Avoiding reperfusion injury after limb revascularization: Experimental observations and recommendations for clinical application

Beyersdorf, Friedhelm; Matheis, G.; Krüger, Stefan; Hanselmann, Anke; Freisleben, Hans-Georg; Zimmer, Guido; Satter, P

doi:10.1016/0741-5214(89)90081-5

Cited by 90 publications

(36 citation statements)

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“…28 Tissue edema was enormously reduced and tissue viability was highly increased, which certainly contributed to the marked preservation of contractility (the Table). These effects were more pronounced in earlier reports 16,35,37 ; however, selective in vivo reperfusion has not been used in rodents before. Therefore, comparability was limited because these data stemmed from isolated rat hind limbs or larger animal models with incomplete ischemia.…”

Section: Discussionmentioning

confidence: 61%

“…15 Limitation of initial blood flow and perfusion pressure, modifications of the reperfusate composition, and hypothermia all have been proposed for many years. 16,17 For instance, hypothermia and low initial flow rates have been shown to decrease the severity of reperfusion injury in skeletal muscle, 18,19 and flow-controlled reperfusion improved sinusoidal microcirculation in rat livers. 20 Filtration of leukocytes reduced reperfusion-related complications in lung and myocardium, 21,22 and use of a substrate-enriched reperfusate led to immediate recovery of contractile muscle function after prolonged warm ischemia.…”

Section: Clinical Perspective P 1928mentioning

confidence: 99%

“…20 Filtration of leukocytes reduced reperfusion-related complications in lung and myocardium, 21,22 and use of a substrate-enriched reperfusate led to immediate recovery of contractile muscle function after prolonged warm ischemia. 16 Numerous additional modifications have been proposed, 9,23 including the administration of free radical scavengers, anticoagulants, and dedicated antiinflammatory and vasodilative agents, as well as the disposal of sequestered blood. However, translation of such strategies to clinical management of acute limb ischemia has remained astonishingly sparse considering the considerable clinical potential that has been reported in preliminary case series.…”

Section: Clinical Perspective P 1928mentioning

confidence: 99%

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Basic Control of Reperfusion Effectively Protects Against Reperfusion Injury in a Realistic Rodent Model of Acute Limb Ischemia

et al. 2008

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Background-Reperfusion injury is insufficiently addressed in current clinical management of acute limb ischemia.Controlled reperfusion carries an enormous clinical potential and was tested in a new reality-driven rodent model. Methods and Results-Acute hind-limb ischemia was induced in Wistar rats and maintained for 4 hours. Unlike previous tourniquets models, femoral vessels were surgically prepared to facilitate controlled reperfusion and to prevent venous stasis. Rats were randomized into an experimental group (nϭ7), in which limbs were selectively perfused with a cooled isotone heparin solution at a limited flow rate before blood flow was restored, and a conventional group (nϭ7; uncontrolled blood reperfusion). Rats were killed 4 hours after blood reperfusion. Nonischemic limbs served as controls. Ischemia/reperfusion injury was significant in both groups; total wet-to-dry ratio was 159Ϯ44% of normal (Pϭ0.016), whereas muscle viability and contraction force were reduced to 65Ϯ13% (Pϭ0.016) and 45Ϯ34% (Pϭ0.045), respectively. Controlled reperfusion, however, attenuated reperfusion injury significantly. Tissue edema was less pronounced (132Ϯ16% versus 185Ϯ42%; Pϭ0.011) and muscle viability (74Ϯ11% versus 57Ϯ9%; Pϭ0.004) and contraction force (68Ϯ40% versus 26Ϯ7%; Pϭ0.045) were better preserved than after uncontrolled reperfusion. Moreover, subsequent blood circulation as assessed by laser Doppler recovered completely after controlled reperfusion but stayed durably impaired after uncontrolled reperfusion (Pϭ0.027). Conclusions-Reperfusion

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Section: Discussionmentioning

confidence: 61%

Section: Clinical Perspective P 1928mentioning

confidence: 99%

Section: Clinical Perspective P 1928mentioning

confidence: 99%

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Basic Control of Reperfusion Effectively Protects Against Reperfusion Injury in a Realistic Rodent Model of Acute Limb Ischemia

et al. 2008

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“…The fact that NO can alter the sensitivity of mitochondria to MPT inducers might be important for some physiological and pathophysiological processes where the mitochondrial permeability transition is implicated. Thus, NO production might influence the development of such pathologies as drug hepatotoxicities [47], glutamate-mediated neuronal injury [48], ischaemidreperfusion [36,37,491, and reperfusion injury after limb revascularization [50] by modulating the amount of mitochondria under MPT state. For example, several studies have shown that NO production can protect the heart against ischaemiaheperfusion injury [51,52].…”

