The application of RIC in the setting of acute stroke is based on pre-clinical models which indicate that RIC can improve penumbral salvage and neurological outcomes [20, 21]. This has been postulated to occur through several mechanisms including increased cerebral blood flow [11], maintenance of dynamic cerebral autoregulation [22], promoting blood–brain barrier integrity [23] and reducing cerebral oedema [24].

Twelve RCTs have looked exclusively at the administration of RIC in the setting of acute ischaemic stroke [25,26,27,28,29,30,31,32,33,34,35,36]. The characteristics and main results of these studies are summarised in Table 3. It is important to note that there are significant methodological differences between the studies in their study populations, RIC protocols, timing of intervention, duration of intervention and outcome measures (clinical, biochemical and radiological). Given this variation, it is difficult to draw any definitive conclusions about the efficacy of RIC.

Hougaard et al. first demonstrated the safety and feasibility of delivering in stroke patients with a proof-of-concept open label study of pre-hospital, unilateral, non-paretic arm RIC in individuals suspected of having acute stroke [25]. Whilst there was no significant effect of a 4 × 5 min cycles of RIC on the MRI endpoints of penumbral salvage, infarct growth or final infarct size, in a voxel-based logistic regression analysis, RIC was associated with reduced tissue risk of infarction [25]. RESCUE BRAIN, a relatively large multi-centre study of RIC in acute ischaemic stroke, demonstrated that there was no significant difference in the percentage change in MRI infarct volume at 24 h with RIC compared to standard medical therapy [26]. Furthermore, RIC was not associated with any improvement in NIHSS at 24 h or mRS at 90 days. This is in contrast with smaller studies from Li et al. (2018) (n = 68) and An et al. (2020) (n = 68) which demonstrated that RIC was associated with improvements in mRS at Day 90 [27, 28]. Importantly, in these latter studies, RIC was repeated daily for up to 14 days rather than a single treatment. It is therefore possible that repeated cycles of RIC may be of greater benefit than a single treatment in the setting of acute ischaemic stroke.

The studies of RIC in acute ischaemic stroke have investigated several blood-borne factors which may explain the mechanism of RIC and/or be candidate biomarkers for monitoring the effect of RIC on an individual level. The RECAST trial demonstrated increased levels of Heat Shock Protein 27 (HSP-27) following RIC [29]. Heat shock protein 27 has been shown to protect against ischaemic injury in pre-clinical models of cardiovascular disease [37]. There is evidence that RIC either reduces or attenuates the rise of S100β in ischaemic stroke [28, 29]. S100β usually rises following ischaemic stroke; this may be proportionate to the magnitude of infarction and associated with blood–brain barrier permeability [38, 39]. As such, reductions in S100β following RIC may signify improvements in blood–brain barrier integrity and reduced neuronal damage. Finally, the rises in vascular endothelial growth factor (VEGF) suggest that RIC may potentially increase angiogenesis in the post-stroke period which, in turn, may impact on post-stroke recovery [28, 29].

The RICAMIS trial is the largest randomised control trial of RIC in ischaemic stroke with 1776 patients recruited. It utilised an intensive protocol of 5 × 5 min cycles of bilateral upper limb RIC at 200 mmHg, twice a day for 2 weeks [35]. The results showed significant improvement in neurological function demonstrated by a higher proportion of individuals with an mRS score of 0–1 at 90 days when treated with RIC compared to patients receiving standard therapy (582 (67.4%) in the RIC group and 566 (62.0%) in the control group; odds ratio, 1.27 [95% CI, 1.05–1.54]; P = 0.02). This result supports the hypothesis that repeated cycles have a more prominent neuroprotective effect as seen in earlier trials [27]. The secondary outcome of the RICAMIS trial showed no significant improvement in neurological function in the short term; the study posited that RIC had a more neurorestorative effect over a long period of time rather than a more immediate neuroprotective effect on penumbral tissue [27]. This was supported by multiple RCTs showing no significant immediate improvement in neurological function and radiological measures of ischaemic stroke [26, 27, 33, 40]. However, a recent trial conducted by Wang et al. provided contradictory evidence; the results show a statistically significant improvement in NIHSS and mRS score at 8 days after starting RIC when compared to control and baseline data [36]. Trial participants underwent 5 cycles of 5 min of bilateral upper limb ischaemic conditioning at 180 mmHg once a day for 7 days. The protocol used was relatively aligned with previous studies, with the exception of a less frequently used reperfusion time of 3 min. The influence of this variation cannot be inferred from current data. Larger trials are needed to determine the impact of each parameter and therefore the most optimal protocol for RIC in the management of acute ischaemic stroke.

