Remote Ischemic Conditioning In Patients Research Articles

Age affects the association of red blood cell indices with efficacy of remote ischemic conditioning in patients with acute moderate ischemic stroke

We conducted a post hoc analysis of Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke (RICAMIS) to investigate whether red blood cell (RBC) indices are associated with efficacy of remote ischemic conditioning (RIC), and whether the association is affected by age. In this post hoc analysis, patients with RBC indices at admission were enrolled. RBC indices including RBC count, hematocrit (HCT), mean corpuscular volume (MCV), hemoglobin (HB), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were analyzed. According to the median of these RBC indices, eligible patients were divided into high and low groups, which were further subdivided into RIC and control subgroups. Primary endpoint was excellent functional outcome defined as a modified Rankin Scale score of 0–1 at 90 days, which was used to evaluate RIC efficacy. RIC efficacy as well as effect of age on RIC efficacy were analyzed across the high and low groups of different RBC indices, and the interaction effects of RBC indices on RIC efficacy were evaluated. A total of 1640 patients were enrolled in the final analysis. In overall patients, no significant interaction effects of RIC intervention by all RBC indices were found, although there was a trend in interaction effect of RIC intervention by MCH (p = 0.116). However, we found an effect of age on the association of MCH with RIC efficacy. In patients over 60 years old, MCH significantly affected RIC efficacy (p = 0.006) and RIC significantly produced a higher proportion of primary outcome in high MCH (72.6% vs. 59.1%, P < 0.001) vs. low MCH group (61.2% vs. 62%, P = 0.829), which was not identified in patients under 60 years old. Furthermore, RIC efficacy decreased with increasing age in patients with low MCH with significant interaction effect (p = 0.012), while RIC efficacy increased with increasing age in patients with high MCH although no significant interaction (p = 0.126). No significant interaction effects of RIC intervention by RBC count, HCT, MCV, HB, and MCHC were found regardless of age. This secondary analysis of RICAMIS suggested that RIC exhibited more obvious benefit in AIS patients over 60 years old with high MCH compared with those with low MCH group, but RBC count, HCT, MCV, HB, and MCHC were not associated with the efficacy of RIC treatment regardless of age.

Remote Ischemic Conditioning With Medical Management or Reperfusion Therapy for Acute Ischemic Stroke: A Systematic Review and Meta-Analysis.

Remote ischemic conditioning (RIC) is a low-cost, accessible, and noninvasive neuroprotective treatment strategy, but its efficacy and safety in acute ischemic stroke are controversial. With the publication of several randomized controlled trials (RCTs) and the recent results of the RESIST trial, it may be possible to identify the patient population that may (or may not) benefit from RIC. This systematic review and meta-analysis aims to evaluate the effectiveness and safety of RIC in patients with ischemic stroke receiving different treatments by pooling data of all randomized controlled studies to date. We searched the PubMed, Embase, Cochrane, Elsevier, and Web of Science databases to obtain articles in all languages from inception until May 25, 2023. The primary outcome was the modified Rankin Scale (mRS) score at the specified endpoint time in the trial. The secondary outcomes were change in NIH Stroke Scale (NIHSS) and recurrence of stroke events. The safety outcomes were cardiovascular events, cerebral hemorrhage, and mortality. The quality of articles was evaluated through the Cochrane risk assessment tool. This study was registered in PROSPERO (CRD42023430073). There were 7,657 patients from 22 RCTs included. Compared with the control group, patients who received RIC did not have improved mRS functional outcomes, regardless of whether they received medical management, reperfusion therapy with intravenous thrombolysis (IVT), or mechanical thrombectomy (MT). In the medical management group, patients who received RIC had decreased incidence of stroke recurrence (risk ratio 0.63, 95% CI 0.43-0.92, p = 0.02) and lower follow-up NIHSS score by 1.72 points compared with the control group (p < 0.00001). There was no increased risk of adverse events including death or cerebral hemorrhage in the IVT or medical management group. In patients with ischemic stroke who are not eligible for reperfusion therapy, RIC did not affect mRS functional outcomes but significantly improved the NIHSS score at the follow-up endpoint and reduced stroke recurrence, without increasing the risk of cerebral hemorrhage or death. In patients who received IVT or MT, the benefit of RIC was not observed.

Effect of Remote Ischemic Conditioning in Ischemic Stroke Subtypes: A Post Hoc Subgroup Analysis From the RESIST Trial.

Remote ischemic conditioning (RIC) is a simple and noninvasive procedure that has proved to be safe and feasible in numerous smaller clinical trials. Mixed results have been found in recent large randomized controlled trials. This is a post hoc subgroup analysis of the RESIST trial (Remote Ischemic Conditioning in Patients With Acute Stroke), investigating the effect of RIC in different acute ischemic stroke etiologies, and whether an effect was modified by treatment adherence. Eligible patients were adults (aged ≥18 years), independent in activities of daily living, who had prehospital stroke symptoms with a duration of less than 4 hours. They were randomized to RIC or sham. The RIC treatment protocol consisted of 5 cycles with 5 minutes of cuff inflation alternating with 5 minutes with a deflated cuff. Acceptable treatment adherence was defined as when at least 80% of planned RIC cycles were received. The analysis was performed using the entire range (shift analysis) of the modified Rankin Scale (ordinal logistic regression). A total of 698 had acute ischemic stroke, 253 (36%) were women, and the median (interquartile range) age was 73 (63-80) years. Median (interquartile range) overall adherence to RIC/sham was 91% (68%-100%). In patients with a stroke due to cerebral small vessel disease, who were adherent to treatment, RIC was associated with improved functional outcome, and the odds ratio for a shift to a lower score on the modified Rankin Scale was 2.54 (1.03-6.25); P=0.042. The association remained significant after adjusting for potential confounders. No significant associations were found with other stroke etiologies, and the overall test for interaction was not statistically significant (χ2, 4.33, P=0.23). In patients with acute ischemic stroke due to cerebral small vessel disease, who maintained good treatment adherence, RIC was associated with improved functional outcomes at 90 days. These results should only serve as a hypothesis-generating for future trials. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03481777.

Randomized feasibility trial of remote ischemic conditioning to enhance resuscitation (RICE)

RationaleRestoration of blood flow after out-of-hospital cardiac arrest (OHCA) is associated with inflammation that causes cellular injury. The extent of this reperfusion injury (RI) is associated with the duration of ischemia and adequacy of resuscitation. Remote ischemic conditioning (RIC) consists of repeated application of non-lethal ischemia then reperfusion to a limb distal to the heart by inflating a blood pressure (BP) cuff. Trials in animal models in cardiac arrest and in humans with acute infarction show RIC reduces RI. ObjectiveWe sought to demonstrate the feasibility and safety of RIC in patients resuscitated from OHCA and transported to hospital. MethodsThis study was conducted under exception from informed consent (EFIC) for emergency research. Eligible subjects were randomized with masked allocation to control (standard care) versus intervention (standard care and RIC). Included were adults with non-traumatic OHCA. The primary outcome was attrition, the proportion of patients enrolled and not on allocated therapy for the study duration. Key secondary outcomes were survival to discharge, neurologic status at discharge, hospital-free survival, and adverse events. Results were summarized descriptively as recommended for pilot studies. ResultsN = 30 patients were enrolled (n = 14 control, n = 16 intervention). Mean age of enrolled patients was 52.5 ± 16.2 years. Eight (27%) were female gender and 7 (23%) had a shockable first recorded rhythm. 100% of enrolled patients completed their allocated study intervention (i.e., 0% attrition). The RIC group had 7 (44%) survival to discharge and median Rankin score of 6 (IQR 1, 6) at discharge as compared to the standard care group which had 6 (43%) survival to discharge and median Rankin score of 6 (IQR 1.5, 6) at discharge. A single patient (6%) in the intervention group had transient occlusion of their upper extremity intravenous line, which immediately resolved on repositioning of the blood pressure cuff. ConclusionApplication of RIC to patients resuscitated from CA and transported to an ED is feasible and safe. An adequately powered trial is required to assess whether RIC is effective at decreasing morbidity and mortality after CA.

Remote Ischemic Conditioning: Challenges and Opportunities.

Remote ischemic conditioning (RIC) has been investigated as a promising, safe, and well-tolerated nonpharmacological therapy for cardio-cerebrovascular disease over the past 3 decades; variable results have been found when it is used in cerebrovascular versus cardiovascular disease. For patients with cardiovascular disease, milestone studies suggest that the roles of RIC may be limited. Recently, however, 2 large trials investigating RIC in patients with cerebrovascular disease found promising results, which may reignite the field's research prospects after its setbacks in the cardiovascular field. This perspectives article highlights several important clinical trials of RIC in the cardio-cerebrovascular disease and describes the many challenges of RIC in clinical translation. Finally, based on the available evidence, several promising research directions such as chronic RIC, early initiation in target population, improvement of compliance, better understanding of dosing, and identification of specific biomarkers are proposed and should be investigated before RIC can become applied into clinical practice for patient benefit.

Remote ischemic conditioning for stroke: A critical systematic review.

Remote ischemic conditioning (RIC) is the application of brief periods of ischemia to an organ or tissue with the aim of inducing protection from ischemia in a distant organ. It was first developed as a cardioprotective strategy but has been increasingly investigated as a neuroprotective intervention. The mechanisms by which RIC achieves neuroprotection are incompletely understood. Preclinical studies focus on the hypothesis that RIC can protect the brain from ischemia reperfusion (IR) injury following the restoration of blood flow after occlusion of a large cerebral artery. However, increasingly, a role of chronic RIC (CRIC) is being investigated as a means of promoting recovery following an ischemic insult to the brain. The recent publication of two large, randomized control trials has provided promise that RIC could improve functional outcomes after acute ischemic stroke, and that there may be a role for CRIC in the prevention of recurrent stroke. Although less developed, there is also proof-of-concept to suggest that RIC may be used to reduce vasospasm after subarachnoid hemorrhage or improve cognitive outcomes in vascular dementia. As a cheap, well-tolerated and almost universally applicable intervention, the motivation for investigating possible benefit of RIC in patients with cerebrovascular disease is great. In this review, we shall review the current evidence for RIC as applied to cerebrovascular disease.

Abstract 213: Remote Ischemic Conditioning To Enhance Resuscitation After Cardiac Arrest

Introduction: Restoration of blood flow after out-of-hospital cardiac arrest (OHCA) induces inflammation that causes cellular injury and death. Remote ischemic conditioning (RIC) consists of brief episodes of ischemia then reperfusion to a limb. Trials in animal models in cardiac arrest and in humans with acute infarction show RIC reduces RI. Objective: We sought to demonstrate the feasibility and safety of RIC in patients resuscitated from OHCA and transported to hospital. Methods: Single site 2-arm, single blind randomized feasibility trial comparing a treatment group receiving RIC versus usual care following OHCA. For patients allocated to the intervention group, RIC was performed via 3 cycles of 5-minutes inflation then 5-minutes deflation of a blood pressure cuff applied to an upper extremity. Included were adults resuscitated from OHCA with non-traumatic etiology of arrest, spontaneous circulation present upon emergency department arrival, no response to verbal commands and ongoing or planned induced hypothermia. Excluded were those with: ST-elevation on first 12-lead ECG obtained after return of spontaneous circulation, do not attempt resuscitation (DNAR) status, drowning or hypothermia as cause of arrest, dialysis fistula in either upper extremity or pre-existing amputation of upper extremity, pregnancy or incarcerated status. The primary outcome was attrition, i.e., the proportion of patients enrolled and not on allocated therapy for the study duration. Results: N=30 patients were enrolled (n=14 control, n=16 intervention). Mean age was 52.5 ± 16.2 years. Twenty-seven percent had female gender and 27% had a shockable first recorded rhythm. There was 0% attrition amongst enrolled patients. Other outcomes are summarized (Table). Conclusions: Application of RIC after OHCA is feasible and safe. An adequately powered trial is required to assess whether RIC is effective at decreasing morbidity and mortality after CA. TABLE: OUTCOMES

Potential Anti-Inflammatory and Anti-Coagulation Effects of One-Time Application of Remote Ischemic Conditioning in Patients With Subacute/Chronic Cerebral Arteriostenosis and Venostenosis.

