心衰超滤治疗保定会20141105

1、心力衰竭的血液超滤治疗Emerging Therapies for Heart Failure:ULTRAFILTRATION冯新庆中国中医科学院西苑医院Heart Failure:A Major Global Health ProblemHeart failure is a major public health problem resulting in substantial morbidity and mortality. Major cost-driver of HF is high incidence of hospitalizationsMost Admitted Patients

2、 Are Volume OverloadedAt HospitalizationADHERE1 Any dyspnea 89% Pulmonary congestion (CXR) 74% Rales 67% Dyspnea at rest 34% Peripheral edema 65%ADHERE Registry. 3rd Qtr 2003 NationalBenchmark Report.Over 90% of All Hospitalizations for Acutely Decompensated Heart Failure (ADHF) Are Due to Fluid Ove

3、rload1The Majority of These Patients Have Failed Treatment With Oral Diuretics21. Aronson. ACC. 2000.2. Adams et al. Am Heart J. 2005;149:209-216.2018/10/2主要治疗目标：清除体液液体潴留是心衰患者住院的主要原因利尿剂不能充分解决心衰的液体潴留All Enrolled Discharges in Over 12 Months (01.01.200312.31.2003)Enrolled Discharges (%)50403020107%6%0

4、13%24%30%15%利尿剂无效50%3%2%(10)Change in Weight (lb)Change in Weight From Admission to DischargeADHERE Registry. 2003 National Benchmark Report. 心力衰竭钠水潴留：机制和后果Chronic Decrease in Cardiac OutputOr Decrease in Peripheral Vascular ResistanceIncreased Cardiac Filling PressuresDe

5、crease Fullness of The Arterial CirculationWater RetentionV2 Receptors StimulationBaroreceptor DesensitizationDecreased Renal Perfusion PressureRenal VasoconstrictionIncreased Sodium and WaterRetentionNonosmotic AVP ReleaseIncreased SNS ActivityIncreased RAAS ActivityDecreased GFRResistance to Natri

6、uretic PeptidesFailure to Escape From AldosteroneIncreased Water and Sodium Reabsorptionin the Proximal TubuleReducedDistal Delivery of SodiumAdapted from Schrier RW: J Am Coll Cardiol 2006; 47:1-8心力衰竭时肾功能恶化与CVP, CI, SBP, PCWP的关系Mullens, W. et al. J Am Coll Cardiol 2009;53:589-596CVP and CI on Admis

7、sion for the Development of WRFMullens, W. et al. J Am Coll Cardiol 2009;53:589-596The Cardiorenal Syndrome of HFIncreased Morbidity and MortalityDevelopment of Diuretic and NatriureticDiuretic TherapyNeurohormonal ActivationResistanceDiminishedBlood FlowImpaired RenalFunctionDecreased RenalPerfusio

8、n超滤在多个环节阻断心肾恶互Pathophysiologic pathways underlying CHF and renal dysfunction. UF could potentially counter certain adverse cardiorenal Interactions and break the vicious cycle.Therapeutic Approaches Block Adaptive Processes Post Diuretic Na Retention Chronic infusionLong-acting diuretics (thiazides,

9、 spironolactone) Structural AdaptationsDCT diuretics (thiazides, spironolactone, ACEI/ARBs) CD diuretics (spironolactone, ACEI/ARBs) Neurohormonal Activation ACE Inhibitors Spironolactone Beta blockers Nesiritide Ultrafiltration利尿剂治疗心衰：两难的抉择？2018/10/2Fluid Removal by UltrafiltrationUltrafiltration c

10、an remove fluid from the blood at the same ratePH OInterstitial Space (Edema)Nathat fluid can be naturally recruited from the tissueThe transient removal of blood elicits a compensatory mechanism, called plasma or intravascular refill (PR), aimed at minimizing this reduction1,22NaKUFKP RP1. Lauer et

11、 al. Arch Intern Med. 1983;99:455-460.2. Marenzi et al. J Am Coll Cardiol. 2001;38:4.NaVascularSpaceVascularNaSpaceUltrafiltration:The Gold Standard for Sodium-Volume RemovalCirculation (Heart Fail).2009;2;499-504Changes in Plasma Volume and Refilling Rate During Ultrafiltration10 5 0 5 10 20 15 10

12、5 Before1234After24h afterUFliterliterliterliterUFUF0 D PV (%)Before1234After24h afterUFliterliterliterliterUFUFPRR (mL/min) Ultrafiltration can be done safely without significant changes in plasma volumePlasma refill rates may decrease as volume removal continuesMarenzi et al. J Am Coll Cardiol. 20

