Remote ischemic preconditioning versus sham-control for prevention of anastomotic leakage after resection for rectal cancer (RIPAL trial): a pilot randomized controlled, triple-blinded monocenter trial.

PURPOSE: Remote ischemic preconditioning (RIPC) reportedly reduces ischemia‒reperfusion injury (IRI) in various organ systems. In addition to tension and technical factors, ischemia is a common cause of anastomotic leakage (AL) after rectal resection. The aim of this pilot study was to investigate the potentially protective effect of RIPC on anastomotic healing and to determine the effect size to facilitate the development of a subsequent confirmatory trial. MATERIALS AND METHODS: Fifty-four patients with rectal cancer (RC) who underwent anterior resection were enrolled in this prospectively registered (DRKS0001894) pilot randomized controlled triple-blinded monocenter trial at the Department of Surgery, University Medicine Mannheim, Mannheim, Germany, between 10/12/2019 and 19/06/2022. The primary endpoint was AL within 30 days after surgery. The secondary endpoints were perioperative morbidity and mortality, reintervention, hospital stay, readmission and biomarkers of ischemia‒reperfusion injury (vascular endothelial growth factor, VEGF) and cell death (high mobility group box 1 protein, HMGB1). RIPC was induced through three 10-min cycles of alternating ischemia and reperfusion to the upper extremity. RESULTS: Of the 207 patients assessed, 153 were excluded, leaving 54 patients to be randomized to the RIPC or the sham-RIPC arm (27 each per arm). The mean age was 61 years, and the majority of patients were male (37:17 (68.5:31.5%)). Most of the patients underwent surgery after neoadjuvant therapy (29/54 (53.7%)) for adenocarcinoma (52/54 (96.3%)). The primary endpoint, AL, occurred almost equally frequently in both arms (RIPC arm: 4/25 (16%), sham arm: 4/26 (15.4%), p = 1.000). The secondary outcomes were comparable except for a greater rate of reintervention in the sham arm (9 (6-12) vs. 3 (1-5), p = 0.034). The median duration of endoscopic vacuum therapy was shorter in the RIPC arm (10.5 (10-11) vs. 38 (24-39) days, p = 0.083), although the difference was not statistically significant. CONCLUSION: A clinically relevant protective effect of RIPC on anastomotic healing after rectal resection cannot be assumed on the basis of these data.

Effect of remote ischemic preconditioning intervention on serum levels of microRNA-582-5p/HMGB1 in patients with acute cerebral infarction.

OBJECTIVE: Acute cerebral infarction (ACI) contributes to disability and death accross the globe. Remote ischemic preconditioning (RIPC) reduces cerebral infarct size and improves neurological function in ACI. We conducted this research to reveal the effects of RIPC intervention on serum levels of microRNA-582-5p (miR-582-5p)/high mobility group box-1 protein (HMGB1), inflammation, oxidative stress and neurological function in patients with ACI. METHODS: In this study, 158 patients with ACI were prospectively selected and randomized into the control (administered symptomatic medication alone) and the RIPC (underwent RIPC of the limbs based on medication) groups, with their clinical baseline data documented. Serum levels of miR-582-5p, and HMGB1 and inflammatory factors [tumor necrosis factor alpha (TNF-α)/interleukin-1beta (IL-1ß)/IL-10] were assessed by RT-qPCR/ELISA, followed by comparisons of oxidative stress indices [glutathione-peroxidase (GSH-Px)/catalase (CAT)/superoxide dismutase (SOD)] using a fully automatic biochemical analyzer. Correlations between serum miR-582-5p with serum HMGB1, and between their levels with TNF-α/IL-1ß/IL-10 were analyzed by Pearson analysis. The NIHSS score/Barthel Index scale were used to assess neurological function/daily living ability. Intervention safety for ACI patients was evaluated. RESULTS: RIPC intervention increased serum miR-582-5p levels and decreased serum HMGB1 levels in ACI patients. RIPC intervention significantly reduced inflammation (diminished TNF-α/IL-1ß levels, increased IL-10 level) and oxidative stress (elevated GSH-Px/CAT/SOD levels) in ACI patients. Serum miR-582-5p was negatively correlated with TNF-α and IL-1ß levels, while positively correlated with IL-10 level, while HMGB1 was positively correlated with TNF-α and IL-1ß levels, while negatively correlated with IL-10 level. miR-582-5p was negatively correlated with HMGB1. RIPC intervention improved neurological function (reduced NIHSS, increased Barthel scores) in ACI patients to some extent. RIPC had certain effectiveness and safety in the treatment of ACI. CONCLUSION: After RIPC intervention, serum miR-582-5p levels were increased, HMGB1 levels were decreased, and inflammation and oxidative stress were reduced in ACI patients, which mitigated neurological deficits, improved patients' ability to perform life activities, and exerted neuroprotective effects to some extent.

