Asymmetric Assembly and Self-Adjuvanted Antigen Delivery Platform for Improved Antigen Uptake and Antitumor Effect.

The development of effective tumor vaccines is an important direction in the field of cancer prevention/immunotherapy. Efficient antigen delivery is essential for inducing effective antitumor responses for tumor vaccines. Lumazine synthase (BLS) from Brucella spp. is a decameric protein with delivery and adjuvant properties, but its application in tumor vaccines is limited. Here, we developed an antigen delivery platform by combining a BLS asymmetric assembly and the Plug-and-Display system of SpyCatcher/SpyTag. An asymmetric assembly system consisting of BLSke and BLSdr was developed to equally assemble two molecules. Then, the MHC-I-restricted ovalbumin peptide (OVA(257-264) SIINFEKL) was conjugated with BLSke, and a cell-penetrating peptide (CPP) KALA was conjugated with BLSdr using the SpyCatcher/SpyTag system. KALA modification enhanced internalization of OVA peptides by DCs as well as promoted the maturation of DCs and the cross-presentation of SIINFEKL. Moreover, the immunotherapy of a KALA-modified vaccine suppressed tumor growth and enhanced CD8+ T cell responses in E.G7-OVA tumor-bearing mice. In the prophylactic model, KALA-modified vaccination showed the most significant protective effect and significantly prolonged the survival period of tumor challenged mice. In conclusion, the asymmetric assembly platform equally assembles two proteins or peptides, avoiding their spatial or functional interference. This asymmetric assembly and Plug-and-Display technology provide a universal platform for rapid development of personalized tumor vaccines.

Preoperative Heart Failure Treatment Prevents Postoperative Cardiac Complications in Patients With Lower Risk: A Retrospective Cohort Study.

OBJECTIVE: The objective of this study was to identify undertreated subgroups of patients with heart failure who would benefit from better perioperative optimization. SUMMARY OF BACKGROUND DATA: Patients with heart failure have increased risks of postoperative cardiac complications after noncardiac surgery. METHODS: In this analysis of hospital registry data of 130,677 patients undergoing noncardiac surgery, the exposure was preoperative history of heart failure. The outcome, cardiac complications, was defined as a composite of myocardial infarction, cardiac arrest, acute heart failure, and mortality within 30 postoperative days. RESULTS: History of heart failure (n = 10,256; 7.9%) was associated with increased risk of cardiac complications [8.1% vs 1.1%; adjusted odds ratio, 2.28 (95% CI, 2.02-2.56); P < 0.001). Patients with heart failure and who carried a lower risk profile had increased risks of postoperative cardiac complications secondary to heart failure [adjusted absolute risk difference, 1.7% (95% CI, 1.4%-2.0%, lower risk); P < 0.001 vs 0.5% (95% CI, -0.6% to 1.6%, higher risk); P = 0.38]. Patients with heart failure and lower risk received a lower level of health care utilization preoperatively, and less frequently received anti-heart failure medications (59% vs 72% and 61% vs 82%; both P < 0.001). These preventive therapies significantly decreased the risk of cardiac complications in patients with heart failure. CONCLUSIONS: In patients with heart failure who have a lower preoperative risk profile, clinicians often make insufficient attempts to optimize their clinical condition preoperatively. Preoperative preventive treatment reduces the risk of postoperative cardiac complications in these lower-risk patients with heart failure.

Reintubation After Lung Cancer Resection: Development and External Validation of a Predictive Score.

BACKGROUND: Reintubation after lung cancer resection is an important quality metric because of increased disability, mortality and cost. However, no validated predictive instrument is in use to reduce reintubation after lung resection. This study aimed to create and validate the PRediction Of REintubation After Lung cancer resection (PROREAL) score. METHODS: The study analyzed lung resection cases from 2 university hospitals. The primary end point was reintubation within 7 days after surgery. Predictors were selected through backward stepwise logistic regression and bootstrap resampling. The investigators used reclassification and receiver-operating characteristic (ROC) curve analyses to assess score performance and compare it with an established score for all surgical patients (Score for Prediction of Postoperative Respiratory Complications [SPORC]). RESULTS: The study included 2672 patients who underwent resection for lung cancer (1754, development cohort; 918, validation cohort) between 2008 and 2020, of whom 71 (2.7%) were reintubated within 7 days after surgery. Identified score variables were surgical extent and approach, American Society of Anesthesiologists physical status, heart failure, renal disease, and diffusing capacity of the lung for carbon monoxide. The score achieved excellent discrimination in the development cohort (ROC AUC, 0.90; 95% CI, 0.87-0.94) and good discrimination in the validation cohort (ROC AUC, 0.74, 95% CI; 0.66-0.82), thus outperforming the SPORC in both cohorts (P < .001 and P = .018, respectively; validation cohort net reclassification improvement, 0.39; 95% CI, 0.18-0.60; P = .001). The score cutoff of ≥5 yielded a sensitivity of 88% (95% CI, 72-95) and a specificity of 81% (95% CI,79-83) in the development cohort. CONCLUSIONS: A simple score (PROREAL) specific to lung cancer predicts postoperative reintubation more accurately than the nonspecific SPORC score. Operative candidates at risk may be identified for preventive intervention or alternative oncologic therapy.

