Remote Preconditioning and Vascular Surgery

Abstract

Remote ischemic preconditioning (RIPC) is a theoretically attractive strategy for organ protection; and phase 2 studies in a variety of settings have yielded promising results. In this article, we review the existing clinical studies on RIPC in vascular surgery. We examine aspects of design that may potentially be optimized in future vascular surgery studies and we highlight some challenges that have emerged since the publication of the Remote Ischaemic Preconditioning for Heart Surgery (RIPHeart) trial and the Effect of Remote Ischaemic Preconditioning on Clinical Outcomes in Patients Undergoing Coronary Artery Bypass Surgery (ERICCA) trial.

Introduction

Patients who are undergoing vascular surgery are a high-risk group because of expected high rates of perioperative complications, such as death, nonfatal myocardial infarction (MI), cerebrovascular accident, and acute kidney injury (AKI). ^{1 ∓3} Multiple risk-reduction strategies have been evaluated but the “silver bullet” for organ protection, if one exists, is evasive. Preoperative risk assessment and optimization is obviously attractive and certainly should be practiced, but there is little supporting hard evidence. ⁴ Prophylactic coronary revascularization often does not improve outcomes, ^{5 ∓8} and it is not recommended in order to exclusively reduce perioperative cardiac events. ⁹ Similarly, prophylactic β-blockade is recommended only for high-risk patients. ⁹ However, there is room for optimism because myocardial conditioning techniques offer sizeable organ protection in animals with induced injuries ¹⁰ and promising effects on surrogate markers for organ injury in human cardiovascular surgery. ¹¹ These factors have led to considerable interest in remote ischemic preconditioning (RIPC) as an organ protective tactic in vascular surgery patients, although progress toward clinical translation has been slow.

Clinical Trials on RIPC in Vascular Surgery

Several small trials evaluated RIPC in the settings of open abdominal aortic aneurysm (AAA) repair, endovascular aneurysm repair (EVAR), carotid endarterectomy, and lower limb surgical revascularization procedures (summarized in Table 1). Most of these exploratory trials yielded neutral results, ¹⁰ which are in contrast to the promising results from many small exploratory trials on RIPC in cardiac surgery. ¹¹ The earliest trial on open AAA repair (n = 82) used iliac artery cross-clamping as the stimulus and remarkably found reduced MI rates with RIPC as well as a significant reduction in cardiac troponin I levels and renal impairment. ¹² However, the subsequent trials failed to show convincing benefits with RIPC. A second AAA trial (n = 40) used an iliac cross-clamping stimulus and did not show a significant effect of RIPC on renal injury. ¹³ In this trial, 4 RIPC patients developed acute limb ischemia following iliac artery clamping, suggesting that there may be a safety concern with such a preconditioning protocol. Murphy et al ¹⁴ (n = 62) found no evidence for organ protection with RIPC in open AAA repair with no significant effect on troponin leakage, MI rates, or kidney injury. Li et al ¹⁵ (n = 62) found surrogate evidence for pulmonary and intestinal protection with RIPC following open AAA repair but no clinical benefits, and they did not evaluate cardiac biomarkers. A trial on carotid endarterectomy (n = 70) did not show neuroprotection or cardioprotection using surrogate markers, and there was no effect on clinical outcomes either. ¹⁶ A small study on EVAR (n = 40) ¹⁷ found surrogate evidence for renoprotection with RIPC but no effect on myocardial injury or clinical outcomes.

Table 1.

Trials on Remote Ischemic Preconditioning in Vascular Surgery.

