Effect of colchicine on perioperative atrial fibrillation and myocardial injury after non-cardiac surgery in patients undergoing major thoracic surgery (COP-AF): an international randomised trial.

BACKGROUND: Higher levels of inflammatory biomarkers are associated with an increased risk of perioperative atrial fibrillation and myocardial injury after non-cardiac surgery (MINS). Colchicine is an anti-inflammatory drug that might reduce the incidence of these complications. METHODS: COP-AF was a randomised trial conducted at 45 sites in 11 countries. Patients aged 55 years or older and undergoing major non-cardiac thoracic surgery were randomly assigned (1:1) to receive oral colchicine 0·5 mg twice daily or matching placebo, starting within 4 h before surgery and continuing for 10 days. Randomisation was done with use of a computerised, web-based system, and was stratified by centre. Health-care providers, patients, data collectors, and adjudicators were masked to treatment assignment. The coprimary outcomes were clinically important perioperative atrial fibrillation and MINS during 14 days of follow-up. The main safety outcomes were a composite of sepsis or infection, and non-infectious diarrhoea. The intention-to-treat principle was used for all analyses. This trial is registered with ClinicalTrials.gov, NCT03310125. FINDINGS: Between Feb 14, 2018, and June 27, 2023, we enrolled 3209 patients (mean age 68 years [SD 7], 1656 [51·6%] male). Clinically important atrial fibrillation occurred in 103 (6·4%) of 1608 patients assigned to colchicine, and 120 (7·5%) of 1601 patients assigned to placebo (hazard ratio [HR] 0·85, 95% CI 0·65 to 1·10; absolute risk reduction [ARR] 1·1%, 95% CI -0·7 to 2·8; p=0·22). MINS occurred in 295 (18·3%) patients assigned to colchicine and 325 (20·3%) patients assigned to placebo (HR 0·89, 0·76 to 1·05; ARR 2·0%, -0·8 to 4·7; p=0·16). The composite outcome of sepsis or infection occurred in 103 (6·4%) patients in the colchicine group and 83 (5·2%) patients in the placebo group (HR 1·24, 0·93-1·66). Non-infectious diarrhoea was more common in the colchicine group (134 [8·3%] events) than the placebo group (38 [2·4%]; HR 3·64, 2·54-5·22). INTERPRETATION: In patients undergoing major non-cardiac thoracic surgery, administration of colchicine did not significantly reduce the incidence of clinically important atrial fibrillation or MINS but increased the risk of mostly benign non-infectious diarrhoea. FUNDING: Canadian Institutes of Health Research, Accelerating Clinical Trials Consortium, Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario, Population Health Research Institute, Hamilton Health Sciences, Division of Cardiology at McMaster University, Canada; Hanela Foundation, Switzerland; and General Research Fund, Research Grants Council, Hong Kong.

Effect of Colchicine on the Risk of Perioperative Acute Kidney Injury: Clinical Protocol of a Substudy of the Colchicine for the Prevention of Perioperative Atrial Fibrillation Randomized Clinical Trial.

Background: Inflammation during and after surgery can lead to organ damage including acute kidney injury. Colchicine, an established inexpensive anti-inflammatory medication, may help to protect the organs from pro-inflammatory damage. This protocol describes a kidney substudy of the colchicine for the prevention of perioperative atrial fibrillation (COP-AF) study, which is testing the effect of colchicine versus placebo on the risk of atrial fibrillation and myocardial injury among patients undergoing thoracic surgery. Objective: Our kidney substudy of COP-AF will determine whether colchicine reduces the risk of perioperative acute kidney injury compared with a placebo. We will also examine whether colchicine has a larger absolute benefit in patients with pre-existing chronic kidney disease, the most prominent risk factor for acute kidney injury. Design and Setting: Randomized, superiority clinical trial conducted in 40 centers in 11 countries from 2018 to 2023. Patients: Patients (~3200) aged 55 years and older having major thoracic surgery. Intervention: Patients are randomized 1:1 to receive oral colchicine (0.5 mg tablet) or a matching placebo, given twice daily starting 2 to 4 hours before surgery for a total of 10 days. Patients, health care providers, data collectors, and outcome adjudicators will be blinded to the randomized treatment allocation. Methods: Serum creatinine concentrations will be measured before surgery and on postoperative days 1, 2, and 3 (or until hospital discharge). The primary outcome of the substudy is perioperative acute kidney injury, defined as an increase (from the prerandomization value) in serum creatinine concentration of either ≥26.5 µmol/L (≥0.3 mg/dL) within 48 hours of surgery or ≥50% within 7 days of surgery. The primary analysis (intention-to-treat) will examine the relative risk of acute kidney injury in patients allocated to receive colchicine versus placebo. We will repeat the primary analysis using alternative definitions of acute kidney injury and examine effect modification by pre-existing chronic kidney disease, defined as a prerandomization estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m2. Limitations: The substudy will be underpowered to detect small effects on more severe forms of acute kidney injury treated with dialysis. Results: Substudy results will be reported in 2024. Conclusions: This substudy will estimate the effect of colchicine on the risk of perioperative acute kidney injury in older adults undergoing major thoracic surgery. Clinical trial registration number: NCT03310125.

