DataSheet_2_The H2S Donor Sodium Thiosulfate (Na2S2O3) Does Not Improve Inflammation and Organ Damage After Hemorrhagic Shock in Cardiovascular Healthy Swine.docx

We previously demonstrated marked lung-protective properties of the H2S donor sodium thiosulfate (Na2S2O3, STS) in a blinded, randomized, controlled, long-term, resuscitated porcine model of swine with coronary artery disease, i.e., with decreased expression of the H2S-producing enzyme cystathionine-γ-lyase (CSE). We confirmed these beneficial effects of STS by attenuation of lung, liver and kidney injury in mice with genetic CSE deletion (CSE-ko) undergoing trauma-and-hemorrhage and subsequent intensive care-based resuscitation. However, we had previously also shown that any possible efficacy of a therapeutic intervention in shock states depends both on the severity of shock as well as on the presence or absence of chronic underlying co-morbidity. Therefore, this prospective, randomized, controlled, blinded experimental study investigated the effects of the STS in cardiovascular healthy swine. After anesthesia and surgical instrumentation, 17 adult Bretoncelles-Meishan-Willebrand pigs were subjected to 3 hours of hemorrhage by removal of 30% of the blood volume and titration of the mean arterial pressure (MAP) ≈ 40 ± 5 mmHg. Afterwards, the animals received standardized resuscitation including re-transfusion of shed blood, fluids, and, if needed, continuous i.v. noradrenaline to maintain MAP at pre-shock values. Animals were randomly allocated to either receive Na2S2O3 or vehicle control starting 2 hours after initiation of shock until 24 hours of resuscitation. The administration of Na2S2O3 did not alter survival during the observation period of 68 hours after the initiation of shock. No differences in cardio-circulatory functions were noted despite a significantly higher cardiac output, which coincided with significantly more pronounced lactic acidosis at 24 hours of resuscitation in the Na2S2O3 group. Parameters of liver, lung, and kidney function and injury were similar in both groups. However, urine output was significantly higher in the Na2S2O3 group at 24 hours of treatment. Taken together, this study reports no beneficial effect of Na2S2O3 in a clinically relevant model of hemorrhagic shock-and-resuscitation in animals without underlying chronic cardiovascular co-morbidity.

我们先前在一项盲法、随机、对照、长期复苏的猪心冠状动脉疾病模型中，即心硫氢酸产生酶半胱氨酸-γ-裂解酶（CSE）表达降低的猪模型中，展示了H2S供体亚硫酸氢钠（Na2S2O3，简称STS）显著的肺保护特性。我们通过证实STS在遗传性CSE缺失（CSE-ko）小鼠创伤和失血后，以及后续基于重症监护的复苏中，减轻肺、肝和肾损伤的益处，进一步确认了这些有益效应。然而，我们先前亦曾表明，任何治疗干预在休克状态下的潜在疗效，既取决于休克的严重程度，也取决于慢性基础合并症的存否。因此，本前瞻性、随机、对照、盲法实验研究旨在探究STS在心血管健康猪中的效应。麻醉和手术器械准备完毕后，17头成年布雷顿塞莱-美山-维勒班猪被实施3小时的失血，通过移除30%的血容量并调整平均动脉压（MAP）至约40±5毫米汞柱。随后，动物接受了标准化复苏，包括回输流失血液、液体，并在必要时持续静脉注射去甲肾上腺素以维持MAP在休克前的水平。动物在休克开始后2小时至24小时复苏期间，随机分配接受Na2S2O3或安慰剂控制。STS的给予并未改变休克开始后68小时观察期间的存活率。尽管心脏输出量显著增加，但未观察到心循环功能上的差异，这与Na2S2O3组在复苏24小时时显著加剧的乳酸酸中毒相吻合。肝脏、肺脏和肾脏功能及损伤参数在两组中相似。然而，在治疗24小时时，Na2S2O3组的尿量显著增加。综上所述，本研究报告了在无潜在慢性心血管合并症动物的出血性休克和复苏临床相关模型中，Na2S2O3无显著有益效应。