Author	Participants	Preconditioning Stimulus	Blinding	Propofol Anesthesia	Outcomes	Results
Ali et al 12	82 patients who underwent open AAA repair	One 10-minute cycle on each leg by sequentially cross-clamping each common iliac artery	Patients and outcome assessors were blinded	Yes	Myocardial injury, MI, renal impairment, death	RIPC reduced myocardial injury, MIs, renal impairment
Walsh et al 13	40 patients who underwent open AAA repair	One 10-minute cycle on each leg by sequentially cross-clamping each common iliac artery	None	Yes	Biochemical measures of renal injury and function, major adverse cardiac events, death	No significant differences
Murphy et al 14	62 patients who underwent open AAA repair	Three 5-minute cycles of cuff-induced upper limb ischemia	Patients, anesthetists, surgeons, investigators were blinded	Yes	Renal injury, MI, myocardial injury, LOS, death	No significant differences
Li et al 15	62 patients who underwent open AAA repair	Three 5-minute cycles of cuff-induced upper limb ischemia	Patients, anesthetists, surgeons, outcome assessors were blinded	Yes	Biochemical measures of lung and intestinal injury, inflammatory markers, ventilator time, ICU- and hospital-free days, new arrhythmias, MI, CHF, neurologic events, dialysis use, upper limb ischemia	Lung and intestinal injury and inflammatory response were reduced with RIPC
Walsh et al 16	70 patients who underwent carotid endarterectomy	One 10-minute cycle on each leg sequentially by cuff inflation	None	Yes	Neurological injury assessed by saccadic latency, myocardial injury, major adverse cardiac events, death	No significant differences
Walsh et al 17	40 patients who underwent EVAR	One 10-minute cycle on each leg sequentially by cuff inflation	None	Yes	Biochemical measures of renal injury and function, myocardial injury, major adverse cardiac events, LOS, death	No significant differences
Healy et al 18	198 patients who underwent open AAA repair, EVAR, carotid endarterectomy, or surgical lower limb revascularization	Four 5-minute cycles of cuff-induced upper limb ischemia	None	Data on anesthesia drugs were not collected	Myocardial injury, a variety of clinical outcomes, renal injury, LOS, postoperative complications	No significant differences
Mouton et al 19	69 patients who underwent open AAA repair or EVAR	Three 5-minute cycles of cuff-induced upper limb ischemia	Anesthetists were unblinded; patients, surgeons and outcome assessors were blinded	No information on anesthetic drugs	Aspects of feasibility, renal injury, cardiac events, myocardial injury, death	No significant differences
Garcia et al 20	201 patients who underwent open AAA repair, EVAR, carotid endarterectomy, or lower limb bypass	Three 5-minute cycles of cuff-induced upper limb ischemia applied at 12 to 24 hours before surgery	Outcome assessors were unblinded; patients, surgeons, anesthetists were blinded	No information on anesthetic drugs	Myocardial injury, MI, renal impairment, readmission, stroke, death	No significant differences
Thomas et al 21	85 patients who underwent intra-abdominal aortic surgery, EVAR, or lower limb bypass	Two sessions of three 5-minute cycles of cuff-induced upper limb ischemia; first session at 24 hours before surgery and second session following anesthesia	Patients and medical teams were blinded but outcome assessors were unblinded	Yes	Myocardial injury, cardiac events, renal impairment, LOS, readmission, reinterventions, death	No significant differences

Abbreviations: AAA, abdominal aortic aneurysm; CHF, congestive heart failure; EVAR, endovascular aneurysm repair; ICU, intensive care unit; LOS, length of stay; MI, myocardial infarction; RIPC, remote ischemic preconditioning.

“All-Comers” Approach

We thought that limited sample size may have been a unifying theme in the above neutral studies and as a result we performed a multicenter exploratory pilot trial ¹⁸ (n = 198) involving patients undergoing a variety of major vascular procedures, thereby facilitating recruitment of a larger cohort than would have been possible if we focused on 1 type of procedure. The primary outcome was myocardial injury and we thought that our “all-comers” approach would efficiently test the hypothesis that RIPC can deliver cardioprotection given that there is a high incidence of troponin leakage in our selected population. ²² We also evaluated a composite clinical outcome, which included a range of important individual clinical outcomes, with a view toward accurate sample size estimation for subsequent studies that could be powered for clinical outcomes. Disappointingly, RIPC did not influence myocardial injury, renal injury, or clinical outcomes but, importantly, we demonstrated feasibility of our study design.

Three other clinical trials also used this “all-comers” approach. Mouton et al evaluated RIPC in patients (n = 69) who were undergoing either EVAR (n = 45) or open AAA repair (n = 24), and the principal focus was on multiple aspects of feasibility. ¹⁹ They also evaluated clinical outcomes and myocardial injury as secondary outcomes. This was the first trial to explicitly assess feasibility as the primary objective, and the report offers key insights for planning and design of larger trials. The trial did not demonstrate evidence for RIPC-induced protection. Garcia et al included 201 patients undergoing open AAA repair, EVAR, carotid endarterectomy, or lower limb bypass procedures and similarly found no surrogate evidence for organ protection and no influence of RIPC on clinical outcomes. ²⁰ Interestingly, they used a cuff-induced upper limb ischemia–reperfusion stimulus at 12 to 24 hours before procedures, thus aiming for the “second window” of protection and simultaneously enhancing the feasibility of blinding. Finally, Thomas et al performed a trial that included 85 patients who underwent intra-abdominal aortic surgery (aortic endarterectomy or open AAA repair), EVAR, or lower limb bypass procedures. They considered the neutral results from the preceding trials and used 2 RIPC applications ²¹ in order to theoretically overlap early and delayed protection. Nonetheless, a neutral result was observed in terms of myocardial injury and clinical outcomes. It is worth noting that 6 of the 10 trials mentioned above were blinded ^{12,14,15,19 ∓21} (Table 1).

Design of Future Studies

Undoubtedly, there is a sense of disappointment that proof of concept is still not established for RIPC in major vascular surgery, despite convincing surrogate evidence for protection in cardiac surgery. Perhaps, RIPC simply offers no additional protection to vascular patients because of advanced systemic atherosclerosis and the possibility that the body may precondition itself through limb claudication or angina. However, given the large global burden of vascular diseases, the high complication rates from interventions and the impressive magnitude of effect of RIPC in animal studies, RIPC nonetheless offers potential and we feel that there is an urgent need for further exploratory work.

