Clinical Experimental & Pharmacology Group, Paterson Institute for Cancer Research, Withington, Manchester, UK.
Clin Drug Investig. 2012 Mar 1;32(3):179-87. doi: 10.2165/11598610-000000000-00000.
Severe sepsis and septic shock have posed significant treatment challenges for many years. Recently, a number of circulating apoptosis biomarkers have emerged, such as full-length and caspase-cleaved cytokeratin 18 (CK18) and nucleosomal DNA (nDNA), that may be predictive of likely outcome. This non-interventional study aimed to assess the ability of enzyme-linked immunosorbent assays (ELISAs) for these biomarkers to provide clinically useful information to guide the management of sepsis.
This study was conducted in patients admitted to the intensive care unit with severe sepsis at five US centres. Blood samples for assessment of plasma levels of full-length CK18 (measured by the M65® ELISA) and caspase-cleaved CK18 (measured by the M30-Apoptosense® ELISA) and nDNA (measured by ELISA) were collected from patients within 2 hours of consent (baseline) and on days 2, 4 and 8. Blood samples from 17 healthy volunteers acted as controls. Levels of each biomarker were presented descriptively.
A total of 22 patients (mean age 60 [range, 24-83] years; 50% male) were included in the study. The mean APACHE II score was 24.4 (range 7-50). One-third of patients had three organ system failures and over one-half had septic shock. Three patients died during the study. Full-length and caspase-cleaved CK18 levels decreased within 48 hours following initiation of treatment of sepsis in patients who survived, whereas increases were observed in the same timeframe in patients who died within 28 days of admission. Baseline nDNA and total soluble CK18 levels (caspase-cleaved and total intact) were significantly (p ≤ 0.05) higher in patients who required renal support than those who did not.
Despite the small numbers of subjects assessed in the current study, these results confirm that measurement of apoptosis biomarkers may help to provide clinically useful information to manage sepsis and expedite development of novel therapeutics. However, further investigations to fully assess their prognostic value are required.
严重脓毒症和脓毒性休克多年来一直是治疗的重大挑战。近年来，已经出现了许多循环凋亡生物标志物，例如全长和半胱天冬酶切割细胞角蛋白 18（CK18）和核小体 DNA（nDNA），它们可能具有预测预后的作用。本项非干预性研究旨在评估这些生物标志物的酶联免疫吸附测定（ELISA）在提供有助于指导脓毒症管理的临床有用信息方面的能力。
本研究在美国 5 个中心的重症监护病房中入组了患有严重脓毒症的患者。在入组同意后 2 小时内（基线）和第 2、4 和 8 天采集患者的血浆样本，用于评估全长 CK18（通过 M65®ELISA 测定）、半胱天冬酶切割 CK18（通过 M30-Apoptosense®ELISA 测定）和 nDNA（通过 ELISA 测定）的血浆水平。17 名健康志愿者的血液样本作为对照。描述性呈现了每种生物标志物的水平。
共有 22 名患者（平均年龄 60 岁[范围 24-83 岁]；50%为男性）纳入了本研究。平均急性生理与慢性健康评分 II（APACHE II）评分为 24.4（范围 7-50）。三分之一的患者存在三个器官系统衰竭，超过一半的患者发生了脓毒性休克。在研究期间，有 3 名患者死亡。在存活患者中，脓毒症治疗开始后 48 小时内全长和半胱天冬酶切割 CK18 水平下降，而在 28 天内死亡的患者中，在同一时间范围内观察到升高。需要肾脏支持的患者的基线 nDNA 和总可溶性 CK18 水平（半胱天冬酶切割和全长）明显（p≤0.05）高于不需要肾脏支持的患者。
尽管目前研究评估的受试者数量较少，但这些结果证实，测定凋亡生物标志物可能有助于提供有助于管理脓毒症和加速开发新型疗法的临床有用信息。然而，需要进一步的研究来充分评估其预后价值。