Intraoperative Hypotension and Acute Kidney Injury, Stroke, and Mortality during and outside Cardiopulmonary Bypass: A Retrospective Observational Cohort Study.

BACKGROUND: In cardiac surgery, the association between hypotension during specific intraoperative phases or vasopressor-inotropes with adverse outcomes remains unclear. This study's hypothesis was that intraoperative hypotension duration throughout the surgery or when separated into hypotension during and outside cardiopulmonary bypass may be associated with postoperative major adverse events. METHODS: This retrospective observational cohort study included data for adults who had cardiac surgery between 2008 and 2016 in a tertiary hospital. Intraoperative hypotension was defined as mean arterial pressure of less than 65 mmHg. The total duration of hypotension was divided into three categories based on the fraction of overall hypotension duration that occurred during cardiopulmonary bypass (more than 80%, 80 to 60%, and less than 60%). The primary outcome was a composite of stroke, acute kidney injury, or mortality during the index hospitalization. The association with the composite outcome was evaluated for duration of hypotension during the entire surgery, outside cardiopulmonary bypass, and during cardiopulmonary bypass and the fraction of hypotension during cardiopulmonary bypass adjusting for vasopressor-inotrope dose, milrinone dose, patient, and surgical factors. RESULTS: The composite outcome occurred in 256 (5.1%) of 4,984 included patient records; 66 (1.3%) patients suffered stroke, 125 (2.5%) had acute kidney injury, and 109 (2.2%) died. The primary outcome was associated with total duration of hypotension (adjusted odds ratio, 1.05; 95% CI, 1.02 to 1.08; P = 0.032), hypotension outside cardiopulmonary bypass (adjusted odds ratio, 1.06; 95% CI, 1.03 to 1.10; P = 0.001) per 10-min exposure to mean arterial pressure of less than 65 mmHg, and fraction of hypotension duration during cardiopulmonary bypass of less than 60% (reference greater than 80%; adjusted odds ratio, 1.67; 95% CI, 1.10 to 2.60; P = 0.019) but not with each 10-min period hypotension during cardiopulmonary bypass (adjusted odds ratio, 1.04; 95% CI, 0.99 to 1.09; P = 0.118), fraction of hypotension during cardiopulmonary bypass of 60 to 80% (adjusted odds ratio, 1.45; 95% CI, 0.97 to 2.23; P = 0.082), or total vasopressor-inotrope dose (adjusted odds ratio, 1.00; 95% CI, 1.00 to 1.00; P = 0.247). CONCLUSIONS: This study confirms previous single-center findings that intraoperative hypotension throughout cardiac surgery is associated with an increased risk of acute kidney injury, mortality, or stroke.

Salivary IgG to SARS-CoV-2 indicates seroconversion and correlates to serum neutralization in mRNA-vaccinated immunocompromised individuals.

BACKGROUND: Immunocompromised individuals are highly susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Whether vaccine-induced immunity in these individuals involves oral cavity, a primary site of infection, is presently unknown. METHODS: Immunocompromised patients (n = 404) and healthy controls (n = 82) participated in a prospective clinical trial (NCT04780659) encompassing two doses of the mRNA BNT162b2 vaccine. Primary immunodeficiency (PID), secondary immunodeficiencies caused by human immunodeficiency virus (HIV) infection, allogeneic hematopoietic stem cell transplantation (HSCT)/chimeric antigen receptor T cell therapy (CAR-T), solid organ transplantation (SOT), and chronic lymphocytic leukemia (CLL) patients were included. Salivary and serum immunoglobulin G (IgG) reactivities to SARS-CoV-2 spike were measured by multiplex bead-based assays and Elecsys anti-SARS-CoV-2 S assay. FINDINGS: IgG responses to SARS-CoV-2 spike antigens in saliva in HIV and HSCT/CAR-T groups were comparable to those of healthy controls after vaccination. The PID, SOT, and CLL patients had weaker responses, influenced mainly by disease parameters or immunosuppressants. Salivary responses correlated remarkably well with specific IgG titers and the neutralizing capacity in serum. Receiver operating characteristic curve analysis for the predictive power of salivary IgG yielded area under the curve (AUC) = 0.95 and positive predictive value (PPV) = 90.7% for the entire cohort after vaccination. CONCLUSIONS: Saliva conveys vaccine responses induced by mRNA BNT162b2. The predictive power of salivary spike IgG makes it highly suitable for screening vulnerable groups for revaccination. FUNDING: Knut and Alice Wallenberg Foundation, Erling Perssons family foundation, Region Stockholm, Swedish Research Council, Karolinska Institutet, Swedish Blood Cancer Foundation, PID patient organization of Sweden, Nordstjernan AB, Center for Medical Innovation (CIMED), Swedish Medical Research Council, and Stockholm County Council (ALF).

