What will it take to change 'may' to will improve?
You mean these earlier pieces of research were not enough to write up a protocol on this?
Leg wraps raise hopes of saved lives after strokes May 2013
Leg compressions may enhance stroke recovery August 2012
Remote Ischemic Conditioning May Improve Disability and Cognition After Acute Ischemic Stroke: A Pilot Randomized Clinical Trial
Alina Poalelungi
Delia Tulbă
Elena Turiac5, 
Bogdan Ovidiu Popescu- 1Department of Neurology, Emergency Clinical Hospital, Bucharest, Romania
- 2Department of Clinical Neurosciences, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- 3Department of Neurology, Colentina Clinical Hospital, Bucharest, Romania
- 4Colentina–Research and Development Center, Colentina Clinical Hospital, Bucharest, Romania
- 5Department of Radiology, Emergency Clinical Hospital, Bucharest, Romania
- 6Laboratory of Cell Biology, Neurosciences and Experimental Myology, “Victor Babeş” National Institute of Pathology, Bucharest, Romania
Background and Aim: Remote ischemic conditioning is a procedure purported to reduce the ischemic injury of an organ. This study aimed to explore the efficiency and safety of remote ischemic conditioning in patients with acute ischemic stroke. We hypothesized that remote ischemic conditioning administered from the first day of hospital admission would improve the infarct volume and clinical outcome at 180 days.
Material and Methods: We performed a unicentric double-blind randomized controlled trial. We included all patients consecutively admitted to an Emergency Neurology Department with acute ischemic stroke, ineligible for reperfusion treatment, up to 24 hours from onset. All subjects were assigned to receive secondary stroke prevention treatment along with remote ischemic conditioning on the non-paretic upper limb during the first 5 days of hospitalization, twice daily - a blood pressure cuff placed around the arm was inflated to 20 mmHg above the systolic blood pressure (up to 180 mmHg) in the experimental group and 30 mmHg in the sham group. The primary outcome was the difference in infarct volume (measured on brain CT scan) at 180 days compared to baseline, whereas the secondary outcomes included differences in clinical scores (NIHSS, mRS, IADL, ADL) and cognitive/mood changes (MoCA, PHQ-9) at 180 days compared to baseline.
Results: We enrolled 40 patients; the mean age was 65 years and 60% were men. Subjects in the interventional group had slightly better recovery in terms of disability, as demonstrated by the differences in disability scores between admission and 6 months (e.g., the median difference score for Barthel was −10 in the sham group and −17.5 in the interventional group, for ADL −2 in the sham group and −2.5 in the interventional group), as well as cognitive performance (the median difference score for MoCA was −2 in the sham group and −3 in the interventional group), but none of these differences reached statistical significance. The severity of symptoms (median difference score for NIHSS = 5 for both groups) and depression rate (median difference score for PHQ-9 = 0 for both groups) were similar in the two groups. The median difference between baseline infarct volume and final infarct volume at 6 months was slightly larger in the sham group compared to the interventional group (p = 0.4), probably due to an initial larger infarct volume in the former.
Conclusion: Our results suggest that remote ischemic conditioning might improve disability and cognition. The difference between baseline infarct volume and final infarct volume at 180 days was slightly larger in the sham group.
Introduction
Stroke is one of the leading causes of mortality and morbidity worldwide, with significant global burden and costs (1). It is the first cause of disability and the second cause of cognitive decline (2). Nevertheless, the only approved treatment for acute ischemic stroke (AIS) (which accounts for 87% of all strokes) (1) is reperfusion therapy (intravenous thrombolysis with alteplase and/or mechanical thrombectomy) (3). Unfortunately, in Romania the treatment of AIS remains extremely limited, mainly because patients do not recognize stroke symptoms/signs and arrive late to the hospital, therefore missing the reperfusion therapeutic window. In these cases, there is a great need for neuroprotective interventions in order to improve the outcome of AIS.
Over the last 20 years, many neuroprotective agents and interventions have been studied. Remote ischemic conditioning (RIC) is a new area of interest in stroke and neuroprotection (4). It is a potential non-invasive intervention meant to induce transient and brief periods of ischemia remote from the ischemic injury site. In AIS, single or repeated cycles of transient limb(s) ischemia followed by reperfusion are employed, usually with a blood pressure cuff inflated to a level above the systolic blood pressure for a few minutes, followed by deflation. This stems from the hypothesis that RIC could prevent cerebral damage after AIS by preventing/reducing the ischemia-reperfusion injury (neuroprotection).
Ischemia-reperfusion injury resulting from arterial occlusion in ischemic stroke is characterized by metabolic dysfunction, apoptosis, necrosis, and local inflammatory processes (5). The neuroprotective mechanism of RIC is not clearly understood, but it has been suggested that it is mediated by humoral, neuronal, and inflammatory pathways (6). Remote ischemic conditioning seemingly involves the transfer of a humoral substance from one organ to another. It triggers the release of humoral factors and local autocoids (adenosine, bradykinin, and gene-related peptide) which activate neurogenic transmission (with involvement of muscle afferents and autonomic nervous system) and involve immune pathways by suppressing proinflammatory genes in immune cells. Furthermore, RIC reduces oxidative damage and suppresses the inflammatory responses in the brain. This mechanism can last days after revascularization. More details can be found in excellent detailed reviews about this topic (4, 7, 8).