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-ĸß2, 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.

Remote ischemic conditioning may improve graft function following kidney transplantation: a systematic review and meta-analysis with trial sequential analysis.

BACKGROUND: Remote ischemic conditioning (RIC) has the potential to benefit graft function following kidney transplantation by reducing ischemia-reperfusion injury; however, the current clinical evidence is inconclusive. This meta-analysis with trial sequential analysis (TSA) aimed to determine whether RIC improves graft function after kidney transplantation. METHODS: A comprehensive search was conducted on PubMed, Cochrane Library, and EMBASE databases until June 20, 2023, to identify all randomized controlled trials that examined the impact of RIC on graft function after kidney transplantation. The primary outcome was the incidence of delayed graft function (DGF) post-kidney transplantation. The secondary outcomes included the incidence of acute rejection, graft loss, 3- and 12-month estimated glomerular filtration rates (eGFR), and the length of hospital stay. Subgroup analyses were conducted based on RIC procedures (preconditioning, perconditioning, or postconditioning), implementation sites (upper or lower extremity), and graft source (living or deceased donor). RESULTS: Our meta-analysis included eight trials involving 1038 patients. Compared with the control, RIC did not significantly reduce the incidence of DGF (8.8% vs. 15.3%; risk ratio = 0.76, 95% confidence interval [CI], 0.48-1.21, P = 0.25, I2 = 16%), and TSA results showed that the required information size was not reached. However, the RIC group had a significantly increased eGFR at 3 months after transplantation (mean difference = 2.74 ml/min/1.73 m2, 95% CI: 1.44-4.05 ml/min/1.73 m2, P < 0.0001, I2 = 0%), with a sufficient evidence suggested by TSA. The secondary outcomes were comparable between the other secondary outcomes. The treatment effect of RIC did not differ between the subgroup analyses. CONCLUSION: In this meta-analysis with trial sequential analysis, RIC did not lead to a significant reduction in the incidence of DGF after kidney transplantation. Nonetheless, RIC demonstrated a positive correlation with 3-month eGFR. Given the limited number of patients included in this study, well-designed clinical trials with large sample sizes are required to validate the renoprotective benefits of RIC. TRIAL REGISTRATION: This systematic review and meta-analysis was registered at the International Prospective Register of Systematic Reviews (Number CRD42023464447).

[Lung-protective effect of esketamine combined with distal limb ischemic preconditioning in elderly patients undergoing thoracoscopic radical surgery for lung cancer: a randomized controlled trial in 160 cases].