Development and external validation of a prognostic model for ischaemic stroke after surgery.

BACKGROUND: There is an under-recognised patient cohort at elevated risk of postoperative ischaemic stroke. We aimed to develop and validate a prognostic model for the identification of such patients at high risk of ischaemic stroke within 1 yr after noncardiac surgery. METHODS: This was a hospital registry study of adult patients undergoing noncardiac surgery between 2005 and 2017 at two independent healthcare networks in Massachusetts, USA without a preoperative indication for therapeutic anticoagulation. Logistic regression was used to fit a model from a priori defined candidate predictors for the outcome 1 yr postoperative ischaemic stroke. To enhance clinical applicability, the model was simplified to a scoring system and externally validated. RESULTS: In the development (n=107 756) and validation (n=141 724) cohorts, 1.4% and 0.5% of patients had an ischaemic stroke up to 1 yr postoperatively. The final model included 13 variables (patient characteristics, comorbidities, procedural factors), considering sub-models conditional on a previous history of ischaemic stroke. Areas under the curve were 0.89 (95% confidence interval 0.89-0.90) and 0.88 (95% confidence interval 0.86-0.89) in the development and validation cohorts. Decision curve analysis indicated positive net benefits superior to other prediction instruments. CONCLUSIONS: Stroke after surgery (STRAS) screening can reliably identify patients with a high risk for ischaemic stroke during the first year after surgery. A STRAS-guided risk stratification may inform the recruitment to future randomised trials testing the efficacy of treatments for the prevention of postoperative ischaemic stroke.

Provider variability in the intraoperative use of neuromuscular blocking agents: a retrospective multicentre cohort study.

OBJECTIVE: To assess variability in the intraoperative use of non-depolarising neuromuscular blocking agents (NMBAs) across individual anaesthesia providers, surgeons and hospitals. DESIGN: Retrospective observational cohort study. SETTING: Two major tertiary referral centres, Boston, Massachusetts, USA. PARTICIPANTS: 265 537 adult participants undergoing non-cardiac surgery between October 2005 and September 2017. MAIN OUTCOME MEASURES: We analysed the variances in NMBA use across 958 anaesthesia and 623 surgical providers, across anaesthesia provider types (anaesthesia residents, certified registered nurse anaesthetists, attendings) and across hospitals using multivariable-adjusted mixed effects logistic regression. Intraclass correlations (ICC) were calculated to further quantify the variability in NMBA use that was unexplained by other covariates. Procedure-specific subgroup analyses were performed. RESULTS: NMBAs were used in 183 242 (69%) surgical cases. Variances in NMBA use were significantly higher among individual surgeons than among anaesthesia providers (variance 1.32 (95% CI 1.06 to 1.60) vs 0.24 (95% CI 0.19 to 0.28), p<0.001). Procedure-specific subgroup analysis of hernia repairs, spine surgeries and mastectomies confirmed our findings: the total variance in NMBA use that was unexplained by the covariate model was higher for surgeons versus anaesthesia providers (ICC 37.0% vs 13.0%, 69.7% vs 25.5%, 69.8% vs 19.5%, respectively; p<0.001). Variances in NMBA use were also partially explained by the anaesthesia provider's hospital network (Massachusetts General Hospital: variance 0.35 (95% CI 0.27 to 0.43) vs Beth Israel Deaconess Medical Center: 0.15 (95% CI 0.12 to 0.19); p<0.001). Across provider types, surgeons showed the highest variance, and anaesthesia residents showed the lowest variance in NMBA use. CONCLUSIONS: There is wide variability across individual surgeons and anaesthesia providers and institutions in the use of NMBAs, which could not sufficiently be explained by a large number of patient-related and procedure-related characteristics, but may instead be driven by preference. Surgeons may have a stronger influence on a key aspect of anaesthesia management than anticipated.

