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.

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.

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.

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.

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.

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).

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.

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.

[Cytosteatonecrosis after breast reconstruction by fat flap with or without ischemic preconditioning]. / Cytostéatonécrose après reconstruction mammaire par lambeau graisseux avec ou sans préconditionnement ischémique.

INTRODUCTION: Cytosteatonecrosis (CTN) is a frequent postoperative complication after breast autologous reconstruction using DIEP (deep inferior epigastric perforator) flap. CTN radiological diagnostic reveals different types of lesions, as nodes or extended fat necrosis, which become in some cases infected, or pass for tumor recurrence after breast cancer treatment. CTN is caused by intraoperative ischemia of the flap, and no current method can prevent postoperative CTN development after DIEP breast reconstruction. Mechanical ischemic preconditioning, consisting in intraoperative briefs consecutive cycles of ischemia reperfusion using vascular clamp upon the graft pedicle, is used in transplantation surgery. This procedure improves the graft tolerance towards ischemic surgical lesions. The aim of this retrospective observational study was to assess PCIM effects on CTN development after DIEP surgery, comparing CTN occurrence after breast reconstruction using DIEP flap with or without intraoperative PCIM. MATERIAL AND METHODS: All patients breats reconstructed using DIEP flap between novembre 2020 and may 2022, presenting 6 months postoperative breast echography were retrospectively included. Primary outcome was the ultrasonic existence of CTN, according to the Wagner classification. Clinical data, postoperative outcomes such as infection, hematoma or surgical revision, and length of stay in hospital were also recorded. RESULTS: Twenty nine patients among which 8 PCIM were included. CTN occurrence rate after PCIM (25%) was quite lower than CTN rate without PCIM (71,4%), although the difference was not significant (P=0,088). Other postoperative complications rates were not significantly different with or without PCIM. CONCLUSION: PCIM seems to improve CTN occurrence after DIEP breast reconstruction, improving fat flap tolerance to ischemic perioperative lesions. Those preliminary results need to be confirmed with clinical prospective study.

Remote ischemic preconditioning for reduction of ischemia-reperfusion injury after hepatectomy: A randomized sham-controlled trial.

BACKGROUND: Remote ischemic preconditioning reduces ischemia-reperfusion injury in patients undergoing hepatectomy. Moreover, there is evidence that the protective effects of remote ischemic preconditioning may be more pronounced in pre-damaged livers. The objective of this trial was to investigate the extent to which remote ischemic preconditioning can attenuate ischemia-reperfusion injury after hepatectomy and Pringle maneuver in patients with chronic liver disease. METHODS: In this randomized, controlled, triple-blind monocenter trial, a total of 102 patients with chronic liver disease and planned hepatectomy were enrolled between December 2019 and March 2022. Eligible patients were randomized to the remote ischemic preconditioning or sham arms. Remote ischemic preconditioning was induced through 3 10-minute cycles of alternating ischemia and reperfusion of the upper extremity. The study was prospectively registered in the German Clinical Trials Registry (DRKS00018931). RESULTS: A total of 102 patients were included in the study and were randomized (51 per arm). The median age was 69.5 years, approximately two-thirds of the patients were male (69/102, 67.7%), and the mean body mass index was 25.6 kg/m2. Most patients were classified as American Society of Anesthesiologists II (55/102, 53.9%) or III (45/102, 44.1%). The primary endpoint, the transaminases on the first postoperative day (alanine aminotransferase /aspartate aminotransferase: remote ischemic preconditioning arm: 250 (35-1721)/320 (42-1525) U/L versus sham control arm: 283 (32-792)/356 (20-1851) U/L, P = .820/0.639), clinical outcomes as well as remote ischemic preconditioning biomarker levels were comparable between both arms. CONCLUSION: Remote ischemic preconditioning did not achieve a significant reduction in postoperative transaminase levels, nor did it affect clinical results and biomarkers.

Short-term Outcomes of Different Techniques for Gastric Ischemic Preconditioning Before Esophagectomy: A Network Meta-analysis.

