Dexamethasone for Cardiac Surgery: A Practice Preference-Randomized Consent Comparative Effectiveness Trial.

BACKGROUND: High-dose corticosteroids have been used to attenuate the inflammatory response to cardiac surgery and cardiopulmonary bypass, but patient outcome benefits remain unclear. Our primary aim was to determine whether using dexamethasone was superior to not using dexamethasone to increase the number of home days in the first 30 days after cardiac surgery. Our secondary aim was to evaluate efficiency, value and impact of the novel trial design. METHODS: This pragmatic, international trial incorporating a prerandomized consent design favoring local practice enrolled patients undergoing cardiac surgery across 7 hospitals in Australia and The Netherlands. Patients were randomly assigned to dexamethasone, 1 mg/kg, or not (control). The primary outcome was the number of days alive and at home up to 30 days after surgery ("home days"). Secondary outcomes included prolonged mechanical ventilation (>48 h), sepsis, renal failure, myocardial infarction, stroke and death. RESULTS: Of 2093 patients assessed for eligibility, 1951 were randomized (median age 63 years, 80% male). The median number of home days was 23.0 (IQR, 20.1 to 24.1) in the dexamethasone group and 23.1 (IQR, 20.1 to 24.6) in the no dexamethasone group; median difference 0.1 (95% CI, -0.3 to 0.5), P=0.66. The rates of prolonged mechanical ventilation, RR 0.72 (95% CI, 0.48 to 1.08), sepsis, RR 1.02 (95% CI, 0.57 to 1.82), renal failure, RR 0.94 (95% CI, 0.80 to 1.12), myocardial infarction, RR 1.20 (95% CI, 0.30 to 4.82), stroke, RR 1.06 (95% CI, 0.54 to 2.08), and death, RR 0.72 (95% CI, 0.22 to 2.35), were comparable between groups (all P>0.10). Dexamethasone reduced intensive care unit stay, median 29 (IQR, 22 to 50) h vs. 43 (24 to 72) h, P=0.004. Our novel trial design was highly efficient (89.3% enrolment). CONCLUSIONS: Among patients undergoing cardiac surgery, high-dose dexamethasone decreased intensive care unit stay but did not increase the number of home days after surgery.

Predicting Death or Disability after Surgery in the Older Adult.

BACKGROUND: Older patients are vulnerable to developing new or worsening disability after surgery. Despite this, patient or surgical characteristics predisposing to postoperative disability are poorly defined. The aim of the study was to develop and validate a model, subsequently transformed to point-score form, to predict 6-month death or disability in older patients after surgery. METHODS: The authors built a prospective, single-center registry to develop and validate the prediction model. The registry included patients 70 yr of age or older undergoing elective and nonelective, cardiac and noncardiac surgery between May 25, 2017, and February 11, 2021, and combined clinical data from the electronic medical record, hospital administrative data (International Classification of Diseases, Tenth Revision, Australian Modification codes) and World Health Organization (Geneva, Switzerland) Disability Assessment Schedule data collected directly from the patients. Death or disability was defined as being dead or having a World Health Organization Disability Assessment Schedule score 16% or greater. Included patients were randomly divided into model development (70%) and internal validation (30%) cohorts. Once constructed, the logistic regression and point-score models were assessed using the internal validation cohort and an external validation cohort comprising data from a separate randomized trial. RESULTS: Of 2,176 patients who completed the World Health Organization Disability Assessment Schedule immediately before surgery, 927 (43%) patients were disabled, and 413 (19%) had significant disability. By 6 months after surgery, 1,640 patients (75%) had data available for the primary outcome analysis. Of these patients, 195 (12%) patients had died, and 691 (42%) were dead or disabled. The developed point-score model included the preoperative World Health Organization Disability Assessment Schedule score, patient age, dementia, and chronic kidney disease. The point score model retained good discrimination in the internal (area under the curve, 0.74; 95% CI, 0.69 to 0.79) and external (area under the curve, 0.77; 95% CI, 0.74 to 0.80) validation data sets. CONCLUSIONS: The authors developed and validated a point score model to predict death or disability in older patients after surgery.

Postoperative anaemia and patient-centred outcomes after major abdominal surgery: a retrospective cohort study.

