Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, Colorado.
Clinical Research Division, 59th Medical Wing, JBSA-Lackland AFB, Texas.
Clin Exp Pharmacol Physiol. 2019 Mar;46(3):216-225. doi: 10.1111/1440-1681.13060.
Early, non-clinical studies support the use of hydroxocobalamin to treat sepsis-induced hypotension, but there is no translational, large animal model. The objective of this study was to compare survival in a sepsis model where large swine had endotoxaemia induced with lipopolysaccharide (LPS) and were treated with intravenous hydroxocobalamin (HOC), noradrenaline (NA), or saline. Thirty swine (45-55 kg) were anaesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring. Hypotension, predefined as 50% of baseline, was induced with LPS. Animals then received HOC, NA, or saline and monitored for 3 hours. The main outcome was survival to the conclusion of the study. Using a power of 80% and an alpha of 0.05, 10 animals were used per group. Secondary outcomes included: mean arterial pressure (MAP), systemic vascular resistance (SVR) and cardiac output (CO) along with several markers of sepsis. No differences were detected between groups at baseline or after hypotension. The survival distributions of the three groups were significantly different with more HOC animals surviving (10/10) compared with NA (8/10) or Saline (5/10) (log-rank P < 0.03). MAP was found to be higher in both the HOC and NA groups and HOC achieved the highest SVR. In this large animal, translational study of an endotoxaemic model of sepsis, hydroxocobalamin improved survival when compared with saline.
早期的非临床研究支持使用羟钴胺治疗脓毒症引起的低血压，但缺乏转化、大动物模型的研究。本研究的目的是比较在伴有内毒素血症的脓毒症模型中，大猪使用静脉注射羟钴胺（HOC）、去甲肾上腺素（NA）或生理盐水治疗的存活率。30 头猪（45-55kg）接受麻醉、插管，并进行连续股动脉和肺动脉压力监测。通过给予脂多糖（LPS）诱导低血压，定义为基线的 50%。然后，动物接受 HOC、NA 或生理盐水治疗，并监测 3 小时。主要结局是存活至研究结束。使用 80%的功率和 0.05 的α值，每组使用 10 只动物。次要结局包括：平均动脉压（MAP）、全身血管阻力（SVR）和心输出量（CO）以及一些脓毒症标志物。在低血压发生前和发生后，各组间的基线或基线后无差异。三组的生存分布有显著差异，HOC 组存活的动物（10/10）多于 NA 组（8/10）或生理盐水组（5/10）（对数秩 P<0.03）。MAP 在 HOC 和 NA 组均较高，且 HOC 组达到最高的 SVR。在这项伴有内毒素血症的脓毒症大动物转化研究中，与生理盐水相比，羟钴胺提高了存活率。
