Pathophysiological mechanisms involved in flap ischemia and its treatment : an experimental study with emphasis on the effects of calcitonin gene-related peptide and spinal cord stimulation on ischemia and manipulation of microcirculation in flaps

Sammanfattning: Flap surgery and microsurgery have expanded the therapeutic options of reconstructive surgery. Partial or total flap necrosis, due to circulatory and metabolic events, is, however, still a significant problem for the plastic surgeon. Many pharmacological and physical attempts have been made to improve blood circulation and survival of flaps in experimental studies and in clinical trials. The aim of the present thesis was: I) the characterization of experimental models of ischemic flaps, where the effects of partial, or global ischemia are studied, and changes in flap perfusion, survival and peptide content are evaluated; II) the effects of local anesthetics and other vasoactive drugs on the smooth muscle tone in isolated human and animal vessels in vitro; III) the effects of calcitonin gene-related peptide (CGRP) and spinal cord stimulation (DCS) on perfusion and survival of an ischemic island flap in the rat. In the methodological studies, rat and rabbit island flap models were characterized. Partial ischemia in the rat model resulted in increased concentration of CGRP in the animal brain, indicating a possible CGRP modulation of the ischemic process. Mechanical stimulation of the feeding artery produced a rapid decrease of the microcirculatory and arterial perfusion, which was promptly reestablished after the occlusion was relieved only if the trauma to the vessel had been minor. Slow recovery was observed if the mechanical stimulation resulted in an endothelial damage. In the rabbit model vein ischemia was more deleterious than global ischemia. Flap losses were observed after 4 hours of vein ischemia and after 16 hours of global ischemia. In the in vitro studies, CGRP, sodium nitroprusside, cromokaline, nicardipine and papaverine caused a dose-dependent relaxation of NE-contracted vessel specimens. Systemic nicardipine and topical papaverine increased the blood flow after microvascular anastomoses. Lidocaine at low concentration did not relax vessel specimens in vitro, and 2% lidocaine did not increase the blood flow after microvascular anastomoses in vivo. Topical administration CGRP after mechanically induced ischernia ischemia significantly improved the microcirculation in the island flap in the rat, and intravenous administration of CGRP in the same model significantly improved flap survival. Preemptive administration of DCS significantly improved microcirculation and survival in island flap model in the rat. The beneficial effect of stimulation seems, at least partly, to be mediated by a peripheral release of CGRP. The methodological studies demonstrate that changes in the arterial blood flow and in the microcirculation correlate with the duration of the ischemia and the severity of periods of the endothelial damage. Short ischemia produces a hyperemic state in the flap while longer times (16 hours) are followed by irreversible changes of flap perfusion. Venous ischemia is more harmful than arterial. Peripheral ischemic processes per se induce an up-regulation of CGRP in peripheral and central nervous systems, possibly as a part of an adaptive response to ischemia. These results support the evidence that sensory neuropeptide CGRP is involved in tissue repair and has a homeostatic effect during ischemia. The sensory neuropeptide CGRP exerts a potent vasodilation in vitro and in vivo, and is able to improve survival of ischemic flaps. It is hypothesized that this substance may be of importance to relieve ischemia in clinical situations. DCS seems able to improve microcirculation and survival in experimental island flap models in the rat, especially if the treatment is given before the ischemic period. The beneficial effect of stimulation seems, at least partly, to be mediated by a peripheral release of the potent vasodilator CGRP. This approach points to a possible method of treating ischemia in microsurgery where a vasospastic component is suspected.

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