Remote Ischemic Postconditioning Research Articles

Pulmonary Protective Effects of Remote Ischaemic Preconditioning with Postconditioning in Patients Undergoing Cardiac Surgery Involving Cardiopulmonary Bypass: A Substudy of the Remote Ischaemic Preconditioning with Postconditioning Outcome trial

The RISPO (Remote Ischemic Preconditioning with Postconditioning Outcome) trial evaluated whether remote ischaemic preconditioning (RIPC) combined with remote ischaemic postconditioning (RIPostC) improves the clinical outcomes of patients undergoing cardiac surgery. This substudy of the RISPO trial aimed to evaluate the effect of RIPC with RIPostC on pulmonary function in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Sixty-five patients were enrolled (32: control and 33: RIPC-RIPostC). In the RIPC-RIPostC group, four cycles of 5min ischaemia and 5min reperfusion were administered before and after CPB to the upper limb. Peri-operative PaO2/FIO2 ratio, intra-operative pulmonary shunt, and dynamic and static lung compliance were determined. The mean PaO2/ FIO2 was significantly higher in the RIPC-RIPostC group at 24h after surgery [290 (96) vs. 387 (137), p=0.001]. The incidence of mechanical ventilation for longer than 48h was significantly higher in the control group (23% vs. 3%, p<0.05). However, there were no significant differences in other pulmonary profiles, post-operative mechanical ventilation time, and duration of intensive care unit stay. In our study, RIPC-RIPostC improved the post-operative 24h PaO2/FIO2 ratio. Remote ischaemic preconditioning-Remote ischaemic postconditioning has limited and delayed pulmonary protective effects in cardiac surgery patients with CPB.

Immediate remote ischemic postconditioning after hypoxia ischemia in piglets protects cerebral white matter but not grey matter

Remote ischemic postconditioning (RIPostC) is a promising therapeutic intervention whereby brief episodes of ischemia/reperfusion of one organ (limb) mitigate damage in another organ (brain) that has experienced severe hypoxia-ischemia. Our aim was to assess whether RIPostC is protective following cerebral hypoxia-ischemia in a piglet model of neonatal encephalopathy (NE) using magnetic resonance spectroscopy (MRS) biomarkers and immunohistochemistry. After hypoxia-ischemia (HI), 16 Large White female newborn piglets were randomized to: (i) no intervention (n = 8); (ii) RIPostC – with four, 10-min cycles of bilateral lower limb ischemia/reperfusion immediately after HI (n = 8). RIPostC reduced the hypoxic-ischemic-induced increase in white matter proton MRS lactate/N acetyl aspartate (p = 0.005) and increased whole brain phosphorus-31 MRS ATP (p = 0.039) over the 48 h after HI. Cell death was reduced with RIPostC in the periventricular white matter (p = 0.03), internal capsule (p = 0.002) and corpus callosum (p = 0.021); there was reduced microglial activation in corpus callosum (p = 0.001) and more surviving oligodendrocytes in corpus callosum (p = 0.029) and periventricular white matter (p = 0.001). Changes in gene expression were detected in the white matter at 48 h, including KATP channel and endothelin A receptor. Immediate RIPostC is a potentially safe and promising brain protective therapy for babies with NE with protection in white but not grey matter.

Failure in neuroprotection of remote limb ischemic postconditioning in the hippocampus of a gerbil model of transient cerebral ischemia

Remote ischemic postconditioning (RIPoC) has been proven to provide potent protection of the heart and brain against ischemia–reperfusion injury. However, despite the evidence of cerebral protection with RIPoC is compelling, RIPoC-mediated neuroprotection against transient cerebral ischemic insult is still mired in controversy. In this study, we examined the effect of RIPoC induced by sublathal transient hind limb ischemia on neuronal death in the hippocampus following 5min of transient cerebral ischemia in gerbils. Animals were randomly assigned to sham-, ischemia-, sham plus (+) RIPoC- and ischemia+RIPoC-groups. RIPoC was induced by three cycles of 5-min and 10-min occlusion–reperfusion of both femoral arteries at predetermined points in time (0, 1, 3, 6, 12 and 24h after transient cerebral ischemia). CV staining, F-J B histofluorescence staining and NeuN immunohistochemistry were carried out to examine neuroprotection in the RIPoC-mediated hippocampus 5days after ischemia–reperfusion. In the ischemia-group, we found a significant loss of pyramidal cells in the stratum pyramidale (SP) of the hippocampal CA1 region at 5days post-ischemia compared with the sham-group. In all of the ischemia+RIPoC-groups, the loss of pyramidal cells in the CA1 region at 5days post-ischemia was not different from that in the ischemia-group. Our present findings indicate that RIPoC does not prevent hippocampal CA1 pyramidal cells from neuronal death induced by transient cerebral ischemia.

