Perioperative Medicine
The Future of Anesthesiology
Cardiac Biomarkers
Cardiac biomarkers is a form of risk assessment. It is being separated out from the rest of the biomarkers given its inclusion in the CCS 2017 guidelines and also its protocol at St. Paul’s Hospital
VISION Part I:
Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery.
Vascular Events In Noncardiac Surgery Patients Cohort Evaluation (VISION) Study Investigators, Devereaux PJ, Chan MT, et al. Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery [published correction appears in JAMA. 2012 Jun 27;307(24):2590]. JAMA. 2012;307(21):2295-2304. doi:10.1001/jama.2012.5502
Bottom line: The VISION study, an international prospective cohort study of ~15000 patients over 45 undergoing non-cardiac surgery requiring hospital admission, showed that peak 4th generation TnT levels of 0.02 ng/mL, 0.03 ng/mL and 0.3 ng/mL independently predicted 30-day mortality post-operatively and may explain ~40% of post-operative deaths. Large, randomized controlled trials are needed to determine whether this risk is modifiable.
Major points:
1. Monitoring TnT values for the first three days after surgery substantially improved 30-day mortality risk prediction compared to using pre-operative risk factors alone.
2. Overall 30-day mortality rate was 1.9% in this study. Of which, 45% of deaths were vascular.
3. 74.2% of patients who developed troponin elevation, did so within 24 hours post-operatively. Median time to PNA diagnosis was 7 days and 10 days for sepsis. Median time to death was 11 days. The timeline from peak TnT to death demonstrates that there is time to intervene.
4. Although half of the deaths are non-vascular, they may also be modifiable through cardiovascular management.
5. Of the pre-operative risk factors, urgent/emergent surgery was the strongest predictor of 30-day mortality.
Noordzij PG, van Geffen O, Dijkstra IM, et al. High-sensitive cardiac troponin T measurements in prediction of non-cardiac complications after major abdominal surgery. Br J Anaesth. 2015;114(6):909-918. doi:10.1093/bja/aev027
Bottom line: This Dutch, single-centre observational cohort study, involving ~200 patients (all of whom had at least one risk factor for coronary artery disease) suggests that half of patients who have a doubling of their 5th generation troponin after major abdominal surgery will have a non-cardiac complication post-operatively. They will also have an increased LOS and higher hospital mortality. More research is needed to elucidate what therapeutic interventions can be implemented to modify this risk.
Major points:
1. Pre-operative troponins were not significantly elevated in those patients who went on to have a post-operative complication compared to those who had an uneventful recovery.
2. Furthermore, 31% of all patients had an elevated baseline cardiac troponin pre-operatively. This suggests that a relative increase in cardiac troponins should be used, as opposed to a peak value.
3. First elevated troponin was in day 1 or day 3 in 91% of patients. An increase in troponin by >100% correctly differentiated between a complicated and non-complicated 30-day post-operative course in 80% of patients with respect to non-cardiac complications. This corresponds to a four-fold increase in risk even when adjusting for other risk factors.
4. The group who had a doubling of their troponin also had a higher mortality rate (12% vs 2%) and a longer length of stay (9 days vs 7 days).
5. Sepsis (13%), pneumonia (10%) and dehiscence (10%) were the most frequent non-cardiac complications.
Devereaux PJ, Duceppe E, Guyatt G, et al. Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): an international, randomised, placebo-controlled trial [published correction appears in Lancet. 2018 Jul 7;392(10141):30]. Lancet. 2018;391(10137):2325-2334. doi:10.1016/S0140-6736(18)30832-8
Bottom line: This international, randomised, placebo controlled trial randomized 1754 patients who had MINS within 35 days to either 110mg twice daily dabigatran or placebo in order to observe the effect of anticoagulation in MINS patients on major vascular complications and major, life-threatening bleeding. The study showed that dabigatran had a number needed to treat to prevent one major vascular complication of 24 and a number need to treat to cause a major life threatening bleed of 54.
The overall mortality was 12% and 9% died before randomization.
