Volleman Carolien, Dubelaar Dionne P C, Phelp Philippa G, Ibelings Roselique, Tuip-de Boer Anita M, Polet Chantal A, van den Bergh Walter M, Vlaar Alexander P J, van den Brom Charissa E
Department of Intensive Care Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Laboratory for Experimental Intensive Care and Anesthesiology (LEICA), Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
BMC Anesthesiol. 2025 Aug 20;25(1):411. doi: 10.1186/s12871-025-03251-3.
Extracorporeal membrane oxygenation (ECMO) is a life-saving treatment, but carries a high risk of complications such as acute kidney injury (AKI). A contributor to AKI is hemolysis, which induces vasoconstriction and renal tubular cytotoxicity. Here, we have investigated a novel hypothesis that ECMO-induced hemolysis contributes to vascular leakage, edema, microcirculatory perfusion disturbances, and AKI in a rat model.
Rats were exposed to 75 min of ECMO or a sham procedure as control (n = 8 per group). Hemodynamic, blood gas, and microcirculatory perfusion parameters were monitored throughout the experiment. Renal vascular leakage and edema were determined by dextran leakage (70 kDa) and wet-to-dry weight ratio. Markers of hemolysis, inflammation, endothelial activation and damage, and AKI were assessed using spectrophotometry, ELISA and Luminex.
Initiation of ECMO increased circulating cell-free hemoglobin (CFHb) compared to baseline (4.01 vs. 1.36 OD, p < 0.001). In parallel, ECMO increased circulating levels of TNFα, IL-6, ICAM-1 and angiopoietin-2, whereas levels in the control group remained stable. The number of continuously perfused vessels (4.36 vs. 13.62 vessels/recording, p < 0.001) and the proportion of perfused vessels (PPV; 23.0 vs. 67.4%, p < 0.001) immediately decreased after initiation of ECMO when compared to controls and remained disturbed one hour after weaning from ECMO. Furthermore, NGAL, a marker of kidney injury, in plasma and urine was higher in the ECMO group compared to the controls (respectively 2191 vs. 410 ng/mL, p < 0.001; 1733 vs. 437 ng/mL, p = 0.0059). Wet-to-dry weight ratio showed increased renal edema in the group undergoing ECMO (4.50 ± 0.27 vs. 3.96 ± 0.16, p < 0.001). Moreover, increasing levels of CFHb in plasma were correlated with a decrease in PPV (r=-0.925, p < 0.001) as well as an increase in plasma NGAL (r = 0.895, p < 0.001) in rats on ECMO.
In conclusion, ECMO-induced hemolysis is paralleled by endothelial damage, microcirculatory perfusion disturbances, and kidney injury in a rat model. Our findings suggest that CFHb plays an important role in the pathophysiology of AKI, possibly via endothelial damage. Future studies should clarify the causal relationship between CFHb and endothelial damage, and explore whether targeting CFHb can improve microvascular perfusion and preserve kidney function during ECMO support.
体外膜肺氧合（ECMO）是一种挽救生命的治疗方法，但具有诸如急性肾损伤（AKI）等并发症的高风险。AKI的一个促成因素是溶血，其可诱导血管收缩和肾小管细胞毒性。在此，我们在大鼠模型中研究了一个新的假说，即ECMO诱导的溶血会导致血管渗漏、水肿、微循环灌注紊乱和AKI。
将大鼠暴露于75分钟的ECMO或作为对照的假手术（每组n = 8）。在整个实验过程中监测血流动力学、血气和微循环灌注参数。通过葡聚糖渗漏（70 kDa）和湿重与干重比来测定肾血管渗漏和水肿。使用分光光度法、酶联免疫吸附测定（ELISA）和Luminex评估溶血、炎症、内皮激活和损伤以及AKI的标志物。
与基线相比，启动ECMO后循环中游离血红蛋白（CFHb）增加（4.01对1.36 OD，p < 0.001）。同时，ECMO使TNFα、IL - 6、ICAM - 1和血管生成素 - 2的循环水平升高，而对照组的水平保持稳定。与对照组相比，启动ECMO后连续灌注血管的数量（4.36对13.62条血管/记录，p < 0.001）和灌注血管比例（PPV；23.0对67.4%，p < 0.001）立即下降，并且在从ECMO撤机1小时后仍处于紊乱状态。此外，与对照组相比，ECMO组血浆和尿液中肾损伤标志物中性粒细胞明胶酶相关脂质运载蛋白（NGAL）更高（分别为2191对410 ng/mL，p < 0.001；1733对437 ng/mL，p = 0.0059）。湿重与干重比显示接受ECMO的组肾水肿增加（4.50±0.27对3.96±0.16，p < 0.001）。此外，在接受ECMO的大鼠中，血浆中CFHb水平的升高与PPV的降低（r = -0.925，p < 0.001）以及血浆NGAL的升高（r = 0.895，p < 0.001）相关。
总之，在大鼠模型中，ECMO诱导的溶血与内皮损伤、微循环灌注紊乱和肾损伤同时出现。我们的研究结果表明CFHb在AKI的病理生理学中起重要作用，可能是通过内皮损伤。未来的研究应阐明CFHb与内皮损伤之间的因果关系，并探索靶向CFHb是否可以改善微循环灌注并在ECMO支持期间保护肾功能。
