Remote ischemic preconditioning for cardioprotection in elective inpatient abdominal surgery - a randomized controlled trial

Stefan Samad Antonowicz, Davina Cavallaro, Nicola Jacques, Abby Brown, Tom Wiggins, James B Haddow, Atul Kapila, Dominic Coull, Andrew Walden, Stefan Samad Antonowicz, Davina Cavallaro, Nicola Jacques, Abby Brown, Tom Wiggins, James B Haddow, Atul Kapila, Dominic Coull, Andrew Walden

Abstract

Background: Perioperative myocardial injury (PMI) is common in elective inpatient abdominal surgery and correlates with mortality risk. Simple measures for reducing PMI in this cohort are needed. This study evaluated whether remote ischemic preconditioning (RIPC) could reduce PMI in elective inpatient abdominal surgery.

Methods: This was a double-blind, sham-controlled trial with 1:1 parallel randomization. PMI was defined as any post-operative serum troponin T (hs-TNT) > 14 ng/L. Eighty-four participants were randomized to receiving RIPC (5 min of upper arm ischemia followed by 5 min reperfusion, for three cycles) or a sham-treatment immediately prior to surgery. The primary outcome was mean peak post-operative troponin in patients with PMI, and secondary outcomes included mean hs-TnT at individual timepoints, post-operative hs-TnT area under the curve (AUC), cardiovascular events and mortality. Predictors of PMI were also collected. Follow up was to 1 year.

Results: PMI was observed in 21% of participants. RIPC did not significantly influence the mean peak post-operative hs-TnT concentration in these patients (RIPC 25.65 ng/L [SD 9.33], sham-RIPC 23.91 [SD 13.2], mean difference 1.73 ng/L, 95% confidence interval - 9.7 to 13.1 ng/L, P = 0.753). The treatment did not influence any secondary outcome with the pre-determined definition of PMI. Redefining PMI as > 5 ng/L in line with recent data revealed a non-significant lower incidence in the RIPC cohort (68% vs 81%, P = 0.211), and significantly lower early hs-TnT release (12 h time-point, RIPC 5.5 ng/L [SD 5.5] vs sham 9.1 ng/L [SD 8.2], P = 0.03).

Conclusions: RIPC did not at reduce the incidence or severity of PMI in these general surgical patients using pre-determined definitions. PMI is nonetheless common and effective cardioprotective strategies are required.

Trial registration: This trial was registered with Clinicaltrials.gov, NCT01850927 , 5th July 2013.

Keywords: General surgery; Ischemic preconditioning; Myocardial injury.

Conflict of interest statement

Ethics approval and consent to participate

The Berkshire 2 National Research Ethics Service provided ethical approval for the study (Reference: 13/SC/0306). Written informed consent was obtained from each participant prior to any data collection or study intervention.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
CONSORT flowchart of participant allocation and progress
Fig. 2
Fig. 2
Mean post-operative high-sensitivity troponin T concentrations in the RIPC and sham-RIPC cohorts. a All patients included b Patients with PMI (any peak > 14 ng/L) c Patients with PMI (any peak > 5 ng/L). Error bars indicated standard deviation. *P < 0.05