Major points:
1. Major vascular complications occurred in 11% of dabigatran group and 15% of placebo group. Dabigatran did not increase the risk of major, life-threatening bleed but did increase the risk of minor bleeding.
2. MINS patients are at high risk of major vascular complications - 1 in 7 in the placebo group had a major vascular complication.
3. Post-operative troponins should be measured regularly as per CCS guidelines to identify MINS patients as they can benefit from anticoagulant therapy.
Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) Study Investigators, Spence J, LeManach Y, et al. Association between complications and death within 30 days after noncardiac surgery. CMAJ. 2019;191(30):E830-E837. doi:10.1503/cmaj.190221
Bottom line: This international, prospective study followed the VISION population, 40 004 patients who underwent inpatient noncardiac surgery until 30-day post-op. They showed a 1.9% mortality rate with 99.3% percent of deaths occurring after the surgical procedure and only 5 deaths (0.7%) in the operating theatre. Furthermore, MINS, major bleeding or sepsis was present in 45% of all deaths. The study highlighted the need for future research on prevention, early detection and management strategies for these complications to reduce perioperative mortality.
Major points:
1. 1.9% of patients died within 30 days after surgery. Curiously, a third of the deaths occurred after hospital discharge suggesting that we need improved monitoring and management of patients after surgery and in the home setting.
2. The median time to death was 11 days. Post-operative death was most common after major general surgery (3.0%) and least common after major urological/gynaecological procedures (0.5%).
3. Major bleeding occurred after 15.6% of surgeries and usually on the day of surgery. It was most common after major orthopaedic surgery (31%).
4. MINS occurred after 13.0% of surgeries. It was most common after vascular surgery (24%) and usually occurred on post-operative day number one.
5. Sepsis complicated 4.5% of surgeries and median time to occurrence was 6 days.
Ruzycki SM, Prystajecky M, Driedger MR, Kachra R. Peri-operative cardiac biomarker screening: a narrative review. Anaesthesia. 2020;75 Suppl 1:e165-e173. doi:10.1111/anae.14920
Bottom line: This Canadian review supports the use of peri-operative biomarker surveillance in high-risk patients undergoing noncardiac surgery. It summarizes the evidence for pre-operative BNP testing and post-operative troponin surveillance as methods for risk-stratification as well as their limitations. Post-operative troponin needs to be assessed for non-cardiac/MINS etiology.
The authors discuss management of patients with abnormal testing results and provide an economic rationale for implementing these risk stratification tools.
Major points:
1. Most guidelines suggest using a clinical risk index and subjective estimation of functional capacity pre-operatively to determine which patients should be referred on for further testing. However, currently available risk indices provide only a moderate discrimination for post-operative cardiovascular complications while subjective assessments are only 20% sensitive for which patients have a METS<4.
2. Pre-operative BNP correctly reclassifies 16% of patients from low to high risk and vice versa. It has a on OR of 19.3 for post-operative cardiovascular complications. It outperforms both functional assessment and echocardiography in predicting post-op morbidity and mortality.
3. Selecting which patients will benefit from pre-operative BNP is difficult. A patient with an elevated pre-op BNP needs to be treated if in decompensated heart failure, counselled about increased peri-operative risks and otherwise proceed to surgery without delay with post-operative monitoring of troponin levels.
4. Patients with elevated post-operative troponin levels need to be assessed urgently to rule out an acute MI, and assessed for systemic illnesses (sepsis, PNA, bleeding are the most common) and treated accordingly. Otherwise, patients are diagnosed with MINS. These patients may benefit from ASA, statin or intensification of their existing cardiovascular therapy (beta-blockers, ACEi etc).
5. MINS management also includes postoperative cardiac risk stratification and potential risk reduction strategies to be implemented.
Alphonsus CS, Govender P, Rodseth RN, Biccard BM. Natriuretic peptide-directed medical therapy: a systematic review. Perioper Med (Lond). 2020;9:5. Published 2020 Feb 18. doi:10.1186/s13741-019-0134-y
Bottom line: This South African systematic review looked at 18 trials on the effects of lowering NT-proBNP and postulated that: (1) NT-proBNP-directed medical therapy does not significantly reduce NT-proBNP levels at 6 months after initiation of therapy; (2) NT-proBNP-directed medical therapy may be associated with decreased mortality in the short-term.
