Bruce Biccard

Association of Postoperative High-Sensitivity Troponin Levels With Myocardial Injury and 30-Day Mortality Among Patients Undergoing Noncardiac Surgery

Importance Little is known about the relationship between perioperative high-sensitivity troponin T (hsTnT) measurements and 30-day mortality and myocardial injury after noncardiac surgery (MINS). Objective To determine the association between perioperative hsTnT measurements and 30-day mortality and potential diagnostic criteria for MINS (ie, myocardial injury due to ischemia associated with 30-day mortality). Design, Setting, and Participants Prospective cohort study of patients aged 45 years or older who underwent inpatient noncardiac surgery and had a postoperative hsTnT measurement. Starting in October 2008, participants were recruited at 23 centers in 13 countries; follow-up finished in December 2013. Exposures Patients had hsTnT measurements 6 to 12 hours after surgery and daily for 3 days; 40.4% had a preoperative hsTnT measurement. Main Outcomes and Measures A modified Mazumdar approach (an iterative process) was used to determine if there were hsTnT thresholds associated with risk of death and had an adjusted hazard ratio (HR) of 3.0 or higher and a risk of 30-day mortality of 3% or higher. To determine potential diagnostic criteria for MINS, regression analyses ascertained if postoperative hsTnT elevations required an ischemic feature (eg, ischemic symptom or electrocardiography finding) to be associated with 30-day mortality. Results Among 21u2009842 participants, the mean age was 63.1 (SD, 10.7) years and 49.1% were female. Death within 30 days after surgery occurred in 266 patients (1.2%; 95% CI, 1.1%-1.4%). Multivariable analysis demonstrated that compared with the reference group (peak hsTnT <5 ng/L), peak postoperative hsTnT levels of 20 to less than 65 ng/L, 65 to less than 1000 ng/L, and 1000 ng/L or higher had 30-day mortality rates of 3.0% (123/4049; 95% CI, 2.6%-3.6%), 9.1% (102/1118; 95% CI, 7.6%-11.0%), and 29.6% (16/54; 95% CI, 19.1%-42.8%), with corresponding adjusted HRs of 23.63 (95% CI, 10.32-54.09), 70.34 (95% CI, 30.60-161.71), and 227.01 (95% CI, 87.35-589.92), respectively. An absolute hsTnT change of 5 ng/L or higher was associated with an increased risk of 30-day mortality (adjusted HR, 4.69; 95% CI, 3.52-6.25). An elevated postoperative hsTnT (ie, 20 to <65 ng/L with an absolute change ≥5 ng/L or hsTnT ≥65 ng/L) without an ischemic feature was associated with 30-day mortality (adjusted HR, 3.20; 95% CI, 2.37-4.32). Among the 3904 patients (17.9%; 95% CI, 17.4%-18.4%) with MINS, 3633 (93.1%; 95% CI, 92.2%-93.8%) did not experience an ischemic symptom. Conclusions and Relevance Among patients undergoing noncardiac surgery, peak postoperative hsTnT during the first 3 days after surgery was significantly associated with 30-day mortality. Elevated postoperative hsTnT without an ischemic feature was also associated with 30-day mortality.

Preoperative Score to Predict Postoperative Mortality (POSPOM)Derivation and Validation

Background:An accurate risk score able to predict in-hospital mortality in patients undergoing surgery may improve both risk communication and clinical decision making. The aim of the study was to develop and validate a surgical risk score based solely on preoperative information, for predicting in-hospital mortality. Methods:From January 1, 2010, to December 31, 2010, data related to all surgeries requiring anesthesia were collected from all centers (single hospital or hospitals group) in France performing more than 500 operations in the year on patients aged 18 yr or older (n = 5,507,834). International Statistical Classification of Diseases, 10th revision codes were used to summarize the medical history of patients. From these data, the authors developed a risk score by examining 29 preoperative factors (age, comorbidities, and surgery type) in 2,717,902 patients, and then validated the risk score in a separate cohort of 2,789,932 patients. Results:In the derivation cohort, there were 12,786 in-hospital deaths (0.47%; 95% CI, 0.46 to 0.48%), whereas in the validation cohort there were 14,933 in-hospital deaths (0.54%; 95% CI, 0.53 to 0.55%). Seventeen predictors were identified and included in the PreOperative Score to predict PostOperative Mortality (POSPOM). POSPOM showed good calibration and excellent discrimination for in-hospital mortality, with a c-statistic of 0.944 (95% CI, 0.943 to 0.945) in the development cohort and 0.929 (95% CI, 0.928 to 0.931) in the validation cohort. Conclusion:The authors have developed and validated POSPOM, a simple risk score for the prediction of in-hospital mortality in surgical patients.