Cardioprotection by combined intrahospital remote ischaemic perconditioning and postconditioning in ST-elevation myocardial infarction: the randomized LIPSIA CONDITIONING trial.

Remote ischaemic conditioning (RIC) and postconditioning (PostC) are both potent activators of innate protection against ischaemia-reperfusion injury and have demonstrated cardioprotection in experimental and clinical ST-elevation myocardial infarction (STEMI) trials. However, their combined effects have not been studied in detail. The aim of this study was to evaluate if the co-application of intrahospital RIC and PostC has a more powerful effect on myocardial salvage compared with either PostC alone or control. This prospective, controlled, single-centre study randomized 696 STEMI patients to one of the following three groups: (i) combined intrahospital RIC + PostC in addition to primary percutaneous coronary intervention (PCI); (ii) PostC in addition to PCI; and (iii) conventional PCI (control). The primary endpoint myocardial salvage index was assessed by cardiac magnetic resonance (CMR) imaging within 3 days after infarction. Secondary endpoints included infarct size and microvascular obstruction (MVO) assessed by CMR. The combined clinical endpoint consisted of death, reinfarction, and new congestive heart failure within 6 months. The primary endpoint myocardial salvage index was significantly greater in the combined RIC + PostC group when compared with the control group (49 [interquartile range 30-72] vs. 40 [interquartile range 16-68], P = 0.02). Postconditioning alone failed to improve myocardial salvage when compared with conventional PCI (P = 0.39). The secondary endpoints, including infarct size and MVO, showed no significant differences between groups. Clinical follow-up at 6 months revealed no differences in the combined clinical endpoint between groups (P = 0.44). Combined intrahospital RIC + PostC in conjunction with PCI in STEMI significantly improves myocardial salvage in comparison with control and PostC. NCT02158468.

Remote Ischemic Postconditioning May Provide Limited Protection in Rats with Subarachnoid Hemorrhage

Background: Subarachnoid hemorrhage (SAH) is a major form of hemorrhagic stroke. It is not known whether remote ischemic postconditioning (RIP), a promising method to induce neuroprotection, can improve neurological outcome after SAH. Methods: SAH was induced by endovascular perforation of a right cerebral artery in adult Sprague-Dawley male rats. RIP was performed 5 minutes later by three cycles of 10 minutes ischemia and 10 minutes reperfusion to the bilateral legs. Results: SAH reduced neurological scores, induced brain edema and increased blood-brain barrier permeability. RIP did not affect the neurological scores and brain edema but partly inhibited the increase of blood-brain barrier permeability after SAH. Conclusions: These results suggested that RIP may not significantly induce neuroprotection against SAH. Citation: Yun-Zhen Wang, Ru-Quan Han, Zhi-Yi Zuo. Remote ischemic postconditioning may provide limited protection in rats with subarachnoid hemorrhage. J Anesth Perioper Med 2015; 2: 231-5. doi: 10.24015/JAPM.2015.0031This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium or format for any lawful purpose. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

The role of p38MAPK signal pathway in the neuroprotective mechanism of limb postconditioning against rat cerebral ischemia/reperfusion injury