References

    1. Devereaux PJ, Chan MT, Alonso-Coello P, Walsh M, Berwanger O, Villar JC, et al. The VISION study investigators. Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery. JAMA. 2012;307:2295–2304. doi: 10.1001/jama.2012.5502.
    1. Noordzij PG, Van Geffen O, Dijkstra IM, Boerma D, Meinders AJ, Rettig TCD, et al. High-sensitive cardiac troponin T measurements in prediction of non-cardiac complications after major abdominal surgery. Br J Anaesth. 2015;114:909–918. doi: 10.1093/bja/aev027.
    1. Devereaux PJ, Biccard BM, Sigamani A, Xavier D, Chan MTV, Srinathan SK, et al. Association of Postoperative High-Sensitivity Troponin Levels with Myocardial Injury and 30-day mortality among patients undergoing noncardiac surgery. JAMA. 2017;317:1642. doi: 10.1001/jama.2017.4360.
    1. Kristensen DS, Knuuti J, Saraste A, Anker S, Erik Bøtker H, De Hert S. 2014 ESC/ESA guidelines on non-cardiac surgery: cardiovascular assessment and management. Eur Heart J. 2014;35(35):2383–2431. doi: 10.1093/eurheartj/ehu285.
    1. Devereaux PJ, Mrkobrada M, Sessler DI, Leslie K, Alonso-Coello P, Kurz A, et al. Aspirin in patients undergoing noncardiac surgery. N Engl J Med. 2014;370:1494–1503. doi: 10.1056/NEJMoa1401105.
    1. Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, Villar JC, et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008;371:1839–1847. doi: 10.1016/S0140-6736(08)60601-7.
    1. Hindler K, Shaw AD, Samuels J, Fulton S, Collard CD, Riedel B. Improved postoperative outcomes associated with preoperative statin therapy. Anesthesiol. 2006;105:1260–1272. doi: 10.1097/00000542-200612000-00027.
    1. Dunkelgrun M, Boersma E, Schouten O, Koopman-van Gemert AWMM, van Poorten F, Bax JJ, et al. Bisoprolol and Fluvastatin for the reduction of perioperative cardiac mortality and myocardial infarction in intermediate-risk patients undergoing noncardiovascular surgery. Ann Surg. 2009;249:921–926. doi: 10.1097/SLA.0b013e3181a77d00.
    1. Kharbanda RK, Mortensen UM, White PA, Kristiansen SB, Schmidt MR, Hoschtitzky JA, et al. Transient limb ischemia induces remote ischemic preconditioning in vivo. Circ. 2002;106:2881–2883. doi: 10.1161/01.CIR.0000043806.51912.9B.
    1. Hausenloy DJ, Yellon DM. The therapeutic potential of ischemic conditioning: an update. Nat Rev Cardiol. 2011;8:619–629. doi: 10.1038/nrcardio.2011.85.
    1. Chen M, Zhang M, Zhang X, Li J, Wang Y, Fan Y, et al. Limb ischemic preconditioning protects endothelium from oxidative stress by enhancing Nrf2 translocation and upregulating expression of Antioxidases. PLoS One. 2015;10:e0128455. doi: 10.1371/journal.pone.0128455.
    1. Hussein AM, Harraz AM, Awadalla A, Barakat N, Khater S, Shokeir AA. Remote limb ischemic preconditioning (rIPC) activates antioxidant and antiapoptotic genes and inhibits proinflammatory cytokine genes in renal ischemia/reperfusion injury. Gen Physiol Biophys. 2016;35:77–86.
    1. Javadov SA, Clarke S, Das M, Griffiths EJ, Lim KHH, Halestrap AP. Ischaemic preconditioning inhibits opening of mitochondrial permeability transition pores in the reperfused rat heart. J Physiol. 2003;549(Pt 2):513–524. doi: 10.1113/jphysiol.2003.034231.
    1. Hausenloy DJ, Candilio L, Evans R, Ariti C, Jenkins DP, Kolvekar S, et al. Remote ischemic preconditioning and outcomes of cardiac surgery. N Engl J Med. 2015;373:1408–1417. doi: 10.1056/NEJMoa1413534.
    1. Meybohm P, Bein B, Brosteanu O, Cremer J, Gruenewald M, Stoppe C, et al. A multicenter trial of remote ischemic preconditioning for heart surgery. N Engl J Med. 2015;373:1397–1407. doi: 10.1056/NEJMoa1413579.
    1. Hausenloy DJ, Mwamure PK, Venugopal V, Harris J, Barnard M, Grundy E, et al. Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. Lancet. 2007;370:575–579. doi: 10.1016/S0140-6736(07)61296-3.
    1. Zarbock A, Schmidt C, Van Aken H, Wempe C, Martens S, Zahn PK, et al. Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery. JAMA. 2015;313:2133. doi: 10.1001/jama.2015.4189.
    1. Ali ZA, Callaghan CJ, Lim E, Ali AA, Nouraei SAR, Akthar AM, et al. Remote ischemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: a randomized controlled trial. Circ. 2007;116(11 SUPPL):I98–105.
    1. Rennie D. CONSORT revised--improving the reporting of randomized trials. JAMA. 2001;285:2006–2007. doi: 10.1001/jama.285.15.2006.
    1. Cleveland JC, Meldrum DR, Cain BS, Banerjee A, Harken AH. Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium. Circ. 1997;96:29–32. doi: 10.1161/01.CIR.96.1.29.
    1. Li F, Yuan Y. Meta-analysis of the cardioprotective effect of sevoflurane versus propofol during cardiac surgery. BMC Anesthesiol. 2015;15:128. doi: 10.1186/s12871-015-0107-8.
    1. Ansley DM, Raedschelders K, Choi PT, Wang B, Cook RC, Chen DDY. Propofol cardioprotection for on-pump aortocoronary bypass surgery in patients with type 2 diabetes mellitus (PRO-TECT II): a phase 2 randomized-controlled trial. Can J Anesth Can d’anesthésie. 2016;63:442–453. doi: 10.1007/s12630-015-0580-z.
