危重症急性呼吸衰竭患者血清 MMP-8 和 TIMP-1：TIMP-1 与 90 天死亡率升高相关。

Serum MMP-8 and TIMP-1 in critically ill patients with acute respiratory failure: TIMP-1 is associated with increased 90-day mortality.

机构信息

From the *Intensive Care Units, Helsinki University Hospital; †Department of Oral and Maxillofacial Diseases, Helsinki University Hospital and Biomedicum Helsinki, Helsinki; ‡Intensive Care Unit, South Carelia Central Hospital, Lappeenranta; and §Department of Anesthesiology and Intensive Care, Kuopio University Hospital, Kuopio, Finland.

出版信息

Anesth Analg. 2014 Apr;118(4):790-8. doi: 10.1213/ANE.0000000000000120.

DOI:10.1213/ANE.0000000000000120

PMID:24651234

Abstract

BACKGROUND

Matrix metalloproteinases (MMPs) likely have an important role in the pathophysiology of acute lung injury. In a recent study, high matrix metalloproteinases (MMP-8) levels in tracheal aspirates of pediatric acute respiratory distress syndrome (ARDS) patients were associated with worse outcome. In patients with sepsis, an imbalance between MMPs and their tissue inhibitors (TIMPs) has been associated with impaired survival. We hypothesized that the elevated systemic MMP-8 and TIMP-1 are associated with worse outcome in acute respiratory failure.

METHODS

This was a substudy of the observational FINNALI study conducted in 25 Finnish intensive care units over an 8-week period. All patients older than 16 years requiring mechanical ventilation for >6 hours were included. MMP-8 and TIMP-1 levels were analyzed from blood samples taken on enrollment in the study and 48 hours later. Laboratory analyses were performed by using immunofluorometric assay for MMP-8 and ELISA for TIMP-1. MMP-8 and TIMP-1 levels were compared between 90-day survivors and nonsurvivors. Survival was compared in quartiles based on TIMP-1 levels, and ROC analysis was performed to calculate areas under the curves. The relationship between MMP-8 and TIMP-1 levels and degree of hypoxemia was examined.

RESULTS

The final analyses included 563 patients. Admission TIMP-1 levels were higher in nonsurvivors, median 367 ng/mL (interquartile range 199-562), than survivors, median 240 ng/mL (interquartile range 142-412), WMWodds 1.68 (95% confidence interval [CI], 1.43-2.08). MMP-8 levels may have differed between survivors and nonsurvivors, WMWodds 1.20 (95% CI, 1.01-1.43), but no difference was found in the MMP-8/TIMP-1 molar ratio, WMWodds 0.83 (95% CI, 0.67-1.04). Difference in survival between quartiles based on TIMP-1 was significant (log-rank, P < 0.001). ROC analysis produced an area under the curve 0.63 (95% CI, 0.58-0.69) for TIMP-1. TIMP-1 was associated with severity of hypoxemia. TIMP-1 levels were higher in an ARDS subgroup than in the whole cohort, WMWodds 1.65 (95% CI, 1.15-2.44).

CONCLUSIONS

MMP-8 levels were possibly higher in 90-day nonsurvivors but performed poorly in predicting outcome. Increased systemic levels of TIMP-1 were associated with more severe hypoxemia and worse outcome in a large cohort of mechanically ventilated critically ill patients and in a subgroup of ARDS patients.

摘要

背景

基质金属蛋白酶（MMPs）可能在急性肺损伤的病理生理学中发挥重要作用。在最近的一项研究中，儿科急性呼吸窘迫综合征（ARDS）患者的气管抽吸物中 MMP-8 水平升高与预后不良有关。在脓毒症患者中，MMP 与组织抑制剂（TIMPs）之间的失衡与生存受损有关。我们假设全身性 MMP-8 和 TIMP-1 升高与急性呼吸衰竭的不良结局有关。

方法

这是在 25 个芬兰重症监护病房进行的观察性 FINNALI 研究的子研究，持续 8 周。所有需要机械通气>6 小时的年龄大于 16 岁的患者均纳入研究。在研究入组时和 48 小时后采集血样，分析 MMP-8 和 TIMP-1 水平。使用免疫荧光测定法检测 MMP-8，酶联免疫吸附试验检测 TIMP-1。比较 90 天幸存者和非幸存者之间的 MMP-8 和 TIMP-1 水平。根据 TIMP-1 水平将幸存者分为四个四分位组，并进行 ROC 分析以计算曲线下面积。还检查了 MMP-8 和 TIMP-1 水平与低氧血症程度之间的关系。

结果

最终分析纳入了 563 名患者。非幸存者的入院 TIMP-1 水平较高，中位数为 367ng/ml（四分位间距 199-562），幸存者的 TIMP-1 水平中位数为 240ng/ml（四分位间距 142-412），WMW 比值为 1.68（95%置信区间 [CI]，1.43-2.08）。幸存者和非幸存者之间 MMP-8 水平可能不同，WMW 比值为 1.20（95%CI，1.01-1.43），但 MMP-8/TIMP-1 摩尔比无差异，WMW 比值为 0.83（95%CI，0.67-1.04）。基于 TIMP-1 的四分位数的生存差异有统计学意义（对数秩检验，P<0.001）。ROC 分析得出 TIMP-1 的曲线下面积为 0.63（95%CI，0.58-0.69）。TIMP-1 与低氧血症的严重程度有关。ARDS 亚组的 TIMP-1 水平高于整个队列，WMW 比值为 1.65（95%CI，1.15-2.44）。