Lorente Leonardo, Martín María M, López Patricia, Ramos Luis, Blanquer José, Cáceres Juan J, Solé-Violán Jordi, Solera Jorge, Cabrera Judith, Argueso Mónica, Ortiz Raquel, Mora María L, Lubillo Santiago, Jiménez Alejandro, Borreguero-León Juan M, González Agustín, Orbe Josune, Rodríguez José A, Páramo José A
Intensive Care Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain.
Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.
PLoS One. 2014 Apr 11;9(4):e94370. doi: 10.1371/journal.pone.0094370. eCollection 2014.
Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) play a role in neuroinflammation after brain trauma injury (TBI). Previous studies with small sample size have reported higher circulating MMP-2 and MMP-9 levels in patients with TBI, but no association between those levels and mortality. Thus, the aim of this study was to determine whether serum TIMP-1 and MMP-9 levels are associated with mortality in patients with severe TBI.
This was a multicenter, observational and prospective study carried out in six Spanish Intensive Care Units. Patients with severe TBI defined as Glasgow Coma Scale (GCS) lower than 9 were included, while those with Injury Severity Score (ISS) in non-cranial aspects higher than 9 were excluded. Serum levels of TIMP-1, MMP-9 and tumor necrosis factor (TNF)-alpha, and plasma levels of tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 plasma were measured in 100 patients with severe TBI at admission. Endpoint was 30-day mortality.
Non-surviving TBI patients (n = 27) showed higher serum TIMP-1 levels than survivor ones (n = 73). We did not find differences in MMP-9 serum levels. Logistic regression analysis showed that serum TIMP-1 levels were associated 30-day mortality (OR = 1.01; 95% CI = 1.001-1.013; P = 0.03). Survival analysis showed that patients with serum TIMP-1 higher than 220 ng/mL presented increased 30-day mortality than patients with lower levels (Chi-square = 5.50; P = 0.02). The area under the curve (AUC) for TIMP-1 as predictor of 30-day mortality was 0.73 (95% CI = 0.624-0.844; P<0.001). An association between TIMP-1 levels and APACHE-II score, TNF- alpha and TF was found.
The most relevant and new findings of our study, the largest series reporting data on TIMP-1 and MMP-9 levels in patients with severe TBI, were that serum TIMP-1 levels were associated with TBI mortality and could be used as a prognostic biomarker of mortality in TBI patients.
基质金属蛋白酶（MMPs）和基质金属蛋白酶组织抑制剂（TIMPs）在脑外伤（TBI）后的神经炎症中起作用。先前样本量较小的研究报道，TBI患者循环中的MMP-2和MMP-9水平较高，但这些水平与死亡率之间无关联。因此，本研究的目的是确定血清TIMP-1和MMP-9水平是否与重度TBI患者的死亡率相关。
这是一项在西班牙六个重症监护病房进行的多中心、观察性前瞻性研究。纳入格拉斯哥昏迷量表（GCS）低于9分的重度TBI患者，排除非颅脑部位损伤严重程度评分（ISS）高于9分的患者。在100例重度TBI患者入院时检测血清TIMP-1、MMP-9和肿瘤坏死因子（TNF）-α水平，以及血浆组织因子（TF）和纤溶酶原激活物抑制剂（PAI）-1水平。终点指标为30天死亡率。
未存活的TBI患者（n = 27）血清TIMP-1水平高于存活患者（n = 73）。我们未发现MMP-9血清水平存在差异。逻辑回归分析显示，血清TIMP-1水平与30天死亡率相关（OR = 1.01；95%CI = 1.001 - 1.013；P = 0.03）。生存分析表明，血清TIMP-1高于220 ng/mL的患者30天死亡率高于水平较低的患者（卡方 = 5.50；P = 0.02）。TIMP-1作为30天死亡率预测指标的曲线下面积（AUC）为0.73（95%CI = 0.624 - 0.844；P<0.001）。发现TIMP-1水平与急性生理与慢性健康状况评分系统II（APACHE-II）评分、TNF-α和TF之间存在关联。
我们的研究是报道重度TBI患者TIMP-1和MMP-9水平数据的最大样本系列，其最相关的新发现是血清TIMP-1水平与TBI死亡率相关，可作为TBI患者死亡率的预后生物标志物。
