2024, Vol. 33
2. 重庆医科大学附属第一医院重症医学科，重庆 400016;
3. 重庆医科大学附属第一医院神经内科，重庆 400016
心脏骤停（cardiac arrest, CA）是全球面临的重大健康威胁[1]，导致美国、欧洲和中国每年数十万人死亡[2-3]。随着精准化、高质量心肺复苏普及，越来越多患者能够恢复自主循环（return of spontaneous circulation, ROSC），但存活比例仍然较低。截至目前，仅22.6%的院内心脏骤停（in-hospital cardiac arrest，IHCA）及1.15%的院外心脏骤停（out of hospital cardiac arrest, OHCA）患者可在出院时存活[4-5]。心脏骤停后综合征（post-cardiac arrest syndrome, PCAS）是CA患者ROSC后预后不良的关键，而全身炎症是PCAS的标志[6]。
CA及复苏引起全身非特异性炎症全面激活。激活的炎症可通过恶化PCAS中的全身缺血再灌注损伤（ischemia-reperfusion injury, IRI）、CA后脑损伤、CA后心脏损伤等多个病理损伤过程，导致患者多器官功能衰竭和死亡[7-8]。近年来，相关研究表明炎症标志物在评估CA患者预后中扮演重要角色，但尚未形成系统综述。同时，心肺复苏后炎症对预后的具体机制及特异性治疗药物的研究仍不够深入。为此，本文旨在系统回顾炎症导致CA患者预后不良的病理生理机制、炎症标志物与患者结局的临床研究和通过抑制炎症改善结局的潜在治疗药物，以期为临床医生通过炎症标志物评估患者预后、精准化抑制炎症及改善结局提供一定的理论基础。本综述架构思维导图见附图 1。
1 炎症导致CA患者结局不良的病理生理机制 1.1 炎症诱发多器官缺血再灌注损伤是不良预后的重要机制IRI是指CA引起缺氧缺血一段时间后，血液供应恢复时引起的组织损伤[9]，重要器官的IRI是ROSC患者的死亡原因之一[10]。炎症反应、氧化应激和线粒体功能障碍是导致ROSC后IRI的关键因素[11]。炎症主要通过中性粒细胞分泌酶（如弹性蛋白酶和金属蛋白酶），引起大脑、心脏和肝脏等组织IRI[12-14]。同时，全身非特异性炎症激活后，白细胞阻塞毛细血管，补体和细胞因子增加血管通透性导致各器官（尤其是脑）IRI进一步恶化[15]。故炎症通过中性粒细胞分泌炎性蛋白酶，白细胞、补体和细胞因子扩大炎症引起ROSC患者许多重要脏器IRI，使其预后不良。
1.2 炎症下调紧密连接蛋白，破坏血脑屏障是神经功能损伤的关键CA存活患者中不足10%的人可完全恢复，神经功能损伤是存活患者长期残疾的主要原因[16]。炎症通过破坏血脑屏障，诱发缺血缺氧性脑损伤是神经功能损害的关键因素[17]。CA后，迅速形成的自由基与氧化剂激活代谢级联反应，导致白细胞与内皮细胞释放大量细胞因子如IL-1、IL-6、IL-8、IL-12、TNF-α和IFN-γ[18], 这些细胞因子激活血管内皮细胞eNOs信号[19]，引起血脑屏障中的紧密连接蛋白（尤其是Claudin-5）下调，导致紧密连接错配及降低[20]。同时，炎症使内皮细胞粘附分子[血管细胞粘附分子1(VCAM-1)、细胞间粘附分子1(ICAM-1)]的表达上调，导致内皮细胞连接障碍，进一步破坏血脑屏障[21]。血脑屏障损伤后，大量的炎性介质和相关损伤物质进入神经中枢，激活小胶质细胞[22]，通过M1途径Toll样受体与(TLR-4)+IFN-γ受体复合物引起血管炎性脑水肿，加重脑缺血，使脑梗死的面积进一步扩大[23-24]。故全身炎症通过下调紧密连接蛋白，破坏血脑屏障是神经功能障碍的关键因素之一。
