Clinical trial NCT02097186: Preconditioning Shields Against Vascular Events in Surgery
Official title: Preconditioning Shields Against Vascular Events in Surgery: A Multi-centre Feasibility Trial of Preconditioning Against Adverse Events in Major Vascular Surgery (Preconditioning-SAVES)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Abdominal Aortic Aneurysm
Carotid Atherosclerosis
Critical Lower Limb Ischaemia
Keywords: Vascular disease
Open aortic aneurysm repair
Endovascular aneurysm repair
Carotid endartrectomy
Lower limb surgical revascularisation
Major lower limb amputation
Lead sponsor: Mid Western Regional Hospital, Ireland
Sponsor class: OTHER
First posted: 2014-03-26
Enrollment: 400
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Major vascular surgery involves operations to repair swollen blood vessels, clear debris from blocked arteries or bypass blocked blood vessels. Patients with these problems are a high-risk surgical group as they have generalized blood vessel disease. These puts them at risk of major complications around the time of surgery such as heart attacks , strokes and death. The mortality following repair of a swollen main artery in the abdomen is about 1 in 20. This contrasts poorly with the 1 per 100 risk of death following a heart bypass. Simple and cost-effective methods are needed to reduce the risks of major vascular surgery. Remote ischaemic preconditioning (RIPC) may be such a technique. To induce RIPC, the blood supply to muscle in the patient's arm is interrupted for about 5 minutes. It is then restored for a further five minutes. This cycle is repeated three more times. The blood supply is interrupted simply by inflating a blood pressure cuff to maximum pressure. This repeated brief interruption of the muscular blood supply sends signals to critical organs such as the brain and heart, which are rendered temporarily resistant to damage from reduced blood supply. Several small randomized clinical trials in patients undergoing different types of major vascular surgery have demonstrated a potential benefit. This large, multi-centre trial aims to determine whether RIPC can reduce complications in routine practice.

Detailed description: The demand for major vascular surgery is increasing \[1\]. Patients requiring procedures such as aortic aneurysm repair, carotid endarterectomy, lower limb surgical re-vascularisation and major lower limb amputation for end-stage vascular disease constitute a high-risk surgical cohort. Peri-operative complications such as myocardial infarction, cerebrovascular accident, renal failure and death are common \[2,3\]. Multiple potential mechanisms may result in these complications. For example, myocardial injury may result from systemic hypotension leading to reduced flow across a tight coronary artery stenosis or, alternatively, it may arise due to acute occlusion when an unstable plaque ruptures. Most strategies aimed at peri-operative risk reduction target a single potential mechanism. For example, beta-blockade may prevent myocardial injury due to overwork, but cannot prevent acute coronary occlusion. There is a requirement for a simple, effective intervention that protects tissues against injury via multiple different mechanisms. Remote ischemic preconditioning (RIPC) may be suitable.

Ischemic preconditioning is a phenomenon whereby a brief period of non-lethal ischemia in a tissue renders it resistant to the effects of a subsequent much longer ischaemic insult. It was first described in the canine heart \[4\]. Subsequent clinical trials showed that ischemic preconditioning reduced heart muscle damage following coronary artery bypass grafting \[5\] and liver dysfunction following hepatic resection \[6\]. Following cardiac surgery, it is associated with a reduction in critical care stay, arrhythmias and inotrope use \[7\]. However, ischemic preconditioning requires direct interference with the target tissues' blood supply, limiting its clinical utility. Further experimental work suggested that brief ischemia in one tissue, such as the kidneys, could confer protection on distant organs such as the heart \[8\]. A similar effect was observed after transient skeletal muscle ischemia \[9-11\]. This effect is referred to as 'preconditioning at a distance' or 'remote ischemic preconditioning' (RIPC).

Eligibility criteria: Inclusion Criteria:

* Age greater than 18 years
* Patient willing to give full informed consent for participation
* Patients undergoing elective carotid endarterectomy or
* Patients undergoing open abdominal aortic aneurysm repair or
* Patients undergoing endovascular abdominal aneurysm repair or
* Patients undergoing surgical lower limb revascularisation (suprainguinal or infrainguinal)

Exclusion Criteria:

* Pregnancy
* Significant upper limb peripheral arterial disease
* Previous history of upper limb deep vein thrombosis
* Patients on glibenclamide or nicorandil (these medications may interfere with RIPC) Patients with an estimated pre-operative glomerular filtration rate \< 30mls/min/1.73m2
* Patients with a known history of myocarditis, pericarditis or amyloidosis
* Patients with an estimated pre-operative glomerular filtration rate \< 30mls/min/1.73m2.
* Patients with severe hepatic disease defined as an international normalised ratio \>2 in the absence of systemic anticoagulation
* Patients with severe respiratory disease (for the trial, defined as patients requiring home oxygen therapy)
* Patients previously enrolled in the trial representing for a further procedure
* Patients with previous axillary surgery