Design of a Randomized Placebo-Controlled Trial to Assess Dabigatran and Omeprazole in Patients with Myocardial Injury after Noncardiac Surgery (MANAGE)

BACKGROUNDnWorldwide approximately 200 million adults undergo major surgery annually, of whom 8 million are estimated to suffer a myocardial injury after noncardiac surgery (MINS). There is currently no trial data informing the management of MINS. Antithrombotic agents such as direct oral anticoagulants might prevent major vascular complications in patients with MINS.nnnMETHODSnThe Management of Myocardial Injury After Noncardiac Surgery (MANAGE) trial is a large international blinded randomized controlled trial of dabigatran vs placebo in patients who suffered MINS. We used a partial factorial design to also determine the effect of omeprazole vs placebo in reducing upper gastrointestinal bleeding and complications. Both study drugs were initiated in eligible patients within 35 days of suffering MINS and continued for a maximum of 2 years. The primary outcome is a composite of major vascular complications for the dabigatran trial and a composite of upper gastrointestinal complications for the omeprazole trial. We present the rationale and design of the trial and baseline characteristics of enrolled patients.nnnRESULTSnThe trial randomized 1754 patients between January 2013 and July 2017. Patients mean age was 69.9 years, 51.1% were male, 14.3% had a history of peripheral artery disease, 6.6% had a history of stroke or transient ischemic attack, 12.9% had a previous myocardial infarction, and 26.0% had diabetes. The diagnosis of MINS was on the basis of an isolated ischemic troponin elevation in 80.4% of participants.nnnCONCLUSIONnMANAGE is the first randomized controlled trial to evaluate a potential treatment of patients who suffered MINS.

A systematic review and consensus definitions for standardised end-points in perioperative medicine: pulmonary complications

Background: There is a need for robust, clearly defined, patient‐relevant outcome measures for use in randomised trials in perioperative medicine. Our objective was to establish standard outcome measures for postoperative pulmonary complications research. Methods: A systematic literature search was conducted using MEDLINE, Web of Science, SciELO, and the Korean Journal Database. Definitions were extracted from included manuscripts. We then conducted a three‐stage Delphi consensus process to select the optimal outcome measures in terms of methodological quality and overall suitability for perioperative trials. Results: From 2358 records, the full texts of 81 manuscripts were retrieved, of which 45 met the inclusion criteria. We identified three main categories of outcome measure specific to perioperative pulmonary outcomes: (i) composite outcome measures of multiple pulmonary outcomes (27 definitions); (ii) pneumonia (12 definitions); and (iii) respiratory failure (six definitions). These were rated by the group according to suitability for routine use. The majority of definitions were given a low score, and many were imprecise, difficult to apply consistently, or both, in large patient populations. A small number of highly rated definitions were identified as appropriate for widespread use. The group then recommended four outcome measures for future use, including one new definition. Conclusions: A large number of postoperative pulmonary outcome measures have been used, but most are poorly defined. Our four recommended outcome measures include a new definition of postoperative pulmonary complications, incorporating an assessment of severity. These definitions will meet the needs of most clinical effectiveness trials of treatments to improve postoperative pulmonary outcomes.

