丙戊酸对致死性失血性休克犬器官功能和预后的影响

目的 探讨组蛋白去乙酰化酶抑制剂丙戊酸(VPA)对致死性失血性休克犬器官功能和预后的影响.方法 20只成年雄性Beagle犬,采用颈总动脉放血(按全身血容量的42%计算)制备失血性休克模型.将模型犬按随机数字表法分为休克对照组和VPA治疗组,每组10只.VPA治疗组于失血后1.5 h静脉注射(静注)VPA 100 mg/kg(溶于20 ml生理盐水),休克对照组在失血后24 h内静注20 ml生理盐水;失血后24 h起两组犬均实施延迟静脉补液.在非麻醉状态下测定犬失血前(0 h)和失血后不同时间点平均动脉压(MAP)及血浆丙氨酸转氨酶(ALT)、肌酐(Cr)和肌酸激酶同工酶(CK-MB),记录尿量及72 h生存率.结果 两组失血后2 h MAP均显著降低;随后VPA治疗组MAP(mm Hg,1 mm Hg=0.133 kPa)迅速回升,于失血后4、8和24 h显著高于相应休克对照组(58.4±7.6比40.3±5.0,84.4±8.0比56.4±4.4,92.6±10.3比72.6±8.9,P＜0.05或P＜0.01).VPA治疗组0～8、8～24、24～48和48～72 h尿量均显著多于休克对照组,但仍显著少于失血前(0 h).两组失血后血浆ALT、Cr和CK-MB均较0 h显著升高;VPA治疗组失血后4 h起器官功能指标显著低于休克对照组[ALT(U/L):80.1±9.8比112.2±10.1;Cr(μmol/L):74.5±8.3比88.0±7.6;CK-MB(kU/L):10.39±1.10比13.67±1.46,P＜0.05或P＜0.01],但失血后72 h仍显著高于0 h(ALT:79.5±7.1比40.5±4.4;Cr:85.6±7.1比46.6±4.8;CK-MB:7.63±0.86比1.66±0.21,均P＜0.01).VPA治疗组失血后72 h生存率显著高于休克对照组[70%(7/10)比20%(2/10),P＜0.05].结论 犬42%血容量失血后静注VPA能有效提高MAP,增加尿量,减轻器官功能损害,提高72 h早期生存率,有潜力成为战争或突发事故及灾害时低血容量休克现场救治的有效药物.

The effects of administration of valproic acid on organ function and outcome in a canine lethal hemorrhagic shock model

Objective To investigate the effects of valproic acid (histone deacetylase inhibitor) on visceral function and outcome in a canine lethal hemorrhage model. Methods Twenty male Beagle canines were subjected to an about 42% of total blood volume loss to reproduce a lethal hemorrhage shock model.Animals were randomly divided into shock control group (SC group) and valproic acid treatment group (VPA group), each group n = 10. Canines in SC group and VPA group were intravenously injected either 20 ml saline or valproic acid (100 mg/kg) in 20 ml saline 1.5 hours after hemorrhage. Canines in each group were given delayed intravenous fluid resuscitation 24 hours after bleeding. The mean arterial pressure (MAP) was measured at 0 hour and at different time points without anesthesia, and the plasma levels of alanine aminotransferase (ALT), creatinine (Cr) and isoenzyme of creatine kinase (CK-MB) were measured before hemorrhage (0 hour), and at different time points after hemorrhage. Urinary output and survival rate 72 hours after hemorrhage were also recorded. Results The levels of MAP in both groups were significantly lowered from 2 hours after bleeding. The level of MAP (mm Hg, 1 mm Hg = 0. 133 kPa) in VPA group recovered rapidly and exceeded with statistically significant difference compared with those of SC group after hemorrhage (4 hours: 58. 4±7.6 vs. 40. 3±:5.0, 8 hours: 84.4±8. 0 vs. 56.4±4.4, 24 hours: 92.6±10. 3vs. 72. 6±8. 9, P＜0. 05 or P＜0. 01). The amount of urinary output of VPA group was significantly higher than that of SC group during the period of 0 -8 hours, 8 -24 hours, 24 -48 hours, and 48 -72 hours, but it was still lower than that before hemorrhage (0 hour). The plasma parameters for visceral function in both groups were significantly elevated compared with 0 hour. The plasma levels of ALT, Cr and CK-MB in VPA group were obviously lower than those in SC group from 4 hours after hemorrhage[at 4 hours after bleeding,ALT (U/L): 80.1±9.8 vs. 112.2±10.1, Cr (μmol/L): 74.5±8.3 vs. 88.0±7.6, CK-MB (kU/L):10. 39± 1.10 vs. 13.67±1.46, P＜0. 05 or P＜0. 01], but the visceral functional parameters at 72 hours after hemorrhage in VPA group were obviously higher than those at 0 hour[ALT (U/L):79.5±7.1 vs.40.5±4.4; Cr (μmol/L): 85.6±7.1 vs. 46.6±4.8; CK-MB (kU/L): 7.63±0.86 vs. 1.66±0.21, all P＜0. 01]. The survival rate of VPA group 72 hours after bleeding was significantly higher than that of SC group[70% (7/10) vs. 20% (2/10), P＜0. 05]. Conclusion The results indicate that intravenous injection of VPA promote MAP, increase urinary output, alleviate visceral injury and improve the survival rate at 72 hours in canines suffering from 42% blood volurne loss, it might be an effective drug for hypovolemic shock, especially in war or other site of mass casualties in an austere environment.