Major points:
1. These findings suggest that a reduction in NT-proBNP levels is not necessarily essential to show a survival benefit, but rather it possible that the actual intensification of medical therapy is really what's important.
2. They postulate that an elevated NT-proBNP may be a surrogate marker for reversibility of volume status derangements and myocyte ischemia; both of which are responsive to medical therapy and have long-term survival benefit.
3. There may be a role for pre-operative targeted therapy to lower the NT-proBNP in high-risk surgical patients in order to improve their overall risk profile.
Duceppe E, Patel A, Chan MTV, et al. Preoperative N-Terminal Pro-B-Type Natriuretic Peptide and Cardiovascular Events After Noncardiac Surgery: A Cohort Study. Ann Intern Med. 2020;172(2):96-104. doi:10.7326/M19-2501
Bottom line: This sub-study involving ~10,000 VISION patients showed that compared to RCRI alone, adding pre-operative NT-proBNP improved risk stratification for post-operative major vascular complications and MINS. The study also suggested a lower NT-proBNP threshold of >200 ng/L (compared to the present threshold of <300 ng/L in the current CCS guidelines) as the definition of "high-risk" for cardiac complications.
Major points:
1. Pre-operative NT-proBNP concentrations, even without RCRI, were independently associated with the occurrence of vascular deaths or MINS at 30 days post-op.
2. A 25.8% improvement in risk reclassification was seen when combining NT-proBNP with RCRI compared to RCRI alone.
3. Compared to previous studies evaluating the predictive value of NT-proBNP, this study had a much larger sample size and so was able to discriminate amongst a number of different NT-proBNP thresholds. Hence, the revised cut-off of >200ng/L for "high-risk".
4. Using the most accurately available pre-operative risk estimation is important for the following reasons: (1) it is ethical to provide the patient with as accurate information as possible to make an informed decision; (2) accurate risk estimation informs pre-operative decision making surrounding surgical approach, anesthetic approach, decisions regarding further pre-operative evaluation and intensity of post-operative surveillance.
5. NT-proBNP less than 200 pg/mL had a risk for death or MI of 3.0% or less, whereas patients with an NT-proBNP between 200 and less than 1500 pg/mL had a risk of 7.9%.
Nagele P. Elevated cardiac troponin before surgery: perhaps not so benign. Br J Anaesth. 2020;124(1):6-7. doi:10.1016/j.bja.2019.10.001
Bottom line: A brief editorial by Dr. Peter Nagele from University of Chicago acknowledging that there is a well-known association between elevated high-sensitivity cardiac troponins pre-operatively with increased post-operative cardiac morbidity and mortality. The exact mechanism behind this association is yet to be elucidated.
The author cites a case-series by Mol et al, which showed that of 10 high-risk vascular patients who had elevated troponins pre-operatively and underwent coronary angiography, 9 of 10 had significant coronary artery disease, four underwent PCI and one underwent a CABG. He goes on to suggest that this is the first piece of evidence that elevated pre-operative troponins may be a sign of previously unrecognized and undiagnosed coronary artery disease.
Writing Committee for the VISION Study Investigators, Devereaux PJ, Biccard BM, et al. Association of Postoperative High-Sensitivity Troponin Levels With Myocardial Injury and 30-Day Mortality Among Patients Undergoing Noncardiac Surgery. JAMA. 2017;317(16):1642-1651. doi:10.1001/jama.2017.4360
Bottom line: This follow-up on the 2012 VISION study used the recently approve high-sensitivity assay on over 21000 patients. The authors validated that MINS was independently associated with increased 30-day mortality (0.6% vs 2.9% MINS & no ischemic feature vs 8.5% MINS & ischemic feature). They defined new thresholds for the hsTnT and provided a new diagnostic criteria for MINS.
MINS is defined as an elevated post-op hsTnT resulting from myocardial ischemia (i.e. not from sepsis or other non-ischemic etiologies) without the requirement of an ischemic feature (i.e. ischemic chest pain or MI-diagnostic ECG).