Predicting the occurrence of major adverse cardiac events within 30 days of a vascular surgery: an empirical comparison of the minimum p value method and ROC curve approach using individual patient data meta-analysis

We aimed to compare the minimum p value method and the area under the receiver operating characteristics (ROC) curve approach to categorize continuous biomarkers for the prediction of postoperative 30-day major adverse cardiac events in noncardiac vascular surgery patients. Individual-patient data from six cohorts reporting B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NTproBNP) were obtained. These biomarkers were dichotomized using the minimum p value method and compared with previously reported ROC curve-derived thresholds using logistic regression analysis. A final prediction model was developed, internally validated, and assessed for its sensitivity to clustering effects. Finally, a preoperative risk score system was proposed. Thresholds identified by the minimum p value method and ROC curve approach were 115.57xa0pg/ml (pxa0<xa00.001) and 116xa0pg/ml for BNP, and 241.7xa0pg/ml (pxa0=xa00.001) and 277.5xa0pg/ml for NTproBNP, respectively. The minimum p value thresholds were slightly stronger predictors based on our logistic regression analysis. The final model included a composite predictor of the minimum p value method’s BNP and NTproBNP thresholds [odds ratio (OR)xa0=xa08.5, pxa0<xa00.001], surgery type (ORxa0=xa02.5, pxa0=xa00.002), and diabetes (ORxa0=xa02.1, pxa0=xa00.015). Preoperative risks using the scoring system ranged from 2 to 49xa0%. The minimum p value method and ROC curve approach identify similar optimal thresholds. We propose to replace the revised cardiac risk index with our risk score system for individual-specific preoperative risk stratification after noncardiac nonvascular surgery.

A meta-analysis of the efficacy of preoperative surgical safety checklists to improve perioperative outcomes

BACKGROUNDnMeta-analyses of the implementation of a surgical safety checklist (SSC) in observational studies have shown a significant decrease in mortality and surgical complications.nnnOBJECTIVEnTo determine the efficacy of the SSC using data from randomised controlled trials (RCTs).nnnMETHODSnThis meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered with PROSPERO (CRD42015017546). A comprehensive search of six databases was conducted using the OvidSP search engine.nnnRESULTSnFour hundred and sixty-four citations revealed three eligible trials conducted in tertiary hospitals and a community hospital, with a total of 6 060 patients. All trials had allocation concealment bias and a lack of blinding of participants and personnel. A single trial that contributed 5 295 of the 6 060 patients to the meta-analysis had no detection, attrition or reporting biases. The SSC was associated with significantly decreased mortality (risk ratio (RR) 0.59, 95% confidence interval (CI) 0.42 - 0.85; p=0.0004; I2=0%) and surgical complications (RR 0.64, 95% CI 0.57 - 0.71; p<0.00001; I2=0%). The efficacy of the SSC on specific surgical complications was as follows: respiratory complications RR 0.59, 95% CI 0.21 - 1.70; p=0.33, cardiac complications RR 0.74, 95% CI 0.28 - 1.95; p=0.54, infectious complications RR 0.61, 95% CI 0.29 - 1.27; p=0.18, and perioperative bleeding RR 0.36, 95% CI 0.23 - 0.56; p<0.00001.nnnCONCLUSIONSnThere is sufficient RCT evidence to suggest that SSCs decrease hospital mortality and surgical outcomes in tertiary and community hospitals. However, randomised evidence of the efficacy of the SSC at rural hospital level is absent.

Aspirin in patients with previous percutaneous coronary intervention undergoing noncardiac surgery

