Advances in Clinical Medicine
Vol. 14  No. 05 ( 2024 ), Article ID: 86957 , 9 pages
10.12677/acm.2024.1451528

脓毒性休克治疗的新进展

李雪1,2,唐帆2,金仕文2,邵宇3,蒋幼凡1*,胡天洋4*

1重庆医科大学附属第二医院呼吸与危重症医学科,重庆

2重庆市南岸区第三人民医院内一科,重庆

3重庆市急救医疗中心(重庆大学附属中心医院)消化内科,重庆

4重庆医科大学附属第二医院精准医学中心,重庆

收稿日期:2024年4月16日;录用日期:2024年5月13日;发布日期:2024年5月20日

摘要

脓毒血症被定义为由于宿主对感染的反应失调而导致的危及生命的器官功能障碍,作为脓毒症的严重亚型,脓毒性休克是指脓毒症并发了严重的循环、细胞和代谢异常,其死亡率显著增加,是重症监护单元患者管理的重点及难点。本文作者检索了近5年关于脓毒性休克治疗的文献,从脓毒性休克药物和非药物治疗手段的新进展两方面进行全面综述,旨在为临床中脓毒性休克治疗提供新的循证依据。

关键词

脓毒血症,脓毒性休克,药物治疗,研究进展

Advances in the Treatment of Septic Shock

Xue Li1,2, Fan Tang2, Shiwen Jin2, Yu Shao3,Youfan Jiang1*, Tianyang Hu4*

1Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing

2Department I of Internal Medicine Ward, The Third People’s Hospital of Nan’an District, Chongqing

3Department of Gastroenterology, Chongqing Emergency Medical Center (Chongqing University Central Hospital) Chongqing

4Precision Medicine Center, The Second Hospital of Chongqing Medical University, Chongqing

Received: Apr. 16th, 2024; accepted: May 13th, 2024; published: May 20th, 2024

ABSTRACT

Sepsis is defined as life-threatening organ dysfunction due to dysregulation of the host response to infection. As a severe subtype of sepsis, septic shock is sepsis complicated by severe circulatory, cellular, and metabolic abnormalities, which is associated with a significant increase in mortality, and is a major focus and difficulty in the management of patients in intensive care units. In this review, the authors searched the literature on the treatment of septic shock in the last 5 years and conducted a comprehensive review in terms of new advances in both pharmacologic and nonpharmacologic therapeutic means for septic shock, aiming to provide a new evidence-based basis for the treatment of septic shock in the clinic.

Keywords:Sepsis, Septic Shock, Pharmacologic Therapy, Research Advances

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

脓毒血症被定义为宿主对感染反应失调引起的危及生命的器官功能障碍(Sepsis-3) [1] 。在临床实践中,器官功能障碍可以通过序贯器官衰竭评分(Sequential Organ Failure Assessment, SOFA)增加2分或以上来表示,并与高于10%的院内死亡率相关。脓毒性休克被定义为脓毒血症的一个亚型,其特别严重的循环、细胞和代谢异常与单独脓毒血症相比具有更大的死亡风险 [1] 。近年来,脓毒性休克的治疗取得了一系列突破性进展,这对降低其死亡风险有重大意义。本文基于近5年来关于脓毒性休克治疗的文献,从药物和非药物治疗手段两个领域对脓毒性休克的治疗进行全面综述,旨在为临床中脓毒性休克治疗提供新的循证依据。

2. 脓毒性休克的药物治疗新进展

2.1. 液体复苏新观念

静脉注射晶体溶液是脓毒血症的基本治疗方法,但晶体成分对患者预后的影响尚不清楚。Brown等人的一项大型随机试验表明,脓毒性休克患者使用平衡晶体与使用生理盐水相比,30天的住院死亡率较低 [2] 。一项平行组、盲法多中心试验表明,在出现毒性休克的儿中,与0.9%生理盐水相比,使用平衡晶体液体复苏可显着降低住院前7天内新发和/或进行性急性肾损伤的发生率 [3] 。近期一项前瞻性随机对照试验初步研究表明,与常规护理相比,限制性复苏策略可以成功减少严重脓毒血症和脓毒性休克患者的静脉输液量,试验中没有观察到死亡率、器官衰竭或不良事件的增加 [4] 。在另一项全球性随机试验中,脓毒性休克的成年患者静脉输液限制并没有导致90天时的死亡人数少于标准静脉输液治疗 [5] 。

