Effects Of Remote Ischemic Conditioning Research Articles

Transcriptomic analysis of the effect of remote ischaemic conditioning in an animal model of necrotising enterocolitis

Necrotising enterocolitis (NEC) has a complex pathophysiology but the common end-point is ischaemia reperfusion injury (IRI) and intestinal necrosis. We have previously reported that RIC significantly reduces the intestinal injury in a rat model of NEC. Here we describe the changes in intestinal mRNA occurring in the intestine of animals exposed to IRI, both with and without RIC. Related rat-pups were randomly assigned to four groups: SHAM, IRI only, RIC only and RIC + IRI. IRI animals, underwent 40 min of intestinal ischaemia, and 90 min of reperfusion. Animals that underwent RIC had three cycles of 5 min of alternating ischaemia/reperfusion by means of a ligature applied to the hind limb. Samples from the terminal ileum were immediately stored in RNA-preserving media for later next generation sequencing and transciptome analysis using R v 3.6.1. Differential expression testing showed that 868 genes differentially expressed in animals exposed to RIC alone compared to SHAM and 135 in the IRI and RIC group compared to IRI alone. Comparison between these two sets showed that 25 genes were differentially expressed in both groups. Pro-inflammatory molecules: NF-ĸβ2, Cxcl1, SOD2 and Map3k8 all show reduced expression in response to RIC. Targeted gene analysis revealed increased expression in PI3K which is part of the so-called RISK-pathway which is a key part of the protective mechanisms of RIC in the heart. Overall, this transcriptomic analysis shows that RIC provides a protective effect to the intestine via anti-inflammatory pathways. This could be particularly relevant to treating and preventing NEC.

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.

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.

The Infarct-Limiting Effect of Remote Ischemic Conditioning in Rats Is Not Affected by Aspirin.

Remote ischemic conditioning (RIC)has been shown to be a powerful cardioprotective therapy in animal models. However, a protective effect in patients presenting with acute myocardial infarction has failed to be confirmed. A recent pre-clinical study reported that aspirin which is routinely given to patients undergoing reperfusion therapy blocked the infarct-limiting effect of ischemic postconditioning. The present study was designed to test whether aspirin could also be blocking the infarct-limiting effect of RIC. This was investigated in vivo using male Sprague Dawley rats (n = 5 to 6 per group) subjected to either 30 min of regional myocardial ischemia, followed by 120-min reperfusion, or additionally to a RIC protocol initiated after 20-min myocardial ischemia. The RIC protocol included four cycles of 5-min hind limb ischemia interspersed with 5-min reperfusion. Intravenous aspirin (30 mg/kg) or vehicle (saline) was administered after 15-min myocardial ischemia. RIC significantly reduced infarct size (IS) normalized to the area at risk, by 47%. Aspirin administration did not affect IS nor did it attenuate the infarct-limiting effect of RIC. Aspirin administration in the setting of myocardial infarction is not likely to interfere with the cardioprotective effect of RIC.

Neuroadaptive Biochemical Mechanisms of Remote Ischemic Conditioning

This review summarizes the currently known biochemical neuroadaptive mechanisms of remote ischemic conditioning. In particular, it focuses on the significance of the pro-adaptive effects of remote ischemic conditioning which allow for the prevention of the neurological and cognitive impairments associated with hippocampal dysregulation after brain damage. The neuroimmunohumoral pathway transmitting a conditioning stimulus, as well as the molecular basis of the early and delayed phases of neuroprotection, including anti-apoptotic, anti-oxidant, and anti-inflammatory components, are also outlined. Based on the close interplay between the effects of ischemia, especially those mediated by interaction of hypoxia-inducible factors (HIFs) and steroid hormones, the involvement of the hypothalamic–pituitary–adrenocortical system in remote ischemic conditioning is also discussed.

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.