Noncardiac surgery is common, with more than 200 million annual procedures worldwide (1, 2). Despite the benefits of noncardiac surgery, major perioperative cardiovascular complications occur and are associated with mortality, prolonged hospitalization, and costs (3, 4). Physicians commonly encounter patients undergoing noncardiac surgery who have had a prior percutaneous coronary intervention (PCI) (5); these patients are at increased risk for major perioperative cardiovascular complications (59). In the POISE-2 (PeriOperative ISchemic Evaluation-2) trial, we randomly assigned 10010 patients having noncardiac surgery to receive aspirin or placebo and showed that aspirin did not prevent the primary composite outcome of death and nonfatal myocardial infarction but did increase the risk for major bleeding (1012). These results influenced perioperative guidelines (13, 14). We reported the 4 planned aspirin subgroup analyses in the main POISE-2 publication (11). When POISE-2 was designed, we did not plan a PCI subgroup analysis because we did not anticipate that physicians would enroll patients with a history of PCI. However, given that investigators enrolled 470 patients with prior PCI and the ongoing uncertainty about the effects of antiplatelet therapy for these patients (15, 16), we did this POISE-2 substudy to determine whether perioperative low-dose aspirin, compared with placebo, affected 30-day events in patients with previous PCI. Methods Design Overview POISE-2 was an international, randomized controlled, factorial trial that separately evaluated the effects of aspirin versus placebo and clonidine versus placebo in patients having noncardiac surgery. Patients were allocated in a 1:1:1:1 ratio to receive aspirin and clonidine, placebo and clonidine, aspirin and placebo, or placebo for both drugs. Full details of the trial design and results are reported elsewhere (1012). Institutional review boards approved the trial before recruitment started at participating centers. Supplement. Supplementary Documents Setting and Participants Patients aged 45 years or older who were having noncardiac surgery with an expected postoperative stay of at least 1 night were eligible if they had or were at risk for atherosclerotic disease. The trial excluded patients who received a bare-metal stent within 6 weeks or a drug-eluting stent within 1 year before randomization because of the risk for stent thrombosis associated with premature antiplatelet withdrawal. Patients who took nonstudy aspirin within 72 hours before surgery were also excluded to ensure unimpaired hemostasis before surgery. Participants were recruited in 135 centers in 23 countries from July 2010 to December 2013. Eighty-two centers from 21 countries enrolled patients with a history of PCI. Research personnel enrolled patients in an initiation stratum if they were not receiving long-term aspirin and in a continuation stratum if they were receiving long-term aspirin (defined as daily aspirin for at least 1 month within the 6 weeks before surgery). Patients in the aspirin continuation stratum had to discontinue aspirin therapy at least 3 days before surgery. Randomization and Interventions After giving written informed consent, patients were randomly assigned before surgery by a 24-hour computerized Internet system that concealed randomization. Block randomization, stratified by center and aspirin stratum, was used. Patients received aspirin or identical-appearing placebo (200 mg) within 4 hours before surgery and continued at a dosage of 100 mg/d for 30 days in the initiation stratum and for 7 days in the continuation stratum, after which patients resumed regular aspirin dosing. Study personnel assessed study drug adherence through nursing records in the hospital and through patient reporting after discharge. Patients, clinicians, data collectors, and outcome adjudicators were blinded to study drug allocation. Patients had a troponin measurement (or creatine kinaseMB if troponin was not available) 6 to 12 hours after surgery and on the first, second, and third days after surgery. Electrocardiography was done when an elevated troponin or creatine kinaseMB level was detected. Research personnel followed patients until 30 days after randomization, collected data, and submitted case report forms and supporting documentation directly to the data management system. Outcomes and Follow-up Outcomes evaluated in this PCI substudy included the primary outcome (a composite of death and nonfatal myocardial infarction) and secondary outcomes (myocardial infarction, all-cause mortality, vascular mortality, stroke, congestive heart failure, composite of major and life-threatening bleeding, major bleeding, life-threatening bleeding, and clinically important hypotension) at 30 days after randomization. Outcome definitions are reported in the Supplement. Blinded outcome adjudicators evaluated the events reported in this substudy, except for congestive heart failure and clinically important hypotension. Their decisions were used in the analyses. Statistical Analysis A statistical analysis plan was finalized before these substudy analyses were begun (Supplement). We expected aspirin to have a greater beneficial effect in patients with a history of PCI than in those without. We analyzed patients in the groups to which they were allocated, according to the intention-to-treat principle. Patients lost to follow-up before day 30 after randomization with no event reported were censored on the last day their status was known. All statistical analyses were done using SAS, version 9.4 (SAS Institute). For the primary and secondary outcomes, we did subgroup analyses based on whether patients had prior PCI (prior PCI vs. no prior PCI). For these subgroup analyses, we used Cox proportional hazards models that incorporated tests of interaction. These models adjusted for clonidine allocation. For the primary outcome, we tested for the proportional hazards assumption by including a timeaspirin allocation interaction term in the Cox proportional hazards model (time log-transformed). We found no evidence that the proportional hazards assumption had been violated; all P values were at least 0.55. We considered a P value for interaction less than 0.05 to be significant and to provide some evidence of a subgroup effect. In instances where the test for interaction was not significant, we considered the overall trial result (with the larger sample size) the likely best estimate of effect for all patients, including those within the subgroups. Estimates of the hazard ratios (HRs) and 2-sided 95% CIs were calculated using the Cox proportional hazards models. We also determined the KaplanMeier estimates of 30-day cumulative risk. We report between-group differences in proportions between the treatment groups as absolute risk reductions (ARRs) and increases (ARIs). We determined the 95% CIs for these differences. Among patients with a history of PCI, we did subgroup analyses based on the type of stent (bare-metal vs. drug-eluting), timing of PCI (1 year vs. >1 year before surgery), and preoperative use of an antiplatelet medication (use within 7 days vs. no use within 7 days before surgery) for the primary outcome. We used the same analytic approach as in the analyses comparing the prior-PCI versus no-prior-PCI subgroups. Role of the Funding Source POISE-2 was supported by grants from the Canadian Institutes of Health Research, the Australian National Health and Medical Research Council, and the Spanish Ministry of Health and Social Policy. Bayer Pharmaceuticals provided the aspirin used in the study, and Boehringer Ingelheim provided the clonidine and some funding. No donor or funder had a role in the design, conduct, data collection, data analyses, or manuscript preparation. The Population Health Research Institute (McMaster University, Hamilton, Ontario, Canada) was the trial coordinating center. The investigators and members of key committees and groups are reported in the Supplement. Results Figure 1 is the study flow diagram; 99.9% of the patients randomly assigned to a treatment group completed the 30-day follow-up. POISE-2 enrolled 470 patients with prior PCI (255, 119, 53, 41, and 2 patients had a bare-metal stent, drug-eluting stent, unknown type of stent, no stent, and uncertainty about whether a stent was used, respectively), of whom 234 were randomly assigned to receive aspirin and 236 placebo. The allocation to receive clonidine was similar between patients with prior PCI (233 patients [49.6%]) and those without (4776 patients [50.1%]) (P= 0.84). The median time from stent placement to noncardiac surgery was 64.0 months (interquartile range, 34.0 to 113.0 months). Figure 1. Study flow diagram. PCI= percutaneous coronary intervention. Table 1 presents the baseline characteristics, medication use, and aspirin strata of patients with and without a history of PCI, by treatment group. Patients with prior PCI had more known coronary artery disease, more commonly took antiplatelet and anticoagulant medications in the 7 days before surgery (nonstudy aspirin, thienopyridine, or direct thrombin or factor Xa inhibitors), and were more commonly in the aspirin continuation stratum than patients without prior PCI. Patients who had not had PCI before surgery were older; were more commonly female; more commonly had major surgery and urgent or emergent surgery; and were more likely to have a history of treated diabetes, hypertension, and smoking in the 2 years before surgery. Table 1. Baseline Characteristics, Medications, and Aspirin Strata Among Patients With and Without Prior PCI, by Treatment Group* Among patients with prior PCI, the baseline characteristics, medications, and aspirin strata were similar in the aspirin and placebo groups. Most patients (>85%) with PCI before surgery were in the continuation stratum; aspirin was withdrawn a median of 6 days (interquartile range, 4 to 8 days) before surge

