
==== Front
BMJ Open
BMJ Open
bmjopen
bmjopen
BMJ Open
2044-6055
BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR

39266309
10.1136/bmjopen-2024-084368
bmjopen-2024-084368
Protocol
Cardiovascular Medicine
1683
1506
Anti-inflammatory effect of colchicine on organ damage during the perioperative period of cardiac surgery: a study protocol for a multicentre, randomised, double-blind, placebo-controlled clinical trial
Li Xin 10s2023039001@pumc.edu.cn

Luo Yuanxi 10luoyx6711@163.com

Cai Xiujuan 220221709@njucm.edu.cn

http://orcid.org/0000-0002-3544-5849
Lv Zhikang 3lvzhikang1996@163.com

Kong Youru 220231802@njucm.edu.cn

Guo Qiuyong 1S2023039003@pumc.edu.cn

Zhu Jiawei 4NJGLYYCardiaczjw@163.com

Pan Tuo 1pan_tuo@126.com

http://orcid.org/0000-0001-6499-1972
Wang Dongjin 134dongjin_wang@126.com

1 Department of Cardiac Surgery, Nanjing Drum Tower Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Graduate School of Peking Union Medical College, Beijing, China
2 Department of Cardiac Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
3 Department of Cardiac Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing, China
4 Department of Cardiac Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China
DrDongjinWang; dongjin_wang@126.com
None declared.

XL and YL contributed equally.

2024
12 9 2024
14 9 e08436817 1 2024
26 8 2024
Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Abstract

Introduction

The systemic inflammatory response syndrome during the perioperative period of cardiac surgery can lead to serious postoperative complications and significantly increase the hospital mortality rate. Colchicine, a widely used traditional anti-inflammatory drug, has good clinical value in cardiovascular anti-inflammatory therapy. Our preliminary single-centre study had confirmed the protective value of colchicine in patients undergoing cardiac surgery with cardiopulmonary bypass. For this multicentre investigation, we aim to further validate the anti-inflammatory and organ-protective effects of low-dose colchicine during the perioperative period in a low-risk population.

Methods and analysis

This study is a multicentre, randomised, double-blind, placebo-controlled clinical trial. A total of 768 patients undergoing elective cardiac surgery will be enrolled from eight heart centres in China. The participants will be randomly assigned to two groups: the colchicine group will receive low-dose colchicine (0.5 mg once-a-day dosing regimen (QD) orally for 3 days before the surgery and 0.5 mg dosing frequency of every other day (QOD) continuously for 10 days after the surgery), whereas the placebo group will be given starch tablets for the same time and dosage. Primary endpoints are the occurrence of postoperative inflammatory diseases, including postoperative atrial fibrillation, acute respiratory distress syndrome, preoperative myocardial injury and post-pericardiotomy syndrome. Secondary endpoints included laboratory tests on postoperative days 1, 3, 5, 7 and 10, intensive care unit data, APACHE II score, Murray lung injury score, medication-related gastrointestinal reactions, 30-day and 90-day all-cause mortality, surgical data, chest radiograph on postoperative days 1, 2 and 3, and chest CT within 14 days after surgery.

Ethics and dissemination

This research has received approval from the Medical Ethics Committee of Affiliated Nanjing Drum Tower Hospital, Nanjing University Medical College (approval number 2023-366-01). The study findings will be made available by publishing them in an open access journal.

Trial registration number

ClinicalTrials.gov (NCT06118034).

Cardiovascular Disease
Adult cardiology
Cardiac surgery
http://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China 82300459 the Affiliated Drum Tower Hospital, Medical School of Nanjing University 2023-LCYJ-ZD-03
==== Body
pmcSTRENGTHS AND LIMITATIONS OF THIS STUDY

This study is the first international, multicentre, randomised, double-blind, placebo-controlled clinical trial.

Dynamic monitoring of the perioperative inflammatory response according to composite endpoint, biomarkers, imaging indicators, and surgical and critical care data.

The prolonged duration of colchicine usage for 10 postoperative days may investigate more differences in biomarkers and clinical endpoints, compared with the previous report.

More collaboration is needed in the future to enable this research to be conducted in ethnically diverse populations.