BACKGROUND: Ischemia at the anastomotic site plays a critical role determinant in the development of anastomosis-related complications after esophagectomy. Gastric ischemic conditioning (GIC) before esophagectomy has been described to improve the vascular perfusion at the tip of the gastric conduit with a potential effect on anastomotic leak (AL) and stenosis (AS) risk minimization. Laparoscopic (LapGIC) and angioembolization (AngioGIC) techniques have been reported. PURPOSE: Compare short-term outcomes among different GIC techniques. MATERIALS AND METHODS: Systematic review and network meta-analysis. One-step esophagectomy (noGIC), LapGIC, and AngioGIC were compared. Primary outcomes were AL, AS, and gastric conduit necrosis (GCN). Risk ratio (RR) and weighted mean difference (WMD) were used as pooled effect size measures, whereas 95% credible intervals (CrIs) were used to assess relative inference. RESULTS: Overall, 1760 patients (14 studies) were included. Of those, 1028 patients (58.4%) underwent noGIC, 593 (33.6%) LapGIC, and 139 (8%) AngioGIC. AL was reduced for LapGIC versus noGIC (RR=0.68; 95% CrI 0.47-0.98) and AngioGIC versus noGIC (RR=0.52; 95% CrI 0.31-0.93). Similarly, AS was reduced for LapGIC versus noGIC (RR=0.32; 95% CrI 0.12-0.68) and AngioGIC versus noGIC (RR=1.30; 95% CrI 0.65-2.46). The indirect comparison, assessed with the network methodology, did not show any differences for LapGIC versus AngioGIC in terms of postoperative AL and AS risk. No differences were found for GCN, pulmonary complications, overall complications, hospital length of stay, and 30-day mortality among different treatments. CONCLUSIONS: Compared to noGIC, both LapGIC and AngioGIC before esophagectomy seem equivalent and associated with a reduced risk for postoperative AL and AS.

In vitro ischemic preconditioning mediates the Ca2+/CaN/NFAT pathway to protect against oxygen-glucose deprivation-induced cellular damage and inflammatory responses.

Oxygen-glucose deprivation (OGD) is a critical model for studying hypoxic-ischemic cerebrovascular disease in vitro. This paper is to investigate the protection of OGD-induced cellular damage and inflammatory responses by OGD preconditioning in vitro, to provide a theoretical basis for OGD preconditioning to improve the prevention and prognosis of ischemic stroke. OGD or OGD preconditioning model was established by culturing the PC12 cell line in vitro, followed by further adding A23187 (calcium ion carrier) or CsA (calcium ion antagonist). Cell viability was detected by MTT, apoptosis by Hoechst 33,258 staining, the levels of TNF-α and IL-1ß mRNA by RT-qPCR and ELISA, and the levels of CaN, NFAT, COX-2 by RT-qPCR and Western blot. Cell viability was decreased, and apoptosis, inflammatory cytokines, and CaN, NFAT, and COX-2 levels were notably increased upon OGD, while OGD pretreatment significantly increased cell viability and decreased apoptosis, inflammation, and the Ca2+/CaN/NFAT pathway. Treatment with A23187 decreased cell viability, promoted apoptosis, and significantly increased TNF-α, IL-1ß, CaN, NFAT, and COX-2 levels, while CsA treatment reduced the opposite results. In vitro OGD preconditioning mediates the Ca2+/CaN/NFAT pathway to protect against OGD-induced cellular damage and inflammatory responses.

Remote ischemic preconditioning reduces mitochondrial apoptosis mediated by calpain 1 activation in myocardial ischemia-reperfusion injury through calcium channel subunit Cacna2d3.

Remote Ischemic Preconditioning (RIPC) can reduce myocardial ischemia-reperfusion injury, but its mechanism is not clear. In order to explore the mechanism of RIPC in myocardial protection, we collected myocardial specimens during cardiac surgery in children with tetralogy of Fallot for sequencing. Our study found RIPC reduces the expression of the calcium channel subunit cacna2d3, thereby impacting the function of calcium channels. As a result, calcium overload during ischemia-reperfusion is reduced, and the activation of calpain 1 is inhibited. This ultimately leads to a decrease in calpain 1 cleavage of Bax, consequently inhibiting increased mitochondrial permeability-mediated apoptosis. Notably, in both murine and human models of myocardial ischemia-reperfusion injury, RIPC inhibiting the expression of the calcium channel subunit cacna2d3 and the activation of calpain 1, improving cardiac function and histological outcomes. Overall, our findings put forth a proposed mechanism that elucidates how RIPC reduces myocardial ischemia-reperfusion injury, ultimately providing a solid theoretical foundation for the widespread clinic application of RIPC.

Cardiac ischemic preconditioning promotes cMyBP-C phosphorylation by inhibiting the calpain-mediated proteolysis.

