Al-Chalabi Ahmed, Matevossian Edouard, von Thaden Anne, Schreiber Catherine, Radermacher Peter, Huber Wolfgang, Perez Ruiz de Garibay Aritz, Kreymann Bernhard
Jamaica Hospital Medical Center, Phase II Building, 8900 Van Wyck Expy Ste 2, Richmond Hill, New York City, NY, 11418, USA.
Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.
Intensive Care Med Exp. 2017 Dec;5(1):31. doi: 10.1186/s40635-017-0144-3. Epub 2017 Jul 4.
Novel extracorporeal procedures are constantly being developed and evaluated for use in patients with sepsis. Preclinical evaluation of such procedures usually requires testing in large animal models. In the present work, the safety and efficacy of a recently developed ADVanced Organ Support (ADVOS) system in a newly developed large animal two-hit model of liver failure combined with endotoxemia were tested.
After establishing the model in more than 50 animals, a randomized study was performed. An inflammatory cholestatic liver injury was initially provoked in pigs. Three days after surgery, endotoxin was gradually administered during 7½ h. Animals were randomized to receive standard medical treatment either with (ADVOS group, n = 5) or without ADVOS (control group, n = 5). The ADVOS treatment was started 2½ h after endotoxemia and continued for 7 h. Survival, cardiovascular, respiratory, renal, liver, coagulation, and cerebral parameters were analyzed.
Three days after surgery, cholestatic injury resulted in hyperbilirubinemia [5.0 mg/dl (IQR 4.3-5.9 mg/dl)], hyperammonemia [292 μg/dl (IQR 291-296 μg/dl)], leukocytosis [20.2 10/μl (IQR 17.7-21.8 10/μl)], and hyperfibrinogenemia [713 mg/dl (IQR 654-803 mg/dl)]. After endotoxemia, the ADVOS procedure stabilized cardiovascular, respiratory, and renal parameters and eliminated surrogate markers as bilirubin [2.3 (IQR 2.3-3.0) vs. 5.5 (IQR 4.6-5.6) mg/dl, p = 0.001] and creatinine [1.4 (IQR 1.1-1.7) vs. 2.3 (IQR 2.1-3.1) mg/dl, p = 0.01]. Mortality: All animals in the ADVOS group survived, while all animals in the control group expired during the 10-h observation period (p = 0.002). No adverse events related to the procedure were observed.
The ADVOS procedure showed a promising safety and efficacy profile and improved survival in a sepsis-like animal model with dysfunction of multiple organs. An amelioration of major organ functions (heart and lung) combined with removal of markers for kidney and liver function was observed.
新型体外治疗方法不断研发并用于脓毒症患者的评估。此类方法的临床前评估通常需要在大型动物模型中进行测试。在本研究中，测试了一种新开发的高级器官支持（ADVOS）系统在新开发的肝衰竭合并内毒素血症大型动物双打击模型中的安全性和有效性。
在50余只动物中建立模型后，进行了一项随机研究。首先在猪身上诱发炎症性胆汁淤积性肝损伤。术后三天，在7.5小时内逐渐给予内毒素。动物被随机分为接受标准药物治疗组（ADVOS组，n = 5）和不接受ADVOS治疗组（对照组，n = 5）。ADVOS治疗在内毒素血症后2.5小时开始，持续7小时。分析了生存率、心血管、呼吸、肾脏、肝脏、凝血和脑参数。
术后三天，胆汁淤积性损伤导致高胆红素血症[5.0mg/dl（四分位间距4.3 - 5.9mg/dl）]、高氨血症[292μg/dl（四分位间距291 - 296μg/dl）]、白细胞增多症[20.2×10⁹/μl（四分位间距17.7 - 21.8×10⁹/μl）]和高纤维蛋白原血症[713mg/dl（四分位间距654 - 803mg/dl）]。内毒素血症后，ADVOS治疗稳定了心血管、呼吸和肾脏参数，并消除了胆红素[2.3（四分位间距2.3 - 3.0）对5.5（四分位间距4.6 - 5.6）mg/dl，p = 0.001]和肌酐[1.4（四分位间距1.1 - 1.7）对2.3（四分位间距2.1 - 3.1）mg/dl，p = 0.01]等替代标志物。死亡率：ADVOS组所有动物存活，而对照组所有动物在10小时观察期内死亡（p = 0.002）。未观察到与该治疗相关的不良事件。
ADVOS治疗在多器官功能障碍的脓毒症样动物模型中显示出有前景的安全性和有效性，并提高了生存率。观察到主要器官功能（心脏和肺）改善，同时清除了肾脏和肝功能标志物。
