Temporal Trends in Mortality of Critically Ill Patients with Sepsis in the United Kingdom, 1988-2019.

Rationale: Sepsis is a frequent cause of ICU admission and mortality. Objectives: To evaluate temporal trends in the presentation and outcomes of patients admitted to the ICU with sepsis and to assess the contribution of changing case mix to outcomes. Methods: We conducted a retrospective cohort study of patients admitted to 261 ICUs in the United Kingdom during 1988-1990 and 1996-2019 with nonsurgical sepsis. Measurements and Main Results: A total of 426,812 patients met study inclusion criteria. The patients had a median (interquartile range) age of 66 (53-75) years, and 55.6% were male. The most common sites of infection were respiratory (60.9%), genitourinary (11.5%), and gastrointestinal (10.3%). Compared with patients in 1988-1990, patients in 2017-2019 were older (median age, 66 vs. 63 yr), were less acutely ill (median Acute Physiology and Chronic Health Evaluation II acute physiology score, 14 vs. 20), and more often had genitourinary sepsis (13.4% vs. 2.0%). Hospital mortality decreased from 54.6% (95% confidence interval [CI], 51.0-58.1%) in 1988-1990 to 32.4% (95% CI, 32.1-32.7%) in 2017-2019, with an adjusted odds ratio of 0.64 (95% CI, 0.54-0.75). The adjusted absolute hospital mortality reduction from 1988-1990 to 2017-2019 was 8.8% (95% CI, 5.6-12.1). Thus, of the observed 22.2-percentage point reduction in hospital mortality, 13.4 percentage points (60% of total reduction) were explained by case mix changes, whereas 8.8 percentage points (40% of total reduction) were not explained by measured factors and may be a result of improvements in ICU management. Conclusions: Over a 30-year period, mortality for ICU admissions with sepsis decreased substantially. Although changes in case mix accounted for the majority of observed mortality reduction, there was an 8.8-percentage point reduction in mortality not explained by case mix.

Effectiveness of Fludrocortisone Plus Hydrocortisone versus Hydrocortisone Alone in Septic Shock: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

Rationale: The use of hydrocortisone in adult patients with septic shock is controversial, and the effectiveness of adding fludrocortisone to hydrocortisone remains uncertain. Objectives: To assess the comparative effectiveness and safety of fludrocortisone plus hydrocortisone, hydrocortisone alone, and placebo or usual care in adults with septic shock. Methods: A systematic review and a Bayesian network meta-analysis of peer-reviewed randomized trials were conducted. The primary outcome was all-cause mortality at last follow-up. Treatment effects are presented as relative risks (RRs) with 95% credible intervals (CrIs). Placebo or usual care was the reference treatment. Measurements and Main Results: Among 7,553 references, we included 17 trials (7,688 patients). All-cause mortality at last follow-up was lowest with fludrocortisone plus hydrocortisone (RR, 0.85; 95% CrI, 0.72-0.99; 98.3% probability of superiority, moderate-certainty evidence), followed by hydrocortisone alone (RR, 0.97; 95% CrI, 0.87-1.07; 73.1% probability of superiority, low-certainty evidence). The comparison of fludrocortisone plus hydrocortisone versus hydrocortisone alone was based primarily on indirect evidence (only two trials with direct evidence). Fludrocortisone plus hydrocortisone was associated with a 12% lower risk of all-cause mortality compared with hydrocortisone alone (RR, 0.88; 95% CrI, 0.74-1.03; 94.2% probability of superiority, moderate-certainty evidence). Conclusions: In adult patients with septic shock, fludrocortisone plus hydrocortisone was associated with lower risk of all-cause mortality at last follow-up than placebo and hydrocortisone alone. The scarcity of head-to-head trials comparing fludrocortisone plus hydrocortisone versus hydrocortisone alone led our network meta-analysis to rely primarily on indirect evidence for this comparison. Although we undertook several sensitivity analyses and assessments, these findings should be considered while also acknowledging the heterogeneity of included trials.

Determinants and practice variability of oxygen administration during surgery in the U.S., a retrospective cohort study.

