Medical Diagnosis
Vol. 14  No. 01 ( 2024 ), Article ID: 82435 , 11 pages
10.12677/MD.2024.141007

降钙素原与白蛋白比值在脓毒症并发急性 呼吸窘迫综合征预后中的评估价值

曹晶*,李勇,陈斌,喻廷凤,何正兵

益阳市中心医院呼吸内科,湖南 益阳

收稿日期:2024年1月3日;录用日期:2024年3月5日;发布日期:2024年3月13日

摘要

目的:探讨降钙素原与白蛋白比值(PAR)在脓毒症并发急性呼吸窘迫综合征(ARDS)预后中的评估价值。方法:回顾性分析2019年9月~2022年9月入住益阳市中心医院呼吸内科重症监护室(Respiratory Intensive Care Unit, RICU)的131例脓毒症并发ARDS患者的临床资料,根据患者28天预后,进一步将脓毒症并发ARDS患者分成生存组(n = 71)和死亡组(n = 60),比较两组降钙素原与白蛋白比值的差异,采用受试者工作曲线(ROC)评估PAR对脓毒症并发ARDS的预后价值;Spearman相关分析分析PAR与SOFA评分的相关性;Cox回归筛选脓毒症并发ARDS预后的独立危险因素;进一步比较不同亚组的PAR水平;最后采用Kaplan-Meier生存分析法比较不同PAR水平患者的生存率。结果:死亡组PAR水平显著高于生存组[0.85 (0.11, 2.84) vs. 0.19 (0.03, 1.01), P = 0.001]。ROC曲线分析表明,PAR判断脓毒症并发ARDS的预后性能最佳,曲线下面积(AUC)为0.725 (95% CI: 0.6141~0.800, P < 0.001),截断值为1.74,敏感度为40.00%,特异度为98.55%。相关性分析表明PAR与SOFA评分成正相关(r = 0.365, P < 0.001)。多因素Cox回归分析表明PAR高水平是脓毒症并发ARDS预后的独立危险因素(HR: 1.316, 95% CI: 1.092~1.584, P = 0.004)。亚组分析表明革兰阴性杆菌组PAR水平显著高于革兰阳性球菌组[1.24 (0.20, 2.65) vs. 0.13 (0.03, 0.79), P < 0.001]。生存分析表明PAR > 1.74的脓毒症并发ARDS患者28-d预后更差(P < 0.001)。结论:PAR对脓毒症并发ARDS患者28 d死亡率有一定的预测价值,当PAR > 1.74时,脓毒症并发ARDS患者28 d死亡率更高。

关键词

脓毒症,急性呼吸窘迫综合征,降钙素原,白蛋白,降钙素原与白蛋白比值

Evaluation of the Prognostic Value of the Procalcitonin to Albumin Ratio in Patients with Sepsis-Induced Acute Respiratory Distress Syndrome

Jing Cao*, Yong Li, Bin Chen, Tingfeng Yu, Zhengbing He

Department of Respiratory Medicine, Yiyang Central Hospital, Yiyang Hunan

Received: Jan. 3rd, 2024; accepted: Mar. 5th, 2024; published: Mar. 13th, 2024

ABSTRACT

Objective: To investigate the prognostic value of serum procalcitonin to albumin ratio (PAR) for the patients with sepsis-induced acute respiratory distress syndrome (ARDS). Methods: To retrospectively analyze the clinical data of 131 patients with sepsis-induced ARDS admitted to the respiratory intensive care unit (RICU) of Yiyang Central Hospital from September 2019 to September 2022. According to the prognosis at 28 d, 131 sepsis patients were divided into survival group (n = 71) and non-survival group (n = 60). PAR levels were compared between different groups. The receiver operating characteristic (ROC) curve was used to evaluate the prognostic value of PAR for sepsis-induced ARDS. Spearman correlation was used to test for an association between PAR and SOFA score. Independent prognostic factors of sepsis-induced ARDS were evaluated using the Cox regression analyses. PAR levels amongst various subgroups were further compared. Finally, the Kaplan-Meier survival analysis was used to compare the survival status of patients with different PAR levels. Results: The PAR level of the non-survival group was significantly higher than that of the survival group [0.85 (0.11, 2.84) vs. 0.19 (0.03, 1.01), P = 0.001]. ROC curve analysis showed that PAR had the best prognostic performance in determining sepsis-induced ARDS, the area under ROC curve of PAR in predicting prognosis was 0.725 (95% CI: 0.6141~0.800, P < 0.001), and the cutoff value, the sensitivity, and the specificity were −1.74, 40.00%, 98.55%, respectively. Correlation analysis suggested a significant positive correlation between serum PAR levels and SOFA scores (r = 0.365, P < 0.001). Multivariate Cox regression analyses indicated that high-level PAR expression served as an independent prognostic factor for poor survival in patients with sepsis-induced ARDS (HR: 1.316, 95% CI: 1.092~1.584, P = 0.004). Subgroup analysis showed that PAR levels were significantly higher in the Gram-negative bacilli group [1.24 (0.20, 2.65)] than in the Gram-positive cocci group [0.13 (0.03, 0.79)]. Kaplan-Meier survival analysis showed that higher PAR levels (>1.74) were correlated with poor 28-day survival in patients with sepsis-induced ARDS (P < 0.001). Conclusion: This study indicates that serum PAR is useful in predicting the 28-day mortality among patients with sepsis-induced ARDS, especially those with serum PAR of more than 1.74.