It has been reported that remote ischemic postconditioning was able to protect from a harmful ischemia occurring in brain. In the present study, we investigated the role of p38 MAPK signal pathway in the process of neuroprotection and anti-apoptosis following remote limb ischemic postconditioning on rat focal cerebral ischemia/reperfusion (I/R) model. Male Sprague–Dawley rats were divided randomly into four groups: the sham-operated group, I/R group, limb ischemic postconditioning (LPostC) group, and LPostC+SB203580 (p38 MAPK inhibitor) group. Focal ischemia was induced by transient middle cerebral artery occlusion. Limb ischemic postconditioning was implemented by brief cycles of femoral artery occlusion. At 24h after modeling, we analyzed the neurological deficit score, assessed the cerebral tissue morphology by H-E staining, and evaluated neuronal apoptosis by TUNEL staining. The protein expression levels of p-p38 or p-ATF2 (phospho-activating transcription factor 2) in the penumbra region were detected by western blotting or immunohistochemical staining. Our findings revealed that LPostC relieved cerebral ischemia/reperfusion injury by decreasing neurological score, improving neuronal morphological changes in the ischemic penumbra area, and reducing neuronal apoptosis. In addition, LPostC or LPostC+SB203580 attenuated the increase in p-p38 and p-ATF2 levels in ischemia/reperfusion brain tissue. These results indicate that the protective effects of LPostC against cerebral I/R injury may be related to the attenuation of neuronal apoptosis and the suppression of p38 MAPK-ATF2 pathway.

TRPV1 activation is involved in the cardioprotection of remote limb ischemic postconditioning in ischemia-reperfusion injury rats

Limb remote ischemic postconditioning (RIPostC) has been proved to be a safe and effective measurement of cardioprotection against ischemia-reperfusion injury. But what bridges the remote organ insult and the cardioprotective effect in heart remains to be elucidated. This study aimed to found that whether TRPV1 may mediate the cardioprotective effect from remote organ to heart and the role of CGRP and SP in this process. We found that RIPostC effectively ameliorated cardiac ischemia/reperfusion injury in terms of limiting infarct size, lowering CK and cTnI release and improving cardiac function. In addition, these cardioprotective effects could be significantly abolished by inhibition of either CGRP or SP receptors with corresponding antagonists (CGRP8-37 for CGRP and RP-67580 for SP) injected before reperfusion. Besides, RIPostC resulted in significantly increase in the levels of CGRP and SP in plasma and hearts, as well as the levels and mRNA expression of CGRP and SP in DRG. The increase in CGRP and SP levels in plasma and hearts were markedly inhibited by TRPV1 receptor antagonist capsazepine. These findings indicate that limb remote ischemic postconditioning could attenuate cardiac ischemia/reperfusion injury in rats, and the cardioprotective mechanism is via TRPV1-mediated upregulation of CGRP and SP, which could subsequently act on their corresponding receptors in heart tissue.

Remote limb ischemic postconditioning protects mouse brain against cerebral ischemia/reperfusion injury via upregulating expression of Nrf2, HO-1 and NQO-1 in mice

Remote ischemic postconditioning (RIPostC) is a promising therapeutic intervention, which has been discovered to reduce ischemia/reperfusion (I/R) injury in heart, kidney, brain and skeletal muscle experimentally. However, its potential protective mechanisms have not been well elucidated. The aim of this study was to investigate the protective effect of RIPostC in cerebral I/R injury and explore the new putative mechanisms of neuroprotection elicited by it. Focal cerebral ischemia was induced by transient middle cerebral artery occlusion (tMCAO) in male CD1 mice. RIPostC was generated by three cycles of 5-min reperfusion/5-min occlusion of the bilateral femoral artery on the bilateral limbs at the onset of middle cerebral artery reperfusion. RIPostC significantly improved neurological outcome, lessened infarct volume and brain edema, upregulated the expression of Nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and quinone oxidoreductase-1 (NQO-1) and activity of superoxide dismutase (SOD), and downregulaed the formation of malondialdehyde (MDA) (p < 0.05). Taken together, these findings demonstrated that RIPostC protected the brain from I/R injury after focal cerebral ischemia by reducing oxidative stress and activating the Nrf2–ARE (antioxidant response element) pathway.