BACKGROUND: The best approaches to supplemental oxygen administration during surgery remain unclear, which may contribute to variation in practice. We aimed to assess determinants of oxygen administration and its variability during surgery. METHODS: Using multivariable linear mixed-effects regression, we measured the associations between intraoperative fraction of inspired oxygen and patient, procedure, medical center, anesthesiologist, and in-room anesthesia provider factors in surgical cases of 120 minutes or longer in adult patients who received general anesthesia with tracheal intubation and were admitted to the hospital after surgery between January 2016 and January 2019 at 42 medical centers across the U.S. participating in the Multicenter Perioperative Outcomes Group data registry. RESULTS: The sample included 367,841 cases (median [25 th, 75 th] age, 59 [47, 69] years; 51.1% women; 26.1% treated with nitrous oxide) managed by 3,836 anesthesiologists and 15,381 in-room anesthesia providers. Median (25 th, 75 th) fraction of inspired oxygen was 0.55 (0.48, 0.61), with 6.9% of cases <0.40 and 8.7% >0.90. Numerous patient and procedure factors were statistically associated with increased inspired oxygen, notably advanced ASA classification, heart disease, emergency surgery, and cardiac surgery, but most factors had little clinical significance (<1% inspired oxygen change). Overall, patient factors only explained 3.5% (95% CI, 3.5 to 3.5) of the variability in oxygen administration and procedure factors 4.4% (4.2 to 4.6). Anesthesiologist explained 7.7% (7.2 to 8.2) of the variability in oxygen administration, in-room anesthesia provider 8.1% (7.8 to 8.4), medical center 23.3% (22.4 to 24.2), and 53.0% (95% CI, 52.4 to 53.6) was unexplained. CONCLUSIONS: Among adults undergoing surgery with anesthesia and tracheal intubation, supplemental oxygen administration was variable and appeared arbitrary. Most patient and procedure factors had statistical but minor clinical associations with oxygen administration. Medical center and anesthesia provider explained significantly more variability in oxygen administration than patient or procedure factors.

New antipsychotic prescription and recurrent infections among adult sepsis survivors: A population-based cohort study.

PURPOSE: Antipsychotic agents, which may increase the risk of infection through dopaminergic dysregulation, are prescribed to a fraction of patients following critical illness. We compared the rate of recurrent sepsis among patients who filled a prescription for antipsychotics with high- or low-D2 affinity. METHODS: Population-based cohort with active comparator design. We included sepsis survivors older than 65 years with intensive care unit admission and new prescription of antipsychotics in Ontario 2008-2019. The primary outcome were recurrent sepsis episodes within 1 year of follow-up. Patients who filled a prescription within 30 days of hospital discharge for high-D2 affinity antipsychotics (e.g., haloperidol) were compared with patients who filled a prescription within 30 days of hospital discharge for low-D2 affinity antipsychotics (e.g., quetiapine). Multivariable zero-inflated Poisson regression models with robust standard errors adjusting for confounding at baseline were used to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI). RESULTS: Overall, 1879 patients filled a prescription for a high-D2, and 1446 patients filled a prescription for a low-D2 affinity antipsychotic. Patients who filled a prescription for a high-D2 affinity antipsychotic did not present a higher rate of recurrent sepsis during 1 year of follow-up, compared with patients who filled a prescription for a low-D2 affinity antipsychotic (IRR: 1.12; 95% CI: 0.94, 1.35). CONCLUSIONS: We did not find conclusive evidence of a higher rate of recurrent sepsis associated with the prescription of high-D2 affinity antipsychotics (compared with low-D2 affinity antipsychotics) by 1 year of follow-up in adult sepsis survivors with intensive care unit admission.

Accounting for Competing Events When Evaluating Long-Term Outcomes in Survivors of Critical Illness.

The clinical trajectory of survivors of critical illness after hospital discharge can be complex and highly unpredictable. Assessing long-term outcomes after critical illness can be challenging because of possible competing events, such as all-cause death during follow-up (which precludes the occurrence of an event of particular interest). In this perspective, we explore challenges and methodological implications of competing events during the assessment of long-term outcomes in survivors of critical illness. In the absence of competing events, researchers evaluating long-term outcomes commonly use the Kaplan-Meier method and the Cox proportional hazards model to analyze time-to-event (survival) data. However, traditional analytical and modeling techniques can yield biased estimates in the presence of competing events. We present different estimands of interest and the use of different analytical approaches, including changes to the outcome of interest, Fine and Gray regression models, cause-specific Cox proportional hazards models, and generalized methods (such as inverse probability weighting). Finally, we provide code and a simulated dataset to exemplify the application of the different analytical strategies in addition to overall reporting recommendations.

Do Thresholds for Invasive Ventilation in Hypoxemic Respiratory Failure Exist? A Cohort Study.