Contexte: L'inflammation pendant et après une intervention chirurgicale peut causer des lésions aux organes, notamment de l'insuffisance rénale aiguë (IRA). La colchicine, un médicament anti-inflammatoire reconnu et bon marché, peut contribuer à protéger les organes contre les lésions pro-inflammatoires. Le présent protocole décrit une sous-étude rénale de l'essai Colchicine for the Prevention of Perioperative atrial fibrillation (COP-AF), qui examine l'effet de la colchicine, par rapport à un placebo, sur le risque de fibrillation auriculaire et de lésion myocardique chez les patients qui subissent une chirurgie thoracique. Objectif: Notre sous-étude rénale de l'essai COP-AF permettra de vérifier si la colchicine réduit le risque d'IRA périopératoire par rapport à un placebo. Nous tenterons également de déterminer si la colchicine présente un plus grand bénéfice absolu pour les patients atteints d'une insuffisance rénale chronique préexistante, laquelle constitue le plus important facteur de risque pour l'IRA. Cadre et type d'étude: Essai clinique à répartition aléatoire visant à démontrer une supériorité. L'étude, qui s'étend de 2018 à 2023, est menée dans 40 centers situés dans 11 pays. Sujets: Des patients (~3200) âgés de 55 ans et plus subissant une chirurgie thoracique majeure. Interventions: Les patients sont répartis 1:1 de façon aléatoire pour recevoir de la colchicine par voie orale (comprimé de 0.5 mg), ou un placebo correspondant, deux fois par jour à partir de 2 à 4 heures avant l'intervention chirurgicale, pour un total de 10 jours. Les patients, les prestataires de soins de santé, les personnes qui collectent les données et celles qui évaluent les résultats ne seront pas informés de l'attribution du traitement. Méthodologie: Les concentrations sériques de créatinine seront mesurées avant l'intervention et aux jours postopératoires 1, 2, et 3 (ou jusqu'au congé de l'hôpital). Le principal critère d'évaluation de cette sous-étude est une IRA périopératoires définie par une hausse (par rapport à la valeur mesurée avant la répartition aléatoire) d'au moins 26.5 µmol/L (≥0.3 mg/dL) de la créatinine sérique dans les 48 heures suivant l'intervention ou d'au moins 50% dans les 7 jours suivants. L'analyze primaire (intention de traiter) examinera le risque relatif d'IRA chez les patients recevant de la colchicine par rapport au placebo. L'analyze primaire sera répétée en utilisant d'autres définitions de l'IRA et nous examinerons la modification de l'effet en présence d'une insuffisance rénale préexistante, définie par un débit de filtration glomérulaire estimé (DFGe) inférieur à 60 mL/min/1.73 m2 avant la répartition aléatoire. Limites: Cette sous-étude ne sera pas assez puissante pour détecter de petits effets sur les formes plus graves d'insuffisance rénale aiguë traitées par dialyze. Résultats: Les résultats de cette sous-étude feront l'objet d'un rapport en 2024. Conclusion: Cette sous-étude permettra d'estimer l'effet de la colchicine sur le risque d'insuffisance rénale aiguë périopératoire chez les adultes âgés qui subissent une chirurgie thoracique majeure. Numéro d'enregistrement de l'essai clinique: NCT03310125.

Bariatric Surgery Performed at a Tertiary Care Hospital and an Ambulatory Hospital: A 5 Year Comparison of Outcomes, OR Efficiencies and Costs.