OBJECTIVE: To evaluate the effect of esketamine combined with distal limb ischemic preconditioning (LIP) for lung protection in elderly patients undergoing thoracoscopic radical surgery for lung cancer. METHODS: This randomized trial was conducted in 160 patients undergoing elective thoracoscopic surgery for lung cancer, who were randomized into control group (with saline injection and sham LIP), esketamine group, LIP group, and esketamine + LIP group (n=40). Before anesthesia induction, according to the grouping, the patients received an intravenous injection with 0.5 mg/kg esketamine or 10 ml saline (in control group). LIP was induced by applying a tourniquet 1-2 cm above the popliteal fossa in the left lower limb to block the blood flow for 5 min for 3 times at the interval of 5 min, and sham LIP was performed by applying the tourniquet without pressurization for 30 min. Oxygenation index (OI) and alveolar-arterial PO2 difference (A-aDO2) were calculated before induction (T0), at 30 min (T0.5) and 1 h (T1) of one-lung ventilation (OLV), and at 1 h after two-lung ventilation (T3). Serum levels of SP-D, CC-16 and TNF-α were measured by ELISA at T0, T1, T2 (2 h of OLV), T3, and 24 h after the operation (T4). The length of hospital stay and postoperative pulmonary complications of the patients were recorded. RESULTS: Compared with those in the control group, the patients in the other 3 groups had significantly lower CC-16, SP-D and TNF-α levels, shorter hospital stay, and lower incidences of lung infection and lung atelectasis (all P < 0.05). Serum CC-16, SP-D and TNF-α levels, hospital stay, incidences of complications were significantly lower or shorter in the combined treatment group than in esketamine group and LIP group (all P < 0.05). CONCLUSION: In elderly patients undergoing thoracoscopic radical surgery for lung cancer, treatment with esketamine combined with LIP can alleviate acute lung injury by enhancing anti-inflammatory response to shorten postoperative hospital stay, reduce lung complications and promote the patients' recovery.

Robust Rat and Mouse Models of Bilateral Renal Ischemia Reperfusion Injury.

BACKGROUND/AIM: Acute and chronic kidney diseases are a major contributor to morbidity and mortality worldwide, with no specific treatments currently available for these. To enable understanding the pathophysiology of and testing novel treatments for acute and chronic kidney disease, a suitable in vivo model of kidney disease is essential. In this article, we describe two reliable rodent models (rats and mice) of efficacious kidney injury displaying acute to chronic kidney injury progression, which is also reversible through novel therapeutic strategies such as ischemic preconditioning (IPC). MATERIALS AND METHODS: We utilized adult male Lewis rats and adult male wildtype (C57BL/6) mice, performed a midline laparotomy, and induced warm ischemia to both kidneys by bilateral clamping of both renal vascular pedicles for a set time, to mimic the hypoxic etiology of disease commonly found in kidney injury. RESULTS: Bilateral ischemia reperfusion injury caused marked structural and functional kidney injury as exemplified by histology damage scores, serum creatinine levels, and kidney injury biomarker levels in both rodents. Furthermore, this effect displayed a dose-dependent response in the mouse model. CONCLUSION: These rodent models of bilateral kidney IRI are reliable, reproducible, and enable detailed mechanistic study of the underlying pathophysiology of both acute and chronic kidney disease. They have been carefully optimised for single operator use with a strong track record of training both surgically trained and surgically naïve operators.

Preconditioning-Induced Facilitation of Lactate Release from Astrocytes Is Essential for Brain Ischemic Tolerance.

A sublethal ischemic episode [termed preconditioning (PC)] protects neurons in the brain against a subsequent severe ischemic injury. This phenomenon is known as brain ischemic tolerance and has received much attention from researchers because of its robust neuroprotective effects. We have previously reported that PC activates astrocytes and subsequently upregulates P2X7 receptors, thereby leading to ischemic tolerance. However, the downstream signals of P2X7 receptors that are responsible for PC-induced ischemic tolerance remain unknown. Here, we show that PC-induced P2X7 receptor-mediated lactate release from astrocytes has an indispensable role in this event. Using a transient focal cerebral ischemia model caused by middle cerebral artery occlusion, extracellular lactate levels during severe ischemia were significantly increased in mice who experienced PC; this increase was dependent on P2X7 receptors. In addition, the intracerebroventricular injection of lactate protected against cerebral ischemic injury. In in vitro experiments, although stimulation of astrocytes with the P2X7 receptor agonist BzATP had no effect on the protein levels of monocarboxylate transporter (MCT) 1 and MCT4 (which are responsible for lactate release from astrocytes), BzATP induced the plasma membrane translocation of these MCTs via their chaperone CD147. Importantly, CD147 was increased in activated astrocytes after PC, and CD147-blocking antibody abolished the PC-induced facilitation of astrocytic lactate release and ischemic tolerance. Taken together, our findings suggest that astrocytes induce ischemic tolerance via P2X7 receptor-mediated lactate release.