Rationale: Invasive ventilation is a significant event for patients with respiratory failure. Physiologic thresholds standardize the use of invasive ventilation in clinical trials, but it is unknown whether thresholds prompt invasive ventilation in clinical practice. Objectives: To measure, in patients with hypoxemic respiratory failure, the probability of invasive ventilation within 3 hours after meeting physiologic thresholds. Methods: We studied patients admitted to intensive care receiving FiO2 of 0.4 or more via nonrebreather mask, noninvasive positive pressure ventilation, or high-flow nasal cannula, using data from the Medical Information Mart for Intensive Care (MIMIC)-IV database (2008-2019) and the Amsterdam University Medical Centers Database (AmsterdamUMCdb) (2003-2016). We evaluated 17 thresholds, including the ratio of arterial to inspired oxygen, the ratio of saturation to inspired oxygen ratio, composite scores, and criteria from randomized trials. We report the probability of invasive ventilation within 3 hours of meeting each threshold and its association with covariates using odds ratios (ORs) and 95% credible intervals (CrIs). Measurements and Main Results: We studied 4,726 patients (3,365 from MIMIC, 1,361 from AmsterdamUMCdb). Invasive ventilation occurred in 28% (1,320). In MIMIC, the highest probability of invasive ventilation within 3 hours of meeting a threshold was 20%, after meeting prespecified neurologic or respiratory criteria while on vasopressors, and 19%, after a ratio of arterial to inspired oxygen of <80 mm Hg. In AmsterdamUMCdb, the highest probability was 34%, after vasopressor initiation, and 25%, after a ratio of saturation to inspired oxygen of <90. The probability after meeting the threshold from randomized trials was 9% (MIMIC) and 13% (AmsterdamUMCdb). In MIMIC, a race/ethnicity of Black (OR, 0.75; 95% CrI, 0.57-0.96) or Asian (OR, 0.6; 95% CrI, 0.35-0.95) compared with White was associated with decreased probability of invasive ventilation after meeting a threshold. Conclusions: The probability of invasive ventilation within 3 hours of meeting physiologic thresholds was low and associated with patient race/ethnicity.

Surgeon Postoperative Opioid Prescribing Intensity and Risk of Persistent Opioid Use Among Opioid-naive Adult Patients: A Population-based Cohort Study.

OBJECTIVE: The aim of this study was to determine the relationship between surgeon opioid prescribing intensity and subsequent persistent opioid use among patients undergoing surgery. SUMMARY BACKGROUND DATA: The extent to which different postoperative prescribing practices lead to persistent opioid use among surgical patients is poorly understood. METHODS: Retrospective population-based cohort study assessing opioid-naive adults who underwent 1 of 4 common surgeries. For each surgical procedure, the surgeons' opioid prescribing intensity was categorized into quartiles based on the median daily dose of morphine equivalents of opioids dispensed within 7 days of the surgical visit for all the surgeons' patients. The primary outcome was persistent opioid use in the year after surgery, defined as 180 days or more of opioids supplied within the year after the index date excluding prescriptions filled within 30 days of the index date. Secondary outcomes included a refill for an opioid within 30 days and emergency department visits and hospitalizations within 1 year. RESULTS: Among 112,744 surgical patients, patients with surgeons in the highest intensity quartile (Q4) were more likely to fill an opioid prescription within 7 days after surgery compared with those in the lowest quartile (Q1) (83.3% Q4 vs 65.4% Q1). In the primary analysis, the incidence of persistent opioid use in the year after surgery was rare in both highest and lowest quartiles (0.3% Q4 vs 0.3% Q1), adjusted odds ratio (AOR) of 1.18, 95% CI 0.83-1.66). However, multiple analyses using stricter definitions of persistent use that included the requirement of a prescription filled within 7 days of discharge after surgery showed a significant association with surgeon quartile (up to an AOR 1.36, 95% CI 1.25, 1.47). Patients in Q4 were more likely to refill a prescription within 30 days (4.8% Q4 vs 4.0% Q1, AOR 1.14, 95% CI 1.04-1.24). CONCLUSIONS: Surgeons' overall prescribing practices may contribute to persistent opioid use and represent a target for quality improvement. However, the association was highly sensitive to the definition of persistent use used.

Risk Factors for Major Cardiovascular Events in Adult Sepsis Survivors: A Population-Based Cohort Study.

OBJECTIVES: To describe risk factors for major cardiovascular events in adults following hospital discharge after sepsis. DESIGN: Population-based cohort study. SETTING: Ontario, Canada (2008-2017). PATIENTS: Adult patients (age 18 yr or older) who survived a first sepsis hospitalization without preexisting cardiovascular disease. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary composite outcome was myocardial infarction, stroke, or cardiovascular death up to 5 years following hospital discharge. We used cause-specific Cox proportional hazards models that accounted for the competing risk of noncardiovascular death to describe factors associated with major cardiovascular events. We identified 268,259 adult patients without cardiovascular disease (median age, 72 yr), of whom 10.4% experienced a major cardiovascular event during a median follow-up of 3 years. After multivariable adjustment, age (hazard ratio [HR], 1.53 for every 10 yr; 95% CI, 1.51-1.54), male sex (HR, 1.23; 95% CI, 1.20-1.26), diabetes mellitus (HR, 1.24; 95% CI, 1.21-1.27), hypertension (HR, 1.34; 95% CI, 1.30-1.38), prevalent atrial fibrillation (HR, 1.46; 95% CI, 1.40-1.52), and chronic kidney disease (HR, 1.11; 95% CI, 1.06-1.16) were associated with major cardiovascular events during long-term follow-up. Sepsis characteristics such as site of infection (pneumonia vs other: HR, 1.09; 95% CI, 1.05-1.12), septic shock (HR, 1.08; 95% CI, 1.05-1.11), and renal replacement therapy (HR, 1.51; 95% CI, 1.38-1.64) were also associated with subsequent cardiovascular events. In an analysis restricting to patients with troponin values measured during the hospitalization (26,400 patients), an elevated troponin was also associated with subsequent cardiovascular events (HR, 1.23; 95% CI, 1.13-1.33). CONCLUSIONS: Classic cardiovascular risk factors, comorbid conditions, and characteristics of the sepsis episode were associated with a higher hazard of major cardiovascular events in adult sepsis survivors. These findings may inform enrichment strategies for future studies.

