VascularPostconditioning of the Lower Limb—Protection Against the Reperfusion Syndrome
Introduction
During major vascular surgeries of the lower limb arteries and the abdominal aorta, the lower extremities are unavoidably subjected to ischemia. Restoration of the blood supply results in a further insult to the tissues, aggravating the injury caused by ischemia, termed as ischemia-reperfusion-injury (IR-injury). The IR-injury of extensive muscle tissue mass and the sensitive vascular tissues and endothelium often leads to systemic complications with distant organ damage of major clinical importance, a phenomenon called reperfusion syndrome [1].
The IR-injury of the vascular endothelium results in endothelial cell dysfunction and local inflammation. This process may give rise to a generalized inflammation (systemic inflammatory response syndrome (SIRS) with activation of different immune cells, release of a vast number of inflammatory mediators, reactive free radicals, and vasoactive substances [2]. This process may cause severe dysfunction and morphologic alteration of distant organs, and progrediate into multiple organ dysfunction syndrome (MODS), consisting of diffuse alveolar damage of the lungs, local inflammatory processes in the liver, increased permeability of the intestinal mucosa, and rhabdomyolysis-induced myohemoglobinuric acute renal failure 3, 4.
Postconditioning is a powerful cardioprotective surgical technique capable of reducing IR-injury in the heart [5]. It consists of several cycles of brief interruptions in the blood supply at the very onset of an organ's reperfusion additionally to its prolonged ischemia.
The aim of the present study was to investigate the application of postconditioning in major vascular surgery for the first time not in terms of the IR-injury of the lower limbs, but in terms of the postoperative complications of these operations, termed as reperfusion syndrome.
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Animals
Male Wistar rats, weighing 250–280 g, were used in the experiment (Charles River Hungary Ltd., Budapest, Hungary). The experimental design was regulated and approved by Act XXVIII of 1998 and Government Decree 243/1998 (XII. 31). In specific, pathogen-free conditions at 22–24 °C, the rats were maintained on standard rat chow and water ad libitum.
Operative Procedure
Animals were anaesthetized with an intraperitoneal injection of ketamine (75 mg/kg) and xylazine (7.5 mg/kg). Deep anesthesia was maintained by the
Histology
No pathologic lesions were found in most samples taken from the rectus femoris muscle. Mild rhabdomyolysis was apparent only in few cases in the control group, but this was far from reaching any significance (Fig. 1).
Sections from each lung of the control rats exhibited partial atelectasis, defined by collapsed and pinched alveoli, thicker and felted alveolar walls, while in the sections of the postconditioned group, only slight alterations were detected (Fig. 2).
Kidney histology showed
Discussion
A clinically most relevant feature of major vascular operations (e.g., aortic aneurysm repairs, reconstructions of the lower extremity arteries) is the necessity for clamping of major arteries. Thus, tissues distal to the clamp incur ischemic-reperfusion injuries, most notably a huge mass of skeletal muscle [7].
We report for the first time that postconditioning may effectively be used in major vascular operations (i.e., aorta-clamping) to reduce the systemic and distant organ complications
Acknowledgments
The authors express their special thanks to Andras Kiss, M.D., Ph.D. and Zsuzsa Schaff, M.D., Ph.D., D.Sc. for their excellent technical assistance and support in the histopathologic analysis. The authors owe thanks to Viktor Hegedus and Anna Blazovics, M.D., Ph.D., D.Sc. for the antioxidant measurements. Grateful acknowledgments are due to Peter Kupcsulik, M.D., Ph.D. for general support. Ildiko Toma, M.D., Ph.D. is thanked for her writing assistance and proofreading.
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Vascular surgery-related organ injury and protective strategies: Update and future prospects
2016, British Journal of AnaesthesiaCitation Excerpt :Activation of these receptors leads to a downward cascade of PI3K,124 which has been associated with the cytoprotective stabilization of mitochondrial membranes on reperfusion125 as discussed above. In animal models, postconditioning has been explored with respect to abdominal aortic surgery looking at the reaction of skeletal muscle, systemic inflammatory reaction and renal function.126–128 One study in rats, cross-clamped the aorta to induce lower limb ischaemia and initiated postconditioning at the start of reperfusion by declamping the aorta for 10 s, then reapplying the clamp for 10 s.
Improvement of small intestinal microcirculation by postconditioning after lower limb ischemia
2015, Microvascular ResearchCitation Excerpt :Postconditioning (PC) is a surgical technique, consisting of brief reperfusion and re-occlusion cycles at the very onset of reperfusion, which were reported to be capable of reducing IR-injury of the lower limbs (Charles et al., 2011; Guo et al., 2011; Liang et al., 2013; Mansour et al., 2012; Sinay et al., 2008). Our previous results showed that postconditioning was able to reduce damages in remote organs such as the lungs and kidneys following lower limb ischemia (Gyurkovics et al., 2011), and it has also been demonstrated that postconditioning is able to limit remote small intestinal mucosal damage (Leng et al., 2011). Nevertheless the remote hemodynamic effects of postconditioning on mucosal microcirculation were not addressed before.
Biochemical markers of acute limb ischemia, rhabdomyolysis, and impact on limb salvage
2014, Seminars in Vascular SurgeryCitation Excerpt :Ischemic post conditioning has been proposed as a means to reduce the physiologic burden of IRI. Defined as the application of repeated cycles of reperfusion and ischemia performed on the ischemic leg at the onset of reperfusion, ischemic post conditioning appears in animal models to be an initially promising intraoperative therapy to mitigate IRI [25–29]. In a human study evaluating the effects of remote ischemia post conditioning in anterior segment ST myocardial infarctions, the investigators found significant reductions in infarct size [30].
Therapeutic option for managing lung injury induced by infrarenal aortic cross-clamping
2013, Journal of Surgical ResearchCitation Excerpt :TNF-α is released in the acute phase of inflammation [29], then its level is decreased in the subacute phase. IL-6 appears mostly in the subacute phase [16]. In our present study PostC was able to reduce the inflammatory response caused by IR according to the found TNF-α level results.
Ischemia postconditioning and mesenchymal stem cells engraftment synergistically attenuate ischemia reperfusion-induced lung injury in rats
2012, Journal of Surgical ResearchCitation Excerpt :Recently, ischemic postconditioning (IPO), defined as a series of rapid intermittent interruptions of blood flow in the early phase of reperfusion [17], has been studied in the heart, brain, kidney, lung, and liver and was demonstrated to result in protection similar to that observed with ischemic preconditioning [18–22]. Several studies have showed that IPO could cause a significant reduction in the systemic inflammatory response, inhibit the expression of apoptotic molecules, and activate endogenous protective molecules [18,23,24]. Therefore, IPO deserves more attention owing to its feasibility and operability in clinic settings.
Remote and local ischemic postconditioning further impaired skeletal muscle mitochondrial function after ischemia-reperfusion
2012, Journal of Vascular Surgery
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These two authors contributed equally to this study.