Remote Ischemic Conditioning: New Adjunct for STEMI Care?

Large, multicenter trials are still in progress, but is RIPC ready for prime time now?

Its 11:00 p.m., and your hospital is alerted by a local EMS agency of a STEMI patient coming in. ETA is seven minutes and the cath lab has been activated. As soon as the patient comes in, you immediately go to the bedside of a 52-year-old male with crushing substernal chest pain. Your team of nurses and technicians quickly verify administration of aspirin, provide more nitroglycerin, bolus heparin, give additional analgesics and administer antiplatelet agents. The cath lab team is en route and will take the patient for primary percutaneous coronary intervention (pPCI). You and your team will make the first medical contact to device time of <90 minutes and give each other a collective “high five.” In the 25 minutes it takes to get the patient upstairs was there anything else that could have been done to improve the patient’s outcome? What if you must transfer the patient an additional 30 minutes or longer to a STEMI receiving center?

Why RIC Can Be Game-Changer
Despite prompt treatment with emergent pPCI, damage to the myocardium results both from the ischemic insult and due to reperfusion injury. Ischemic conditioning has been studied for more than 30 years to activate physiologic responses that mitigate damage during the ischemic insult and also as a result of reperfusion. Murray et al. first described the concept of ischemic preconditioning, showing that brief periods of ischemia and reperfusion preceding a 40 minute period of coronary artery occlusion led to a 75% reduction in ultimate myocardial infarct size [1]. While the mechanisms for ischemic conditioning are not fully understood, it is believed to release nitric oxide, inflammatory modulators, hypoxia inducible factor and mitochondrial mediators. These processes mitigate the effects of ischemia on tissues and block signals for apoptosis (programmed cell death) after an ischemic event among other effects. Think of this as activation of the body’s natural response to protect itself from ischemic events, which occurs through signals in both humoral and neurogenic pathways. In 2002, Kharbanda et al. demonstrated that a similar effect could be obtained when ischemic conditioning was performed by means of inflating and deflating a blood pressure cuff on a limb [2]. When ischemic conditioning is performed after an ischemic event has begun and before reperfusion, it is called remote peri-ischemic conditioning (RIPC).

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Previous Studies—Takeaways
Ischemic conditioning has been studied in a variety of conditions resulting in tissue ischemia and has demonstrated the greatest benefit in patients with STEMI who are receiving immediate coronary intervention [3]. These patients have a greater burden of ongoing ischemia and are at risk of reperfusion injury once the blocked blood vessel has been opened. RIPC has also been studied in conjunction with tPA for stroke and though it failed to show differences in penumbral or infarct size, when controlled for differences in patient perfusion RIPC demonstrated a reduction in risk of tissue infarction [4].

Other applications of RIPC have produced inconsistent results, most notably in coronary artery bypass grafting, abdominal aneurysm repair, carotid endarterectomy and elective PCI. RIPC did not demonstrate reductions in infarct size during these procedures, which are already maximized to mitigate the effects of temporary ischemia and may be limited by a ceiling effect with respect to reducing infarction of tissue.

The STEMI Connection
Four randomized controlled studies have shown improved outcomes in STEMI patients. The most impactful of these studies has been by the CONDI investigators, who evaluated the use of RIPC during ambulance transport to a STEMI receiving center for pPCI. Through the performance of four 5-minute cycles of limb ischemia and reperfusion, Botker et al. demonstrated a 12% increase in mean myocardial salvage index and improved left ventricular function in high-risk patients [5]. In a five-year follow-up study of the same patient cohort, Sloth et al. demonstrated a reduction in all-cause mortality (4.0% versus 12.0%, p=0.027) and major adverse cardiovascular events (13.5% versus 25.6%, p=0.018) [6]. Other randomized studies have demonstrated improvement in surrogate markers of myocardial infarct size, including increased ST-elevation resolution and reduced cardiac enzyme release [^7,8], and confirmed a decrease in myocardial infarct size on magnetic resonance imaging [^9]. Recent studies have aimed to evaluate additional clinical benefits of RIPC, including renal protection and reduced incidence of clinical heart failure [^10,11].

