Remote Ischemic Conditioning Group Research Articles

Association of systolic blood pressure variability with remote ischemic conditioning in acute ischemic stroke

Systolic blood pressure variability (SBPV) is associated with outcome in acute ischemic stroke. Remote ischemic conditioning (RIC) has been demonstrated to be effective in stroke and may affect blood pressure. Relationship between SBPV and RIC treatment after stroke warrants investigation. A total of 1707 patients from per-protocol analysis set of RICAMIS study were included. The SBPV was calculated based on blood pressure measured at admission, Day 7, and Day 12. (I) To investigate the effect of SBPV on efficacy of RIC in stroke, patients were divided into High and Low categories in each SBPV parameter. Primary outcome was excellent functional outcome at 90 days. Compared with Control, efficacy of RIC in each category and interaction between categories were investigated. (II) To investigate the effect of RIC treatment on SBPV, SBPV parameters were compared between RIC and Control groups. Compared with Control, a higher likelihood of primary outcome in RIC was found in high category (max–min: adjusted risk difference [RD] = 7.2, 95% CI 1.2–13.1, P = 0.02; standard deviation: adjusted RD = 11.5, 95% CI 1.6–21.4, P = 0.02; coefficient of variation: adjusted RD = 11.2, 95% CI 1.4–21.0, P = 0.03). Significant interaction of RIC on outcomes were found between High and Low standard deviations (adjusted P < 0.05). No significant difference in SBPV parameters were found between treatment groups. This is the first report that Chinese patients with acute moderate ischemic stroke and presenting with higher SBPV, who were non-cardioemoblic stroke and not candidates for intravenous thrombolysis or endovascular therapy, would benefit more from RIC with respect to functional outcomes at 90 days, but 2-week RIC treatment has no effect on SBPV during hospital.

Remote Ischemic Conditioning to Reduce Perihematoma Edema in Patients with Intracerebral Hemorrhage (RICOCHET): A Randomized Control Trial.

Background: Early perihematomal edema (PHE) growth is associated with worse functional outcomes at 90 days. Remote Ischemic conditioning (RIC) may reduce perihematomal inflammation if applied early to patients with intracerebral hemorrhage (ICH). We hypothesize that early RIC, delivered for seven days in patients with spontaneous ICH, may reduce PHE growth. Methods: ICH patients presenting within 6 h of symptom onset and hematoma volume < 60 milliliters (mL) were randomized to an RIC + standard care or standard care (SC) group. The primary outcome measure was calculated edema extension distance (EED), with the cm assessed on day seven. Results: Sixty patients were randomized with a mean ± SD age of 57.5 ± 10.8 years, and twenty-two (36.7%) were female. The relative baseline median PHE were similar (RIC group 0.75 (0.5-0.9) mL vs. SC group 0.91 (0.5-1.2) mL, p = 0.30). The median EEDs at baseline were similar (RIC group 0.58 (0.3-0.8) cm vs. SC group 0.51 (0.3-0.8) cm, p = 0.76). There was no difference in the median day 7 EED (RIC group 1.1 (0.6-1.2) cm vs. SC group 1 (0.9-1.2) cm, p = 0.75). Conclusions: Early RIC therapy delivered daily for seven days was feasible. However, no decrease in EED was noted with the intervention.

Rationale and Design of the IMPROVE Trial: A Multicenter, Randomized, Controlled, Open-label, Blinded-endpoint Trial Assessing the Efficacy of Remote Ischemic Conditioning in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting.

Despite the appearance of off-pump coronary artery bypass grafting (CABG), ischemia-reperfusion injury (IRI) in the perioperative period still arouses concerns of clinicians. Remote ischemic conditioning (RIC) is the process of repeated ischemia and reperfusion in the peripheral vessels, which is proven to reduce IRI in vital organs. However, the effect of RIC in patients undergoing off-pump CABG is still unclear. This IMPROVE trial is a national, multicenter, randomized, controlled, open-label, blinded-endpoint clinical trial designed to assess whether RIC intervention can improve short-term prognosis of patients undergoing off-pump CABG. It plans to enroll 648 patients who will be randomly assigned into a RIC group or control group. Patients in the RIC group will receive four cycles of 5min of pressurization (about 200mmHg) and 5min of rest in the 3days before and 7days after the surgery. The primary outcome is the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) within the 3-month follow-up. MACCE is defined as all-cause death, myocardial infarction, stroke, and coronary revascularization surgery. NCT06141525 (ClinicalTrials.gov).