Small sample sizes and heterogeneity in terms of procedures, patients, and outcomes may have contributed to the neutral results to date, but we think that future trials should also consider lessons from RIPHeart ²³ and ERICCA ²⁴ —7 of the 10 vascular trials outlined above reported the use of propofol anesthesia, ^{12 ∓17,21} (Table 1) and the remaining trials did not provide specific details on anesthetic drugs and included diverse procedures ^{18 ∓20} with varying risk profiles. In the context of RIPHeart and ERICCA, there is an argument in favor of standardized nonpropofol anesthesia and homogenous patient cohorts in future exploratory trials. Notwithstanding this, prior to the publication of the RIPHeart and ERICCA reports, we designed and commenced a further multicenter phase 2 trial involving different vascular procedures and nonstandardized anesthesia. ²⁵ The design of this trial was largely based upon our experiences in our pilot study outlined above. Recruitment is ongoing and we think it will be well-powered for the primary outcome of myocardial injury although there may be drawbacks regarding the “all-comers” design we chose. A large-scale trial powered for clinical outcomes is not justifiable at present in the context of vascular surgery given that the phase 2 trials to date have not demonstrated benefits with surrogate outcomes.

It may also be timely to consider the relationship between the magnitude of the injurious stimulus and the potential benefit of RIPC. Put simply, are we expecting too much from RIPC? Murry’s observations that intermittent ischemia protected against subsequent prolonged ischemic insults are well-known. Less attention is paid to his other observation that preconditioning had no impact if the subsequent ischemic time approached 6 hours, that is, if the insult is large enough, preconditioning protection is overwhelmed. Most of the large trials conducted to date have used patient populations (coronary artery bypass, valvular surgery, and aneurysm repair) where significant ischemia–reperfusion injury is unavoidable. Is the insult simply too large for RIPC to protect against? While our pilot trial ¹⁸ demonstrated no overall benefit, we did note that myocardial injury was halved by RIPC in the subgroup undergoing lower limb revascularization. These procedures for chronic lower limb ischemia involve a lesser physiological “hit” than aneurysm repairs. Clearly, no conclusions should be drawn from a post hoc subgroup observation, but the potential for RIPC to provide protection in certain vascular surgery subgroups needs to be evaluated further. In addition, vascular surgery patients are subject to other procedures (angioplasty, contrast-enhanced scans, etc) in which RIPC may have a role to play. Remote ischemic preconditioning may have a role in ameliorating contrast-induced AKI in these settings. ^26,27 Should the focus move to the potential benefit of the intervention in other settings such as protection against contrast-induced AKI, in which the injurious stimulus is less severe?

Sukkar et al recently published the results of an exhaustive review of ischemic conditioning. ²⁸ They evaluated the results of all published randomized trials of ischemic conditioning (pre-, peri-, and postconditioning) in all clinical settings. For the primary end point of death, they identified trials reporting data from over 11 000 patients with 424 reported deaths. Conditioning had no detectable effect on mortality (risk ratio: 0.96; 95% CI: 0.80-1.16). However, there were some indicators of potential benefit. The effect on MI was less clear, however, with the analysis of 714 events from 8451 participants in 32 trials yielding a risk ratio of 0.84 (95% CI: 0.69-1.03). Results of further ongoing trials may clarify the effect on MI. Moreover, the team did observe a potential benefit with respect to AKI (risk ratio: 0.83; 95% CI: 0.71-0.97), although the benefit was largely restricted to the lower grades of AKI. Wide variance in the definitions of AKI across trials make it difficult to draw conclusions from pooled data. The clinical relevance overall of an intervention that only appears to protect against lower levels of AKI may also be debated. Progressive renal dysfunction is an issue following vascular surgery interventions. ²⁹ Could RIPC ameliorate the initial injury and therefore improve the long-term renal outcomes? If so, it may be a clinically useful intervention.

Conclusion

There is an urgent need for additional effective strategies for organ protection in major vascular surgery, and RIPC holds much promise in this regard. The magnitude of effect of RIPC is surprisingly large in animal studies, and results from phase 2 studies in human cardiac surgery are convincing, although limited to surrogate biochemical outcomes. Clinical translation has been disappointingly slow, but we think that this should absolutely not discourage future research on this widely available, cheap, and practically risk-free intervention. RIPHeart and ERICCA should not be considered nails in the coffin of RIPC but rather as valuable lessons for the design of future studies. In the context of vascular surgery, we think that there is now a strong rationale for exploratory studies on homogenous cohorts of patients with standardized nonpropofol anesthesia. Remote ischemic preconditioning-induced protection cannot be absolute, and there may be subgroups of vascular procedures or patients that may be more likely to benefit. Identifying these may be the key to confirming proof of concept in vascular surgery.