Remote ischemic conditioning (RIC) is an extremely simple, non-invasive, and cost-effective method with a neuroprotective effect. This study aimed to evaluate the immediate effects of one-time application of RIC on inflammation and coagulation in patients with chronic cerebral vascular stenosis, and compare the different effects of RIC on cerebral arteriostenosis and cerebral venostenosis. A total of 47 patients with defined cerebral arteriostenosis (n=21) or venostenosis (n=26) were prospectively enrolled. RIC intervention was given once with 5 cycles of inflating and deflating for 5 minutes alternately. Blood was sampled 5 minutes before and after RIC for inflammatory and thrombophilia biomarkers. Differences in inflammatory and thrombotic variables at differing time points in the group were assessed using paired t tests or Wilcoxon matched-pairs signed-rank test. Patients with cerebral arteriostenosis had a higher level of pre-RIC neutrophil-to-lymphocyte ratio ( P =0.034), high-sensitivity C-reactive protein ( P =0.037), and fibrinogen ( P =0.002) than that with cerebral venostenosis. In the arterial group, levels of fibrinogen ( P =0.023) decreased, and interleukin-6 levels were elevated ( P =0.019) after a single RIC. Age was negatively related to interleukin-6, C-reactive protein, and fibrinogen. One-time RIC interventions may show seemingly coexisted proinflammatory and anti-coagulation effects of a single bout on patients with cerebral arteriostenosis. Older age was a negative predictor for multiple biomarkers in the cerebral arteriostensosis group. The protective effect of RIC on cerebral venostenosis patients needs to be further studied in a larger sample size.

Repetitive application of remote ischemic conditioning (RIC) in patients with peripheral arterial occlusive disease (PAOD) as a non-invasive treatment option: study protocol for a randomised controlled clinical trial

BackgroundThe best medical treatment (BMT) for most patients with early stage of peripheral arterial occlusive disease (PAOD) is often limited to gait training and pharmacological therapy besides endovascular surgery. The application of remote ischemic conditioning (RIC) has been described as a promising experimental strategy for the improvement of therapeutic outcome in cardiovascular disease but has not proven beneficial effects in clinical practice and treatment of PAOD yet.MethodsHere we describe a prospective, randomized trial for the evaluation of possible effects of repeated application of RIC in patients with PAOD. This monocentric study will enrol 200 participants distributed to an intervention group receiving RIC + BMT and a control group only receiving BMT for four weeks. Patients are at least 18 years of age and have diagnosed PAOD Fontaine stage II b. Pain-free and total walking distance will be measured via treadmill test (primary endpoints). In addition, ankle-brachial index (ABI) and quality of life (QoL) will be assessed using the SF-36 and VascuQoL-6 questionnaire. Moreover, evaluation of markers for atherosclerosis, angiogenic profiling and mononuclear cell characterization will be performed using biochemical assays, proteome profiling arrays and flow cytometry (secondary endpoints).DiscussionOur prospective, randomized monocentric trial is the first of its kind to analyse the effects of chronic and repetitive treatment with RIC in patients with PAOD and might provide important novel information on the molecular mechanisms associated with RIC in PAOD patients.Trial registration: Prospectively registered in the German Clinical Trials Register (Deutsche Register Klinischer Studien) Registration number: DRKS00025735; Date of registration: 01.07.2021.

Chronic remote ischemic conditioning for symptomatic internal carotid or middle cerebral artery occlusion: A prospective cohort study.