Nonopioid Analgesic Prescriptions Filled after Surgery among Older Adults in Ontario, Canada: A Population-based Cohort Study.

BACKGROUND: The objective was to assess changes over time in prescriptions filled for nonopioid analgesics for older postoperative patients in the immediate postdischarge period. The authors hypothesized that the number of patients who filled a nonopioid analgesic prescription increased during the study period. METHODS: The authors performed a population-based cohort study using linked health administrative data of 278,366 admissions aged 66 yr or older undergoing surgery between fiscal year 2013 and 2019 in Ontario, Canada. The primary outcome was the percentage of patients with new filled prescriptions for nonopioid analgesics within 7 days of discharge, and the secondary outcome was the analgesic class. The authors assessed whether patients filled prescriptions for a nonopioid only, an opioid only, both opioid and nonopioid prescriptions, or a combination opioid/nonopioid. RESULTS: Overall, 22% (n = 60,181) of patients filled no opioid prescription, 2% (n = 5,534) filled a nonopioid only, 21% (n = 59,608) filled an opioid only, and 55% (n = 153,043) filled some combination of opioid and nonopioid. The percentage of patients who filled a nonopioid prescription within 7 days postoperatively increased from 9% (n = 2,119) in 2013 to 28% (n = 13,090) in 2019, with the greatest increase for acetaminophen: 3% (n = 701) to 20% (n = 9,559). The percentage of patients who filled a combination analgesic prescription decreased from 53% (n = 12,939) in 2013 to 28% (n = 13,453) in 2019. However, the percentage who filled both an opioid and nonopioid prescription increased: 4% (n = 938) to 21% (n = 9,880) so that the overall percentage of patients who received both an opioid and a nonopioid remained constant over time 76% (n = 18,642) in 2013 to 75% (n = 35,391) in 2019. CONCLUSIONS: The proportion of postoperative patients who fill prescriptions for nonopioid analgesics has increased. However, rather than a move to use of nonopioids alone for analgesia, this represents a shift away from combination medications toward separate prescriptions for opioids and nonopioids.

Oxygenation thresholds for invasive ventilation in hypoxemic respiratory failure: a target trial emulation in two cohorts.

BACKGROUND: The optimal thresholds for the initiation of invasive ventilation in patients with hypoxemic respiratory failure are unknown. Using the saturation-to-inspired oxygen ratio (SF), we compared lower versus higher hypoxemia severity thresholds for initiating invasive ventilation. METHODS: This target trial emulation included patients from the Medical Information Mart for Intensive Care (MIMIC-IV, 2008-2019) and the Amsterdam University Medical Centers (AmsterdamUMCdb, 2003-2016) databases admitted to intensive care and receiving inspired oxygen fraction ≥ 0.4 via non-rebreather mask, noninvasive ventilation, or high-flow nasal cannula. We compared the effect of using invasive ventilation initiation thresholds of SF < 110, < 98, and < 88 on 28-day mortality. MIMIC-IV was used for the primary analysis and AmsterdamUMCdb for the secondary analysis. We obtained posterior means and 95% credible intervals (CrI) with nonparametric Bayesian G-computation. RESULTS: We studied 3,357 patients in the primary analysis. For invasive ventilation initiation thresholds SF < 110, SF < 98, and SF < 88, the predicted 28-day probabilities of invasive ventilation were 72%, 47%, and 19%. Predicted 28-day mortality was lowest with threshold SF < 110 (22.2%, CrI 19.2 to 25.0), compared to SF < 98 (absolute risk increase 1.6%, CrI 0.6 to 2.6) or SF < 88 (absolute risk increase 3.5%, CrI 1.4 to 5.4). In the secondary analysis (1,279 patients), the predicted 28-day probability of invasive ventilation was 50% for initiation threshold SF < 110, 28% for SF < 98, and 19% for SF < 88. In contrast with the primary analysis, predicted mortality was highest with threshold SF < 110 (14.6%, CrI 7.7 to 22.3), compared to SF < 98 (absolute risk decrease 0.5%, CrI 0.0 to 0.9) or SF < 88 (absolute risk decrease 1.9%, CrI 0.9 to 2.8). CONCLUSION: Initiating invasive ventilation at lower hypoxemia severity will increase the rate of invasive ventilation, but this can either increase or decrease the expected mortality, with the direction of effect likely depending on baseline mortality risk and clinical context.