PURPOSE: To explore change in 30-day post-operative complications, operative times, operating room (OR) efficiencies for bariatric surgery performed at a tertiary care hospital (TH) and an ambulatory hospital with overnight stay (AH) within one hospital network over 5 years; and to compare perioperative costs at the TH and AH. MATERIALS AND METHODS: We performed a retrospective analysis of existing data from a cohort of consecutive adult patients who underwent primary laparoscopic Roux-en-Y gastric bypass (LRYGB) and sleeve gastrectomy (LSG) between September 2016 and August 2021 at TH and AH. RESULTS: A total of 805 patients (762 LRYGB, 43 LSG) had surgery at AH, while 109 (92 LRYGB, 17 LSG) at TH. OR times for LRYGB and LSG performed at AH were significantly shorter versus TH (150 ± 24 vs 178 ± 51 min; p < 0.01) and (123 ± 24 vs 147 ± 34 min; p = 0.01). OR turnovers (19.2 ± 6.0 min vs 28.1 ± 6.1 min; p < 0.01) and Post Anesthetic Care Unit (PACU) times (2.4 ± 0.6 h vs 3.1 ± 1.5 h; p < 0.01) were significantly faster at AH versus TH. Proportion of patients requiring transfer for a complication from AH to TH remained constant over time (range 1.5-6.2%/year; p = 0.14). 30-day complication rates were similar between AH and TH (5.5-11% vs 0-15%; p = 0.12). LRYGB and LSG costs were similar between AH and TH (8,855 ± 1,328CAD vs 8,799 ± 2,729CAD; p = 0.91 and 8,763 ± 1,449CAD vs 7,857 ± 1,825CAD; p = 0.41). CONCLUSION: There was no difference in 30-day post-operative complications for LRYGB and LSG performed at AH and TH. Performing bariatric surgery at AH has the benefit of improved OR efficiency without a significant difference in total perioperative costs.

Rationale and design of the colchicine for the prevention of perioperative atrial fibrillation in patients undergoing major noncardiac thoracic surgery (COP-AF) trial.

BACKGROUND: Perioperative atrial fibrillation (AF) and myocardial injury after noncardiac surgery (MINS) are common complications after noncardiac surgery. Inflammation has been implicated in the pathogenesis of both disorders. The COP-AF trial tests the hypothesis that colchicine reduces the incidence of perioperative AF and MINS in patients undergoing major noncardiac thoracic surgery. METHODS AND RESULTS: The 'COlchicine for the Prevention of Perioperative Atrial Fibrillation' (COP-AF) trial is an international, blinded, randomized trial that compares colchicine to placebo in patients aged at least 55 years and undergoing major noncardiac thoracic surgery with general anesthesia. Exclusion criteria include a history of AF and a contraindication to colchicine (eg, severe renal dysfunction). Oral colchicine at a dose of 0.5 mg or matching placebo is given within 4 hours before surgery. Thereafter, patients receive colchicine 0.5 mg or placebo twice daily for a total of 10 days. The 2 independent co-primary outcomes are clinically important perioperative AF (including atrial flutter) and MINS during 14 days of follow-up. The main safety outcomes are sepsis or infection and non-infectious diarrhea. We aim to enroll 3,200 patients from approximately 40 sites across 11 countries to have at least 80% power for the independent evaluation of the 2 co-primary outcomes. The COP-AF main results are expected in 2023. CONCLUSIONS: COP-AF is a large randomized and blinded trial designed to determine whether colchicine reduces the risk of perioperative AF or MINS in patients who have major noncardiac thoracic surgery.

ISHLT consensus statement: Perioperative management of patients with pulmonary hypertension and right heart failure undergoing surgery.

Pulmonary hypertension (PH) is a risk factor for morbidity and mortality in patients undergoing surgery and anesthesia. This document represents the first international consensus statement for the perioperative management of patients with pulmonary hypertension and right heart failure. It includes recommendations for managing patients with PH being considered for surgery, including preoperative risk assessment, planning, intra- and postoperative monitoring and management strategies that can improve outcomes in this vulnerable population. This is a comprehensive document that includes common perioperative patient populations and surgical procedures with unique considerations.

Safety and outcomes of performing laparoscopic Roux-en-Y gastric bypass and sleeve gastrectomy at an ambulatory site of a tertiary care hospital in Ontario.