Neuroprotection by peripheral nerve electrical stimulation and remote postconditioning against acute experimental ischaemic stroke

Objective:Local electrical stimulation (ES) was reported to protect the brain during ischaemic injury, while the protective effect of limb remote ischaemic postconditioning (RIPostC) was confirmed. The aim of this study was to explore whether remote peripheral nerve ES exerted neuroprotection and whether this procedure shared the same neuroprotective mechanism underlying RIPostC.Methods:Stroke in Sprague-Dawley rats was induced by distal middle cerebral artery occlusion (dMCAO). Rats were divided into five groups: dMCAO, RIPostC, ES, nerve resection (NR) + ES and RIPostC+ES. Twenty-four hours after reperfusion, rats were examined for neurobehavioural function, including forelimb fault placing test, Ludmila Belayev 12 score test, and infarct volume. The expression of Bcl-2 and cleaved-caspase-3 in ischaemic cortex was assessed by Western blot.Results:In forelimb fault placing test, as compared to the highest score in the stroke-only group, RIPostC, ES and RIPostC+ES groups showed a significantly (P < 0.01) lower score. The results were similar for the Ludmila Belayev 12 score test. The infarct volume of the treatment groups also exhibited significant (P < 0.01) reduction as compared to the stroke-only group. The volume of infarct tissue in the combination of RIPostC+ES was significantly less than RIPostC and ES alone (P < 0.05). Furthermore, NR blocked the ES's protection (P < 0.05) as compared to the ES group by using above-mentioned methods. Bcl-2 was upregulated, while cleaved-caspase-3 was downregulated in the experimental groups as compared to the control group. No difference was found among the experimental groups.Discussion:Peripheral nerve ES appears to have a neuroprotective effect in a rat dMCAO model. This effect may indicate a neural protective mechanism underlying beneficial effect of RIPostC.

κ-Opioid receptors are involved in enhanced cardioprotection by combined fentanyl and limb remote ischemic postconditioning.

The combination of various interventions to obtain enhanced cardioprotection is always an important area of research focus. This randomized experiment was designed to assess whether combined fentanyl and limb remote ischemic postconditioning produced enhanced protection against myocardial ischemia/reperfusion injury in an in vivo rat model, and to determine if κ-opioid receptors were implicated in the cardioprotection of these interventions. Seventy-two rats were exposed to a 30-min myocardial ischemia followed by a 180-min reperfusion. Half of the rats (36) were randomized into four different groups receiving control treatment, fentanyl postconditioning, limb remote ischemic postconditioning, and combined fentanyl and limb remote ischemic postconditioning. The remaining 36 rats were also randomized into four groups receiving the same interventions as the above groups following the intravenous administration of a κ-opioid receptor antagonist, nor-binaltorphimine, before myocardial ischemia. At the end of reperfusion, both serum cardiac troponin I and infarct size were determined. Both fentanyl postconditioning and limb remote ischemic postconditioning significantly decreased the infarct size and serum cardiac troponin I level, and combined fentanyl and limb remote ischemic postconditioning produced enhanced cardioprotection on the infarct size-sparing effect. The use of nor-binaltorphimin to block κ-opioid receptors eliminated cardioprotection by fentanyl postconditioning and enhanced cardioprotection by combined fentanyl and limb remote ischemic postconditioning, but did not change cardioprotection by limb remote ischemic postconditioning. Combined fentanyl and limb remote ischemic postconditioning produced enhanced protection against myocardial ischemia/reperfusion injury. κ-Opioid receptors are essential for cardioprotection by fentanyl postconditioning and enhanced cardioprotection by combined fentanyl and limb remote ischemic postconditioning; however, they do not play a pivotal role in cardioprotection by limb remote ischemic postconditioning.

Remote ischemic conditioning: A novel way to treat ischemia-related injury of limbs

Remote ischemic conditioning (RIC) including remote ischemic preconditioning (RIPC) and remote ischemic postconditioning (RIPostC) is widely reported to be able to prevent many organs, such as heart, brain, and skeletal muscle from ischemia-related injury. However, the clinical application of RIC is confined to treating myocardial infarction and stroke. Since RIC could prevent skeletal muscle from ischemia-related injury, and was effective in heart and brain treatments, we hypothesized RIC could treat ischemia-related injury of limbs, such as diabetic foot, Buerger’s disease, plantation of severed limb, and crush injury. As we know, many researches not only proved the promising clinical applications of RIC, but also researched the mechanisms in animal models. Our hypothesis could be confirmed by these researches.