Abstract 61: The Effect of Remote Ischemic Conditioning in Stroke Subtypes: A Subgroup Analysis From the RESIST Trial

Introduction: Remote ischemic conditioning (RIC) is a simple and non-invasive procedure that has proved safe and feasible in numerous smaller clinical trials. Still, mixed results have been found in recent large randomized controlled trials. Here we present a predefined subgroup analysis of the RESIST trial on the effect of RIC in subgroups of acute ischemic stroke (AIS) and whether this effect is modified by adherence to RIC. Methods: The subgroups were defined as large artery atherosclerotic disease (LAA), small vessel disease (SVD), cardioembolic, and unknown/other/multiple/rare, and were based on ICD-10 discharge diagnoses assigned by the treating physician to define stroke etiology. Acceptable treatment adherence was defined as at least 80% received out of planned cycles. The outcome analysis used the entire range (‘shift analysis’) of the 90-day modified Rankin Scale score (ordinal logistic regression). ClinicalTrials.gov:NCT03481777. Results: A total of 902 patients were included in the target population group, 466 in the sham group, and 436 in the RIC group. RIC did not significantly improve functional outcome in adherent patients with LAA, cardioembolic or multiple/unknown etiologies. In SVD patients (n=94), with good treatment adherence, RIC treatment was associated with a significantly improved 90-day functional outcome, unadjusted OR (95% CI): 2.47 (1.01-6.02), p= 0.047. In patients with SVD, 4 patients (8%) in the RIC group compared to 0 patients in the sham group had atrial fibrillation (AF), p=0.050. The association remained significant after adjusting for AF, adjusted OR (95% CI): 2.64 (1.07-6.54), p= 0.035. Conclusions: In patients with AIS due to SVD, who had good treatment adherence, RIC treatment was associated with improved functional outcome at 90 days. These results are encouraging but should only be hypothesis-generating for future studies.

Targeting blood brain barrier-Remote ischemic conditioning alleviates cognitive impairment in female APP/PS1 rats.

Alzheimer's disease (AD) is a significant global health concern, and it is crucial that we find effective methods to prevent or slow down AD progression. Recent studies have highlighted the essential role of blood vessels in clearing Aβ, a protein that contributes to AD. Scientists are exploring blood biomarkers as a potential tool for future AD diagnosis. One promising method that may help prevent AD is remote ischemic conditioning (RIC). RIC involves using sub-lethal ischemic-reperfusion cycles on limbs. However, a comprehensive understanding of how RIC can prevent AD and its long-term effectiveness is still lacking. Further research is essential to fully comprehend the potential benefits of RIC in preventing AD. Female wild-type (WT) and APP/PS1 transgenic rats, aged 12 months, underwent ovariectomy and were subsequently assigned to WT, APP/PS1, and APP/PS1 + RIC groups. RIC was conducted five times a week for 4 weeks. The rats' depressive and cognitive behaviors were evaluated using force swimming, open-field tests, novel objective recognition, elevated plus maze, and Barnes maze tests. Evaluation of the neurovascular unit (NVU), synapses, vasculature, astrocytes, and microglia was conducted using immunofluorescence staining (IF), Western blot (WB), and transmission electron microscopy (TEM). Additionally, the cerebro-vasculature was examined using micro-CT, and cerebral blood flow (CBF) was measured using Speckle Doppler. Blood-brain barrier (BBB) permeability was determined by measuring the Evans blue leakage. Finally, Aβ levels in the rat frontal cortex were measured using WB, ELISA, or IF staining. RIC enhanced memory-related protein expression and rescued depressive-like behavior and cognitive decline in APP/PS1 transgenic rats. Additionally, the intervention protected NVU in the rat frontal cortex, as evidenced by (1) increased expression of TJ (tight junction) proteins, pericyte marker PDGFRβ, and glucose transporter 1 (GLUT1), as well as decreased VCAM1; (2) mitigation of ultrastructure impairment in neuron, cerebral vascular, and astrocyte; (3) upregulation of A2 astrocyte phenotype markers and downregulation of A1 phenotype markers, indicating a shift toward a healthier phenotype. Correspondingly, RIC intervention alleviated neuroinflammation, as evidenced by the decreased Iba1 level, a microglia marker. Meanwhile, RIC intervention elevated CBF in frontal cortex of the rats. Notably, RIC intervention effectively suppressed Aβ toxicity, as demonstrated by the enhancement of α-secretase and attenuation of β-secretase (BACE1) and γ- secretase and Aβ1-42 and Aβ1-40 levels as well. Chronic RIC intervention exerts vascular and neuroprotective roles, suggesting that RIC could be a promising therapeutic strategy targeting the BBB and NVU during AD development.