Introduction

The systemic inflammatory response syndrome (SIRS) during the perioperative period of cardiac surgery can result in severe postoperative complications and a notable elevation in hospital mortality rates.1 2 The SIRS can be triggered by surgical trauma, cardiopulmonary bypass (CPB) technology and anesthesia-related factors during the perioperative period of cardiac surgery. This can result in the release of inflammatory factors, leading to a high incidence of life-threatening complications such as acute respiratory distress syndrome (ARDS), preoperative myocardial injury (PMI), post-pericardiotomy syndrome (PPS) and increased hospital mortality rate.36 Pathophysiological changes related to inflammation during cardiac surgery include the activation of endothelial cells, white blood cells (WBC), platelets, the complement system and coagulation.710 Particularly notable is the activation of neutrophils by complement, inflammatory cytokines (interleukin (IL)-6, IL-8), coagulation enzymes, reactive oxygen species (ROS) and endotoxins, among other pro-inflammatory mediators.11 Activated neutrophils can infiltrate the myocardium, leading to severe ischemia-reperfusion injury.12

Previous medical literature suggests colchicine has been shown to reduce neutrophil activity by inhibiting neutrophil chemotaxis and adhesion, leading to a decrease in the overall inflammatory response. This reduction in inflammation has been found to significantly lower the incidence of perioperative myocardial injury, decrease the occurrence of postoperative atrial fibrillation (POAF) and effectively reduce all-cause mortality in patients with coronary artery disease, ultimately extending their survival time.1323 Furthermore, previous studies have shown that in patients with acute lung injury after cardiac surgical procedures, inhibition of neutrophil activation is effective in mitigating the occurrence of adverse events (AEs).24 In our previous single-centre, randomised, single-blind, placebo-controlled clinical trial, we also observed the efficacy of low-dose colchicine in reducing perioperative myocardial injury in non-coronary artery bypass grafting (non-CABG) cardiac surgery patients.25 However, it is important to note that this study has limitations as it was conducted at a single centre and in a single-blind manner with relatively few inflammatory biomarkers included.

Therefore, the purpose of this study was to conduct a multicentre, large-sample, randomised, controlled, double-blind clinical trial in Chinese to further validate the anti-inflammatory and organ-protective effects of low-dose colchicine during the perioperative period in a low-risk population.

Methods

Study design

This study is a multicentre, randomised, double-blind, placebo-controlled clinical trial following the steps outlined in the flowchart below (figure 1). It will be conducted in eight heart centres in China, including Nanjing Drum Tower Hospital, Ruijin Hospital Affiliated to The Shanghai Jiao Tong University Medical School, The First Affiliated Hospital Zhejiang University School of Medicine, The First Affiliated Hospital of Harbin Medical University, Yangzhou First People’s Hospital, Central Hospital Affiliated to Shandong First Medical University, The First People’s Hospital of Changzhou and Xinhua Hospital of Ili Prefecture. At least 768 participants will be assigned at random to receive colchicine tablets or starch tablets (0.5 mg QD for 3 days preoperatively and 0.5 mg QOD for 10 days postoperatively) for the same duration. It is expected that the recruitment will be completed within 30 months. The study is set to commence on 28 January 2024, with primary measurements to be collected by 31 August 2026.

Figure 1 Flowchart of the participants through the trial.

Patients

Inclusion criteria

Aged between 50 and 80 years, male or female.

Patients undergoing elective cardiac surgery.

Have signed the informed consent form (ICF).

Exclusion criteria

Patients undergoing emergency surgery.

Patients undergoing deep hypothermic circulatory arrest surgery.

Preoperative predicted mortality >3% according to European System for Cardiac Operative Risk Evaluation II.26

Patients undergoing off-pump CABG surgery.

Patients undergoing left or right ventricular outflow tract obstruction surgery.

Patients undergoing complex corrective surgery for congenital heart disease.

Patients with an expected CPB exceeding 180 min or an anticipated aortic cross-clamp time exceeding 120 min.

Patients expected to have a postoperative endotracheal tube removal time exceeding 24 hours.

Patients with prolonged fasting or inability to self-feed.

A history of malignant tumour.