BACKGROUND: Compared with anaemia before surgery, the underlying pathogenesis and implications of postoperative anaemia are largely unknown. METHODS: This retrospective cohort study analysed prospective data obtained from 2983 adult patients across 47 centres enrolled in a clinical trial evaluating restrictive and liberal intravenous fluids. The primary endpoint was persistent disability or death up to 90 days after surgery. Secondary endpoints included major septic complications, hospital stay, and patient quality of recovery using a 15-item quality of recovery (QoR-15) score, hospital re-admissions, and disability-free survival up to 12 months after surgery. Anaemia and disability were defined according to the WHO definitions. Multivariable regression was used to adjust for baseline risk and surgery. RESULTS: A total of 2983 patients met inclusion criteria for this study, of which 78.5% (95% confidence interval [CI], 76.7-80.1%) had postoperative anaemia. Patients with postoperative anaemia had a higher adjusted risk of death or disability up to 90 days after surgery when compared with those without anaemia: 18.2% vs 9.2% (risk ratio [RR]=1.51; 95% CI, 1.10-2.07, P=0.011); lower QoR-15 scores on Day 3 and Day 30, 105 (95% CI, 87-119) vs 114 (95% CI, 99-128; P<0.001), and 130 (95% CI, 112-140) vs 139 (95% CI, 121-144; P<0.011), respectively; higher adjusted risk of a composite of mortality/septic complications, 2.01 (95% CI, 1.55-42.67; P<0.001); unplanned admission to ICU (RR=2.65; 95% CI, 1.65-4.23; P<0.001); and longer median (inter-quartile range [IQR]) hospital stays, 6.6 (4.4-12.4) vs 3.7 (2.5-6.5) days (P<0.001). CONCLUSIONS: Postoperative anaemia is common and is independently associated with poor outcomes after surgery. Optimal prevention and treatment strategies need to be investigated. CLINICAL TRIAL REGISTRATION: NCT04978285 (ClinicalTrials.gov).

Consumer Engagement in Perioperative Clinical Trials.

Consumer engagement (patient and public involvement) in perioperative medicine research is in its infancy. The patient experience and family/carer perspectives can provide an extra layer of insight to give more understanding as to what, why, and how we do research. Patients who have undergone surgery have a unique understanding of the issues, concerns, wants, and needs that they learned as a patient-they, therefore, can be considered as a professional given their experience(s)-thus warranting recognition as a partner in research. Knowledge of the consumer engagement literature and availability of resources should support anesthesia researchers aiming to include these perspectives in their research. This includes several existing engagement frameworks and assessment tools. We provide a framework for consumer engagement for adoption into anesthesia and other perioperative research. By incorporating the patient or caregiver into the design, funding application(s), data collection, and interpretation of the findings can be beneficial to all. This includes promoting knowledge and access to clinical trials, the wording of participant consent and information forms, methods of data collection, selection of important outcomes, and dissemination of results.

Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery.

BACKGROUND: Guidelines to promote the early recovery of patients undergoing major surgery recommend a restrictive intravenous-fluid strategy for abdominal surgery. However, the supporting evidence is limited, and there is concern about impaired organ perfusion. METHODS: In a pragmatic, international trial, we randomly assigned 3000 patients who had an increased risk of complications while undergoing major abdominal surgery to receive a restrictive or liberal intravenous-fluid regimen during and up to 24 hours after surgery. The primary outcome was disability-free survival at 1 year. Key secondary outcomes were acute kidney injury at 30 days, renal-replacement therapy at 90 days, and a composite of septic complications, surgical-site infection, or death. RESULTS: During and up to 24 hours after surgery, 1490 patients in the restrictive fluid group had a median intravenous-fluid intake of 3.7 liters (interquartile range, 2.9 to 4.9), as compared with 6.1 liters (interquartile range, 5.0 to 7.4) in 1493 patients in the liberal fluid group (P<0.001). The rate of disability-free survival at 1 year was 81.9% in the restrictive fluid group and 82.3% in the liberal fluid group (hazard ratio for death or disability, 1.05; 95% confidence interval, 0.88 to 1.24; P=0.61). The rate of acute kidney injury was 8.6% in the restrictive fluid group and 5.0% in the liberal fluid group (P<0.001). The rate of septic complications or death was 21.8% in the restrictive fluid group and 19.8% in the liberal fluid group (P=0.19); rates of surgical-site infection (16.5% vs. 13.6%, P=0.02) and renal-replacement therapy (0.9% vs. 0.3%, P=0.048) were higher in the restrictive fluid group, but the between-group difference was not significant after adjustment for multiple testing. CONCLUSIONS: Among patients at increased risk for complications during major abdominal surgery, a restrictive fluid regimen was not associated with a higher rate of disability-free survival than a liberal fluid regimen and was associated with a higher rate of acute kidney injury. (Funded by the Australian National Health and Medical Research Council and others; RELIEF ClinicalTrials.gov number, NCT01424150 .).

Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery.

BACKGROUND: Tranexamic acid reduces the risk of bleeding among patients undergoing cardiac surgery, but it is unclear whether this leads to improved outcomes. Furthermore, there are concerns that tranexamic acid may have prothrombotic and proconvulsant effects. METHODS: In a trial with a 2-by-2 factorial design, we randomly assigned patients who were scheduled to undergo coronary-artery surgery and were at risk for perioperative complications to receive aspirin or placebo and tranexamic acid or placebo. The results of the tranexamic acid comparison are reported here. The primary outcome was a composite of death and thrombotic complications (nonfatal myocardial infarction, stroke, pulmonary embolism, renal failure, or bowel infarction) within 30 days after surgery. RESULTS: Of the 4662 patients who were enrolled and provided consent, 4631 underwent surgery and had available outcomes data; 2311 were assigned to the tranexamic acid group and 2320 to the placebo group. A primary outcome event occurred in 386 patients (16.7%) in the tranexamic acid group and in 420 patients (18.1%) in the placebo group (relative risk, 0.92; 95% confidence interval, 0.81 to 1.05; P=0.22). The total number of units of blood products that were transfused during hospitalization was 4331 in the tranexamic acid group and 7994 in the placebo group (P<0.001). Major hemorrhage or cardiac tamponade leading to reoperation occurred in 1.4% of the patients in the tranexamic acid group and in 2.8% of the patients in the placebo group (P=0.001), and seizures occurred in 0.7% and 0.1%, respectively (P=0.002 by Fisher's exact test). CONCLUSIONS: Among patients undergoing coronary-artery surgery, tranexamic acid was associated with a lower risk of bleeding than was placebo, without a higher risk of death or thrombotic complications within 30 days after surgery. Tranexamic acid was associated with a higher risk of postoperative seizures. (Funded by the Australian National Health and Medical Research Council and others; ATACAS Australia New Zealand Clinical Trials Registry number, ACTRN12605000557639 .).

Stopping vs. Continuing Aspirin before Coronary Artery Surgery.

BACKGROUND: Most patients with coronary artery disease receive aspirin for primary or secondary prevention of myocardial infarction, stroke, and death. Aspirin poses a risk of bleeding in patients undergoing surgery, but it is unclear whether aspirin should be stopped before coronary artery surgery. METHODS: We used a 2-by-2 factorial trial design to randomly assign patients who were scheduled to undergo coronary artery surgery and were at risk for perioperative complications to receive aspirin or placebo and tranexamic acid or placebo. The results of the aspirin trial are reported here. Patients were randomly assigned to receive 100 mg of aspirin or matched placebo preoperatively. The primary outcome was a composite of death and thrombotic complications (nonfatal myocardial infarction, stroke, pulmonary embolism, renal failure, or bowel infarction) within 30 days after surgery. RESULTS: Among 5784 eligible patients, 2100 were enrolled; 1047 were randomly assigned to receive aspirin and 1053 to receive placebo. A primary outcome event occurred in 202 patients in the aspirin group (19.3%) and in 215 patients in the placebo group (20.4%) (relative risk, 0.94; 95% confidence interval, 0.80 to 1.12; P=0.55). Major hemorrhage leading to reoperation occurred in 1.8% of patients in the aspirin group and in 2.1% of patients in the placebo group (P=0.75), and cardiac tamponade occurred at rates of 1.1% and 0.4%, respectively (P=0.08). CONCLUSIONS: Among patients undergoing coronary artery surgery, the administration of preoperative aspirin resulted in neither a lower risk of death or thrombotic complications nor a higher risk of bleeding than that with placebo. (Funded by the Australian National Health and Medical Research Council and others; Australia New Zealand Clinical Trials Registry number, ACTRN12605000557639.).