Remote Ischemic Conditioning for Motor Recovery after Acute Ischemic Stroke.

Remote ischemic conditioning (RIC) has shown an impressive neuroprotective effect on acute ischemic stroke (AIS) in animal experiments. But whether chronic RIC improves long-term functional outcomes remains unclear. We performed a non-randomized controlled trial. Eligible patients (aged 18 -80 y) with hemiplegia caused by AIS were allocated to the RIC group and the control group. All participants received normal protocol rehabilitation therapy. Patients in the RIC group underwent RIC twice daily for 90 days. The outcome included the 90-day Fugl-Meyer Assessment (FMA) scores and modified Rankin's scale (mRS) scores, as well as changes in angiogenesis-related factors in serum from baseline to 90 days. Twenty-seven patients were included in the analysis (13 in the RIC group and 14 in the control group). There was no significant difference in 90-day total FMA scores between the two groups. Lower limb FMA scores at day 90 were significantly higher in the RIC group (32.8±8.7 vs. 24.8±5.4, adjusted P=0.042). The proportion of favorable outcome (mRS<2) was higher in the RIC group than that in the control group, but no significant difference was detected (8 [61.5%] vs. 7 [50%], P=0.705). A significant increase has been found in the level of epidermal growth factor (EGF) in serum (9.4 [1.1 to 25.7] vs. -8.7 [-15.1 to 4.7], P=0.036) after chronic RIC procedure. This study investigated the role that RIC plays in AIS recovery, especially in motor function. RIC may have beneficial effects on lower limbs recovery by enhancing the EGF level. The effect of RIC on motor recovery should be further validated in future studies.

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 ischaemic conditioning for fatigue after stroke (RICFAST): A pilot randomised controlled trial

BackgroundPost stroke fatigue (PSF) affects 50 % of stroke survivors, and can be disabling. Remote ischaemic conditioning (RIC), can preserve mitochondrial function, improve tissue perfusion and may mitigate PSF. This pilot randomised controlled trial evaluates the safety and feasibility of using RIC for PSF and evaluated measures of cellular bioenergetics. Methods24 people with debilitating PSF (7 item Fatigue Severity Score, FSS-7 > 4) were randomised (1:1) in this single-centre phase 2 study to RIC (blood pressure cuff inflation around the upper arm 200 mmHg for 5 min followed by 5 min of deflation), or sham (inflation pressure 20 mmHg), repeated 4 cycles, 3 times per week for 6 weeks. Primary outcomes were safety, acceptability, and compliance. Secondary outcomes included FSS-7, 6 min walking test (6MWT), peak oxygen consumption (V̇O2peak), ventilatory anaerobic threshold (VAT), and muscle adenosine triphosphate (ATP) content measured using 31-phosphorous magnetic resonance spectroscopy of tibialis anterior. ResultsRIC was safe (no serious adverse events, adverse events mild) and adherence excellent (91 % sessions completed). Exploratory analysis revealed lower FSS-7 scores in the RIC group compared to sham at 6 weeks (between group difference FSS-7 -0.7, 95 %CI -2.0 to 0.6), 3 months (-1.0, 95 %CI -2.2 to 0.2) and 6 months (-0.9, 95 %CI -2.0 to 0.2). There were trends towards increased VAT, increased muscle ATP content and improved 6MWT in the RIC group. DiscussionRIC is safe and acceptable for people with PSF and may result in clinically meaningful improvements in fatigue and muscle bioenergetics that require further investigation in larger studies.

