Giovanna Lurati Buse

Rivastigmine for the prevention of postoperative delirium in elderly patients undergoing elective cardiac surgery : A randomized controlled trial

Objective:Cardiac surgery is frequently followed by postoperative delirium, which is associated with increased 1-year mortality, late cognitive deficits, and higher costs. Currently, there are no recommendations for pharmacologic prevention of postoperative delirium. Impaired cholinergic transmission is believed to play an important role in the development of delirium. We tested the hypothesis that prophylactic short-term administration of oral rivastigmine, a cholinesterase inhibitor, reduces the incidence of delirium in elderly patients during the first 6 days after elective cardiac surgery. Design:Double-blind, randomized, placebo-controlled trial. Setting:One Swiss University Hospital. Patients:One hundred twenty patients aged 65 or older undergoing elective cardiac surgery with cardiopulmonary bypass. Intervention:Patients were randomly assigned to receive either placebo or 3 doses of 1.5 mg of oral rivastigmine per day starting the evening before surgery and continuing until the evening of the sixth postoperative day. Measurements and Main Results:The primary predefined outcome was delirium diagnosed with the Confusion Assessment Method within 6 days postoperatively. Secondary outcome measures were the results of daily Mini-Mental State Examinations and clock drawing tests, and the use of a rescue treatment consisting of haloperidol and/or lorazepam in patients with delirium. Delirium developed in 17 of 57 (30%) and 18 of 56 (32%) patients in the placebo and rivastigmine groups, respectively (p = 0.8). There was no treatment effect on the time course of Mini-Mental State Examinations and clock drawing tests (p = 0.4 and p = 0.8, respectively). There was no significant difference in the number of patients receiving haloperidol (18 of 57 and 17 of 56, p = 0.9) or lorazepam (38 of 57 and 35 of 56, p = 0.6) in the placebo and rivastigmine groups, respectively. Conclusion:This negative or, because of methodologic issues, possibly failed trial does not support short-term prophylactic administration of oral rivastigmine to prevent postoperative delirium in elderly patients undergoing elective cardiac surgery with cardiopulmonary bypass.

Randomized Comparison of Sevoflurane Versus Propofol to Reduce Perioperative Myocardial Ischemia in Patients Undergoing Noncardiac Surgery

Background— Volatile anesthetics provide myocardial preconditioning in coronary surgery patients. We hypothesized that sevoflurane compared with propofol reduces the incidence of myocardial ischemia in patients undergoing major noncardiac surgery. Methods and Results— We enrolled 385 patients at cardiovascular risk in 3 centers. Patients were randomized to maintenance of anesthesia with sevoflurane or propofol. We recorded continuous ECG for 48 hours perioperatively, measured troponin T and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) on postoperative days 1 and 2, and evaluated postoperative delirium by the Confusion Assessment Method. At 6 and 12 months, we contacted patients by telephone to assess major adverse cardiac events. The primary end point was a composite of myocardial ischemia detected by continuous ECG and/or troponin elevation. Additional end points were postoperative NT-proBNP concentrations, major adverse cardiac events, and delirium. Patients and outcome assessors were blinded. We tested dichotomous end points by &khgr;2 test and NT-proBNP by Mann–Whitney test on an intention-to-treat basis. Myocardial ischemia occurred in 75 patients (40.8%) in the sevoflurane and 81 (40.3%) in the propofol group (relative risk, 1.01; 95% confidence interval, 0.78–1.30). NT-proBNP release did not differ across allocation on postoperative day 1 or 2. Within 12 months, 14 patients (7.6%) suffered a major adverse cardiac event after sevoflurane and 17 (8.5%) after propofol (relative risk, 0.90; 95% confidence interval, 0.44–1.83). The incidence of delirium did not differ (11.4% versus 14.4%; P=0.379). Conclusions— Compared with propofol, sevoflurane did not reduce the incidence of myocardial ischemia in high-risk patients undergoing major noncardiac surgery. The sevoflurane and propofol groups did not differ in postoperative NT-proBNP release, major adverse cardiac events at 1 year, or delirium. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00286585.

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 21 842 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.