脓毒血症和脓毒性休克是肝硬化患者住院和死亡的常见原因 [6] [7] 。一项单中心进行的开放标签试验表明,与生理盐水相比,人血白蛋白在逆转脓毒血症引起的低血压方面是安全和有益的,可改善肝硬化脓毒血症患者的全身血流动力学、组织灌注和院内短期生存的临床评估参数 [8] 。另一项随机对照试验表明,在肝硬化和脓毒血症引起的低血压患者中,20%白蛋白比血浆溶解剂能更快地改善血流动力学和乳酸清除率,而28天生存率相似 [9] 。

2.2. 血管活性药物

2.2.1. 去甲肾上腺素

在脓毒性休克期间,即使是最严重的患者,通常只有在纠正循环衰竭的低血容量成分后才开始输注血管升压药 [10] 。然而,在某些情况下,应考虑尽早给予去甲肾上腺素,同行液体复苏。早期开始去甲肾上腺素给药的选择应根据患者的情况进行调整。从逻辑上讲,应该首先针对严重低血压的患者,当动脉张力非常低时,如低舒张压(例如≤40 mmHg)或高舒张压休克指数(心率/舒张压) (例如≥3)。对于可能发生液体积聚或液体积聚特别有害的患者(例如,在急性呼吸窘迫综合征或腹内高压的情况下),还应考虑早期给予去甲肾上腺素 [11] 。Permpikul等人的一项II期试验表明早期使用去甲肾上腺素进行脓毒性休克抢救时,早期去甲肾上腺素使用和增加6小时的休克控制显著相关 [12] 。在与多巴胺和多巴酚丁胺相比,去甲肾上腺素在改善老年脓毒血症患者的血流动力学指标、血管弹性和降低炎症因子水平方面效果更好 [13] 。另有临床研究表明,去甲肾上腺素联合乌司他丁治疗脓毒性休克,提高了治疗效率,缩短了休克好转和住院时间,降低了医院死亡率,提高了患者的生存率,安全性较高 [14] 。而去甲肾上腺素中添加特利加压素治疗可改善脓毒性休克患者的肾灌注,增加每搏输出量,并降低去甲肾上腺素剂量和患者心率 [15] 。

2.2.2. 血管紧张素II

一项研究 [16] 表明血管紧张素II在提高分布性休克患者血压方面比安慰剂更有效,同时可保持儿茶酚胺水平恒定。当减少儿茶酚胺用量代替血管紧张素II治疗时,相对于安慰剂,次要终点SOFA总分没有变化。在28天的研究期间,与安慰剂相比,死亡率呈一致下降趋势。根据评估血压影响的特殊方案评估所达成的协议,这项研究的数据支持了美国食品和药物管理局(FDA)批准血管紧张素II在美国上市。

2.2.3. 其他血管活性药物

一项单中心随机对照试验表明,在脓毒性休克患者中,24小时内开始亚甲蓝治疗可以缩短血管加压药停用时间,并增加28天时的无血管加压药天数,并可减少在重症监护单元(ICU)和医院的住院时间,且没有产生不良影响 [17] 。对患有难治性脓毒性休克的早产儿进行亚甲蓝治疗后,全身血管阻力和动脉血压迅速增加,且副作用最小 [18] 。

Adly等人做了一项随机对照临床试验,对象为60名脓毒性休克复苏患者,参与者被随机分为两组:去甲肾上腺素组(静脉注射去甲肾上腺素)和米多君组(静脉注射去甲肾上腺素 + 口服米多君),结果显示米多君组和去甲肾上腺素组,去甲肾上腺素给药的中位持续时间分别为4天和6天(p = 0.001)。与去甲肾上腺素组相比,米多君组去甲肾上腺素撤药时间显著缩短了52.5小时,米多君组和去甲肾上腺素组相比死亡率减少了30%。总之,脓毒性休克患者使用米多君可显着缩短静脉注射去甲肾上腺素的持续时间、脓毒性休克恢复期时间,并降低患者死亡率 [19] 。此外,当米多君添加到静脉升压药中时,可显着加速脓毒性休克患者的乳酸清除 [20] 。