Keywords:Sepsis, Acute Respiratory Distress Syndrome, Procalcitonin, Albumin, Procalcitonin to Albumin Ratio

Copyright © 2024 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

脓毒症(Sepsis)是包括生理、生物和生化异常的临床综合征,由机体对感染的反应失调引起 [1] ,具有高发病率及死亡率 [2] 。器官衰竭是脓毒症最常见的并发症之一,而肺是脓毒症病程中最容易累及的靶器官。脓毒症并发呼吸衰竭可进展为急性肺损伤(Acute Lung Injury, ALI)或急性呼吸窘迫综合征(Acute Respiratory Distress Syndrom, ARDS),常伴有肺上皮细胞凋亡,肺上皮破坏,屏障功能障碍,促炎与抗炎因子失衡等病理生理过程 [3] 。目前研究发现细胞凋亡、内皮损伤功能障碍、免疫功能紊乱、线粒体功能障碍 [1] [4] [5] [6] [7] [8] 等过程与脓毒症并发ARDS的发生、发展密切相关,如间充质干细胞可通过CXCL12/CXCR4轴抑制ARDS引起的肺泡上皮细胞凋亡 [9] ,此外,虽然肺内皮功能障碍在ARDS的病理生理学中经常被忽视,但临床前模型已经确定内皮功能障碍可能是肺水肿发展的原因 [10] 。还有研究发现肺部感染时,肺组织细胞和外周血单核细胞源性巨噬细胞平衡可能是炎症平衡的一个重要标志。炎性的外周单核/巨噬细胞的过度激活在免疫过度及炎症因子风暴中起到核心作用,多种机制可诱导外周单核/巨噬细胞的过度激活 [11] 。同时,国外一项研究表明衣康酸通过挽救线粒体功能障碍和抑制cGAS/STING通路改善ARDS肺泡巨噬细胞焦亡 [12] ,进一步证实了线粒体功能障碍与脓毒症并发ARDS之间的潜在关系。

降钙素原与白蛋白比值(procalcitonin-to-albumin ratio, PAR)作为一种新型生物标志物,有研究发现PAR与新生儿脓毒症的严重程度密切相关 [13] ,还有研究发现PAR可作为ARDS患者预后的关键指标 [14] 。PAR一方面考虑到脓毒症并发ARDS患者的炎症状况,另一方面结合了患者的营养状态,有望成为脓毒症并发ARDS预后判断的潜在指标。然而目前相关报道仍比较少,本研究旨在探讨降钙素原与白蛋白比值在脓毒症并发ARDS患者预后评估中的临床价值,为临床判断脓毒症并发ARDS的预后提供理论策略和参考依据。

2. 资料与方法

2.1. 研究对象及分组

回顾性分析2019年9月至2022年9月益阳市中心医院呼吸内科重症监护室(RICU)收治的131例脓毒症并发ARDS患者的临床资料,所有患者均符合脓毒症最新指南Sepsis 3.0 [15] 中的诊断标准,ARDS的诊断标准均符合柏林定义 [16] 。根据28 d的生存情况将脓毒症并发ARDS患者分为死亡组(n = 60)和生存组(n = 71)。排除标准:(1) 患者年龄<18岁或>80岁;(2) 近3个月内使用过人血白蛋白及丙种球蛋白;(3) 孕妇或哺乳期妇女;(4) 合并基础肺脏疾病的如:肺结核、尘肺、肺癌等;(5) 各系统恶性肿瘤及血液疾病;(6) 影响序贯器官衰竭评分(SOFA)评分的准确评估;(7) 入院不足24小时及资料不全者。本研究经益阳市中心医院伦理委员会批准,并获得患者知情同意。