Effects of Volatile Anesthetics on Postoperative Ischemic Stroke Incidence.

Background Preclinical studies suggest that volatile anesthetics decrease infarct volume and improve the outcome of ischemic stroke. This study aims to determine their effect during noncardiac surgery on postoperative ischemic stroke incidence. Methods and Results This was a retrospective cohort study of surgical patients undergoing general anesthesia at 2 tertiary care centers in Boston, MA, between October 2005 and September 2017. Exclusion criteria comprised brain death, age <18 years, cardiac surgery, and missing covariate data. The exposure was defined as median age-adjusted minimum alveolar concentration of all intraoperative measurements of desflurane, sevoflurane, and isoflurane. The primary outcome was postoperative ischemic stroke within 30 days. Among 314 932 patients, 1957 (0.6%) experienced the primary outcome. Higher doses of volatile anesthetics had a protective effect on postoperative ischemic stroke incidence (adjusted odds ratio per 1 minimum alveolar concentration increase 0.49, 95% CI, 0.40-0.59, P<0.001). In Cox proportional hazards regression, the effect was observed for 17 postoperative days (postoperative day 1: hazard ratio (HR), 0.56; 95% CI, 0.48-0.65; versus day 17: HR, 0.85; 95% CI, 0.74-0.99). Volatile anesthetics were also associated with lower stroke severity: Every 1-unit increase in minimum alveolar concentration was associated with a 0.006-unit decrease in the National Institutes of Health Stroke Scale (95% CI, -0.01 to -0.002, P=0.002). The effects were robust throughout various sensitivity analyses including adjustment for anesthesia providers as random effect. Conclusions Among patients undergoing noncardiac surgery, volatile anesthetics showed a dose-dependent protective effect on the incidence and severity of early postoperative ischemic stroke.

REsidual Neuromuscular Block Prediction Score Versus Train-of-Four Ratio and Respiratory Outcomes: A Retrospective Cohort Study.

BACKGROUND: Residual neuromuscular blockade is associated with an increased incidence of postoperative respiratory complications. The REsidual neuromuscular block Prediction Score (REPS) identifies patients at high risk for residual neuromuscular blockade after surgery. METHODS: A total of 101,510 adults undergoing noncardiac surgery under general anesthesia from October 2005 to December 2018 at a tertiary care center in Massachusetts were analyzed for the primary outcome of postoperative respiratory complications (invasive mechanical ventilation requirement within 7 postoperative days or immediate postextubation desaturation [oxygen saturation {Spo2} <90%] within 10 minutes). The primary objective was to assess the association between the REPS and respiratory complications. The secondary objective was to compare REPS and train-of-four (TOF) ratio <0.90 on the strength of their association with respiratory complications. RESULTS: A high REPS (≥4) was associated with an increase in odds of respiratory complications (adjusted odds ratio [OR], 1.13 [95% confidence interval {CI}, 1.06-1.21]; P < .001). In 6224 cases with available TOF ratio measurements, a low TOF ratio (<0.9) was associated with respiratory complications (adjusted OR, 1.43 [95% CI, 1.11-1.85]; P = .006), whereas a high REPS was not (adjusted OR, 0.96 [95% CI, 0.74-1.23]; P = .73) (P = .018 for comparison between ORs). CONCLUSIONS: The REPS may be implemented as a screening tool to encourage clinicians to use quantitative neuromuscular monitoring in patients at risk of residual neuromuscular blockade. A positive REPS should be followed by a quantitative assessment of the TOF ratio.

Discharge Prediction for Patients Undergoing Inpatient Surgery: Development and validation of the DEPENDENSE score.

BACKGROUND: A substantial proportion of patients undergoing inpatient surgery each year is at risk for postoperative institutionalization and loss of independence. Reliable individualized preoperative prediction of adverse discharge can facilitate advanced care planning and shared decision making. METHODS: Using hospital registry data from previously home-dwelling adults undergoing inpatient surgery, we retrospectively developed and externally validated a score predicting adverse discharge. Multivariable logistic regression analysis and bootstrapping were used to develop the score. Adverse discharge was defined as in-hospital mortality or discharge to a skilled nursing facility. The model was subsequently externally validated in a cohort of patients from an independent hospital. RESULTS: In total, 106 164 patients in the development cohort and 92 962 patients in the validation cohort were included, of which 16 624 (15.7%) and 7717 (8.3%) patients experienced adverse discharge, respectively. The model was predictive of adverse discharge with an area under the receiver operating characteristic curve (AUC) of 0.87 (95% CI 0.87-0.88) in the development cohort and an AUC of 0.86 (95% CI 0.86-0.87) in the validation cohort. CONCLUSION: Using preoperatively available data, we developed and validated a prediction instrument for adverse discharge following inpatient surgery. Reliable prediction of this patient centered outcome can facilitate individualized operative planning to maximize value of care.

