Surgical trauma, inflammation and tissue injury
Abstract: Surgical tissue trauma is a strong stimulus for local inflammation, including leukocyte recruitment. While such a response may be of importance for the defense against microorganisms, it is also clear that inflammation may contribute to further tissue injury. After skin flap surgery, both decreased blood perfusion and inflarnmation may contribute to necrosis fon-nation in flap tissue. In this thesis, based on an experimental skin flap model in the rat, the potential negative effects of the inflammatory response on tissue viability were examined, with special reference to the role of neutrophils in the development of post-surgical skin necrosis. We found that the survival rate and degree of inflammation in rat skin flaps varied significantly with the time lag between transportation of the animals from the supplier and flap surgery, apparently in relation to the level of environmental stress. Thus, as compared to acclimatized rat, flap survival was increased and neutrophil recruitment decreased in recently transported animals. Moreover, plasma corticosterone levels were elevated during the first days of acclimatization, and treatment of rats accustomed to their new environment with the glucocorticoid dexamethasone increased flap survival and decreased neutrophil accumulation to levels near those observed in animals operated on arrival. Treatment with leukotriene-synthesis inhibitors significantly increased skin flap survival, while a cysteinyl-leukotriene receptor antagonist did not. These findings suggest that leukotrienes are involved in the development of necrosis in surgical skin flaps in the rat, possibly via leukotriene B4-induced neutrophil recruitment. Survival of rat skin flaps was significantly increased by i.v. treatment with a monoclonal antibody blocking rat leukocyte CD18 function. This antibody also significantly inhibited accumulation of neutrophils in the flap tissue, strongly suggesting that neutrophil recruitment plays an important role in the development tissue necrosis in this experimental flap model. Systemic perioperative treatment with heparin significantly increased the viability of skin flaps in the rat. This effect of heparin appeared to correlate with its ability to prolong clotting time, but not with the degree of total flap blood flow or surgery-induced neutrophil accumulation in the flap. Similar effects on flap viability were observed with the low molecular weight heparin dalteparin, which had minor effects on clotting time and significantly reduced flap neutrophil recruitment without affecting leukocyte rolling. While treatment with heparins may be useful as prophylaxis or for salvage of threatened surgical flaps, their mechanism(s) of action need further investigation. Very low doses of calcitonin-gene related peptide i.p. significantly improved the survival of rat skin flaps. This beneficial effect by CGRP appeared to be related to a reduction in the surgically induced neutrophil recruitment into the flap, and not to hemodynamic changes. Taken together, while being an important host-defence mechanism, surgically induced inflammation, and in particular neutrophil recruitment, appears to be detrimental to skin flap survival. Thus, in efforts to improve skin flap viability, it may be of value to consider anti-inflammatory treatment in addition to agents that increase tissue blood flow.
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