BACKGROUND: In Ontario, bariatric surgery is publicly funded and is performed only in accredited tertiary care hospitals. The purpose of our study was to report on the safety and outcomes of performing bariatric surgery at an ambulatory site of a tertiary care hospital in southern Ontario. METHODS: We conducted a retrospective cohort study of all adult (age ≥ 18 yr) patients who underwent primary laparoscopic Roux-en-Y gastric bypass (LRYGB) or laparoscopic sleeve gastrectomy (LSG) at the ambulatory site of our tertiary care hospital between September 2016 and August 2018. The 2 sites are 1.4 km apart. Patient demographic characteristics, duration of surgery, intraoperative and 90-day postoperative complications, number of transfers and readmission to the tertiary care hospital, and emergency department visits were collected. RESULTS: A total of 314 patients (285 women [90.8%] and 29 men [9.2%] with a mean age of 41.8 yr [standard deviation (SD) 8.9 yr]) underwent surgery: LRYGB in 295 cases (93.9%) and LSG in 19 (6.0%). The mean body mass index was 45.3 (SD 5.1), the median American Society of Anesthesiologists score was 3 (range 2-4), and the median Edmonton Obesity Staging System score was 2 (range 0-4). The mean operative time was 119.8 (SD 23.1) minutes for LRYGB and 96.2 (SD 22.0) minutes for LSG, and the mean length of stay was 2.1 (SD 0.6) days and 2.1 (SD 0.2) days, respectively. Thirteen patients (4.1%) required transfer to the tertiary care hospital for a postoperative complication. Of 312 patients, 29 (9.3%) presented to emergency department within 90 days after surgery, and 8 (2.6%) required readmission to hospital; no deaths were reported. CONCLUSION: The findings suggest that LRYGB and LSG can be performed safely at an ambulatory site of a tertiary care hospital. However, caution should be exercised in performing these procedures at an ambulatory site without a tertiary care hospital affiliation, as patients may require urgent transfer for a serious postoperative complication.

Risk of perioperative blood transfusions and postoperative complications associated with serotonergic antidepressants in older adults undergoing hip fracture surgery.

Serotonergic antidepressants (SAds) are associated with bleeding-related adverse events. An increased risk of bleeding with SAds may have important implications in surgical settings. Our study evaluates the risk of red blood cell (RBC) transfusions and postoperative complications associated with SAds among older adults undergoing hip fracture surgery. We conducted a retrospective cohort study of individuals 66 years or older who underwent hip fracture surgery in Ontario, Canada. The risk of RBC transfusion among current users of SAds and nonserotonergic antidepressants (NSAds) was compared with recent former SAd users. Secondary outcomes included measures of postoperative morbidity and mortality. Subgroup analyses were undertaken in groups who were coprescribed other medications known to effect bleeding. Multivariable logistic regression was utilized to determine the odds ratios (ORs) for antidepressants and postoperative outcomes. A total 11,384 individuals were included in the study sample. Current SAd users had an increased risk of RBC transfusion compared with recent former users of SAds (OR, 1.28; 95% confidence interval, 1.14-1.43) as did current NSAd users (OR, 1.17; 95% confidence interval, 1.03-1.33). The risk of RBC transfusion with SAds or NSAds was further increased among individuals receiving antiplatelet agents. However, postoperative morbidity and mortality were not increased among either group of antidepressant users. In conclusion, SAds are associated with an increased risk of RBC transfusions, although this does not appear to result in major postoperative complications. Clinicians should be aware of this increased risk, although routine discontinuation of antidepressants before surgery is likely unwarranted in most cases.

A review of epidemiological evidence for general anesthesia as a risk factor for Alzheimer's disease.

Exposure to surgery and general anesthesia (GA) has been hypothesized to be a potential risk factor for the development of Alzheimer's disease (AD). Some basic science research studies have demonstrated AD pathology in animals following exposure to inhalational anesthetics. However, controversy exists as to whether GA is associated with an elevated risk of developing AD in human populations. While randomized controlled clinical trials would provide the strongest evidence for a causal relationship between exposure to surgery under GA and the subsequent development of AD, to date there have not been any trials to address this important question. Therefore, a potential relationship between GA and AD must currently be examined using observational methods. A recent meta-analysis of case-control studies (N = 15) did not find that AD was associated with prior exposure to GA (OR = 1.05, 95% CI: 0.93-1.19, p = 0.4). A limited number of retrospective cohort studies have likewise not provided definitive information supporting an association. Therefore, at the present time there is limited information to support the hypothesis of AD developing as a consequence of GA, although there are few high quality studies in this area. Given the high prevalence and impact of AD, and the relatively frequent exposure of large populations to surgical procedures, the association between AD and GA requires further study.

