西维来司钠对重度烧冲复合伤犬急性肺损伤的影响

Effects of sivelestat on acute lung injury in dogs with severe burn-blast combined injury Wang Yihe,

目的观察并探讨西维来司钠在重度烧冲复合伤犬急性肺损伤中的作用。方法将32只清洁级健康雄性Beagle犬按随机数字表法分为未致伤组、复合伤对照组、复合伤＋小剂量西维来司钠组、复合伤＋大剂量西维来司钠组，每组8只。除未致伤组不致伤外，其余3组犬均致重度烧冲复合伤，伤后均按Parkland公式输入生理盐水；复合伤＋小剂量西维来司钠组和复合伤＋大剂量西维来司钠组犬同时再分别给予西维来司钠O．5、2．0mg·kg^-1·h^-1治疗，均为24h连续静脉滴注，持续2d。对复合伤犬，伤后6h行CT检查观察肺部损伤情况；伤后2、6、12、24、48h，监测平均动脉压（MAP）、呼吸频率（RR）、血管外肺水（EVLW）、肺血管通透性指数（PVPI）、PaO2、PaCO2，ELISA法检测血清中性粒细胞弹性蛋白酶（NE）及TNF-α、IL-8浓度；伤后48h将犬放血处死取肺组织测算肺湿干质量比。未致伤组犬于以上相同时相点行相关检测。对数据行重复测量方差分析和LSD检验。结果（1）复合伤对照组和复合伤＋小剂量西维来司钠组犬部分扫描层次内有渗出性改变，未致伤组和复合伤＋大剂量西维来司钠组犬各扫描层次均未见明显异常。（2）4组犬各时相点MAP组间两两比较差异均无统计学意义（P值均大于0．05）。未致伤组犬各时相点RR值与另3组比较均差异明显（P值均小于0．05），3组复合伤犬伤后6、12、24、48hEVLW和PVPI与未致伤组比较均差异明显（P值均小于0．05）。复合伤十小剂量西维来司钠组犬伤后12、24、48hRR值、EVLW与复合伤＋大剂量两维来司钠组比较均差异明显（P值均小于0．05）。复合伤＋小剂量西维来司钠组犬伤后24、48hPVPI与复合伤＋大剂量西维来司钠组比较均差异明显（P值均小于0．05）。（3）未致伤组犬各时相点PaO2、PaCO2与另3组比较均差异明显（P值均小于0．05）。复合伤＋小剂量西维来司钠组犬伤后12、24、48hPaO2与复合伤＋大剂量西维来司钠组比较均差异明显（P值均小于O．05）。复合伤＋小剂量西维来司钠组犬伤后24、48hPaCO2与复合伤＋大剂量西维来司钠组比较均差异明显（P值均小于0．05）。（4）未致伤组犬各时相点NE（伤后2h除外）、TNF-α、IL-8与另3组比较均差异明显（P〈0．05或P〈0．01）。伤后2、6、12、24、48h，未致伤组、复合伤对照组、复合伤＋小剂量西维来司钠组、复合伤＋大剂量西维来司钠组犬的NE分别为（69±21）、（83±24）、（80±20）、（75±17）、（72±27）pg／mL，（66±24）、（196±20）、（231±26）、（252±25）、（266±22）pg／mL，（7l±22）、（180±27）、（214±21）、（194±24）、（218±20）pg／mL，（68±22）、（136±24）、（153±22）、（146±26）、（150±28）pg／mL。复合伤＋大剂量西维来司钠组犬伤后6、12、24、48hNE与复合伤对照组、复合伤＋小剂量西维来司钠组比较均差异明显（P值均小于0．05）。复合伤＋小剂量西维来司钠组犬伤后24、48hTNF-α与复合伤对照组、复合伤＋大剂量西维来司钠组比较均差异明显（P值均小于0．05）。复合伤＋小剂量西维来司钠组犬伤后24、48hIL-8与复合伤＋大剂量西维来司钠组比较均差异明屁（P值均小于0．05）。（5）伤后48h，复合伤＋小剂量西维来司钠组和复合伤＋大剂量西维来司钠组犬肺湿干质量比与复合伤对照组比较均差异明显（P值均小于0．05），复合伤＋大剂量西维来司钠组犬与复合伤＋小剂量西维来司钠组比较差异有统计学意义（P〈0．05）。结论烧冲复合伤后早期应用西维来司钠（尤其是大剂量）可以改善血气分析指标、减轻肺水肿、降低血清中炎症因子水平，达到保护肺组织的治疗效果。