Major points:
1. The overall mortality rate was 1.2%. The mortality rate increased with increasing post-operative hsTnT: 20-65 ng/L (3.0%), 65-1000ng/L (9.1%) and >1000ng/L (29.6%). Furthermore, patients who had a change in their post-op hsTnT compared to pre-op of >5ng/L had a mortality rate 3.0% compared to 0.5% for those with <5ng/L change.
2. Elevated post-op hsTnT was defined as: (a) hsTnT > 65 ng/L OR (b) hsTnT btw 20-65 & with a change of >5 ng/L. A total of 4385 patients (19.7%) had an elevated post-op troponin. 11% of these were found to be non-ischemic, non-MINS. Perioperative complications associated with increased 30-day mortality are: MINS, major bleeding, sepsis, new atrial fibrillation and stroke.
3. A total of 3904 patients (17.9%) fulfilled the criteria for MINS. The majority (94.1%) were diagnosed by day 2 post-op. 21.7% fulfilled universal definition of MI (elevated hsTnT with 1 or more ischemic features) but interestingly, 68% did not experience any ischemic symptoms. This suggests that a large number of post-operative MIs would have went on unnoticed if post-operative troponins were not measured.
4. Furthermore, 93.1% of patients who developed MINS were asymptomatic - these diagnoses would have also been missed if post-operative troponins were not measured. The theory is that the majority of MINS occur within 2 days post-op, during a time when post-operative analgesia might mask ischemic symptoms.
5. In patients who had elevated perioperative troponins, 13.8% of patients had their peak hsTnT occur pre-operatively -- suggesting that MINS might be overestimated if we do not measure pre-operative troponins.
Holse C, Aasvang EK, Vester-Andersen M, Rasmussen LS, Wetterslev J, Christensen R, Jorgensen LN, Pedersen SS, Loft FC, Troensegaard H, Mørkenborg ML, Stisen ZR, Rünitz K, Eiberg JP, Hansted AK, Meyhoff CS; VIXIE Trial Group. Hyperoxia and Antioxidants for Myocardial Injury in Noncardiac Surgery: A 2 × 2 Factorial, Blinded, Randomized Clinical Trial. Anesthesiology. 2022 Mar 1;136(3):408-419. doi: 10.1097/ALN.0000000000004117. Erratum in: Anesthesiology. 2022 Jul 20;: PMID: 35120193.
Bottom line: This blinded, randomized, clinical trial of 576 patients found no statistically or clinically significant differences in degree of myocardial injuries following major non-cardiac surgery when comparing perioperative 0.80 FIO2 to 0.30 FIO2 and antioxidants to placebo in patients with cardiac risk factors.
Major points:
1. Higher FiO2 (0.80) does not appear to increase risk for MINS within the first 3 post-operative days.
2. Antioxidants (Vitamin C and N-acetylcystine) do not appear to decrease risk for MINS within the first 3 post-operative days.
3. Primary outcome was the degree of MINS as assessed by measuring the area under the curve (AUC) of troponin measurements in the first days after surgery.
4. Secondary outcomes were all-cause mortality, nonfatal MI, and nonfatal serious adverse event within 30 days.
5. Importantly, this study was not powered to detect differences in pulmonary outcomes, and other larger studies have found increased pulmonary complications with higher FiO2.
POISE Study Group, Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, Villar JC, Xavier D, Chrolavicius S, Greenspan L, Pogue J, Pais P, Liu L, Xu S, Málaga G, Avezum A, Chan M, Montori VM, Jacka M, Choi P. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008 May 31;371(9627):1839-47. doi: 10.1016/S0140-6736(08)60601-7. Epub 2008 May 12. PMID: 18479744.
Bottom line: Although initiation of beta-blockers (in this study: metoprolol) during the preoperative period reduced the risk of perioperative MI, routine preoperative initiation appears to increase the risk of mortality and stroke, which nullifies the cardioprotective effects.
