N-Acetylcystein verbessert das Überleben kritisch perfundierter Lappen durch Reduktion der leukozytären Entzündungsreaktion und durch Protektion der nutritiven Kapillarperfusion

Abstract

Introduction: Persistent ischemia is often associated with the release of reactive oxygen species and endothelial dysfunction. Accordingly, tissue inflammation may result in wound breakdown and tissue necrosis. Antioxidative treatment has been attributed tissue-protective effects by inhibiting the activation of transcription factor NF-κB which decreases the accumulation of free radicals and by preventing the expression of adhesion molecule. The aim of the study was therefore to examine the influence of two potent antioxidative drugs N-Acetylcysteine (NAC) and Trolox on the microcirculation and on ischemia-induced inflammation in critically perfused flap tissue. Material & Methods: A randomly perfused musculocutaneous flap integrated in a dorsal skinfold chamber of C57/BL6-mice was used as a model of persistent ischemia. NAC (10 mg/kg bodyweight (bw) sc 1x/d; n = 7) and Trolox (6 mg/kg bw 2x/d; n = 7) were administered 30 minutes before surgery and were continued until day 10 after flap elevation (induction of ischemia), respectively. Arteriolar diameter, functional capillary density (FCD), angiogenesis (mean vessel density; MVD) and flap necrosis were assessed with repetitive intravital epi-fluorescence microscopy over a 10 day observation period. Ischemia-induced inflammatory response was determined by leukocyte-endothelial cell interaction and apoptotic cell death. Results: Persistent ischemia induced a manifest inflammatory response within the critically perfused central flap area of control animals which was seen significantly decreased following antioxidative treatment (NAC: 189 ± 49 rollers/min/mm; Trolox: 202 ± 39 rollers/min/mm; control: 504 ± 54 rollers/min/mm; p < 0.001 vs control). This decreased inflammatory response was associated with reduced apoptotic cell death (NAC: 62 ± 8 cells/mm2; Trolox: 53 ± 16 cells/mm2; control: 194 ± 23 cells/mm2; p < 0.05). In contrast, significant arteriolar dilation and hence improved arteriolar bloodflow was observed in animals treated with NAC only which resulted in a maintained FCD (NAC: 203 ± 13 cm/cm2 (p < 0.05 vs control); Trolox 127 ± 25 cm/cm2; control: 91 ± 27 cm/cm2) and in a significant reduction of flap necrosis (NAC: 34 ± 5 % of the total flap area (p < 0.05 vs control); Trolox: 42 ± 5 %; control: 55 ± 6 %). Newly formed capillaries were not observed. Conclusion: Our results show that NAC and Trolox are able to significantly reduce both ischemia induced inflammatory response and apoptotic cell death. However, only prolonged administration of NAC is able to induce a dilatory response resulting in increased blood flow and maintained nutritive perfusion within critically perfused flap tissue. The combination of a decreased inflammatory response associated to a dilatory response assures an improved flap survival. Accordingly, administration of NAC seems a promising non-invasive method to reduce ischemia-related complications in elective surgery at risk of wound breakdown and tissue necrosis.