High sensitivity troponin T concentrations in patients undergoing noncardiac surgery: A prospective cohort study☆

OBJECTIVES To determine the proportion of noncardiac surgery patients exceeding the published 99th percentile or change criteria with the high sensitivity Troponin T (hs-TnT) assay. DESIGN AND METHODS We measured hs-TnT preoperatively and postoperatively on days 1, 2 and 3 in 325 adults. RESULTS Postoperatively 45% (95% CI: 39-50%) of patients had hs-TnT≥14ng/L and 22% (95% CI:17-26%) had an elevation (≥14ng/L) and change (>85%) in hs-TnT. CONCLUSION Further research is needed to inform the optimal hs-TnT threshold and change in this setting.

The prognostic value of troponin release after adult cardiac surgery — a meta-analysis

To assess the accuracy of increased troponin (Tn) concentrations for the prediction of mid-term (> or = 12 months) mortality after coronary artery bypass graft (CABG) and valve surgery, we performed a systematic review identifying all studies reporting on the association between postoperative troponin release and mortality after cardiac surgery. Studies were identified through 30 April 2008 by electronic searches of the MEDLINE, EMBASE and BIOSIS databases. Two reviewers independently selected studies, assessed methodological quality and extracted the data. We primarily considered mid-term (> or = 12 months) and secondarily short-term (< or = 30 days) all-cause mortality. A bivariate random-effects model was used to study determinants and to pool measures of prognostic accuracy of Tn. Seventeen studies fulfilled the inclusion criteria with a total of 237 mid-term deaths in 5189 patients and 296 short-term deaths in 9703 patients. The diagnostic odds ratio of increased Tn concentrations was 5.46 (95% confidence interval (CI) 2.0-14.6) for mid-term mortality and 6.57 (95% CI 4.3-10.1) for short-term mortality after adult cardiac surgery. Alternatively expressed, for troponin elevation, the sensitivity was 0.45 (0.26-0.67) and the specificity 0.87 (0.73-0.90) to predict mid-term mortality. The sensitivity was 0.59 (0.48-0.69) and the specificity 0.82 (0.72-0.89) for short-term mortality. Between-study variability was high. In conclusion, this meta-analysis provides evidence for an association between postoperative Tn release with mid- and short-term all-cause mortality after adult cardiac surgery. However, differences in populations, timing of Tn testing, Tn subunit and Tn assays make definitive conclusions about effect size and cut-off values difficult.

A preliminary report on the prognostic significance of preoperative brain natriuretic peptide and postoperative cardiac troponin in patients undergoing major vascular surgery.

BACKGROUND: Associations between preoperative elevation of brain natriuretic peptide (BNP) or postoperative elevation of cardiac troponins (cTn) with major adverse cardiac events (MACE) after major surgery have been shown previously. In this study, we evaluated the added value of preoperative BNP with postoperative cTn levels for the prediction of MACE in patients undergoing major vascular surgery. METHODS: This is a prospectively prespecified, secondary analysis of data from a cohort of 133 clinically stable patients undergoing major vascular surgery enrolled in a clinical trial evaluating the effectiveness of the sympathetic nervous system-inhibiting drug moxonidine on reducing MACE. Concentrations of BNP and cTn were determined before surgery, and concentrations of cTn were measured immediately after surgery and on postoperative days 1, 2, 3, and 7. The primary end point was the occurrence of MACE (defined as any hospitalization for myocardial revascularization, acute coronary syndrome, acute congestive heart failure, or death by any cause) within 1 yr after surgery. Patients were evaluated for MACE by hospital chart review during hospitalization and by telephone interviews 12 mo after surgery. RESULTS: Within 1 yr after surgery, 19 patients (14%) had a MACE, including 14 patients (11%) who died. After adjustment for age, gender, and the revised cardiac risk index, preoperative BNP elevation ≥50 pg/mL was associated with MACE (adjusted hazard ratio [HR]: 6.5, 95% confidence interval [CI]: 1.4–29.5) regardless of the subsequent cTn I concentrations. The combination of preoperative BNP elevation ≥50 pg/mL and postoperative cTn I elevation ≥2 ng/mL was associated with MACE (adjusted HR: 25.2, 95% CI: 5.0–128.4) and all-cause mortality (adjusted HR: 18.7, 95% CI: 3.1–112.5). The negative predictive value of a normal preoperative BNP value for subsequent adverse events was 0.965 (95% CI: 0.879–0.996). CONCLUSION: These data suggest that measurement of preoperative BNP concentrations in addition to postoperative cTn concentrations provides additive prognostic information for MACE and mortality after major vascular surgery.