Remote Ischemic Conditioning for Acute Stroke

Despite some promising preclinical and clinical data, it remains uncertain whether remote ischemic conditioning (RIC) with transient cycles of limb ischemia and reperfusion is an effective treatment for acute stroke. To evaluate the effect of RIC when initiated in the prehospital setting and continued in the hospital on functional outcome in patients with acute stroke. This was a randomized clinical trial conducted at 4 stroke centers in Denmark that included 1500 patients with prehospital stroke symptoms for less than 4 hours (enrolled March 16, 2018, to November 11, 2022; final follow-up, February 3, 2023). The intervention was delivered using an inflatable cuff on 1 upper extremity (RIC cuff pressure, ≤200 mm Hg [n = 749] and sham cuff pressure, 20 mm Hg [n = 751]). Each treatment application consisted of 5 cycles of 5 minutes of cuff inflation followed by 5 minutes of cuff deflation. Treatment was started in the ambulance and repeated at least once in the hospital and then twice daily for 7 days among a subset of participants. The primary end point was improvement in functional outcome measured as a shift across the modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) at 90 days in the target population with a final diagnosis of ischemic or hemorrhagic stroke. Among 1500 patients who were randomized (median age, 71 years; 591 women [41%]), 1433 (96%) completed the trial. Of these, 149 patients (10%) were diagnosed with transient ischemic attack and 382 (27%) with a stroke mimic. In the remaining 902 patients with a target diagnosis of stroke (737 [82%] with ischemic stroke and 165 [18%] with intracerebral hemorrhage), 436 underwent RIC and 466 sham treatment. The median mRS score at 90 days was 2 (IQR, 1-3) in the RIC group and 1 (IQR, 1-3) in the sham group. RIC treatment was not significantly associated with improved functional outcome at 90 days (odds ratio [OR], 0.95; 95% CI, 0.75 to 1.20, P = .67; absolute difference in median mRS score, -1; -1.7 to -0.25). In all randomized patients, there were no significant differences in the number of serious adverse events: 169 patients (23.7%) in the RIC group with 1 or more serious adverse events vs 175 patients (24.3%) in the sham group (OR, 0.97; 95% CI, 0.85 to 1.11; P = .68). Upper extremity pain during treatment and/or skin petechia occurred in 54 (7.2%) in the RIC group and 11 (1.5%) in the sham group. RIC initiated in the prehospital setting and continued in the hospital did not significantly improve functional outcome at 90 days in patients with acute stroke. ClinicalTrials.gov Identifier: NCT03481777.

Safety and efficacy of remote ischemic conditioning in adult moyamoya disease patients undergoing revascularization surgery: a pilot study.

Revascularization surgery for patients with moyamoya disease (MMD) is very complicated and has a high rate of postoperative complications. This pilot study aimed to prove the safety and efficacy of remote ischemic conditioning (RIC) in adult MMD patients undergoing revascularization surgery. A total of 44 patients with MMD were enrolled in this single-center, open-label, prospective, parallel randomized study, including 22 patients assigned to the sham group and 22 patients assigned to the RIC group. The primary outcome was the incidence of major neurologic complications during the perioperative period. Secondary outcomes were the modified Rankin Scale (mRS) score at discharge, at 90 days post-operation, and at 1 year after the operation. The outcome of safety was the incidence of adverse events associated with RIC. Blood samples were obtained to monitor the serum concentrations of cytokines (VEGF, IL-6). No subjects experienced adverse events during RIC intervention, and all patients could tolerate the RIC intervention in the perioperative period. The incidence of major neurologic complications was significantly lower in the RIC group compared with the control group (18.2% vs. 54.5%, P = 0.027). The mRS score at discharge in the RIC group was also lower than the control group (0.86 ± 0.99 vs. 1.18 ± 1.22, P = 0.035). In addition, the serum IL-6 level increased significantly at 7 days after bypass surgery in the control group and the serum level of VEGF at 7 days post-operation in the RIC group. In conclusion, our study demonstrated the neuroprotective effect of RIC by reducing perioperative complications and improving cerebral blood flow in adult MMD patients undergoing revascularization surgery. Thus, RIC seems to be a potential treatment method for MMD. ClinicalTrials.gov, identifier: NCT05860946.

