Period Of Ischemia Research Articles

Use of Near-InfraRed Spectroscopy (NIRS) during Vascular Occlusion Test (VOT) for predicting an increase in oxygen consumption after fluid challenge in circulatory shock patients

Background: The goal of fluid challenge (FC) is to increase cardiac output (CO) and oxygen delivery (DO2) (known as fluid responders) to correct tissue hypoxia. To optimize fluid administration, fluid challenge (FC) during dependence of oxygen consumption on oxygen delivery (VO2/DO2 dependency) would correct tissue hypoxia confirmed by an increase of oxygen consumption (VO2) and oxygen delivery (DO2) after FC (known as VO2 responders) and get more benefit from a reduction in tissue hypoxia. Markers of anaerobic metabolisms, such as blood lactate concentration or the ratio of venous-arterial CO2 tension difference (P(cv-a)CO2) over arterial-to-venous oxygen content difference (C(a-cv)O2), can predict VO2 responders but still have several limitations. Therefore, near-infrared spectroscopy (NIRS) has been developed to evaluate tissue perfusion, presented as tissue oxygen saturation (StO2), at the bedside. Combining StO2 with the vascular occlusive test (VOT) and introducing a short period of forearm ischemia is a non-invasive technique to examine microvascular alterations at the bedside. However, a study validating the ability of these variables to predict VO2 response has not been conducted. Methods: We plan to conduct a single-center prospective study on circulatory failure patients. The cardiac index (CI), oxygen delivery (DO2), oxygen consumption (VO2), arterial lactate, central venous oxygen saturation (ScvO2), ratio of venous-arterial carbon dioxide tension to arterial-to-central venous oxygen content difference (P(cv-a)CO2/ C(a-cv)O2), and tissue oxygen saturation measured by near-infrared spectroscopy (NIRS) probe during vascular occlusion test variables (NIRS-VOT variables) will be collected before and after the fluid challenge. Hypothesis: We hypothesize that markers of reactive hyperemia by NIRs will predict an increase in VO2 after FC in patients with circulatory shock. Ethics: The study protocol has been approved by the ethics committee of the faculty of medicine, Ramathibodi Hospital, Mahidol University (COA. MURA2022/80).

Prophylactic Treatment of Intestinal Ischemia-Reperfusion Injury Reduces Mucosal Damage and Improves Intestinal Absorption.

Intestinal ischemia-reperfusion injury (i-IRI) involves a blood flow interruption in an intestinal segment followed by blood flow restoration. When blood flow is restored, oxidative and inflammatory molecules are distributed throughout the bloodstream, triggering both local and systemic damage. Our goal was to evaluate the potential of three antioxidant and/or anti-inflammatory compounds (curcumin, dexmedetomidine and α-tocopherol) to prevent or reverse local and systemic damage induced by i-IRI. i-IRI was induced by placing a microvascular clip in the superior mesenteric artery of female WAG/RijHsd rats; the clip was removed after 1h and reperfusion was allowed for 4h. Curcumin (200 mg/kg, orally), α-tocopherol (20 mg/kg, i.p.), and dexmedetomidine (5 or 20 µg/kg, s.c.; DEX5 and DEX20, respectively) were administered. Blood and terminal ileum specimens were collected for biochemical and histological determination. Furthermore, D-xylose absorption test was performed to evaluate intestinal absorption; after completing the 1-hour ischemia and 4-hour reperfusion period, 1 mL of aqueous D-xylose solution (0.615 mg/mL) was administered orally, and one hour later, plasma D-xylose levels were quantified. The histological injury degree (HID) measured by the Chiu scale was significantly reduced when the treatments were applied (non-treated rats, 2.6 ± 0.75; curcumin, 1.54 ± 0.8; DEX5, 1.47 ± 0.7; DEX20 1.14 ± 0.5; and α-tocopherol, 1.01 ± 0.6); intestinal absorptive capacity also improved in all cases healthy rats (2.06 ± 0.07 µg/mL; non-treated, 1.18 ± 0.07 µg/mL; curcumin 1.76 ± 0.3 µg/mL; DEX5, 2.29 ± 0.2 µg/mL; DEX20, 2.25 ± 0.26 µg/mL; and α-tocopherol 1.66 ± 0.21 µg/mL). However, it failed to reduce liver enzyme levels. Finally, only dexmedetomidine significantly reduced urea and creatinine levels compared to non-treated animals. All drugs were effective in reducing HID, although α-tocopherol was effective to a greater extent. Only dexmedetomidine reverted intestinal absorption to normal values of healthy animals.