Effect of remote limb ischemic postconditioning combined with electro-acupuncture postconditioning on focal cerebral ischemia-reperfusion injury in rats

Objective To evaluate the effect of remote limb ischemic postconditioning(RLIP)combined with electro-acupuncture postconditioning(EAP)on focal cerebral ischemia-reperfusion(I/R)injury in rats. Methods Seventy male Sprague-Dawley rats, weighing 220-250 g, were randomly assigned into 5 groups(n=14 each)using a random number table: sham operation group(group S), group I/R, RLIP group, EAP group and RLIP combined with EAP group(group RLIP+ EAP). Focal cerebral I/R was induced by middle cerebral artery occlusion(MCAO). MCAO was maintained for 120 min.The animals were subjected to 3 cycles of 15 min ischemia of bilateral hind limbs followed by 30 s reperfusion starting from onset of reperfusion.Dazhui and Baihui acupoints were stimulated with electric stimulator(frequency 15 Hz/2 Hz, intensity 1 mA)for 30 min starting from onset of reperfusion.Neurological deficit scores(NDSs)were evaluated at 24 h of reperfusion.The animals were then sacrificed and brains were removed to measure the infarct size and for microscopic examination of pathological changes in hippocampal CA1 region.The number of survival neurons was counted.The apoptosis in neurons was determined by TUNEL.Apoptosis index was calculated. Results Compared with group S, the NDSs, percentage of cerebral infarct size and AI were significantly increased, and the number of survival neurons was decreased in the other four groups.Compared with group I/R, the NDSs, percentage of cerebral infarct size and AI were significantly decreased, and the number of survival neurons was increased in EAP, RLIP and RLIP+ EAP groups.Compared with RLIP and EAP groups, the NDSs, percentage of cerebral infarct size and AI were significantly decreased, and the number of survival neurons was increased in group RLIP+ EAP. Conclusion The combination of RLIP and EAP provides better efficacy than either alone in attenuating focal cerebral I/R injury in rats. Key words: Electric stimulation therapy; Brain; Reperfusion injury; Extremities; Ischemic postconditioning

Remote ischemic pre- and postconditioning improve postresuscitation myocardial and cerebral function in a rat model of cardiac arrest and resuscitation.

Cardiac arrest and resuscitation are models of whole body ischemia reperfusion injury. Postresuscitation myocardial and cerebral dysfunction are major causes of high mortality and morbidity. Remote ischemic postconditioning has been proven to provide potent protection of the heart and brain against ischemia reperfusion injury. In this study, we investigated the effects of remote ischemic postconditioning on postresuscitation myocardial and cerebral function in a rat model of cardiac arrest and resuscitation. Prospective, randomized, controlled experimental study. University-affiliated animal research institution. Twenty-eight healthy male Sprague-Dawley rats. The animals were randomized into four groups: 1) remote ischemic preconditioning initiated 40 minutes before induction of ventricular fibrillation, 2) remote ischemic postconditioning initiated coincident with the start of cardiopulmonary resuscitation, 3) remote ischemic postconditioning initiated 5 minutes after successful resuscitation, and 4) control. Remote ischemic pre- and postconditioning was induced by four cycles of 5 minutes of limb ischemia, followed by 5 minutes of reperfusion. Ventricular fibrillation was induced and untreated for 6 minutes while defibrillation was attempted after 8 minutes of cardiopulmonary resuscitation. The animals were then monitored for 4 hours and observed for an additional 68 hours after resuscitation. Hemodynamic measurements and myocardial function, including cardiac output, left ventricular ejection fraction, and myocardial performance index, were measured at baseline and hourly for 4 hours after resuscitation. Postresuscitation cerebral function was evaluated by neurologic deficit score at 24-hour intervals for a total of 72 hours. Consequently, significantly better myocardial and cerebral function with a longer duration of survival were observed in the three groups treated with remote ischemic pre- and postconditioning. In a rat model of cardiac arrest and resuscitation, remote ischemic pre-and postconditioning attenuated postresuscitation myocardial and cerebral dysfunction and improved the duration of survival.