    1. Kottenberg E, Thielmann M, Bergmann L, Heine T, Jakob H, Heusch G, et al. Protection by remote ischemic preconditioning during coronary artery bypass graft surgery with isoflurane but not propofol - a clinical trial. Acta Anaesthesiol Scand. 2012;56:30–38. doi: 10.1111/j.1399-6576.2011.02585.x.
    1. De Hert S, Vlasselaers D, Barbé R, Ory J-P, Dekegel D, Donnadonni R, et al. A comparison of volatile and non volatile agents for cardioprotection during on-pump coronary surgery. Anaesthesia. 2009;64:953–960. doi: 10.1111/j.1365-2044.2009.06008.x.
    1. Giannitsis E, Kurz K, Hallermayer K, Jarausch J, Jaffe AS, Katus HA. Analytical validation of a high-sensitivity cardiac troponin T assay. Clin Chem. 2010;56:254–261. doi: 10.1373/clinchem.2009.132654.
    1. Yang L, Wang G, Du Y, Ji B, Zheng Z. Remote ischemic preconditioning reduces cardiac troponin i release in cardiac surgery: a meta-analysis. J Cardiothorac Vasc Anesth. 2014;28:682–689. doi: 10.1053/j.jvca.2013.05.035.
    1. D’Ascenzo F, Cavallero E, Moretti C, Omedè P, Sciuto F, I a R, et al. Remote ischaemic preconditioning in coronary artery bypass surgery: a meta-analysis. Heart. 2012;98:1267–1271. doi: 10.1136/heartjnl-2011-301551.
    1. Kavsak PA, Walsh M, Srinathan S, Thorlacius L, Buse GL, Botto F, et al. High sensitivity troponin T concentrations in patients undergoing noncardiac surgery: a prospective cohort study. Clin Biochem. 2011;44:1021–1024. doi: 10.1016/j.clinbiochem.2011.05.017.
    1. Devereaux PJ. Characteristics and short-term prognosis of perioperative myocardial infarction in patients undergoing noncardiac surgery: a cohort study. Ann Intern Med. 2011;154:523–528. doi: 10.7326/0003-4819-154-8-201104190-00003.
    1. Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional ischemic “preconditioning” protects remote virgin myocardium from subsequent sustained coronary occlusion. Circ. 1993;87:893–899. doi: 10.1161/01.CIR.87.3.893.
    1. Thielmann M, Kottenberg E, Kleinbongard P, Wendt D, Gedik N, Pasa S, et al. Cardioprotective and prognostic effects of remote ischaemic preconditioning in patients undergoing coronary artery bypass surgery: a single-centre randomised, double-blind, controlled trial. Lancet. 2013;382:597–604. doi: 10.1016/S0140-6736(13)61450-6.
    1. Candilio L, Malik A, Ariti C, Barnard M, Di Salvo C, Lawrence D, et al. Effect of remote ischaemic preconditioning on clinical outcomes in patients undergoing cardiac bypass surgery: a randomised controlled clinical trial. Heart. 2015;101:185–192. doi: 10.1136/heartjnl-2014-306178.
    1. Brevoord D, Kranke P, Kuijpers M, Weber N, Hollmann M, Preckel B. Remote ischemic conditioning to protect against ischemia-reperfusion injury: a systematic review and meta-analysis. PLoS One. 2012;7:1–11. doi: 10.1371/journal.pone.0042179.
    1. Healy DA, Khan WA, Wong CS, Moloney MC, Grace PA, Coffey JC, et al. Remote preconditioning and major clinical complications following adult cardiovascular surgery: systematic review and meta-analysis. Int J Cardiol. 2014;176:20–31. doi: 10.1016/j.ijcard.2014.06.018.
    1. Bautin AE, Galagudza MM, Datsenko SV, Tashkhanov DM, Marichev AO, Bakanov AI, et al. Effects of remote ischemic preconditioning on perioperative period in elective aortic valve replacement. Anesteziol Reanimatol. 2014;(3):11–7. PMID 25306677.
    1. Heusch G, Gersh BJ. ERICCA and RIPHeart: two nails in the coffin for cardioprotection by remote ischemic conditioning? Probably not! Eur Heart J. 2016;37:200–202. doi: 10.1093/eurheartj/ehv606.
    1. Cheung CX, Healy DA, Walsh SR. Remote preconditioning and cardiac surgery: regrouping after remote ischemic preconditioning for heart surgery (RIPHeart) and effect of remote ischemic preconditioning on clinical outcomes in patients undergoing coronary artery bypass surgery (ERICCA) J Thorac Dis. 2016;8:E197–E199. doi: 10.21037/jtd.2016.01.81.
    1. Pearse RM, Moreno RP, Bauer P, Pelosi P, Metnitz P, Spies C, et al. Mortality after surgery in Europe: a 7 day cohort study. Lancet. 2012;380:1059–1065. doi: 10.1016/S0140-6736(12)61148-9.
    1. Devereaux PJ, Xavier D, Pogue J, Guyatt G, Sigamani A, Garutti I, et al. Characteristics and short-term prognosis of perioperative myocardial infarction in patients undergoing noncardiac surgerya cohort study. Ann Intern Med. 2011;154:523–528. doi: 10.7326/0003-4819-154-8-201104190-00003.
    1. Gorgun E, Lan BY, Aydinli HH, Reed GW, Menon V, Sessler DI, et al. Troponin elevation after colorectal surgery: significance and management. Ann Surg. 2016;264:605–611. doi: 10.1097/SLA.0000000000001854.
    1. Gupta PK, Gupta H, Sundaram A, Kaushik M, Fang X, Miller WJ, et al. Development and validation of a risk calculator for prediction of cardiac risk after surgery. Circ. 2011;124:381–387. doi: 10.1161/CIRCULATIONAHA.110.015701.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit