袢利尿剂与噻嗪类利尿剂诱导的电解质并发症的时间进程Authors:https://search.uptodate.live/contents /zh-Hans/time-course-of-loop-and-thiazide-diuretic-induced-electr olyte-complications/contributorsDCraigBrater,MDhttps://search. uptodate.live/contents/zh-Hans/time-course-of-loop-and-thiazide-d iuretic-induced-electrolyte-complications/contributorsDavidHEll ison,MD,FASN,FAHASectionEditors:https://search.uptodate.live/ contents/zh-Hans/time-course-of-loop-and-thiazide-diuretic-induce d-electrolyte-complications/contributorsRichardHSterns,MDhttps ://search.uptodate.live/contents/zh-Hans/time-course-of-loop-and- thiazide-diuretic-induced-electrolyte-complications/contributorsM ichaelEmmett,MDDeputyEditor:https://search.uptodate.live/conte nts/zh-Hans/time-course-of-loop-and-thiazide-diuretic-induced-ele ctrolyte-complications/contributorsJohnPForman,MD,MSc翻译:https ://search.uptodate.live/contents/zh-Hans/time-course-of-loop-and- thiazide-diuretic-induced-electrolyte-complications/contributors余 永武,副主任医师https://search.uptodate.live/contents/zh-Hans/time-cours e-of-loop-and-thiazide-diuretic-induced-electrolyte-complications /contributor-disclosureContributorDisclosures我们的所有专题都会依据新发表的证据和h ttps://www-uptodate-cn--bjmu.naihes.cn/home/%E7%BC%96%E8%BE%91%E5 %8E%9F%E5%88%99同行评议过程而更新。文献评审有效期至:?2020-11.?|?专题最后更新日期:?2019-09-1 1.Thereisanewerversionofthistopicavailablein?https://sea rch.uptodate.live/contents/time-course-of-loop-and-thiazide-diure tic-induced-electrolyte-complications?search=%E5%88%A9%E5%B0%BF%E 5%89%82&source=Out+of+date+-+zh-HansEnglish.该主题有一个新的https://searc h.uptodate.live/contents/time-course-of-loop-and-thiazide-diureti c-induced-electrolyte-complications?search=%E5%88%A9%E5%B0%BF%E5% 89%82&source=Out+of+date+-+zh-Hans英文版本。引言袢利尿剂或噻嗪类利尿剂治疗可能导致各种体液和电解 质并发症,包括容量不足、氮质血症、低钾血症、代谢性碱中毒、低钠血症、高尿酸血症和低镁血症[https://search.uptod ate.live/contents/zh-Hans/time-course-of-loop-and-thiazide-diuret ic-induced-electrolyte-complications/abstract/11]。此外,保钾利尿剂(https: //search.uptodate.live/contents/zh-Hans/92480?search=%E5%88%A9%E5 %B0%BF%E5%89%82&topicRef=2356&source=see_link阿米洛利、https://search. uptodate.live/contents/zh-Hans/92478?search=%E5%88%A9%E5%B0%BF%E5 %89%82&topicRef=2356&source=see_link氨苯蝶啶和盐皮质激素受体拮抗剂)可引起高钾血症和代谢性酸中 毒,而碳酸酐酶抑制剂(如,https://search.uptodate.live/contents/zh-Hans/92684? search=%E5%88%A9%E5%B0%BF%E5%89%82&topicRef=2356&source=see_link乙 酰唑胺)可引起低钾血症和代谢性酸中毒。目前尚不太清楚的是这些并发症发生的时间进程,得到最多研究的是袢利尿剂和噻嗪类利尿剂相关并发症 的时间进程。假定利尿剂剂量和膳食溶质(如,钠和钾)及水的摄入量相对恒定,且患者的血流动力学稳定,如果会出现上述并发症,则大多数会发 生在治疗后的前2-3周(https://search.uptodate.live/contents/zh-Hans/image?i mageKey=NEPH%2F74940&topicKey=NEPH%2F2356&search=%E5%88%A9%E5%B0% BF%E5%89%82&source=see_link图1)[https://search.uptodate.live/cont ents/zh-Hans/time-course-of-loop-and-thiazide-diuretic-induced-el ectrolyte-complications/abstract/1-31-3]。