A Tool to Predict Readmission to the Intensive Care Unit in Surgical Critical Care Patients-The RISC Score.

BACKGROUND: Readmission to the Intensive Care Unit (ICU) is associated with a high risk of in-hospital mortality and higher health care costs. Previously published tools to predict ICU readmission in surgical ICU patients have important limitations that restrict their clinical implementation. We sought to develop a clinically intuitive score that can be implemented to predict readmission to the ICU after surgery or trauma. We designed the score to emphasize modifiable predictors. METHODS: In this retrospective cohort study, we included surgical patients requiring critical care between June 2015 and January 2019 at Beth Israel Deaconess Medical Center, Harvard Medical School, MA, USA. We used logistic regression to fit a prognostic model for ICU readmission from a priori defined, widely available candidate predictors. The score performance was compared with existing prediction instruments. RESULTS: Of 7,126 patients, 168 (2.4%) were readmitted to the ICU during the same hospitalization. The final score included 8 variables addressing demographical factors, surgical factors, physiological parameters, ICU treatment and the acuity of illness. The maximum score achievable was 13 points. Potentially modifiable predictors included the inability to ambulate at ICU discharge, substantial positive fluid balance (>5 liters), severe anemia (hemoglobin <7 mg/dl), hyperglycemia (>180 mg/dl), and long ICU length of stay (>5 days). The score yielded an area under the receiver operating characteristic curve of 0.78 (95% CI 0.74-0.82) and significantly outperformed previously published scores. The performance of the underlying model was confirmed by leave-one-out cross-validation. CONCLUSION: The RISC-score is a clinically intuitive prediction instrument that helps identify surgical ICU patients at high risk for ICU readmission. The simplicity of the score facilitates its clinical implementation across surgical divisions.

Joint preoperative transthoracic and intraoperative transoesophageal echocardiographic assessment of functional mitral regurgitation severity provides better association with long-term mortality.

OBJECTIVES: Functional mitral regurgitation (MR) is observed with ischaemic heart disease or aortic valve disease. Assessing the value of mitral valve repair or replacement (MVR/P) is complicated by frequent discordance between preoperative transthoracic echocardiographic (pTTE) and intraoperative transoesophageal echocardiographic (iTOE) assessment of MR severity. We examined the association of pTTE and iTOE with postoperative mortality in patients with or without MR, at the time of coronary artery bypass grafting (CABG) and/or aortic valve replacement without MVR/P. METHODS: Medical records of 6629 patients undergoing CABG and/or aortic valve replacement surgery with or without functional MR and who did not undergo MVR/P were reviewed. MR severity assessed by pTTE and iTOE were examined for association with postoperative mortality using proportional hazards regression while accounting for patient and operative characteristics. RESULTS: In 72% of 709 patients with clinically significant (moderate or greater) functional MR detected by pTTE, iTOE performed after induction of anaesthesia demonstrated a reduction in MR severity, while 2% of patients had increased severity of MR by iTOE. iTOE assessment of MR was better associated with long-term postoperative mortality than pTTE in patients with moderate MR [hazard ratio (HR) 1.31 (1.11-1.55) vs 1.02 (0.89-1.17), P-value for comparison of HR 0.025] but was not different for more than moderate MR [1.43 (0.96-2.14) vs 1.27 (0.80-2.02)]. CONCLUSIONS: In patients undergoing CABG and/or aortic valve replacement without MVR/P, these findings support intraoperative reassessment of MR severity by iTOE as an adjunct to pTTE in the prediction of mortality. Alone, these findings do not yet provide evidence for an operative strategy.

Association Between Intraoperative Hypotension and Postoperative Adverse Outcomes in Patients Undergoing Vascular Surgery - A Retrospective Observational Study.