2.2. 临床资料收集

利用医院信息系统(Hospital Information System, HIS)查阅并收集研究对象的临床资料,记录两组间的一般资料(年龄、性别、是否吸烟/饮酒、是否合并高血压/糖尿病等)、临床表现(生命体征、感染途径及入住RICU天数等),并计算入院时的SOFA评分。

2.3. 实验室指标

收集研究对象入住RICU 24 h内的外周静脉血,保存于含有肝素或乙二胺四乙酸的采血管,以3500 r/min离心10 min。采用XN-9000自动血细胞分析仪(日本Sysmex公司)测量白细胞(WBC)、中性粒细胞、淋巴细胞、单核细胞、红细胞(RBC)、血红蛋白(Hb)、血细胞比容(HCT)及血小板(PLT)水平;采用Burgess Hill全自动免疫分析仪(英国Roche Diagnostic公司)检测降钙素原(PCT)水平;采用全自动蛋白分析仪(德国DIASYS公司)检测C反应蛋白(CRP)水平;采用7600 Series自动生化分析仪(日本HITACHI公司)检测总胆红素(TBI)、直接胆红素、间接胆红素、谷丙转氨酶、谷草转氨酶、白蛋白、肌酐(Cr)、尿素氮(BUN)、总胆固醇、甘油三酯的水平。采用丹麦雷诺ABL800FLEX血气分析仪检测血气各项指标;采用离子选择电极法[日立仪器(苏州)有限公司]检测血清钾、血清钠的水平。

2.4. PAR对脓毒症并发ARDS预后判断的评估价值

采用受试者工作特征(ROC)曲线评估各指标对脓毒症ARDS预后的判断价值;采用Spearman相关分析判断PAR与SOFA评分的相关性;采用Cox风险模型分析脓毒症ARDS患者的预后危险因素。根据约登指数选取PAR对脓毒症ARDS患者28 d病死率的最佳预测值(cut-off)值,以PAR水平的截断值(1.74)为界,将131患者分为两组,其中≥1.74组28人,<1.74组103人,采用Kaplan-Meier生存分析比较两组28 d病死率,并用log-rank法比较生存曲线的差异。

2.5. 统计学处理

采用SPSS 26.0软件及Graphad Prism 9.0进行统计分析及图标绘制。计数资料以例(%)表示,组间比较采用x2检验或fisher确切概率法;符合正态分布的计量资料以 x ¯ ± s 表示,两组比较采用独立样本t检验;不符合正态分布的计量资料以M (Q1, Q3)表示,两组比较采用Mann-Whitney U检验。P < 0.05为差异有统计学意义。

3. 结果

3.1. 生存组与死亡组一般资料比较

131例脓毒症并发ARDS患者中,生存组71例,死亡组60例。脓毒症致ARDS的病因以肺部感染最为多见。脓毒症并发ARDS死亡组患者的呼吸频率较生存组患者快,差异存在统计学意义(P < 0.05);两组年龄、性别、体温、心率、收缩压、舒张压、吸烟、饮酒差异无统计学意义(P > 0.05) (表1)。

Table 1. Comparison of the general information between survival group and non-survival group in patients with sepsis-induced ARDS

表1. 脓毒症合并ARDS生存组与死亡组患者一般资料比较

3.2. 生存组与死亡组临床指标比较

与脓毒症并发ARDS生存组比较,死亡组淋巴细胞、间接胆红素、白蛋白、入住ICU时间等指标降低,血肌酐、尿素氮、降钙素原、PAR、SOFA评分等指标升高,差异有统计学意义(P < 0.05);两组其余实验室指标差异无统计学意义(P > 0.05) (表2)。

Table 2. Comparison of the clinical information between survival group and non-survival group

表2. 脓毒症合并ARDS生存组与死亡组患者临床资料比较

续表

注:pH.酸碱度;PCT.降钙素原;ALB.白蛋白;SOFA.序贯器官衰竭评分;APACHE.急性生理与慢性健康评分;ICU.重症监护室。

3.3. ROC曲线分析各指标判断脓毒症并发ARDS预后的价值

ROC曲线分析结果显示PAR判断脓毒症并发ARDS预后的价值最高,AUC最大,诊断敏感度40%,特异度98.55%;其次为SOFA评分和降钙素原(表3图1)。

Table 3. ROC analysis for laboratory indexes on sepsis-induced ARDS prognosis

表3. 各指标判断脓毒症并发ARDS预后的ROC曲线分析结果

注:AUC.曲线下面积;CI.置信区间。

Figure 1. ROC curves for the top three indicators of prognostic in sepsis-induced ARDS