2.3. 抗生素

脓毒血症指南强烈推荐及时的抗菌药物疗和源头控制,尚未发生脓毒性休克的患者可通过早期抗感染治疗获益,抗感染治疗可以防止病情进一步恶化,且充足的抗生素剂量可能会改善危重患者的预后,但由于药代动力学的改变和变化而具有挑战性。一项随机盲法临床试验在伊朗两家医院共136例入住ICU的患者中进行,拟探索延长输注氨苄青霉素/舒巴坦是否让患者获益,如果根据Cockrorft-Gault公式估算的肾小球滤过率高于60 ml/min,参与者将随机接受每8小时一次的9克氨苄西林/舒巴坦延长(输注4小时)或间歇(输注30分钟)静脉输注。结果发现,延长输液组的ICU死亡率和住院死亡率明显低于间歇输液组 [21] 。河南省26家医院的一项随机对照试验纳入了对多粘菌素B敏感的碳青霉烯类耐药革兰氏阴性菌引起的脓毒血症/脓毒性休克患者,患者被随机分为高剂量组或低剂量组,分别接受150 mg负荷剂量/每12 h 75 mg和100 mg负荷剂量/每12 h 50 mg,结果表明每12小时150 mg的固定多粘菌素B负荷剂量和75 mg的维持剂量对于这类者是安全的,并可以改善长期生存 [22] 。

Roggeveen等人开发了一种用于床边、实时、数据驱动和个性化抗生素剂量的决策支持系统:AutoKinetics。在这项随机临床试验中,脓毒血症或脓毒性休克的危重患者被随机分配至Auto Kinetics剂量或标准剂量组,使用了四种抗生素:万古霉素、环丙沙星、美罗培南和头孢曲松用于患者的治疗,结果表明,在危重患者中,个性化给药是可行、安全的,并且可以显着提高环丙沙星的目标实现率 [23] 。该系统为抗生素的合理、有效利用提供了新思路。

2.4. 控制心率药物

2.4.1. 胺碘酮、普罗帕酮

脓毒性休克急性发作的室上性心律失常可导致血流动力学障碍。胺碘酮和普罗帕酮都是可用的干预措施,而一项双中心、前瞻性对照平行组双盲试验表明,与胺碘酮相比,普罗帕酮不能提供更好的24小时心律控制,但可以提供更快的心脏复律和更少的心律失常复发,特别是对于左心房未扩张的患者 [24] 。

2.4.2. 艾司洛尔

一项前瞻性随机对照试验表明,脓毒性休克患者心动过速明显增加死亡风险,艾司洛尔可通过控制心率降低死亡率 [25] 。另一项单中心前瞻性随机对照研究也表明,在脓毒血症性肌病患者中,应用艾司洛尔降低心率可降低其短期死亡率,同时不损害心肌收缩力 [26] ,但并没有改善血管收缩剂的要求或休克逆转的时间 [27] 。此外,一项多中心、开放标签、随机对照试验提示,兰地洛尔使更多脓毒血症相关快速心律失常患者在24小时心率达到60~94 bpm,并显着降低新发心律失常的发生率。兰地洛尔的耐受性也良好,但由于脓毒血症和脓毒性休克患者存在低血压风险,因此应在适当监测血压和心率的情况下使用 [28] 。

2.4.3. 伊伐布雷定

脓毒性休克患者持续性心动过速预示不良预后。肠内伊伐布雷定能有效降低脓毒性休克和持续性心动过速患者的心率,改善血流动力学参数和心功能,而不增加不良事件的发生率 [29] 。

2.5. 激素

氢化可的松、维生素C和维生素B1的组合治疗已被提议作为败血症和败血症休克患者的潜在治疗方法。与氢化可的松单药治疗相比,三药联用治疗脓毒性休克可显著缩短休克解除的时间 [30] ,减少血管升压药的使用时间和休克持续时间方面显示出显著的效果 [31] ,但在降低院内死亡率或28/30天死亡率方面没有显著效果,故早期使用三联疗法并未带来生存益处 [32] 。同时,三联疗法在治疗中还观察到血管加压药使用量减少和乳酸清除速度加快 [33] 。此外,一项随机对照、开放性试验表示,与连续输注相比,间歇性推注氢化可的松与第7天较高的休克反转有关 [34] 。再者,持续输注氢化可的松并没有导致脓毒性休克的90天死亡率下降 [35] 。

