Levosimendan

治疗急性肾损伤的新药 New drugs for acute kidney injury Citation: Hariri G, Legrand M. New drugs for acute kidney injury. J Intensive Med. 2024;5(1):3–11. doi: 10.1016/j.jointm.2024.08.001. 核心结论 急性肾损伤（AKI）在重症及围术期患者中发病率高达30%-60%，目前仍无高级别证据支持的预防或治疗药物。本文系统综述了基于最新病理生理机制（炎症应答、代谢重编程、血流动力学调节、补体活化及细胞凋亡/修复）的在研新药，涵盖碱性磷酸酶、Reltecimod、血管紧张素II、维生素B3类、CD39重组蛋白、Ravulizumab、siRNA QPI-1002及间充质干细胞等。多项II/III期临床试验正在评估其疗效，为降低AKI发生率及严重程度带来新希望。 正文 急性肾损伤（AKI）是全球性健康问题，每年影响超过1300万人，并导致约170万例死亡[1]。从病理生理角度看，AKI以肾小球滤过率（GFR）快速下降为特征，数小时或数日内表现为血清肌酐急剧升高。2004年之前由于缺乏统一定义，AKI的诊断标准从轻度肌酐升高至需要肾脏替代治疗（RRT）范围广泛[2]。RIFLE、AKIN及KDIGO分级系统的建立，依据血清肌酐和尿量变化提供了结构化诊疗路径，实现了早期识别与干预[3-5]。在重症监护环境中，AKI发病率异质性较大（15%-60%），且与死亡率升高、住院时间延长及慢性肾脏病（CKD）风险增加密切相关[6-8]。尽管过去二十年危重症患者管理取得显著进步，但预防或治疗AKI的有效药物干预仍十分缺乏。近期对AKI病理生理机制的深入理解揭示了炎症、代谢紊乱及细胞修复障碍等共同通路，为新型药物研发提供了方向（图1，表1）。 图1：重症及围术期急性肾损伤预防或治疗新药的作用机制概览。HGF: 肝细胞生长因子；MSC: 间充质干细胞。 基于上述机制，目前处于研发阶段的药物涵盖了免疫调节、血流动力学优化、细胞能量代谢支持、补体抑制及抗凋亡/促修复等多个维度。下文按照靶点分类逐一阐述代表性药物的临床证据。1. 炎症调控 碱性磷酸酶（ALP）可通过去磷酸化脂多糖（LPS）及胞外ATP/ADP，减轻Toll样受体介导的先天免疫反应。STOP-AKI试验（n=301）中，重组ALP（ilofotase alfa）虽未改善7天肾功能，但28天肌酐清除率提升18.5 mL/min（95%CI: 5.3-31.7），死亡率降低（14.4% vs 26.7%）[18]。然而后续III期REVIVAL试验（n=655）未显示28天全因死亡率获益，但MAKE90复合终点（56.7% vs 64.6%, P=0.02）提示可能降低RRT需求[19]。针对CSA-AKI的II期预防试验（NCT06168799）正在进行。 Reltecimod是一种靶向T细胞表面CD28的肽类，可调节脓毒症免疫应答。在坏死性软组织感染III期试验中虽未达到主要复合终点，但第14天SOFA评分改善（65.1% vs 52.6%, P=0.04）[24]。目前针对KDIGO 2-3期AKI合并腹腔脓毒症的III期试验（NCT03403751）正在评估28天AKI恢复率。 活性维生素D（骨化三醇）可通过下调核因子κB减轻炎症。但ACTIVATE-AKI试验（NCT02962102）未显示7天内死亡或RRT需求的显著差异。RBT-1（锡原卟啉+蔗糖铁）通过上调HO-1、铁蛋白发挥预适应保护，PROTECT III期研究（n=400）正在进行，主要终点为死亡、透析需求、ICU住院日及30天再入院复合指标。 TIN816（重组CD39）可水解胞外ATP/ADP，抑制炎症及血小板聚集。针对SA-AKI的II期试验（NCT05996835）以第1-8天时间校正肌酐清除率曲线下面积为主要终点；CSA-AKI预防试验（NCT05524051）计划纳入120例患者。2. 血流动力学调节 血管紧张素II选择性收缩肾出球小动脉，提升GFR。ATHOS-3试验显示，血管紧张素II显著提高顽固性血管扩张性休克患者3小时平均动脉压（69.9% vs 23.4%, OR=7.95）[46]，且在需RRT的亚组中28天生存率更高（53% vs 30%）[47]。预防CSA-AKI的可行性研究提示AKI发生率降低（25% vs 38%, P=0.31），III期试验（NCT05199493）正在开展。 血管加压素：心脏术后血管麻痹性休克患者中，血管加压素较去甲肾上腺素显著降低CSA-AKI（10.3% vs 35.8%, P<0.0001）[52]；但在脓毒性休克中未显示AKI预防获益。个体患者数据Meta分析提示可能降低RRT需求（RR=0.86）。两项RCT（NCT04602767, NCT06125184）将进一步明确。 左西孟旦：钙增敏剂兼有入球小动脉扩张作用。心脏手术Meta分析显示可减少CSA-AKI（OR=0.51）及RRT（OR=0.43），但大型RCT未证实获益[57]。LEVO-AKI试验（NCT02531724）正在评估已发生CSA-AKI的治疗效果。3. 细胞代谢与线粒体功能 维生素B3类（烟酰胺、烟酰胺核糖）通过补充NAD+保护肾小管。心脏手术II期试验显示烟酰胺使AKI发生率降低35%[59]。多项RCT正在验证其预防CSA-AKI（NCT04750616）、肾移植后移植物功能（NCT05513807）及脓毒性休克相关AKI（NCT04589546）的疗效。ASP1128（PPARδ调节剂）在心脏手术高危患者中未减少AKI发生率（24.6% vs 21%, P=0.595）[62]。SIRT1激活剂NRPT（烟酰胺核糖+紫檀芪）II期试验（NCT04342975）正在主动脉弓置换患者中评估预防效果。 表1：重症及围术期急性肾损伤预防/治疗新药汇总 药物 机制 靶点 相关临床试验 研究人群 Angiotensin II 血流动力学 肾出球小动脉 NCT05199493 预防CSA-AKI Angiotensin II 血流动力学 肾出球小动脉 NCT04592744 肝移植后AKI预防 Angiotensin II 血流动力学 肾出球小动脉 NCT04901169 肝移植后AKI预防 Vasopressin 血流动力学 V1a受体 NCT04602767 预防CSA-AKI Vasopressin 血流动力学 V1a受体 NCT06125184 预防SA-AKI(脓毒性休克) Levosimendan 血流动力学/正性肌力 肾入球小动脉 NCT02531724 CSA-AKI治疗 Reltecimod 免疫调节 CD28 NCT03403751 SA-AKI(腹腔脓毒症) Activated vitamin D 免疫调节 NF-κB NCT02962102 高危患者AKI预防 ALP (Ilofotase alfa) 免疫调节 TLR-4/LPS NCT06168799 预防CSA-AKI RBT-1 缺血预适应 HO-1/铁蛋白 PROTECT study 预防CSA-AKI TIN816 ATP/ADP水解 CD39 NCT05996835 SA-AKI TIN816 ATP/ADP水解 CD39 NCT05524051 预防CSA-AKI Vitamin B3 (Nicotinamide) 细胞代谢 NAD+合成 NCT04750616 预防CSA-AKI Nicotinamide 细胞代谢 NAD+ NCT05513807 肾移植后移植物功能延迟 NR (Nicotinamide riboside) NAD+前体 SIRT1 NCT04818216 COVID-19相关AKI ASP1128 PPARδ激动剂 脂肪酸氧化 II期(已停止) CSA-AKI高危 NRPT (NR+Pterostilbene) SIRT1激活 NAD+/SIRT1 NCT04342975 主动脉弓置换后AKI预防 Ravulizumab 补体C5抑制剂 C5 NCT05746559 预防CSA-AKI siRNA QPI-1002 抗凋亡 p53 NCT02610296 肾移植后移植物功能延迟 HGF-mimetic (BB3) 细胞修复/抗凋亡 cMet/Bcl-2 NCT02771509 预防CSA-AKI Mesenchymal Stem Cells 免疫调节/修复 多靶点 NCT04445220 COVID-19合并RRT Umbilical cord MSC 组织修复 多靶点 NCT04194671 AKI治疗 补体抑制剂Ravulizumab（长效C5单抗）在COVID-19相关AKI的小样本试验中显示透析需求降低（P=0.03），III期ARTEMIS试验（NCT05746559）正在心脏手术CKD患者中验证其预防CSA-AKI的效果。4. 凋亡抑制与细胞修复 siRNA药物QPI-1002（靶向p53）在心脏手术高危患者中使AKI发生率降低13%（37% vs 50%, P=0.02）[75]，但MAKE90无差异；III期预防试验因无效而终止。HGF模拟物BB3在肾移植后未改善360天eGFR（P=0.32）[80]，GUARD试验（NCT02771509）正在评估其对CSA-AKI的预防效果。间充质干细胞（MSC）在CSA-AKI的II期试验中未显示获益，但体外扩增MSC可能具有免疫修复潜力，相关试验仍在进行（NCT04445220, NCT04194671）。 综上所述，目前尚无获批的AKI特效药，但基于精准病理生理靶点的多种药物已进入后期临床试验阶段，为改善重症及手术患者AKI结局带来了切实希望。 参考文献 Mehta R.L., Cerdá J., Burdmann E.A., Tonelli M., García-García G., Jha V., et al. 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Stem Cell Transl Med. 2021;10:1588–1601. doi: 10.1002/sctm.21-0043. 如果这篇文献综述对您的临床工作有所帮助，欢迎点击文末的“赞”与“推荐(小爱心)”，或转发分享至科室群，让更多同道看到本文；也期待您在留言区留下宝贵见解，与我们交流临床实践中的类似挑战。 【 获取完整版原文 】 请点击左下角 「阅读原文」 下载完整 PDF 文件。