Cardioprotection by remote ischemic conditioning: Mechanisms and clinical evidences.

In remote ischemic conditioning (RIC), several cycles of ischemia and reperfusion render distant organ and tissues more resistant to the ischemia-reperfusion injury. The intermittent ischemia can be applied before the ischemic insult in the target site (remote ischemic preconditioning), during the ischemic insult (remote ischemic perconditioning) or at the onset of reperfusion (remote ischemic postconditioning). The mechanisms of RIC have not been completely defined yet; however, these mechanisms must be represented by the release of humoral mediators and/or the activation of a neural reflex. RIC has been discovered in the heart, and has been arising great enthusiasm in the cardiovascular field. Its efficacy has been evaluated in many clinical trials, which provided controversial results. Our incomplete comprehension of the mechanisms underlying the RIC could be impairing the design of clinical trials and the interpretation of their results. In the present review we summarize current knowledge about RIC pathophysiology and the data about its cardioprotective efficacy.

Effects of Limb Remote Postconditioning on Apoptosis and Long-Term Neurological Outcomes of Focal Cerebral Ischemia/Reperfusion Injury in Rats

Background and Purpose: Remote ischemic postconditioning (RPostC) is an emerging concept for cerebral infarction protection, and it has better application prospects in clinical practice. However, little is known about the neuroprotection mechanisms of RPostC in cerebral ischemia/reperfusion (I/R) injury. In the present study, we investigated the effects of RPostC on neural cells apoptosis and long-term neurological outcomes in focal cerebral I/R injury in the rat middle cerebral artery occlusion model. Methods: Focal cerebral ischemia was induced by middle cerebral artery occlusion using the intraluminal filament technique in male rats. RPostC was generated by 3 cycles of femoral artery 10-minute occlusion/reperfusion on the right limb at the onset of middle cerebral artery reperfusion. Adult male wistar rats were treated with remote post conditioning after 90 minutes of occlusion (beginning of reperfusion). Infarct volumes were assessed at 24h and 21d of stroke onset. Neurological scores were assessed at 24h and 3d,5d, 7d,10d, 14, 21d after the onset of middle cerebral artery reperfusion. Apoptosis-related molecules were studied at 24h of stroke onset by Western blotting. Results: RPostC treatment up-regulated Bcl-2 and heat-shock protein 70 (HSP70) expression and downregulated Bax expression. RPostC treatment also reduced infarct volumes at 24h and 21d, meanwhile, it also improved the neurologic scores and the long-term neurological outcomes compared with the I/R-only group. Conclusion: These findings indicate that RPostC inhibits focal cerebral I/R injury and improves the neurological outcomes. This neuroprotective effect is likely achieved by anti-apoptotic mechanisms.

Neural transmission pathways are involved in the neuroprotection induced by post- but not perischemic limb remote conditioning

Background: Remote ischemic preconditioning (PreC) and postconditioning (PostC) have all been shown to be neuroprotective against ischemia/reperfusion (I/R) injury. However, the underlying mechanisms of ischemic perconditioning (PerC) remain largely unknown. This study aimed to investigate the potential role of neural transmission pathways in the transference of protective signals evoked by PerC. Materials and Methods: Male Sprague-Dawley rats were randomly allocated into 12 groups [sham, middle cerebral artery occlusion (MCAO), MCAO+PerC, MCAO+PerC+vehicle, MCAO+PerC+Capsaicin, MCAO+PerC+sham, MCAO+PerC+denervation, MCAO+PostC, MCAO+PostC+vehicle, MCAO+PostC+sham, MCAO+PostC+Capsaicin, MCAO+PerC+denervation]. The I/R model was established by 90-min occlusion of the right middle cerebral artery and subsequent 24 h reperfusion. Remote conditioning was induced with three cycles of 10 min ischemia/10 min reperfusion of the femoral arteries bilaterally. Nerve block was conducted by local capsaicin treatment of exposed nerves or femoral and sciatic nerve transection. Cerebral infarct volumes were quantified by 2, 3, 4-triphenytetrazolium-chloride stain assay. The phosphorylation of Akt was detected by Western blot. Results: Remote ischemic PerC and PostC therapies reduced the infarct size and attenuated neurological deficits. Blocking the neural transmission pathways abolished the protective effect of PostC but had no effect on PerC. Further, blocking the neural transmission pathways reduced periinfarct Akt activation of PostC but had no effect on PerC. Conclusion: Unlike PostC, neural transmission pathways may not play a significant role in the transference of PerC-induced neuroprotection after I/R injury.