Impact of inflammatory preconditioning on murine microglial proteome response induced by focal ischemic brain injury.

Preconditioning with lipopolysaccharide (LPS) induces neuroprotection against subsequent cerebral ischemic injury, mainly involving innate immune pathways. Microglia are resident immune cells of the central nervous system (CNS) that respond early to danger signals through memory-like differential reprogramming. However, the cell-specific molecular mechanisms underlying preconditioning are not fully understood. To elucidate the distinct molecular mechanisms of preconditioning on microglia, we compared these cell-specific proteomic profiles in response to LPS preconditioning and without preconditioning and subsequent transient focal brain ischemia and reperfusion, - using an established mouse model of transient focal brain ischemia and reperfusion. A proteomic workflow, based on isolated microglia obtained from mouse brains by cell sorting and coupled to mass spectrometry for identification and quantification, was applied. Our data confirm that LPS preconditioning induces marked neuroprotection, as indicated by a significant reduction in brain infarct volume. The established brain cell separation method was suitable for obtaining an enriched microglial cell fraction for valid proteomic analysis. The results show a significant impact of LPS preconditioning on microglial proteome patterns by type I interferons, presumably driven by the interferon cluster regulator proteins signal transducer and activator of transcription1/2 (STAT1/2).

Remote ischaemic preconditioning for transcatheter aortic valve replacement: a protocol for a systematic review with meta-analysis and trial sequential analysis.

INTRODUCTION: Transcatheter aortic valve replacement (TAVR) has become an important treatment in patients with aortic valve disease with the continuous advancement of technology and the improvement of outcomes. However, TAVR-related complications still increase patient morbidity and mortality. Remote ischaemic preconditioning (RIPC) is a simple procedure that provides perioperative protection for many vital organs. However, the efficiency of RIPC on TAVR remains unclear based on inconsistent conclusions from different clinical studies. Therefore, we will perform a protocol for a systematic review and meta-analysis to identify the efficiency of RIPC on TAVR. METHODS AND ANALYSIS: English databases (PubMed, Web of Science, Ovid Medline, Embase and Cochrane Library), Chinese electronic databases (Wanfang Database, VIP Database and China National Knowledge Infrastructure) and trial registry databases will be searched from inception to December 2023 to identify randomised controlled trials of RIPC on TAVR. We will calculate mean differences or standardised mean differences with 95% CIs for continuous data, and the risk ratio (RR) with 95% CIs for dichotomous data by Review Manager version 5.4. Fixed-effects model or random-effects model will be used according to the degree of statistical heterogeneity assessed by the I-square test. We will evaluate the risk of bias using the Cochrane risk-of-bias tool 2 and assess the evidence quality of each outcome by the Grading of Recommendations Assessment, Development and Evaluation. The robustness of outcomes will be evaluated by trial sequential analysis. In addition, we will evaluate the publication bias of outcomes by Funnel plots and Egger's regression test. ETHICS AND DISSEMINATION: Ethical approval was not required for this systematic review protocol. The results will be disseminated through peer-reviewed publications. PROSPERO REGISTRATION NUMBER: CRD42023462926.

Therapeutic gene delivery by mesenchymal stem cell for brain ischemia damage: Focus on molecular mechanisms in ischemic stroke.

Cerebral ischemic damage is prevalent and the second highest cause of death globally across patient populations; it is as a substantial reason of morbidity and mortality. Mesenchymal stromal cells (MSCs) have garnered significant interest as a potential treatment for cerebral ischemic damage, as shown in ischemic stroke, because of their potent intrinsic features, which include self-regeneration, immunomodulation, and multi-potency. Additionally, MSCs are easily obtained, isolated, and cultured. Despite this, there are a number of obstacles that hinder the effectiveness of MSC-based treatment, such as adverse microenvironmental conditions both in vivo and in vitro. To overcome these obstacles, the naïve MSC has undergone a number of modification processes to enhance its innate therapeutic qualities. Genetic modification and preconditioning modification (with medications, growth factors, and other substances) are the two main categories into which these modification techniques can be separated. This field has advanced significantly and is still attracting attention and innovation. We examine these cutting-edge methods for preserving and even improving the natural biological functions and therapeutic potential of MSCs in relation to adhesion, migration, homing to the target site, survival, and delayed premature senescence. We address the use of genetically altered MSC in stroke-induced damage. Future strategies for improving the therapeutic result and addressing the difficulties associated with MSC modification are also discussed.

