Impacts of antipsychotic medication prescribing practices in critically ill adult patients on health resource utilization and new psychoactive medication prescriptions.

BACKGROUND: Antipsychotic medications are commonly prescribed to critically ill adult patients and initiation of new antipsychotic prescriptions in the intensive care unit (ICU) increases the proportion of patients discharged home on antipsychotics. Critically ill adult patients are also frequently exposed to multiple psychoactive medications during ICU admission and hospitalization including benzodiazepines and opioid medications which may increase the risk of psychoactive polypharmacy following hospital discharge. The associated impact on health resource utilization and risk of new benzodiazepine and opioid prescriptions is unknown. RESEARCH QUESTION: What is the burden of health resource utilization and odds of new prescriptions of benzodiazepines and opioids up to 1-year post-hospital discharge in critically ill patients with new antipsychotic prescriptions at hospital discharge? STUDY DESIGN & METHODS: We completed a multi-center, propensity-score matched retrospective cohort study of critically ill adult patients. The primary exposure was administration of ≥1 dose of an antipsychotic while the patient was admitted in the ICU and ward with continuation at hospital discharge and a filled outpatient prescription within 1-year following hospital discharge. The control group was defined as no doses of antipsychotics administered in the ICU and hospital ward and no filled outpatient prescriptions for antipsychotics within 1-year following hospital discharge. The primary outcome was health resource utilization (72-hour ICU readmission, 30-day hospital readmission, 30-day emergency room visitation, 30-day mortality). Secondary outcomes were administration of benzodiazepines and/or opioids in-hospital and following hospital discharge in patients receiving antipsychotics. RESULTS: 1,388 propensity-score matched patients were included who did and did not receive antipsychotics in ICU and survived to hospital discharge. New antipsychotic prescriptions were not associated with increased health resource utilization or 30-day mortality following hospital discharge. There was increased odds of new prescriptions of benzodiazepines (adjusted odds ratio [aOR] 1.61 [95%CI 1.19-2.19]) and opioids (aOR 1.82 [95%CI 1.38-2.40]) up to 1-year following hospital discharge in patients continuing antipsychotics at hospital discharge. INTERPRETATION: New antipsychotic prescriptions at hospital discharge are significantly associated with additional prescriptions of benzodiazepines and opioids in-hospital and up to 1-year following hospital discharge.

STOP Signs: A Population-based Interrupted Time Series Analysis of Antibiotic Duration for Complicated Intraabdominal Infection Before and After the Publication of a Landmark RCT.

OBJECTIVE: To determine if the STOP-IT randomized controlled trial changed antibiotic prescribing in patients with Complicated Intraabdominal Infection (CIAI). SUMMARY OF BACKGROUND DATA: CIAI is common and causes significant morbidity. In May 2015, the STOP-IT randomized controlled trial showed equivalent outcomes between four-day and clinically determined antibiotic duration. METHODS: This was a population-based retrospective cohort study using interrupted time series methods. The STOP-IT publication date was the exposure. Median duration of inpatient antibiotic prescription was the outcome. All adult patients admitted to four hospitals in Calgary, Canada between July 2012 and December 2018 with CIAI who survived at least four days following source control were included. Analysis was stratified by infectious source as appendix or biliary tract (group A) versus other (group B). RESULTS: Among 4384 included patients, clinical and demographic attributes were similar before vs after publication. In Group A, median inpatient antibiotic duration was 3 days and unchanged from the beginning to the end of the study period [adjusted median difference -0.00 days, 95% confidence interval (CI) -0.37 - 0.37 days]. In Group B, antibiotic duration was shorter at the end of the study period (7.87 vs 6.73 days; -1.14 days, CI-2.37 - 0.09 days), however there was no change in trend following publication (-0.03 days, CI -0.16 - 0.09). CONCLUSIONS: For appendiceal or biliary sources of CIAI, antibiotic duration was commensurate with the experimental arm of STOP-IT. For other sources, antibiotic duration was long and did not change in response to trial publication. Additional implementation science is needed to improve antibiotic stewardship.

