The current systematic review of remote ischemic perconditioning (RIPerC) in IS patients has revealed a noticeable number of trials registered in clinicaltrials.gov, especially in the last three years. Globally, a broad heterogeneity is observed among RCTs regarding the number of recruited patients, inclusion criteria, number of RIPerC applied cycles, location of the application, and the main endpoints. Despite the high heterogeneity of current studies, they would all contribute to improve RIPerC effects and mechanisms of action.
The first published evidence of RIPerC in IS patients was limited to patients underwent intravenous alteplase therapy (rt-PA)(21) . According to new advances in stroke, five new studies have been focused on patients treated with endovascular therapy. However, preclinical data have demonstrated that RIC during acute ischemia is effective when applied both alone and in combination with revascularization therapies (24). For that, results of the largest RCTs (REMOTE-CAT, SERIC AIS, RESIST(14) and RICAMIS), which include IS patients regardless of the acute applied treatment, would be of enormous interest.
A drawback of applying RIC manually in Hougaard et al. study(21) was that only one out of three patients fully complete the cycles. Therefore, 14 out of 17 new trials use automatic devices. Another important issue is the number of cycles and the place of application. Most RIC trials in Cardiology (25, 26) and the first trials in IS used the four-cycle protocol, probably due to literature tradition. Preconditioning was first demonstrated in a dog model of myocardial ischemia using a four-cycle protocol (27). Afterwards, both RIC before ischemia (28) and RIC during ischemia were first documented using the same protocol (29). The neutral clinical results of Hougaard et al.(21) and Pico et al. (20) trials arise the need to increase the RIC stimulus and repetitions. Recent studies in preclinical models also addressed it to optimize the efficacy and duration of RIPerC (30). In a rat model of cerebral ischemia, Ren et al. reported that repeated remote post-conditioning during 14 days after reperfusion significantly decrease the volume of infarction by acting again reperfusion injury (31). There are some successful experiences in chronic postconditioning among intracranial stenosis patients (32) and in patients with cerebral small-vessel disease (33) using five-cycle protocol. REMOTE-CAT and RESIST trials proposed a five-cycle protocol. RIPerC and postconditioning combined during 4 to 7 days is included in one arm of RESIST trial(14), ReCAST-2 (17), REPOST(16) and SERIC-AIS trial. Although, the quantity of muscle mass affects the efficacy of the intervention (34), only one study proposed RIC application in a leg (20). It has been described that one in four IS patients has silent peripheral arterial disease (35), for that it has suggested that the upper arm would be the best location because of safety reasons. One and two-limb conditioning were equally protective according to preclinical models (30). Transfer of the cerebral protective stimulus is not well understood (36), sensory signal is crucial for the remote signaling to the brain (37), for that tourniquet should be performed in the non-affected arm.
A prehospital administration of RIC in the ambulance transportation of IS patients was first proposed by Hougard et al.(21) and it is established in REMOTE-CAT and RESIST(14) trials due to lack of RIC effect by time (38). An increased proportion of patients with transient symptoms in the intervention group was observed in the Hougard et al. (21) trial, nonetheless, only the Face Arm Speech Test was used. It was not clear whether it was a RIC’s effect or there was a bias in the selection. Now, both trials (REMOTE-CAT and RESIST(14)) have a pre-hospital screening performed by RACE and PreSS scores, respectively. Patients should be properly balanced using prehospital stroke scores.
Although RIC has been reported to improve the clinical evolution of myocardial infarction patients and reduce the final lesion size (25, 39), a recent large RCT with more than 5000 patients reported no effects on clinical outcomes (40). But we would anticipate that RIC effects in IS patients might be different. Cerebral and heart ischemia have their own particularities (41). IS has a variety of pathogenic mechanisms not present in heart ischemia. The rupture or erosion of vulnerable plaques in coronary arteries are the common cause of heart ischemia (42), while the embolism from arterial or heart sources is the main cause of IS (43).
Implications for future research
Currently, there a few on-going randomized clinical trials that will provide valuable information on RIPerC in ischemic stroke patients. However, future studies should carefully examine patient recruitment, RIPerC application settings, proper outcome measurements and neuroimaging follow-up protocols. All these optimization and efforts will improve the current knowledge and address new medical strategies and management of stroke patients.
According to the RESCUE BRAIN study(20), the application of RIC during/after partial or complete reperfusion was futile, and it did not reduce the consequences of reperfusion injury. So, RIC might be applied differently than in this study. In this line, preclinical data and results from pilot studies showed that RIC should be applied as soon as possible, preferable during the patient transportation to a Hospital (prehospital setting, ambulance) to avoid the penumbral tissue recruitment, and extend the time window for the application of reperfusion therapies. In this context, an early triage and stratification of the patients using prehospital scales are essential, and it will also help in the randomization process of the clinical trials (REMOTE-CAT (NCT03375762) and RESIST(14). The accuracy of prehospital scales is fundamental to identify or confirm a possible early prehospital treatment effect, like it was suspected in previous studies(21).. For that, the initial use of prehospital scales is a strong recommendation along RIPerC application in a prehospital setting and/or as soon as symptoms are detected.
Automatic devices should be used to ensure completion of cycles and to document the treatment compliance. Another reason for the futile results of RESCUE BRAIN(20) study and the study of Hougaard et al. (21) would be that the 4x5 cycles of RIPerC stimulus was not sufficient. To overcome this issue, the increase up to five cycles and/or the stimulus repetition twice daily for the first 5 or 7 days would be an option. In the other hand, another strategy would be to improve selection of included patients.
Although the underlying mechanisms of RIC are still not fully known, some recent preclinical studies have showed an enhancement of collateral circulation(44, 45). Collateral status correlates with stroke severity and reperfusion outcomes, due to their ability to restrict the growth of penumbral territory(46). For that, the role of collaterals is essential in large vessel occlusion (LVO) patients, those are also candidates to receive mechanical thrombectomy(47, 48) in the admitted hospital, or candidates to transfer into a Comprehensive Stroke center. So, LVO patients would be a group of special interest on RIC effects.
Recently published data highlight that RIC is safe and feasible(17-21), similarly to RCTs involving patients with myocardial infarction(25). For that, the main outcomes of the ongoing and future RCTs on RIPerC have high clinical interest. According to stroke treatment academic industry roundtable (STAIR) recommendations(49), the 24-hour NIHSS, 7-day mRS and the 90-day mRS should be considered to be the standard clinical endpoints in acute stroke trials. Follow-up infarct volume on brain imaging is also useful, based on preclinical data that reported an effect of RIC on final brain infarction volume when it was used alone or in combination with alteplase(24). It is also recommended by STAIR(49) and The Stroke Imaging Research (STIR) group(47). This imaging strategy has the advantage that requires small sample sizes. Concretely, it is estimated that sample sizes based on lesion volumes should be about one fourth of those based on mRS(50).