Importance of intraoperative oliguria during major abdominal surgery: findings of the Restrictive versus Liberal Fluid Therapy in Major Abdominal Surgery trial.

BACKGROUND: The association between intraoperative oliguria during major abdominal surgery and the subsequent development of postoperative acute kidney injury (AKI) remains poorly defined. We hypothesised that, in such patients, intraoperative oliguria would be an independent predictor of subsequent AKI. METHODS: We performed a post hoc analysis of data from the Restrictive versus Liberal Fluid Therapy in Major Abdominal Surgery (RELIEF) trial of conservative vs liberal fluid therapy during and after major abdominal surgery. We used χ2, logistic regression, and fractional polynomials to study the association between intraoperative oliguria defined as a urinary output <0.5 ml kg-1 h-1 and the development of postoperative AKI defined by the Kidney Disease Improving Global Outcomes consensus criteria. RESULTS: We included 2444 of 2983 patients from the RELIEF trial in this study. A total of 889 patients (36%) met oliguric criteria intraoperatively. Oliguria occurred in 35% of those without AKI, and 44%, 48%, and 45% of those who developed postoperative AKI Stages 1-3, respectively (P<0.001 for trend). Intraoperative oliguria was associated with an increased risk of AKI, risk ratio: 1.38 (95% confidence interval: 1.14-1.44; P<0.001), but greater intensity of oliguria (urine output <0.3 ml kg-1 h-1) did not increase this risk further. Most patients with oliguria did not develop AKI; the positive predictive value of oliguria was 25.5%, and the negative predictive value was 81.6%. CONCLUSIONS: Intraoperative oliguria, defined as urine output <0.5 ml kg-1 h-1, was relatively common and was associated with postoperative AKI. However, the predictive utility of oliguria for AKI was low, whilst its absence had a good predictive value for an AKI-free postoperative course. CLINICAL TRIAL REGISTRATION: NCT01424150.

Postoperative critical care and high-acuity care provision in the United Kingdom, Australia, and New Zealand.

BACKGROUND: Decisions to admit high-risk postoperative patients to critical care may be affected by resource availability. We aimed to quantify adult ICU/high-dependency unit (ICU/HDU) capacity in hospitals from the UK, Australia, and New Zealand (NZ), and to identify and describe additional 'high-acuity' beds capable of managing high-risk patients outside the ICU/HDU environment. METHODS: We used a modified Delphi consensus method to design a survey that was disseminated via investigator networks in the UK, Australia, and NZ. Hospital- and ward-level data were collected, including bed numbers, tertiary services offered, presence of an emergency department, ward staffing levels, and the availability of critical care facilities. RESULTS: We received responses from 257 UK (response rate: 97.7%), 35 Australian (response rate: 32.7%), and 17 NZ (response rate: 94.4%) hospitals (total 309). Of these hospitals, 91.6% reported on-site ICU or HDU facilities. UK hospitals reported fewer critical care beds per 100 hospital beds (median=2.7) compared with Australia (median=3.7) and NZ (median=3.5). Additionally, 31.1% of hospitals reported having high-acuity beds to which high-risk patients were admitted for postoperative management, in addition to standard ICU/HDU facilities. The estimated numbers of critical care beds per 100 000 population were 9.3, 14.1, and 9.1 in the UK, Australia, and NZ, respectively. The estimated per capita high-acuity bed capacities per 100 000 population were 1.2, 3.8, and 6.4 in the UK, Australia, and NZ, respectively. CONCLUSIONS: Postoperative critical care resources differ in the UK, Australia, and NZ. High-acuity beds may have developed to augment the capacity to deliver postoperative critical care.

Implication of Major Adverse Postoperative Events and Myocardial Injury on Disability and Survival: A Planned Subanalysis of the ENIGMA-II Trial.