Protocol and statistical analysis plan for the identification and treatment of hypoxemic respiratory failure and acute respiratory distress syndrome with protection, paralysis, and proning: A type-1 hybrid stepped-wedge cluster randomised effectiveness-implementation study.

Objective: To describe a study protocol and statistical analysis plan (SAP) for the identification and treatment of hypoxemic respiratory failure (HRF) and acute respiratory distress syndrome (ARDS) with protection, paralysis, and proning (TheraPPP) study prior to completion of recruitment, electronic data retrieval, and analysis of any data. Design: TheraPPP is a stepped-wedge cluster randomised study evaluating a care pathway for HRF and ARDS patients. This is a type-1 hybrid effectiveness-implementation study design evaluating both intervention effectiveness and implementation; however primarily powered for the effectiveness outcome. Setting: Seventeen adult intensive care units (ICUs) across Alberta, Canada. Participants: We estimate a sample size of 18816 mechanically ventilated patients, with 11424 patients preimplementation and 7392 patients postimplementation. We estimate 2688 sustained ARDS patients within our study cohort. Intervention: An evidence-based, stakeholder-informed, multidisciplinary care pathway called Venting Wisely that standardises diagnosis and treatment of HRF and ARDS patients. Main outcome measures: The primary outcome is 28-day ventilator-free days (VFDs). The primary analysis will compare the mean 28-day VFDs preimplementation and postimplementation using a mixed-effects linear regression model. Prespecified subgroups include sex, age, HRF, ARDS, COVID-19, cardiac surgery, body mass index, height, illness acuity, and ICU volume. Results: This protocol and SAP are reported using the Standard Protocol Items: Recommendations for Interventional Trials guidance and the Guidelines for the Content of Statistical Analysis Plans in Clinical Trials. The study received ethics approval and was registered (ClinicalTrials.gov-NCT04744298) prior to patient enrolment. Conclusions: TheraPPP will evaluate the effectiveness and implementation of an HRF and ARDS care pathway.

Identification of hypercoagulability with thrombelastography in patients with hip fracture receiving thromboprophylaxis.

Background: Venous thromboembolism (VTE) is the second most common complication after hip fracture surgery. We used thrombelastography (TEG), a whole-blood, point-of-care test that can provide an overview of the clotting process, to determine the duration of hypercoagulability after hip fracture surgery. Methods: In this prospective study, consecutive patients aged 51 years or more with hip fractures (trochanteric region or neck) amenable to surgical treatment who presented to the emergency department were eligible for enrolment. Thrombelastography, including calculation of the coagulation index (CI) (combination of 4 TEG parameters for an overall assessment of coagulation) was performed daily from admission until 5 days postoperatively, and at 2 and 6 weeks postoperatively. All patients received 28 days of thromboprophylaxis. We used single-sample t tests to compare mean maximal amplitude (MA) values (a measure of clot strength) to the hypercoagulable threshold of greater than 65 mm, a predictor of in-hospital VTE. Results: Of the 35 patients enrolled, 11 (31%) were hypercoagulable on admission based on an MA value greater than 65 mm, and 29 (83%) were hypercoagulable based on a CI value greater than 3.0; the corresponding values at 6 weeks were 23 (66%) and 34 (97%). All patients had an MA value greater than 65 mm at 2 weeks. Patients demonstrated normal coagulation on admission (mean MA value 62.2 mm [standard deviation (SD) 6.3 mm], p = 0.01) but became significantly hypercoagulable at 2 weeks (mean 71.6 mm [SD 2.6 mm], p < 0.001). There was a trend toward persistent hypercoagulability at 6 weeks (mean MA value 66.2 mm [SD 3.8 mm], p = 0.06). Conclusion: More than 50% of patients remained hypercoagulable 6 weeks after fracture despite thromboprophylaxis. Thrombelastography MA thresholds or a change in MA over time may help predict VTE risk; however, further study is needed.