1.3 炎症抑制心肌收缩功能、诱导心室电重构导致心脏损伤自主循环恢复后，聚集于心脏的中性粒细胞和C4d[25]使TNF-α、IL-1b和IL-6大量增加，导致患者血流动力学不稳定和心肌收缩功能下降[26]。此外，激活的炎性小体，TLR4/NF-κB信号通路和单核细胞模式识别受体信号通路均通过炎症反应进一步加剧心肌功能障碍[27]，而C-反应蛋白(c-reactive protein, CRP)、IL-1和IL-6使心室细胞的KCNJ2K+通道大幅下调[28-29]，导致患者心室电重构（心室复极化减慢，QT间期显著延长）。心室电重构不仅加剧心肌功能障碍[30]，还能通过心率失常与再次CA恶化心脏功能[31]。故炎症反应通过抑制心肌收缩，影响电生理过程是导致心肌损伤的重要病生机制。
1.4 炎症通过肺-肠轴和肺脑耦合机制导致肺损伤心搏停止后，由于肠系膜缺血，肠道细菌增殖，肠道屏障功能受损，细菌和病原体相关分子模式（pattern-recognition receptors, PAMPs）通过Toll样受体激活中性粒细胞与血小板[32]，并经肠系膜淋巴-胸导管系统迁移至肺血管，激活肺部免疫系统，增加肺毛细血管通透性，造成肺间质水肿[33]。这种肠道内产生的PAMPs通过肠系膜淋巴管、胸导管进入肺血管系统被称为“肺-肠轴”[34]。肺-肠轴是导致呼吸功能障碍的重要因素，但中性粒细胞从缺血性损伤的脑组织优先迁移到肺部，并引起局部炎症的“肺-脑耦合”作用[35]也不可忽略。CA引起低血压造成脑干功能不全，对肺血管交感刺激增加，导致血管通透性增加而加重肺间质水肿，从而导致神经源性肺损伤[36]。更重要的是，脑损伤后活化的中性粒细胞迅速通过跨内皮方式迁移至肺[37]，内毒素、TNF-α使其顺应性降低，滞留于肺毛细血管，加剧其炎症反应[38]。同时，炎症还使中性粒细胞表面TLRs受体高表达，进一步加重肺损伤[39]。由此，受损的肠道和大脑激活炎症介质, 通过肺-肠轴与肺脑耦合机制聚集于肺部，是导致病人呼吸功能障碍和急性肺损伤的主要因素。炎症反应导致ROSC患者预后不良的病理生理机制详见附图 2。
2 CA患者预后相关的炎症标志物 2.1 血常规相关的标志物中性粒细胞（neutrophil, NE）作为抵御感染的第一道防线，参与了许多炎症疾病的发生发展[40]，同时也通过多种病理机制加重PCAS发展[35]。首先，未成熟/总中性粒细胞比值（I/T-G）升高是全身炎症的标志[41]，入院时I/T-G比值能够预测OHCA患者ICU病死率（AUC=0.82）[42]；ROSC后第8天δ中性粒细胞（未成熟粒细胞）指数 > 4.1%时，患者30 d内死亡风险显著上升（HR=3.227，95%CI: 1.485~6.967，P=0.001）[43]。其次，NE活化标志物—髓过氧化物酶（MPO）升高与ROSC后早期神经功能紊乱显著正相关（OR=3.18，95%CI: 1.25~8.11）[44]。NE活化后通过释放中性粒细胞细胞外陷阱（neutrophil extracellular traps, NETs）发挥先天免疫作用，NETs的形成与CA患者预后不良密切相关，循环中的NETs每增加500 GE/mL，患者24 h内和院内死亡风险分别增加1.75和1.36倍[45]，OHCA患者2 h内NETs≥1 170 GE/mL，院内死亡风险约增加12倍（OR=12.35，P=0.023）[46]。另外，入院时NETs的基质金属蛋白酶-9（MMP-9）[47]和12 h的组蛋白H3（NETs结构蛋白）升高[48]也是影响患者预后的重要因素，NETs诱导剂高迁移率组蛋白1（HMGB1）[49]与CA患者神经功能损害密切相关[50]，Omura等[51]研究发现入院时HMGB-1水平预测30 d神经系统结局AUC值高达0.864（95%CI: 0.702~1.000）。最后，中性粒细胞释放的蛋白酶（肝素结合蛋白、中性粒细胞明胶酶相关蛋白）升高亦可作为CA患者神经系统结局不良[52]、ICU早期死亡[53]及院内死亡[54]的早期预测指标。中性粒细胞相关标记物与CA患者临床结局密切相关，但既往研究集中于OHCA患者短期结局，未进行长期随访，并且中性粒细胞相关的标志物未在临床运用中常规测量，有必要进一步评价其临床价值。