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.

Variation in Bed-to-Physician Ratios During Weekday Daytime Hours in ICUs in Australia and New Zealand.

OBJECTIVES: To determine common "bed-to-physician" ratios during weekday hours across ICUs and assess factors associated with variability in this ratio. DESIGN: Retrospective cohort study. SETTING: All ICUs in Australia/New Zealand that participated in a staffing survey administered in 2017-2018. PATIENTS: ICU admissions from 2016 to 2018. METHODS: We linked survey data with patient-level data. We defined: 1) bed-to-intensivist ratio as the number of usually available ICU beds divided by the number of onsite weekday daytime intensivists; and 2) bed-to-physician ratio as the number of available ICU beds divided by the total number of physicians (intensivists + nonintensivists, including trainees). We calculated the median and interquartile range (IQR) of bed-to-intensivist ratio and bed-to-physician ratios during weekday hours. We assessed variability in each by type of hospital and ICU and by severity of illness of patients, defined by the predicted hospital mortality. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 123 (87.2%) of Australia/New Zealand ICUs that returned staffing surveys, 114 (92.7%) had an intensivist present during weekday daytime hours, and 116 (94.3%) reported at least one nonintensivist physician. The median bed-to-intensivist ratio was 8.0 (IQR, 6.0-11.4), which decreased to a bed-to-physician ratio of 3.0 (IQR, 2.2-4.9). These ratios varied with mean severity of illness of the patients in the unit. The median bed-to-intensivist ratio was highest (13.5) for ICUs with a mean predicted mortality > 2-4%, and the median bed-to-physician ratio was highest (5.7) for ICUs with a mean predicted mortality of > 4-6%. Both ratios decreased and plateaued in ICUs with a mean predicted mortality for patients greater than 8% (median bed-to-intensivist ratio range, 6.8-8.0, and bed-to-physician ratio range of 2.4-2.7). CONCLUSIONS: Weekday bed-to-physician ratios in Australia/New Zealand ICUs are lower than the bed-to-intensivist ratios and have a relatively fixed ratio of less than 3 for units taking care of patients with a higher average severity of illness. These relationships may be different in other countries or healthcare systems.

Outcomes After Direct Discharge Home From Critical Care Units: A Population-Based Cohort Analysis.

OBJECTIVES: To compare health service use and clinical outcomes for patients with and without direct discharge to home (DDH) from ICUs in Ontario. DESIGN: Population-based, observational, cohort study using propensity scoring to match patients who were DDH to those not DDH and a preference-based instrumental variable (IV) analysis using ICU-level DDH rate as the IV. SETTING: ICUs in Ontario. PATIENTS: Patients discharged home from a hospitalization either directly or within 48 hours of care in an ICU between April 1, 2015, and March 31, 2017. INTERVENTION: DDH from ICU. MEASUREMENTS AND MAIN RESULTS: Among 76,737 patients in our cohort, 46,859 (61%) were DDH from the ICU. In the propensity matched cohort, the odds for our primary outcome of hospital readmission or emergency department (ED) visit within 30 days were not significantly different for patients DDH (odds ratio [OR], 1.00; 95% CI, 0.96-1.04), and there was no difference in mortality at 90 days for patients DDH (OR, 1.08; 95% CI, 0.97-1.21). The effect on hospital readmission or ED visits was similar in the subgroup of patients discharged from level 2 (OR, 0.98; 95% CI, 0.92-1.04) and level 3 ICUs (OR, 1.02; 95% CI, 0.96-1.09) and in the subgroups with cardiac conditions (OR, 1.03; 95% CI, 0.96-1.12) and noncardiac conditions (OR, 0.98; 95% CI, 0.94-1.03). Similar results were obtained in the IV analysis (coefficient for hospital readmission or ED visit within 30 d = -0.03 ± 0.03 ( se ); p = 0.3). CONCLUSIONS: There was no difference in outcomes for patients DDH compared with ward transfer prior to discharge when two approaches were used to minimize confounding within a large health systemwide observational cohort. We did not evaluate how patients are selected for DDH. Our results suggest that with careful patient selection, this practice might be feasible for routine implementation to ensure efficient and safe use of limited healthcare resources.

