Preconditioning Shields Against Vascular Events in Surgery (SAVES), a multicentre feasibility trial of preconditioning against adverse events in major vascular surgery: study protocol for a randomised control trial

Donagh Healy, Mary Clarke-Moloney, Brendan Gaughan, Siobhan O'Daly, Derek Hausenloy, Faisal Sharif, John Newell, Martin O'Donnell, Pierce Grace, John F Forbes, Walter Cullen, Eamon Kavanagh, Paul Burke, Simon Cross, Joseph Dowdall, Morgan McMonagle, Greg Fulton, Brian J Manning, Elrasheid A H Kheirelseid, Austin Leahy, Daragh Moneley, Peter Naughton, Emily Boyle, Seamus McHugh, Prakash Madhaven, Sean O'Neill, Zenia Martin, Donal Courtney, Muhammed Tubassam, Sherif Sultan, Damian McCartan, Mekki Medani, Stewart Walsh, Donagh Healy, Mary Clarke-Moloney, Brendan Gaughan, Siobhan O'Daly, Derek Hausenloy, Faisal Sharif, John Newell, Martin O'Donnell, Pierce Grace, John F Forbes, Walter Cullen, Eamon Kavanagh, Paul Burke, Simon Cross, Joseph Dowdall, Morgan McMonagle, Greg Fulton, Brian J Manning, Elrasheid A H Kheirelseid, Austin Leahy, Daragh Moneley, Peter Naughton, Emily Boyle, Seamus McHugh, Prakash Madhaven, Sean O'Neill, Zenia Martin, Donal Courtney, Muhammed Tubassam, Sherif Sultan, Damian McCartan, Mekki Medani, Stewart Walsh

Abstract

Background: Patients undergoing vascular surgery procedures constitute a 'high-risk' group. Fatal and disabling perioperative complications are common. Complications arise via multiple aetiological pathways. This mechanistic redundancy limits techniques to reduce complications that target individual mechanisms, for example, anti-platelet agents. Remote ischaemic preconditioning (RIPC) induces a protective phenotype in at-risk tissue, conferring protection against ischaemia-reperfusion injury regardless of the trigger. RIPC is induced by repeated periods of upper limb ischaemia-reperfusion produced using a blood pressure cuff. RIPC confers some protection against cardiac and renal injury during major vascular surgery in proof-of-concept trials. Similar trials suggest benefit during cardiac surgery. Several uncertainties remain in advance of a full-scale trial to evaluate clinical efficacy. We propose a feasibility trial to fully evaluate arm-induced RIPC's ability to confer protection in major vascular surgery, assess the incidence of a proposed composite primary efficacy endpoint and evaluate the intervention's acceptability to patients and staff.

Methods/design: Four hundred major vascular surgery patients in five Irish vascular centres will be randomised (stratified for centre and procedure) to undergo RIPC or not immediately before surgery. RIPC will be induced using a blood pressure cuff with four cycles of 5 minutes of ischaemia followed by 5 minutes of reperfusion immediately before the start of operations. There is no sham intervention. Participants will undergo serum troponin measurements pre-operatively and 1, 2, and 3 days post-operatively. Participants will undergo 12-lead electrocardiograms pre-operatively and on the second post-operative day. Predefined complications within one year of surgery will be recorded. Patient and staff experiences will be explored using qualitative techniques. The primary outcome measure is the proportion of patients who develop elevated serum troponin levels in the first 3 days post-operatively. Secondary outcome measures include length of hospital and critical care stay, unplanned critical care admissions, death, myocardial infarction, stroke, mesenteric ischaemia and need for renal replacement therapy (within 30 days of surgery).

Discussion: RIPC is novel intervention with the potential to significantly improve perioperative outcomes. This trial will provide the first evaluation of RIPC's ability to reduce adverse clinical events following major vascular surgery.

Trial registration: www.clinicaltrials.gov NCT02097186 Date Registered: 24 March 2014.

Figures

Figure 1
Figure 1
Participant flow through the trial. AAA – abdominal aortic aneurysm; CEA – carotid endarterectomy; ECG –electrocardiography; EVAR – endovascular abdominal aneurysm repair; PIL – patient information leaflet; RIPC – remote ischaemic preconditioning.