Section: Discussionmentioning

confidence: 99%

Modulation of the Mitochondrial Permeability Transition by Nitric Oxide

Balakirev

Khramtsov

Zimmer

1997

European Journal of Biochemistry

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105

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The influence of nitric oxide on mitochondrial permeability transition (MPT) phenomenon was studied. NO was generated by photolysis of S-nitroso-N-acetylcysteine, AcCys(NO), with green light (2 = 550 nm). Two distinct effects of nitric oxide on rat liver mitochondria were identified. First, NO accelerated an onset of swelling in Caz'-loaded mitochondria in a cyclosporin-A-sensitive manner acting as an inducer of permeability transition. This was, apparently, a result of irreversible alteration of mitochondrial function accompanying the inhibition of respiratory chain in the presence of calcium. Formation of ESR-visible iron-sulfur dinitrosyl complexes (g = 2.041) could also contribute to the irreversible changes resulting in MPT induction. Second, NO changed significantly the response of mitochondria to Ca'+/phosphate-induced MPT, acting as a regulator of permeability transition. In this case the action of nitric oxide led to division of the mitochondria into two subpopulations: one which underwent the rapid permeability transition and another in which the MPT was inhibited. The effect of NO on Ca2+/Pi-induced MPT was transient and resulted from reversible inhibition of cytochrome oxidase followed by the changes in transmembrane potential and Ca2+ distribution. The characteristic time of duration of these NO modulated effects depended on nitric oxide as well as on oxygen concentrations. With increasing NO at fixed oxygen concentrations, this time levelled off to reach a maximum value which was inversely related to the oxygen concentration. It is concluded that under physiological condition the duration of reversible NO effects on mitochondrial function could be determined by oxygen concentration.Keywords: nitric oxide ; mitochondrial permeability transition.Nitric oxide (NO) plays multiple roles in diverse physiological processes, including relaxation of smooth muscle, neurotransmission, inhibition of platelet aggregation and killing of pathogens [l]. At the present time a large body of evidence has accumulated suggesting an important role of NO and peroxynitrite (the product of NO interaction with superoxide) in modulation of mitochondrial function. It has been shown that nitric oxide can reversibly inhibit mitochondrial respiration by competing with oxygen at cytochrome oxidase [2, 31. On the other hand, the fonnation of peroxynitrite from NO and mitochondria-derived superoxide can cause the irreversible inhibition of complexes 1-111 leading to mitochondrial dysfunction [4, 51. It has been proposed that NO exerts some of its main physiological and pathological effects by shifting ATP/ADP due to inhibition of respiratory chain [6]. It has also been shown that nitric oxide influences the mitochondrial Caz+ metabolism. Thus both NO and peroxynitrite are able to induce mitochondrial Ca*+ efflux by distinct and apparently specific pathways 17, 81. Calcium efflux induced by nitric oxide could contribute significantly to cellular damage during NO overproduction [9].It is now generally believed that mitochondrial C...

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“…Nevertheless, a substantial percentage of the injury is generated on reperfusion, and some experimental and clinical data suggest that careful control of both the composition and the physical conditions of the initial reperfusion may prevent the development of this injury. [4][5] Here we report our initial clinical experience with controlled limb reperfusion in two patients with severe limbthreatening ischemia.…”

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confidence: 99%

25.7 Successful controlled limb reperfusion after severe prolonged ischemia

Defraigne¹

1997

Cardiovascular Surgery

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Controlled limb reperfusion was performed in two patients who were admitted for lower limb-threatening ischemia as a result of embolism. After embolectomy, the inflow blood was drained with a cannula and mixed with a crystalloid solution to obtain an hyperosmolar, hypocalcemic, alkalotic, and substrate-enriched (aspartate, glutamate) reperfusate. This reperfusate was reinjected with a roller pump for 30 minutes through two cannulas inserted in the profunda and superficial femoral arteries. Temperature, intraarterial pressures, and flow were closely controlled. No complications occurred, and complete recovery of motor and sensory functions were observed, with restoration of pedal pulses.Revascularization of a limb after a severe and prolonged period of ischemia may be associated with several local and systemic complications ("revascularization syndrome") that lead to high rates of mortality and amputation. [1][2][3] Current therapies are generally directed against complications after they occur, once revascularization is completed. Nevertheless, a substantial percentage of the injury is generated on reperfusion, and some experimental and clinical data suggest that careful control of both the composition and the physical conditions of the initial reperfusion may prevent the development of this injury. 4-5Here we report our initial clinical experience with controlled limb reperfusion in two patients with severe limbthreatening ischemia. CASE REPORTS Case 1.A 75-year-old woman was admitted for acute bilateral lower limb ischemia (pallor, cyanosis, profound sensory loss, and complete paralysis). Symptoms were present since 4 hours before admission. Eighteen months earlier the patient underwent an aortobifemoral bypass procedure with terminoterminal proximal anastomosis. Two months before, the patient was asymptomatic with bilaterally palpated pedal pulses. On examination, no arterial pulses were palpated bilaterally and no distal venous and arterial Doppler signals were audible. Considering the bilaterality of the ischemia and the absence of claudication before die present episode, massive embolism was considered. No arteriogram was obtained, and the patient was immediately transferred into the operating room.After induction of general anesthesia, heart rate, electrocardiogram, central venous pressure (CVP), blood pressure, urine output, and rectal temperature were monitored continuously. The common, superficial, and profunda femoral arteries and the graft limbs were exposed bilaterally via groin incisions. The right and left limbs were treated sequentially. After administration of heparin (3 mg/kg), a 3 cm longitudinal arteriotomy was performed on the graft limbs and prolonged on the origin of the superficial femoral arteries. Proximal and distal thrombectomies were performed with a Fogarty catheter. A wire-enforced 22F cannula (inflow cannula, Jostra Medizintechnick, Hechinger, Germany) was introduced into the graft limb from the arteriotomy to aspirate oxygenated blood and was connected to the inflow line of the r...

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Avoiding reperfusion injury after limb revascularization: Experimental observations and recommendations for clinical application

Cited by 90 publications

References 50 publications

Basic Control of Reperfusion Effectively Protects Against Reperfusion Injury in a Realistic Rodent Model of Acute Limb Ischemia

Basic Control of Reperfusion Effectively Protects Against Reperfusion Injury in a Realistic Rodent Model of Acute Limb Ischemia

Modulation of the Mitochondrial Permeability Transition by Nitric Oxide

25.7 Successful controlled limb reperfusion after severe prolonged ischemia

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