Accelerated care versus standard care among patients with hip fracture: the HIP ATTACK pilot trial

Background: A hip fracture causes bleeding, pain and immobility, and initiates inflammatory, hypercoagulable, catabolic and stress states. Accelerated surgery may improve outcomes by reducing the duration of these states and immobility. We undertook a pilot trial to determine the feasibility of a trial comparing accelerated care (i.e., rapid medical clearance and surgery) and standard care among patients with a hip fracture. Methods: Patients aged 45 years or older who, during weekday, daytime working hours, received a diagnosis of a hip fracture requiring surgery were randomly assigned to receive accelerated or standard care. Our feasibility outcomes included the proportion of eligible patients randomly assigned, completeness of follow-up and timelines of accelerated surgery. The main clinical outcome, assessed by data collectors and adjudicators who were unaware of study group allocations, was a major perioperative complication (i.e., a composite of death, preoperative myocardial infarction, myocardial injury after noncardiac surgery, pulmonary embolism, pneumonia, stroke, and life-threatening or major bleeding) within 30 days of randomization. Results: Of patients eligible for inclusion, 80% consented and were randomly assigned to groups (30 to accelerated care and 30 to standard care) at 2 centres in Canada and 1 centre in India. All patients completed 30-day follow-up. The median time from diagnosis to surgery was 6.0 hours in the accelerated care group and 24.2 hours in the standard care group (p < 0.001). A major perioperative complication occurred in 9 (30%) of the patients in the accelerated care group and 14 (47%) of the patients in the standard care group (hazard ratio 0.60, 95% confidence interval 0.26–1.39). Interpretation: These results show the feasibility of a trial comparing accelerated and standard care among patients with hip fracture and support a definitive trial. Trial registration: ClinicalTrials.gov, no. NCT01344343.

The predictive value of preoperative natriuretic peptide concentrations in adults undergoing surgery: a systematic review and meta-analysis.

BACKGROUND: Several studies have evaluated preoperative B-type natriuretic peptides (NPs) for predicting mortality after surgery; however, the number of deaths in each study was small, limiting the power of these studies. We conducted a systematic review and meta-analysis of studies addressing preoperative NP levels to predict mortality after cardiac and noncardiac surgery. METHODS: We searched MEDLINE and EMBASE using the terms “natriuretic peptides,” “surgery or surgical procedures,” and a validated combination of prognostic and diagnostic terms. Two investigators independently assessed studies for eligibility and extracted data. The end points were all-cause mortality at ≥6 months and at ⩽90 days. We used a bivariate model to derive measures of prognostic accuracy and their heterogeneity. We calculated the pooled positive predictive value (PPV) and negative predictive value (NPV) by Bayesian Markov chain Monte Carlo methods. RESULTS: Of the 1558 retrieved articles, 23 studies satisfied the predefined eligibility criteria. After cardiac surgery, the diagnostic odds ratio of NP was 4.11 (95% confidence interval, 2.22–7.60) for ≥6-month mortality, the PPV 0.17 (95% Bayesian confidence interval, 0.07–0.36), and the NPV 0.96 (0.90–0.98). After noncardiac surgery, the diagnostic odds ratio of NP was 4.97 (3.06–8.07) for ≥6-month mortality. The corresponding PPV was 0.24 (0.14–0.38) and the NPV 0.94 (0.88–0.97). Results were similar for ⩽90-day mortality. CONCLUSIONS: Preoperative NP concentrations were associated with mortality after cardiac and noncardiac surgery. NP had high NPVs for both types of surgery suggesting that preoperative NP concentrations may be helpful in preoperative risk stratification.