References

    1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124–36. doi: 10.1161/01.CIR.74.5.1124.
    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;370:575–9. doi: 10.1016/S0140-6736(07)61296-3.
    1. Clavien PA, Selzner M, Rudiger HA, Graf R, Kadry Z, Rousson V, et al. A prospective randomized study in 100 consecutive patients undergoing major liver resection with versus without ischemic preconditioning. Ann Surg. 2003;238:843–50. doi: 10.1097/01.sla.0000098620.27623.7d.
    1. Walsh SR, Tang TY, Kullar P, Jenkins DP, Dutka DP, Gaunt ME. Ischaemic preconditioning during cardiac surgery: systematic review and meta-analysis of perioperative outcomes in randomised clinical trials. Eur J Cardiothorac Surg. 2008;34:985–94. doi: 10.1016/j.ejcts.2008.07.062.
    1. Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional ischemic ‘preconditioning‘ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation. 1993;87:893–9. doi: 10.1161/01.CIR.87.3.893.
    1. Birnbaum Y, Hale SL, Kloner RA. 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. 1997;96:1641–6. doi: 10.1161/01.CIR.96.5.1641.
    1. Chambers BR, Donnan GA. Carotid endarterectomy for asymptomatic carotid stenosis. Cochrane Database Syst Rev. 2005;4
    1. Greenhalgh RM, Brown LC, Kwong GP, Powell JT, Thompson SG, EVAR trial participants Comparison of endovascular aneurysm repair with open repair in patients with abdominal aortic aneurysm (EVAR trial 1), 30-day operative mortality results: randomised controlled trial. Lancet. 2004;364:843–8. doi: 10.1016/S0140-6736(04)16979-1.
    1. Ali ZA, Callaghan CJ, Lim E, Ali AA, Nouraei SA, Akthar AM, et al. Remote ischemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: a randomized controlled trial. Circulation. 2007;116(11 Suppl):I98–105.
    1. Walsh SR, Sadat U, Boyle JR, Tang TY, Lapsley M, Norden AG, et al. Remote ischemic preconditioning for renal protection during elective open infrarenal abdominal aortic aneurysm repair: randomized controlled trial. Vasc Endovascular Surg. 2010;44:334–40. doi: 10.1177/1538574410370788.
    1. Walsh SR, Boyle JR, Tang TY, Sadat U, Cooper DG, Lapsley M, et al. Remote ischemic preconditioning for renal and cardiac protection during endovascular aneurysm repair: a randomized controlled trial. J Endovasc Ther. 2009;16:680–9. doi: 10.1583/09-2817.1.
    1. Walsh SR, Nouraei SA, Tang TY, Sadat U, Carpenter RH, Gaunt ME. Remote ischemic preconditioning for cerebral and cardiac protection during carotid endarterectomy: results from a pilot randomized clinical trial. Vasc Endovascular Surg. 2010;44:434–9. doi: 10.1177/1538574410369709.
    1. Li C, Li YS, Xu M, Wen SH, Yao X, Wu Y, et al. Limb remote ischemic preconditioning for intestinal and pulmonary protection during elective open infrarenal abdominal aortic aneurysm repair: a randomized controlled trial. Anesthesiology. 2013;118:842–52. doi: 10.1097/ALN.0b013e3182850da5.
    1. Rahman IA, Mascaro JG, Steeds RP, Frenneaux MP, Nightingale P, Gosling P, et al. Remote ischemic preconditioning in human coronary artery bypass surgery: from promise to disappointment? Circulation. 2010;122(11 Suppl):S53–9. doi: 10.1161/CIRCULATIONAHA.109.926667.
    1. Takagi H, Umemoto T. Remote ischemic preconditioning for cardiovascular surgery: an updated meta-analysis of randomized trials. Vasc Endovascular Surg. 2011;45:511–3. doi: 10.1177/1538574410379654.