Contexte: La thromboembolie veineuse (TEV) est la deuxième complication la plus courante après une chirurgie pour fracture de la hanche. Nous avons eu recours à la thromboélastographie, un test de sang total effectué au point d'intervention et donnant une idée du processus de coagulation, pour évaluer la durée de l'hypercoagulabilité à la suite d'une chirurgie pour fracture de la hanche. Méthodes: Cette étude prospective a été menée auprès de patients consécutifs admissibles de 51 ans et plus qui se sont présentés à l'urgence pour une fracture de la hanche (région trochantérienne ou col du fémur) pouvant faire l'objet d'un traitement chirurgical. Une thromboélastographie (TEG), qui comprenait le calcul de l'indice de coagulation (IC) [combinaison de 4 paramètres du TEG permettant une évaluation globale de la coagulation], a été réalisée chaque jour, de l'admission au cinquième jour postopératoire, de même qu'à 2 et à 6 semaines postopératoires. Tous les patients ont suivi une thromboprophylaxie de 28 jours. Nous avons réalisé des tests t pour échantillon unique afin de comparer l'amplitude maximale (AM) moyenne (une mesure de la résistance d'un caillot) au seuil d'hypercoagulabilité de plus de 65 mm, un prédicteur de TEV à l'hôpital. Résultats: Des 35 patients recrutés, 11 (31 %) présentaient une hypercoagulabilité à l'admission selon une AM supérieure à 65 mm, et 29 (83 %) présentaient une hypercoagulabilité selon un IC supérieur à 3,0; les valeurs correspondantes à 6 semaines étaient de 23 (66 %) et de 34 (97 %), respectivement. Tous les patients avaient une AM de plus de 65 mm à 2 semaines. Dans l'ensemble, les patients avaient une coagulation normale à l'admission (AM moyenne 62,2 mm [écart type (E.T.) 6,3 mm], p = 0,01), mais présentaient une hypercoagulabilité importante à 2 semaines (moyenne 71,6 mm [E.T. 2,6 mm], p < 0,001). L'hypercoagulabilité avait tendance à persister à 6 semaines (AM moyenne 66,2 mm [E.T. 3,8 mm], p = 0,06). Conclusion: Malgré la thromboprophylaxie, plus de 50 % des patients présentaient toujours une hypercoagulabilité 6 semaines après leur fracture. Les seuils d'AM à la thromboélastographie et les changements de l'AM au fil du temps pourraient aider à prédire le risque de TEV, mais d'autres études sur le sujet sont nécessaires.

Exploratory Evaluation of the Relationship Between iNKT Cells and Systemic Cytokine Profiles of Critically Ill Patients with Neurological Injury.

BACKGROUND: Neurological injury can alter the systemic immune system, modifying the functional capacity of immune cells and causing a dysfunctional balance of cytokines, although mechanisms remain incompletely understood. The objective of this study was to assess the temporal relationship between changes in the activation status of circulating invariant natural killer T (iNKT) cells and the balance of plasma cytokines among critically ill patients with neurological injury. METHODS: We conducted an exploratory prospective observational study of adult (18 years or older) intensive care unit (ICU) patients with acute neurological injury (n = 20) compared with ICU patients without neurological injury (n = 22) and healthy controls (n = 10). Blood samples were collected on days 1, 2, 4, 7, 14, and 28 following ICU admission to analyze the activation status of circulating iNKT cells by flow cytometry and the plasma concentration of inflammation-relevant immune mediators, including T helper 1 (TH1) and T helper 2 (TH2) cytokines, by multiplex bead-based assay. RESULTS: Invariant natural killer T cells were activated in both ICU patient groups compared with healthy controls. Neurological patients had decreased levels of multiple immune mediators, including TH1 cytokines (interferon-γ, tumor necrosis factor-α, and interleukin-12p70), indicative of immunosuppression. This led to a greater than twofold increase in the ratio of TH2/TH1 cytokines early after injury (days 1 - 2) compared with healthy controls, a shift that was also observed for ICU controls. Systemic TH2/TH1 cytokine ratios were positively associated with iNKT cell activation in the neurological patients and negatively associated in ICU controls. These relationships were strongest for the CD4+ iNKT cell subset compared with the CD4- iNKT cell subset. The relationships to individual cytokines similarly differed between patient groups. Forty percent of the neurological patients developed an infection; however, differences for the infection subgroup were not identified. CONCLUSIONS: Critically ill patients with neurological injury demonstrated altered systemic immune profiles early after injury, with an association between activated peripheral iNKT cells and elevated systemic TH2/TH1 cytokine ratios. This work provides further support for a brain-immune axis and the ability of neurological injury to have far-reaching effects on the body's immune system.