Abstract 305: Remote Ischemic Postconditioning Alone and Combined with Therapeutic Hypothermia Improve Neurological Outcomes After Cardiopulmonary Resuscitation in a Porcine Model

Introduction: The degree of post-resuscitation cerebral injury is an important determinant on the outcomes for CA victims.We previously demonstrated remote ischemic pre- and post-conditioning equally attenuated post-CPR cerebral dysfunction in a rat model. Here we investigated the effects of remote ischemic post-conditioning (RIpostC) alone and combined with therapeutic hypothermia (TH) on the neurological outcomes after CPR. Hypothesis: RIpostC would improve post-CPR neurological function and cerebral injury, which would be enhanced by its combination with TH. Methods: Twenty-one male domestic pigs weighing 37 ± 2 kg were subjected to 10 mins of untreated VF followed by 5 mins of CPR. The animals were randomized to RIpostC, RIpostC+TH or control. Coincident with the start of CPR, RIpostC was induced by four cycles of 5 mins of limb ischemia followed by 5 mins of reperfusion. At 5 mins after resuscitation, TH was implemented by surface cooling to reach a temperature of 32-34 °C until 4 hrs post-resuscitation, followed by a rewarming rate of 1°C/h for 4 hrs. The resuscitated animals were observed for 72 hrs. Results: Six of the seven animals in each group were successfully resuscitated. Significantly better neurological function was observed in the RIpostC group than in the control group. Surprisingly the combined RIpostC and TH further improved post-CPR neurological function, which was significantly better than that in the RIpostC and control groups. There was less cerebral injury in the animals that received RIpostC alone and combined with TH; which was significantly better at 48 and 72 hrs post-resuscitation when compared to the control group. Furthermore, significantly less cerebral injury was measured at 72 hrs in the combination group than in the RIpostC group (Table). Conclusion: In a porcine model of CA, RIpostC significantly improved post-resuscitation neurological function and cerebral injury. Its combination with TH further enhanced its protective effects

Abstract 138: Remote Ischemic Postconditioning Alleviates Postresuscitation Inflammatory Response and Pulmonary Edema in a Porcine Model of Cardiac Arrest

Introduction: Systemic ischemia-reperfusion injury produced by CA and resuscitation can result in severe post-cardiac arrest syndrome; which includes systemic inflammatory response and multiple organ dysfunction syndrome such as acute pulmonary edema. We previously demonstrated that remote ischemic post-conditioning (RIpostC) improved post-resuscitation myocardial and cerebral function in a rat model of CA. In this study, we investigated the effects of RIpostC on inflammatory response and pulmonary edema after CPR in a porcine model. Hypothesis: RIpostC would alleviate post-resuscitation inflammatory response and pulmonary edema in a porcine model of CA. Methods: Fourteen male domestic pigs weighing 37 ± 2 kg were utilized. Ventricular fibrillation was electrically induced and untreated for 10 mins. The animals were then randomized to receive RIpostC or control. Coincident with the start of CPR, RIpostC was induced by four cycles of 5 mins of limb ischemia and then 5 mins of reperfusion. Defibrillation was attempted after 5 mins of CPR. The resuscitated animals were monitored for 4 hrs and observed for an additional 68 hrs. Results: Six of the seven animals in each group were successfully resuscitated. After resuscitation, significantly lower levels of tumor necrosis factor-α and interleukin-6 were measured in the animals that received RIpostC when compared with the control group. Post-resuscitation extra-vascular lung water index was lower in the RIpostC group than in the control group; in which the differences were significant at 2,3 and 4 hrs (Table). Conclusion: In a porcine model of CA, RIpostC significantly alleviates post-resuscitation inflammatory response and pulmonary edema.