    1. Healy DA, Carroll PJ, Clarke Moloney M, Tang TY, Grace PA, Kiernan TJ, 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. Healy DA, Clarke-Moloney M, McHugh SM, Grace PA, Walsh SR. Remote ischaemic preconditioning as a method for perioperative cardioprotection: Concepts, applications and future directions. Int J Surg. 2014;12:1093–9. doi: 10.1016/j.ijsu.2014.08.352.
    1. Devereaux PJ, Goldman L, Cook DJ, Gilbert K, Leslie K, Guyatt GH. Perioperative cardiac events in patients undergoing noncardiac surgery: a review of the magnitude of the problem, the pathophysiology of the events and methods to estimate and communicate risk. CMAJ. 2005;173:627–34. doi: 10.1503/cmaj.050011.
    1. Heusch G. Cardioprotection: chances and challenges of its translation to the clinic. Lancet. 2013;381:166–75. doi: 10.1016/S0140-6736(12)60916-7.
    1. POISE Study Group, Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K,et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008;371:1839–47.
    1. McFalls EO, Ward HB, Moritz TE, Goldman S, Krupski WC, Littooy F, et al. Coronary-artery revascularization before elective major vascular surgery. N Engl J Med. 2004;351:2795–804. doi: 10.1056/NEJMoa041905.
    1. Garcia S, Moritz TE, Goldman S, Littooy F, Pierpont G, Larsen GC, et al. Perioperative complications after vascular surgery are predicted by the revised cardiac risk index but are not reduced in high-risk subsets with preoperative revascularization. Circ Cardiovasc Qual Outcomes. 2009;2:73–7. doi: 10.1161/CIRCOUTCOMES.108.827683.
    1. Poldermans D, Schouten O, Vidakovic R, Bax JJ, Thomson IR, Hoeks SE, et al. A clinical randomized trial to evaluate the safety of a noninvasive approach in high-risk patients undergoing major vascular surgery: the DECREASE-V Pilot Study. J Am Coll Cardiol. 2007;49:1763–9. doi: 10.1016/j.jacc.2006.11.052.
    1. Schouten O, van Kuijk JP, Flu WJ, Winkel TA, Welten GM, Boersma E, et al. Long-term outcome of prophylactic coronary revascularization in cardiac high-risk patients undergoing major vascular surgery (from the randomized DECREASE-V Pilot Study) Am J Cardiol. 2009;103:897–901. doi: 10.1016/j.amjcard.2008.12.018.
    1. Fleisher LA, Beckman JA, Brown KA, Calkins H, Chaikof E, Fleischmann KE, et al. American College of Cardiology/American Heart Association Task Force on Practice, G. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery) Anesth Analg. 2008;106:685–712. doi: 10.1213/01/ane.0000309024.28586.70.
    1. Leung MK, Irwin MG. Perioperative cardioprotection. F1000Prime Rep. 2013;5:7.
    1. Hausenloy DJ, Candilio L, Laing C, Kunst G, Pepper J, Kolvekar S, et al. Effect of remote ischemic preconditioning on clinical outcomes in patients undergoing coronary artery bypass graft surgery (ERICCA): rationale and study design of a multi-centre randomized double-blinded controlled clinical trial. Clin Res Cardiol. 2012;101:339–48. doi: 10.1007/s00392-011-0397-x.
    1. Garcia S, Marston N, Sandoval Y, Pierpont G, Adabag S, Brenes J, et al. Prognostic value of 12-lead electrocardiogram and peak troponin I level after vascular surgery. J Vasc Surg. 2013;57:166–72. doi: 10.1016/j.jvs.2012.06.084.
    1. Baio G. Bayesian methods in health economics. Boca Raton, FL: Chapman Hall/CRC Press; 2012.
    1. Jackson CH, Thompson SG, Sharples LD. Accounting for uncertainty in health economic decision models by using model averaging. J R Stat Soc Ser A Stat Soc. 2009;172:383–404. doi: 10.1111/j.1467-985X.2008.00573.x.
    1. Braun V, Clarke V. Using thematic analysis in psychology. Qual Res Psychol. 2006;3:77–101. doi: 10.1191/1478088706qp063oa.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