图1. 判断脓毒症并发ARDS预后效能前三位指标的ROC曲线

3.4. 脓毒症预后相关危险因素的Cox回归分析

Spearman相关分析表明,PAR与SOFA评分呈正相关(r = 0.365, P < 0.001) (图2)。单因素Cox回归分析结果显示:高水平白蛋白是脓毒症ARDS患者预后的保护性因素;高水平血肌酐、尿素氮、降钙素原、PAR、SOFA评分是脓毒症ARDS预后的危险因素;进一步多因素Cox回归分析发现高水平白蛋白是脓毒症ARDS的保护性因素,高水平降钙素原、PAR与SOFA评分是脓毒症ARDS的独立危险因素(表4)。

Figure 2. Spearman correlation analysis between PCT/ALB levels and SOFA score

图2. PCT/ALB水平与SOFA评分的相关性分析

Table 4. 脓毒症合并ARDS预后相关危险因素的Cox回归分析

表4. Cox regression analyses to predict prognosis in patients with sepsis-induced ARDS

注:HR.危险比;CI.置信区间。

3.5. 不同亚组脓毒症ARDS患者PAR水平的比较

将脓毒症ARDS患者分为不同亚组,根据细胞种类不同,将脓毒症ARDS患者分为革兰阴性杆菌组(n = 59)与革兰阳性球菌(n = 72),两组间PAR水平差异有统计学意义(P < 0.05);在不同性别、ARDS严重程度分型、感染源是否来自肺部等亚组中PAR水平无统计学差异(P > 0.05) (见表5)。

Table 5. Comparison of PCT/ALB levels between subgroups

表5. 脓毒症合并ARDS不同亚组的PCT/ALB水平比较

3.6. 生存曲线分析

生存曲线分析结果显示,SOFA评分 ≥ 7,PAR ≥ 1.74的脓毒症ARDS患者的28 d病死率高于SOFA评分 < 7,PAR < 1.74的脓毒症ARDS患者,差异具有统计学意义(P < 0.05) (见图3)。

Figure 3. Comparison of Kaplan-Meier survival curves of patients with different SOFA scores and serum PCT/ALB levels

图3. 不同SOFA评分和PCT/ALB水平患者生存曲线比较

4. 讨论

本研究发现PAR与脓毒症并发ARDS的不良预后密切相关。我们发现,在脓毒症并发ARDS患者中,PAR升高与SOFA评分、28 d不良预后显著相关,PAR是脓毒症并发ARDS的独立危险因素,ROC曲线显示PAR对脓毒症ARDS患者的28 d死亡率有较好的预测能力。既往研究已发现一些生物标志物(肝素结合蛋白、miR-424、Mucin1、Endocan) [17] 及评分系统(肺损伤预测评分、衍生评分系统)对脓毒症相关ARDS的预后具有一定的价值,然而生物标志物检测方法复杂、费用昂贵,目前难以广泛应用于临床,评分系统复杂、费时,不被临床医师的青睐,因此寻找简便的指标预测脓毒症并发ARDS患者的预后至关重要。

降钙素原(Procalcitonin, PCT)是由116个氨基酸组成的激素,分子量约为14KD,11号染色体上降钙素I基因(CALC-I)的表达产物,在人体内的稳定性良好。在正常情况下,CALC-I几乎全部由神经内分泌甲状腺C细胞并储存在高尔基体内,在外周血中几乎检测不到 [18] 。在全身感染期间,许多炎症细胞因子(IFN-γ、TNF-α、IL-6等)被激活,炎症细胞因子促进CALC-I表达上调,导致循环中PCT的释放量增加 [19] 。目前PCT在临床应用中不断得到深化及拓展,有研究 [20] 发现当PCT的最佳截断值为6.5 ng/ml时能预测心肺旁路手术后患者发生ARDS (AUC: 0.734, 95% CI: 0.680~0.783, P < 0.001),也是发生ARDS的独立危险因素(OR 1.165, 95% CI: 1.106~1.226)。在儿童血液肿瘤的患儿中研究 [21] 发现外源性肺ARDS (脓毒症所致)患儿PCT水平明显高于肺ARDS患儿,提示患儿病情更重、病死率更高。最近的研究也发现PCT水平升高与COVI-19 (Coronavirus Disease 2019, COVI-19)相关ARDS重症监护室获得性感染的发生有关 [22] 。当然也有学者发现 [23] 在多发伤、大面积烧伤以及胰腺炎等所致的ARDS患者中PCT水平同样会升高,提示PCT对脓毒症ARDS与其他病因鉴别价值有限。在本研究中同样发现PCT对预测脓毒症ARDS患者预后的价值不高(AUC: 0.657, 95% CI: 0.569~0.737, P = 0.001)。