Patients with unstable preoperative vital signs requiring intra-aortic balloon pump (IABP), extracorporeal membrane oxygenation (ECMO) assistance or endotracheal tube-assisted ventilation.

A history of cardiac surgery.

Patients with preoperative gastrointestinal symptoms, such as nausea, vomiting and diarrhoea.

Patients with a history of dialysis before surgery.

Patients with a history of atrial fibrillation before surgery.

Patients on long-term hepatorenal protective medications.

Patients with hepatic and renal insufficiency (Child-Pugh class B or C, estimated glomerular filtration rate <35 mL/min/1.73 m2).

Patients with abnormal baseline inflammatory markers (IL-6>10 pg/mL, procalcitonin (PCT)>0.5 ng/mL and C reactive protein (CRP)>10 mg/L).

Patients diagnosed with infectious diseases, inflammatory immune diseases or tumour.

Patients who have received immunosuppressive or anti-inflammatory treatment.

Patients allergic or intolerant to colchicine.

Breastfeeding or pregnant women.

Other situations were deemed inappropriate for participation in the study by the investigator.

Blinding

This study follows a double-blind design to ensure blinding during the experiment. The control drug is a placebo that has been specially produced to have the same appearance as the colchicine drug. It prevents subjects, drug distribution centre staff and trial personnel from identifying the type of drug by appearance. Blinding procedures will be carried out based on random information, with the experimental and placebo drugs being classified, coded and labelled. Each trial drug is randomly assigned a unique identification code for the subject. An emergency letter is also provided for each coded drug to allow for emergency unblinding if necessary. The inspectors and researchers involved in the trial must remain unaware of the drug assignments throughout the study, and all records related to the blinding process must be preserved.

After the trial commences, clinical physicians are responsible for recruiting subjects who meet the inclusion criteria and assigning them random numbers in the order of selection. The names and random numbers of the subjects are recorded and saved by the clinical physicians, whereas the drug administrators handle the distribution and recovery of the drugs. Both the distribution and recovery processes are recorded and filed. Before unblinding the trial, all participants are kept unaware of the grouping of the subjects.

Unblinding

Unblinding occurs only when drug information is necessary for the medical treatment of the subjects. In the event of a medical emergency, where it is crucial to determine the type of medication the subject is taking, the main researchers and sponsors should be notified as soon as possible before unblinding the investigational drug. The main researcher should conduct emergency unblinding via emergency letters to obtain subject-specific subgroup information. Sponsors must be contacted within 24 hours of unblinding if they were not contacted before unblinding. The researcher must record the unblinding date, location, reason, person responsible, main researcher and relevant personnel from the drug clinical trial institution and make detailed records in the case report form (CRF). Subjects who undergo emergency unblinding will be considered dropout cases.

Randomisation

The randomisation process will be conducted by a research assistant who will not be involved in the study intervention or evaluation. CABG differs from other surgeries for the primary endpoint. The incidence of POAF and PPS after CABG is different from valve surgery, and postoperative troponin varies.4 27 At the same time, we considered a possible effect that patients undergoing CABG take aspirin preoperatively and postoperatively, which may mitigate oxidative stress and inflammatory responses.28 29 We use stratified block randomisation to reduce outcome bias and extreme randomness. Participants will be categorised according to the type of surgery they are undergoing (CABG or non-CABG) and subsequently assigned to either the colchicine or placebo group in a 1:1 ratio. For each stratum, a sequentially numbered randomisation list will be generated using the ‘Central Code Random Number Table’ with block lengths randomly set at 2 or 4. Patients will be enrolled in a 1:1 ratio and assigned a number based on the date they sign the ICF. The randomisation table will be provided by qualified personnel to ensure unbiased allocation.

Intervention

All patients underwent cardiac surgery following standard protocols by Prof. Dong-Jin Wang. The project aims to collect efficacy and safety indicators at specific time points during the perioperative period. These time points include 3 days before elective surgery and days 1, 3, 5, 7, 10, 30 and 90 after the surgery.

Before participating in the project, all patients will be required to sign the ICF and will be assigned random numbers. Each patient will undergo regular examinations, including echocardiography, brain and chest CT, coronary arteriography (for patients older than 50 years) and various laboratory tests. Patients in the colchicine treatment group will receive colchicine tablets (0.5 mg QD) for the last 3 days before the operation and the first 10 days (0.5 mg QOD) after trachea intubation is removed. Patients in the placebo group will receive starch tablets following the same schedule. The specific surgical procedure will be determined based on the patient’s diagnosis.

Furthermore, the study will document the details of surgical procedures, the utilisation of various instruments and complications. This information will provide a comprehensive overview of the treatment process. Clinical data will be comprehensively collected using CRF.

Outcome measures

Primary outcome

The primary outcome is the composite endpoint outcome event, including:

POAF: Onset of new atrial fibrillation in patients within 10 days post-surgery.

PMI: Patient’s high-sensitivity cardiac troponin T (hs-cTnT) exceeds 0.8 ng/L on the first day after surgery, and there is an increase of 10% or more on the second day compared with the first day postoperatively.30 31

ARDS within 10 days post-surgery.32

PPS within 14 days post-surgery.33

Secondary outcomes

Laboratory tests on postoperative days 1, 3, 5, 7 and 10, including the oxygenation index or SpO2/FIO2, WBC, neutrophil count, IL-1β, IL-6, IL-8, tumour necrosis factor-alpha (TNF-α), CRP, PCT, myoglobin, creatine kinase-MB, hs-cTnT, neutrophil elastase, myeloperoxidase, alanine transaminase, aspartate transaminase, total bilirubin, serum creatinine and estimated glomerular filtration rate.

Intensive care unit (ICU) data, including mechanical ventilation time, ICU stay duration, the use of continuous renal replacement therapy, IABP, ECMO, etc.

APACHE II score, Murray lung injury score, medication-related gastrointestinal reactions, postoperative drainage and temperature and 30-day and 90-day all-cause mortality will be included.

Surgical data, including operation choice, CPB time, aortic cross-clamp time, surgery time, blood transfusion volume, types and dosages of intraoperative medications, etc.

Chest radiograph on postoperative days 1, 2 and 3, and chest CT within 14 days after surgery (grade I includes no apparent infiltration, grade II includes point-like or patchy infiltrates and grade III includes large consolidated infiltrates).

Safety assessment

Colchicine, a medication with a long history of clinical use, is well-known for being well-tolerated. The main adverse effect of colchicine is gastrointestinal reactions, such as an increase in bowel movements or changes in stool consistency, compared with before taking the medication. Other serious AEs include the use of mechanical assistive devices like ECMO and IABP, as well as respiratory and cardiac arrest, all-cause death, systemic inflammation spread and sepsis. Any AEs that occur during the study will be recorded, assessed and treated. Detailed information about these events will be documented in the CRF. The grading of AEs will follow the guidelines outlined in the Common Terminology Criteria for Adverse Events V.5.0. Any serious AEs will be promptly reported to the Medical Ethics Committee of Affiliated Nanjing Drum Tower Hospital, Nanjing University Medical College. In addition, the frequency of the AEs will be calculated.

Sample size calculation

This study is a multicentre, randomised, double-blind, placebo-controlled clinical trial. The composite outcome indicators assessed in the study include POAF, ARDS, PMI and PPS. Previous literature indicates that the incidence rates of these outcomes after cardiac surgery are approximately 60% for POAF,3438 16% for ARDS,32 39 40 32% for PMI41 and 29% for PPS.42 43 Therefore, the sample size for this trial will be calculated based on the reported incidence rates from the literature. Assuming that colchicine can reduce the incidence of these outcomes by 30%, with a bilateral effects α=0.0125 and a confidence level of 80%, the sample size for the treatment group (N1) was calculated to be 167 cases, and the sample size for the control group (N2) was calculated to be 167 cases.22 25 44 Accounting for a potential 15% loss of follow-up or refusal of follow-up, a minimum of 192 study subjects were required. Using a stratified block randomisation method, 192 cases were allocated to each group (CABG-colchicine treatment, CABG-control group, non-CABG-control treatment and non-CABG-colchicine treatment), resulting in a total of at least 768 study subjects included in the study.

