{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T14:05:24Z","timestamp":1791986724634,"version":"4.4.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>To evaluate the association between tramadol use and short-term outcomes, including 28-day mortality, intensive care unit (ICU) mortality, and ICU length of stay, in critically ill patients undergoing cardiac surgery.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This retrospective cohort study included 3,544 participants from the MIMIC-IV database. A comprehensive analytical approach was employed, including multivariate Cox regression, subgroup analysis, propensity score matching (PSM), inverse probability weighting (IPW), doubly robust estimation, and E-value calculation. Receiver operating characteristic (ROC) curves and the DeLong test were used to compare the predictive performance of different opioids, and SHAP analysis was employed for model interpretation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Tramadol use was consistently associated with a significant reduction in 28-day mortality across all models. The hazard ratios (HR) ranged from 0.305 to 0.341 after rigorous adjustment and matching (all\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05). Subgroup analyses demonstrated the robustness of this protective association, and a significant interaction was observed with respect to surgery type after PSM. Furthermore, tramadol demonstrated superior predictive performance for 28-day mortality (AUC = 0.603) compared to other opioids, including fentanyl, hydromorphone, morphine, and oxycodone AUC range: 0.523\u20130.597). However, no significant association was found with secondary outcomes like ICU mortality or length of stay.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Tramadol administration is independently associated with a significantly lower risk of 28-day mortality in cardiac surgery patients, showing better predictive utility than other common opioids, which may inform postoperative analgesic strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1770570","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T07:04:27Z","timestamp":1768547067000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Tramadol use is associated with reduced 28-day mortality in ICU patients after cardiac surgery: a retrospective study based on the MIMIC-IV database"],"prefix":"10.3389","volume":"17","author":[{"given":"Jingyan","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, The Second Affiliated Hospital Zhejiang University School of Medicine","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Second Affiliated Hospital Zhejiang University School of Medicine","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongqing","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Second Affiliated Hospital Zhejiang University School of Medicine","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.jclinane.2016.10.030","article-title":"The effect of tramadol plus paracetamol on consumption of morphine after coronary artery bypass grafting","volume":"36","author":"Altun","year":"2017","journal-title":"J. Clin. Anesth."},{"key":"B2","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1186\/s12879-025-10817-6","article-title":"Remdesivir associated with reduced mortality in hospitalized COVID-19 patients: treatment effectiveness using real-world data and natural language processing","volume":"25","author":"Arribas Lopez","year":"2025","journal-title":"BMC Infect. Dis."},{"key":"B3","first-page":"395","article-title":"Tramadol, pharmacology, side effects, and serotonin syndrome: a review","volume":"18","author":"Beakley","year":"2015","journal-title":"Pain Physician"},{"key":"B4","doi-asserted-by":"publisher","first-page":"413","DOI":"10.4103\/0253-7613.135954","article-title":"Does tramadol affect coagulation status of patients with malignancy?","volume":"46","author":"Bilir","year":"2014","journal-title":"Indian J. Pharmacol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1186\/s12877-024-04933-2","article-title":"Comparative safety of tramadol and other opioids following total hip and knee arthroplasty","volume":"24","author":"Bosco","year":"2024","journal-title":"BMC Geriatr."},{"key":"B6","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1007\/s11864-023-01091-2","article-title":"Effects of opioids on immune and endocrine function in patients with cancer pain","volume":"24","author":"Bradley","year":"2023","journal-title":"Curr. Treat. Options Oncol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1080\/17460441.2017.1377697","article-title":"Discovery and development of tramadol for the treatment of pain","volume":"12","author":"Bravo","year":"2017","journal-title":"Expert Opin. Drug Discov."},{"key":"B8","doi-asserted-by":"publisher","first-page":"3657","DOI":"10.3390\/jcm12113657","article-title":"Opioid-free anesthesia for open radical cystectomy is feasible and accelerates return of bowel function: a matched cohort study","volume":"12","author":"Burkhard","year":"2023","journal-title":"J. Clin. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e30","DOI":"10.1016\/j.medine.2024.07.009","article-title":"Towards better mortality prediction in cancer patients in the ICU: a comparative analysis of prognostic scales: systematic literature review","volume":"48","author":"Cabrera","year":"2024","journal-title":"Med. Intensiva Engl. Ed."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e87","DOI":"10.3346\/jkms.2021.36.e87","article-title":"Effect of opioids on all-cause mortality and opioid addiction in total hip arthroplasty: a Korea nationwide cohort study","volume":"36","author":"Cha","year":"2021","journal-title":"J. Korean Med. Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1555","DOI":"10.1007\/s44197-024-00307-4","article-title":"Variation of all-cause mortality with fat-free mass index (FFMI) and fat mass index (FMI) in individuals with asthma: results from the NHANES database retrospective cohort study","volume":"14","author":"Chen","year":"2024","journal-title":"J. Epidemiol. Glob. Health"},{"key":"B12","doi-asserted-by":"publisher","first-page":"28735","DOI":"10.1021\/acsnano.4c07615","article-title":"Machine learning elucidates design features of plasmid deoxyribonucleic acid lipid nanoparticles for cell type-preferential transfection","volume":"18","author":"Cheng","year":"2024","journal-title":"ACS Nano"},{"key":"B13","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1056\/NEJMoa2000803","article-title":"High-sensitivity troponin I after cardiac surgery and 30-Day mortality","volume":"386","author":"Devereaux","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1007\/s10787-017-0431-3","article-title":"Tramadol ameliorates behavioural, biochemical, mitochondrial and histological alterations in ICV-STZ-induced sporadic dementia of Alzheimer's type in rats","volume":"26","author":"Dhull","year":"2018","journal-title":"Inflammopharmacology"},{"key":"B15","doi-asserted-by":"publisher","first-page":"110468","DOI":"10.1016\/j.mehy.2020.110468","article-title":"The plausible mechanisms of tramadol for treatment of COVID-19","volume":"146","author":"El-Ashmawy","year":"2021","journal-title":"Med. Hypotheses"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e237","DOI":"10.1093\/eurjpc\/zwab176","article-title":"Tramadol use increases mortality and risk of major adverse cardiovascular events in rheumatoid arthritis patients: evidence from a population-based cohort study","volume":"29","author":"Gau","year":"2022","journal-title":"Eur. J. Prev. Cardiol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1007\/s40264-023-01351-y","article-title":"Adverse drug reactions to opioids: a study in a national pharmacovigilance database","volume":"46","author":"Gustafsson","year":"2023","journal-title":"Drug Saf."},{"key":"B18","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1007\/s40264-018-00786-y","article-title":"All-cause mortality associated with tramadol use: a case-crossover study","volume":"42","author":"Jeong","year":"2019","journal-title":"Drug Saf."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41597-022-01899-x","article-title":"MIMIC-IV, a freely accessible electronic health record dataset","volume":"10","author":"Johnson","year":"2023","journal-title":"Sci. Data"},{"key":"B20","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1016\/j.bja.2019.09.004","article-title":"Tramadol use is associated with enhanced postoperative outcomes in breast cancer patients: a retrospective clinical study with in vitro confirmation","volume":"123","author":"Kim","year":"2019","journal-title":"Br. J. Anaesth."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-025-04102-x","article-title":"Cardiovascular outcomes of semaglutide and tirzepatide for patients with type 2 diabetes in clinical practice","author":"Kruger","year":"2025","journal-title":"Nat. Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1213\/ANE.0000000000001683","article-title":"Trends in tramadol: pharmacology, metabolism, and misuse","volume":"124","author":"Miotto","year":"2017","journal-title":"Anesth. Analg."},{"key":"B23","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1080\/15360288.2020.1817227","article-title":"Clinical tolerability and safety of tramadol in hospitalized patients","volume":"34","author":"Mohan","year":"2020","journal-title":"J. Pain Palliat. Care Pharmacother."},{"key":"B24","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1080\/14740338.2024.2392863","article-title":"Evaluating potential unexpected adverse events and mortality after oral analgesics administration in fracture care-a cohort study","volume":"24","author":"Muhammad","year":"2025","journal-title":"Expert Opin. Drug Saf."},{"key":"B25","doi-asserted-by":"publisher","first-page":"2575","DOI":"10.1016\/j.jcin.2024.07.032","article-title":"Conduction disturbances after transcatheter aortic valve replacement: an update on epidemiology, preventive strategies, and management","volume":"17","author":"Nuche","year":"2024","journal-title":"JACC Cardiovasc Interv."