OBJECTIVE: Intraoperative hypotension (IOH) is associated with adverse outcomes. It could be challenging to define IOH in vascular surgical patients with increased baseline blood pressure (BP). The authors studied the relationship between (1) absolute and relative BP thresholds of IOH, (2) preoperative pulse pressure (PP) and isolated systolic hypertension, and (3) endovascular versus open surgical approach with adverse outcomes in vascular surgical patients. DESIGN: Retrospective observational study. SETTING: Teaching hospital. PATIENTS: A total of 566 vascular surgical patients from 2011 to 2018. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: BP thresholds were as follows: IOH - absolute mean arterial pressure (MAP) <65 mmHg, relative MAP >20% decrease from baseline, preoperative PP hypertension - PP >40 mmHg, isolated systolic hypertension - baseline systolic BP ≥140 mmHg with diastolic BP <90 mmHg. Thresholds were characterized by (1) total duration and (2) area under the curve. Primary outcome was a composite of postoperative in-hospital complications (acute kidney injury, stroke, myocardial infarction, congestive heart failure, and mortality). Forty-six (8.1%) patients had in-hospital complications. Only IOH duration-MAP <65 mmHg (odds ratio 1.01; 95% confidence interval 1.00-1.02; p = 0.004) was significantly associated with outcome. No associations were found with MAP >20% decrease from baseline and preoperative BP. Significant interaction was observed with the surgical approach and outcome (p = 0.031), which was stronger after 60 minutes of IOH in endovascular approach. CONCLUSION: Longer periods of IOH (MAP <65 mmHg for >60 minutes) during endovascular surgery were associated with adverse outcomes. Relative fall in BP from baseline, preoperative isolated systolic, and PP hypertension were not associated with postoperative complications.

Supraglottic airway device versus tracheal intubation and the risk of emergent postoperative intubation after general anaesthesia in adults: a retrospective cohort study.

BACKGROUND: We examined the association between emergent postoperative tracheal intubation and the use of supraglottic airway devices (SGAs) vs tracheal tubes. METHODS: We included data from adult noncardiac surgical cases under general anaesthesia between 2008 and 2018. We only included cases (n=59 991) in which both airways were deemed to be feasible options. Multivariable logistic regression, instrumental variable analysis, propensity matching, and mediation analysis were used. RESULTS: Use of a tracheal tube was associated with a higher risk of emergent postoperative intubation (adjusted absolute risk difference [ARD]=0.80%; 95% confidence interval (CI), 0.64-0.97; P<0.001), and a higher risk of post-extubation hypoxaemia (ARD=3.9%; 95% CI, 3.4-4.4; P<0.001). The effect was modified by the use of non-depolarising neuromuscular blocking agents (NMBAs); mediation analyses revealed that 28.9% (95% CI, 14.4-43.4%; P<0.001) of the main effect was attributable to NMBA. Airway management modified the association of NMBA and risk of emergent postoperative intubation (Pinteraction=0.02). Patients managed with an SGA had higher odds of NMBA-associated reintubation compared to patients managed with a tracheal tube (adjusted odds ratio [aOR]=3.65, 95% CI, 1.99-6.67 vs aOR=1.68, 95% CI, 1.29-2.18 [P<0.001], respectively). CONCLUSIONS: In patients undergoing procedures under general anaesthesia that could be managed with either SGA or tracheal tube, use of an SGA was associated with lower risk of emergent postoperative intubation. The effect can partly be explained by use of NMBAs. Use of NMBAs in patients with an SGA appears to increase the risk of emergent postoperative intubation.

Effects of night surgery on postoperative mortality and morbidity: a multicentre cohort study.

BACKGROUND: Surgery at night (incision time 17:00 to 07:00 hours) may lead to increased postoperative mortality and morbidity. Mechanisms explaining this association remain unclear. METHODS: We conducted a multicentre retrospective cohort study of adult patients undergoing non-cardiac surgery with general anaesthesia at two major, competing tertiary care hospital networks. In primary analysis, we imputed missing data and determined whether exposure to night surgery affects 30-day mortality using a mixed-effects model with individual anaesthesia and surgical providers as random effects. Secondary outcomes were 30-day morbidity and the mediating effect of blood transfusion rates and provider handovers on the effect of night surgery on outcomes. We further tested for effect modification by surgical setting. RESULTS: Among 350 235 participants in the primary imputed cohort, the mortality rate was 0.9% (n=2804/322 327) after day and 3.4% (n=940/27 908) after night surgery. Night surgery was associated with an increased risk of mortality (ORadj 1.26, 95% CI 1.15 to 1.38, p<0.001). In secondary analyses, night surgery was associated with increased morbidity (ORadj 1.41, 95% CI 1.33 to 1.48, p<0.001). The proportion of patients receiving intraoperative blood transfusion and anaesthesia handovers were higher during night-time, mediating 9.4% (95% CI 4.7% to 14.2%, p<0.001) of the effect of night surgery on 30-day mortality and 8.4% (95% CI 6.7% to 10.1%, p<0.001) of its effect on morbidity. The primary association was modified by the surgical setting (p-for-interaction<0.001), towards a greater effect in patients undergoing ambulatory/same-day surgery (ORadj 1.81, 95% CI 1.39 to 2.35) compared with inpatients (ORadj 1.17, 95% CI 1.02 to 1.34). CONCLUSIONS: Night surgery was associated with an increased risk of postoperative mortality and morbidity. The effect was independent of case acuity and was mediated by potentially preventable factors: higher blood transfusion rates and more frequent provider handovers.

