A pilot study investigating the effects of remote ischemic preconditioning in high-risk cardiac surgery using a randomised controlled double-blind protocol

  • Paul Jeffrey YoungEmail author
  • Paul Dalley
  • Alexander Garden
  • Christopher Horrocks
  • Anne La Flamme
  • Barry Mahon
  • John Miller
  • Janine Pilcher
  • Mark Weatherall
  • Jenni Williams
  • William Young
  • Richard Beasley
Original Contribution


The efficacy of remote ischemic preconditioning (RIPC) in high-risk cardiac surgery is uncertain. In this study, 96 adults undergoing high-risk cardiac surgery were randomised to RIPC (3 cycles of 5 min of upper-limb ischemia induced by inflating a blood pressure cuff to 200 mmHg with 5 min of reperfusion) or control. Main endpoints were plasma high-sensitivity troponin T (hsTNT) levels at 6 and 12 h, worst post-operative acute kidney injury (AKI) based on RIFLE criteria, and noradrenaline duration. hsTNT levels were log-normally distributed and higher with RIPC than control at 6-h post cross-clamp removal [810 ng/ml (IQR 527–1,724) vs. 634 ng/ml (429–1,012); ratio of means 1.41 (99.17% CI 0.92–2.17); P=0.04] and 12 h [742 ng/ml (IQR 427–1,700) vs. 514 ng/ml (IQR 356–833); ratio of means 1.56 (99.17% CI 0.97–2.53); P=0.01]. After adjustment for baseline confounders, the ratio of means of hsTNT at 6 h was 1.23 (99.17% CI 0.88–1.72; P=0.10) and at 12 h was 1.30 (99.17% CI 0.92–1.84; P=0.05). In the RIPC group, 35/48 (72.9%) had no AKI, 5/48 (10.4%) had AKI risk, and 8/48 (16.7%) had either renal injury or failure compared to the control group where 34/48 (70.8%) had no AKI, 7/48 (14.6%) had AKI risk, and 7/48 (14.6%) had renal injury or failure (Chi-squared 0.41; two degrees of freedom; P = 0.82). RIPC increased post-operative duration of noradrenaline support [21 h (IQR 7–45) vs. 9 h (IQR 3–19); ratio of means 1.70 (99.17% CI 0.86–3.34); P=0.04]. RIPC does not reduce hsTNT, AKI, or ICU-support requirements in high-risk cardiac surgery.


Cardioprotection Cardiac surgery Remote ischemic preconditioning Reperfusion 



This study was funded by unrestricted grants from the New Zealand Lotteries Commission and the National Heart Foundation of New Zealand.

Conflicts of interest


Supplementary material

395_2012_256_MOESM1_ESM.doc (100 kb)
Electronic supplementary material (DOC 100 kb)