Remote ischemic conditioning attenuates oxidative stress and inflammation via the Nrf2/HO-1 pathway in MCAO mice

The protective effects of remote ischemic conditioning (RIC) on acute ischemic stroke have been reported. However, the protective mechanisms of RIC have not been fully elucidated. This study aimed to investigate whether RIC could reduce oxidative stress and inflammatory responses in middle cerebral artery occlusion (MCAO)-reperfusion mice via the nuclear factor-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. C57BL/6 mice were subjected to MCAO and underwent RIC twice daily at 1, 3, and 7 days after MCAO. ML385 was used to specifically inhibit Nrf2 in MCAO mice. Neurological deficit scores, infarct volume, and hematoxylin-eosin (HE) staining were assessed. Oxidative stress levels were assessed based on total antioxidant capacity (TAC), malonaldehyde (MDA), superoxide dismutase (SOD), and glutathione/glutathione disulfide (GSH/GSSG). mRNA levels were detected using real-time polymerase chain reaction (PCR), and protein levels were detected using western blotting and enzyme-linked immunosorbent assay (ELISA). Protein localization was investigated using immunofluorescence staining. RIC significantly reduced infarct volume and improved neurological function and histological changes after MCAO. RIC significantly increased TAC, SOD, and GSH/GSSG levels and decreased MDA levels. RIC significantly increased Nrf2 and HO-1 mRNA levels and decreased Keap1, NLRP3, and Cleaved Caspase-1 mRNA levels. RIC significantly increased Nrf2, HO-1, and NQO1 protein expression and decreased Keap1, NLRP3, Cleaved Caspase-1, Cleaved IL-1β, IL-6, and TNF-α protein expression. RIC promoted the activation and translocation of Nrf2 into the nucleus. The protective effects of RIC were abolished by ML385 treatment. In conclusion, our findings suggest that RIC alleviates oxidative stress and inflammatory responses via the Nrf2/HO-1 pathway, which in turn improves neurobehavioral function. RIC may provide novel therapeutic options for acute ischemic stroke.

Effects of remote ischemic conditioning on conditioned pain modulation and cardiac autonomic modulation in women with knee osteoarthritis: placebo-controlled randomized clinical trial protocol

BackgroundIt is estimated that over 240 million people worldwide have osteoarthritis, which is a major contributor to chronic pain and central changes in pain processing, including endogenous pain modulation. The autonomic nervous system plays a crucial role in the pain regulatory process. One of the main mechanisms of remote ischemic conditioning is neuronal signaling from the preconditioned extremity to the heart. This study aims to analyze the acute effect of remote ischemic conditioning on local pain, conditioned pain modulation, and cardiac autonomic control in women with knee osteoarthritis and to see if there is a correlation between them.MethodsWomen more than 50 years with knee osteoarthritis diagnosed according to the American College of Rheumatology criteria in the postmenopausal period will be considered eligible. The study will have blind randomization, be placebo-controlled, and be balanced in a 1:1 ratio. The total of 44 participants will be divided into two groups (22 participants per group): (i) remote ischemic conditioning and (ii) placebo remote ischemic conditioning. Protocol consisting of four cycles of total ischemia, followed immediately by four cycles of 5 min of vascular reperfusion, totaling 40 min. The primary outcomes in the protocol are conditioned pain modulation, which has the pressure pain threshold (kgf/cm2) as its primary outcome measure, and cardiac autonomic modulation, which has the indices found in heart rate variability as its primary outcome measure. Comparisons will be performed using generalized linear mixed models fitted to the data. For correlation, the Pearson or Spearman test will be used depending on the normality of the data. All analyses will assume a significance level of p < 0.05.DiscussionIt is believed that the results of this study will present a new perspective on the interaction between the pain processing system and the cardiovascular system; they will provide the professional and the patient with a greater guarantee of cardiovascular safety in the use of the intervention; it will provide knowledge about acute responses and this will allow future chronic intervention strategies that aim to be used in the clinical environment, inserted in the multimodal approach, for the treatment of osteoarthritis of the knee.Trial registrationClinicalTrials.gov NCT05059652. Registered on 30 August 2021. Last update on 28 March 2023.

P.085 The effect of remote ischemic conditioning on cognitive and radiological outcomes in cerebrovascular diseases: a systematic review

Background: The effect of remote ischemic conditioning on cognitive and radiological outcomes in patients with cerebrovascular disease is uncertain. We performed a systematic review to evaluate the effects of remote ischemic conditioning on cognitive and radiological outcomes in patients with cerebrovascular diseases. Methods: A systematic search using relevant keywords and database specific terms was conducted in MEDLINE, Embase, and Web of Science from inception to October 27 2022. Results: A total of 4269 articles were screened, of which 20 were included. Ten papers assessing cognitive outcomes were included, with 5/10 reporting improvements in cognitive scores relative to a control group. Sixteen papers reporting on radiologic outcomes were included, three reporting on changes in infarct volume, and four on lesion volume. Improvement in infarct and lesion volume was reported in 1/3 studies and 4/4 studies respectively, however there was considerable variation in the time between assessments (range 1-365 days). Nine papers assessing blood flow changes were found, of which 3/8 using transcranial doppler reported improved blood flow velocity post intervention. Conclusions: The articles identified suggest that remote ischemic conditioning may provide improvement for both cognitive and radiological outcomes in patients with cerebrovascular diseases, however future well-designed studies are needed to determine degree of benefit.