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Keys To Performing RIPC Correctly 
RIPC may be performed using only a manual blood pressure cuff and a timer. The cuff is inflated on a limb to 200 mmHg for five minutes, followed by a five-minute period of deflation repeated for four cycles. The entire procedure can be completed in under 25 minutes and performed in conjunction with other bedside interventions for STEMI. RIPC is a simple and inexpensive intervention that can be performed while preparing for or transporting to pPCI. In some patients, even a single cycle of RIPC may release sufficient mediators to be beneficial [^12]. Studies are currently underway to determine the optimal location, number of cycles, and timing of RIPC, which may differ between patients based on body habitus, history of diabetes, and other patient factors. The procedure is well tolerated by most patients and adverse effects have not been identified.

Is RIPC Ready for Prime Time?
While a large multicenter randomized controlled trial remains underway, the evidence thus far is compelling [^13]. We have implemented and demonstrated the feasibility of performing RIPC during interfacility air medical transfer of STEMI patients prior to pPCI [^14]. We have identified that the procedure produces only limited discomfort and can be performed without increasing bedside times or distraction from other medical interventions. Recent publication of our clinical data has shown renal protection and lower in-hospital mortality associated with the technique when used in interfacility helicopter transport or STEMI patients for STEMI [^11] as well as reduced incidence of clinical heart failure [^10]. Definitive evidence is still lacking, but this technique shows significant promise as a simple means to meaningfully impact morbidity and mortality in STEMI. RIPC awaits high quality confirmatory studies before it can be strongly endorsed. No adverse consequence of the use of the blood pressure cuff technique in this setting has been shown; therefore, systems may consider its use if they carefully monitor the effects of the intervention and avoid it becoming a distraction for the proven components of the STEMI bundle of care.

REFERENCES

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1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124-36.
2. Kharbanda RK, Mortensen UM, White PA, et al. Transient limb ischemia induces remote ischemic preconditioning in vivo. Circulation 2002;106:2881-3.
3. Frumkin K, Bloom AS. Ischemic Conditioning: Implications for Emergency Medicine. Ann Emerg Med 2016;68:268-74.
4. Hougaard KD, Hjort N, Zeidler D, et al. Remote ischemic perconditioning as an adjunct therapy to thrombolysis in patients with acute ischemic stroke: a randomized trial. Stroke 2014;45:159-67.
5. Botker HE, Kharbanda R, Schmidt MR, et al. 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 2010;375:727-34.
6. Sloth AD, Schmidt MR, Munk K, et al. Improved long-term clinical outcomes in patients with ST-elevation myocardial infarction undergoing remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention. Eur Heart J 2014;35:168-75.
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9. White SK, Frohlich GM, Sado DM, et al. Remote ischemic conditioning reduces myocardial infarct size and edema in patients with ST-segment elevation myocardial infarction. JACC Cardiovasc Interv 2015;8:178-88.
10. Ladejobi A, Wayne M, Martin-Gill C, et al. Association of remote ischemic peri-conditioning with reduced incidence of clinical heart failure after primary percutaneous coronary intervention. Cardiovasc Revasc Med 2016.
11. Olafiranye O, Ladejobi A, Wayne M, et al. Renal Protection Using Remote Ischemic Peri-Conditioning During Inter-Facility Helicopter Transport of Patients With ST-Segment Elevation Myocardial Infarction: A Retrospective Study. J Interv Cardiol 2016;29:603-11.
12. Zografos TA, Katritsis GD, Tsiafoutis I, Bourboulis N, Katsivas A, Katritsis DG. Effect of one-cycle remote ischemic preconditioning to reduce myocardial injury during percutaneous coronary intervention. Am J Cardiol 2014;113:2013-7.
13. Aarhus University Hospital. Effect of RIC on Clinical Outcomes in STEMI Patients Undergoing pPCI (CONDI2). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2016 Oct 25]. Available from: http://clinicaltrials.gov/show/NCT01857414.
14. Martin-Gill C, Wayne M, Guyette FX, Olafiranye O, Toma C. Feasibility of Remote Ischemic Peri-conditioning during Air Medical Transport of STEMI Patients. Prehosp Emerg Care 2016;20:82-9.