Impact of Ketamine on Analgosedative Consumption in Critically Ill Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: The aim of this study was to synthesize evidence available on continuous infusion ketamine versus nonketamine regimens for analgosedation in critically ill patients. DATA SOURCES: A search of MEDLINE, EMBASE, CINAHL, CDSR, and ClinicalTrials.gov was performed from database establishment to November 2021 using the following search terms: critical care, ICU, ketamine, sedation, and anesthesia. All studies included the primary outcome of interest: daily opioid and/or sedative consumption. STUDY SELECTION AND DATA EXTRACTION: Relevant human studies were considered. Randomized controlled trials (RCT), quasi-experimental studies, and observational cohort studies were eligible. Two reviewers independently screened articles, extracted data, and appraised studies using the Cochrane RoB and ROBINS-I tools. DATA SYNTHESIS: A total of 13 RCTs, 5 retrospective, and 1 prospective cohort study were included (2255 participants). The primary analysis of six RCTs demonstrated reduced opioid consumption with ketamine regimens (n = 494 participants, -13.19 µg kg-1 h-1 morphine equivalents, 95% CI -22.10 to -4.28, P = 0.004). No significant difference was observed in sedative consumption, duration of mechanical ventilation (MV), ICU or hospital length of stay (LOS), intracranial pressure, and mortality. Small sample size of studies may have limited ability to detect true differences between groups. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This meta-analysis examining ketamine use in critically ill patients is the first restricting analysis to RCTs and includes up-to-date publication of trials. Findings may guide clinicians in consideration and dosing of ketamine for multimodal analgosedation. CONCLUSION: Results suggest ketamine as an adjunct analgosedative has the potential to reduce opioid exposure in postoperative and MV patients in the ICU. More RCTs are required before recommending routine use of ketamine in select populations.

Attention to Immortal Time Bias in Critical Care Research.

Observational studies in critical care medicine offer a popular and practical approach to questions of treatment effectiveness. Although observational research is widely understood to be susceptible to design and interpretation challenges, one well-described source of bias-immortal time bias (ITB)-is frequently present yet often overlooked. ITB may be introduced by study design oversights or mishandled during data analysis. When present, ITB can create inappropriate estimates of the benefit or harm of an exposure or intervention. Studies examining treatments in critically ill patients may be particularly susceptible to ITB, with consequences for clinical adoption and design and initiation of randomized trials. In this Critical Care Perspective, we illustrate the persistent problem of ITB in observational research using recent studies of hydrocortisone, ascorbic acid, and thiamine therapy in patients with sepsis and septic shock. Of the eight studies examined, none contained enough design or reporting elements to rule out the presence of ITB. To mitigate the influence of ITB in future observational studies, we present a novel checklist to help readers assess the features of study design, analysis, and reporting that introduce ITB or obscure its presence. We recommend that commonly used tools designed to evaluate observational research studies should include an ITB assessment.

Informing Healthcare Decisions with Observational Research Assessing Causal Effect. An Official American Thoracic Society Research Statement.

Rationale: Decisions in medicine are made on the basis of knowledge and reasoning, often in shared conversations with patients and families in consideration of clinical practice guideline recommendations, individual preferences, and individual goals. Observational studies can provide valuable knowledge to inform guidelines, decisions, and policy.Objectives: The American Thoracic Society (ATS) created a multidisciplinary ad hoc committee to develop a research statement to clarify the role of observational studies-alongside randomized controlled trials (RCTs)-in informing clinical decisions in pulmonary, critical care, and sleep medicine.Methods: The committee examined the strengths of observational studies assessing causal effects, how they complement RCTs, factors that impact observational study quality, perceptions of observational research, and, finally, the practicalities of incorporating observational research into ATS clinical practice guidelines.Measurements and Main Results: There are strengths and weakness of observational studies as well as RCTs. Observational studies can provide evidence in representative and diverse patient populations. Quality observational studies should be sought in the development of ATS clinical practice guidelines, and medical decision-making in general, when 1) no RCTs are identified or RCTs are appraised as being of low- or very low-quality (replacement); 2) RCTs are of moderate quality because of indirectness, imprecision, or inconsistency, and observational studies mitigate the reason that RCT evidence was downgraded (complementary); or 3) RCTs do not provide evidence for outcomes that a guideline committee considers essential for decision-making (e.g., rare or long-term outcomes; "sequential").Conclusions: Observational studies should be considered in developing clinical practice guidelines and in making clinical decisions.

Trends in postoperative opioid prescribing in Ontario between 2013 and 2019: a population-based cohort study.