Ischemic preconditioning (IPC) has been considered as the most important mean to protect against ischemia/reperfusion (I/R) induced heart injury. It has been reported that cardiac myosin binding protein-C (cMyBP-C) phosphorylation plays an essential role in cardiac protection against I/R-induced heart injury. However, it is still obscured whether IPC-mediated cardiac protection is causally related to cMyBP-C phosphorylation and proteolysis and, if so, what the underlying mechanism is. In this study, IPC was found to increase the phosphorylation level of cMyBP-C, companying with the decreased calpain activity in the collected perfusate samples. Mechanistically, we confirmed that IPC promoted cMyBP-C phosphorylation and inhibited calpain-mediated cMyBP-C proteolysis. Moreover, inhibition of calpain activity significantly increased the phosphorylated cMyBP-C level by using calpain inhibitor (MG-101), and subsequently promoted stabilization and secretion of cMyBP-C. Functionally, adeno-associated virus (AAV)-mediated overexpression of mutated phosphorylation motif site of cMyBP-C exhibited impaired IPC-mediated cardiac protection via proteolysis of the full-length cMyBP-C protein. We concluded that IPC promoted cMyBP-C phosphorylation via inhibition of calpain-mediated proteolysis and participated in IPC-mediated protection against I/R induced heart injury.

Effect of remote ischemic preconditioning on lung function after surgery under general anesthesia: a systematic review and meta-analysis.

Remote ischemic preconditioning (RIPC) protects organs from ischemia-reperfusion injury. Recent trials showed that RIPC improved gas exchange in patients undergoing lung or cardiac surgery. We performed a systematic search to identify randomized controlled trials involving RIPC in surgery under general anesthesia. The primary outcome was the PaO2/FIO2 (P/F) ratio at 24 h after surgery. Secondary outcomes were A-a DO2, the respiratory index, duration of postoperative mechanical ventilation (MV), incidence of acute respiratory distress syndrome (ARDS), and serum cytokine levels. The analyses included 71 trials comprising 7854 patients. Patients with RIPC showed higher P/F ratio than controls (mean difference [MD] 36.6, 95% confidence interval (CI) 12.8 to 60.4, I2 = 69%). The cause of heterogeneity was not identified by the subgroup analysis. Similarly, A-a DO2 (MD 15.2, 95% CI - 29.7 to - 0.6, I2 = 87%) and respiratory index (MD - 0.17, 95% CI - 0.34 to - 0.01, I2 = 94%) were lower in the RIPC group. Additionally, the RIPC group was weaned from MV earlier (MD - 0.9 h, 95% CI - 1.4 to - 0.4, I2 = 78%). Furthermore, the incidence of ARDS was lower in the RIPC group (relative risk 0.73, 95% CI 0.60 to 0.89, I2 = 0%). Serum TNFα was lower in the RIPC group (SMD - 0.6, 95%CI - 1.0 to - 0.3 I2 = 87%). No significant difference was observed in interleukin-6, 8 and 10. Our meta-analysis suggested that RIPC improved oxygenation after surgery under general anesthesia.Clinical trial number: This study protocol was registered in the University Hospital Medical Information Network (registration number: UMIN000030918), https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000035305.

PREVENTION OF PATHOLOGICAL EFFECT OF ISCHEMIA-REPERFUSION IN LIVER RESECTION BY SEVOFLURANE PRECONDITIONING.

BACKGROUND: The intermittent Pringle maneuver remains the major technique for controlling hemorrhage during liver surgery. Nevertheless, this procedure involves a risk of triggering a cascade of pathological changes resulting in the ischemia-reperfusion injury (I/R) effect. The pharmacological prevention of this I/R injury represents a promising approach. The aim of the study was to compare the effects of pharmacological preconditioning with sevoflurane and propofol-based intravenous anesthesia on the postoperative function of the liver as the primary end-point. MATERIALS AND METHODS: A prospective cohort study includes the analysis of the data of 73 patients who underwent liver surgery. In the study group (n = 41), preconditioning with sevoflurane inhalation was provided 30 minutes prior to liver resection. In the control group (n = 32), sevoflurane preconditioning was not provided. The primary endpoints were blood lactate concentration shortly after the surgery and one day later; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities on postoperative Days 1, 3, and 5 as markers of hepatocyte damage. RESULTS: On postoperative Day 1, in patients of the study group, lactate decreased to preoperative levels, while in the control group, lactate content increased as compared to both preoperative levels and the levels immediately after liver resection. A significant difference in AST activity levels between the groups was registered on Day 5, although this difference was not clinically relevant. The decrease in the prothrombin index in the study group on Day 3 was superior to that in the control group. The multiple regression analysis demonstrated a moderate positive association between the number of resected liver segments and the markers of the functional state of the liver in the study group while in the control group, such association was not significant. CONCLUSION: The protective effect of sevoflurane on the postoperative function of the liver is manifested by the lower level of blood lactate and the stable level of transaminase activity.