Major points:
1. From this study, it is not recommended to empirically start beta blockers on the day of surgery. Of note, the study is criticized for initiating high dose metoprolol (100mg controlled release pre-op, and 200mg post op). Future studies investigating dose, and timing of initiation (e.g. 24-48h pre-operatively) are ongoing.
2. This trial illustrates, and emphasizes, the importance of hemodynamic control during the perioperative period. Clinically significant hypotension and bradycardia was predictive of perioperative non-fatal stroke, and death.
3. Preoperative initiation of beta blockers may delay the diagnosis/recognition of infections/sepsis by masking typical hemodynamic responses, leading to delayed antibiotic initiation, and ultimately increased mortality.
4. Two thirds of POISE I patients who did have MI did not experience ischemic symptoms. These MIs without symptoms were independent predictors of 30 day mortality. These findings demonstrated benefit to three day postoperative troponin monitoring.
Kovacs MJ, Wells PS, Anderson DR, Lazo-Langner A, Kearon C, Bates SM, Blostein M, Kahn SR, Schulman S, Sabri E, Solymoss S, Ramsay T, Yeo E, Rodger MA; PERIOP2 Investigators. Postoperative low molecular weight heparin bridging treatment for patients at high risk of arterial thromboembolism (PERIOP2): double blind randomised controlled trial. BMJ. 2021 Jun 9;373:n1205. doi: 10.1136/bmj.n1205. PMID: 34108229; PMCID: PMC8188228.
Bottom line: Evidence from this trial and others is mounting which suggests that low molecular weight heparin bridging is unnecessary for patients on Warfarin with low thromboembolism risk when undergoing elective surgery.
Major points:
1. Patients with atrial fibrillation or mechanical heart valves (MHV) are typically on long term anticoagulation with Warfarin or a direct oral anticoagulant (DOAC). When patients on warfarin are brought to the OR for elective surgery, their anticoagulation is often “bridged” with a shorter acting anticoagulant (such as low molecular weight heparin) to balance the risk of perioperative bleeding and thrombus. This RCT looked to examine the efficacy and safety of dalteparin postoperative bridging for patients with A fib or a single MHV on Warfarin.
2. At 90 days post-op, there was no significant difference in major thromboembolism, major bleeding and composite major thromboembolism + major bleeding between patients who received LMWH bridging and those who did not.
3. This finding was consistent for both A Fib patients and MHV patients, although the number of subjects in the MHV group was underpowered.
4. This was the first RCT in patients with MHV to address this question. One other RCT (BRIDGE Trial) and meta-analysis (Siegal et al., 2012) have shown lack of reduction of thromboembolism with bridging, and potentially increased risk of major bleeding in bridged patients.
5. Of note, the PERIOP2 trial only assessed the safety and efficacy of postoperative bridging, as all patients were bridged pre-op, compared to the BRIDGE trial, which assessed pre-operative and post-operative bridging, but did not include any patients with MHV.
Azizi PM, Wijeysundera DN, Wijeysundera HC, Austin PC, Jerath A, Kayssi A, Ko DT. Association Between Hospital Postoperative Troponin Use and Patient Outcomes After Vascular Surgery. Anesth Analg. 2023 Sep 1;137(3):629-637. doi: 10.1213/ANE.0000000000006411. Epub 2023 Mar 8. PMID: 36913232.
Bottom line: Patients who had vascular surgery at hospitals that tested postoperative troponin more frequently had fewer major adverse cardiovascular events after surgery.
Major points:
1. Higher troponin testing rate was associated with lower adjusted hazard ratios for major adverse cardiac event at 30 days (0.94; 95% confidence interval [CI], 0.89–0.98) and at 1 year (0.97; 95% CI, 0.94–0.99) for each 10% increase in hospital troponin test rate.
2. Hospital-level troponin testing intensity was defined as the proportion of patients who received postop troponin testing within 2 days after surgery. Patients were categorized by low-intensity testing (21.6%), medium-intensity testing (35.8%) and high-intensity testing (77.5%).
3. Hospitals with high-testing intensity had higher rates of postoperative cardiology referrals, cardiovascular testing, and rates of new cardiovascular prescriptions.