relationship between periods of high ICU strain and acute hospital mortality was strongest when bed census was composed of higher acuity patients (odds ratio, 1.05; 95% CI, 1.01-1.10; p = 0.03). No relationship was seen between high strain and ICU mortality. CONCLUSIONS: In closed staffing models of care, variations in bed census within individual ICUs was associated with patient's predicted risk of acute hospital mortality, particularly when its standardized bed census consisted of sicker patients.

Long-Term Quality of Life After Extracorporeal Membrane Oxygenation in ARDS Survivors: Systematic Review and Meta-Analysis.

PURPOSE: Extracorporeal membrane oxygenation (ECMO) is an increasingly prevalent treatment for acute respiratory failure (ARF). To evaluate the impact of ECMO support on long-term outcomes for critically ill adults with ARF. METHODS: We searched electronic databases 1948 through to November 30 2016; selected controlled trials or observational studies of critically ill adults with acute respiratory distress syndrome, examining long-term morbidity specifically health-related quality of life (HRQL); 2 authors independently selected studies, extracted data, and assessed methodological quality. ANALYSIS: Of the 633 citations, 1 randomized controlled trial and 5 observational studies met the selection criteria. Overall quality of observational studies was moderate to high (mean score on Newcastle-Ottawa scale, 7.2/9; range, 6-8). In 3 studies (n = 245), greater decrements in HRQL were seen for survivors of ECMO when compared to survivors of conventional mechanical ventilation (CMV) as measured by the Short Form 36 (SF-36) scores ([ECMO-CMV]: 5.40 [95% confidence interval, CI, 4.11 to 6.68]). As compared to CMV survivors, those who received ECMO experienced significantly less psychological morbidity (2 studies; n = 217 [ECMO-CMV]: mean weighted difference [MWD], -1.31 [95% CI, -1.98 to -0.64] for depression and MWD, -1.60 [95% CI, -1.80 to -1.39] for anxiety). CONCLUSIONS: Further studies are required to confirm findings and determine prognostic factors associated with more favorable outcomes in survivors of ECMO.

Sleep and Pathological Wakefulness at the Time of Liberation from Mechanical Ventilation (SLEEWE). A Prospective Multicenter Physiological Study.

Rationale: Abnormal patterns of sleep and wakefulness exist in mechanically ventilated patients. Objectives: In this study (SLEEWE [Effect of Sleep Disruption on the Outcome of Weaning from Mechanical Ventilation]), we aimed to investigate polysomnographic indexes as well as a continuous index for evaluating sleep depth, the odds ratio product (ORP), to determine whether abnormal sleep or wakefulness is associated with the outcome of spontaneous breathing trials (SBTs). Methods: Mechanically ventilated patients from three sites were enrolled if an SBT was planned the following day. EEG was recorded using a portable sleep diagnostic device 15 hours before the SBT. The ORP was calculated from the power of four EEG frequency bands relative to each other, ranging from full wakefulness (2.5) to deep sleep (0). The correlation between the right and left hemispheres' ORP (R/L ORP) was calculated. Measurements and Main Results: Among 44 patients enrolled, 37 had technically adequate signals: 11 (30%) passed the SBT and were extubated, 8 (21%) passed the SBT but were not deemed to be clinically ready for extubation, and 18 (49%) failed the SBT. Pathological wakefulness or atypical sleep were highly prevalent, but the distribution of classical sleep stages was similar between groups. The mean ORP and the proportion of time in which the ORP was >2.2 were higher in extubated patients compared with the other groups (P < 0.05). R/L ORP was significantly lower in patients who failed the SBT, and the area under the receiver operating characteristic curve of R/L ORP to predict failure was 0.91 (95% confidence interval, 0.75-0.98). Conclusions: Patients who pass an SBT and are extubated reach higher levels of wakefulness as indicated by the ORP, suggesting abnormal wakefulness in others. The hemispheric ORP correlation is much poorer in patients who fail an SBT.

One-Year Outcomes in Caregivers of Critically Ill Patients.

BACKGROUND: Few resources are available to support caregivers of patients who have survived critical illness; consequently, the caregivers' own health may suffer. We studied caregiver and patient characteristics to determine which characteristics were associated with caregivers' health outcomes during the first year after patient discharge from an intensive care unit (ICU). METHODS: We prospectively enrolled 280 caregivers of patients who had received 7 or more days of mechanical ventilation in an ICU. Using hospital data and self-administered questionnaires, we collected information on caregiver and patient characteristics, including caregiver depressive symptoms, psychological well-being, health-related quality of life, sense of control over life, and effect of providing care on other activities. Assessments occurred 7 days and 3, 6, and 12 months after ICU discharge. RESULTS: The caregivers' mean age was 53 years, 70% were women, and 61% were caring for a spouse. A large percentage of caregivers (67% initially and 43% at 1 year) reported high levels of depressive symptoms. Depressive symptoms decreased at least partially with time in 84% of the caregivers but did not in 16%. Variables that were significantly associated with worse mental health outcomes in caregivers were younger age, greater effect of patient care on other activities, less social support, less sense of control over life, and less personal growth. No patient variables were consistently associated with caregiver outcomes over time. CONCLUSIONS: In this study, most caregivers of critically ill patients reported high levels of depressive symptoms, which commonly persisted up to 1 year and did not decrease in some caregivers. (Funded by the Canadian Institutes of Health Research and others; ClinicalTrials.gov number, NCT00896220.).