静脉泵入给药技术凭借剂量精准可控、起效迅速及时、调节便捷灵活以及血药浓度稳定持久等显著优势，已确立为现代临床急救、重症监护（ICU）及各专科疾病规范化治疗的核心给药方式。从心血管内科的血压心率调控，到急诊科的休克复苏，再到消化内科的止血抑酸、神经科的癫痫持续状态处理，静脉泵入技术广泛应用于多学科危急重症的救治一线。然而，该技术的高风险性同样不容忽视：药物的规范配制是否严谨、泵速滴定是否精准、给药途径选择是否得当，以及用药全程的监护是否严密，直接决定了治疗的成败与患者的生命安全。任何细微的操作失误或监测疏忽，都可能引发低血压休克、恶性心律失常、呼吸抑制甚至死亡等严重后果。因此，掌握静脉泵入药物的标准化操作流程与核心监护要点，是每一位临床医护人员必须夯实的基本功。 鉴于此，我们系统梳理并汇总了临床中高频使用静脉泵入药物，旨在为一线医护提供一份科学、客观、可落地的实操指南。我们将这些药物科学划分为六大类别：降压调心率类、抗心律失常类、扩血管改善心肌循环类、正性肌力与血管活性类、消化科止血抑酸利尿类，以及降糖镇静解毒类。针对每一种药物，本文详细解析了其规格属性、标准配制方案（明确溶媒选择与浓度计算）、精准用法用量（包含基于体重的换算实操示例与剂量滴定原则），并重点阐述了临床核心注意事项，涵盖不良反应的识别与处理、给药途径的特殊要求、严格的配伍禁忌及特定禁忌人群筛查。所有内容均严格依据最新药品说明书及权威临床诊疗指南制定，力求数据准确、逻辑清晰。需要强调的是，临床实际应用必须结合患者的年龄、体重、病情严重程度、合并症情况及药物过敏史进行个体化调整。(一)降压、调心率类药物 此类药物是高血压急症、危象及围手术期血流动力学调控的核心手段，涵盖硝普钠、艾司洛尔、地尔硫卓和乌拉地尔等关键品种。它们通过扩张血管、阻断β受体或抑制钙离子内流等不同机制，迅速降低外周阻力、减慢心率并改善心肌供氧，从而在数分钟至数小时内稳定患者生命体征。临床应用中必须严格遵循“小剂量起始、逐步滴定”的原则，依据患者体重及实时血压、心率反应精细调整泵速，既要避免因降压过快导致脑灌注不足或心肌缺血，又要防止剂量不足延误救治，确保治疗的安全性与有效性。 在具体操作层面，每种药物均有独特的配制要求、监测重点及禁忌人群，需医护人员高度警惕。例如，硝普钠需全程避光以防氰化物中毒，艾司洛尔强调负荷量与维持量的无缝衔接，地尔硫卓严禁与葡萄糖配伍且需注意房室传导阻滞风险，而乌拉地尔则需防范体位性低血压。所有药物在使用过程中均需持续监测心电图及有创或无创血压，一旦出现严重低血压、心动过缓或传导阻滞等不良反应，应立即减量或停药并给予对症处理，严禁突然停药以免引起病情反跳，同时对于肝肾功能不全、妊娠及特定心脏传导障碍患者需严格筛选适用人群。 表1. 高血压急症核心用药对比 (二)抗心律失常类药物 此类药物是纠正室上性及室性快速性心律失常、治疗严重心动过缓及传导阻滞的关键手段，涵盖胺碘酮与异丙肾上腺素等核心品种。它们通过抑制心肌自律性、减慢传导速度或激动β受体增强传导等不同机制，旨在恢复窦性心律或维持有效的心室率，从而保障心脏泵血功能。临床应用中必须严格遵循“负荷剂量+维持剂量”的给药原则，依据患者实时心电图反应精细调整泵速，既要迅速控制恶性心律失常，又要高度警惕药物本身可能诱发的新发心律失常（如尖端扭转性室速或室性早搏），确保在纠正心律紊乱的同时不加重心脏负担。 在具体操作层面，两类药物的配制规范与监测重点截然不同，需医护人员严格执行。胺碘酮作为广谱抗心律失常药，严禁使用生理盐水配制以防沉淀，必须全程使用5%葡萄糖溶液，且需密切监测QT间期及甲状腺功能，防止长期用药导致的肺纤维化等严重不良反应；而异丙肾上腺素主要用于提升心率，需严格控制滴速以避免心率过快诱发心肌缺血或室性心律失常，且禁用于冠心病及心肌梗死患者。所有药物在使用过程中均需持续心电监护，一旦出现严重低血压、传导阻滞恶化或新发恶性心律失常，应立即停药并给予电复律、阿托品或拮抗剂等对症处理，同时注意药物间的相互作用，如胺碘酮与华法林合用需大幅调整抗凝剂量。 表2. 高血压急症核心用药对比 (三)扩血管、改善心肌循环类药物 此类药物是冠心病、心绞痛及急性心力衰竭治疗的核心手段，涵盖硝酸甘油、硝酸异山梨酯和左西孟旦等关键品种。