有此时间限制的原因是最初的溶质和水丢失会导致代偿 性变化,从而限制进一步的丢失。因此,在溶质和水丢失的初始阶段后,一个新的稳定状态出现了,即溶质和水的摄入量与排泄量大致相当,与利尿 剂治疗使用之前的状态一样。这种现象称为利尿剂制动(diureticbraking)。(参见https://search.upto date.live/contents/zh-Hans/general-principles-of-disorders-of-wat er-balance-hyponatremia-and-hypernatremia-and-sodium-balance-hypo volemia-and-edema?sectionName=%E7%A8%B3%E5%AE%9A%E7%8A%B6%E6%80%8 1&search=%E5%88%A9%E5%B0%BF%E5%89%82&topicRef=2356&anchor=H838162 389&source=see_link“水平衡紊乱(低钠血症和高钠血症)和钠平衡紊乱(低血容量和水肿)的一般原理”,关于‘稳定状态 ’一节)然而,噻嗪类利尿剂引起的低钠血症是这个时间进程中的例外。尽管早期的研究表明,噻嗪类利尿剂引起的低钠血症发生在开始药物治疗后 的14日内[https://search.uptodate.live/contents/zh-Hans/time-course-o f-loop-and-thiazide-diuretic-induced-electrolyte-complications/ab stract/44];但后来的研究提示,低钠血症出现的时间范围宽泛得多。例如,一项涉及1275例个体的回顾性队列研究发现,用药开始 后到低钠血症发生的中位时间为1.75年[https://search.uptodate.live/contents/zh-Hans /time-course-of-loop-and-thiazide-diuretic-induced-electrolyte-co mplications/abstract/55]。同样,一项系统评价发现,尽管用药开始后到低钠血症发生的平均时间为19日,但低钠血 症始发时间介于1-3650日不等[https://search.uptodate.live/contents/zh-Hans/ti me-course-of-loop-and-thiazide-diuretic-induced-electrolyte-compl ications/abstract/66]。噻嗪类利尿剂相关低钠血症的时间进程存在广泛差异,可能表示有多种机制参与了患者接受该治疗 后的水平衡改变。(参见https://search.uptodate.live/contents/zh-Hans/diuretic -induced-hyponatremia?search=%E5%88%A9%E5%B0%BF%E5%89%82&topicRef =2356&source=see_link“利尿剂相关性低钠血症”)钠与水的丢失利尿剂治疗引起的初始水钠丢失会引发各种钠保留因子的 增加(如,血管紧张素Ⅱ、醛固酮和去甲肾上腺素),也可能引起体循环血压的降低[https://search.uptodate.liv e/contents/zh-Hans/time-course-of-loop-and-thiazide-diuretic-indu ced-electrolyte-complications/abstract/2,72,7]。这些钠保留力最终与利尿剂的钠消耗活性 相平衡。当这种情况发生时,一个新的稳定状态出现了,即钠和水的摄入量与排泄量大致相等。此时将不会发生进一步的利尿(除非利尿剂剂量或给 药频率增加)。当使用袢利尿剂时,在开始治疗后的前几日,一定量的钠丢失致使细胞外液量保持降低。当使用噻嗪类利尿剂时,在初始的盐和水丢 失后,会有一段盐和水的正平衡期,这使细胞外液量恢复到接近(但不足以到达)基线水平。暂不明确这种继发性反应的发生机制。(参见http s://search.uptodate.live/contents/zh-Hans/use-of-thiazide-diureti cs-in-patients-with-primary-essential-hypertension?sectionName=%E 6%8A%97%E9%AB%98%E8%A1%80%E5%8E%8B%E7%9A%84%E6%9C%BA%E5%88%B6&sea rch=%E5%88%A9%E5%B0%BF%E5%89%82&topicRef=2356&anchor=H2&source=se e_link“噻嗪类利尿剂用于原发性(特发性)高血压”,关于‘抗高血压的机制’一节)除了急性神经内分泌反应外,结构性适应也参与长期 利尿治疗引发的代偿性钠保留。实验动物研究表明,使用袢利尿剂时,亨利袢排出的https://search.uptodate.live /contents/zh-Hans/92589?search=%E5%88%A9%E5%B0%BF%E5%89%82&topicR ef=2356&source=see_link氯化钠增加,从而导致远端肾小管和皮质集合管的肥大和钠重吸收能力增加[https:// search.uptodate.live/contents/zh-Hans/time-course-of-loop-and-thi azide-diuretic-induced-electrolyte-complications/abstract/8,98,9] ;使用噻嗪类利尿剂时,氯化钠排出的增加和继而引起的肥大反应仅限于皮质集合管[https://search.uptodate.liv e/contents/zh-Hans/time-course-of-loop-and-thiazide-diuretic-indu ced-electrolyte-complications/abstract/9,109,10]。间接证据表明,人类中也有同样的现 象。