Myocardial injury in patients undergoing vascular surgery

Background: Cardiac complications are one of the most common complications after non-cardiac surgery. Perioperative myocardial injury (PMI), defined as a perioperative rise in troponin, is in turn, one of the most common cardiac complications after noncardiac surgery. PMI is associated with increased short- and long-term mortality after non-cardiac surgery. The overarching aim of this thesis was to find potentially preventable risk factors for PMI and study the effect of PMI on different organ systems.

Aims: Study I aimed to study the association between supplementary oxygen, in non-hypoxemic patients, and major postoperative complications, PMI and postoperative elevation in N-terminal pro-B-type natriuretic peptide (NT proBNP). Study II aimed to study the association between PMI, preoperative high-sensitivity cardiac troponin T (hs-cTnT) and NT-proBNP, respectively, and non-cardiac complications. Study III aimed to explore the association between predefined thresholds for intraoperative hypotension (IOH) (systolic, mean, and diastolic arterial pressure) and tachycardia, and PMI. Study IV aimed to determine if the postoperative increase in troponin, in patients with PMI, is associated with newly found regional wall motion abnormality (RWMA) or perioperative change in other echocardiographic parameters commonly used to describe cardiac morphology and function.

Materials and Methods: Study I was a single-blinded, multicenter, randomized controlled trial in patients undergoing vascular surgery. Patients were randomized to group H (Hyperoxia) F;O2250 % and a target SpO2 > 98 % or group N (Normoxia) F;O2 = 0.21 % and a target SpO2 ≥ 90 %. The primary endpoint was postoperative complications within 30 days after surgery. The secondary endpoints were PMI and postoperative elevation in NT-proBNP, determined by hs-cTnT and NT-proBNP preoperatively and at 4, 24 and 48h after surgery. The secondary outcomes were one-year mortality. Data was analyzed using Fisher's exact test or General estimating equations (GEE) as appropriate. Study II was a post-hoc analysis of Study I. The primary outcome was NCC, defined the same as in Study I, with the exclusion of cardiac complications. Data was analyzed using GEE or logistic regression as appropriate. Study III was a single-center, prospective observational trial in patients undergoing vascular surgery. Absolute and relative thresholds were used to define intraoperative systolic, mean, and diastolic arterial hypotension, measured every 15 seconds by invasive arterial pressure monitoring and heart rate using the Philips IntelliVue X3 monitor. Decision tree machine-learning (ML) models were used to explore which thresholds for IOH and tachycardia best predict PMI. A whitebox-model was used to prioritize clinical utility and transparency over the performance of the ML model. Study IV was a prospective observational sub-study nested within Study III. The primary outcome was newly detected RWMA (hypokinesia or akinesia) determined by a blinded assessor comparing pre- and postoperative transthoracic echocardiography (TTE). Data was analysed using an exact logistic regression model.

Results: In Study I, 191 patients were randomized. Seven patients were excluded after randomization, mostly due to canceled operations and equipment problems. A per-protocol principle was used for analysis. In total, postoperative complications were incurred by 43 out of 94 patients (46%) in group H and 36 out of 90 patients (40%) in group N (p = 0.46). The incidence of PMI was 27 % in group H and 22 % in group N (p = 0.41). At one-year follow-up, one patient had died in group H. In Study II, NCC was incurred by 67 patients (36 %). There was a significant association between PMI and NCC, OR 2.71 (95 % CI 1.33-5.55, p = 0.01). No association was found between pre-operative hs-cTnT or NT-proBNP and NCC. In Study IV, 498 patients were included. In total, 99 patients (20 %) incurred PMI. Thresholds based on absolute diastolic arterial pressure (DAP) had the strongest correlation with PMI and the ML model with DAP <44 mmHg was most predictive of PMI. The ML model had an F1 score of 0.67 and a weighted average F1 score of 0.76. No association was found between tachycardia and PMI. In total, 30 patients from Study III were included in Study IV. Three were excluded due to poor image quality. Seven patients (26 %) incurred the primary outcome of newly detected RWMA. A total of 16 patients (59 %) had RWMA on the preoperative TTE. Each 5 ng/L increase in delta hs-cTnT was associated with an increased odds of newly detected RWMA, OR 1.094 (95 % CI 1.020-1.196, P = 0.003). A similar increase in delta hs-cTnT was also associated with an increased odds of a perioperative reduction in ejection fraction, OR (1.054, 95 % CI 1.007- 1.124, P = 0.024).

Conclusion: No difference was found in the incidence of postoperative complications or perioperative myocardial injury in non-hypoxemic patients randomized to a fraction of inspired oxygen of 0.21 or 20.50. There is an association between perioperative myocardial injury and an increased risk of non-cardiac complications. However, no association was found between preoperative levels of high-sensitivity cardiac troponin T and N-terminal pro-B- type natriuretic peptide, and non-cardiac complications. An absolute, not relative, intraoperative hypotension threshold based on diastolic arterial pressure, and not systolic or mean arterial pressure, or tachycardia, was most predictive of perioperative myocardial injury. In patients with perioperative myocardial injury, there is an association between a postoperative increase in troponin and a newly detected decrease in regional and global cardiac function. Pre- and postoperative transthoracic echocardiography may be needed to distinguish between old and newly detected perioperative changes in cardiac function

List of scientific papers

I. POSTOPERATIVE COMPLICATIONS AND MYOCARDIAL INJURY IN PATIENTS RECEIVING AIR OR OXYGEN. PROSPECTIVE, RANDOMISED AND PILOT STUDY. Valadkhani A, Henningsson R, Nordström JL. Granström A, Hallqvist L, Wahlgren CM, Peterzén B, Eriksson J, Bell M, Gupta A. Acta anaesthesiologica Scandinavica. 2022;66(10):1185-1192. https://doi.org/10.1111/aas.14136

II. PERIOPERATIVE MYOCARDIAL INJURY IS ASSOCIATED WITH INCREASED POSTOPERATIVE NON-CARDIAC COMPLICATIONS IN PATIENTS UNDERGOING VASCULAR SURGERY: A POST HOC ANALYSIS OF A RANDOMISED CLINICAL PILOT TRIAL. Valadkhani A, Gupta A, Bell M. Perioperative medicine (London, England). 2023;12(1):58 https://doi.org/10.1186/s13741-023-00350-y

III. DIASTOLIC VERSUS SYSTOLIC OR MEAN INTRAOPERATIVE HYPOTENSION AS PREDICTIVE OF PERIOPERATIVE MYOCARDIAL INJURY IN A WHITE-BOX MACHINE-LEARNING MODEL. Valadkhani A, Gupta A, Cauli G, Nordström JL, Rohi A, Tufexis P, Hällsjö Sander C, Jacobsson M, Bell, M. Anesthesia and analgesia. Published online February 20, 2025. https://doi.org/10.1213/ANE.0000000000007379

IV. CARDIAC FUNCTION IN PATIENTS WITH PERIOPERATIVE MYOCARDIAL INJURY. A PROSPECTIVE OBSERVATIONAL SUB-STUDY. Valadkhani A, Gupta A, Mellbin L, Bell M. [Submitted]