BACKGROUND: Globally, >300 million patients have surgery annually, and ≤20% experience adverse postoperative events. We studied the impact of both cardiac and noncardiac adverse events on 1-year disability-free survival after noncardiac surgery. METHODS: We used the study cohort from the Evaluation of Nitrous oxide in Gas Mixture of Anesthesia (ENIGMA-II) trial, an international randomized trial of 6992 noncardiac surgical patients. All were ≥45 years of age and had moderate to high cardiac risk. The primary outcome was mortality within 1 postoperative year. We defined 4 separate types of postoperative adverse events. Major adverse cardiac events (MACEs) included myocardial infarction (MI), cardiac arrest, and myocardial revascularization with or without troponin elevation. MI was defined using the third Universal Definition and was blindly adjudicated. A second cohort consisted of patients with isolated troponin increases who did not meet the definition for MI. We also considered a cohort of patients who experienced major adverse postoperative events (MAPEs), including unplanned admission to intensive care, prolonged mechanical ventilation, wound infection, pulmonary embolism, and stroke. From this cohort, we identified a group without troponin elevation and another with troponin elevation that was not judged to be an MI. Multivariable Cox proportional hazard models for death at 1 year and assessments of proportionality of hazard functions were performed and expressed as an adjusted hazard ratio (aHR) and 95% confidence intervals (CIs). RESULTS: MACEs were observed in 469 patients, and another 754 patients had isolated troponin increases. MAPEs were observed in 631 patients. Compared with control patients, patients with a MACE were at increased risk of mortality (aHR, 3.36 [95% CI, 2.55-4.46]), similar to patients who suffered a MAPE without troponin elevation (n = 501) (aHR, 2.98 [95% CI, 2.26-3.92]). Patients who suffered a MAPE with troponin elevation but without MI had the highest risk of death (n = 116) (aHR, 4.29 [95% CI, 2.89-6.36]). These 4 types of adverse events similarly affected 1-year disability-free survival. CONCLUSIONS: MACEs and MAPEs occur at similar frequencies and affect survival to a similar degree. All 3 types of postoperative troponin elevation in this analysis were associated, to varying degrees, with increased risk of death and disability.

Serious adverse event reporting in investigator-initiated clinical trials.

Reporting adverse events (AEs) and serious AEs (SAEs) are practical steps to ensure safety for volunteers and patients in medical research involving medications, treatments and devices. However, the burden and cost of reporting should be proportionate with the public health benefit of this information. Unfortunately, in Australia there is clear evidence of ever-increasing requirements from sponsors and ethics committees to report AEs and SAEs unnecessarily, leading to a decrease in the uptake of research, particularly less well funded investigator-initiated trials. We believe that individual AE reports to ethics committees serve no useful purpose, because in most cases the study group identity (drug exposure) is not known in studies with blinded treatment arms and their value is limited. Pragmatic, investigator-initiated Phase IV clinical trials of post-marketed drugs or devices are needed to understand their role in everyday clinical practice. In this setting, the workload and costs of systematic, complete reporting of all AEs and SAEs (independent of whether these are treatment-related) is wasteful, and mostly unnecessary. A trial data safety and monitoring committee is in the unique position of being able to review safety information according to the blinded treatment arms of the study. This enables safety data to be analysed appropriately and a summary report provided to the trial steering committee, principal investigators and the relevant ethics committees in a meaningful way. Defined trial endpoints do not need to be reported as safety events (because they are being properly monitored and analysed).

The safety of addition of nitrous oxide to general anaesthesia in at-risk patients having major non-cardiac surgery (ENIGMA-II): a randomised, single-blind trial.

BACKGROUND: Nitrous oxide is commonly used in general anaesthesia but concerns exist that it might increase perioperative cardiovascular risk. We aimed to gather evidence to establish whether nitrous oxide affects perioperative cardiovascular risk. METHODS: We did an international, randomised, assessor-blinded trial in patients aged at least 45 years with known or suspected coronary artery disease having major non-cardiac surgery. Patients were randomly assigned via automated telephone service, stratified by site, to receive a general anaesthetic with or without nitrous oxide. Attending anaesthetists were aware of patients' group assignments, but patients and assessors were not. The primary outcome measure was a composite of death and cardiovascular complications (non-fatal myocardial infarction, stroke, pulmonary embolism, or cardiac arrest) within 30 days of surgery. Our modified intention-to-treat population included all patients randomly assigned to groups and undergoing induction of general anaesthesia for surgery. This trial is registered at ClinicalTrials.gov, number NCT00430989. FINDINGS: Of 10,102 eligible patients, we enrolled 7112 patients between May 30, 2008, and Sept 28, 2013. 3543 were assigned to receive nitrous oxide and 3569 were assigned not to receive nitrous oxide. 3483 patients receiving nitrous oxide and 3509 not receiving nitrous oxide were assessed for the primary outcome. The primary outcome occurred in 283 (8%) patients receiving nitrous oxide and in 296 (8%) patients not receiving nitrous oxide (relative risk 0·96, 95% CI 0·83­1·12; p=0·64). Surgical site infection occurred in 321 (9%) patients assigned to nitrous oxide, and in 311 (9%) patients in the no-nitrous oxide group (p=0·61), and severe nausea and vomiting occurred in 506 patients (15%) assigned to nitrous oxide and 378 patients (11%) not assigned to nitrous oxide (p<0·0001). INTERPRETATION: Our findings support the safety profile of nitrous oxide use in major non-cardiac surgery. Nitrous oxide did not increase the risk of death and cardiovascular complications or surgical-site infection, the emetogenic effect of nitrous oxide can be controlled with antiemetic prophylaxis, and a desired effect of reduced volatile agent use was shown. FUNDING: Australian National Health and Medical Research Council; Australian and New Zealand College of Anaesthetists; Heart and Stroke Foundation of Quebec, Heart and Stroke Foundation of Ontario, Canada; General Research Fund of the Research Grant Council, Hong Kong Special Administrative Region, China.