  1. 1.
    Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P (2004) Acute renal failure: definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 8:R204–R212. doi: 10.1186/cc2872 PubMedCrossRefGoogle Scholar
  2. 2.
    Birnbaum Y, Hale SL, Kloner RA (1997) Ischemic preconditioning at a distance: reduction of myocardial infarct size by partial reduction of blood supply combined with rapid stimulation of the gastrocnemius muscle in the rabbit. Circulation 96:1641–1646. doi: 10.1161/01.CIR.96.5.1641 PubMedGoogle Scholar
  3. 3.
    Botker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sorensen HT, Redington AN, Nielsen TT (2010) Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet 375:727–734. doi: 10.1016/S0140-6736(09)62001-8 PubMedCrossRefGoogle Scholar
  4. 4.
    Breivik L, Helgeland E, Aarnes EK, Mrdalj J, Jonassen AK (2011) Remote postconditioning by humoral factors in effluent from ischemic preconditioned rat hearts is mediated via PI3 K/Akt-dependent cell-survival signaling at reperfusion. Basic Res Cardiol 106:135–145. doi: 10.1007/s00395-010-0133-0 PubMedCrossRefGoogle Scholar
  5. 5.
    Cheung MM, Kharbanda RK, Konstantinov IE, Shimizu M, Frndova H, Li J, Holtby HM, Cox PN, Smallhorn JF, Van Arsdell GS, Redington AN (2006) Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans. J Am Coll Cardiol 47:2277–2282. doi: 10.1016/j.jacc.2006.01.066 PubMedCrossRefGoogle Scholar
  6. 6.
    Choi YS, Shim JK, Kim JC, Kang KS, Seo YH, Ahn KR, Kwak YL (2011) Effect of remote ischemic preconditioning on renal dysfunction after complex valvular heart surgery: a randomized controlled trial. J Thorac Cardiovasc Surg 142:148–154. doi: 10.1016/j.jtcvs.2010.11.018 PubMedCrossRefGoogle Scholar
  7. 7.
    Fellahi JL, Hanouz JL, Gue X, Monier E, Guillou L, Riou B (2008) Kinetic analysis of cardiac troponin I release is no more accurate than a single 24-h measurement in predicting in-hospital outcome after cardiac surgery. Eur J Anaesthesiol 25:490–497. doi: 10.1017/S0265021508003827 PubMedCrossRefGoogle Scholar
  8. 8.
    Gho BC, Schoemaker RG, van den Doel MA, Duncker DJ, Verdouw PD (1996) Myocardial protection by brief ischemia in noncardiac tissue. Circulation 94:2193–2200PubMedGoogle Scholar
  9. 9.
    Gunaydin B, Cakici I, Soncul H, Kalaycioglu S, Cevik C, Sancak B, Kanzik I, Karadenizli Y (2000) Does remote organ ischaemia trigger cardiac preconditioning during coronary artery surgery? Pharmacol Res 41:493–496. doi: 10.1006/phrs.1999.0611 PubMedCrossRefGoogle Scholar
  10. 10.
    Hanouz JL, Yvon A, Massetti M, Lepage O, Babatasi G, Khayat A, Bricard H, Gerard JL (2002) Mechanisms of desflurane-induced preconditioning in isolated human right atria in vitro. Anesthesiology 97:33–41PubMedCrossRefGoogle Scholar
  11. 11.
    Hausenloy DJ, Baxter G, Bell R, Botker HE, Davidson SM, Downey J, Heusch G, Kitakaze M, Lecour S, Mentzer R, Mocanu MM, Ovize M, Schulz R, Shannon R, Walker M, Walkinshaw G, Yellon DM (2010) Translating novel strategies for cardioprotection: the Hatter workshop recommendations. Basic Res Cardiol 105:677–686. doi: 10.1007/s00395-010-0121-4 PubMedCrossRefGoogle Scholar
  12. 12.
    Hausenloy DJ, Mwamure PK, Venugopal V, Harris J, Barnard M, Grundy E, Ashley E, Vichare S, Di Salvo C, Kolvekar S, Hayward M, Keogh B, MacAllister RJ, Yellon DM (2007) Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. Lancet 370:575–579. doi: 10.1016/S0140-6736(07)61296-3 PubMedCrossRefGoogle Scholar
  13. 13.
    Heusch G, Musiolik J, Kottenberg E, Peters J, Jakob H, Thielmann M (2012) STAT5 activation and cardioprotection by remote ischemic preconditioning in humans. Circ Res 110:111–115. doi: 10.1161/CIRCRESAHA.111.259556 PubMedCrossRefGoogle Scholar
  14. 14.