Data collection and statement section

This study uses electronic data management and DAS for EDC (V.6.0). The data administrator designs and constructs an electronic CRF (eCRF) based on the trial protocol. Once the test is passed and approval is obtained from the sponsor, the eCRF is released for use. The eCRF data are sourced from the original records, and the data entry personnel promptly input the subject visit data into the electronic data collection (EDC) following the eCRF filling instructions. Throughout the study, data will be monitored and validated on a regular basis. The study will be monitored annually from the start of the study by the Medical Ethics Committee of the Affiliated Nanjing Drum Tower Hospital, Nanjing University Medical College.

Statistical analyses

We will use SAS software (V.9.4) for data processing and analysis. Quantitative variables are usually categorised as continuous variables and discrete variables. Continuous variables will be presented as mean±SD and discrete variables will be presented as M (interquartile range) or M (P25, P75). Qualitative variables will be presented as number and percentage (n, %). To test the difference between two groups, t-test will be used for quantitative variables that follow a normal distribution and have homogeneity of variance. Otherwise, we will perform the Wilcoxon rank-sum test. For Qualitative variable, we will use the χ2 test or Fisher’s exact probability method. A p value of <0.05 will be considered statistically significant. To analyse the data for different scenarios, the full analysis set, PPS, and safety set will be created.

In security analysis, the χ2 test or Fisher’s exact test was used to compare the incidence of AEs in each group. The AEs, laboratory test results and vital signs that occurred in this study were also tabulated to describe how they changed before and after the study and how they were related to the study drug when abnormal changes occurred.

Interim analysis

Interim analysis will not be performed.

Quality control

Inspectors check the consistency between eCRF data and source data to ensure accuracy. And any questions that existed are raised by the system or by inspectors, data administrators. Researchers are responsible for promptly answering these questions. Approval from the data administrators and inspector is required for any changes, and further questions may be raised if necessary until the data are clean. Once data entry is completed and verified on-site, the researcher conducts an electronic signature review and confirmation. And re-signing is required for any data revisions. After researchers, sponsors, statistical analysts and data administrator jointly sign the database lock record, data administrator performs the database lock. Data administrators then submit the database to statisticians and generate each subject’s eCRF. Once the statistical analysis is completed, data administrators close the database. All collected raw data are archived in the CRF format, and eCRF is generated and uploaded to the Chinese Clinical Trial Public Management Platform. Ethics Committee of Affiliated Nanjing Drum Tower Hospital, Nanjing University Medical College, will monitor the safety of this study and review the study results.

Patient and public involvement

Patients and the public did not have a role in formulating the research question, selecting outcome measures, designing the trial, recruiting participants or overseeing its implementation. However, trial findings will be shared with participants through the publication of results and direct consultations with trial clinicians once the trial is completed.

Discussion

Surgical trauma and the use of CPB during cardiac surgery often lead to inflammation-related changes in the body.45 46 Several studies have investigated the role of the inflammatory response in PPS, POAF and postoperative acute lung injury.24 25 47 Colchicine, a medication, has been found to reduce the inflammatory response through various mechanisms, such as decreasing the adhesion responsiveness of neutrophils and inhibiting the activation of neutrophil extracellular traps.48 49 Based on these studies, it is reasonable to hypothesise that colchicine may improve the prognosis of patients who have undergone cardiac surgery by inhibiting the perioperative inflammatory response.

Giannopoulos et al reported that continuous administration of low-dose colchicine (0.5 mg two times per day) during perioperative period reduced markers of myocardial injury after CABG.8 Our preliminary study also demonstrated that the perioperative application of low-dose colchicine effectively protected the myocardium.25 However, it is important to note that the previous trial was limited by its small sample size, single-centre design, randomisation, single-blind methodology and placebo control, thus providing limited evidence.

To gain a comprehensive understanding of the effects of low-dose colchicine on multiple organ injury in cardiac surgery, we propose a multicentre, large-sample randomised, controlled, double-blind clinical trial.

One advantage of our study is that we aim to expand on the current knowledge by including additional inflammatory biomarkers such as IL-10, IL-8 and TNF-1β to predict myocardial ischaemia-reperfusion injury. Furthermore, we will assess the impact of low-dose colchicine on the heart, lungs, liver and kidneys during the perioperative period to determine its potential protective effect on these organs. This will provide further evidence for the use of colchicine in the cardiovascular community. In addition, we will document the Murray Lung Injury Score, mechanical ventilation hours and inflammatory markers including CRP, PCT and NE to obtain a more comprehensive assessment of lung condition.