2.6. 营养支持

有关ICU循环休克患者肠内营养实践的时机和有效性的现实证据有限。一个来自国际多中心实用随机临床试验的数据集分析,在患有循环性休克机械通气患者(该研究中55%的患者合并脓毒性休克)中,与延迟肠内营养相比,早期肠内营养与改善临床结果相关(包括无需血管活性药物天数增加、更多存活天数和需要更短的机械通气时间等等),但在调整疾病严重程度后不再相关 [36] 。因此在脓毒性休克亚组中,营养支持的确切作用仍有待探索。

2.7. 抗凝治疗

一项前瞻性随机对照临床试验研究结果表明,在严重脓毒血症/脓毒性休克患儿出现明显弥漫性血管内凝血分期之前,在“机会窗”内早期使用冰冻血浆输血、低剂量肝素和氨甲环酸联合治疗与更好的生存结果和预防进展为明显弥漫性血管内凝血病有关,而不增加出血风险 [37] 。此外,重组人可溶性血栓调节蛋白是一种用于治疗弥散性血管内凝血的新型治疗剂。脓毒性休克时严重呼吸衰竭的进展可能与肺泡内凝血/纤溶障碍有关。日本一项回顾性研究表明,给与重组人可溶性血栓调节蛋白治疗与脓毒血症合并严重呼吸衰竭患者死亡率的降低呈正相关 [38] 。

2.8. 其他药物

2.8.1. 左西孟旦

在一项前瞻性、单盲、随机对照研究表明,与多巴酚丁胺相比,左西孟旦在改善重症脓毒血症/脓毒性休克心肌病患者心功能、减少心肌损伤、缩短机械通气时间方面更有效 [39] 。

2.8.2. 心脉隆注射液

脓毒血症引起的心肌功能障碍对脓毒血症休克期间的心血管功能障碍有显着影响。一项多中心、随机、双盲、平行组试验表明,对患者注射心脉隆注射液比安慰剂更有效地降低舒张期脓毒血症引起的心肌功能障碍的发生率,同时心脉隆注射液组对血清脑利钠肽浓度的改善也更有效。因此,心脉隆注射液可以有效且安全地改善脓毒血症/脓毒性休克患者的心功能 [40] 。

2.8.3. 血必净

研究表明,联合血必净治疗脓毒性休克可在一定程度上减轻机体炎症反应,从而减少机械通气时间、缩短ICU住院时间、降低住院总费用,但无法降低脓毒性休克患者的28天死亡率 [41] 。

2.8.4. 利尿合剂

有研究报道,小剂量呋塞米和氨茶碱对脓毒性休克患者肾功能的保护作用虽较差,但可缩短连续性肾脏替代治疗(Continuous Renal Replacement Therapy, CRRT)时间,并改善患者预后 [42] 。

2.8.5. 山莨菪碱

山莨菪碱是从中药中提取的一种具有较强抗炎作用的药物。一个前瞻性的、多中心的随机对照试验表明,山莨菪碱可作为脓毒性休克患者常规治疗的重要辅助手段,降低患者28天死亡率 [43] 。

2.8.6. 乌司他丁

一项随机对照试验表明,乌司他丁联合常规治疗能明显控制肝脓肿合并脓毒性休克患者的感染症状,改善器官功能并缩短治疗时间 [44] 。

2.8.7. 抗氧化药物

研究表明,维生素 E、褪黑激素等抗氧化药物治疗与标准治疗相结合可降低脓毒性休克患者的多器官功能衰竭、氧化应激和炎症等,改善患者预后 [45] 。

3. 脓毒性休克的非药物治疗

3.1. 血液净化

通过清除血液中的炎症介质,可以提高脓毒性休克患者的细胞免疫功能,血液净化可以改善脓毒性休克患者的血流动力学。一项随机对照试验表明,对于未达到6小时初始恢复目标和/或液体超负荷 > 10%的脓毒性休克患儿,早期血液净化治疗可快速控制病情、缩短病程、加速免疫重建 [46] 。CRRT是治疗脓毒性休克相关急性肾损伤的良好治疗方法,可改善生化指标并保护肾功能 [47] 。一项临床试验研究报告,其使用oXiris®膜治疗需要CRRT的脓毒性休克患者的经验,对于最严重的患者,观察到的生存率高于根据严重程度评分(SAPS II)预测的生存率,血流动力学状态和乳酸血症也有所改善,尤其是腹内脓毒血症和革兰氏阴性菌感染 [48] 。使用oXiris®膜还可以改善合并急性肾损伤的严重手术脓毒性休克患者初始CRRT期间的血流动力学状态 [49] 。一项单中心交叉随机研究,在脓毒性休克和严重急性肾损伤患者中,中截留量连续静脉–静脉血液透析(MCO-CVVHD)与高通量膜连续静脉–静脉血液透析滤过(CVVHDF)清除尿毒症毒素的效果相当。此外,MCO-CVVHD与血流动力学改善相关 [50] 。