研究显示与对照者相比,接受袢利尿剂治疗1个月的受试者在停用利尿剂24小时后,出现袢利尿剂效果减弱(伴肾单位其他某些部位钠重吸收 增加)和噻嗪类利尿剂效果增强,提示噻嗪类利尿剂敏感部位(可能是远端小管)的钠重吸收增加(https://search.uptoda te.live/contents/zh-Hans/image?imageKey=NEPH%2F53198&topicKey=NEP H%2F2356&search=%E5%88%A9%E5%B0%BF%E5%89%82&source=see_link图2)[h ttps://search.uptodate.live/contents/zh-Hans/time-course-of-loop- and-thiazide-diuretic-induced-electrolyte-complications/abstract/ 1111]。尽管这些研究发现主要见于无水肿的高血压患者[https://search.uptodate.live/contents /zh-Hans/time-course-of-loop-and-thiazide-diuretic-induced-electr olyte-complications/abstract/2,72,7],但相同的原则也适用于水肿状态,如心力衰竭[https:/ /search.uptodate.live/contents/zh-Hans/time-course-of-loop-and-th iazide-diuretic-induced-electrolyte-complications/abstract/33]。然而 ,对于处在Frank-Starling曲线平台部分(而非升支)的患者,重新达到稳定状态所需时间可能会更长(https://sear ch.uptodate.live/contents/zh-Hans/image?imageKey=PC%2F58693&topic Key=NEPH%2F2356&search=%E5%88%A9%E5%B0%BF%E5%89%82&source=see_lin k图3)。在这种情况下,初始体液丢失会降低心内充盈压而不会降低心输出量。因此,激素的反调节反应不会得到激活,利尿作用将持续至前向 性心输出量开始下降。(参见https://search.uptodate.live/contents/zh-Hans/use-of -diuretics-in-patients-with-heart-failure?search=%E5%88%A9%E5%B0% BF%E5%89%82&topicRef=2356&source=see_link“利尿剂在心力衰竭患者中的应用”和https:/ /search.uptodate.live/contents/zh-Hans/pathophysiology-of-heart-f ailure-with-reduced-ejection-fraction-hemodynamic-alterations-and -remodeling?search=%E5%88%A9%E5%B0%BF%E5%89%82&topicRef=2356&sour ce=see_link“心力衰竭病理生理学:左室压力-容积和其他血流动力学关系”)患者在新的稳定状态下处于钠平衡,但其每日钠排泄模 式发生改变:利尿剂作用期间钠会丢失,而钠保留力活性增强会使当日其余时段的钠排泄量极低[https://search.uptodat e.live/contents/zh-Hans/time-course-of-loop-and-thiazide-diuretic -induced-electrolyte-complications/abstract/77]。由于患者体重稳定时,每日钠排泄量与 摄入量大致相等,故虽然会有一些误差[https://search.uptodate.live/contents/zh-Hans/t ime-course-of-loop-and-thiazide-diuretic-induced-electrolyte-comp lications/abstract/1212],仍应收集24小时尿液来评估患者对限钠饮食的依从性,但随机尿标本的尿钠浓度往往具有 误导性,会随利尿剂给药后的时间不同而变化。(参见https://search.uptodate.live/contents/col lection-of-a-24-hour-urine-specimen-beyond-the-basics?search=%E5% 88%A9%E5%B0%BF%E5%89%82&topicRef=2356&source=see_link“Patientedu cation:Collectionofa24-hoururinespecimen(BeyondtheBasics )”)钠保留力激活的另一个特征是静脉给予首剂利尿剂时,尿钠排泄反应最大;例如,即便静脉持续输注袢利尿剂,尿钠排泄通常也会在前12小 时内开始减少(https://search.uptodate.live/contents/zh-Hans/image?imageK ey=PC%2F75714&topicKey=NEPH%2F2356&search=%E5%88%A9%E5%B0%BF%E5%8 9%82&source=see_link图4)[https://search.uptodate.live/contents/zh -Hans/time-course-of-loop-and-thiazide-diuretic-induced-electroly te-complications/abstract/1313]。假设没有药物吸收障碍,这一原则也适用于口服治疗。(参见https: //search.uptodate.live/contents/zh-Hans/causes-and-treatment-of-r efractory-edema-in-adults?search=%E5%88%A9%E5%B0%BF%E5%89%82&topi cRef=2356&source=see_link“成人难治性水肿的病因和治疗”)患者因原发性肾钠潴留而出现容量明显扩张时(如,急 性肾小球肾炎或急/慢性肾脏病),稳态建立的顺序有所不同。在这种情况下,由于持续存在血容量过多,肾素-血管紧张素系统受到抑制,不会被 初始的钠丢失所激活。