Tolerogenic CD11c+dendritic cells regulate CD4+Tregs in replacing delayed ischemic preconditioning to alleviate ischemia-reperfusion acute kidney injury.

Ischemia-reperfusion injury (IRI) is one of the primary clinical causes of acute kidney injury (AKI). The key to IRI lies in immune-inflammatory damage, where dendritic cells (DCs) play a central role in eliciting immune responses within the context of inflammation induced by ischemia-reperfusion. Our previous study has confirmed that delayed ischemic preconditioning (DIPC) can reduce the kidney injury by mediating DCs to regulate T-cells. However, the clinical feasibility of DIPC is limited, as pre-clamping of the renal artery is not applicable for the prevention and treatment of ischemia-reperfusion acute kidney injury (I/R-AKI) in clinical patients. Therefore, the infusion of DCs as a substitute for DIPC presents a more viable strategy for preventing renal IRI. In this study, we further evaluated the impact and mechanism of infused tolerogenic CD11c+DCs on the kidneys following IRI by isolating bone marrow-derived dendritic cells and establishing an I/R-AKI model after pre-infusion of DCs. Renal function was significantly improved in the I/R-AKI mouse model after pre-infused with CD11c+DCs. The pro-inflammatory response and oxidative damage were reduced, and the levels of T helper 2 (Th2) cells and related anti-inflammatory cytokines were increased, which was associated with the reduction of autologous DCs maturation mediated by CD11c+DCs and the increase of regulatory T-cells (Tregs). Next, knocking out CD11c+DCs, we found that the reduced immune protection of tolerogenic CD11c+DCs reinfusion was related to the absence of own DCs. Together, pre-infusion of tolerogenic CD11c+DCs can replace the regulatory of DIPC on DCs and T-cells to alleviate I/R-AKI. DC vaccine is expected to be a novel avenue to prevent and treat I/R-AKI.

Effects of remote ischemic preconditioning in hepatectomy: a systematic review and meta-analysis.

BACKGROUND: Animal experiments have confirmed that remote ischemic preconditioning (RIPC) can reduce hepatic ischemia-reperfusion injuries (HIRIs), significantly improving early tissue perfusion and oxygenation of the residual liver after resections, accelerating surgical prognoses, and improving survival rates. However, there is still controversy over the role of RIPC in relieving HIRI in clinical studies, which warrants clarification. This study aimed to evaluate the beneficial effects and applicability of RIPC in hepatectomy and to provide evidence-based information for clinical decision-making. METHODS: Randomized controlled trials (RCTs) evaluating the efficacy and safety of RIPC interventions were collected, comparing RIPC to no preconditioning in patients undergoing hepatectomies. This search spanned from database inception to January 2024. Data were extracted independently by two researchers according to the PRISMA guidelines. The primary outcomes assessed were postoperative alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TBIL), and albumin (ALB) levels. The secondary outcomes assessed included duration of surgery and Pringle, length of postoperative hospital stay, intraoperative blood loss and transfusion, indocyanine green (ICG) clearance, hepatocyte apoptosis index, postoperative complications, and others. RESULTS: Ten RCTs were included in this meta-analysis, with a total of 865 patients (428 in the RIPC group and 437 in the control group). ALT levels in the RIPC group were lower than those in the control group on postoperative day (POD) 1 (WMD = - 59.24, 95% CI: - 115.04 to - 3.45; P = 0.04) and POD 3 (WMD = - 27.47, 95% CI: - 52.26 to - 2.68; P = 0.03). However, heterogeneities were significant (I2 = 89% and I2 = 78%), and ALT levels on POD 3 were unstable based on a sensitivity analysis. AST levels on POD 1 in the RIPC group were lower than those in the control group (WMD = - 50.03, 95% CI: - 94.35 to - 5.71; P = 0.03), but heterogeneity was also significant (I2 = 81%). A subgroup analysis showed no significant differences in ALT and AST levels on POD 1 between groups, regardless of whether the Pringle maneuver or propofol was used for anesthesia (induction only or induction and maintenance, P > 0.05). The remaining outcome indicators were not statistically significant or could not be analyzed due to lack of sufficient data. CONCLUSION: RIPC has some short-term liver protective effects on HIRIs during hepatectomies. However, there is still insufficient evidence to encourage its routine use to improve clinical outcomes. TRIAL REGISTRATION: The protocol of this study was registered with PROSPERO (CRD42022333383).