PURPOSE: Many hospital and provincial-level recommendations now advise a tailored approach to postoperative opioid prescribing; recent trends in postoperative prescribing at the population level have not been well described. METHODS: This population-based cohort study included opioid-naïve patients ≥ 18 yr of age who underwent one of 16 surgical procedures with varying anticipated postoperative pain between July 2013 and March 2020. We evaluated the rate of filled opioid prescriptions within seven days postoperatively, the total morphine milligram equivalent (MME) dose, duration, and type of the first opioid prescription. We then compared the MMEs in initial opioid prescriptions with available procedure-specific recommendations. RESULTS: The sample included 900,989 opioid-naïve patients (mean [standard deviation (SD)] age of 50 [17] 31 yr; 66% women). The percentage of patients filling an opioid prescription within 7 days postoperatively increased from 65% in 2013 to 69% in 2016, and returned to the baseline (65%) in 2019. The mean (SD) MMEs dispensed increased until 2015/2016 and then declined (226 [176] MMEs in 2013, 240 [202] MMEs in 2016, and 175 [175] MMEs in 2019). The most frequently prescribed opioid in 2013 was oxycodone compared with hydromorphone in 2019. Among patients who filled an opioid prescription in 2013, 67% were prescribed an opioid dose higher than those in one set of available prescribing recommendations, while in 2019, 41% were prescribed doses above those stated in recommendations. CONCLUSION: While the proportion of patients filling an opioid prescription postoperatively remained s during the study period, MMEs decreased after 2016. Opioid prescribing remained significantly higher than available prescribing recommendations, particularly among low pain procedures. These findings highlight the need to identify strategies that improve adherence to surgery-specific prescribing guidelines in North America.

RéSUMé: OBJECTIF: De nombreuses recommandations à l'échelle hospitalière et provinciale préconisent aujourd'hui une approche personnalisée de la prescription d'opioïdes postopératoires; les tendances récentes de la prescription postopératoire au niveau de la population n'ont pas été bien décrites. MéTHODE: Cette étude de cohorte basée sur la population englobait des patients naïfs aux opioïdes et âgés de ≥ 18 ans ayant bénéficié de l'une de 16 interventions chirurgicales entraînant une douleur postopératoire anticipée variable entre juillet 2013 et mars 2020. Nous avons évalué le taux d'ordonnances d'opioïdes remplies dans les sept jours suivant l'opération, la dose totale d'équivalent en milligrammes de morphine (EMM), ainsi que la durée et le type de la première ordonnance d'opioïdes. Nous avons ensuite comparé les EMM des ordonnances initiales d'opioïdes avec les recommandations spécifiques à l'intervention disponibles. RéSULTATS: L'échantillon comprenait 900 989 patients naïfs aux opioïdes (âge moyen [écart type (ET)] de 50 [17] ans; 66 % de femmes). La proportion de patients remplissant une ordonnance d'opioïdes dans les 7 jours suivant l'opération est passée de 65 % en 2013 à 69 % en 2016, et est revenue à la valeur de référence (65 %) en 2019. Les EMM moyens (ET) administrés ont augmenté jusqu'en 2015-2016, puis ont diminué (226 [176] EMM en 2013, 240 [202] EMM en 2016 et 175 [175] EMM en 2019). L'opioïde le plus fréquemment prescrit en 2013 était l'oxycodone par rapport à l'hydromorphone en 2019. Parmi les patients qui ont rempli une ordonnance d'opioïdes en 2013, 67 % se sont vu prescrire une dose d'opioïdes supérieure à celle d'un ensemble de recommandations de prescription disponibles, tandis qu'en 2019, 41 % se sont vu prescrire des doses supérieures à celles indiquées dans les recommandations. CONCLUSION: Alors que la proportion de patients remplissant une ordonnance d'opioïdes en période postopératoire est restée stable au cours de la période d'étude, les EMM ont diminué après 2016. La prescription d'opioïdes est demeurée beaucoup plus élevée que les recommandations de prescription disponibles, en particulier dans le cas d'interventions à faible douleur. Ces résultats soulignent la nécessité d'identifier des stratégies pour améliorer l'adhérence aux recommandations de prescription spécifiques au type de chirurgie en Amérique du Nord.

Preoperative Sedative-hypnotic Medication Use and Adverse Postoperative Outcomes.