Primary outcomes:
measure: Serum troponin levels
timeFrame: 3 days
Secondary outcomes:
measure: Composite Major Adverse Clinical Events
timeFrame: 30 day
measure: Duration of post-operative hospital stay
timeFrame: 30 day
measure: Duration of intensive care unit stay
timeFrame: 30 day
measure: Unplanned critical care unit admission
timeFrame: 30 day
measure: Acute kidney injury score in first three peri-operative days
timeFrame: 3 days
measure: Post-operative complications
timeFrame: 30 day
measure: Mortality
timeFrame: 1 year
measure: Cardiac or cerebral event
timeFrame: 1 year
measure: Acute upper limb ischaemia
timeFrame: 24 hours post-operatively
measure: Acute upper limb deep vein thrombosis
timeFrame: 10 days
measure: Serial troponin I results
timeFrame: 3 days
Other outcomes:
measure: Acceptability of RIPC to patients
timeFrame: 6 weeks
measure: Acceptability and barriers to implementation among healthcare professionals.
timeFrame: 24 months
Locations:
city: Cork
country: Ireland
facility: Cork University Hospital
city: Dublin
country: Ireland
facility: Beaumont Hospital
city: Dublin
country: Ireland
facility: St James's Hospital
city: Galway
country: Ireland
facility: University Hospital Galway
city: Limerick
country: Ireland
facility: University Hospital Limerick (AKA MidWestern Regional Hospital)
city: Waterford
country: Ireland
facility: Waterford Regional Hospital
Study officials:
affiliation: Mid Western Regional Hospital and University of Limerick
name: Stewart R Walsh, Mch FRCS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Anderson PL, Gelijns A, Moskowitz A, Arons R, Gupta L, Weinberg A, Faries PL, Nowygrod R, Kent KC. Understanding trends in inpatient surgical volume: vascular interventions, 1980-2000. J Vasc Surg. 2004 Jun;39(6):1200-8. doi: 10.1016/j.jvs.2004.02.039.
citation: Chambers BR, Donnan GA. Carotid endarterectomy for asymptomatic carotid stenosis. Cochrane Database Syst Rev. 2005 Oct 19;2005(4):CD001923. doi: 10.1002/14651858.CD001923.pub2.
citation: 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 Sep 4-10;364(9437):843-8. doi: 10.1016/S0140-6736(04)16979-1.
citation: Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986 Nov;74(5):1124-36. doi: 10.1161/01.cir.74.5.1124.
citation: Jenkins DP, Pugsley WB, Alkhulaifi AM, Kemp M, Hooper J, Yellon DM. Ischaemic preconditioning reduces troponin T release in patients undergoing coronary artery bypass surgery. Heart. 1997 Apr;77(4):314-8. doi: 10.1136/hrt.77.4.314.
citation: Clavien PA, Selzner M, Rudiger HA, Graf R, Kadry Z, Rousson V, Jochum W. A prospective randomized study in 100 consecutive patients undergoing major liver resection with versus without ischemic preconditioning. Ann Surg. 2003 Dec;238(6):843-50; discussion 851-2. doi: 10.1097/01.sla.0000098620.27623.7d.
citation: 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 Nov;34(5):985-94. doi: 10.1016/j.ejcts.2008.07.062. Epub 2008 Sep 9.
citation: Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional ischemic 'preconditioning' protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation. 1993 Mar;87(3):893-9. doi: 10.1161/01.cir.87.3.893.
citation: 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 Sep 2;96(5):1641-6. doi: 10.1161/01.cir.96.5.1641.
citation: Kharbanda RK, Mortensen UM, White PA, Kristiansen SB, Schmidt MR, Hoschtitzky JA, Vogel M, Sorensen K, Redington AN, MacAllister R. Transient limb ischemia induces remote ischemic preconditioning in vivo. Circulation. 2002 Dec 3;106(23):2881-3. doi: 10.1161/01.cir.0000043806.51912.9b.
citation: Oxman T, Arad M, Klein R, Avazov N, Rabinowitz B. Limb ischemia preconditions the heart against reperfusion tachyarrhythmia. Am J Physiol. 1997 Oct;273(4):H1707-12. doi: 10.1152/ajpheart.1997.273.4.H1707.
citation: Healy D, Clarke-Moloney M, Gaughan B, O'Daly S, Hausenloy D, Sharif F, Newell J, O'Donnell M, Grace P, Forbes JF, Cullen W, Kavanagh E, Burke P, Cross S, Dowdall J, McMonagle M, Fulton G, Manning BJ, Kheirelseid EA, Leahy A, Moneley D, Naughton P, Boyle E, McHugh S, Madhaven P, O'Neill S, Martin Z, Courtney D, Tubassam M, Sultan S, McCartan D, Medani M, Walsh S. 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. Trials. 2015 Apr 23;16:185. doi: 10.1186/s13063-015-0678-1.