Anthracyclines and Biomarkers of Myocardial Injury: The Effect of Remote Ischemic Conditioning

BackgroundRemote ischemic conditioning (RIC) has been beneficial in laboratory studies of anthracycline cardiotoxicity, but its effects in patients is not established. ObjectivesThe authors studied the effect of RIC on cardiac biomarkers and function during and after anthracycline chemotherapy. MethodsThe ERIC-Onc study (Effect of Remote Ischaemic Conditioning in Oncology Patients; NCT02471885) was a randomized, single-blind, sham-controlled study of RIC at each chemotherapy cycle. The primary endpoint was troponin T (TnT) during chemotherapy and up to 1 year. Secondary outcomes included cardiac function, major adverse cardiovascular events (MACE), and MACE or cancer death. Cardiac myosin-binding-protein C (cMyC) was investigated in parallel with TnT. ResultsThe study was prematurely halted after the evaluation of 55 patients (RIC n = 28, sham n = 27). Biomarkers increased from baseline to cycle 6 of chemotherapy for all patients (median TnT 6 [IQR: 4-9] ng/L to 33 [IQR: 16-36)] ng/L; P ≤ 0.001; cMyC 3 (IQR: 2-5) ng/L to 47 (IQR: 18-49) ng/L; P ≤ 0.001). Mixed-effects regression analysis for repeated measures showed no difference in TnT between the 2 groups (RIC vs sham, mean difference 3.15 ng/L; 95% CI: −0.04 to 6.33; P = 0.053), or cMyC (RIC vs sham, mean difference 4.17 ng/L; 95% CI: −0.12 to 8.45; P = 0.056). There were more MACE and cancer deaths in the RIC group (11 vs 3; HR: 0.25; 95% CI: 0.07-0.90; P = 0.034), with more cancer deaths (8 vs 1; HR: 0.21; 95% CI: 0.04-0.95; P = 0.043) at 1 year. ConclusionsTnT and cMyC significantly increased during anthracycline chemotherapy with 81% having a TnT ≥14 ng/L at cycle 6. RIC did not affect the rise in biomarkers, but there was a small increase in early cancer deaths, possibly related to the greater proportion of patients with metastatic disease randomized to the RIC group (54%vs 37%). (Effect of Remote Ischaemic Conditioning in Oncology Patients [ERIC-ONC]; NCT02471885)

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.

Remote ischemic conditioning-induced hyperacute and acute responses of plasma proteome in healthy young male adults: a quantitative proteomic analysis.

Long-term remote ischemic conditioning (RIC) has been proven to be beneficial in multiple diseases, such as cerebral and cardiovascular diseases. However, the hyperacute and acute effects of a single RIC stimulus are still not clear. Quantitative proteomic analyses of plasma proteins following RIC application have been conducted in preclinical and clinical studies but exhibit high heterogeneity in results due to wide variations in experimental setups and sampling procedures. Hence, this study aimed to explore the immediate effects of RIC on plasma proteome in healthy young adults to exclude confounding factors of disease entity, such as medications and gender. Young healthy male participants were enrolled after a systematic physical examination and 6-month lifestyle observation. Individual RIC sessions included five cycles of alternative ischemia and reperfusion, each lasting for 5 min in bilateral forearms. Blood samples were collected at baseline, 5 min after RIC, and 2 h after RIC, and then samples were processed for proteomic analysis using liquid chromatography-tandem mass spectrometry method. Proteins related to lipid metabolism (e.g., Apolipoprotein F), coagulation factors (hepatocyte growth factor activator preproprotein), members of complement cascades (mannan-binding lectin serine protease 1 isoform 2 precursor), and inflammatory responses (carboxypeptidase N catalytic chain precursor) were differentially altered at their serum levels following the RIC intervention. The most enriched pathways were protein glycosylation and complement/coagulation cascades. One-time RIC stimulus may induce instant cellular responses like anti-inflammation, coagulation, and fibrinolysis balancing, and lipid metabolism regulation which are protective in different perspectives. Protective effects of single RIC in hyperacute and acute phases may be exploited in clinical emergency settings due to apparently beneficial alterations in plasma proteome profile. Furthermore, the beneficial effects of long-term (repeated) RIC interventions in preventing chronic cardiovascular diseases among general populations can also be expected based on our study findings. ClinicalTrials.gov, NCT03105141.