淋巴细胞（lymphocyte, LYM）是衡量免疫功能的重要标志。LYM下降与OHCA患者不良结局密切相关，研究发现OHCA患者入院时LYM < 1 000 /mm3，神经功能结局不良风险增加175%[55]，这可能与CA和复苏激活下丘脑-垂体-肾上腺轴和严重的免疫抑制有关。同时，LYM亚型也是CA患者结局潜在预测标志物，Ryzhov等[56]研究表明CD73+LYM升高可以提高CA患者出院生存率，主要是通过生成腺苷进一步抑制炎症，但CD73+LYM对结局的具体预测价值尚不清楚。同时，其他LYM亚型（如CD45）对CA患者结局的预测价值和病生机制也值得进一步探索。
单核细胞（monocytes, LCM）根据受体表达情况可分为经典单核细胞（CM）、中间单核细胞（IM）和非经典单核细胞（NCM）3个亚群。ROSC后，30 d内死亡患者的NCM显著下降，6个月内死亡患者的CM在复苏后早期显著下降（-7.7%，P=0.015），而IM显著增加（+136.1%，P=0.006）[57]。同时，LCM通过模式识别受体（PRR）迁移至炎症部位，故PRR在PCAS中启动和延续炎症也起重要作用，研究发现30d结局不良的CA患者PRR的TLR2，IRAK3，IRAK4，NLRP3和CASP1的mRNA水平均显著降低[58]。但上述研究均为小样本CA患者与19例冠状动脉疾病患者进行比较，进一步扩大样本量探究LCM亚型及其受体对CA患者中的预测价值至关重要。
红细胞分布宽度（red blood cell distribution width, RDW）是衡量红细胞变异性的常用指标，与炎症的激活密切相关[59]，既往大量研究表明RDW升高与CA患者结局不良有关。对于OHCA患者，入院时RDW≥15%，出院神经功能结局不良风险增加2.04倍[60]；RDW > 15.4%，30 d内死亡风险增加1.95倍[61]。对于IHCA患者，复苏后1 h内RDW < 15.5%与出院存活率独立相关，但OR值仅为0.19[62]，因此，RDW能否作为IHCA患者结局预测指标还应进一步探讨。同时，RDW相关新型炎症指标（如RDW-乳酸比值）对CA患者结局的预测价值也值得探讨。
血小板（platelet，PLT）通过释放炎症介质，诱导中性粒细胞活化及与白细胞形成聚集体等，在全身炎症反应中起着重要作用[63-64]。Kim等[65]研究发现ROSC后第7天PLT下降与长期神经系统结局不良(OR=0.975, 95%CI, 0.961~0.989)及死亡(OR=0.986，95%CI: 0.975~0.997)独立相关，但PLT降低是否为CA患者结局保护因素需进一步验证。另外，平均血小板体积（mean platelet volume，MPV）增加被认为是血小板活化的特征，可作为CA患者预后标志物，Chung等[66]研究表明，入院时MPV升高是OHCA患者30 d死亡的独立预测因素（HR=1.36，95%CI: 1.06~1.75）。既往对于PLT相关标志物与CA患者预后分析为回顾性研究，不排除存在选择偏倚，故其能否作为早期预后标志物应进一步在大规模前瞻性研究中探索。