Measurement of disability-free survival after surgery.

BACKGROUND: Survival and freedom from disability are arguably the most important patient-centered outcomes after surgery, but it is unclear how postoperative disability should be measured. The authors thus evaluated the World Health Organization Disability Assessment Schedule 2.0 in a surgical population. METHODS: The authors examined the psychometric properties of World Health Organization Disability Assessment Schedule 2.0 in a diverse cohort of 510 surgical patients. The authors assessed clinical acceptability, validity, reliability, and responsiveness up to 12 months after surgery. RESULTS: Criterion and convergent validity of World Health Organization Disability Assessment Schedule 2.0 were supported by good correlation with the 40-item quality of recovery scale at 30 days after surgery (r = -0.70) and at 3, 6, and 12 months after surgery with physical functioning (The Katz index of independence in Activities of Daily Living; r = -0.70, r = -0.60, and rho = -0.47); quality of life (EQ-5D; r = -0.57, -0.60, and -0.52); and pain interference scores (modified Brief Pain Inventory Short Form; r = 0.72, 0.74, and 0.81) (all P < 0.0005). Construct validity was supported by increased hospital stay (6.9 vs. 5.3 days, P = 0.008) and increased day 30 complications (20% vs. 11%, P = 0.042) in patients with new disability. There was excellent internal consistency with Cronbach's α and split-half coefficients greater than 0.90 at all time points (all P < 0.0005). Responsiveness was excellent with effect sizes of 3.4, 3.0, and 1.0 at 3, 6, and 12 months after surgery, respectively. CONCLUSIONS: World Health Organization Disability Assessment Schedule 2.0 is a clinically acceptable, valid, reliable, and responsive instrument for measuring postoperative disability in a diverse surgical population. Its use as an endpoint in future perioperative studies can provide outcome data that are meaningful to clinicians and patients alike.

Nitrous Oxide and Serious Long-term Morbidity and Mortality in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II Trial.

BACKGROUND: The Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II trial randomly assigned 7,112 noncardiac surgery patients at risk of perioperative cardiovascular events to 70% N2O or 70% N2 groups. The aim of this follow-up study was to determine the effect of nitrous oxide on a composite primary outcome of death and major cardiovascular events at 1 yr after surgery. METHODS: One-year follow-up was conducted via a medical record review and telephone interview. Disability was defined as a Katz index of independence in activities of daily living score less than 8. Adjusted odds ratios and hazard ratios were calculated as appropriate for primary and secondary outcomes. RESULTS: Among 5,844 patients evaluated at 1 yr, 435 (7.4%) had died, 206 (3.5%) had disability, 514 (8.8%) had a fatal or nonfatal myocardial infarction, and 111 (1.9%) had a fatal or nonfatal stroke during the 1-yr follow-up period. Exposure to nitrous oxide did not increase the risk of the primary outcome (odds ratio, 1.08; 95% CI, 0.94 to 1.25; P = 0.27), disability or death (odds ratio, 1.07; 95% CI, 0.90 to 1.27; P = 0.44), death (hazard ratio, 1.17; 95% CI, 0.97 to 1.43; P = 0.10), myocardial infarction (odds ratio, 0.97; 95% CI, 0.81 to 1.17; P = 0.78), or stroke (odds ratio, 1.08; 95% CI, 0.74 to 1.58; P = 0.70). CONCLUSION: These results support the long-term safety of nitrous oxide administration in noncardiac surgical patients with known or suspected cardiovascular disease.