Objective To observe and study the effects of sivelestat on acute lung injury in dogs with severe burn-blast combined injury. Methods Thirty-two male beagle dogs of clean grade were divid- ed into 4 groups ： uninjured group （U） , combined injury control group （CIC） , combined injury ＋ low dose of sivelestat group （ CI ＋ LS） , combined injury ＋ high close of sivelestat group （ CI ＋ HS） , with 8 dogs in each group. Except for the dogs in group U which were not injured, the dogs in the other 3 groups were in- flicted with severe burn-blast combined injury. According to the Parkland formula, the dogs in groups U and CIC were infused with physiological saline, and the dogs in groups CI ＋ LS and CI ＋ HS received sivelestat with the dosage of O. 5 and 2.0 mg·kg^-1·h^-1 respectively in addition. The 24 h continuous intravenous infusion was carried out for 2 days. At post injury hour （PIH） 6, CT scanning was conducted to observe the lung damage. At PIH 2, 6, 12, 24, and 48, mean arterial pressure （MAP）, respiratory rate （RR）, extra vascular lung water （EVLW） , pulmonary vascular permeability index （PVPI） , PaO2, and PaCO2 were measured ; the contents of neutrophil elastase （NE） , IL-8, and TNF-α were determined by ELISA. At PIH 48, all the dogs were sacrificed, and the lung tissues were harvested to measure the wet to dry lung weight ratio. The same examination was carried out in the dogs of the group U at the same time points. Data were processed with analysis of variance of repeated measurement and LSD test. Results （ 1 ） CT images showed some exudative lesions in the dogs of groups CIC and CI ＋ LS but not in the dogs of groups U and CI ＋ HS. （2） No statistically significant differences were observed in MAP at each time point between every two groups （with P values above 0.05）. The RR values in group U were significantly different from those of the other 3 groups at all time points （with P values below 0.05）. The values of EVLW and PVPI in 3 com- bined injury groups were significantly different from those in group U at PIH 6, 12, 24, and 48 （with P val- ues below 0. 05）. The values of RR and EVLW in group CI ＋ LS were significantly different from those in group CI＋HS at PIH 12, 24, and 48 （withPvalues belowO. 05）. The values of PVPI in group CI＋LS were significantly different from those in group CI ＋ HS at PIH 24 and 48 （ with P values below 0.05 ）. （3） The levels of PaO2 and PaCO2 showed significant differences between group U and the other 3 groups at each time point （ with P values below 0.05 ）. The levels of PaO2 in group CI ＋ LS were significantly different from those in CI ＋ HS group at PIH 12, 24, and 48 （ with P values below 0.05 ）. The level of PaCO2 showed sig- nificant differences between group CI ＋ LS and group CI ＋ HS at PIH 24 and 48 （ with P values below 0.05 ）. （4） The contents of NE （except for PIH 2） , TNF-α, and IL-8 showed significant differences between group U and the other3 groups at each time point （ P 〈0.05 orP 〈0.01）. At PIH2, 6, 12, 24, and 48, the contents of NE in groups U, CIC, CI＋LS, and CI＋HS were respectively （69 ±21）, （83 ±24）, （80 ± 20）, （75 ± 17）, （72 ＋27） pg/mL; （66 ±24）, （196 ＋20）, （231 ±26）, （252 ±25）, （266 ±22） pg/mL; （71 ±22）, （180±27）, （214±21）, （194±24）, （218 ±20） pg/mL; （68 ＋22）, （136 ±24）, （153 ± 22 ） , （ 146 ± 26） , （ 150± 28 ） pg/mL. NE values in group CI ＋ HS were statistically different from those in groups CIC and CI ＋ LS at PIH 6, 12, 24, and 48 （ with P values below O. 05）. The contents of TNF-α in group CI ＋ LS were statistically different from those in groups CIC and CI ＋ HS at PIH 24 and 48 （ with P val- ues below 0. 05）. The contents of IL-8 in group CI ＋ LS were statistically different from those in group CI ＋ HS at PIH 24 and 48 （ with P values below 0.05 ）. （5） At PIH 48, the wet to dry lung weight ratio of group CIC was statistically different from that in group CI ＋ LS or group CI ＋ HS （ with P values below 0.05 ） ; there was also difference between group CI ＋ LS and group CI ＋ HS （ P 〈 0.05）. Conclusions Sivelestat, es- pecially in a high dose, exerts a protective effect in acute lung injury after burn-blast combined injury through improving the index of blood gas analysis, ameliorating pulmonary edema, and lowering the produc- tion of pro-inflammatory mediators.