Comparison between Myocardial Glycogen Storage in CABG after Using Blood Cardioplegia versus HTK Solution

Abstract Background Inadequate myocardial protection in long ischaemic periods followed by reperfusion is an issue of concern in cardiac surgery. Cardioplegic solutions improve the tolerance to ischaemia and reperfusion by preserving myocardial energy reserves, preventing osmotic and electrolyte imbalances and buffering acidosis. Objective This somewhat surprising given the high number of procedures performed worldwide with this cardioplegic solution. As such, the purpose of this study was to assess the safety of the HTK solution when compared with our standard blood cardioplegia in coronary artery bypass graft operations via assessment of myocardial glycogen storage. Patients and Methods This was a retrospective, convenient, non- randomized study conducted on 40 consecutive patients who underwent isolated elective CABG at department of cardiothoracic surgery at Ain Shams University Hospitals. The aim of the study was to compare early outcomes of Custodiol versus blood cardioplegia in coronary artery bypass graft surgery via assessment of glycogen storage in myocarduim via assessment of myocardial glycogen storage. at Ain Shams University Hospitals. Results There was no statistically significant difference between the two groups of myocardial glycogen storage post-operative. Conclusion There was statistically significant difference between the pre and post-operative in both custodial and blood cardioplegia. There was no statistically significant difference between the two groups of myocardial protection in mortality and morbidity. Custodiol cardioplegia is an easy technique and simple without need of preparation or repeated administration.

Upfront Normothermic Machine Perfusion for a Liver Graft with Severe Macrovesicular Steatosis: A Proof-of-Concept Case

Graft steatosis has been associated with inferior outcomes after liver transplantation. Given the rising prevalence of obesity and fatty liver disease, strategies allowing safe and successful utilization of fatty liver grafts are needed. Liver preservation by normothermic machine perfusion (NMP) allows reducing ischemia-reperfusion injury, extending preservation time and assessing graft viability prior to implantation into the recipient. NMP can be initiated at the donor hospital using a transportable device (referred to as upfront NMP or normothermic machine preservation) or after a period of cold ischemia (known as back-to-base). In this report, we present the case of a graft from an HCV-positive DBD donor with 70% macrovesicular steatosis, which was successfully preserved and transplanted using upfront NMP. This approach was key to minimize initial injury to the graft and allowed assessing its viability before transplantation, while improving transplant logistics. Upfront NMP represents a promising approach to enhance the transplantation of fatty liver grafts.

Conductivity reactivity index for monitoring of cerebrovascular autoregulation in early cerebral ischemic rabbits

BackgroundCerebrovascular autoregulation (CVAR) is the mechanism that maintains constant cerebral blood flow by adjusting the caliber of the cerebral vessels. It is important to have an effective, contactless way to monitor and assess CVAR in patients with ischemia.MethodsThe adjustment of cerebral blood flow leads to changes in the conductivity of the whole brain. Here, whole-brain conductivity measured by the magnetic induction phase shift method is a valuable alternative to cerebral blood volume for non-contact assessment of CVAR. Therefore, we proposed the correlation coefficient between spontaneous slow oscillations in arterial blood pressure and the corresponding magnetic induction phase shift as a novel index called the conductivity reactivity index (CRx). In comparison with the intracranial pressure reactivity index (PRx), the feasibility of the conductivity reactivity index to assess CVAR in the early phase of cerebral ischemia has been preliminarily confirmed in animal experiments.ResultsThere was a significant difference in the CRx between the cerebral ischemia group and the control group (p = 0.002). At the same time, there was a significant negative correlation between the CRx and the PRx (r = − 0.642, p = 0.002) after 40 min after ischemia. The Bland–Altman consistency analysis showed that the two indices were linearly related, with a minimal difference and high consistency in the early ischemic period. The sensitivity and specificity of CRx for cerebral ischemia identification were 75% and 20%, respectively, and the area under the ROC curve of CRx was 0.835 (SE = 0.084).ConclusionThe animal experimental results preliminarily demonstrated that the CRx can be used to monitor CVAR and identify CVAR injury in early ischemic conditions. The CRx has the potential to be used for contactless, global, bedside, and real-time assessment of CVAR of patients with ischemic stroke.

Remote ischemic conditioning for stroke: A critical systematic review.

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

Study of morphological transformation and features of vascular blood flow of the wall of the small and large intestine in the simulation of ischemia in the experiment

Introduction. Ischemia of the small and large intestine of various degree was simulated in 45 sexually mature male rats of the Wistar line weighing 150-200 g on the basis of the Department of Experimental Medicine with vivarium at Privolzhsky Research Medical University. Аim. To present in an experiment the effect of different degrees of occlusive ischemia on the morphological transformation of the intestinal wall and the level of changes in blood flow.Materials and methods. The anesthetized animals underwent a median laparotomy with subsequent differentiation of the intestinal divisions: the jejunal section was selected in the small intestine, the ascending section was selected in the large intestine. With the help of a nylon thread (5-0), the blood supplying arcades of these zones were ligated and further exposed for 40, 60 and 120 minutes. During the indicated periods of ischemia, the average rate of blood supply in capillary microvessels located at a depth of 0.5-1.0 mm was estimated in relative units on 1.0 mm2-area (LACC-02, NPP Lazma, Russia). After the assessment of vascular blood flow was completed, ischemic intestinal areas were sampled for morphological examination. The study results were processed using Excel application and STADIA statistical package. Results. In the course of study, the authors registered clear relationships between blood flow parameters in different parts of the intestine and the duration of ischemia. Local trophic disturbance was combined with a transformation in the histoarchitectonics of the intestinal wall. It is noted that adaptive-regenerative mechanisms provide tissue stress reduction in 120 min. due to compensatory mechanisms of blood supply contributing to the restoration of the "villus-crypt" system of the mucous membrane.Conclusion. Thus, in case of local ischemia in the small and large intestine, the tissue structure is restored due to adaptive mechanisms of blood supply, this preserves the viability and functionality of the intestinal wall.

Involvement of Proteasomal and Endoplasmic Reticulum Stress in Neurodegeneration After Global Brain Ischemia

A brief period of transient global brain ischemia leads to selective ischemic neurodegeneration associated with death of hippocampal CA1 pyramidal neurons days after reperfusion. The mechanism of such selective and delayed neurodegeneration is still uncertain. Our work aimed to study the involvement of proteasomal and endoplasmic reticulum (ER) stress in ischemic neurodegeneration. We have performed laser scanning confocal microscopy analysis of brain slices from control and experimental animals that underwent global brain ischemia for 15 min and varying times of reperfusion. We have focused on ubiquitin, PUMA, a proapoptotic protein of the Bcl-2 family overexpressed in response to both proteasomal and ER stress, and p53, which controls expression of PUMA. We have also examined the expression of HRD1, an E3 ubiquitin ligase that was shown to be overexpressed after ER stress. We have also examined potential crosstalk between proteasomal and ER stress using cellular models of both proteasomal and ER stress. We demonstrate that global brain ischemia is associated with an appearance of distinct immunoreactivity of ubiquitin, PUMA and p53 in pyramidal neurons of the CA1 layer of the hippocampus 72 h after ischemic insults. Such changes correlate with a delay and selectivity of ischemic neurodegeneration. Immunoreactivity of HRD1 observed in all investigated regions of rat brain was transiently absent in both CA1 and CA3 pyramidal neurones 24 h after ischemia in the hippocampus, which does not correlate with a delay and selectivity of ischemic neurodegeneration. We do not document significant crosstalk between proteasomal and ER stress. Our results favour dysfunction of the ubiquitin proteasome system and consequent p53-induced expression of PUMA as the main mechanisms responsible for selective and delayed degeneration of pyramidal neurons of the hippocampal CA1 layer in response to global brain ischemia.

