Alqahtani Mashael F, Smith Craig M, Weiss Scott L, Dawson Susan, Ralay Ranaivo Hantamalala, Wainwright Mark S
Department of Pediatrics, Divisions of Critical Care, Ann & Robert. H. Lurie Children's Hospital of Chicago, Northwestern Feinberg School of Medicine, Chicago, Illinois, United States of America.
Department of Pediatrics, Divisions of Neurology, Ann & Robert. H. Lurie Children's Hospital of Chicago, Northwestern Feinberg School of Medicine, Chicago, Illinois, United States of America.
PLoS One. 2016 Apr 18;11(4):e0153645. doi: 10.1371/journal.pone.0153645. eCollection 2016.
Elevated plasma concentrations of matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), mid-regional pro-atrial natriuretic peptide (mrProANP), and adipocyte fatty-acid-binding proteins (A-FaBPs) have been investigated as biomarkers for sepsis or detection of acute neurological injuries in adults, but not children. We carried out a single-center, prospective observational study to determine if these measures could serve as biomarkers to identify children with sepsis. A secondary aim was to determine if these biomarkers could identify children with neurologic complications of sepsis. A total of 90 patients ≤ 18 years-old were included in this study. 30 with severe sepsis or septic shock were compared to 30 age-matched febrile and 30 age-matched healthy controls. Serial measurements of each biomarker were obtained, beginning on day 1 of ICU admission. In septic patients, MMP9-/TIMP-1 ratios (Median, IQR, n) were reduced on day 1 (0.024, 0.004-0.174, 13), day 2 (0.020, 0.002-0.109, 10), and day 3 (0.018, 0.003-0.058, 23) compared with febrile (0.705, 0.187-1.778, 22) and healthy (0.7, 0.4-1.2, 29) (p< 0.05) controls. A-FaBP and mrProANP (Median, IQR ng/mL, n) were elevated in septic patients compared to control groups on first 2 days after admission to the PICU (p <0.05). The area under the curve (AUC) for MMP-9/TIMP-1 ratio, mrProANP, and A-FaBP to distinguish septic patients from healthy controls were 0.96, 0.99, and 0.76, respectively. MMP-9/TIMP-1 ratio was inversely and mrProANP was directly related to PIM-2, PELOD, and ICU and hospital LOS (p<0.05). A-FaBP level was associated with PELOD, hospital and ICU length of stay (p<0.05). MMP-9/TIMP-1 ratio associated with poor Glasgow Outcome Score (p<0.05). A-FaBP levels in septic patients with neurological dysfunction (29.3, 17.2-54.6, 7) were significantly increased compared to septic patients without neurological dysfunction (14.6, 13.3-20.6, 11). MMP-9/TIMP-1 ratios were significantly lower, while A-FaBP and mrProANP were higher in septic patients compared to the control groups. Each biomarker was associated with hospital morbidity and length of stay. These results suggest that these biomarkers merit further prospective study for the early identification of children with sepsis.
血浆中基质金属蛋白酶-9（MMP-9）、金属蛋白酶组织抑制剂-1（TIMP-1）、中段心房利钠肽原（mrProANP）和脂肪细胞脂肪酸结合蛋白（A-FaBPs）浓度升高已被作为成人脓毒症或急性神经损伤检测的生物标志物进行研究，但在儿童中尚未开展此类研究。我们进行了一项单中心前瞻性观察性研究，以确定这些指标是否可作为识别儿童脓毒症的生物标志物。次要目的是确定这些生物标志物是否能识别出患有脓毒症神经并发症的儿童。本研究共纳入90例18岁及以下患者。将30例严重脓毒症或脓毒性休克患者与30例年龄匹配的发热儿童及30例年龄匹配的健康对照进行比较。从入住重症监护病房（ICU）第1天开始，对每个生物标志物进行连续测量。在脓毒症患者中，与发热（0.705，0.187 - 1.778，22）和健康（0.7，0.4 - 1.2，29）对照组相比，MMP9/TIMP-1比值（中位数、四分位数间距、例数）在第1天（0.024，0.004 - 0.174，13）、第2天（0.020，0.002 - 0.109，10）和第3天（0.018，0.003 - 0.058，23）降低（p<0.05）。入住儿科重症监护病房（PICU）后的头2天，与对照组相比，脓毒症患者的A-FaBP和mrProANP（中位数、四分位数间距ng/mL、例数）升高（p<0.05）。MMP-9/TIMP-1比值、mrProANP和A-FaBP区分脓毒症患者与健康对照的曲线下面积（AUC）分别为0.96、0.99和0.76。MMP-9/TIMP-1比值与PIM-2、PELOD以及ICU和住院时间呈负相关，mrProANP与之呈正相关（p<0.05）。A-FaBP水平与PELOD、住院和ICU住院时间相关（p<0.05）。MMP-9/TIMP-1比值与格拉斯哥预后评分差相关（p<0.05）。与无神经功能障碍的脓毒症患者（14.6，13.3 - 20.6，11）相比，有神经功能障碍的脓毒症患者的A-FaBP水平（29.3，17.2 - 54.6，7）显著升高。与对照组相比，脓毒症患者的MMP-9/TIMP-1比值显著降低，而A-FaBP和mrProANP则更高。每个生物标志物都与医院发病率和住院时间相关。这些结果表明，这些生物标志物值得进一步进行前瞻性研究，以早期识别儿童脓毒症。