Ischemic preconditioning increases spinal excitability and voluntary activation during maximal plantar flexion contractions in men.

The enigmatic benefits of acute limb ischemic preconditioning (IP) in enhancing muscle force and exercise performance have intrigued researchers. This study sought to unravel the underlying mechanisms, focusing on increased neural drive and the role of spinal excitability while excluding peripheral factors. Soleus Hoffmann (H)-reflex /M-wave recruitment curves and unpotentiated supramaximal responses were recorded before and after IP or a low-pressure control intervention. Subsequently, the twitch interpolation technique was applied during maximal voluntary contractions to assess conventional parameters of neural output. Following IP, there was an increase in both maximum normalized force and voluntary activation (VA) for the plantar flexor group, with negligible peripheral alterations. Greater benefits were observed in participants with lower VA levels. Despite greater H-reflex gains, soleus volitional (V)-wave and sEMG amplitudes remained unchanged. In conclusion, IP improves muscle force via enhanced neural drive to the muscles. This effect appears associated, at least in part, to reduced presynaptic inhibition and/or increased motoneuron excitability. Furthermore, the magnitude of the benefit is inversely proportional to the skeletal muscle's functional reserve, making it particularly noticeable in under-recruited muscles. These findings have implications for the strategic application of the IP procedure across diverse populations.

The effect of short-term remote ischemic preconditioning on endothelial function of patients with chronic kidney disease: A randomized pilot study.

AIM: Patients with chronic kidney disease (CKD) are more susceptible to endothelial dysfunction and cardiovascular disease (CV). Remote ischemic preconditioning (rIPC) has been proven efficient in improving endothelial function and lowering the risk of CV. However, the safety and effect of rIPC on endothelial function in patients with CKD have not been effectively assessed. METHODS: 45 patients with CKD (average estimated glomerular filtration rate: 48.4 mL/min/1.73 m2) were randomly allocated to either 7-day daily upper-arm rIPC (4 × 5 min 200 mmHg, interspaced by 5-min reperfusion) or control (4 × 5 min 60 mmHg, interspaced by 5-min reperfusion). Vascular endothelial function was assessed by natural log-transformed reactive hyperemia index (LnRHI) before and after a 7-day intervention. Arterial elasticity was assessed by augmentation index (AI). RESULTS: The results showed that LnRHI could be improved by rIPC treatment (Pre = 0.57 ± 0.04 vs. Post = 0.67 ± 0.04, p = .001) with no changes relative to control (Pre = 0.68 ± 0.06 vs. Post = 0.64 ± 0.05, p = .470). Compared with the control group, the improvement of LnRHI was greater after rIPC treatment (rIPC vs. Control: 0.10 ± 0.03 vs. -0.04 ± 0.06, between-group mean difference, -0.15 [95% CI, -0.27 to -0.02], p = .027), while there was no significant difference in the change of AI@75 bpm (p = .312) between the two groups. CONCLUSION: RIPC is safe and well tolerated in patients with CKD. This pilot study suggests that rIPC seems to have the potential therapeutic effect to improve endothelial function. Of note, further larger trials are still warranted to confirm the efficacy of rIPC in improving endothelial function in CKD patients.