13、01;38:963-968.Hemodynamic Effects of UF in CHF5.0 4.0 3.0 2.0 Before1CO (L/m)234After24h after70 60 50 40 30 Before1SV (mL)234After24h afterUFliterliterliterliterUFUFUFliterliterliterliterUFUF25 20 15 10 5 RAP (mmHg)30 25 20 15 PWP (mmHg)0 - BeforeUF1liter2liter3liter4literAfter UF24h after UF10 - B

14、eforeUF1liter2liter3liter4literAfterUF24h afterUFMarenzi et al. J Am Coll Cardiol. 2001;38:963-968.Ultrafiltration Device: Dedicated to Heart Failure 小膜面积滤器0.1-0.3 m2 低血流速度 (10-50 ml/min) 低体外循环容积 65 ml (total) 外周浅表静脉或中心静脉 不需要透析技术支持AccessReturnEffluentEnhanced Sodium Extraction with Ultrafiltration C

15、ompared to Intravenous Diuretics 15 hospitalized ADHF patients with presumed diuretic resistance and clinical evidence of volume overload. Urine electrolyte concentrations measured after a dose of IVD. UF was then begun and ultrafiltrate electrolyte concentrations were measured 8 hours later and com

16、pared to the initial urine values.Ali SS et al. Congest Heart Fail. 2009; 15: 1-4超滤的排钠能力是利尿剂的2倍P= 0.000025IVD UFmg/dLP= 0.000017P= 0.017钠钾镁Ali SS et al. Congest Heart Fail. 2009; 15:1-4Sustained Improvement in Functional Capacity after UF in CHF: Failure of Furosemide to Provide the Same Result 16 s

17、table, NYHA II-III chronic HF patients matched by age, gender and peak VO2 Randomized to isolated ultrafiltration (500 cc/h) or IV furosemide Removal of the same amount of fluid in both arms ( 1,600 cc) Measurement of hemodynamics, peak VO2, NE, PRA and Aldosterone at baseline, end of treatment and

18、3 monthsAgostoni PG et al. Am J Med 1994; 96:191-9Ultrafiltration vs. Furosemide in HFBody WeightPlasma Renin Activitykg 3%210-1*-2-3*16012080400-40* p0.01 vs. day 0 * *0123430900123490UF (n=8; 1710 ml)Furosemide (n=8; 248 mg i.v.)daydayAgostoni PG et al. Am J Med 1994; 96:191-9Ultrafiltration vs. F

19、urosemide inHFml/kg/min2019Peak VO2Tolerance Time*seconds600*18 500* p 0.3 mg/dl from baseline) while demonstrating signs and symptoms of persistent congestion Primary endpoint Change in sCr and weight together as a “bivariate” endpoint assessed at96 hrs post enrollment Secondary Endpoint PE assesse

20、d at days 1-3 and 7 days Treatment failure, weight and fluid loss, clinical decongestion, peak sCr, change in electrolytes, LOS, biomarkers, change in diuretic doses all at various time pointsCARESS-HF Clinical Trial Primary endpoint Change in sCr and weight together as a “bivariate” endpointassesse

21、d at 96 hrs post enrollmentRed= UltrafiltrationBlack= Stepped Pharmacologic Care临床研究方兴未艾：正在进行的临床研究（1）1. Study of Heart Failure Hospitalizations After Aquapheresis Therapy Compared to Intravenous Diuretic Treatment （AVOID-HF）超滤和利尿剂对照的多中心试验，预计入选810例心衰患者，迄今最大样本量的随机对照研究。研究目的是进一步证实和扩展UNLOAD研究的结论：和利尿剂对比，超

22、滤治疗能减少心衰发生率。现正招募入选病人，预期2016年5月完成。临床研究方兴未艾：正在进行的临床研究（2）2. Assessment of Coronary Flow Reserve in Heart Failure Patients After Ultrafiltration Versus DiureticsEvaluate the effects of ultrafiltration (UF) compared to intravenous diuretic therapy on myocardial blood flow (MBF) and coronary flow reserve(

23、CFR), as assessed by positron emission tomography (PET), in patients with acutely decompensated heart failure (ADHF).用PET检查评价，与利尿剂对照，研究超滤治疗对心衰患者心肌血流和冠脉血流储备的作用。2018/10/2临床研究方兴未艾：正在进行的临床研究（3）3. Feasibility Assessment of the Aquadex FlexFlow Ultrafiltration System in Treating Non Hospitalized Heart Fai