AimsRemote ischemic conditioning (RIC) has been demonstrated to reduce recurrent stroke in patients with intracranial artery stenosis. This study aimed to evaluate the effects of RIC in patients with the symptomatic internal carotid artery (ICA) or middle cerebral artery (MCA) occlusion.MethodsThis study is based on a high‐volume single‐center prospective cohort study in China, which included patients with symptomatic ICA or MCA occlusion with impaired hemodynamics and receiving chronic RIC. Clinical follow‐up visits were performed regularly, and cardio‐cerebrovascular events were assessed.ResultsIn total, 131 patients (68 with ICA occlusion and 63 with MCA occlusion; mean age, 52.6 ± 13.7 years; stroke, 73.5%; transient ischemic attack TIA, 26.5%) qualified for the analysis; the mean follow‐up period was 8.8 years (range, 3–14 years). The compliance of RIC was 95.6 ± 3.7%, and no associated severe adverse events happened. The annual risk of ischemic stroke and ischemic cerebrovascular events was 2.4% and 3.3%, respectively. The cumulative probabilities of ischemic cerebrovascular events and major adverse cardiovascular and cerebrovascular events were 32.8% and 44.8% at 14 years, respectively.ConclusionIn patients with symptomatic ICA or MCA occlusion with impaired hemodynamics, chronic RIC is well‐tolerated, and it appears to be associated with a low annual risk of ischemic stroke and cardio‐cerebrovascular events.

Cardioprotection of Repeated Remote Ischemic Conditioning in Patients With ST-Segment Elevation Myocardial Infarction.

BackgroundRepeated remote ischemic conditioning (RIC) after myocardial infarction (MI) has been shown to improve left ventricular (LV) remodeling in the experimental studies, but its cardioprotective effect in patients with ST-segment elevation myocardial infarction (STEMI) is still unknown.ObjectiveTo investigate whether repeated RIC started early after primary percutaneous coronary intervention (PCI) can improve LV function in patients with STEMI.MethodsPatients with STEMI treated by primary PCI were included and randomized to the repeated RIC group (n = 30) or the control group (n = 30). RIC was started within 24 h after PCI and repeated daily for 1 week, using an Auto RIC device. 3D speckle-tracking echocardiography (STE) was used to assessed LV function. The primary study endpoint was the change in LV global longitudinal strain (GLS) from baseline to 1 month after PCI.ResultsThe repeated RIC group and the control group were well-matched at baseline including mean GLS (−9.8 ± 2.6% vs. −10.1 ± 2.5%, P = 0.62). Despite there was no significant difference in mean GLS at 1 month between the two groups (−11.9 ± 2.1% vs. −10.9 ± 2.7%, P = 0.13), the mean change in GLS from baseline to 1 month was significantly higher in the treatment group than in the control group (−2.1 ± 2.5% vs. −0.8 ± 2.3%, P = 0.04). There were no significant differences in the changes in global circumferential strain (GCS), global area strain (GAS), global radial strain (GRS), LV ejection fraction (LVEF), LV end-diastolic volume (LVEDV), and LV end-systolic volume (LVESV) between the two groups. Peak creatine kinase isoenzyme-MB, peak high-sensitivity troponin T, and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels at 24 h after PCI did not differ significantly between the two groups, but NT-proBNP levels at 1 week were significantly lower in the treatment group than in the control group [357.5 (184.8–762.8) vs. 465.0 (305.8–1525.8) pg/ml, P = 0.04].ConclusionDaily repeated RIC started within 24 h after PCI can improve GLS and reduce plasma NT proBNP levels in patients with STEMI.

Effect of Remote Ischemic Conditioning in Patients with ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis

Effect of Remote Ischemic Conditioning in Patients with ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis

The Impact of Serial Remote Ischemic Conditioning on Dynamic Cerebral Autoregulation and Brain Injury Related Biomarkers.