其他研究发现,急诊绿色通道下应用胸腺肽α1联合血液净化可有效改善脓毒血症/脓毒性休克患者免疫功能和心肌功能,减轻炎症反应,为脓毒性休克患者的有效治疗提供了更大的保障 [51] 。体外血液灌流可以通过靶向细胞因子或细菌内毒素(如脂多糖/LPS)来改善脓毒性休克患者的病程和结果。一项多中心随机对照试验结果表明,靶向LPS进行体外血液灌流是一种安全的方法,可消除腹腔内脓毒血症患者的脓毒性休克,并使临床和病理相关生物标志物正常化 [52] 。

3.2. 辅助治疗技术

在脉搏指示连续心排血量监测(Pulse index Continuous Cardiac Output, PiCCO)技术的监测和指导下,可以改善心肌损伤合并脓毒性休克患者的护理效果、生存率和预后 [53] 。经腹超声联合PiCCO能够更好地指导脓毒性休克患者的液体复苏,对脓毒性休克患者的生存结局具有一定的预测价值 [54] 。

在脓毒性休克的初始复苏过程中,优化左心室–动脉耦合与乳酸清除率的改善相关,同时可能对预后产生有益影响。与传统的快速补液相比,床旁经胸壁超声(Transthoracic Echocardiography, TTE)监测被动抬腿试验指导的早期液体复苏治疗策略能够更好地改善组织器官的灌注和氧合水平,避免快速补液引起的肺水肿,缩短脓毒性休克患者的住院时间,但研究发现对其医院死亡率没有显着影响 [55] 。

3.3. 神经肌肉电刺激

研究发现,早期穴位电刺激可改善重症监护病房获得性无力脓毒性休克患者下肢肌肉衰退情况 [56] 。神经肌肉电刺激作为预防重症监护病房获得性无力的新的治疗方案,在脓毒血症/脓毒性休克患者中取得了良好的效果 [57] 。

4. 小结与展望

本文综述了近年来对于脓毒性休克治疗进展,为患者的治疗提供了大量的临床循证依据。随着近年来诊断和治疗的技术进步,脓毒血症/脓毒性休克的死亡率逐渐下降,但由于人口老龄化和脓毒血症/脓毒性休克发病率不断上升,加上人们越来越认识到的脓毒血症/脓毒性休克所致的长期身体、心理和认知障碍,表明脓毒血症/脓毒性休克造成了日益严重的公共卫生问题。虽然早期识别和改善急性发作的管理会带来好处,但要大幅减轻脓毒血症/脓毒性休克相关疾病的负担,需要整个医疗系统采取行动。

在当前大数据时代,大数据将成为医疗健康领域的重要推动力量,基于大数据寻求脓毒性休克的最佳治疗测量已成为可能。通过利用大数据技术对脓毒性休克患者的医疗数据进行深入的分析和挖掘,可以发现新的规律和知识,为疾病的预防和治疗提供更加准确和个性化的方案。同时,当前我们已处在人工智能的背景下,人工智能在医疗领域的应用和发展已经开始改变医疗服务的格局和形式。通过人工智能技术,结合影像组学等多模态数据,对于脓毒性休克患者的医疗服务可以更加精准和高效,提高了患者诊断和治疗的准确性和效率。这些先进技术或许在未来可为脓毒性休克患者的治疗提供更为精准而高效的服务。

基金项目

重庆市科学技术局重庆市自然科学基金博士后项目(CSTB2023NSCQ-BHX0001,基于机器学习算法的脓毒性休克预后预测模型的建立与应用研究)与安徽省呼吸系病临床基础省重点实验室自主选题项目(HX2023Z02, 脓毒症相关急性呼吸窘迫综合征预后预测模型的建立与应用)。

文章引用

李 雪,唐 帆,金仕文,邵 宇,蒋幼凡,胡天洋. 脓毒性休克治疗的新进展
Advances in the Treatment of Septic Shock[J]. 临床医学进展, 2024, 14(05): 1079-1087. https://doi.org/10.12677/acm.2024.1451528

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  58. NOTES

    *通讯作者。

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