Cost-Effectiveness Studies in the ICU: A Systematic Review.

OBJECTIVES: Cost-effectiveness analyses are increasingly used to aid decisions about resource allocation in healthcare; this practice is slow to translate into critical care. We sought to identify and summarize original cost-effectiveness studies presenting cost per quality-adjusted life year, incremental cost-effectiveness ratios, or cost per life-year ratios for treatments used in ICUs. DESIGN: We conducted a systematic search of the English-language literature for cost-effectiveness analyses published from 1993 to 2018 in critical care. Study quality was assessed using the Drummond checklist. SETTING: Critical care units. PATIENTS OR SUBJECTS: Critical care patients. INTERVENTIONS: Identified studies with cost-effectiveness analyses. MEASUREMENTS AND MAIN RESULTS: We identified 97 studies published through 2018 with 156 cost-effectiveness ratios. Reported incremental cost-effectiveness ratios ranged from -$119,635 (hypothetical cohort of patients requiring either intermittent or continuous renal replacement therapy) to $876,539 (data from an acute renal failure study in which continuous renal replacement therapy was the most expensive therapy). Many studies reported favorable cost-effectiveness profiles (i.e., below $50,000 per life year or quality-adjusted life year). However, several therapies have since been proven harmful. Over 2 decades, relatively few cost-effectiveness studies in critical care have been published (average 4.6 studies per year). There has been a more recent trend toward using hypothetical cohorts and modeling scenarios without proven clinical data (2014-2018: 19/33 [58%]). CONCLUSIONS: Despite critical care being a significant healthcare cost burden there remains a paucity of studies in the literature evaluating its cost effectiveness.

Models of Peer Support to Remediate Post-Intensive Care Syndrome: A Report Developed by the Society of Critical Care Medicine Thrive International Peer Support Collaborative.

OBJECTIVES: Patients and caregivers can experience a range of physical, psychologic, and cognitive problems following critical care discharge. The use of peer support has been proposed as an innovative support mechanism. DESIGN: We sought to identify technical, safety, and procedural aspects of existing operational models of peer support, among the Society of Critical Care Medicine Thrive Peer Support Collaborative. We also sought to categorize key distinctions between these models and elucidate barriers and facilitators to implementation. SUBJECTS AND SETTING: Seventeen Thrive sites from the United States, United Kingdom, and Australia were represented by a range of healthcare professionals. MEASUREMENTS AND MAIN RESULTS: Via an iterative process of in-person and email/conference calls, members of the Collaborative defined the key areas on which peer support models could be defined and compared, collected detailed self-reports from all sites, reviewed the information, and identified clusters of models. Barriers and challenges to implementation of peer support models were also documented. Within the Thrive Collaborative, six general models of peer support were identified: community based, psychologist-led outpatient, models-based within ICU follow-up clinics, online, groups based within ICU, and peer mentor models. The most common barriers to implementation were recruitment to groups, personnel input and training, sustainability and funding, risk management, and measuring success. CONCLUSIONS: A number of different models of peer support are currently being developed to help patients and families recover and grow in the postcritical care setting.

Challenges in conducting long-term outcomes studies in critical care.

PURPOSE OF REVIEW: Evaluating longer term mortality, morbidity, and quality of life in survivors of critical illness is a research priority. This review details the challenges of long-term follow-up studies of critically ill patients and highlights recently proposed methodological solutions. RECENT FINDINGS: Barriers to long-term follow-up studies of critical care survivors include high rates of study attrition because of death or loss to follow-up, data missingness from experienced morbidity, and lack of standardized outcome as well as reporting of key covariates. A number of recent methods have been proposed to reduce study patients attrition, including minimum data set selection and visits to transitional care or home settings, yet these have significant downsides as well. Conducting long-term follow-up even in the absence of such models carries a high expense, as personnel are very costly, and patients/families require reimbursement for their time and inconvenience. SUMMARY: There is a reason why many research groups do not conduct long-term outcomes in critical care: it is very difficult. Challenges of long-term follow-up require careful consideration by study investigators to ensure our collective success in data integration and a better understanding of underlying mechanisms of mortality and morbidity seen in critical care survivorship.