12-Month Outcome After Cardiac Surgery: Prediction by Troponin T in Combination With the European System for Cardiac Operative Risk Evaluation

BACKGROUND The prognostic value of troponin T for midterm outcome in cardiac surgery is insufficiently known. We aimed to assess the value of troponin T to predict 12-month outcome after cardiac surgery, as a single predictor and in combination with the European system for cardiac operative risk evaluation (EuroSCORE). METHODS This cohort study included consecutive patients undergoing on-pump cardiac surgery between January 2005 and December 2006. We evaluated postoperative troponin T (TNT) on days 1 and 2 and the EuroSCORE as predictor variables. The primary composite endpoint was all-cause mortality or any major adverse cardiac event (MACE) at 12 months. Logistic regression was used to study the prognostic effect of TNT in a univariate analysis and after adjustment for EuroSCORE. The area under the receiver-operator curve (AUC) was calculated to report the discriminatory performance of the models. RESULTS Seven hundred forty-one patients were available for analysis. Within 12 months after surgery, 92 (12.4%) patients had a MACE, 48 (6.5%) of whom died. A multivariate model of continuous TNT and the continuous logistic EuroSCORE showed a significant independent association between TNT and the composite endpoint (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.02 to 1.04 per 0.1 microg/L increase in TNT). The AUC for the prediction of the composite endpoint of the model combining TNT and the EuroSCORE was 0.72; when based on EuroSCORE alone it was 0.64 (p < 0.0001). CONCLUSIONS Postoperative TNT increase (per 0.1 microg/L) is a strong independent predictor of 12-month outcome after on-pump cardiac surgery. Updating the preoperative EuroSCORE risk with postoperative TNT allows for better prediction of 12-month MACE and all-cause mortality.

Perioperative Myocardial Injury After Noncardiac Surgery: Incidence, Mortality, and Characterization

Background: Perioperative myocardial injury (PMI) seems to be a contributor to mortality after noncardiac surgery. Because the vast majority of PMIs are asymptomatic, PMI usually is missed in the absence of systematic screening. Methods: We performed a prospective diagnostic study enrolling consecutive patients undergoing noncardiac surgery who had a planned postoperative stay of ≥24 hours and were considered at increased cardiovascular risk. All patients received a systematic screening using serial measurements of high-sensitivity cardiac troponin T in clinical routine. PMI was defined as an absolute high-sensitivity cardiac troponin T increase of ≥14 ng/L from preoperative to postoperative measurements. Furthermore, mortality was compared among patients with PMI not fulfilling additional criteria (ischemic symptoms, new ECG changes, or imaging evidence of loss of viable myocardium) required for the diagnosis of spontaneous acute myocardial infarction versus those that did. Results: From 2014 to 2015 we included 2018 consecutive patients undergoing 2546 surgeries. Patients had a median age of 74 years and 42% were women. PMI occurred after 397 of 2546 surgeries (16%; 95% confidence interval, 14%–17%) and was accompanied by typical chest pain in 24 of 397 patients (6%) and any ischemic symptoms in 72 of 397 (18%). Crude 30-day mortality was 8.9% (95% confidence interval [CI], 5.7–12.0) in patients with PMI versus 1.5% (95% CI, 0.9–2.0) in patients without PMI (P<0.001). Multivariable regression analysis showed an adjusted hazard ratio of 2.7 (95% CI, 1.5–4.8) for 30-day mortality. The difference was retained at 1 year with mortality rates of 22.5% (95% CI, 17.6–27.4) versus 9.3% (95% CI, 7.9–10.7). Thirty-day mortality was comparable among patients with PMI not fulfilling any other of the additional criteria required for spontaneous acute myocardial infarction (280/397, 71%) versus those with at least 1 additional criterion (10.4%; 95% CI, 6.7–15.7, versus 8.7%; 95% CI, 4.2–16.7; P=0.684). Conclusions: PMI is a common complication after noncardiac surgery and, despite early detection during routine clinical screening, is associated with substantial short- and long-term mortality. Mortality seems comparable in patients with PMI not fulfilling any other of the additional criteria required for spontaneous acute myocardial infarction versus those patients who do. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02573532.