2.2 血常规相关复合标志物中性粒细胞-淋巴细胞比值（neutrophil-lymphocyte ratio, NLR）是目前广泛运用的新型全身炎症标志物，反映了先天性免疫和适应性免疫应答之间的平衡。接受低温治疗（TTM）但在院内死亡的CA患者，其NLR显著高于幸存者（24.9 vs. 17.5, P=0.014）[67]，Chang等[68]认为NLR在心血管疾病中的预测价值较白细胞或中性粒细胞计数更高。Weiser等[69]在一项含1 000多例OHCA患者的大型回顾性队列研究中发现，患者入院时NLR≥6，长期病死率显著增高（OR=1.52，95%CI: 1.03~2.24）, 在调整CA原因、骤停时间以及最高白细胞等混杂因素后，ROSC后72 h NLR≥6与患者6个月神经系统结局不良独立相关（OR=3.299，95%CI: 1.080~10.081）[70]。综上，NLR≥6可能是OHCA患者预后不良的重要截断值，但既往研究NLR的测量时间点并不相同，因此，进一步探索NLR的最优测量时间从临床研究走向临床应用的必要步骤。对于IHCA患者，Patel等[71]证实，ROSC后24 h内NLR≥4.55是30 d内死亡的独立预测因子（OR=5.20，CI: 1.5~18.3，P=0.01），但该研究是一项仅包含了153例患者的回顾性研究，故临床上能否将NLR≥4.55作为最优截断值需谨慎考虑。大量研究证明NLR是CA患者结局的预测因子，进一步探索相关病生机制及潜在治疗靶点是改善患者结局的关键。
血小板-淋巴细胞比值（platelet-lymphocyte ratio, PLR）是心血管疾病一种新颖、简单、廉价和快速预后的炎症标志物[72]，较高的PLR反映了患者更严重的全身炎症和免疫抑制状态。研究发现ROSC后72 h内PLR≥180是IHCA患者30 d内死亡的独立危险因素（HR=2.99, 95%CI: 1.44~6.21）[73]，本研究运用时间依赖COX回归分析了72 h内PLR多次测量结果，不仅更贴合临床实际，增加了结论可靠性，还使PLR在临床运用时不易受到某些治疗及相关延迟因素的影响。
γ-谷氨酰转肽酶-血小板比例（gamma-glutamyl transpeptidase-platelet ratio, GPR）是通过GGT和PLT计算快速获得的新型炎症指标，与多种心血管疾病预后密切相关。Zhao等[74]首次探讨了GPR与CA患者预后的关系，结果发现GPR > 0.486与ICU病死率、院内病死率和3个月神经系统不良结局均独立相关，但其预测价值需进一步研究证实。同时，该研究通过GPR的三分位数将患者分为三组，故GPR > 0.486能否作为CA患者预后的最佳分界值也需谨慎考虑。
2.3 细胞因子细胞因子作为分子信使，刺激免疫细胞增殖、分化，促进白细胞向损伤部位趋化，参与免疫和炎症反应的放大和调节，白介素是临床广泛运用的细胞因子。研究发现，院内死亡的CA患者的IL-1、IL-6、IL-8和IL-10均高于幸存者(P < 0.001)[75]，1周内死亡的患者IL-8显著较高[76]。其中，IL-6对CA患者的预测价值已被多次探讨，结果表明，入院时IL-6升高是OHCA患者血管加压药使用增加、出院病死率及12个月神经功能结局差的独立预后因素[77-79]，但其对IHCA患者结局的预测性能还应进一步探讨。另外，Zhuang等[80]在一项前瞻性观察性研究中首次证明了ROSC后第7天的IL-17(AUC=0.85)和IL-23(AUC=1)是CA患者结局的良好预测指标。生长分化因子15（GDF-15）是一种应激反应蛋白，可作为多种心血管疾病预后判断的标志物，Rueda等[81]研究证明GDF-15升高是是心源性OHCA患者神经系统不良结局的早期、独立预测因子，(OR=3.74，95%CI: 1.32~10.60，P=0.013)，随后Richter等[82]表明GDF-15可进一步作为CA患者长期神经系统结局不良的预测因素。目前尚无研究探索ROSC后GDF-15随病程的变化和最佳测量时间点。细胞因子是简单易得的炎症标志物，对CA患者结局具有较强的预测作用，而统一临床截断值与寻找最佳测量时间点是其从临床研究转化为运用的必要步骤。