Ethics approval

This research has received approval from the Medical Ethics Committee of Affiliated Nanjing Drum Tower Hospital, Nanjing University Medical College (approval number: 2023-366-01). Patients will be provided with comprehensive study information and ample time to make a decision. Consent will be obtained through an ICF, and patients will have the right to withdraw at any point, even after signing the ICF. The study findings will be made available by publishing them in an open access journal.

Review Process File
12 09 2024

Funding: Fundings for Clinical Trials from the Affiliated Drum Tower Hospital, Medical School of Nanjing University (No. 2023-LCYJ-ZD-03) and National Natural Science Foundation of China (82300459, 82241212)

Prepublication history for this paper is available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2024-084368 ).

Patient consent for publication: Not applicable.

Provenance and peer review: Not commissioned; externally peer reviewed.

Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.
==== Refs
References

1 Roach GW Kanchuger M Mangano CM et al Adverse cerebral outcomes after coronary bypass surgery. Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators N Engl J Med 1996 335 1857 63 10.1056/NEJM199612193352501 8948560
2 Paparella D Yau TM Young E Cardiopulmonary bypass induced inflammation: pathophysiology and treatment. An update Eur J Cardiothorac Surg 2002 21 232 44 10.1016/s1010-7940(01)01099-5 11825729
3 Lehto J Kiviniemi T Postpericardiotomy syndrome after cardiac surgery Ann Med 2020 52 243 64 10.1080/07853890.2020.1758339 32314595
4 Bessissow A Khan J Devereaux PJ et al Postoperative atrial fibrillation in non-cardiac and cardiac surgery: an overview J Thromb Haemost 2015 13 Suppl 1 S304 12 10.1111/jth.12974 26149040
5 Rong LQ Di Franco A Gaudino M Acute respiratory distress syndrome after cardiac surgery J Thorac Dis 2016 8 E1177 86 10.21037/jtd.2016.10.74 27867583
6 Rahimi K Banning AP Cheng ASH et al Prognostic value of coronary revascularisation-related myocardial injury: a cardiac magnetic resonance imaging study Heart 2009 95 1937 43 10.1136/hrt.2009.173302 19687014
7 Chenoweth DE Cooper SW Hugli TE et al Complement activation during cardiopulmonary bypass: evidence for generation of C3a and C5a anaphylatoxins N Engl J Med 1981 304 497 503 10.1056/NEJM198102263040901 7453783
8 Despotis GJ Joist JH Anticoagulation and anticoagulation reversal with cardiac surgery involving cardiopulmonary bypass: an update J Cardiothorac Vasc Anesth 1999 13 18 29 10468245
9 Morse DS Adams D Magnani B Platelet and neutrophil activation during cardiac surgical procedures: impact of cardiopulmonary bypass Ann Thorac Surg 1998 65 691 5 10.1016/s0003-4975(97)01425-2 9527196
10 Rothenburger M Trösch F Markewitz A et al Leukocyte activation and phagocytotic activity in cardiac surgery and infection Cardiovasc Surg 2002 10 470 5 10.1016/s0967-2109(02)00016-9 12379405
11 Smedly LA Tonnesen MG Sandhaus RA et al Neutrophil-mediated injury to endothelial cells. Enhancement by endotoxin and essential role of neutrophil elastase J Clin Invest 1986 77 1233 43 10.1172/JCI112426 3485659
12 Jordan JE Zhao ZQ Vinten-Johansen J The role of neutrophils in myocardial ischemia-reperfusion injury Cardiovasc Res 1999 43 860 78 10.1016/s0008-6363(99)00187-x 10615413
13 Tardif J-C Kouz S Waters DD et al Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction N Engl J Med 2019 381 2497 505 10.1056/NEJMoa1912388 31733140
14 Nidorf SM Eikelboom JW Budgeon CA et al Low-dose colchicine for secondary prevention of cardiovascular disease J Am Coll Cardiol 2013 61 404 10 10.1016/j.jacc.2012.10.027 23265346
