Preconditioning Shields Against Vascular Events in Surgery (SAVES-F)

Preconditioning Shields Against Vascular Events in Surgery: A Multi-centre Feasibility Trial of Preconditioning Against Adverse Events in Major Vascular Surgery (Preconditioning-SAVES)

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.

Study Overview

• Status: Unknown
• Conditions: Carotid Atherosclerosis; Abdominal Aortic Aneurysm; Critical Lower Limb Ischaemia
• Intervention / Treatment: Procedure: Remote ischaemic preconditioning

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).

• Study Type: Interventional
• Enrollment (Anticipated): 400
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mary Clarke Moloney, PhD; Phone Number: 0035361482736; Email: mary.clarkemoloney@hse.ie

Study Locations

• Ireland
  • Cork, Ireland, 000
    • Not yet recruiting
    • Cork University Hospital
    • Contact: Greg Fulton; Email: greg.fulton@hse.ie
    • Principal Investigator: Greg Fulton
    • Sub-Investigator: Brian Manning
  • Dublin, Ireland, 000
    • Recruiting
    • Beaumont Hospital
    • Contact: Darragh Moneley; Phone Number: 0035301809 3092
    • Principal Investigator: Darragh Moneley
    • Sub-Investigator: Austin Leahy
  • Dublin, Ireland, 000
    • Recruiting
    • St James's Hospital
    • Contact: Prakash Madhavan; Email: pmadhavan@stjames.ie
    • Principal Investigator: Prakash Madhavan
    • Sub-Investigator: Zenia Martin
    • Sub-Investigator: Dermot Moore
    • Sub-Investigator: Sean O'Neill
  • Galway, Ireland, 00
    • Recruiting
    • University Hospital Galway
    • Contact: Stewart R Walsh; Email: STEWARTREDMOND.WALSH@nuigalway.ie
    • Principal Investigator: Stewart R Walsh
  • Limerick, Ireland, 000
    • Recruiting
    • University Hospital Limerick (AKA MidWestern Regional Hospital)
    • Contact: Mary Clarke Moloney, PhD; Phone Number: 0035361482736; Email: mary.clarkemoloney@hse.ie
    • Sub-Investigator: Mary Clarke Moloney, PhD.
    • Principal Investigator: Eamon Kavanagh
    • Sub-Investigator: Paul Burke
  • Waterford, Ireland, 000
    • Recruiting
    • Waterford Regional Hospital
    • Contact: Simon Cross
    • Principal Investigator: Simon Cross
    • Sub-Investigator: Joseph Dowdall