ObjectiveRecent studies have demonstrated the positive roles of remote ischemic conditioning (RIC) in patients with cerebrovascular diseases; however, the mechanisms remain unclear. This study aimed to explore the effect of serial RIC on dynamic cerebral autoregulation (dCA) and serum biomarkers associated with brain injury, both of which are related to the prognosis of cerebrovascular disease.MethodsThis was a self-controlled interventional study in healthy adults. The RIC was conducted twice a day for 7 consecutive days (d1–d7) and comprised 4 × 5-min single arm cuff inflation/deflation cycles at 200 mmHg. All participants underwent assessments of dCA ten times, including baseline, d1, d2, d4, d7, d8, d10, d14, d21, and d35 of the study. Blood samples were collected four times (baseline, d1, d7, and d8) immediately after dCA measurements. The transfer function parameters [phase difference (PD) and gain] were used to quantify dCA. Four serum biomarkers associated with brain injury, ubiquitin C-terminal hydrolase-L1, neuron-specific enolase, glial fibrillary acidic protein, and S100β were tested.ResultsTwenty-two healthy adult volunteers (mean age 25.73 ± 1.78 years, 3 men [13.6%], all Asian) were enrolled in this study. Bilateral PD values were significantly higher since four times of RIC were completed (d2) compared with PD values at baseline (left: 53.31 ± 10.53 vs. 45.87 ± 13.02 degree, p = 0.015; right: 54.90 ± 10.46 vs. 45.96 ± 10.77 degree, p = 0.005). After completing 7 days of RIC, the significant increase in dCA was sustained for at least 28 days (d35, left: 53.11 ± 14.51 degree, P = 0.038; right: 56.95 ± 14.57 degree, p < 0.001). No difference was found in terms of different serum biomarkers related to brain injury before and after RIC.ConclusionThe elevation in dCA was detected immediately after four repeated times of RIC, and 7-day consecutive RIC induced a sustained increase in dCA for at least 28 days and did not affect blood biomarkers of brain injury in healthy adults. These results will help us to formulate detailed strategies for the safe and effective application of RIC in patients with cerebrovascular disease.

Relationship between plasma Neuregulin-1 and cardiac function in patients with ST-elevation myocardial infarction.

Neuregulin-1 (NRG-1) is a stress-mediated transmembrane growth factor. Reduced myocardial damage and higher NRG-1 levels upon treatment with remote ischemic conditioning (RIC) has been described in rats. However, the role of NRG-1 in patients with acute myocardial infarction (MI) is unknown. Thus, we conducted a post hoc analysis of a randomized controlled trial that tested RIC in patients with MI scheduled for primary percutaneous coronary intervention (PCI). Blood was drawn from 30 patients before RIC/PCI, within 1 hour, 4 days and 1 month later. Median left ventricular ejection fraction (LVEF) in the overall study population following MI was 48.5%. NRG-1 plasma levels decreased significantly following PCI/RIC and remained decreased up to 1 month following MI (p < 0.0001). We observed no association of NRG-1 with other variables, including total ischemic time, LVEF or RIC. Thus, we identified NRG-1 may be independently affected by MI. However, further large clinical trials are warranted to clarify this hypothesis.

Bioassays of Humoral Cardioprotective Factors Released by Remote Ischemic Conditioning in Patients Undergoing Coronary Artery Bypass Surgery.

Remote ischemic conditioning (RIC) induces the release of circulating cardioprotective factors and attenuates myocardial ischemia/reperfusion injury. Evidence for such humoral cardioprotective factor(s) is derived from transfer with plasma (derivatives) from one individual undergoing RIC to another individual's heart, even across species. With transfer into an isolated perfused heart, only a single plasma (derivative) sample can be studied with infarct size as endpoint, and therefore the comparison of samples before and after RIC or between RIC and placebo is hampered by the inter-individual variation of infarct sizes in isolated perfused hearts. We therefore developed a preparation of cardiomyocytes from a single mouse heart, where aliquots of the same heart can undergo hypoxia/reoxygenation (H/R) with exposure to buffer, RIC, or placebo samples without or with pharmacological blockade. To validate this approach, we used plasma dialysates taken before and after RIC from patients undergoing coronary bypass grafting who had experienced protection by RIC (troponin release ↓ by 28% vs placebo). The cardiomyocyte bioassay had little variation after H/R with buffer (mean ± standard deviation; 7% ± 2% viable cells) and demonstrated preserved viability after RIC (15% ± 5% vs 6% ± 3% before). For comparison, infarct size in isolated mouse hearts after global ischemia and reperfusion was 22% ± 14% of left ventricular mass after versus 42% ± 14% before RIC. Stattic, an inhibitor of signal transducer and activator of transcription (STAT)3 protein, abrogated protection in the cardiomyocytes. We have thus established a cardiomyocyte bioassay to analyze RIC's protection which minimizes inter-individual variation and the use of animals.