15 Bouabdallaoui N Tardif J-C Waters DD et al Time-to-treatment initiation of colchicine and cardiovascular outcomes after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT) Eur Heart J 2020 41 4092 9 10.1093/eurheartj/ehaa659 32860034
16 Giannopoulos G Angelidis C Kouritas VK et al Usefulness of colchicine to reduce perioperative myocardial damage in patients who underwent on-pump coronary artery bypass grafting Am J Cardiol 2015 115 1376 81 10.1016/j.amjcard.2015.02.036 25784519
17 Imazio M Trinchero R Brucato A et al COlchicine for the Prevention of the Post-pericardiotomy Syndrome (COPPS): a multicentre, randomized, double-blind, placebo-controlled trial Eur Heart J 2010 31 2749 54 10.1093/eurheartj/ehq319 20805112
18 Imazio M Brucato A Ferrazzi P et al Colchicine reduces postoperative atrial fibrillation: results of the Colchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS) atrial fibrillation substudy Circulation 2011 124 2290 5 10.1161/CIRCULATIONAHA.111.026153 22090167
19 Alunno A Carubbi F Ferri C Colchicine and cardiovascular prevention Eur J Intern Med 2024 121 30 4 10.1016/j.ejim.2023.12.028 38171936
20 Shvartz V Le T Enginoev S et al Colchicine in cardiac surgery: the COCS randomized clinical trial J Cardiovasc Dev Dis 2022 9 363 10.3390/jcdd9100363 36286314
21 Shvartz V Le T Kryukov Y et al Colchicine for prevention of atrial fibrillation after cardiac surgery in the early postoperative period J Clin Med 2022 11 1387 10.3390/jcm11051387 35268478
22 Agarwal S Beard CW Khosla J et al Safety and efficacy of colchicine for the prevention of post-operative atrial fibrillation in patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials Europace 2023 25 euad169 10.1093/europace/euad169 37341446
23 Ge P Fu Y Su Q et al Colchicine for prevention of post-operative atrial fibrillation: meta-analysis of randomized controlled trials Front Cardiovasc Med 2022 9 1032116 10.3389/fcvm.2022.1032116 36531704
24 Pan T Tuoerxun T Chen X et al The neutrophil elastase inhibitor, sivelestat, attenuates acute lung injury in patients with cardiopulmonary bypass Front Immunol 2023 14 1082830 10.3389/fimmu.2023.1082830 36761773
25 Pan T Jiang C-Y Zhang H et al The low-dose colchicine in patients after non-CABG cardiac surgery: a randomized controlled trial Crit Care 2023 27 49 10.1186/s13054-023-04341-9 36747296
26 Nashef SAM Roques F Sharples LD et al EuroSCORE II Eur J Cardiothorac Surg 2012 41 734 44 10.1093/ejcts/ezs043 22378855
27 Tamarappoo BK Klein AL Post-pericardiotomy syndrome Curr Cardiol Rep 2016 18 116 10.1007/s11886-016-0791-0 27761786
28 Ikonomidis I Andreotti F Economou E et al Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin Circulation 1999 100 793 8 10.1161/01.cir.100.8.793 10458713
29 Berg K Langaas M Ericsson M et al Acetylsalicylic acid treatment until surgery reduces oxidative stress and inflammation in patients undergoing coronary artery bypass grafting Eur J Cardiothorac Surg 2013 43 1154 63 10.1093/ejcts/ezs591 23209276
30 Thygesen K Alpert JS Jaffe AS et al Fourth universal definition of myocardial infarction (2018) Eur Heart J 2019 40 237 69 10.1093/eurheartj/ehy462 30165617
31 Mauermann E Bolliger D Fassl J et al Association of troponin trends and cardiac morbidity and mortality after on-pump cardiac surgery Ann Thorac Surg 2017 104 1289 97 10.1016/j.athoracsur.2017.03.003 28935302
32 Ranieri VM Rubenfeld GD Thompson BT et al Acute respiratory distress syndrome: the Berlin Definition JAMA 2012 307 2526 33 10.1001/jama.2012.5669 22797452