First Characterization of Tissue Oxygen Saturation Recovery Patterns in Pediatric Cardiac Surgery Patients Undergoing Remote Ischemic Preconditioning and the Association With Clinical Outcomes.

OBJECTIVE: This study aimed to delineate the recovery patterns of regional oxygen saturation (SrO2) in pediatric cardiac surgery patients subjected to remote ischemic preconditioning (RIPC), utilizing near-infrared spectroscopy (NIRS) for quantification. It also sought to establish the correlation between these perfusion patterns and postoperative clinical outcomes. DESIGN: A prospective longitudinal observational study. SETTING: The study was conducted at Fundación Valle Del Lili, a high-complexity service provider institution in Fundación Valle Del Lili. PARTICIPANTS: Pediatric patients (younger than 18 years of age) scheduled for elective cardiac surgery requiring cardiopulmonary bypass between August 2022 and July 2023. INTERVENTIONS: RIPC was performed after anesthetic induction, involving cycles of ischemia and reperfusion on a lower limb. Monitoring included SrO2 using NIRS. MEASUREMENTS AND MAIN RESULTS: The study identified 4 distinct patterns of SrO2 during RIPC. Findings demonstrated a significant association between the negative SrO2 pattern and increased postoperative adverse events, including extended hospital stays and higher mortality, while a positive pattern was associated with better outcomes. CONCLUSIONS: Specific patterns of SrO2 response to RIPC may serve as important indicators for risk stratification in congenital heart surgery. This study illustrated the potential of NIRS in detecting hypoxic states and predicting postoperative outcomes, emphasizing the need for standardized clinical interpretation of RIPC patterns.

Effect of remote ischemic preconditioning on postoperative cognitive dysfunction in adult patients with general anesthesia: a meta-analysis.

BACKGROUND: Remote ischemic preconditioning (RIPC) is proven to have neuroprotective protective effects. Nevertheless, the impact of RIPC on postoperative cognitive dysfunction (POCD) in patients undergoing general anesthesia is controversial. This meta-analysis of randomized controlled trials (RCTs) aimed to assess the effect of RIPC on POCD in adults after general anesthesia. METHODS: Relevant literature was obtained by searching Embase, PubMed, Web of Science, Cochrane Library, Wanfang, and China National Knowledge Infrastructure (CNKI) databases in July 2022. RCTs were included to assess the influences of RIPC on POCD in adults following general anesthesia. Two investigators independently performed literature screening, data extraction, and quality assessment based on the inclusion and exclusion criteria. The incidence of POCD, operation time, and hospital stay were analyzed by Review manager5.4 software. RESULTS: Thirteen RCTs with 1122 participants were selected for this meta-analysis. Compared to the control group, RIPC decreased the incidence of POCD (OR = 0.50, 95% CI 0.31-0.82), as well as reduced the duration of hospitalization (MD = - 0.98, 95% CI - 1.69 to - 0.27), but did not prolong operative time (MD = - 2.65, 95% CI - 7.68 to 2.37). CONCLUSION: RIPC reduced the incidence of POCD in adult patients after general anesthesia and accelerated their discharge.

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

BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03481777.

Association between Ranolazine, Ischemic Preconditioning, and Cardioprotection in Patients Undergoing Scheduled Percutaneous Coronary Intervention.