The antihypertensive effect of remote ischemic conditioning in spontaneously hypertensive rats.

Limb remote ischemic conditioning (LRIC) may be an effective method to control hypertension. This study investigated whether LRIC decreases blood pressure by regulating the hypertensive inflammatory response in spontaneously hypertensive rats (SHR). The SHR and aged-matched Wistar rats with different ages were randomly assigned to the SHR group, SHR+LRIC group, Wistar group, and Wistar + LRIC group. LRIC was conducted by tightening a tourniquet around the upper thigh and releasing it for three cycles daily (10 mins x3 cycles). Blood pressure, the percentage of monocytes and T lymphocytes, and the concentration of pro-inflammatory cytokines in the blood were analyzed. The blood pressure of SHR was significantly higher than that of age-matched Wistar rats. LRIC decreased blood pressure in SHR at different ages (4, 8, and 16 weeks old), but had no effect on the blood pressure in Wistar rats. Flow cytometry analysis showed that blood monocytes and CD8 T cells of SHR were higher than those of Wistar rats. LRIC significantly decreased the percentage of monocytes and CD8 T cells in SHR. Consistent with the changes of immune cells, the levels of plasma IL-6 and TNF-α in SHR were also higher. And LRIC attenuated the plasma IL-6 and TNF-α levels in SHR. LRIC may decreased the blood pressure via modulation of the inflammatory response in SHR.

Effect of remote ischemic conditioning on heart rate responses to walking in people with multiple sclerosis

Remote ischemic conditioning (RIC), exposure of body parts to brief periods of circulatory occlusion and reperfusion, has been shown to improve cardiovascular responses to exercise in healthy individuals but its effects in people with MS are unknown. This study aimed to assess the effect of RIC on heart rate responses to walking in people with MS. Double blind randomized controlled trial. Multiple sclerosis clinic of tertiary care center teaching hospital in the United Kingdom. Three cycles of RIC were delivered by occluding the upper arm with a blood pressure cuff inflated to a pressure of 30 mmHg above the systolic blood pressure. In the sham group, the blood pressure cuff was inflated to 30 mmHg below diastolic blood pressure. Heart rate responses to the 6-minute walk test (6MWT), the tolerability of RIC using a numerical rating scale for discomfort (0-10), and adverse events were studied. Seventy-five participants (RIC -38 and Sham-37) completed the study. RIC was well tolerated. Compared to sham, RIC significantly decreased the rise in heart rate (P = 0.04) and percentage of predicted maximum heart rate (P = 0.016) after the 6MWT. RIC was well tolerated and improved the heart rate response to walking in people with MS. Further studies on RIC in the management of MS are needed.

A review of remote ischemic conditioning as a potential strategy for neural repair poststroke.

Ischemic stroke is one of the major disabling health-care problem and multiple different approaches are needed to enhance rehabilitation, in which neural repair is the structural basement. Remote ischemic conditioning (RIC) is a strategy to trigger endogenous protect. RIC has been reported to play neuroprotective role in acute stage of stroke, but the effect of RIC on repair process remaining unclear. Several studies have discovered some overlapped mechanisms RIC and neural repair performs. This review provides a hypothesis that RIC is a potential therapeutic strategy on stroke rehabilitation by evaluating the existing evidence and puts forward some remaining questions to clarify and future researches to be performed in the field.

Effect of Remote Ischaemic Conditioning on the Inflammatory Cytokine Cascade of COVID-19 (RIC in COVID-19): a Randomized Controlled Trial