Effect of remote limb ischemic postconditioning on level of adiponectin during myocardial ischemia-reperfusion in rats

Objective To evaluate the effect of remote limb ischemic postconditioning on the level of adiponectin during myocardial ischemia-reperfusion (I/R) in rats.Methods Fifty-seven male Sprague-Dawley rats,aged 8 weeks,weighing 250-350 g,were randomly divided into 3 groups (n =19 each):sham operation group (group S); group I/R; remote limb ischemic postconditioning group (group RLIP).Myocardial ischemia was induced by occlusion of anterior descending branch of left coronary artery for 30 min followed by 180 min reperfusion in urethane-anesthetized rats.In group S,the anterior descending branch was only exposed but not ligated.The animals underwent 10 min ischemia of bilateral hind limbs starting from 20 min of occlusion of the anterior descending branch,followed by reperfusion in RLIP group.The changes in S-T segment were recorded at 30,60,120 and 180 min of reperfusion.At 180 min of reperfusion,the blood samples were taken from the jugular vein for determination of serum levels of creatine kinase MB (CK-MB) and cardiac troponin Ⅰ (cTnⅠ).The animals were then sacrificed and hearts were removed for measurement of myocardial infarct size (IS) and adiponectin contents in myocardial tissues (by ELISA).Results Compared with group S,S-T segment was significantly elevated at each time point,myocardial IS,and serum cTnⅠ and CK-MB levels were increased,and adiponectin contents were decreased in I/R and RLIP groups.Compared with group I/R,elevation of S-T segment was significantly decreased at each time point,myocardial IS,and serum cTnⅠ and CK-MB levels were decreased,and adiponectin contents were increased in RLIP group.Conclusion The mechanism by which remote limb ischemic postconditioning reduces myocardial I/R injury is related to increased level of adiponectin in the myocardium of rats. Key words: Adiponectin ; Myocardial reperfusion injury ; Extremities ; Ischemic postconditioning

Remote ischemic postconditioning: harnessing endogenous protection in a murine model of vascular cognitive impairment.

We previously reported that remote limb ischemic conditioning (RLIC; PERconditioning) during acute stroke confers neuroprotection, possibly due to increased cerebral blood flow (CBF). Vascular cognitive impairment (VCI) is a growing threat to public health without any known treatment. The bilateral common carotid artery stenosis (BCAS) mouse model is regarded as the most valid model for VCI. We hypothesized that RLIC (postconditioning; RIPostC) will augment CBF during chronic cerebral hypoperfusion (CCH) and prevent cognitive impairment in the BCAS model. BCAS using customized microcoil was performed in C57/B6 male mice to establish CCH. A week after the BCAS surgery, mice were treated with RIPostC-therapy once daily for 2 weeks. CBF was measured with laser speckle contrast imager at different time points. Cognitive testing was performed at 4-week post-BCAS, and brain tissue was harvested for biochemistry. BCAS led to chronic hypoperfusion resulting into impaired cognitive function as tested by novel object recognition (NOR). Histological examinations revealed that BCAS triggered inflammatory responses and caused frequent vacuolization and cell death. BCAS also increased the generation and accumulation of amyloid beta protein (Aβ), resulting into the loss of white matter (WM) and myelin basic protein (MBP). RIPostC-therapy showed both acute increase as well as sustained improvement in CBF even after the cessation of therapy for a week. RIPostC improved cognitive function, inhibited inflammatory responses, prevented the cell death, reduced the generation and accumulation of Aβ, and protected WM integrity. RIPostC is effective in the BCAS model and could be an attractive low-cost conventional therapy for aged individuals with VCI. The mechanisms by which RIPostC improves CBF and attenuates tissue damage need to be investigated in the future.Electronic supplementary materialThe online version of this article (doi:10.1007/s12975-014-0374-6) contains supplementary material, which is available to authorized users.