IC87201, a PSD-95/nNOS Inhibitor, Ameliorates Heart Rate Variability in the Rat Model of Middle Cerebral Artery Occlusion

Objective: Assessment of heart rate variability (HRV) is a non-invasive and reliable method to evaluate autonomic disorders after cerebral ischemia. The present study was conducted to investigate the therapeutic potential of IC87201 in reducing post-stroke cardiac dysfunction. Materials and methods: Cerebral ischemia was induced by the middle cerebral artery occlusion (MCAO) method in 15 anesthetized adult male rats in three MCAO, MCAO+ DXM, and MCAO+ IC87201 groups, for one hour. Electrocardiogram was recorded before, and 48 hours after ischemia and drug administration, and HRV parameters were calculated from R-R intervals. In the treatment groups, IC87201 and Dextromethorphan hydrobromide monohydrate (DXM) were injected after an ischemic period. Results: After brain ischemia, the R-R interval decreased and consequently heart rate increased. The R-R intervals were used to extract the HRV frequency and time domains, including normalized low frequency (LF), high frequency (HF), LF/HF ratio, and standard deviation of R-R interval (SDRR). Normalized LF and LF/HF ratio enhanced 48 hours after ischemia, while normalized HF and SDRR significantly reduced compared to the pre-ischemic state. All HRV parameters had returned to their pre-ischemic level 48 hours after IC87201 and DXM administration, except SDRR, which recovered only in the IC87201 administered group. Conclusion: Based on our findings, it can be concluded that cerebral ischemia significantly worsens HRV parameters as a result of sympathetic overactivity. These changes were reversed by administering DXM and IC87201, but IC87201 has generally been more effective in lowering lesions. As a result, IC87201 can be introduced as an effective substance for the treatment of post-ischemic cardiac side effects.

Altered tissue oxygenation in patients with post COVID-19 syndrome.

Post COVID-19 syndrome (PCS) is a complex condition with partly substantial impact on patients' social and professional life and overall life quality. Currently, the underlying cause(s) of PCS are unknown. Since PCS-specific symptoms could be associated with systemic alterations in tissue oxygen supply, we aimed to investigate changes in tissue oxygenation in patients with PCS. A case-control study including 30 PCS patients (66.6 % males, 48.6 ± 11.2 years, mean time after (first) acute infection: 324 days), 16 cardiologic patients (CVD) (65.5 % males, 56.7 ± 6.3 years) and 11 young healthy controls (55 % males, 28.5 ± 7.4 years) was conducted. Near infrared spectroscopy (NIRS) was used to assess changes in tissue oxygenation during an arterial occlusion protocol on the non-dominant forearm (brachioradialis, 760/850 nm, 5 Hz). The protocol included 10-min rest, a 2-min baseline measurement followed by a 3-min ischemic period (upper-arm cuff, 50 mmHg above resting systolic blood pressure) and a 3-min reoxygenation period. PCS patients were grouped by presence of arterial hypertension and elevated BMI to assess the impact of risk factors. No differences in mean tissue oxygenation in the pre-occlusion phase existed between groups (p ≥ 0.566). During ischemia, comparisons of linear regressions slopes revealed slower oxygen desaturation for PCS patients (-0.064 %/s) compared to CVD patients (-0.08 %/s) and healthy subjects (-0.145 %/s) (p < 0.001). After cuff release, slowest speed for reoxygenation was detected in PCS patients at 0.84 %/s compared to CVD patients (1.04 %/s) and healthy controls (CG: 2.07 %/s) (p < 0.001). The differences between PCS patients and CVD patients during ischemia remained significant also after correction for risk factors. Analyses of complications during acute infection, persistence of PCS symptoms (time after acute infection), or PCS severity (number of lead symptoms) as confounding factors did not reveal a significant effect. This study provides evidence that the rate of tissue oxygen consumption is persistently altered in PCS and that PCS patients show an even slower decline in tissue oxygenation during occlusion than CVD patients. Our observations may at least partly explain PCS-specific symptoms such as physical impairment and fatigue.

Assessment of Squalene-Adenosine Nanoparticles in Two Rodent Models of Cardiac Ischemia-Reperfusion.