OBJECTIVE: To determine the association between preoperative benzodiazepine and nonbenzodiazepine receptor agonist ("Z-drugs") use and adverse outcomes after surgery. BACKGROUND: Prescriptions for benzodiazepines and Z-drugs have increased over the past decade. Despite this, the association of preoperative benzodiazepines and Z-drug receipt with adverse outcomes after surgery is unknown. METHODS: Using the Optum Clinformatics Datamart, we performed a retrospective cohort study of adults 18 years or older who underwent any of 10 common surgical procedures between 2010 and 2015. The principal exposure was one or more filled prescriptions for a benzodiazepine or Z-drug in the 90 days before surgery. The primary outcome was any emergency department visit or hospital admission for either (1) a drug related adverse medical event or overdose or (2) a traumatic injury in the 30 days after surgery. RESULTS: Of 785,346 patients meeting inclusion criteria, 94,887 (12.1%) filled a preoperative prescription for a benzodiazepine or Z-drug. From multivariable logistic regression, benzodiazepine or Z-drug use was associated with an increased odds of an adverse postoperative event [odds ratio 1.13; 95% confidence interval: 1.08-1.18). In a separate regression, coprescription of benzodiazepines or Z-drugs with opioids was associated with a 1.45 odds of an adverse postoperative event (95% confidence interval: 1.37-1.53). CONCLUSIONS: Preoperative benzodiazepines and Z-drug use is common and associated with increased odds of adverse outcomes after surgery, particularly when coprescribed with opioids. Counseling on appropriate benzodiazepine and Z-drug use in advance of elective surgery may potentially increase the safety of surgical care.

The associations between direct and delayed critical care unit admission with mortality and readmissions among patients with heart failure.

BACKGROUND: Although greater than 20% of patients hospitalized with heart failure (HF) are admitted to a critical care unit, associated outcomes, and costs have not been delineated. We determined 30-day mortality, 30-day readmissions, and hospital costs associated with direct or delayed critical care unit admission. METHODS: In a population-based analysis, we compared HF patients who were admitted to critical care directly from the emergency department (direct), after initial ward admission (delayed), or never admitted to critical care during their hospital stay (ward-only). RESULTS: Among 178,997 HF patients (median age 80 [IQR 71-86] years, 49.6% men) 36,175 (20.2%) were admitted to critical care during their hospitalization (April 2003 to March 2018). Critical care patients were admitted directly from the emergency department (direct, 81.9%) or after initial ward admission (delayed, 18.1%). Multivariable-adjusted hazard ratios (HR) for all-cause 30-day mortality were: 1.69 for direct (95% confidence interval [CI]; 1.55, 1.84) and 4.92 for delayed (95% CI; 4.26, 5.68) critical care-admitted compared to ward-only patients. Multivariable-adjusted repeated events analysis demonstrated increased risk for all-cause 30-day readmission with both direct (HR 1.04, 95% CI; 1.01, 1.08, P = .013) and delayed critical care unit admissions (HR 1.20, 95% CI; 1.13, 1.28, P < .001). Median 30-day costs were $12,163 for direct admissions, $20,173 for delayed admissions, and $9,575 for ward-only patients (P < .001). CONCLUSIONS: While critical care unit admission indicates increased risk of mortality and readmission at 30 days, those who experienced delayed critical care unit admission exhibited the highest risk of death and highest costs of care.

Surviving Sepsis Campaign Guidelines on the Management of Adults With Coronavirus Disease 2019 (COVID-19) in the ICU: First Update.

BACKGROUND: The coronavirus disease 2019 pandemic continues to affect millions worldwide. Given the rapidly growing evidence base, we implemented a living guideline model to provide guidance on the management of patients with severe or critical coronavirus disease 2019 in the ICU. METHODS: The Surviving Sepsis Campaign Coronavirus Disease 2019 panel has expanded to include 43 experts from 14 countries; all panel members completed an electronic conflict-of-interest disclosure form. In this update, the panel addressed nine questions relevant to managing severe or critical coronavirus disease 2019 in the ICU. We used the World Health Organization's definition of severe and critical coronavirus disease 2019. The systematic reviews team searched the literature for relevant evidence, aiming to identify systematic reviews and clinical trials. When appropriate, we performed a random-effects meta-analysis to summarize treatment effects. We assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach, then used the evidence-to-decision framework to generate recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. RESULTS: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued nine statements (three new and six updated) related to ICU patients with severe or critical coronavirus disease 2019. For severe or critical coronavirus disease 2019, the panel strongly recommends using systemic corticosteroids and venous thromboprophylaxis but strongly recommends against using hydroxychloroquine. In addition, the panel suggests using dexamethasone (compared with other corticosteroids) and suggests against using convalescent plasma and therapeutic anticoagulation outside clinical trials. The Surviving Sepsis Campaign Coronavirus Diease 2019 panel suggests using remdesivir in nonventilated patients with severe coronavirus disease 2019 and suggests against starting remdesivir in patients with critical coronavirus disease 2019 outside clinical trials. Because of insufficient evidence, the panel did not issue a recommendation on the use of awake prone positioning. CONCLUSION: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued several recommendations to guide healthcare professionals caring for adults with critical or severe coronavirus disease 2019 in the ICU. Based on a living guideline model the recommendations will be updated as new evidence becomes available.