Study protocol for a randomised controlled trial evaluating the effects of the orexin receptor antagonist suvorexant on sleep architecture and delirium in the intensive care unit.

INTRODUCTION: Insomnia frequently occurs in patients admitted to an intensive care unit (ICU). Sleep-promoting agents may reduce rapid eye movement sleep and have deliriogenic effects. Suvorexant (Belsomra) is an orexin receptor antagonist with Food and Drug Administration (FDA) approval for the treatment of adult insomnia, which improves sleep onset and maintenance as well as subjective measures of quality of sleep. This trial will evaluate the efficacy of postoperative oral suvorexant treatment on night-time wakefulness after persistent sleep onset as well as the incidence and duration of delirium among adult cardiac surgical patients. METHODS AND ANALYSIS: In this single-centre, randomised, double-blind, placebo-controlled trial, we will enrol 120 patients, aged 60 years or older, undergoing elective cardiac surgery with planned postoperative admission to the ICU. Participants will be randomised to receive oral suvorexant (20 mg) or placebo one time a day starting the night after extubation. The primary outcome will be wakefulness after persistent sleep onset. The secondary outcome will be total sleep time. Exploratory outcomes will include time to sleep onset, incidence of postoperative in-hospital delirium, number of delirium-free days and subjective sleep quality. ETHICS AND DISSEMINATION: Ethics approval was obtained through the 'Committee on Clinical Investigations' at Beth Israel Deaconess Medical Center (protocol number 2019P000759). The findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: This trial has been registered at clinicaltrials.gov on 17 September 2019 (NCT04092894).

Impact of Left Atrial Appendage Exclusion on Short-Term Outcomes in Isolated Coronary Artery Bypass Graft Surgery.

BACKGROUND: The objective of this study was to evaluate the impact of left atrial appendage (LAA) exclusion on short-term outcomes in patients with atrial fibrillation undergoing isolated coronary artery bypass graft surgery. METHODS: We queried the 2010 to 2014 National Readmissions Database for patients who underwent coronary artery bypass graft repair with and without LAA ligation by using International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes (International Classification of Diseases, Ninth Revision, Clinical Modification: 36.1xx). Only patients with a history of atrial fibrillation were included in our analysis. The primary outcome of our study was 30-day readmissions following discharge. Secondary outcomes were in-hospital mortality and stroke. To assess the postoperative outcomes, we used multivariate logistic regression models to adjust for clinical and demographic covariates. RESULTS: In total, we analyzed 253 287 patients undergoing coronary artery bypass graft surgery, 7.0% of whom received LAA closure. LAA exclusion was associated with a greater risk of postoperative respiratory failure (8.2% versus 6.2%, P<0.0001) and acute kidney injury (21.8% versus 18.5%, P<0.0001), but it did not significantly change the rate of blood transfusions or occurrence of cardiac tamponade. LAA exclusion was associated with a nonsignificant reduction in stroke (7.9% versus 8.6%, P=0.12), no difference in in-hospital mortality (2.2% versus 2.2% P=0.99), and a greater risk of 30-day readmission (16.0% versus 9.6%, P<0.0001). After covariate adjustment, LAA ligation remained a significant predictor of 30-day readmission (odds ratio, 1.640 [95% CI, 1.603-1.677], P<0.0001). CONCLUSIONS: LAA exclusion during isolated coronary artery bypass graft surgery in patients with atrial fibrillation is associated with a higher rate of 30-day readmission. Postoperative measures to mitigate the loss of the hormonal and hemodynamic effects of the LAA may increase the therapeutic benefit of this procedure.

Cardiac surgical outcome prediction by blood pressure variability indices Poincaré plot and coefficient of variation: a retrospective study.