    Hong DM, Mint JJ, Kim JH, Sohn IS, Lim TW, Lim YJ, Bahk JH, Jeon Y (2010) The effect of remote ischaemic preconditioning on myocardial injury in patients undergoing off-pump coronary artery bypass graft surgery. Anaesth Intensive Care 38:924–929PubMedGoogle Scholar
  15. 15.
    Hu ZY, Liu J (2009) Mechanism of cardiac preconditioning with volatile anaesthetics. Anaesth Intensive Care 37:532–538PubMedGoogle Scholar
  16. 16.
    Karuppasamy P, Chaubey S, Dew T, Musto R, Sherwood R, Desai J, John L, Shah AM, Marber MS, Kunst G (2011) Remote intermittent ischemia before coronary artery bypass graft surgery: a strategy to reduce injury and inflammation? Basic Res Cardiol 106:511–519. doi: 10.1007/s00395-011-0185-9 PubMedCrossRefGoogle Scholar
  17. 17.
    Kottenberg E, Thielmann M, Bergmann L, Heine T, Jakob H, Heusch G, Peters J (2012) Protection by remote ischemic preconditioning during coronary artery bypass graft surgery with isoflurane but not propofol: a clinical trial. Acta Anaesthesiol Scand 56:30–38. doi: 10.1111/j.1399-6576.2011.02585.x PubMedCrossRefGoogle Scholar
  18. 18.
    Lange M, Redel A, Smul TM, Lotz C, Nefzger T, Stumpner J, Blomeyer C, Gao F, Roewer N, Kehl F (2009) Desflurane-induced preconditioning has a threshold that is lowered by repetitive application and is mediated by beta 2-adrenergic receptors. J Cardiothorac Vasc Anesth 23:607–613. doi: 10.1053/j.jvca.2009.01.016 PubMedCrossRefGoogle Scholar
  19. 19.
    Lange M, Smul TM, Blomeyer CA, Redel A, Klotz KN, Roewer N, Kehl F (2006) Role of the beta1-adrenergic pathway in anesthetic and ischemic preconditioning against myocardial infarction in the rabbit heart in vivo. Anesthesiology 105:503–510PubMedCrossRefGoogle Scholar
  20. 20.
    Li L, Luo W, Huang L, Zhang W, Gao Y, Jiang H, Zhang C, Long L, Chen S (2010) Remote perconditioning reduces myocardial injury in adult valve replacement: a randomized controlled trial. J Surg Res 164:e21–e26. doi: 10.1016/j.jss.2010.06.016 PubMedCrossRefGoogle Scholar
  21. 21.
    Lim SY, Yellon DM, Hausenloy DJ (2010) The neural and humoral pathways in remote limb ischemic preconditioning. Basic Res Cardiol 105:651–655. doi: 10.1007/s00395-010-0099-y PubMedCrossRefGoogle Scholar
  22. 22.
    Liu Y, Sato T, O’Rourke B, Marban E (1998) Mitochondrial ATP-dependent potassium channels: novel effectors of cardioprotection? Circulation 97:2463–2469. doi: 10.1161/01.CIR.97.24.2463 PubMedGoogle Scholar
  23. 23.
    Nashef SA, Roques F, Michel P, Gauducheau E, Lemeshow S, Salamon R (1999) European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg 16:9–13. doi: 10.1016/S1010-7940(99)00134-7 PubMedCrossRefGoogle Scholar
  24. 24.
    Nesher N, Alghamdi AA, Singh SK, Sever JY, Christakis GT, Goldman BS, Cohen GN, Moussa F, Fremes SE (2008) Troponin after cardiac surgery: a predictor or a phenomenon? Ann Thorac Surg 85:1348–1354. doi: 10.1016/j.athoracsur.2007.12.077 PubMedCrossRefGoogle Scholar
  25. 25.
    Oxman T, Arad M, Klein R, Avazov N, Rabinowitz B (1997) Limb ischemia preconditions the heart against reperfusion tachyarrhythmia. Am J Physiol 273:H1707–H1712PubMedGoogle Scholar
  26. 26.
    Peters J (2011) Remote ischaemic preconditioning of the heart: remote questions, remote importance, or remote preconditions? Basic Res Cardiol 106:507–509. doi: 10.1007/s00395-011-0187-7 PubMedCrossRefGoogle Scholar
  27. 27.
    Rahman IA, Mascaro JG, Steeds RP, Frenneaux MP, Nightingale P, Gosling P, Townsend P, Townend JN, Green D, Bonser RS (2010) Remote ischemic preconditioning in human coronary artery bypass surgery: from promise to disappointment? Circulation 122:S53–S59. doi: 10.1161/circulationaha.109.926667 PubMedCrossRefGoogle Scholar
  28. 28.
    Schultz JE, Hsu AK, Gross GJ (1996) Morphine mimics the cardioprotective effect of ischemic preconditioning via a glibenclamide-sensitive mechanism in the rat heart. Circ Res 78:1100–1104PubMedGoogle Scholar