PurposePatients hospitalized with COVID-19 may develop a hyperinflammatory, dysregulated cytokine “storm” that rapidly progresses to acute respiratory distress syndrome, multiple organ dysfunction, and even death. Remote ischaemic conditioning (RIC) has elicited anti-inflammatory and cytoprotective benefits by reducing cytokines following sepsis in animal studies. Therefore, we investigated whether RIC would mitigate the inflammatory cytokine cascade induced by COVID-19.MethodsWe conducted a prospective, multicentre, randomized, sham-controlled, single-blind trial in Brazil and South Africa. Non-critically ill adult patients with COVID-19 pneumonia were randomly allocated (1:1) to receive either RIC (intermittent ischaemia/reperfusion applied through four 5-min cycles of inflation (20 mmHg above systolic blood pressure) and deflation of an automated blood-pressure cuff) or sham for approximately 15 days. Serum was collected following RIC/sham administration and analyzed for inflammatory cytokines using flow cytometry. The endpoint was the change in serum cytokine concentrations. Participants were followed for 30 days.ResultsEighty randomized participants (40 RIC and 40 sham) completed the trial. Baseline characteristics according to trial intervention were overall balanced. Despite downward trajectories of all cytokines across hospitalization, we observed no substantial changes in cytokine concentrations after successive days of RIC. Time to clinical improvement was similar in both groups (HR 1.66; 95% CI, 0.938–2.948, p 0.08). Overall RIC did not demonstrate a significant impact on the composite outcome of all-cause death or clinical deterioration (HR 1.19; 95% CI, 0.616–2.295, p = 0.61).ConclusionRIC did not reduce the hypercytokinaemia induced by COVID-19 or prevent clinical deterioration to critical care.Trial RegistrationClinicalTrials.gov Identifier: NCT04699227.

Acute Microcirculatory Effects of Remote Ischemic Conditioning in Superficial Partial Thickness Burn Wounds.

Microcirculation is a critical factor in burn wound healing. Remote ischemic conditioning (RIC) has been shown to improve microcirculation in healthy skin and demonstrated ischemic protective effects on heart, kidney, and liver cells. Therefore, we examined microcirculatory effects of RIC in partial thickness burn wounds. The hypothesis of this study is that RIC improves cutaneous microcirculation in partial thickness burn wounds. Twenty patients with partial thickness burn wounds within 48 hours after trauma were included in this study. RIC was performed with an upper arm blood pressure cuff on a healthy upper arm using three ischemia cycles (5 min inflation to 200 mm Hg) followed by 10-minute reperfusion phases. The third and final reperfusion phase lasted 20 minutes. Microcirculation of the remote (lower/upper extremities or torso) burn wound was continuously quantified, using a combined Laser Doppler and white light spectrometry. The capillary blood flow in the burn wounds increased by a maximum of 9.6% after RIC (percentage change from baseline; P < .01). Relative hemoglobin was increased by a maximum of 2.8% (vs. baseline; P < .01), while cutaneous tissue oxygen saturation remained constant (P > .05). RIC improves microcirculation in partial thickness burn wounds by improving blood flow and elevating relative hemoglobin.

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.

Effects of remote ischemic conditioning on sleep complaints in Parkinson's disease-rationale, design, and protocol for a randomized controlled study.

ObjectiveSleep disturbances are common non-motor symptoms of Parkinson's disease. The symptoms affect the quality of patients' life by impeding normal sleep cycles and causing excessive daytime sleepiness. Remote Ischemic Conditioning (RIC) is a therapy often used for ischemic stroke patients to minimize infarct size and maximize post-stroke neurological function. Animal experiments have shown that RIC plays a protective role for retinal ganglion cells and other critical areas of the brain of Parkinson's disease. However, whether RIC improves excessive daytime sleepiness (EDS) for patients with Parkinson's disease remains to be determined.MethodsThis is a single-center, double-blind, and randomized controlled trial, which includes patients with Parkinson's disease with EDS. All recruited patients will be randomly assigned either to the RIC or the control group (i.e., sham-RIC) with 20 patients in each group. Both groups receive RIC or sham-RIC treatment once a day for 28 days within 24 h of enrollment. Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), Parkinson Disease Sleep Scale-2 (PDSS-2), Parkinson's Disease Questionnaire39 (PDQ39) score scales, and adverse events, such as inability to tolerate the treatment leading to suspension of the study or objective signs of tissue or neurovascular injury caused by RIC and/or sham-RIC are evaluated at 7, 14, 28, and 90 days after enrollment.ResultsThe primary goal of this study is to assess the feasibility of the treatments in patients with Parkinson's disease by measuring serious RIC-related adverse events and any reduced incidence of adverse events during the trial and to study potential efficacy, improvement of patients' excessive daytime sleepiness, quality of life-based on ESS, PSQI, PDSS-2, and PDQ39 scores. The secondary goal is to confirm the safety of the treatments.ConclusionThis study is a prospective randomized controlled trial to determine the safety, feasibility, and potential efficacy of RIC for patients with Parkinson's disease associated with EDS.