ALB是由肝脏分泌的一种小分子蛋白质,在血浆中的半寿期约为15~19天,是血浆中含量最多的蛋白质,占血浆总蛋白的40%~60%,具有维持血浆胶体渗透压、调节血管内外体液分布、抗炎、抗氧化、免疫调节等生理功能与作用 [24] [25] [26] 。白蛋白水平降低提示机体营养不良,特别是呼吸肌的营养不良引起功能障碍,氧合功能下降 [27] [28] 。另外,血浆蛋白水平降低,削弱了机体清除氧自由基及对抗氧化应激的能力,肺氧化损伤的风险增加,肺表面活性物质的失活造成低氧血症、二氧化碳潴留、肺顺应性下降而发展为ARDS [29] [30] [31] [32] [33] 。既往有研究发现低血浆蛋白水平与肺血管通透性增加和肺损伤有关,能预测ARDS的发生 [34] 。而Su [35] 的研究发现与脓毒症相关ARDS患者相比,COVI-19相关ARDS患者的白蛋白水平降低及恢复时间均较为短暂,提示白蛋白的变化水平对评估COVI-19病后康复有一定的潜力。与本研究的结果一致,Aman等人 [34] 发现血浆白蛋白水平是急性肺损伤/急性呼吸窘迫综合征危重患者或危重患者肺血管通透性和肺损伤程度的标志物。而you等人 [36] 的研究同样发现低蛋白是新生儿脓毒症ARDS的独立危险因素,为我们的结果进一步提供了支持。

尽管目前许多炎征标志物对脓毒症及其并发症的诊断有一定帮助,但在预后评估的价值有限,另外一些评分系统 [37] 对于脓毒症及其并发症的病情严重程度及预后的预测有一定的价值,但因评分系统主观性较强,在危重症患者中的判断难以把握 [38] 。因此寻找高预测价值的标志物评估对脓毒症ARDS患者的预后具有重要意义,及时制定个体化的治疗方案,患者将得到极大的临床获益。PAR是由PCT与ALB组成,既结合了患者的炎症情况,同时兼顾患者的营养状况。本研究通过多绘制ROC曲线发现PAR的曲线下面积最大(AUC: 0.725, 95% CI: 0.641~0.800, <0.001),提示PAR对脓毒症ARDS患者的预后有一定的预测价值,与王玉 [10] 等人的研究结果一致。进一步通过多因素Cox回归分析发现PAR是脓毒症ARDS的独立危险因素,但因ALB、PCT与PAR存在共线性,PAR与SOFA评分存在正相关故本研究不再深入研究。本研究还发现,PAR ≥ 1.74的脓毒症ARDS患者病死率高于PAR < 1.74的患者,原因可能是PAR升高提示机体的炎症更重,营养更差,治疗更为棘手,故预后更差。

本研究也存在一些局限性:(1) 为单中心回顾性研究,样本量有限,无法排除选择偏倚的影响;(2)脓毒症ARDS患者往往入院时病情危急,仅分析患者入院后24 h内的检测指标,机体应激反应有可能延迟,结果可信度欠佳;(3) 只对28 d病死率进行分析,时间较短,应进行更长时间的随访,从而对预后进行更充分地评估。

综上所述,本研究结果表明,PAR在脓毒症ARDS死亡组更高,与脓毒症ARDS患者28天病死率有一定关系,且与SOFA评分呈正相关,PAR ≥ 1.74时,患者更容易死亡。

文章引用

曹 晶,李 勇,陈 斌,喻廷凤,何正兵. 降钙素原与白蛋白比值在脓毒症并发急性呼吸窘迫综合征预后中的评估价值
Evaluation of the Prognostic Value of the Procalcitonin to Albumin Ratio in Patients with Sepsis-Induced Acute Respiratory Distress Syndrome[J]. 医学诊断, 2024, 14(01): 45-55. https://doi.org/10.12677/MD.2024.141007

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  39. NOTES

    *通讯作者。

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