},{"key":"B26","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s44158-025-00258-7","article-title":"Comparative efficacy of remifentanil and fentanyl in mechanically ventilated ICU patients: a systematic review and meta-analysis on ventilation duration and delirium incidence","volume":"5","author":"Okano","year":"2025","journal-title":"J. Anesth. Analg. Crit. Care"},{"key":"B27","doi-asserted-by":"publisher","first-page":"9574395","DOI":"10.1155\/2018\/9574395","article-title":"Tramadol-induced mood elevation in a patient with no previous psychiatric history","volume":"2018","author":"Osman","year":"2018","journal-title":"Case Rep. Psychiatry"},{"key":"B28","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1093\/ehjcvp\/pvad061","article-title":"Platelet inhibition with orodispersible ticagrelor in acute coronary syndromes according to morphine use: the TASTER study final results","volume":"9","author":"Parodi","year":"2023","journal-title":"Eur. Heart J. Cardiovasc Pharmacother."},{"key":"B29","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1186\/s12933-025-02644-5","article-title":"Stress hyperglycemia ratio and machine learning model for prediction of all-cause mortality in patients undergoing cardiac surgery","volume":"24","author":"Pei","year":"2025","journal-title":"Cardiovasc Diabetol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1161\/CIRCULATIONAHA.124.068312","article-title":"Coronary artery bypass grafting: past and future","volume":"150","author":"Ruel","year":"2024","journal-title":"Circulation"},{"key":"B31","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1007\/s11912-021-01121-y","article-title":"New insights on tramadol and immunomodulation","volume":"23","author":"Saeed","year":"2021","journal-title":"Curr. Oncol. Rep."},{"key":"B32","doi-asserted-by":"publisher","first-page":"206","DOI":"10.3344\/kjp.2018.31.3.206","article-title":"The impact of caudally administrated tramadol on immune response and analgesic efficacy for pediatric patients: a comparative randomized clinical trial","volume":"31","author":"Sayed","year":"2018","journal-title":"Korean J. Pain"},{"key":"B33","doi-asserted-by":"publisher","first-page":"388","DOI":"10.5152\/tud.2020.20227","article-title":"The effect of tramadol on oxidative stress total antioxidant levels in rats with renal ischemia-reperfusion injury","volume":"46","author":"Sen","year":"2020","journal-title":"Turk J. Urol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"2424","DOI":"10.1053\/j.jvca.2025.05.020","article-title":"Temporal trends and severity of postoperative delirium in cardiac surgery: insights from a systematic review and meta-analysis","volume":"39","author":"Shamsi","year":"2025","journal-title":"J. Cardiothorac. Vasc. Anesth."},{"key":"B35","volume-title":"A language and environment for statistical computing_","author":"Team","year":"2024"},{"key":"B36","doi-asserted-by":"publisher","first-page":"e007862","DOI":"10.1161\/CIRCIMAGING.118.007862","article-title":"Multiple and mixed valvular heart diseases","volume":"11","author":"Unger","year":"2018","journal-title":"Circ. Cardiovasc Imaging"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v045.i03","article-title":"Mice: multivariate imputation by chained equations in R","volume":"45","author":"van Buuren","year":"2011","journal-title":"J. Stat. Softw."},{"key":"B38","doi-asserted-by":"publisher","first-page":"268","DOI":"10.7326\/M16-2607","article-title":"Sensitivity analysis in observational research: introducing the E-Value","volume":"167","author":"VanderWeele","year":"2017","journal-title":"Ann. Intern Med."},{"key":"B39","doi-asserted-by":"publisher","first-page":"zrae113","DOI":"10.1093\/bjsopen\/zrae113","article-title":"Association of postoperative opioid type with mortality and readmission rates: Multicentre retrospective cohort study","volume":"8","author":"Winther","year":"2024","journal-title":"BJS Open"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1567158","DOI":"10.3389\/fneur.2025.1567158","article-title":"Associations of serum neurofilament and asthma: evidence from the NHANES 2013-2014","volume":"16","author":"Yang","year":"2025","journal-title":"Front. Neurol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"e127","DOI":"10.3346\/jkms.2021.36.e127","article-title":"Effect of opioids on all-cause mortality and sustained opioid use in elderly patients with hip fracture: a Korea nationwide cohort study","volume":"36","author":"Yoo","year":"2021","journal-title":"J. Korean Med. Sci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1001\/jama.2019.1347","article-title":"Association of tramadol with all-cause mortality among patients with osteoarthritis","volume":"321","author":"Zeng","year":"2019","journal-title":"JAMA"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1453835","DOI":"10.3389\/fphar.2024.1453835","article-title":"Comparison of the effects of perioperative fentanyl and morphine use on the short-term prognosis of patients with cardiac surgery in the ICU","volume":"15","author":"Zhong","year":"2024","journal-title":"Front. Pharmacol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1770570\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T07:35:26Z","timestamp":1771918526000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1770570\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,16]]},"references-count":43,"alternative-id":["10.3389\/fphar.2026.1770570"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1770570","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,16]]},"article-number":"1770570"}}