它们通过释放一氧化氮扩张冠脉及全身血管，或通过钙离子增敏机制增强心肌收缩力并降低心脏前后负荷，从而迅速改善心肌供血供氧、缓解心绞痛症状并提升心功能。临床应用中必须严格遵循“小剂量起始、逐步滴定”的原则，依据患者实时血压、心率及症状反应精细调整泵速，既要避免因降压过快导致冠状动脉灌注不足而加重心肌缺血或引发脑供血障碍，又要防止剂量不足延误救治，确保在改善血流动力学的同时维持器官灌注安全。 在具体操作层面，每种药物均有独特的配制规范、容器要求及禁忌症，需医护人员高度警惕。例如，硝酸甘油具有极强的塑料吸附性，必须使用玻璃瓶配合专用非吸附输液器以防药效减半；左西孟旦则需严格依据血压决定是否给予负荷剂量，低血压患者严禁静推以免诱发休克；硝酸异山梨酯作为长效制剂，需注意预防耐药性并采取偏心给药策略。所有药物在使用过程中均需持续监测心电图及有创或无创血压，一旦出现严重低血压、反射性心动过速或心律失常等不良反应，应立即减量或停药并给予补液、升压等对症处理，同时对于青光眼、颅内高压及严重低血压患者需严格筛选适用人群。 表3. 冠心病与心力衰竭核心用药对比 (四)正性肌力、血管活性类药物 此类药物是感染性休克、心源性休克及急性心力衰竭抢救的生命线，涵盖米力农、多巴胺及多巴酚丁胺等关键品种。它们通过抑制磷酸二酯酶或激动不同肾上腺素能受体，发挥增强心肌收缩力、调节血管张力（收缩或扩张）及改善肾灌注等多重作用，从而迅速提升心输出量、纠正严重低血压并恢复器官灌注。临床应用中必须严格遵循“个体化滴定”原则，依据患者的血流动力学状态（如血压、心率、尿量、中心静脉压）精准调整剂量：米力农需警惕负荷剂量引发的低血压，多巴胺则需根据治疗目标（扩肾血管、强心或升压）严格区分剂量范围，既要避免因剂量不足导致休克难以纠正，又要防止剂量过大诱发恶性心律失常或组织缺血坏死。 在具体操作层面，给药途径的安全性与监测的实时性是救治成功的关键。由于多巴胺/多巴酚丁胺具有极强的血管刺激性，优先选择中心静脉输注，若必须经外周给药需严防药液外渗，一旦发生应立即使用酚妥拉明局部封闭以防皮肤坏死；米力农虽刺激性较小，但连续使用需监测血小板及肝功能。所有药物在使用过程中均需持续监测有创血压、心电图及尿量，出现严重低血压、心动过速或室性心律失常时应立即减量或停药，并给予补液扩容、抗心律失常等对症处理。此外，需注意药物间的协同与拮抗作用，如与洋地黄合用易致心律失常，与硝酸酯类合用需防血压骤降，对于肥厚型梗阻性心肌病、严重心律失常及甲状腺功能亢进患者应严格禁用或慎用。 表4. 休克与心力衰竭急救核心用药对比 (五)消化科止血、抑酸、利尿类药物 此类药物是上消化道出血、急性胰腺炎及急性心力衰竭伴水肿救治的关键手段，涵盖重组人脑利钠肽、呋塞米、垂体后叶素、艾司奥美拉唑、奥曲肽及生长抑素等核心品种。它们通过利钠利尿降低心脏负荷、强力抑制胃酸分泌以稳定血凝块、收缩内脏血管降低门脉压力或扩张全身血管改善心功能等多重机制，迅速控制出血、缓解水肿并稳定血流动力学。临床应用中必须严格遵循个体化滴定原则，依据患者实时尿量、电解质、血压、出血症状及门脉压力变化精细调整剂量：利尿剂需严防低钾低钠诱发心律失常，止血药需警惕血管过度收缩导致心肌缺血或血压骤升，而脑利钠肽则需密切监控低血压风险，确保在纠正病理状态的同时维持内环境稳定。 在具体操作层面，每种药物均有独特的配制规范、给药连续性要求及禁忌症，需医护人员高度警惕。例如，生长抑素半衰期极短，换药间隔严禁超过1分钟以防出血反跳；艾司奥美拉唑严禁使用葡萄糖配制且需注意与氯吡格雷的相互作用；垂体后叶素因强烈收缩血管，严禁用于高血压、冠心病及妊娠期妇女；重组人脑利钠肽与呋塞米联用时需大幅减量以防严重低血压和电解质紊乱。