Background and Objectives: Remote ischemic preconditioning (RIPC) has demonstrated efficacy in protecting against myocardial ischemia-reperfusion injury when applied before percutaneous coronary revascularization. Ranolazine, an anti-ischemic drug, has been utilized to minimize ischemic events in chronic angina patients. However, there is a lack of trials exploring the combined effects of ranolazine pretreatment and RIPC in patients undergoing percutaneous coronary interventions (PCIs). Materials and Methods: The present study is a prospective study which enrolled 150 patients scheduled for nonemergent percutaneous coronary revascularization. Three groups were formed: a control group undergoing only PCIs, an RIPC group with RIPC applied to either upper limb before the PCI (preconditioning group), and a group with RIPC before the PCI along with prior ranolazine treatment for stable angina (ranolazine group). Statistical analyses, including ANOVAs and Kruskal-Wallis tests, were conducted, with the Bonferroni correction for type I errors. A repeated-measures ANOVA assessed the changes in serum enzyme levels (SGOT, LDH, CRP, CPK, CK-MB, troponin I) over the follow-up. Statistical significance was set at p < 0.05. Results: The ranolazine group showed (A) significantly lower troponin I level increases compared to the control group for up to 24 h, (B) significantly lower CPK levels after 4, 10, and 24 h compared to the preconditioning group (p = 0.020, p = 0.020, and p = 0.019, respectively) and significantly lower CPK levels compared to the control group after 10 h (p = 0.050), and (C) significantly lower CK-MB levels after 10 h compared to the control group (p = 0.050). Conclusions: This study suggests that combining RIPC before scheduled coronary procedures with ranolazine pretreatment may be linked to reduced ischemia induction, as evidenced by lower myocardial enzyme levels.

Endothelial Cell Apoptosis but Not Necrosis Is Inhibited by Ischemic Preconditioning.

This study aimed to assess the influence of ischemic preconditioning (IP) on hypoxia/reoxygenation (HR)-induced endothelial cell (EC) death. Human umbilical vein endothelial cells (HUVECs) were subjected to 2 or 6 h hypoxia with subsequent reoxygenation. IP was induced by 20 min of hypoxia followed by 20 min of reoxygenation. Necrosis was assessed by the release of lactate dehydrogenase (LDH) and apoptosis by double staining with propidium iodide/annexin V (PI/AV), using TUNEL test, and Bcl-2 and Bax gene expression measured using RT-PCR. In PI/AV staining, after 24 h of reoxygenation, 30-33% of EC were necrotic and 16-21% were apoptotic. In comparison to HR cells, IP reduced membrane apoptosis after 24 h of reoxygenation by 50% but did not influence EC necrosis. Nuclear EC apoptosis affected about 15-17% of EC after 24 h of reoxygenation and was reduced with IP by 55-60%. IP was associated with a significantly higher Bcl-2/Bax ratio, at 8 h 2-4 times and at 24 h 2-3 times as compared to HR. Longer hypoxia was associated with lower values of Bcl-2/Bax ratio in EC subjected to HR or IP. IP delays, without reducing, the extent of HR-induced EC necrosis but significantly inhibits their multi-level evaluated apoptosis.

Randomized controlled trial of remote ischemic preconditioning in children having cardiac surgery.

BACKGROUND: Children undergoing cardiac surgery are at risk for acute kidney injury (AKI) and cardiac dysfunction. Opportunity exists in protecting end organ function with remote ischemic preconditioning. We hypothesize this intervention lessens kidney and myocardial injury. METHODS: We conducted a randomized, double blind, placebo controlled trial of remote ischemic preconditioning in children undergoing cardiac surgery. Pre-specified end points are change in creatinine, estimated glomerular filtration rate, development of AKI, B-type natriuretic peptide and troponin I at 6, 12, 24, 48, 72 h post separation from bypass. RESULTS: There were 45 in the treatment and 39 patients in the control group, median age of 3.5 and 3.8 years, respectively. There were no differences between groups in creatinine, cystatin C, eGFR at each time point. There was a trend for a larger rate of decrease, especially for cystatin C (p = 0.042) in the treatment group but the magnitude was small. AKI was observed in 21 (54%) of control and 16 (36%) of treatment group (p = 0.094). Adjusting for baseline creatinine, the odds ratio for AKI in treatment versus control was 0.31 (p = 0.037); adjusting for clinical characteristics, the odds ratio was 0.34 (p = 0.056). There were no differences in natriuretic peptide or troponin levels between groups. All secondary end points of clinical outcomes were not different. CONCLUSIONS: There is suggestion of RIPC delivering some kidney protection in an at-risk pediatric population. Larger, higher risk population studies will be required to determine its efficacy. Trial registration and date: Clinicaltrials.gov NCT01260259; 2021.