33 Adler Y Charron P Imazio M et al 2015 ESC Guidelines for the diagnosis and management of pericardial diseases: The Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC)Endorsed by: The European Association for Cardio-Thoracic Surgery (EACTS) Eur Heart J 2015 36 2921 64 10.1093/eurheartj/ehv318 26320112
34 Swinkels BM de Mol BA Kelder JC et al New-onset postoperative atrial fibrillation after aortic valve replacement: effect on long-term survival J Thorac Cardiovasc Surg 2017 154 492 8 10.1016/j.jtcvs.2017.02.052 28390762
35 Bramer S van Straten AHM Soliman Hamad MA et al New-onset postoperative atrial fibrillation predicts late mortality after mitral valve surgery Ann Thorac Surg 2011 92 2091 6 10.1016/j.athoracsur.2011.06.079 21978874
36 Carter-Storch R Dahl JS Christensen NL et al Postoperative atrial fibrillation after aortic valve replacement is a risk factor for long-term atrial fibrillation Interact Cardiovasc Thorac Surg 2019 29 378 85 10.1093/icvts/ivz094 30977792
37 Fragão-Marques M Mancio J Oliveira J et al Gender differences in predictors and long-term mortality of new-onset postoperative atrial fibrillation following isolated aortic valve replacement surgery Ann Thorac Cardiovasc Surg 2020 26 342 51 10.5761/atcs.oa.19-00314 32350163
38 Helgadottir S Sigurdsson MI Ingvarsdottir IL et al Atrial fibrillation following cardiac surgery: risk analysis and long-term survival J Cardiothorac Surg 2012 7 87 10.1186/1749-8090-7-87 22992266
39 Cheng ZB Chen H Higher incidence of acute respiratory distress syndrome in cardiac surgical patients with elevated serum procalcitonin concentration: a prospective cohort study Eur J Med Res 2020 25 11 10.1186/s40001-020-00409-2 32228702
40 Tamura T Shikata F Kitamura T et al Predictive role of regional thigh tissue oxygen saturation monitoring during cardiopulmonary bypass in lung injury after cardiac surgery J Artif Organs 2024 10.1007/s10047-024-01438-y
41 Thielmann M Sharma V Al-Attar N et al ESC joint working groups on cardiovascular surgery and the cellular biology of the heart position paper: perioperative myocardial injury and infarction in patients undergoing coronary artery bypass graft surgery Eur Heart J 2017 38 2392 407 10.1093/eurheartj/ehx383 28821170
42 Imazio M Brucato A Ferrazzi P Colchicine for prevention of postpericardiotomy syndrome and postoperative atrial fibrillation: the COPPS-2 randomized clinical trial JAMA 2014 312 1016 23 10.1001/jama.2014.11026 25172965
43 Sevuk U Bilgic A Altindag R et al Value of the neutrophil-to-lymphocyte ratio in predicting post-pericardiotomy syndrome after cardiac surgery Eur Rev Med Pharmacol Sci 2016 20 906 11 27010149
44 Dupuis J Sirois MG Rhéaume E et al Colchicine reduces lung injury in experimental acute respiratory distress syndrome PLoS One 2020 15 e0242318 10.1371/journal.pone.0242318 33264297
45 Boyle EM Jr Pohlman TH Johnson MC et al Endothelial cell injury in cardiovascular surgery: the systemic inflammatory response Ann Thorac Surg 1997 63 277 84 10.1016/s0003-4975(96)01061-2 8993292
46 Miller BE Levy JH The inflammatory response to cardiopulmonary bypass J Cardiothorac Vasc Anesth 1997 11 355 66 10.1016/s1053-0770(97)90106-3 9161905
46 Zhang H Han X Pan T et al Evaluation of low-dose colchicine in patients with cardiopulmonary bypass: study protocol for a randomised controlled trial BMJ Open 2022 12 e050577 10.1136/bmjopen-2021-050577
48 Deftereos S Giannopoulos G Papoutsidakis N et al Colchicine and the heart: pushing the envelope J Am Coll Cardiol 2013 62 1817 25 10.1016/j.jacc.2013.08.726 24036026
49 Li Y-W Chen S-X Yang Y et al Colchicine inhibits NETs and alleviates cardiac remodeling after acute myocardial infarction Cardiovasc Drugs Ther 2024 38 31 41 10.1007/s10557-022-07326-y 35900652