An enhanced recovery after surgery program for hip and knee arthroplasty.

OBJECTIVE: To institute and evaluate the benefits of an enhanced recovery after surgery (ERAS) program across three hospitals in Victoria. DESIGN, SETTING AND PARTICIPANTS: We used a before-and-after quality improvement study design consisting of three phases: pre-ERAS program data collection from March to September 2012; ERAS training and implementation during September 2012; and change performance measurement following ERAS implementation from October 2012 to May 2013. MAIN OUTCOME MEASURES: The primary end point was duration of hospital stay after knee or hip arthroplasty. Secondary end points were adherence to the ERAS bundle, and process and patient recovery characteristics. RESULTS: We enrolled 412 patients to the pre-ERAS (existing-practice) phase and compared them with 297 patients in the ERAS phase. For ERAS patients, compared with existing-practice patients, hospital stay was reduced (geometric mean, 5.3 [SD, 1.6] v 4.9 [SD, 1.6] days; P < 0.001) and there was a significant improvement in the proportion of patients ready for discharge on Day 3 after surgery (41% v 59%; P < 0.001). The most common reason for delayed discharge was patients waiting for review or access to rehabilitation services. There were markedly improved indicators of processes and outcomes of care, including improved patient education, reduced fasting times, less blood loss, better analgesia, earlier ambulation and improved overall quality of recovery. CONCLUSION: We found that an ERAS program could be successfully implemented in elective joint arthroplasty, leading to a shorter duration of hospital stay. We recommend this orthopaedic ERAS pathway.

Is Preoperative Endothelial Dysfunction a Potentially Modifiable Risk Factor for Renal Injury Associated With Noncardiac Surgery?

OBJECTIVES: To determine whether preoperative endothelial dysfunction provides risk stratification for perioperative renal injury in patients undergoing noncardiac surgery. The relationship between perioperative renal injury and myocardial injury after noncardiac surgery (MINS) was explored secondarily. DESIGN: An observational study. SETTING: Two academic medical centers. PARTICIPANTS: A total of 218 patients scheduled to undergo intermediate or high-risk noncardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Endothelial dysfunction was identified preoperatively by a Reactive Hyperemia-Peripheral Arterial Tonometry (RH-PAT) index. Renal injury was defined by peak delta serum creatinine (ΔSCr) or creatinine-based kidney disease: Improving global outcomes acute kidney injury (AKI) criteria within 7 days postoperatively. MINS was defined by peak troponin ≥0.04 µg/L within 3 days postoperatively. AKI occurred in 22 patients (10.1%). Median RH-PAT index within the study cohort was 1.64 (range 1.03-4.96) and did not differ between patients with or without AKI. When adjusted for covariates, there was no association between RH-PAT index and either AKI or peak ΔSCr. MINS occurred in 32 patients (14.7%) and was associated independently with the outcome of AKI (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.2-10.8; p = 0.02) and peak ΔSCr (ß-regression coefficient 23; 95% CI, 9-37; p = 0.002). Co-occurrence of AKI and MINS portended a marked increase in 30-day mortality (OR, 43; 95% CI, 6-305; p = 0.001) and delayed time to discharge (hazard ratio, 0.27; 95% CI, 0.13-0.54; p = 0.001). CONCLUSIONS: For patients undergoing noncardiac surgery, preoperative endothelial function assessed by noninvasive peripheral arterial tonometry was not associated with perioperative AKI. Perioperative renal injury was associated strongly with MINS, and this may represent a mechanism by which AKI increases adverse outcomes.

A mixed methods study protocol to identify research priorities for perioperative medicine in Australia.

