Department of OUTCOMES RESEARCH

Perioperative Myocardial Injury Daniel I. Sessler, M.D. Michael Cudahy Professor and Chair Department of OUTCOMES RESEARCH Cleveland Clinic www.or.org

Perioperative Mortality Intraoperative mortality rare Thirty-day mortality 1% in the United States 2% worldwide for inpatients ≥45 years old 1000 times more common than intraop mortality “Myocardial Injury after Non-cardiac Surgery” = MINS

Surgery is a Major Cause of Death Bartels, Anesthesiology 2013

Causes of Postoperative Death (%) Adjusted HR (95% CI) Attributable Fraction Myocardial injury 18 4 (3-5) 24 Major bleeding 14 3 (2-4) Sepsis 4 5 (4-7) 9 New AF 1 2 (1-3) 2 Stroke 0.3 5 (3-10) VISION: Devereaux, JAMA 2017

Common, Silent, and Deadly MI incidence 4% among inpatients >45 years Mortality is 4% at 30 days Myocardial Injury after Non-cardiac Surgery “MINS” 18% of inpatients >45 yrs have troponin increase 93% without symptoms It’s not just “troponitis” 8.5% have MI, cardiac arrest, or death

High-sensitivity Troponin T Only 22% met Universal Definition of MI — but they still died Population attributable risks: Age – 40%, MINS – 34%, and sepsis – 30%. Mortality increase by squares: 2, 3, 5, 8, 15.

MINS (Troponin T Increase) Outcome No MINS (n = 13,822), % MINS (n = 1,194), % OR (95% CI) Nonfatal arrest 0.1 0.8 15 (6-37) CHF 1.0 9.4 10 (8-13) Stroke 0.4 1.9 5 (3-8) Death 1.1 9.8 Composite 2.4 18.8 10 (8-12) VISION: Devereaux JAMA 2012; Botto, Anesthesiology 2014

Post-Op Troponin & Long-term Death Beattie, JACC 2017

Professional Society Guidance Universal Definition of MI “Routine monitoring of cardiac biomarkers in high-risk patients … after major surgery is therefore recommended.” Canadian Cardiovascular Society “Daily troponin measurements for 2-3 days in patients with moderate cardiovascular risk

Troponin Monitoring Who: inpatient surgery and: When Age >45 years and ≥1 risk cardiovascular risk factor Age >65 years When Preoperatively 25% elevated preoperatively, mostly chronically First two days while hospitalized 94% of elevations detected within 2 days Response thresholds Preoperative-to-postoperative increase >5 ng/L and postoperative >20 ng/L Postoperative >65 ng/L

Elevated Troponin? Cardiology consult Occasional patients need catheterization ± angioplasty Discussion of risk Aspirin (22% secondary reduction) ± statins or ACEIs Only one-third of MINS patients current treated Heart rate and hypertension control Lifestyle Smoking cessation Reasonable diet Exercise

Risk Prediction Revised Cardiac Risk Index Exercise tolerance Well validated But assigns >50% patients to “intermediate risk” Exercise tolerance Neither patients nor physicians estimate well Unclear if exercise tolerance is predictive Stress echo Expensive and virtually useless CT angiography Worsens clinical risk assessment

Brain Natiuretic Protein Rodseth, J Am Coll Card, 2014 Enhances Revised Cardiac Risk Index Correctly identifies 16% more high-risk patients Correctly identifies 15% more low-risk patients BNP MI or Death Risk <100 ng/mL 5% >250 27% NT pro-BNP Risk of MI or Death <300 ng/mL 5% 901-3000 26% >3000 40% Optimal ng/mL threshold is BNP <92 or NT pro-BNP <300

Preoperative Troponin Nagele, Am Heart J, 2013

Prevention: POISE-1 8,350 at-risk inpatients >45 years randomized Metoprolol 100 mg extended-release for 30 days Placebo Primary outcome: death, MI, cardiac arrest Fewer composite outcomes: 5.8% vs. 6.9% More strokes: 4.1% vs. 2.2% More death: 3.1% vs. 2.3% Beta blockers prevent MI, but increase death Devereaux, Lancet, 2008