BACKGROUND: Recent literature suggests a significant association between blood pressure variability (BPV) and postoperative outcomes after cardiac surgery. However, its outcome prediction ability remains unclear. Current prediction models use static preoperative patient factors. We explored the ability of Poincaré plots and coefficient of variation (CV) by measuring intraoperative BPV in predicting adverse outcomes. METHODS: In this retrospective, observational, cohort study, 3687 adult patients (> 18 years) undergoing cardiac surgery requiring cardio-pulmonary bypass from 2008 to 2014 were included. Blood pressure variability was computed by Poincare plots and CV. Standard descriptors (SD) SD1, SD2 were measured with Poincare plots by ellipse fitting technique. The outcomes analyzed were the 30-day mortality and postoperative renal failure. Logistic regression models adjusted for preoperative and surgical factors were constructed to evaluate the association between BPV parameters and outcomes. C-statistics were used to analyse the predictive ability. RESULTS: Analysis found that, 99 (2.7%) patients died within 30 days and 105 (2.8%) patients suffered from in-hospital renal failure. Logistic regression models including BPV parameters (standard descriptors from Poincare plots and CV) performed poorly in predicting postoperative 30-day mortality and renal failure [Concordance(C)-Statistic around 0.5]. They did not add any significant value to the standard STS risk score [C-statistic: STS alone 0.7, STS + BPV parmeters 0.7]. CONCLUSIONS: In conclusion, BP variability computed from Poincare plots and CV were not predictive of mortality and renal failure in cardiac surgical patients. Patient comorbid conditions and other preoperative factors are still the gold standard for outcome prediction. Future directions include analysis of dynamic parameters such as complexity of physiological signals in identifying high risk patients and tailoring management accordingly.

Comparison of Glycemic Variability Indices: Blood Glucose, Risk Index, and Coefficient of Variation in Predicting Adverse Outcomes for Patients Undergoing Cardiac Surgery.

OBJECTIVES: Fluctuations in blood glucose (glycemic variability) increase the risk of adverse outcomes. No universally accepted tool for glycemic variability exists during the perioperative period. The authors compared 2 measures of glycemic variability-(1) coefficient of variation (CV) and (2) the Blood Glucose Risk Index (BGRI)-in predicting adverse outcomes after cardiac surgery. DESIGN: Prospective, observational study. SETTING: Single-center, teaching hospital. PARTICIPANTS: A total of 1,963 adult patients undergoing cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Postoperative blood glucose levels were measured hourly for the first 24 hours and averaged every 4 hours (4, 8, 12, 16, 20, and 24 hours). Glycemic variability was measured by CV and the BGRI. The primary outcome, major adverse events (MAEs), was a predefined composite of postoperative complications (death, reoperation, deep sternal infection, stroke, pneumonia, renal failure, tamponade, and myocardial infarction). Logistic regression models were constructed to evaluate the association. Predictive ability was measured using C-statistics. Major adverse events were seen in 170 (8.7%) patients. Only the fourth quartile of CV showed association (odds ratio [OR] 1.91; 95% confidence interval [CI] [1.19-3.14]; p = 0.01), whereas BGRI was related significantly to MAE (OR 1.20; 95% CI [1.10-1.32]; p < 0.0001). The predictive ability of CV and BGRI increased on adding the standard Society of Thoracic Surgeons (STS) risk index. The C-statistic for STS was 0.68, whereas STS + CV was 0.70 (p = 0.012) and STS + BGRI was 0.70 (p = 0.012). CONCLUSION: Both CV and the BGRI had good predictive ability. The BGRI being a continuous variable could be a preferred measure of glycemic variability in predicting adverse outcomes (cutoff value 2.24) after cardiac surgery.

Association between propofol dose and 1-year mortality in patients with or without a diagnosis of solid cancer.

BACKGROUND: Preclinical data suggest suppression of cancer proliferation by propofol, and retrospective studies suggest improved survival after cancer surgery with propofol-based anaesthesia. METHODS: To determine whether propofol dose administered for anaesthesia is associated with 1-yr mortality in patients with and without a diagnosis of solid cancer, we analysed adult patients undergoing monitored anaesthesia care or general anaesthesia at two academic medical centres in Boston, MA, USA. Logistic regression with interaction term analysis was applied with propofol dose (mg kg-1) as primary and diagnosis of solid cancer as co-primary exposure, and 1-yr mortality as the primary outcome. RESULTS: Of 280 081 patient cases, 10 744 (3.8%) died within 1 yr. Increasing propofol dose was associated with reduced odds of 1-yr mortality (adjusted odds ratio [aOR] 0.93 per 10 mg kg-1; 95% confidence interval [CI]: 0.89-0.98; absolute risk reduction fifth vs first quintile 0.5%; 95% CI: 0.2-0.7). This association was modified by a diagnosis of solid cancer (P<0.001 for interaction). Increasing propofol dose was associated with reduced odds of 1-yr mortality in patients without solid cancer (aOR: 0.78; 95% CI: 0.71-0.85), but not in patients with solid cancer (0.99; 0.94-1.04), a finding that was replicated when examining 5-yr mortality. CONCLUSIONS: Increasing propofol dose is associated with lower 1-yr mortality in patients without, but not in patients with, a diagnosis of solid cancer. We found evidence for competing effects, modifying the association between propofol dose and mortality.