Department of Anesthesiology and Pain Relief Center, The University of Tokyo Hospital, Tokyo, Japan.
Department of Pain and Palliative Medicine, The University of Tokyo Hospital, Tokyo, Japan.
PLoS One. 2019 Oct 1;14(10):e0222721. doi: 10.1371/journal.pone.0222721. eCollection 2019.
Delirium is the most common postoperative complication of the central nervous system (CNS) that can trigger long-term cognitive impairment. Its underlying mechanism is not fully understood, but the dysfunction of the blood-brain barrier (BBB) has been implicated. The serum levels of the axonal damage biomarker, phosphorylated neurofilament heavy subunit (pNF-H) increase in moderate to severe delirium patients, indicating that postoperative delirium can induce irreversible CNS damage. Here, we investigated the relationship among postoperative delirium, CNS damage and BBB dysfunction, using pNF-H as reference.
Blood samples were collected from 117 patients within 3 postoperative days. These patients were clinically diagnosed with postoperative delirium using the Confusion Assessment Method for the Intensive Care Unit. We measured intercellular adhesion molecule-1, platelet and endothelial cell adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and P-selectin as biomarkers for BBB disruption, pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6), and pNF-H. We conducted logistic regression analysis including all participants to identify independent biomarkers contributing to serum pNF-H detection. Next, by multiple regression analysis with a stepwise method we sought to determine which biomarkers influence serum pNF-H levels, in pNF-H positive patients.
Of the 117 subjects, 41 were clinically diagnosed with postoperative delirium, and 30 were positive for serum pNF-H. Sensitivity and specificity of serum pNF-H detection in the patients with postoperative delirium were 56% and 90%, respectively. P-selectin was the only independent variable to associate with pNF-H detection (P < 0.0001) in all 117 patients. In pNF-H positive patients, only PECAM-1 was associated with serum pNF-H levels (P = 0.02).
Serum pNF-H could be an objective delirium biomarker, superior to conventional tools in clinical settings. In reference to pNF-H, P-selectin may be involved in the development of delirium-related CNS damage and PECAM-1 may contribute to the progression of delirium- related CNS damage.
谵妄是中枢神经系统（CNS）术后最常见的并发症，可引发长期认知障碍。其潜在机制尚不完全清楚，但血脑屏障（BBB）功能障碍已被牵涉其中。在中度至重度谵妄患者中，轴索损伤生物标志物磷酸化神经丝重亚单位（pNF-H）的血清水平升高，表明术后谵妄可导致中枢神经系统不可逆转的损伤。在这里，我们使用 pNF-H 作为参考，研究了术后谵妄、中枢神经系统损伤和 BBB 功能障碍之间的关系。
在术后 3 天内，从 117 名患者中采集血液样本。这些患者使用 ICU 意识模糊评估法（CAM-ICU）临床诊断为术后谵妄。我们测量了细胞间黏附分子-1、血小板和内皮细胞黏附分子-1、血管细胞黏附分子-1、E-选择素和 P-选择素作为 BBB 破坏的生物标志物，以及促炎细胞因子（肿瘤坏死因子-α、白细胞介素-1β、白细胞介素-6）和 pNF-H。我们对所有参与者进行了逻辑回归分析，以确定有助于检测血清 pNF-H 的独立生物标志物。接下来，我们通过逐步多元回归分析，确定了哪些生物标志物影响 pNF-H 阳性患者的血清 pNF-H 水平。
在 117 名受试者中，41 名临床诊断为术后谵妄，30 名血清 pNF-H 阳性。术后谵妄患者血清 pNF-H 检测的敏感性和特异性分别为 56%和 90%。在所有 117 名患者中，P-选择素是唯一与 pNF-H 检测相关的独立变量（P<0.0001）。在 pNF-H 阳性患者中，只有 PECAM-1 与血清 pNF-H 水平相关（P=0.02）。
血清 pNF-H 可能是一种客观的谵妄生物标志物，优于临床环境中的常规工具。参照 pNF-H，P-选择素可能参与了谵妄相关中枢神经系统损伤的发展，PECAM-1 可能促进了谵妄相关中枢神经系统损伤的进展。