Reperfusion injuries after a period of cardiac ischemia are known to lead to pathological modifications or even death. Among the different therapeutic options proposed, adenosine, a small molecule with platelet anti-aggregate and anti-inflammatory properties, has shown encouraging results in clinical trials. However, its clinical use is severely limited because of its very short half-life in the bloodstream. To overcome this limitation, we have proposed a strategy to encapsulate adenosine in squalene-based nanoparticles (NPs), a biocompatible and biodegradable lipid. Thus, the aim of this study was to assess, whether squalene-based nanoparticles loaded with adenosine (SQAd NPs) were cardioprotective in a preclinical cardiac ischemia/reperfusion model. Obtained SQAd NPs were characterized in depth and further evaluated in vitro. The NPs were formulated with a size of about 90 nm and remained stable up to 14 days at both 4 °C and room temperature. Moreover, these NPs did not show any signs of toxicity, neither on HL-1, H9c2 cardiac cell lines, nor on human PBMC and, further retained their inhibitory platelet aggregation properties. In a mouse model with experimental cardiac ischemia-reperfusion, treatment with SQAd NPs showed a reduction of the area at risk, as well as of the infarct area, although not statistically significant. However, we noted a significant reduction of apoptotic cells on cardiac tissue from animals treated with the NPs. Further studies would be interesting to understand how and through which mechanisms these nanoparticles act on cardiac cells.

Changes in the amino acid pool in the rat parietal lobe and hippocampus with incomplete cerebral ischemia

Introduction. Amino acids and their derivatives are involved in synaptic transmission as neurotransmitters and neuromodulators, and some of them are involved in the formation of neurotransmitters of the nervous system. Therefore, the study of the state of the amino acid pool in incomplete cerebral ischemia plays a significant role.The objective was to assess the nature of changes in amino acid pool and evaluate their participation in oxidative processes in rats with incomplete cerebral ischemia.Methods and materials. The experiments were carried out on 16 male outbred white rats weighing 260±20 g in compliance with the requirements of the Directive of the European Parliament and of the Council No. 2010/63/EU of September 22, 2010 on the protection of animals used for scientific purposes.Results. Compared with the indicators in the control group, rats with an ischemic period of 1 hour in the parietal lobe had a decrease in the content of sulfur-containing amino acids: methionine by 12 % and cysteate by 28 %. In addition, there was an increase of L-arginine in the parietal lobe by 39 %, and in the hippocampus – by 56 %.Conclusions. The following changes are characteristic for one-hour incomplete cerebral ischemia: a decrease in the content of sulfur-containing amino acids, with a decrease in both methionine and an increase in the content of L-arginine. Changes in the parietal lobe and hippocampus had a similar nature, except for the absence of a drop in the level of cysteate in the hippocampus, as a reflection of the higher sensitivity of the parietal lobe to oxygen deficiency, compared with the hippocampus.

#6287 EFFECT OF REMOTE ISCHEMIC PRECONDITIONING ON NUTRITIONAL STATUS, COGNITIVE FUNCTION, AND BONE IN HEMODIALYSIS PATIENTS: A RANDOMIZED CONTROLLED TRIAL