Post hoc analyses were conducted on RICAMIS data [41,42,43]. The first analysis examined the effect of patient sex on RIC efficacy. For the primary outcome (mRS scores of 0–1 within 90 days), RIC yielded an adjusted OR of 1.379 [95% CI 1.045–1.820] in men and 1.628 [95% CI 1.134–2.339] in women [41]. Secondary outcomes showed no sex differences. Whilst RIC improved functional outcomes in both sexes, females saw a notably greater improvement in primary outcomes. The second analysis looked at the relationship between onset to treatment time (OTT) and RIC outcomes [42]. Of the 863 patients in the RIC group, 387 received RIC within 24 h of symptom onset (early RIC group) and 476 received RIC after 24 h. The early RIC group had 70.0% of its patients achieve mRS scores of 0–1 at 90 days, whilst the late RIC group achieved 65.3% and the control group 62.0%. The early RIC group significantly outperformed the control, whereas the late RIC group did not. The secondary outcome of proportion of patients having mRS scores of 0–2 mirrored the primary results, but there were no significant differences in other secondary outcomes among the three groups. These findings align with prior studies emphasising the benefits of early RIC introduction [24, 28, 29]. The third analysis looked at the impact of diabetes and raised fasting blood glucose (FBG) on RIC’s therapeutic effect [43]. A larger proportion of non-diabetic patients achieved better functional outcomes (mRS 0–1) with RIC than diabetic patients (7.3% vs. 5.5%). Similar trends were observed concerning FBG. Earlier trials have indicated that diabetes and hyperglycemia diminish RIC’s cardioprotective effects [44]. This study revealed a similar impact on RIC's neuroprotective effect.

Three trials have explored the efficacy of RIC as adjunct therapy to thrombolysis in the management of acute ischaemic stroke [28, 30, 34]. Animal models have shown that a combination of IV thrombolysis and RIC can significantly reduce infarct volume and improve neurological outcome [45, 46]. The first clinical trial conducted by Che et al. (2018) showed that combination therapy significantly improved neurological outcomes at 30 days when compared to tPA only [30]. However, no significant difference was seen between both groups at 90 days, this is due to the small nature of the study and all participants scoring less than 15 on NIHSS at baseline and therefore have good prognosis over 3 months, thus making it difficult to ascertain the efficacy of RIC as most patients show significant or full recovery with thrombolysis alone. The results showed that combination therapy accelerated recovery as a significant improvement can be seen at 30 days when compared to control but similar results at 90 days. Larger trials with more severe NIHSS-scoring patients are needed to assess the impact of RIC in combination with thrombolysis. An et al. (2020) conducted the second trial exploring the effectiveness of tPA with RIC, this trial recruited 68 patients scoring less than 25 on NIHSS [28]. The results show marked improvement in the mRS score at 90 days and also showed significantly lower s100b and higher VEGF when compared to baseline and control at discharge. Biomarker results suggest that the combination of RIC and tPA confers a neuroprotective effect on the central nervous system. The final trial conducted by He et al. (2022) showed that RIC administered 2 to 3 h after thrombolysis causes significant improvement in NIHSS and Glasgow Outcome Score (GOS) at follow-up 6 months after treatment, with no significant increase in adverse events [34]. Whilst the exact mechanism of RIC is still being explored, preclinical studies have suggested that RIC complements thrombolysis treatment as it confers local central nervous system (CNS) resistance to reperfusion injury by prolonging local activation of the Akt pathway [45,46,47]. Activation of the Akt pathway has been shown to significantly reduce infarct volume by upregulating nitric oxide, therefore promoting endovascular homeostasis [46, 47].