National priorities for perioperative research in South Africa

BACKGROUNDnPerioperative research is currently unco-ordinated in South Africa (SA), with no clear research agenda.nnnOBJECTIVEnTo determine the top ten national research priorities for perioperative research in SA.nnnMETHODSnA Delphi technique was used to establish consensus on the top ten research priorities.nnnRESULTSnThe top ten research priorities were as follows: (i) establishment of a national database of (a) critical care outcomes, and (b) critical care resources; (ii) a randomised controlled trial of preoperative B-type natriuretic peptide-guided medical therapy to decrease major adverse cardiac events following non-cardiac surgery; (iii) a national prospective observational study of the outcomes associated with paediatric surgical cases; (iv) a national observational study of maternal and fetal outcomes following operative delivery in SA; (v) a stepped-wedge trial of an enhanced recovery after surgery programme for (a) surgery, (b) obstetrics, (c) emergency surgery, and (d) trauma surgery; (vi) a stepped-wedge trial of a surgical safety checklist on patient outcomes in SA; (vii) a prospective observational study of perioperative outcomes after surgery in district general hospitals in SA; (viii) short-course interventions to improve anaesthetic skills in rural doctors; (ix) studies of the efficacy of simulation training to improve (a) patient outcomes, (b) team dynamics, and (c) leadership; and (x) development and validation of a risk stratification tool for SA surgery based on the South African Surgical Outcomes Study (SASOS) data.nnnCONCLUSIONSnThese research priorities provide the structure for an intermediate-term research agenda.