Background: Clinical research in perioperative medicine requires the perspectives of patients and caregivers to increase its relevance and quality, benefiting both researchers and the community. Identifying these priorities will enable researchers, funders, and governing bodies to efficiently use scarce funding and resources. We aim to identify the top 10 research priorities in perioperative medical research in Australia. Methods: A mixed-methods, exploratory-sequential design will be conducted. The study will include five phases. Initially, a published open-ended survey gathered responses from the population (researchers, healthcare workers, and consumers) regarding uncertainties/questions relevant to the population about perioperative medical research. We collected 544 questions and quantitatively analysed and grouped them according to the Standardised Endpoints in Perioperative Medicine-Core Outcomes Measures in Perioperative and Anaesthetic Care (StEP-COMPAC) endpoints. Using multicriteria decision-making software, workshops combining the population will be conducted to determine the top 10 priorities for perioperative medicine research for the Australian population. Ethics and dissemination: Ethical approval to conduct the study was obtained from the Alfred Health (Australia) Human Research Ethics Committee (ID: 171/19). The findings will be disseminated in peer review publications, conferences, and dissemination across perioperative research networks. The top 10 priorities will be available to inform research funders, grant submissions, guidelines, and the population.

Consumer engagement and patient reported outcomes in perioperative clinical trials in Australia: a systematic review.

BACKGROUND: Consumer engagement in clinical research is increasingly being prioritized by major funders such as the Australian National Health and Medical Research Council. METHODS: We performed a systematic literature search of the Cochrane library, Embase, CINAHL PubMed and Medline to identify randomized clinical trials in surgery with perioperative outcomes conducted in Australia. All publications underwent review and thematic analysis to identify levels of consumer engagement and the inclusion of patient-reported outcome measures (PROMS). RESULTS: From 5373 records, the full texts of 809 articles were retrieved, of which 41 clinical trials met the inclusion criteria. PROMS were identified in 63% of the trials as a primary or secondary outcome. Despite multiple available checklists and analysis tools, less than 2% of studies documented any consumer engagement apart from PROMS. CONCLUSION: There was very little consumer engagement in formulation, management, conduct and dissemination of the trial findings.

Methylomic and transcriptomic characterization of postoperative systemic inflammatory dysregulation.

In this study, we define and validate a state of postoperative systemic inflammatory dysregulation (PSID) based on postoperative phenotypic extremes of plasma C-reactive protein concentration following major abdominal surgery. PSID manifested clinically with significantly higher rates of sepsis, complications, longer hospital stays and poorer short, and long-term outcomes. We hypothesized that PSID will be associated with, and potentially predicted by, altered patterns of genome-wide peripheral blood mononuclear cell differential DNA methylation and gene expression. We identified altered DNA methylation and differential gene expression in specific immune and metabolic pathways during PSID. Our findings suggest that dysregulation results in, or from, dramatic changes in differential DNA methylation and highlights potential targets for early detection and treatment. The combination of altered DNA methylation and gene expression suggests that dysregulation is mediated at multiple levels within specific gene sets and hence, nonspecific anti-inflammatory treatments such as corticosteroids alone are unlikely to represent an effective therapeutic strategy.

COVID-19 risk in elective surgery during a second wave: a prospective cohort study.

BACKGROUND: The COVID-19 pandemic has greatly affected access to elective surgery, largely because of concerns for patients and healthcare workers. A return to normal surgery workflow depends on the prevalence and transmission of coronavirus in elective surgical patients. The aim of this study was to determine the prevalence of active SARS-coronavirus-2 infection during a second wave among patients admitted to hospital for elective surgery in Victoria. METHODS: Prospective cohort study across eight hospitals in Victoria during July-August 2020 was conducted enrolling adults and children admitted to hospital for elective surgery or interventional procedure requiring general anaesthesia. Study outcomes included a positive polymerase chain reaction (PCR) test for SARS-CoV-2 in the preoperative period (primary outcome), and for those with a negative test preoperatively, the incidence of a positive PCR test for SARS-CoV-2 in the post-operative period. RESULTS: We enrolled 4965 elective adult and paediatric surgical patients from 15 July to 31 August 2020. Four patients screened negative on questionnaire but had a positive PCR test for coronavirus, resulting in a Bayesian estimated prevalence of 0.12% (95% probability interval 0-0.26%). There were no reports of healthcare worker infections linked to elective surgery during and up to 2 weeks after the study period. CONCLUSION: The prevalence of SARS-CoV-2 in asymptomatic elective surgical patients during a second wave was approximately 1 in 833. Given the very low likelihood of coronavirus transmission, and with existing current hospital capacity, recommencement of elective surgery should be considered. A coronavirus screening checklist should be mandated for surgical patients.