因此,第2次和接下来几次给药可能产生与第1次给药一样强的尿钠排泄效果,直至排出大部分过多液体。然而,即使在这种 情况下,第1次产生的效果仍然最强。钾丢失适用于钠丢失的情况也适用于利尿剂引起的其他丢失,包括钾的丢失。低钾血症的发生会限制进一步的 钾丢失(https://search.uptodate.live/contents/zh-Hans/image?imageKey= NEPH%2F74940&topicKey=NEPH%2F2356&search=%E5%88%A9%E5%B0%BF%E5%89 %82&source=see_link图1),这种效果通过在醛固酮敏感的远端肾单位的主细胞钾分泌减少和闰细胞钾重吸收增加来介导的 。然而,尿钾排泄的持续时间可能比尿钠排泄长数日[https://search.uptodate.live/contents/zh- Hans/time-course-of-loop-and-thiazide-diuretic-induced-electrolyt e-complications/abstract/1414],因为低血容量介导的醛固酮分泌增加会抵消低钾血症的抑制作用。(参见ht tps://search.uptodate.live/contents/zh-Hans/evaluation-of-the-adu lt-patient-with-hypokalemia?search=%E5%88%A9%E5%B0%BF%E5%89%82&to picRef=2356&source=see_link“成人低钾血症的评估”)当单独使用袢利尿剂或噻嗪类利尿剂时,需要补充钾的情况 很少,但当两者联合使用时,补充钾的可能性会高得多。暂不清楚是否应对开始袢利尿剂或噻嗪类利尿剂治疗的患者经验性补钾。一项大型队列研究 纳入了约650,000例接受袢利尿剂治疗的患者,接受小于或大于40mg/dhttps://search.uptodate.live /contents/zh-Hans/92487?search=%E5%88%A9%E5%B0%BF%E5%89%82&topicR ef=2356&source=see_link呋塞米治疗的同时补钾使患者的8年相对死亡风险分别降低了7%和16%[https:// search.uptodate.live/contents/zh-Hans/time-course-of-loop-and-thi azide-diuretic-induced-electrolyte-complications/abstract/1515]。虽 然仍需开展进一步研究,但应监测接受利尿剂治疗的患者是否存在低钾血症并予以治疗,。总结与推荐●利尿剂治疗可能导致体液和电解质并发症。 这主要涉及容量不足、氮质血症和低钾血症,但代谢性碱中毒、低钠血症、高尿酸血症和低镁血症也可能发生。假设利尿剂剂量及饮食和水的摄入量 相对恒定,且患者的血流动力学稳定,除了低钠血症的大多数上述问题发生在治疗开始后的前2-3周。噻嗪类利尿剂相关低钠血症的出现时间可能 晚得多,因此需要持续监测。(参见上文https://search.uptodate.live/contents/zh-Hans/t ime-course-of-loop-and-thiazide-diuretic-induced-electrolyte-comp lications?search=%E5%88%A9%E5%B0%BF%E5%89%82&topicRef=2338&source =see_link‘引言’)●利尿剂治疗所致初始钠和水丢失会引起各种钠保留因子的增加,这些因子的效应最终等于利尿剂的钠消耗活性。当 发生这种情况时,形成了新的稳定状态。此时不会再有进一步的利尿作用,但在开始治疗后的前几日,一定量的钠丢失致使细胞外液量降低。这种持 续性的容量不足是利尿剂对高血压或水肿的治疗有效的原因。患者在新的稳定状态下处于钠平衡,但其每日钠排泄模式发生改变:利尿剂作用期间钠 会丢失,而钠保留力活性增强会使当日其余时段的钠排泄量极低。(参见上文https://search.uptodate.live/co ntents/zh-Hans/time-course-of-loop-and-thiazide-diuretic-induced- electrolyte-complications?search=%E5%88%A9%E5%B0%BF%E5%89%82&topi cRef=2338&source=see_link‘钠与水的丢失’)●类似的情况也适用于利尿剂引起的其他丢失,包括钾丢失。低钾血症 的发生将限制进一步的钾丢失。然而,尿钾排泄的持续时间可能比尿钠排泄长数日。(参见上文https://search.uptodate .live/contents/zh-Hans/time-course-of-loop-and-thiazide-diuretic- induced-electrolyte-complications?search=%E5%88%A9%E5%B0%BF%E5%89 %82&topicRef=2338&source=see_link‘钾丢失’)使用UpToDate临床顾问须遵循https://s earch.uptodate.live/legal/license用户协议.参考文献RoseBD,PostTW.Clini calPhysiologyofAcid-BaseandElectrolyteDisorders,5thed,Mc Graw-Hill,NewYork2001.p.453.https://search.uptodate.live/cont ents/zh-Hans/time-course-of-loop-and-thiazide-diuretic-induced-el ectrolyte-complications/abstract/2BockHA,SteinJH.Diureticsan dthecontrolofextracellularfluidvolume:roleofcounterregul ation.SeminNephrol1988;8:264.https://search.uptodate.live/con 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