Whilst animal studies provide sufficient evidence to the efficacy of RIC in the management of ischaemic stroke, more robust clinical trials are needed to identify optimal RIC parameters in the management of acute ischaemic stroke in patients. Current data suggest RIC is a safe and effective measure that can be used in conjunction with established treatments to significantly improve neurological outcomes and prognosis. Further qualitative studies on the experience of applying RIC in time-critical situations such as delivery of thrombolysis and mechanical thrombectomy will be an important guide to the practical aspects of therapy delivery in clinical practice.

There are two distinct paradigms for the application of RIC to subacute and chronic stroke. The first is centred around using repeated cycles of RIC to induce protective effects against future vascular events. The second concerns the potential for RIC to improve functional recovery in both subacute and chronic stroke.

The majority of studies investigating the utility of RIC in the prevention of recurrent stroke involve repeated, daily cycles of RIC in populations with symptomatic intracranial stenosis [48,49,50,51,52]. This was first demonstrated by Meng et al. who randomised 103 individuals with symptomatic intracranial stenosis to either twice daily, bilateral upper limb RIC for 300 days or usual medical therapy. The proportion of individuals who developed recurrent stroke at 300 days was 7.9% in the RIC group compared to 26.7% in the control group. Furthermore, there were no major, treatment-related adverse events. Similarly, daily RIC for 180 days in individuals aged 80–95 with symptomatic intracranial stenosis was associated with a lower frequency of recurrent stroke and TIA compared to sham RIC [48].

Pre-clinical studies have identified several mechanisms by which chronic RIC may mitigate the impact of vascular events [53]. These include improved mitochondrial function [13, 14], reduced platelet activity [54, 55], increased angiogenesis and cerebral blood flow [11, 45], improved endothelial function and reduced oxidative stress and systemic inflammation [56,57,58]. Some of these mechanisms have been substantiated in clinical studies of RIC. With regard to cerebral blood flow, RIC has been associated with increased cerebral perfusion on SPECT, reductions in peak systolic blood flow velocity at sites of stenosis on transcranial Doppler [48] and increases in mean blood flow velocity in the major intracranial vessels [51]. Increases in VEGF seen 10 days after RIC indicate that the improvements in cerebral blood flow may be driven by increased collateral circulation [50]. Meng et al. demonstrated that RIC was associated with an increase in plasma levels of tissue plasminogen activator and reductions in fibrinogen and plasminogen activator inhibitor-1 (PAI-1) indicating that repeated cycles of RIC may alter the balance between thrombosis and haemostasis towards a reduction in ischaemia [49]. Whilst there is some evidence that RIC may improve brachial artery flow mediated dilatation (FMD), a marker of endothelial function, in individuals with chronic stroke [59], the ERICS trial did not demonstrate any improvements in FMD after 12 weeks of RIC in patients with recent ischaemic stroke [40].

Meng et al. also demonstrated that RIC may accelerate neurological recovery from stroke [49]. After 180 days of bilateral upper limb RIC in individuals aged 80–95 with symptomatic intracranial stenosis, the average NIHSS and mRS scores in the RIC-treated group were 2.97 ± 1.97 and 1.4 ± 1.0, respectively, which were both significantly lower than the control group values of 4.82 ± 2.72 and 2.3 ± 1.1 (all p < 0.01). Consistent with this, Xu et al. found that 6 months of RIC in symptomatic intracranial stenosis, in addition to reducing risk of new infarcts, was also associated with a higher likelihood of improvement in function compared to sham (as measured by the New Injury Severity Score and Barthel Index) [51]. In this study, RIC was associated with increased cerebral blood flow velocity, reduced MMP-9 and increased BDNF suggesting that improved cerebral perfusion, blood–brain barrier integrity and neurogenesis may underlie the effect of long-term RIC in neurological recovery after stroke. It is important, however, to note that the improvement in neurological function may relate to spontaneous recovery after stroke and the reduction in risk of further infarction rather than necessarily being due to direct effects on neurological recovery.

The RICA trial conducted by Hou et al. is the largest RIC trial in neurology. It randomised 3033 patients with symptomatic intracranial atherosclerotic stenosis [