Validating the utilisation of venous bicarbonate as a predictor of acute kidney injury in crush syndrome from sjambok injuries

BACKGROUNDnCrush injury secondary to sjambok beatings is a well-described phenomenon in southern Africa. Owing to a number of factors, it can result in acute kidney injury (AKI). In 1992, Muckart et al. described a risk stratification system using venous bicarbonate (VB) that can be used in the management of these patients.nnnOBJECTIVEnTo validate this score in the modern era of AKI risk stratification.nnnMETHODSnA retrospective study was performed on a local trauma database from June 2010 to December 2012. All patients with crush injury from sjambok/blunt instrument beatings were included in the analysis. VB was compared with the Kidney Disease Improving Global Outcomes scoring system for AKI. Serum base excess (BE) and creatine kinase were also examined as biomarkers. The endpoints were the need for renal replacement therapy (RRT) and mortality.nnnRESULTSnThree hundred and ten patients were included. The overall mortality rate was 1.9%, 14.8% of patients had AKI, and 3.9% required RRT. Both VB and BE performed well in RRT prediction, with areas under the receiver operating characteristic curve of 0.847 (95% confidence interval (CI) 0.756 - 0.938; p<0.001) and 0.871 (95% CI 0.795 - 0.947; p<0.001), respectively. The sensitivity and specificity of BE were 83.3% and 80.2% at an optimal cut-point of -7.25 mmol/L, while those of VB were 83.3% and 79.5% at an optimal cut-point of 18.85xa0mmol/L. VB was significantly different across the AKI risk groups (p<0.001), in keeping with the original Muckart risk stratification system.nnnCONCLUSIONnThe risk stratification score using VB is valid and should continue to be used as a tool in the management of patients with sjambok injuries. BE performs well in predicting the need for RRT, with a value of <-7.25 mmol/L indicating severe injury.

Barriers to clinical research in Africa: a quantitative and qualitative survey of clinical researchers in 27 African countries

Background: There is a need for high quality research to improve perioperative patient care in Africa. The aim of this study was to understand the particular barriers to clinical research in this environment. Methods: We conducted an electronic survey of African Surgical Outcomes Study (ASOS) investigators, including 29 quantitative Likert scale questions and eight qualitative questions with subsequent thematic analysis. Protocol compliant and non‐compliant countries were compared according to WHO statistics for research and development, health workforce data, and world internet statistics. Results: Responses were received from 134/418 of invited researchers in 24/25 (96%) of participating countries, and three non‐participating countries. Barriers included lack of a dedicated research team (47.7%), reliable internet access (32.6%), staff skilled in research (31.8%), and team commitment (23.8%). Protocol compliant countries had significantly more physicians per 1000 population (4 vs 0.9, P<0.01), internet penetration (38% vs 28%, P=0.01) and published clinical trials (1461 vs 208, P<0.01) compared with non‐compliant countries. Facilitators of research included establishing a research culture (86.9%), simple data collection tools (80%), and ASOS team interaction (77.9%). Most participants are interested in future research (93.8%). Qualitative data reiterated human resource, financial resource, and regulatory barriers. However, the desire to contribute to an African collaboration producing relevant data to improve patient outcomes was expressed strongly by ASOS investigators. Conclusions: Barriers to successful participation in ASOS related to resource limitations and not motivation of the clinician investigators. Practical solutions to individual barriers may increase the success of multi‐centre perioperative research in Africa.