Remote ischemic conditioning in the treatment of acute cerebral infarction: A case control study

ObjectiveThis paired case-control study aimed to evaluate the efficacy and safety of remote ischemic conditioning (RIC) in patients with acute cerebral infarction (CI) and explore potential serological markers of RIC. MethodsPatients with acute CI (<72 h) were matched 1:1 according to age, sex, and CI conditions and were divided into the RIC group and the control group. The RIC group received RIC intervention for 7 days on top of routine treatment, while the control group received a sham RIC. The curative effects and adverse reactions were observed. ResultA total of 66 patients (mean age 60.00 ± 11.37 years; mean time of acute CI onset 32.91 ± 17.94 h) completed the study. The National Institute of Health stroke scale score on day 7, modified Rankin Scale scores on day 7 and day 90 were significantly lower than the baseline in the RIC group (P < 0.001, P = 0.003, P = 0.004, respectively) but not in the control group (P = 0.056, P = 0.169, P = 0.058, respectively). RIC was well-tolerated, and no adverse events were reported. Both plasma hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor increased in the RIC group from day 0 to day 7, while they decreased in the control group. The changes in plasma HIF-1α in the RIC group were statistically different from those in the control group (P = 0.006). ConclusionEarly and short-term RIC treatment was well-tolerated and effective in improving the prognosis in acute CI. HIF-1α can be recognized as a biomarker for evaluating the efficacy of RIC treatment.

Time from Onset to Remote Ischemic Conditioning and Clinical Outcome After Acute Moderate Ischemic Stroke.

We conducted a post hoc exploratory analysis of Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke (RICAMIS) to determine whether early remote ischemic conditioning (RIC) initiation after stroke onset was associated with clinical outcome in patients with acute moderate ischemic stroke. In RICAMIS, patients receiving RIC treatment in the intention-to-treat analysis were divided into 2 groups based on onset-to-treatment time (OTT): early RIC group (OTT ≤ 24 hours) and late RIC group (OTT 24-48 hours). Patients receiving usual care without RIC treatment from intention-to-treat analysis were assigned as the control group. The primary outcome was excellent functional outcome at 90 days. Among 1,776 patients from intention-to-treat analysis, 387 were in the early RIC group, 476 in the late RIC group, and 913 in the control group. In the post hoc exploratory analysis, a higher proportion of excellent functional outcome was found in the early RIC versus control group (adjusted absolute difference = 8.1%, 95% confidence interval [CI] = 2.5%-13.8%, p = 0.005), but no difference in outcomes was detected in the late RIC versus control group (adjusted absolute difference = 3.3%, 95% CI = -2.1% to 8.6%, p = 0.23), or in the early RIC versus late RIC group (adjusted absolute difference = 5.0%, 95% CI = -1.3% to 11.2%, p = 0.12). Similar results were found in the per-protocol analysis. Among patients with acute moderate ischemic stroke who are not candidates for intravenous thrombolysis or endovascular therapy, early RIC initiation within 24 hours of onset may be associated with higher likelihood of excellent clinical outcome. ANN NEUROL 2023.

Effect of remote ischemic conditioning on the immune-inflammatory profile in patients with traumatic hemorrhagic shock in a randomized controlled trial

Resuscitation induced ischemia/reperfusion predisposes trauma patients to systemic inflammation and organ dysfunction. We investigated the effect of remote ischemic conditioning (RIC), a treatment shown to prevent ischemia/reperfusion injury in experimental models of hemorrhagic shock/resuscitation, on the systemic immune-inflammatory profile in trauma patients in a randomized trial. We conducted a prospective, single-centre, double-blind, randomized, controlled trial involving trauma patients sustaining blunt or penetrating trauma in hemorrhagic shock admitted to a Level 1 trauma centre. Patients were randomized to receive RIC (four cycles of 5-min pressure cuff inflation at 250 mmHg and deflation on the thigh) or a Sham intervention. The primary outcomes were neutrophil oxidative burst activity, cellular adhesion molecule expression, and plasma levels of myeloperoxidase, cytokines and chemokines in peripheral blood samples, drawn at admission (pre-intervention), 1 h, 3 h, and 24 h post-admission. Secondary outcomes included ventilator, ICU and hospital free days, incidence of nosocomial infections, 24 h and 28 day mortality. 50 eligible patients were randomized; of which 21 in the Sham group and 18 in the RIC group were included in the full analysis. No treatment effect was observed between Sham and RIC groups for neutrophil oxidative burst activity, adhesion molecule expression, and plasma levels of myeloperoxidase and cytokines. RIC prevented significant increases in Th2 chemokines TARC/CCL17 (P < 0.01) and MDC/CCL22 (P < 0.05) at 24 h post-intervention in comparison to the Sham group. Secondary clinical outcomes were not different between groups. No adverse events in relation to the RIC intervention were observed. Administration of RIC was safe and did not adversely affect clinical outcomes. While trauma itself modified several immunoregulatory markers, RIC failed to alter expression of the majority of markers. However, RIC may influence Th2 chemokine expression in the post resuscitation period. Further investigation into the immunomodulatory effects of RIC in traumatic injuries and their impact on clinical outcomes is warranted.ClinicalTrials.gov number: NCT02071290.

Protective role of remote ischemic conditioning in renal transplantation and partial nephrectomy: A systematic review and meta-analysis of randomized controlled trials.

Studies have shown that remote ischemic conditioning (RIC) can effectively attenuate ischemic-reperfusion injury in the heart and brain, but the effect on ischemic-reperfusion injury in patients with kidney transplantation or partial nephrectomy remains controversial. The main objective of this systematic review and meta-analysis was to investigate whether RIC provides renal protection after renal ischemia-reperfusion injury in patients undergoing kidney transplantation or partial nephrectomy. A computer-based search was conducted to retrieve relevant publications from the PubMed database, Embase database, Cochrane Library and Web of Science database. We then conducted a systematic review and meta-analysis of randomized controlled trials that met our study inclusion criteria. Eleven eligible studies included a total of 1,145 patients with kidney transplantation or partial nephrectomy for systematic review and meta-analysis, among whom 576 patients were randomly assigned to the RIC group and the remaining 569 to the control group. The 3-month estimated glomerular filtration rate (eGFR) was improved in the RIC group, which was statistically significant between the two groups on kidney transplantation [P < 0.001; mean difference (MD) = 2.74, confidence interval (CI): 1.41 to 4.06; I 2 = 14%], and the 1- and 2-day postoperative Scr levels in the RIC group decreased, which was statistically significant between the two groups on kidney transplantation (1-day postoperative: P < 0.001; MD = 0.10, CI: 0.05 to 0.15, I 2 = 0; 2-day postoperative: P = 0.006; MD = 0.41, CI: 0.12 to 0.70, I 2 = 0), but at other times, there was no significant difference between the two groups in Scr levels. The incidence of delayed graft function (DGF) decreased, but there was no significant difference (P = 0.60; 95% CI: 0.67 to 1.26). There was no significant difference between the two groups in terms of cross-clamp time, cold ischemia time, warm ischemic time, acute rejection (AR), graft loss or length of hospital stay. Our meta-analysis showed that the effect of remote ischemia conditioning on reducing serum creatinine (Scr) and improving estimate glomerular filtration rate (eGFR) seemed to be very weak, and we did not observe a significant protective effect of RIC on renal ischemic-reperfusion. Due to small sample sizes, more studies using stricter inclusion criteria are needed to elucidate the nephroprotective effect of RIC in renal surgery in the future.

Remote Ischemic Conditioning in Pediatric Cancer Patients Receiving Anthracycline Chemotherapy: A Sham-Controlled Single-Blind Randomized Trial

BackgroundAnthracycline cardiotoxicity is a concern in survivors of childhood cancers. Recent evidence suggests that remote ischemic conditioning (RIC) may offer myocardial protection. ObjectivesThis randomized sham-controlled single-blind study tested the hypothesis that RIC may reduce myocardial injury in pediatric cancer patients receiving anthracycline chemotherapy. MethodsWe performed a phase 2 sham-controlled single-blind randomized controlled trial to determine the impact of RIC on myocardial injury in pediatric cancer patients receiving anthracycline-based chemotherapy. Patients were randomized to receive RIC (3 cycles of 5-minute inflation of a blood pressure cuff placed over 1 limb to 15 mm Hg above systolic pressure) or sham intervention. The intervention was applied within 60 minutes before initiation of the first dose and before up to 4 cycles of anthracycline therapy. The primary outcome was the plasma high-sensitivity cardiac troponin T (hs-cTnT) level. The secondary outcome measures included echocardiographic indexes of left ventricular systolic and diastolic function and the occurrence of cardiovascular events. ResultsA total of 68 children 10.9 ± 3.9 years of age were randomized to receive RIC (n = 34) or sham (n = 34) intervention. Plasma levels of hs-cTnT showed a progressive increase across time points in the RIC (P < 0.001) and sham (P < 0.001) groups. At each of the time points, there were no significant differences in hs-cTnT levels or LV tissue Doppler and strain parameters between the 2 groups (all P > 0.05). None of the patients developed heart failure or cardiac arrhythmias. ConclusionsRIC did not exhibit cardioprotective effects in childhood cancer patients receiving anthracycline-based chemotherapy. (Remote Ischaemic Preconditioning in Childhood Cancer [RIPC]; NCT03166813)

Effect of Remote Ischemic Conditioning vs Usual Care on Neurologic Function in Patients With Acute Moderate Ischemic Stroke

Preclinical and clinical studies have suggested a neuroprotective effect of remote ischemic conditioning (RIC), which involves repeated occlusion/release cycles on bilateral upper limb arteries; however, robust evidence in patients with ischemic stroke is lacking. To assess the efficacy of RIC for acute moderate ischemic stroke. This multicenter, open-label, blinded-end point, randomized clinical trial including 1893 patients with acute moderate ischemic stroke was conducted at 55 hospitals in China from December 26, 2018, through January 19, 2021, and the date of final follow-up was April 19, 2021. Eligible patients were randomly assigned within 48 hours after symptom onset to receive treatment with RIC (using a pneumatic electronic device and consisting of 5 cycles of cuff inflation for 5 minutes and deflation for 5 minutes to the bilateral upper limbs to 200 mm Hg) for 10 to 14 days as an adjunct to guideline-based treatment (n = 922) or guideline-based treatment alone (n = 971). The primary end point was excellent functional outcome at 90 days, defined as a modified Rankin Scale score of 0 to 1. All end points had blinded assessment and were analyzed on a full analysis set. Among 1893 eligible patients with acute moderate ischemic stroke who were randomized (mean [SD] age, 65 [10.3] years; 606 women [34.1%]), 1776 (93.8%) completed the trial. The number with excellent functional outcome at 90 days was 582 (67.4%) in the RIC group and 566 (62.0%) in the control group (risk difference, 5.4% [95% CI, 1.0%-9.9%]; odds ratio, 1.27 [95% CI, 1.05-1.54]; P = .02). The proportion of patients with any adverse events was 6.8% (59/863) in the RIC group and 5.6% (51/913) in the control group. Among adults with acute moderate ischemic stroke, treatment with remote ischemic conditioning compared with usual care significantly increased the likelihood of excellent neurologic function at 90 days. However, these findings require replication in another trial before concluding efficacy for this intervention. ClinicalTrials.gov Identifier: NCT03740971.

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.

Effects of ischemic conditioning on head and neck free flap oxygenation: a randomized controlled trial

Flap failure after microvascular reconstructive surgery is a rare but devastating complication caused by reperfusion injury and tissue hypoperfusion. Remote ischemic conditioning (RIC) provides protection against ischemia/reperfusion injury and reduces tissue infarction. We hypothesized that RIC would enhance flap oxygenation and exert organ-protective effects during head and neck free flap reconstructive surgery. Adult patients undergoing free flap transfer surgery for head and neck cancer were randomized to receive either RIC or sham-RIC during surgery. RIC consisted of four cycles of 5-min ischemia and 5-min reperfusion applied to the upper or lower extremity. The primary endpoint, tissue oxygen saturation of the flap, was measured by near-infrared spectroscopy on the first postoperative day. Organ-protective effects of RIC were evaluated with infarct size of rat hearts perfused with plasma dialysate from patients received RIC or sham-RIC. Between April 2018 and July 2019, 50 patients were randomized (each n = 25) and 46 were analyzed in the RIC (n = 23) or sham-RIC (n = 23) groups. Tissue oxygen saturation of the flap was similar between the groups (85 ± 12% vs 83 ± 9% in the RIC vs sham-RIC groups; P = 0.471). Myocardial infarct size after treatment of plasma dialysate was significantly reduced in the RIC group (44 ± 7% to 26 ± 6%; P = 0.018) compared to the sham-RIC group (42 ± 6% to 37 ± 7%; P = 0.388). RIC did not improve tissue oxygenation of the transferred free flap in head and neck cancer reconstructive surgery. However, there was evidence of organ-protective effects of RIC in experimental models.Trial registration: Registry number of ClinicalTrials.gov: NCT03474952.

