Department of Anesthesiology and Intensive Care, University of Muenster, Muenster, Germany.
Crit Care Med. 2011 Jan;39(1):119-25. doi: 10.1097/CCM.0b013e3181fa3898.
The vasopressor effect of arginine vasopressin, a mixed V1a/V2 receptor (V1aR/V2R) agonist, is mediated through the V1aR. Because V2R stimulation may aggravate sepsis-induced vasodilation, fluid accumulation, and microvascular thrombosis, a higher V1aR vs. V2R selectivity might be advantageous. The objective of this study was to elucidate the effects of a first-line therapy with the selective V1aR agonist Phe2-Orn8-Vasotocin vs. arginine vasopressin or norepinephrine on cardiopulmonary hemodynamics and organ function in ovine septic shock.
Randomized controlled laboratory experiment.
University animal research facility.
: Twenty-four chronically instrumented sheep.
After the onset of fecal peritonitis-induced septic shock (mean arterial pressure <60 mm Hg), sheep were randomly assigned to receive first-line treatment with Phe2-Orn8-Vasotocin (0.05 μg·kg·h), arginine vasopressin (0.05 μg·kg·h), or normal saline (each n = 8). In all groups, open-label norepinephrine was additionally titrated up to 1 μg·kg·min to maintain mean arterial pressure at 70 ± 5 mm Hg, if necessary.
Compared with single norepinephrine therapy, the selective V1aR agonist Phe2-Orn8-Vasotocin reduced norepinephrine requirements (2-6 hrs: p < .05 each) and fluid accumulation (p = .043). In addition, mean arterial pressure (6-10 hrs: p < .05 each), pulmonary gas exchange (8-10 hrs: p < .05 each), and global oxygen transport (10 hrs: p < .05 each) were improved by Phe2-Orn8-Vasotocin vs. both other groups. Despite similar preload left ventricular stroke work index was higher in Phe2-Orn8-Vasotocin- than in arginine vasopressin-treated animals (10 hrs: p = .02). Metabolic dysfunction (base excess, lactate concentrations) and renal dysfunction (urinary output, creatinine clearance) were attenuated by Phe2-Orn8-Vasotocin infusion when compared with arginine vasopressin and single norepinephrine therapy. Immunohistochemical analyses of lung tissue revealed higher hemeoxygenase-1 and lower 3-nitrotyrosine concentrations in Phe2-Orn8-Vasotocin-treated animals vs. both other groups (p < .05 each). In addition, the selective V1aR agonist Phe2-Orn8-Vasotocin slightly prolonged survival when compared with arginine vasopressin (p = .01) and standard treatment with norepinephrine (p = .003).
Selective V1aR agonism appears to be superior to the V1aR/V2R agonist arginine vasopressin and single norepinephrine infusion for hemodynamic support in septic shock.
血管加压素作为一种混合 V1a/V2 受体（V1aR/V2R）激动剂，其升压作用是通过 V1aR 介导的。由于 V2R 刺激可能加重脓毒症引起的血管扩张、液体积聚和微血管血栓形成，因此更高的 V1aR 与 V2R 选择性可能更有利。本研究旨在阐明一线治疗选择 V1aR 激动剂 Phe2-Orn8-Vasotocin 与血管加压素或去甲肾上腺素对绵羊脓毒性休克心肺血液动力学和器官功能的影响。
随机对照实验室实验。
大学动物研究设施。
24 只慢性仪器化绵羊。
在粪便性腹膜炎引起的脓毒性休克发作后（平均动脉压 <60mmHg），绵羊被随机分配接受一线治疗，分别给予 Phe2-Orn8-Vasotocin（0.05μg·kg·h）、血管加压素（0.05μg·kg·h）或生理盐水（每组 n=8）。在所有组中，如果需要，还另外滴定去甲肾上腺素以达到 1μg·kg·min，以维持平均动脉压在 70±5mmHg。
与单一去甲肾上腺素治疗相比，选择性 V1aR 激动剂 Phe2-Orn8-Vasotocin 减少了去甲肾上腺素的需求（2-6 小时：p<0.05）和液体积聚（p=0.043）。此外，与其他两组相比，平均动脉压（6-10 小时：p<0.05）、肺气体交换（8-10 小时：p<0.05）和全身氧输送（10 小时：p<0.05）均得到改善。尽管左心室射血工作指数的前负荷相似，但 Phe2-Orn8-Vasotocin 治疗组的指数高于血管加压素治疗组（10 小时：p=0.02）。与血管加压素和单一去甲肾上腺素治疗相比，Phe2-Orn8-Vasotocin 输注可减轻代谢功能障碍（碱剩余、乳酸浓度）和肾功能障碍（尿量、肌酐清除率）。与其他两组相比，肺组织的免疫组织化学分析显示，血红素加氧酶-1 浓度较高，3-硝基酪氨酸浓度较低（p<0.05）。此外，与血管加压素相比，选择性 V1aR 激动剂 Phe2-Orn8-Vasotocin 略微延长了生存时间（p=0.01），与标准去甲肾上腺素治疗相比（p=0.003）。
与 V1aR/V2R 激动剂血管加压素和单一去甲肾上腺素输注相比，选择性 V1aR 激动剂似乎更有利于脓毒性休克的血流动力学支持。