2.4 C反应蛋白及衍生物CRP是廉价、广泛使用，且被证明是比白细胞计数更可靠的心血管疾病预后标志物，Dell'anna等[83]和Schriefl等[84]均证明入院时CRP升高与OHCA患者神经系统结局不良独立相关。同时，PTX3（CRP同族炎症蛋白）也可作为OHCA患者结局的预测标志物，研究发现，患者入住ICU时PTX3 > 24 ng/mL，发生MODS风险增加92%，ICU死亡风险增加54%[85]。复合炎症标志物因预测性能通常优于单一炎症指标已受到广泛关注，C反应蛋白-白蛋白比值（C-reactive protein-albumin ratio, CAR）是目前被广泛认为比单独使用CRP或白蛋白更有用的新型炎症指标，Bingol Tanriverdi等[86]首次证明了CAR是OHCA患者院内病死率的独立预测指标(OR=1.971，95%CI: 1.327~2.930，P=0.001)，随后Kim等[87]研究发现，CAR还可作为OHCA患者长期结局的独立预测指标。目前研究主要集中探讨CRP及相关标志物对OHCA患者的预测价值，其对IHCA患者的预测效能也值得进一步探索。此外，CRP衍生的新型炎症评分（如炎症-免疫-营养评分）对CA患者预后的预测价值尚不明确。
2.5 降钙素原及衍生物降钙素原（procalcitonin，PCT）不仅能反映炎症的严重程度[88]，也是CA患者结局的有效预测因子。Fries等[89]在2003年首次证实了14 d神经结局不良的OHCA患者，入院时PCT水平显着升高(379 vs. 0.29, P=0.0002)，随后Bro-Jeppesen等[7]研究发现，ROSC后24 h的PCT水平可作为OHCA患者短期病死率独立预测因子（HR=1.20，P=0.02），一项前瞻性队列发现入院较高的PCT水平与患者住院期间血流动力学不稳定和长期神经系统结局不良密切相关[90]，当PCT水平高于16 ng/mL，患者意识不能恢复[91]。同时，PCT的预测价值已得到Meta研究证实，在含1 065例CA患者的二次分析中，作者发现ROSC后0~48 h内PCT升高与患者不良结局相关，但临床运用时应当注意，PCT并不能作为CA患者早发感染和并发肺炎的标志物[92-94]。另外，Yoon等[95]研究发现PCT-白蛋白原比值能比PCT更有效地预测OHCA患者短期神经系统结局，进一步探索其他PCT新型炎症标志物对CA患者的预测价值可能是后期研究的方向。
2.6 补体成分补体的过度激活与病理性炎症损伤密切相关[96]，多项研究证实其可作为CA患者预后预测指标。Jenei等[97]运用多因素COX回归证实补体激活程度（C3a/C3比值）是CA昏迷患者短期结局不良的独立预后因素，Langeland等[98]发现若入院时补体活化产物TCC水平增加2倍，30 d病死率几乎增加1倍（OR=1.81），Chaban等[99]表明入院时补体活化产物SC5b-9水平与OHCA患者长期神经系统不良结局相关。此外，Bro-Jeppesen等[100]首次提出补体活化相调节蛋白MAP 19升高是OHCA患者临床结局改善的保护因素（HR=0.48, 95%CI: 0.31~0.75, P=0.001），这与其限制补体激活密切相关，但具体机制还需进一步探讨。值得注意的是，补体在患者间绝对值变化很大，临床上不应将其作为决定性的预后标志物。