Abstract Background and Aims Remote ischemic preconditioning (RIPC) is a process in which a brief period of ischemia is induced in one part of the body to protect another part from damage due to subsequent periods of more severe ischemia. Hemodialysis sessions are considered an ischemic process because it involves reducing blood flow to certain parts of the body, which can lead to tissue damage .Malnutrition, deterioration of cognitive function, bone disorders, cardiovascular disease, and hemodynamic instability can result from ischemia induced by hemodialysis sessions. These adverse effects increase mortality in HD patients. RIPC has been studied as a potential therapeutic strategy to reduce the risk of cardiovascular events in hemodialysis patients; however, the effect of RIPC on cognitive function, nutritional status, and bone disorder among hemodialysis patients has not been enough studied. Aim: to assess the effect of remote ischemic preconditioning on nutritional status, bone disorders, and cognitive function in hemodialysis patients at the urology and nephrology center, Mansoura University. Method Fifty patients who received regular hemodialysis for more than one year in our dialysis unit were included. The patients were randomized (single-blind) into two groups a control group (20 patients) and an intervention group (30 patients). Before each HD session, sphygmomanometer cuffs was placed around the non-vascular access arm. Three cycles of ischemia for five minutes were performed followed by reperfusion for five minutes. Ischemia was induced by inflating the sphygmomanometer cuffs to 200 mmHg. This maneuver was done before each HD session for 12 weeks. The Montreal Cognitive Assessment (MOCA) was used to assess cognitive function. The nutritional state was assessed by anthropometric measurement (body weight, BMI), laboratory (serum albumin and serum cholesterol), and Subjective Global Assessment Form (SGA). Serum calcium (s.Ca) and serum phosphorus (s.po), serum alkaline phosphate (s. ALP) and intact parathyroid hormone (iPTH) were used as indices for bone profile. Results The intervention group include 30 patient with mean age (36+/-10), 19 male (63.3%) and 11 females (36.7%). The control group include 20 patient with mean age (46+/-9), 12 male (60%) and eight female (40%). None of these patients’ demographic data (age, sex, original kidney disease, and duration of dialysis) were significantly different between the study groups (P&amp;gt;0.05). MOCA test score at baseline was (24.5 +/-2.6) at intervention group and (24.4+/-3.2) at control group, and after 12 weeks intervention was (24.8 +/-2.2) at intervention group and (24.4+/-2.8) at control group. there were no statistical significance regarding cognitive function between the two group over time (p = 0.4). NO significant Statistical changes in anthropometric measurements (Body weight (p = 0.3) and BMI (P = 0.6) were found between the two groups. Additionally, no significant changes (serum albumin and cholesterol) were detected. SGA score at baseline was at intervention group (1.2+/-0.4) and control group (1.1 +/- 0.3), and after 12 week was at the intervention group (1.4 +/-0.5) and control group (1.6 +/-0.5). SGA showed no statistical significance between the two groups over time (p = 0.2). No significant statistical changes regarding bone profile (s.ca (p = 0.5), s.PO (p = 0.2), s.ALP (p = 0.7) and iPTH (p = 0.5)). Conclusion Although some studies showed a beneficial effect of RIBC on reduction of cardiovascular risk, our study found no significant effect on cognitive function, nutritional status, and bone disorders among hemodialysis patients.

Complement activation and kidney transplantation; a complex relationship

Although kidney transplantation is the best treatment for end stage kidney disease, the benefits are limited by factors such as the short fall in donor numbers, the burden of immunosuppression and graft failure. Although there have been improvements in one-year outcomes, the annual rate of graft loss beyond the first year has not significantly improved, despite better therapies to control the alloimmune response. There is therefore a need to develop alternative strategies to limit kidney injury at all stages along the transplant pathway and so improve graft survival. Complement is primarily part of the innate immune system, but is also known to enhance the adaptive immune response. There is increasing evidence that complement activation occurs at many stages during transplantation and can have deleterious effects on graft outcome. Complement activation begins in the donor and occurs again on reperfusion following a period of ischemia. Complement can contribute to the development of the alloimmune response and may directly contribute to graft injury during acute and chronic allograft rejection. The complexity of the relationship between complement activation and allograft outcome is further increased by the capacity of the allograft to synthesise complement proteins, the contribution complement makes to interstitial fibrosis and complement’s role in the development of recurrent disease. The better we understand the role played by complement in kidney transplant pathology the better placed we will be to intervene. This is particularly relevant with the rapid development of complement therapeutics which can now target different the different pathways of the complement system. Combining our basic understanding of complement biology with preclinical and observational data will allow the development and delivery of clinical trials which have best chance to identify any benefit of complement inhibition.

CARC18: Donor Heart Refusal Following Circulatory Death: An Analysis Of UNOS Refusal Codes