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Remote ischaemic preconditioning; Remote ischaemic preconditioning will be performed in the same manner as several previous trials. Immediately after induction of anaesthesia, a standard, CE-approved blood pressure cuff will be placed around one arm of the patient. It will then be inflated to a pressure of 200mmHg for 5 minutes. For patients with a systolic blood pressure >185mmHg, the cuff will be inflated to at least 15mmHg above the patient's systolic blood pressure. The cuff will then be deflated and the arm allowed reperfuse for 5 minutes. This will be repeated so that each patient receives a total of 4 ischaemia-reperfusion cycles. In all other respects, the procedure and peri-operative care will follow the routine practices of the surgeons and anaesthetists involved.	Procedure: Remote ischaemic preconditioning; Ischaemic preconditioning is a phenomenon whereby a brief period of non-lethal ischaemia in a tissue renders it resistant to the effects of a subsequent much longer ischaemic insult. Remote ischaemic preconditioning works on the theory that brief ischaemia in one tissue could confer protection on distant organs.; Other Names: RIPC
No Intervention: Control to remote preconditioning group; Patients randomised to this group will receive routine pre-operative, peri-operative and post operative care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum troponin levels	The trial is intended to pragmatically evaluate the potential of RIPC to improve clinical outcomes among patients undergoing major vascular surgery in routine clinical practice. For the pilot trial, a surrogate marker of efficacy will be used, namely serum troponin I levels. The primary efficacy outcome will be a comparison of the proportion of patients in each arm of the trial who develop a serum troponin level in excess of the upper limit of normal in the first three post-operative days.	3 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite Major Adverse Clinical Events	The primary endpoint for the trial will be Major Adverse Clinical Events. This is a composite endpoint comprising any of: cardiovascular death, myocardial infarction, new onset arrhythmia requiring treatment, cardiac arrest, congestive cardiac failure, cerebrovascular accident, renal failure requiring renal replacement therapy, mesenteric ischaemia requiring intervention or biopsy proven ischaemic colitis, urgent cardiac revascularisation. All participants will undergo a serum troponin levels and 12-lead electrocardiogram on the second post-operative day to screen for silent peri-operative myocardial infarction. Trial ECGs and troponin levels will be interpreted by a blinded trial cardiologist.	30 day
Duration of post-operative hospital stay	The duration of hospital stay and ITU stay have a major impact on health service resource utilisation, and are factors which can be influenced by surgery.	30 day
Duration of intensive care unit stay	The duration of hospital stay and ITU stay have a major impact on health service resource utilisation, and are factors which can be influenced by surgery.	30 day
Unplanned critical care unit admission	The duration of hospital stay and ITU stay have a major impact on health service resource utilisation, and are factors which can be influenced by surgery.	30 day
Acute kidney injury score in first three peri-operative days	The Acute Kidney Injury Score will be calculated over the first three peri-operative days. Creatinine will be measured daily as part of routine care. Urine volumes will be calculated from the fluid balance charts maintained as part of usual care.	3 days
Post-operative complications	Postoperative complications will be recorded and results from both groups compared.	30 day
Mortality	Death within one year of surgery will be determined by contacting the patient's general practitioner.	1 year
Cardiac or cerebral event	Major adverse cardiac or cerebral event (myocardial infarction, cardiac death, cerebrovascular accident) within 1 year of surgery will be determined by contacting the patient's general practitioner for details.	1 year
Acute upper limb ischaemia	Acute upper limb ischaemia - This is defined as the development of ischaemia in the arm used for the preconditioning stimulus requiring systemic anti-coagulation, radiological intervention or surgical intervention. The arm will be assessed at the end of surgery to identify if ischaemia is present.	24 hours post-operatively
Acute upper limb deep vein thrombosis	Acute upper limb deep vein thrombosis - This is defined as the development of thrombus within the subclavian, axillary or brachial vein, which may develop up to 10 days post procedure, confirmed in duplex ultrasound and in the same arm as used for the RIPC stimulus.	10 days
Serial troponin I results	A comparison of the area under the curve of serial troponin I	3 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acceptability of RIPC to patients	For patients, particularly those undergoing regional anaesthesia rather than general, the intervention may be burdensome and uncomfortable which may negatively impact upon likely adoption of this intervention into routine practice.In order to explore these potential issues, this feasibility trial will include a qualitative evaluation of acceptability to patients together with a qualitative evaluation of any perceived barriers to implementation. This evaluation will take the form of a semi-structured phone interview.	6 weeks
Acceptability and barriers to implementation among healthcare professionals.	Healthcare professionals at participating practices will be asked to complete a self-administered electronic questionnaire at the end of the study period. The questionnaire will elicit data on profession and practice details, their perceived experience of trial involvement, and open-ended questions to elicit information regarding attitudes to trial involvement, willingness to recruit participants, difficulties that arose during the trial and potential barriers to further research or routine clinical use of the trial intervention.	24 months

Collaborators and Investigators

• Sponsor: Mid Western Regional Hospital, Ireland
• Investigators: Principal Investigator: Stewart R Walsh, MCh FRCS, Mid Western Regional Hospital and University of Limerick

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (Anticipated): April 1, 2016
• Study Completion (Anticipated): August 1, 2017

Study Registration Dates

• First Submitted: March 24, 2014
• First Submitted That Met QC Criteria: March 25, 2014
• First Posted (Estimate): March 26, 2014

Study Record Updates

• Last Update Posted (Estimate): December 12, 2014
• Last Update Submitted That Met QC Criteria: December 11, 2014
• Last Verified: December 1, 2014

More Information

Terms related to this study

• Keywords: Endovascular aneurysm repair; Vascular disease; Major lower limb amputation; Open aortic aneurysm repair; Carotid endartrectomy; Lower limb surgical revascularisation
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Aortic Diseases; Ischemia; Carotid Artery Diseases; Atherosclerosis; Aneurysm; Aortic Aneurysm; Aortic Aneurysm, Abdominal
• Other Study ID Numbers: SAVES-F