所有药物在使用过程中均需持续监测生命体征及实验室指标，一旦出现严重低血压、恶性心律失常、过敏休克或止血失败等情况，应立即停药并给予补液、升压、抗过敏或更换治疗方案等对症处理，确保救治安全有效。 表5. 消化急症与心衰利尿止血核心用药对比 (六)降糖、镇静、解毒类药物 此类药物涵盖血糖调控、镇静镇痛及中毒解救三大领域，主要应用于高血糖急症、ICU与手术镇静、癫痫持续状态以及阿片类或急性酒精中毒等危急重症。临床用药需高度关注患者的血糖波动、镇静深度、意识水平及呼吸状况，通过精准把控剂量来规避低血糖、镇静过深、呼吸抑制及解毒不彻底等风险。其中，胰岛素用于快速降糖但需严防低血糖与低血钾；咪达唑仑与地西泮虽能有效镇静抗惊厥，但需警惕呼吸抑制及依赖性，且地西泮严禁稀释；纳络酮作为特异性拮抗剂，能迅速逆转中枢抑制，但需注意诱发戒断反应及血压心率波动。 在具体执行中，各类药物均有严格的配制与监测要求：胰岛素需按体重计算泵速并每小时监测血糖，配合补液与补钾；咪达唑仑采用“负荷+维持”给药，依据Ramsay评分滴定，过量可用氟马西尼解救；地西泮必须原液输注以防结晶，推注过快易致心跳骤停，需备齐急救设备；纳络酮则需根据中毒类型调整负荷与维持剂量，密切观察瞳孔与呼吸恢复情况，防止症状反复。所有药物在配制后均需在24小时内使用完毕（地西泮除外，因其不配制），且多数需单独通路输注，确保用药安全有效。 表6. 降糖、镇静、解毒核心用药对比 (七)总结 综上所述，静脉泵入技术作为危急重症救治的核心手段，其疗效与风险高度依赖于剂量的精准调控。本文系统解析的十种精神及相关急救药物，均呈现显著的剂量依赖性药理特征：微小剂量差异即可导致治疗窗内的疗效突变或窗外的毒性反应。临床实践必须严格遵循个体化滴定原则，依托实时血流动力学及生化监测，动态平衡获益与风险。临床实践中，需夯实标准化操作功底，警惕配伍禁忌与不良反应，确保在复杂病理状态下实现给药方案的科学优化，最终保障患者生命安全与治疗质量。 参考文献： [1] Roydhouse SA, Carland JE, Debono DS, Baysari MT, Reuter SE, Staciwa AJ, Sandhu APK, Day RO, Stocker SL. Accuracy of documented administration times for intravenous antimicrobial drugs and impact on dosing decisions. Br J Clin Pharmacol. 2021 Nov;87(11):4273-4282. doi: 10.1111/bcp.14844. [2] Dondelinger R. Intravenous pumps. Biomed Instrum Technol. 2014 May-Jun;48(3):211-5. doi: 10.2345/0899-8205-48.3.211. [3] Trim JC, Roe J. Practical considerations in the administration of intravenous vasoactive drugs in the critical care setting: the double pumping or piggyback technique-part one. Intensive Crit Care Nurs. 2004 Jun;20(3):153-60. doi: 10.1016/j.iccn.2004.02.006. 作者介绍：Ketty，主要从事药物研发和科普，制药行业政策和发展研究工作。 立即扫码加入药事纵横交流群