Purpose: Due to the severe shortage of donor hearts, many patients with end-stage cardiac disease die before receiving potentially lifesaving transplantation. In the past, heart donation was restricted to donation after brain death (DBD). Utilizing hearts following controlled donation after circulatory determined death (DCD) is a promising development that could significantly increase the number of hearts available for transplantation. Recent studies demonstrate that survival following transplantation of controlled DCD hearts achieves results similar to transplantation using DBD hearts. Currently, the majority of DCD hearts are discarded because most do not meet the strict criteria required for controlled DCD. Of those that meet controlled DCD criteria, the majority are still refused by the recipient institutions. We sought to explore this discrepancy and characterize the reasons that institutions refuse hearts that appear to meet controlled DCD criteria. Methods: All United Network for Organ Sharing (UNOS) refusal codes used for both DCD and DBD donors in the United States for the years 2021 and 2022 were compiled and analyzed. Rates of donor heart refusal were compared using a Z-test. Odds ratios (OR) with 95% confidence intervals (CI) were calculated to characterize the basis for DCD heart refusal. Results: During the study period 83.3% (2,578/3,094) of potential DCD hearts were declined for transplantation, while 35.5% (3,770/10,610) of potential DBD hearts were declined (p<0.01). Specifically, in 2022 refusal code data demonstrated that DCD hearts were more likely to be declined due to prolonged warm ischemic time than DBD hearts (OR 2.781; 95% CI, 4.253-1.818; p<0.01) and more likely to be declined due to organ preservation concerns (OR 1.612; 95% CI, 2.044-1.272; p<0.01). The most frequently used refusal code for DCD hearts was neurological function. In 2022, 29% (24,989/86,196) of all DCD refusals were attributed to neurological function, presumably because retained neurological function prolonged the period of warm ischemia. Conclusion: The high DCD refusal rates do not appear to align with previous publications showing that results following transplantation of controlled DCD hearts are similar to DBD. Further analysis of transplant recipient team criteria that result in DCD heart refusal should be considered. Understanding and addressing the specific reasons for refusal may substantially increase the number of donor hearts available for transplantation.

Soluble Urokinase Plasminogen Activator Receptor (suPAR) Promotes Cardioprotective Intracellular Signalling in Myocardial Ischaemia

Soluble urokinase Plasminogen Activator Receptor (suPAR) is an emerging biomarker of inflammation capable of predicting cardiovascular outcomes. However, the biological activity of suPAR on the heart is poorly understood. Potential cardiac intracellular signalling pathways triggered by suPAR were explored. Isolated Langendorff rat hearts undergoing global ischaemia received treatment with either suPAR infusion or perfusion buffer (controls). Proteins were extracted from hearts for each treatment group, and Troponin T in rat outflow perfusates following ischaemia were measured. The phosphorylation status of each kinase was characterised using a phospho-specific antibody and a ratio of phosphorylation to the total protein was calculated. Analysis between treatment groups was performed with unpaired t-test with Welch’s correction. Hearts receiving suPAR treatment after ischaemia showed a 1.4-fold increase in Akt phosphorylation, and a 1.6-fold increase in Akt phosphorylation if suPAR was given before ischaemia. The ratio of p-Akt/Akt was 1.83±0.14 (n=7) in the post-ischaemic suPAR treatment group vs 1.3±0.04 (n=6) in controls (p=0.007). Pre-ischaemic suPAR treatment gave a p-Akt/Akt ratio of 1.08±0.03 (n=8) vs 0.67±0.11 (n=5) in controls (p=0.01). Upstream signalling ERK1 and ERK2 phosphorylation also increased at 2.6-fold (p=0.009) and 1.9-fold (p=0.01), respectively, in suPAR treated heart vs controls. Finally, suPAR treated hearts obtained lower Troponin T values compared with controls after recovery from ischaemia (p<0.001). suPAR infusion promoted the phosphorylation of ERK and Akt kinases in isolated rat heart tissue and reduced related cardiac troponin release after a period of global no-flow ischaemia. These actions suggest that suPAR is a novel activator of the reperfusion injury salvage kinase (RISK) pathway.

Machine perfusion and the prevention of ischemic type biliary lesions following liver transplant: What is the evidence?