Prevention: ENIGMA-2 Background Hypothesis N2O increases plasma homocysteine N2O impairs endothelial function Hypothesis N2O increases 30-day death or major CV events MI required troponin elevation & clinical event Randomized trial in 7,000 high-risk patients 70% nitrous oxide 70% nitrogen Myles, Lancet, 2014

Prevention: POISE-2 Surgery Aspirin Clonidine Inflammatory response activates platelets Promotes tachycardia Aspirin Impairs platelet aggregation Prevents non-operative primary & secondary MI Clonidine Moderates central sympathetic activation Heart rate control Less hypotension than beta blockers Devereaux, NEJM (2 papers) 2014

POISE-2 Design Inpatients >45 years at cardiovascular risk Blinded 2 X 2 factorial trial Aspirin 100 mg/day vs. placebo for 7 or 30 days Clonidine 75 µg/day vs. placebo for 72 hours Primary outcome Death or MI within 30 days MI required troponin elevation and clinical events Safety outcomes Life-threatening bleeding (i.e., required reoperation) Clinically important hypotension (syst < 90 mmHg & Rx) Clinically important bradycardia (HR <55/min & Rx)

Aspirin, Death & MI 20% increase in major bleeding

POISE-2 Results, Clonidine 30-50% increase in hypotension & bradycardia %

No Safe Prophylaxis for MI POISE-1: Beta blockers Decrease myocardial infarctions by 30% Cause devastating strokes and death ENIGMA-2 Nitrous oxide has no effect on MI POISE-2 Aspirin does not reduce MI; life-threatening bleeding Clonidine doesn’t reduce MI; bradycardia & hypotension

Association Between MAP & Death Mascha, Anesth 2015

Hypotension & Myocardial Injury

Hypotension and AKI Salmasi, Anesthesiology 2017

Vasopressors do not Worsen AKI 1,080 Matched patients Major spine surgery With and without phenylephrine infusion Farag, unpublished

Timing of Hypotension Maheshwari, unpublished

Futier, et al. JAMA 2017 Randomized trial, n=292 high-risk patients Norepinephrine to keep systolic pressure ±10% Ephedrine for systolic pressure <80 mmHg Primary outcome Systemic inflammation and organ failure 56/147 versus 75/145 patients Relative risk 0.73 [95% CI: 0.56, 0.94], P=0.02 Considerations Actual difference in systolic pressure only 6 mmHg Most difference in kidney injury & mental status Only 1 myocardial infarction

Hold ACEIs and ARBs Roshanov, Anesthesiology 2017. Holding ACEIs and ARBs on the day of surgery reduced hypotension and the risk of a composite of death, MINS, or stroke by about 20%.

Tachycardia Hardly Matters Ruetzler, unpublished Abbott reports increased MINS & MI with heart rate >100 b/min; A&A 2017

High Risk on Surgical Wards Heart attacks occur postoperatively 94% within two days 50% of deaths during initial hospitalization Ward hypoxemia and hypotension Common, profound, and prolonged Cannot be reliably predicted

Blinded Saturation Over Time Sun, A&A 2015

Hypoxemic Episode Duration Nurses missed 90% of patients who had 1 continuous hour of saturation <90% 34

Continuous Ward Hypotension (n=265) Nurses missed 70% of patients with MAP <65 mmHg for 15 minutes Chang, unpublished

Postop Hypotension Matters Too Sessler Anesthesiology, in press Adjusted for baseline risk and hypotension in previous periods

Pain and MINS Adjusted for baseline risk, type and duration of surgery, etc. Turan, unpublished

ICU Hypotension & MINS Khanna, unpublished MINS/Mortality <90 mmHg ≥90 mmHg Hazard ratio (95% CI) (Per 10 mmHg difference) (versus 90 mmHg) Khanna, unpublished

ICU Hypotension & AKI

Summary Myocardial injury after non-cardiac surgery Monitor troponin Common, deadly, and mostly silent Monitor troponin Inpatients >45 years at risk, & all inpatients >65 years Preoperatively and first two postoperative days while hospitalized Risk stratification RCRI, NT-Pro-BNP, and preoperative troponin all help No known safe prophylaxis Keep intraoperative MAP >65mmHg; prevent postoperative hypotension Hold ACEIs and ARBs on the day of surgery

Department of OUTCOMES RESEARCH