Development and validation of delirium prediction model for critically ill adults parameterized to ICU admission acuity.

BACKGROUND: Risk prediction models allow clinicians to forecast which individuals are at a higher risk for developing a particular outcome. We developed and internally validated a delirium prediction model for incident delirium parameterized to patient ICU admission acuity. METHODS: This retrospective, observational, fourteen medical-surgical ICU cohort study evaluated consecutive delirium-free adults surviving hospital stay with ICU length of stay (LOS) greater than or equal to 24 hours with both an admission APACHE II score and an admission type (e.g., elective post-surgery, emergency post-surgery, non-surgical) in whom delirium was assessed using the Intensive Care Delirium Screening Checklist (ICDSC). Risk factors included in the model were readily available in electric medical records. Least absolute shrinkage and selection operator logistic (LASSO) regression was used for model development. Discrimination was determined using area under the receiver operating characteristic curve (AUC). Internal validation was performed by cross-validation. Predictive performance was determined using measures of accuracy and clinical utility was assessed by decision-curve analysis. RESULTS: A total of 8,878 patients were included. Delirium incidence was 49.9% (n = 4,431). The delirium prediction model was parameterized to seven patient cohorts, admission type (3 cohorts) or mean quartile APACHE II score (4 cohorts). All parameterized cohort models were well calibrated. The AUC ranged from 0.67 to 0.78 (95% confidence intervals [CI] ranged from 0.63 to 0.79). Model accuracy varied across admission types; sensitivity ranged from 53.2% to 63.9% while specificity ranged from 69.0% to 74.6%. Across mean quartile APACHE II scores, sensitivity ranged from 58.2% to 59.7% while specificity ranged from 70.1% to 73.6%. The clinical utility of the parameterized cohort prediction model to predict and prevent incident delirium was greater than preventing incident delirium by treating all or none of the patients. CONCLUSIONS: Our results support external validation of a prediction model parameterized to patient ICU admission acuity to predict a patients' risk for ICU delirium. Classification of patients' risk for ICU delirium by admission acuity may allow for efficient initiation of prevention measures based on individual risk profiles.

Standardized Management for Hypoxemic Respiratory Failure and ARDS: Systematic Review and Meta-analysis.

BACKGROUND: Treatment of hypoxemic respiratory failure (HRF) and ARDS is complex. Standardized management of HRF and ARDS may improve adherence to evidence-informed practice and improve outcomes. RESEARCH QUESTION: What is the effect of standardized treatment compared with usual care on survival of patients with HRF and ARDS? STUDY DESIGN AND METHODS: MEDLINE, EMBASE, Cochrane, CINAHL, Scopus, and Web-of-Science were searched (inception to 2018). Included studies were randomized clinical trials or quasi-experimental studies that examined the effect of standardized treatment (care-protocol, care-pathway, or bundle) compared with usual treatment among mechanically ventilated adult patients admitted to an ICU with HRF or ARDS. Study characteristics, pathway components, and patient outcomes were abstracted independently by two reviewers. RESULTS: From 15,932 unique citations, 14 studies were included in the systematic review (three randomized clinical trials and 11 quasi-experimental studies). Twelve studies (including 5,767 patients) were included in the meta-analysis. Standardized management of HRF was associated with a 23% relative reduction in mortality (relative risk, 0.77; 95% CI, 0.65-0.91; I2, 70%; P = .002). In studies targeting patients with ARDS (n = 8), a 21% pooled mortality reduction was observed (relative risk, 0.79; 95% CI, 0.71-0.88; I2, 3.1%). Standardized management was associated with increased 28-day ventilator-free days (weighted mean difference, 3.48 days; 95% CI, 2.43-4.54 days; P < .001). Standardized management was also associated with a reduction in tidal volume (weighted mean difference, -1.80 mL/kg predicted body weight; 95% CI, -2.80 to -0.80 mL/kg predicted body weight; P < .001). Meta-regression demonstrated that the reduction in mortality was associated with provision of lower tidal volume (P = .045). INTERPRETATION: When compared with usual treatment, standardized treatment of patients with HRF and ARDS is associated with increased ventilator-free days, lower tidal volume ventilation, and lower mortality. ICUs should consider the use of standardized treatment to improve the processes and outcomes of care for patients with HRF and ARDS. CLINICAL TRIAL REGISTRATION: PROSPERO; No.: CRD42019099921; URL: www.crd.york.ac.uk/prospero/.