The widespread uptake of different machine perfusion (MP) strategies for liver transplant has been driven by an effort to minimize graft injury. Damage to the cholangiocytes during the liver donation, preservation, or early posttransplant period may result in stricturing of the biliary tree and inadequate biliary drainage. This problem continues to trouble clinicians, and may have catastrophic consequences for the graft and patient. Ischemic injury, as a result of compromised hepatic artery flow, is a well-known cause of biliary strictures, sepsis, and graft failure. However, very similar lesions can appear with a patent hepatic artery and these are known as ischemic type biliary lesions (ITBL) that are attributed to microcirculatory dysfunction rather than main hepatic arterial compromise. Both the warm and cold ischemic period duration appear to influence the onset of ITBL. All of the commonly used MP techniques deliver oxygen to the graft cells, and therefore may minimize the cholangiocyte injury and subsequently reduce the incidence of ITBL. As clinical experience and published evidence grows for these modalities, the impact they have on ITBL rates is important to consider. In this review, the evidence for the three commonly used MP strategies (abdominal normothermic regional perfusion [A-NRP], hypothermic oxygenated perfusion [HOPE], and normothermic machine perfusion [NMP] for ITBL prevention has been critically reviewed. Inconsistencies with ITBL definitions used in trials, coupled with variations in techniques of MP, make interpretation challenging. Overall, the evidence suggests that both HOPE and A-NRP prevent ITBL in donated after circulatory death grafts compared to cold storage. The evidence for ITBL prevention in donor after brain death grafts with any MP technique is weak.

Secondary Cold Ischemia After Normothermic Machine Perfusion: A Drawback to Centralized Organ Perfusion Centers?

Secondary Cold Ischemia After Normothermic Machine Perfusion: A Drawback to Centralized Organ Perfusion Centers?

Comparison of Different Ex-Vivo Preservation Strategies on Cardiac Metabolism in an Animal Model of Donation after Circulatory Death.

Transplantation of heart following donation after circulatory death (DCD) was recently introduced into clinical practice. Ex vivo reperfusion following DCD and retrieval is deemed necessary in order to evaluate the recovery of cardiac viability after the period of warm ischemia. We tested the effect of four different temperatures (4 °C-18 °C-25 °C-35 °C) on cardiac metabolism during 3-h ex vivo reperfusion in a porcine model of DCD heart. We observed a steep fall in high-energy phosphate (ATP) concentrations in the myocardial tissue at the end of the warm ischemic time and only limited regeneration during reperfusion. Lactate concentration in the perfusate increased rapidly during the first hour of reperfusion and slowly decreased afterward. However, the temperature of the solution does not seem to have an effect on either ATP or lactate concentration. Furthermore, all cardiac allografts showed a significant weight increase due to cardiac edema, regardless of the temperature.

Severe muscle damage after a short period of ischemia and reperfusion in an animal model

BackgroundSkeletal muscle ischemia-reperfusion injuries result in a loss of contractile function, leading to limb disability or amputation. Ischemia causes hypoxia and cellular energy failure, which is aggravated by reperfusion due to the inflammatory response and oxidative stress. The consequences of the injury vary according to the duration of the period of ischemia and reperfusion. Therefore, the present work aims to evaluate ischemia-reperfusion injuries induced in the skeletal muscles of Wistar rats submitted to 3 different application periods based on morphological and biochemical parameters. MethodsFor this, a tourniquet was applied to the root of the animals’ hind limbs, occluding arterial and venous blood flow, and it was followed by reperfusion—the removal of the tourniquet. The groups were: control (without tourniquet); I30'/R60' (30 minutes of ischemia and 1 hour of reperfusion); I120'/R120' (2 hours and 2 hours); and I180'/R180' (3 hours and 3 hours). ResultsAll ischemia-reperfusion groups showed characteristics of muscle injury. Microscopic analyses of the extensor digitorum longus, soleus, tibialis anterior, and gastrocnemius muscles showed a significant increase in the number of injured muscle fibers in the ischemia-reperfusion groups compared to the control group. There were also significant differences between the ischemia-reperfusion groups in all muscles, showing a progressive increase in the degree of injury. The quantification of the number of injured muscle fibers between the muscles revealed that at I30'/R60', the soleus muscles had a higher number of injuries in relation to the other muscles, with statistical significance. In the I120'/R120' group, the gastrocnemius muscles presented a significantly greater number of injured fibers. There were no significant differences in the I180'/R180' group. The serum levels of creatine kinase in the I180'/R180' group were significantly higher than in the control and I30'/R60' groups. ConclusionsTherefore, it was evident that the 3 ischemia-reperfusion models used were capable of causing cell damage, with these findings being more pronounced in the I180'/R180' group.