Remote Ischemic Conditioning May Improve Disability and Cognition After Acute Ischemic Stroke: A Pilot Randomized Clinical Trial.

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.

Safety and efficacy of remote ischemic conditioning for the treatment of intracerebral hemorrhage: A proof-of-concept randomized controlled trial.

Remote ischemic conditioning can promote hematoma resolution, attenuate brain edema, and improve neurological recovery in animal models of intracerebral hemorrhage. This study aimed to evaluate the safety and preliminary efficacy of remote ischemic conditioning in patients with intracerebral hemorrhage. In this multicenter, randomized, controlled trial, 40 subjects with supratentorial intracerebral hemorrhage presenting within 24-48 h of onset were randomly assigned to receive medical therapy plus remote ischemic conditioning for consecutive seven days or medical therapy alone. The primary safety outcome was neurological deterioration within seven days of enrollment, and the primary efficacy outcome was the changes of hematoma volume on CT images. Other outcomes included hematoma resolution rate at 7 days ([hematoma volume at 7 days - hematoma volume at baseline]/hematoma volume at baseline), perihematomal edema (PHE), and functional outcome at 90 days. The mean age was 59.3 ± 11.7 years and hematoma volume was 13.9 ± 4.5 mL. No subjects experienced neurological deterioration within seven days of enrollment, and no subject died or experienced remote ischemic conditioning-associated adverse events during the study period. At baseline, the hematoma volumes were 14.19 ± 5.07 mL in the control group and 13.55 ± 3.99 mL in the remote ischemic conditioning group, and they were 8.54 ± 3.99 mL and 6.95 ± 2.71 mL at seven days after enrollment, respectively, which is not a significant difference (p > 0.05 each). The hematoma resolution rate in the remote ischemic conditioning group (49.25 ± 9.17%) was significantly higher than in the control group (41.92 ± 9.14%; MD, 7.3%; 95% CI, 1.51-13.16%; p = 0.015). The absolute PHE volume was 17.27 ± 8.34 mL in the control group and 12.92 ± 7.30 mL in the remote ischemic conditioning group at seven days after enrollment, which is not a significant between-group difference (p = 0.087), but the relative PHE in the remote ischemic conditioning group (1.77 ± 0.39) was significantly lower than in the control group (2.02 ± 0.27; MD, 0.25; 95% CI, 0.39-0.47; p = 0.023). At 90-day follow-up, 13 subjects (65%) in the remote ischemic conditioning group and 12 subjects (60%) in the control group achieved favorable functional outcomes (modified Rankin Scale score ≤ 3), which is not a significant between-group difference (p = 0.744). Repeated daily remote ischemic conditioning for consecutive seven days was safe and well tolerated in patients with intracerebral hemorrhage, and it may be able to improve hematoma resolution rate and reduce relative PHE. However, the effects of remote ischemic conditioning on the absolute hematoma and PHE volume and functional outcomes in this patient population need further investigations.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03930940.

Remote ischemic conditioning in active ulcerative colitis: An explorative randomized clinical trial

Remote ischemic conditioning (RIC) by repetitive brief periods of limb ischemia and reperfusion renders organs more resistant to ischemic injury. The protection is partly through down-regulation of the inflammatory response. Our aim was to investigate the clinical and anti-inflammatory effects of RIC in patients with active ulcerative colitis (UC). We included 22 patients with active UC in this explorative, randomized, sham-controlled clinical trial. The patients were randomly assigned 1:1 to RIC (induced in the arm through four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff) or sham (incomplete inflation of the blood-pressure cuff) once daily for 10 days. Outcome variables were measured at baseline and on day 11. When compared with sham, RIC did not affect inflammation in the UC patients measured by fecal calprotectin, plasma C-reactive protein, Mayo Score, Mayo Endoscopic Subscore, Nancy Histological Index or inflammatory cytokines involved in UC and RIC. The mRNA and miRNA expression profiles in the UC patients were measured by RNA sequencing and multiplexed hybridization, respectively, but were not significantly affected by RIC. We used the Langendorff heart model to assess activation of the organ protective mechanism induced by RIC, but could not confirm activation of the organ protective mechanism in the UC patients.