Adverse Events After Transition From ICU to Hospital Ward: A Multicenter Cohort Study.

OBJECTIVES: To examine adverse events and associated factors and outcomes during transition from ICU to hospital ward (after ICU discharge). DESIGN: Multicenter cohort study. SETTING: Ten adult medical-surgical Canadian ICUs. PATIENTS: Patients were those admitted to one of the 10 ICUs from July 2014 to January 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two ICU physicians independently reviewed progress and consultation notes documented in the medical record within 7 days of patient's ICU discharge date to identify and classify adverse events. The adverse event data were linked to patient characteristics and ICU and ward physician surveys collected during the larger prospective cohort study. Analyses were conducted using multivariable logistic regression. Of the 451 patients included in the study, 84 (19%) experienced an adverse event, the majority (62%) within 3 days of transfer from ICU to hospital ward. Most adverse events resulted only in symptoms (77%) and 36% were judged to be preventable. Patients with adverse events were more likely to be readmitted to the ICU (odds ratio, 5.5; 95% CI, 2.4-13.0), have a longer hospital stay (mean difference, 16.1 d; 95% CI, 8.4-23.7) or die in hospital (odds ratio, 4.6; 95% CI, 1.8-11.8) than those without an adverse event. ICU and ward physician predictions at the time of ICU discharge had low sensitivity and specificity for predicting adverse events, ICU readmissions, and hospital death. CONCLUSIONS: Adverse events are common after ICU discharge to hospital ward and are associated with ICU readmission, increased hospital length of stay and death and are not predicted by ICU or ward physicians.

Variation in estimated glomerular filtration rate at dialysis initiation in children.

BACKGROUND: Data guiding the timing of dialysis initiation in children are limited. We sought to determine current practice and secular trends in Canada with respect to the timing of dialysis initiation in children based on estimated glomerular filtration rate (eGFR). METHODS: This observational study included incident chronic dialysis patients aged ≤21 years identified from the Canadian Organ Replacement Register who started dialysis in Canada between January 2001 and December 2010 at any of the nine participating Canadian centers (n = 583). Youth were categorized utilizing CKiD Schwartz eGFR into ≥10.5 (higher) or <10.5 ml/min/1.73 m2 (lower) eGFR groups. Differences at dialysis initiation by facility and region were examined, and secular trends were determined. RESULTS: Median eGFR at dialysis initiation was 8.1 (interquartile range 5.4-11.0) ml/min/1.73 m2. Overall, 29 % of the patients started dialysis with an eGFR of ≥10.5 ml/min/1.73 m2. The proportion of children starting with higher eGFR increased from 27.3 % in 2001 to 35.4 % in 2010 (p = 0.04) and differed by treatment facility (12-70 %; p = 0.0001). Factors associated with higher eGFR at dialysis initiation in the adjusted regression model were female sex [odds ratio (OR) 1.48; 95 % confidence interval (CI) 1.02-2.14], genetic cause of end-stage kidney disease (OR 2.77; 95 % CI 1.37-5.58) and living ≥50 km from treatment facility (OR 1.47; 95 % CI 1.01-2.14). CONCLUSIONS: One-third of the children were found to have initiated dialysis with an eGFR ≥10.5 ml/min/1.73 m2, however significant practice variation exists with respect to timing of dialysis initiation by treatment facility. More data is required to evaluate the clinical implications of this practice variation.