Daily Remote Ischemic Conditioning Can Improve Cerebral Perfusion and Slow Arterial Progression of Adult Moyamoya Disease-A Randomized Controlled Study.

Background and PurposeMoyamoya disease (MMD) is a complicated cerebrovascular disease with recurrent ischemic or hemorrhagic events. This study aimed to prove the safety and efficacy of remote ischemic conditioning (RIC) on MMD.MethodsIn total, 34 patients with MMD participated in this pilot, prospective randomized controlled study for 1 year. 18 patients were allocated into the RIC group, and 16 patients accepted routine medical treatment only. RIC-related adverse events were recorded. The primary outcome was the improvement ratio of mean cerebral blood flow (mCBF) in middle cerebral artery territory measured by multidelay pseudocontinuous arterial spin labeling, and the secondary outcomes were the cumulative incidence of major adverse cerebrovascular events (MACEs), the prevalence of stenotic-occlusive progression, and periventricular anastomosis at 1-year follow-up.ResultsIn total, 30 of the 34 patients with MMD completed the final follow-up (17 in the RIC group and 13 in the control group). No adverse events of RIC were observed. The mCBF improvement ratio of the RIC group was distinctively higher compared with the control group (mCBF−whole-brain: 0.16 ± 0.15 vs. −0.03 ± 0.13, p = 0.001). Stenotic-occlusive progression occurred in 11.8% hemispheres in the RIC group and 38.5% in the control group (p = 0.021). The incidence of MACE was 5.9% in the RIC group and 30.8% in the control group (hazard ratio with RIC, 0.174; 95% CI, 0.019–1.557; p = 0.118). No statistical difference was documented in the periventricular anastomosis between the two groups after treatment.ConclusionsRemote ischemic conditioning has the potential to be a safe and effective adjunctive therapy for patients with MMD largely due to improving cerebral blood flow and slowing the arterial progression of the stenotic-occlusive lesions. These findings warrant future studies in larger trials.

Remote Ischemic Conditioning in the Prevention for Stroke-Associated Pneumonia: A Pilot Randomized Controlled Trial.

BackgroundDespite the continuing effort in investigating the preventive therapies for stroke-associated pneumonia (SAP), which is closely associated with unfavorable outcomes, conclusively effective therapy for the prevention of SAP is still lacking. Remote ischemic conditioning (RIC) has been proven to improve the survival in the sepsis model and inflammatory responses have been indicated as important mechanisms involved in the multi-organ protection effect of RIC. This study aimed to assess the safety and the preliminary efficacy of RIC in the prevention of SAP in patients with acute ischemic stroke.MethodsWe performed a proof-of-concept, pilot open-label randomized controlled trial. Eligible patients (age > 18 years) within 48 h after stroke onset between March 2019 and October 2019 with acute ischemic stroke were randomly allocated (1:1) to the RIC group and the control group. All participants received standard medical therapy. Patients in the RIC group underwent RIC twice daily for 6 consecutive days. The safety outcome included any adverse events associated with RIC procedures. The efficacy outcome included the incidence of SAP, changes of immunological profiles including mHLA-DR, TLR-2, and TLR-4 as well as other plasma parameters from routine blood tests.ResultsIn total, 46 patients aged 63.1 ± 12.5 years, were recruited (23 in each group). Overall, 19 patients in the RIC group and 22 patients in the control group completed this study. No severe adverse event was attributed to RIC procedures. The incidence of SAP was lower in the remote ischemic conditioning group (2 patients [10.5%]) than that in the control group (6 patients [27.3%]), but no significant difference was detected in both univariate and multivariate analysis (p = 0.249 and adjusted p = 0.666). No significance has been found in this pilot trial in the level of immunological profiles HLA-DR, TLR4 and TLR2 expressed on monocytes as well as blood parameters tested through routine blood tests between the two groups (p > 0.05). The IL-6 and IL-1β levels at day 5 after admission in the RIC group were lower than those in the control group (p < 0.05).InterpretationThis proof-of-concept pilot randomized controlled trial was to investigate RIC as a prevention method for SAP. Remote ischemic conditioning is safe in the prevention of SAP in patients with acute ischemic stroke. The preventive effect of RIC on SAP should be further validated in future studies.