Remote Ischemic Conditioning in Patients with Acute Coronary Syndromes: A Systematic Review with Meta-Analysis and Trial Sequential Analysis.

ObjectiveTo evaluate the efficacy of remote ischemic conditioning (RIC) as compared to no conditioning on clinical endpoints in acute coronary syndromes (ACS) patients undergoing percutaneous coronary intervention (PCI).DesignSystematic review of randomized clinical trials (RCTs).Material and MethodsLiterature was searched up to September 13, 2019, and we identified a total of 13 RCTs. The efficacy of RIC on incidence of clinical events during follow-up was quantified by the rate ratio (RR) with its 95% confidence interval (CI), and we used fixed and random effects models to synthetize the results. Small-study effect was evaluated, and controlled for by the trim-and-fill method. Heterogeneity between studies was examined by subgroup and meta-regression analyses. The risk of false-positive results in meta-analysis was evaluated by trial sequential analysis (TSA).ResultsPooled analysis of 13 trials (7183 patients) showed that RIC compared to no conditioning revealed a non-significant risk reduction on endpoint mortality (RR=0.81, 95% CI: 0.56–1.17) during a median follow-up time of 1 year (range: 0.08–3.8) with low heterogeneity (I2=16%). Controlling for small-study effect showed no efficacy of RIC (adjusted RR: 1.03, 95% CI: 0.66–1.59). Pooled effect of RIC on the incidence of myocardial infarction (MI) from 11 trials (6996 patients) was non-significant too (RR=0.85, 95% CI: 0.62–1.18), with no observed heterogeneity (I2=0%) or small-study effect. A similar lack of efficacy was found in endpoint congestive heart failure (CHF) from 6 trials including 6098 patients (RR=0.71, 95% CI: 0.44–1.15), with moderate heterogeneity (I2=30%). TSAs showed that the pooled estimates from the cumulative meta-analyses were true negative with adequate power.ConclusionEvidence from this updated systematic review demonstrates no beneficial effect of RIC on the incidence of clinical endpoint mortality, MI and CHF during a median follow-up of 1 year in ACS patients undergoing PCI.

Effect of Remote Ischemic Conditioning in Patients With Takotsubo Syndrome After Acute Stroke: Study Protocol for a Randomized Controlled Trial.

Introduction: Takotsubo syndrome (TTS) is an acute heart failure syndrome which is preceded by a variety of emotional or physical triggers, with central nervous system conditions being an important trigger. Remote ischemic conditioning (RIC) is a promising interventional treatment based on the probability that both TTS and acute coronary syndrome may respond similarly to interventions. The heart protection effect of RIC has been repeatedly confirmed in animal models and observational clinical trials; however, it has never been studied in patients with TTS after acute stroke in randomized clinical trials with a higher level of evidence. The present study will be a proof-of-concept study to determine whether RIC can reduce cardiac injury and eventually improve the heart function and clinical outcomes of TTS patients after acute stroke.Methods and Analysis: A single-center, outcome-assessor-blinded, randomized controlled trial (RCT) will be conducted to evaluate the effect of RIC in TTS patients after acute stroke. Major eligibility criteria include TTS patients diagnosed with acute stroke, which can be confirmed on computed tomography or magnetic resonance imaging; patients aged 18–75 years; patients admitted to a hospital within 48 h after the onset of acute stroke; and patients diagnosed with Takotsubo cardiomyopathy with an InterTAK diagnostic score ≥50. A total of 60 eligible patients will be randomly allocated into either the RIC or the control group. The primary endpoint is a composite of death from any cause and major adverse cardiac and cerebrovascular events during the in-hospital period and at the 1- and 6-month follow-up.Ethics and dissemination: This study has been approved by the Medical Ethics Committee of Xuanwu Hospital, Capital Medical University ([2017] 072). The study findings will be presented at international conferences and published in a peer-reviewed journal.Trial registration: This study has been prospectively registered in the Chinese Clinical Trial Registry on September 10, 2018 (ChiCTR1800018290).