2.7 白蛋白白蛋白不仅可维持血浆渗透压，还通过结合、运输炎症物质及促进抗炎因子释放而抑制炎症[101]，已在心血管疾病中逐渐受到重视。Matsuyama等[102]首次证明入院时白蛋白 < 3.5 g/L的OHCA患者，出现长期不良神经结局的可能性是正常患者的3.5倍；Lee等[103]在一项含3 837例CA患者的Meta研究中已证实白蛋白浓度降低可作为CA患者结局不良的早期预测因子，但结果存在一定异质性。近期，白蛋白相关的炎症标志物（如PNI评分），已被证明对心血管疾病患者短期结局具有更好的预测性能[104]，但其在PCAS损伤进展期的动态变化和对IHCA患者短期结局中的预后意义尚不清楚。此外，临床实践中补充白蛋白，纠正患者低白蛋白血症能否改善患者炎症反应和提高临床结局也值得进一步探讨。
2.8 其他新型炎症标志物—可溶性细胞死亡配体可溶细胞性配体（sPD-L1）与受体结合后可抑制免疫功能，引发组织炎性损伤，与许多癌症预后不良密切相关，Sumiyoshi等[105]首次发现sPD-L1升高还可作为CA患者发生MODS的潜在标志物，但本研究仅包含30例OHCA患者，因此其预后效能需在大样本队列研究中进一步证实。另外，如细胞分布宽度/血小板、平均血小板体积/血小板等新型炎症标志物对CA患者预后价值目前均处于未知领域。与CA患者预后相关的炎症标志物详见附图 3。
3 CA患者炎症相关潜在治疗药物CA是发病率高、进展快、治疗费用昂贵且预后差的危重型疾病，目前尚无特异性治疗方式。心脏骤停后，缺血-再灌注损伤诱发全身炎症反应是导致患者死亡的重要因素，故许多临床医师致力于通过抑制炎症而改善患者预后，具体研究总结见附表 1。目前研究发现：血脂康（TLR4/NF-κB信号通路抑制剂）[106]、MCC950（IL-1β抑制剂）[107]、硫化钠（Na2S）[108]、SB-3CT（MMP-9抑制剂）[109]、米诺环素（TNF-α抑制剂）[110]、HBHP（HMGB1抑制剂）[111]和氢化可的松[112]均能抑制全身炎症，降低血脑屏障通透性进而改善实验对象神经系统结局与生存情况。同时，infliximab（TNF-α特异性抗体）[113]，Sivelestat（中性粒细胞弹性蛋白酶抑制剂）[114]和tocilizumab（IL-6特异性受体拮抗剂）[115]可显抑制全身炎症反应，减轻CA心肌损伤程度。此外，IL-8单克隆抗体可减轻中性粒细胞聚集于肺部，减轻家兔肺部缺血再灌注损伤[116]。以上药物（见附表 1）均通过特异性靶点减轻CA后全身炎症反应及器官损伤，是患者潜在治疗药物，但目前大多仅处于动物实验阶段。对于病理生理机制具有差异的患者，上述药物的临床意义、治疗效果和药物不良事件风险急待进一步考证。
4 总结与展望目前CA患者的结局并未随着治疗理念与策略的更新而有效改善，早期评估患者结局与严重分层后制定个性化治疗策略对于改善患者预后至关重要。本文就炎症导致CA患者预后不良的病理生理机制、预后相关炎症标志物及潜在治疗药进行了初步总结。综上所述，CA发生后全身非特异性炎症激活并导致患者多器官功能衰竭和死亡，炎症影响预后不良病理生理机制包括诱发多器官IRI、下调紧密连接蛋白破坏等血脑屏障、抑制心肌收缩功能诱导心室电重构、通过肺-肠轴和肺脑耦合导致肺损伤。炎症标志物有助于早期评估心CA患者预后，进行病情严重程度分层，并指导制定个性化治疗策略，但目前相关聚焦于OHCA患者，且大多数研究均为小样本研究（见附图 4）。另外，对于新型复合炎症标志物和PCAS后炎症指标动态变化的预测价值研究尚处于起步阶段。在临床实践中进一步挖掘实惠易得的新型或复合炎症标志物，将炎症指标与临床、电生理检查相结合以及持续关注病程中炎症标志物的动态变化对于早期准确识别预后不良的个体、改善患者结局具有重要意义。同时，目前特异性靶向抑制CA后全身炎症药物的相关研究大多仍处于临床前研究，如何让药物从研究走向临床运用，使CA患者获益也值得充分探讨。
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