Effects of cholinesterase inhibitors on postoperative outcomes of older adults with dementia undergoing hip fracture surgery.

OBJECTIVES: Cholinesterase inhibitors (ChEIs) may interact with muscle relaxants given during general anesthesia (GA), increasing the risk of postoperative complications. We evaluated the effects of ChEIs on the postoperative outcomes of older adults who underwent hip fracture surgery. DESIGN: Population-based cohort study using linked administrative databases. PARTICIPANTS: All individuals with dementia age 66 years or older, who underwent hip fracture surgery between April 1, 2003, and December 31, 2007, in Ontario, Canada. EXPOSURES: Use of any ChEI (donepezil, rivastigmine, or galantamine) before surgery. OUTCOMES: The primary composite outcome included any of the following: 30-day postoperative mortality; intensive care unit admissions; or in-hospital resuscitation. Secondary outcomes included postoperative respiratory failure and pneumonia. ANALYSIS: We stratified the study sample on the basis of residence (community or long-term care [LTC]) and type of anesthetic (general or regional) to create four residence/anesthesia groups. We used propensity scores to match users and nonusers of ChEIs within the residence/anesthesia strata. We then calculated the relative risks (RR) and 95% confidence intervals (CI) for outcomes associated with ChEIs in the matched groups. RESULTS: A total of 624 pairs of individuals from the community and 725 pairs from LTC were created among individuals who received GA. High rates of postoperative mortality and complications were observed in both ChEI users and nonusers. The RR of the primary outcome associated with ChEI use for individuals receiving GA was 0.88 (95% CI: 0.68-1.16; χ2 = 0.93; df = 1; p = 0.34) and 0.82 (95% CI: 0.63-1.04; χ2 = 2.59; df = 1; p = 0.11) in the community and LTC groups, respectively. In addition, ChEIs were not associated with any significant increased risk of postoperative respiratory complications. CONCLUSIONS: ChEI use was not associated with an increased risk of postoperative complications among older adults with dementia who underwent hip fracture surgery. However, the poor postoperative outcomes overall reinforced the need to prevent fractures and improve outcomes in this population.

Microsatellite mutations of transforming growth factor-beta receptor type II and caspase-5 occur in human precursor T-cell lymphoblastic lymphomas/leukemias in vivo but are not associated with hMSH2 or hMLH1 promoter methylation.

In solid cancers, defective DNA mismatch repair (MMR) is most commonly caused by hMSH2 or hMLH1 mutations, or epigenetic silencing of hMLH1 by promoter hypermethylation, and results in the acquisition of characteristic frameshift microsatellite mutations of mononucleotide repeats located within the coding regions of defined target genes. We previously identified hMSH2 mutations in T-cell lymphoblastic lymphoma (T-LBL) patient tumor samples and others have reported coding region microsatellite mutations in T-cell acute lymphoblastic leukemia (T-ALL) cell lines. Thus, while MMR gene mutations are known to occur in some human T-lymphoblastic tumors in vivo, it is still unknown if the coding region microsatellite mutations detected in human cell lines also occur in vivo or if hMLH1 or hMSH2 promoter hypermethylation contributes to defective MMR in these tumors. We analyzed the TGFbetaRII (A)10 and caspase-5 (A)10 coding region repeats in 16 human T-LBL/ALL patient tumor samples and identified six with microsatellite mutations in one or both repeats. There was no evidence of hMSH2 or hMLH1 promoter methylation as assessed by standard methylation specific PCR or by a novel temporal temperature gradient electrophoresis (TTGE) method that analyzed 25 and 30 CpG sites in the hMLH1 and hMSH2 promoters, respectively. Our results indicate that coding region microsatellite mutations characteristic of defective MMR occur in some human T-LBL/ALL in vivo but not as a consequence of hMLH1 or hMSH2 promoter hypermethylation. Furthermore, the identification of TGFbetaRII and caspase-5 coding region mutations in vivo implicates these genes in the pathogenesis of human T-LBL/ALL.