  29. 29.
    Longacre LS, Kloner RA, Arai AE, Baines CP, Bolli R, Braunwald E, Downey J, Gibbons RJ, Gottlieb RA, Heusch G, Jennings RB, Lefer DJ, Mentzer RM, Murphy E, Ovize M, Ping P, Przyklenk K, Sack MN, Vander Heide RS, Vinten-Johansen J, Yellon DM (2011) New horizons in cardioprotection: recommendations from the 2010 National Heart, Lung, and Blood Institute Workshop. Circulation 124:1172–1179. doi: 10.1161/CIRCULATIONAHA.111.032698 CrossRefGoogle Scholar
  30. 30.
    Siami S, Bailly-Salin J, Polito A, Porcher R, Blanchard A, Haymann JP, Laborde K, Maxime V, Boucly C, Carlier R, Annane D, Sharshar T (2010) Osmoregulation of vasopressin secretion is altered in the postacute phase of septic shock. Crit Care Med 38:1962–1969. doi: 10.1097/CCM.0b013e3181eb9acf PubMedGoogle Scholar
  31. 31.
    Thielmann M, Kottenberg E, Boengler K, Raffelsieper C, Neuhaeuser M, Peters J, Jakob H, Heusch G (2010) Remote ischemic preconditioning reduces myocardial injury after coronary artery bypass surgery with crystalloid cardioplegic arrest. Basic Res Cardiol 105:657–664. doi: 10.1007/s00395-010-0104-5 PubMedCrossRefGoogle Scholar
  32. 32.
    Venugopal V, Hausenloy DJ, Ludman A, Di Salvo C, Kolvekar S, Yap J, Lawrence D, Bognolo J, Yellon DM (2009) Remote ischaemic preconditioning reduces myocardial injury in patients undergoing cardiac surgery with cold-blood cardioplegia: a randomised controlled trial. Heart 95:1567–1571. doi: 10.1136/hrt.2008.155770 PubMedCrossRefGoogle Scholar
  33. 33.
    Venugopal V, Laing CM, Ludman A, Yellon DM, Hausenloy D (2010) Effect of remote ischemic preconditioning on acute kidney injury in nondiabetic patients undergoing coronary artery bypass graft surgery: a secondary analysis of 2 small randomized trials. Am J Kidney Dis 56:1043–1049. doi: 10.1053/j.ajkd.2010.07.014 PubMedCrossRefGoogle Scholar
  34. 34.
    Vermes E, Mesguich M, Houel R, Soustelle C, Le Besnerais P, Hillion ML, Loisance D (2000) Cardiac troponin I release after open heart surgery: a marker of myocardial protection? Ann Thorac Surg 70:2087–2090PubMedCrossRefGoogle Scholar
  35. 35.
    Wagner R, Piler P, Bedanova H, Adamek P, Grodecka L, Freiberger T (2010) Myocardial injury is decreased by late remote ischaemic preconditioning and aggravated by tramadol in patients undergoing cardiac surgery: a randomised controlled trial. Interact Cardiovasc Thorac Surg 11:758–762. doi: 10.1510/icvts.2010.243600 PubMedCrossRefGoogle Scholar
  36. 36.
    Xie JJ, Liao XL, Chen WG, Huang DD, Chang FJ, Chen W, Luo ZL, Wang ZP, Ou JS (2011) Remote ischaemic preconditioning reduces myocardial injury in patients undergoing heart valve surgery: randomised controlled trial. Heart. doi: 10.1136/heartjnl-2011-300860 Google Scholar
  37. 37.
    Zimmerman RF, Ezeanuna PU, Kane JC, Cleland CD, Kempananjappa TJ, Lucas FL, Kramer RS (2011) Ischemic preconditioning at a remote site prevents acute kidney injury in patients following cardiac surgery. Kidney Int 80:861–867. doi: 10.1038/ki.2011.156 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Paul Jeffrey Young
    • 1
    • 2
    Email author
  • Paul Dalley
    • 1
  • Alexander Garden
    • 1
    • 3
  • Christopher Horrocks
    • 1
  • Anne La Flamme
    • 3
  • Barry Mahon
    • 1
  • John Miller
    • 3
  • Janine Pilcher
    • 2
  • Mark Weatherall
    • 2
    • 4
  • Jenni Williams
    • 3
  • William Young
    • 1
  • Richard Beasley
    • 1
    • 2
  1. 1.Wellington Hospital, Capital and Coast District Health BoardWellingtonNew Zealand
  2. 2.Medical Research Institute of New ZealandWellingtonNew Zealand
  3. 3.School of Biological SciencesVictoria University of WellingtonWellingtonNew Zealand
  4. 4.University of Otago, WellingtonWellingtonNew Zealand

Personalised recommendations