Ischemic conditioning was introduced in Cardiology in 1986 by Murry et al. who performed short repetitive occlusion/reperfusion of the coronary artery in canine models and observed a significant reduction in infarct size (9). Subsequent studies showed that ischemic conditioning can also be applied remote from the ischemic injury site. Brief episodes of ischemia-reperfusion in a distant organ (e.g., upper or lower limb) were proposed to exert a neuroprotective effect (10). Various studies indicated that limb RIC is neuroprotective in animal models of stroke (11, 12).
In AIS, RIC can be applied prior to the ischemic event (remote ischemic preconditioning), during the ischemic event (remote ischemic perconditioning), or after the vascular event (remote ischemic postconditioning). A mechanical tourniquet or automatic device placed around an arm or leg is meant to perform repetitive cycles of inflation and deflation. Most of the clinical studies chose to perform 3 to 5 cycles of transient limb ischemia, with different duration of mechanical vessel occlusion, ranging from 3 to 5 min. The most frequent site of limb conditioning was a single-arm (13). These protocols were influenced by the Cardiological ischemic conditioning protocols, but currently it is unknown whether these differences modify the efficacy of RIC. The major advantage of remote ischemic perconditioning is the broad therapeutic window- although time-sensitive, it can be carried out even after exceeding the therapeutic window for reperfusion treatment (thrombolysis/thrombectomy).
There is a limited number of clinical trials evaluating the efficacy of RIC in the treatment AIS. The majority of these ongoing trials explore the benefits, feasibility, and risks of applying RIC as soon as possible (even from the ambulance) after AIS onset (14). In particular, they focus on the effect of RIC on clinical outcome scales and final infarct volume.
From all the clinical trials employing RIC in patients with AIS, Purroy F et al. identified only four randomized controlled trials with completed and published data (15). The first study on RIC in AIS was conducted by Hougaard KD et al. in 2014 (14). They tested the effect of RIC vs. sham performed during the prehospital phase (in the ambulance) in AIS patients, in conjunction with thrombolysis. The primary outcome was the penumbra salvage, with a follow-up at 90 days. Overall, a final infarct volume analysis suggested that prehospital RIC might have immediate neuroprotective effects (14). In the RECAST and RECAST-II, England et al. investigated the effect of RIC vs. sham in patients with hyperacute AIS (26 patients recruited within 24 h of stroke onset and 60 patients enrolled within 6 h of stroke onset, respectively) by inducing transient non-paretic arm ischemia through a manual standard blood pressure cuff (16, 17). The primary outcome was feasibility, whereas the second outcome included functional outcomes. The duration of follow-up was 90 days. The conclusion was that RIC applied twice daily is feasible, well-tolerated, with no serious adverse events, and good adherence in hyperacute stroke (16, 17). Che et al. investigated and demonstrated the feasibility and safety of arm RIC after thrombolysis in 30 patients with AIS (18). The multicenter RESCUE BRAIN trial conducted by Pico et al. inquired whether leg RIC reduces final ischemic volume after AIS. They included 188 patients with confirmed carotid ischemic stroke within 6 hours of symptoms onset and concluded that treatment with RIC during and after AIS reperfusion therapy does not significantly reduce the brain infarct volume growth (19). Considering recent data and evidence, RIC is a simple, inexpensive, well-tolerated intervention, posing minimal risk. Clinical trials have demonstrated the feasibility of delivering RIC at different stages of hospitalization for AIS.
In 2018, Zhao et al. conducted a meta-analysis aiming to assess the benefits and harms of RIC in preventing or treating AIS (20). They included seven randomized controlled studies of RIC vs. sham in subjects with either AIS, chronic cerebral ischemia (i.e., 14 days after symptoms onset)/gradual onset cerebral ischemia, or intracranial/extracranial moderate/severe stenosis/confirmed occlusion, encompassing different protocols for RIC. Out of these, three trials on the effects of RIC on ischemic stroke prevention were included in the analysis, whereas four trials analyzed the effects of RIC on ischemic stroke treatment. The latter category included two studies enrolling patients with cerebral small vessel disease and two studies with AIS subjects. By combining their results, the overall effect (i.e., stroke severity- final infarct volume and clinical scores) was not significantly different between the intervention and sham group in AIS patients (20).
Since clinical trials have employed different RIC protocols in AIS patients, their cumulative results should be interpreted with caution. Temporal inclusion criteria had great variability. Remote ischemic conditioning was initiated during transportation to the hospital or immediately after admission. It was employed isolated or as add-on therapy to revascularization (alteplase or endovascular methods). The procedure was also different among studies, with various repetitions per day or number of days of RIC, possibly responsible for the inconsistent results. Notably, there were significant differences in main endpoints. Some studies focused on final infarct volume, whereas others addressed clinical stroke severity after RIC. Further trials with uniform and standardized protocols might fill in these gaps and provide better knowledge of RIC mechanisms and effects.
Our study aims to explore the efficiency and safety of RIC applied to the non-paretic upper limb in patients with AIS ineligible for reperfusion treatment. We hypothesize that RIC administered from the first day of AIS improves the final infarct volume and clinical outcome at 6 months. Details of the trial design have already been published (21).
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