24、lure Patients in Dedicated Heart Failure Centers研究超滤在日常门诊，不用住院，治疗心衰。为在社区医院开展超滤治疗，针对心衰进行二级预防，奠定基础。2018/10/2Guidelines Update for the Use of UF in HFExpert GroupACC/AHA 2013CommentUltrafiltration may be considered for patients with obvious volume overload to alleviate congestive symptoms and fluid wei

25、ght (Level B). Ultrafiltration may be considered for patients with refractory congestion not responding to medical therapy (Level C)ACC/AHA 2009Ultrafiltration is reasonable for patients with refractory congestion not responding to to medical therapy (II a, Level B).If the degree of renal dysfunctio

26、n is severe or if edema becomes resistant to treatment, ultrafiltration or hemofiltration may be needed to achieve adequate control of fluid retention. This can produce clinical benefits and may restore responsiveness to conventional doses of loop diuretics.CVVS 2009In highly selected patients and u

27、nder experienced supervision, intermittent slow continuous veno-venous ultrafiltration may be considered.ESC 2008Ultrafiltration may be considered to reduce fluid overload (pulmonary and/or peripheral oedema) in selected patients and correct hyponatremia in symptomatic patients refractory to diureti

28、cs. (IIa, Level B)Guidelines Update for the Use of UF in HFEcpert GroupACC/AHA 2005CommentIf the degree of renal dysfunction is severe or if edema becomes resistant to treatment, ultrafiltration or hemofiltration may be needed to achieve adequate control of fluid retention. This can produce clinical

29、 benefits and may restore responsiveness to conventional doses of loop diuretics.ESC2005In chronic heart failure, ultrafiltration can resolve pulmonary edema and overhydration in case of refractoriness to pharmacological therapies. In most patients with severe disease the relief is temporary. In acu

30、te heart failure, ultrafitration or dialysis can be considered if other strategies are ineffective.CVVS 2007In highly selected patients, intermittent slow continuous veno-venous ultrafiltration may be considered. This should be performed in consultation with a nephrologist or a specialist physician*

31、 who has experience using ultrafiltration in a setting of close inpatient observation.Managing Volume Overload in Acute Decompensated Heart Failure：Conclusions Optimal volume management in ADHF requires in depth knowledge of the mechanisms leading to salt and water retention despite hypervolemia. Ap

32、art from intrinsic renal insufficiency, venous congestion, rather than reduced CO, may be the primary hemodynamic factor driving WRF in ADHF pts. Loop diuretics reduce congestion, but their effectiveness is reduced by excess salt intake, underlying CKD, renal adaptation to diuretics and neurohormona

33、l activation Compared with removal of hypotonic fluid with diuretics, withdrawal of isotonic fluid with ultrafiltration may result in enhanced sodium extraction, lesser neurohormonal activation, and improved outcomes A consensus definition of the cardiorenal syndrome may help to design RCTs aimed at

34、 identifying pathophysiologically sound interventions targeting specific patient populationsTHANKSFor Your Attention2013年ACCF/AHA心衰处理指南，增加了超滤治疗推荐 超滤推荐Class IIb1. Ultrafiltrationmaybeconsideredforpatientswith obviousvolumeoverloadtoalleviatecongestive symptoms and fluid weight.(Level of Evidence: B)2

35、. Ultrafiltrationmaybeconsideredforpatientswith refractorycongestionnotrespondingtomedical therapy. (Level of Evidence: C)2018/10/2EUPHORIA Trial: Length of Stay776554Patients43312102 Days3 Days4 Days5 Days10 DaysCostanzo et al. J Am Coll Cardiol. 2005;46:2047-2051.EUPHORIA Trial: Clinical and Labor

36、atory OutcomesVariablePre-UFDisch.30 Days90 DaysP ValueWeight (kg)87 2381 2284 2180 18.006SBP (mmHg)120 17114 22120 26116 24.306Cr (mg/dL)2.12 0.62.20 0.82.38 1.12.18 0.7.532BNP(pg/mL)1236 747988 847816 494NA.03NYHA FC IV39 %37 %5 %11%.063Costanzo et al. J Am Coll Cardiol. 2005;46:2047-2051.EUPHORIA

37、 Trial: Conclusions Early ultrafiltration in patients with fluid overload and diuretic resistance permitted the discharge of 60% of high risk ADHF patients in 3 days A treatment strategy to use ultrafiltration early in patients with volume overload and evidence of diuretic resistance results in redu

38、ced length of stay and improved clinical status Improvements in clinical status are preserved for 30 90 days following hospitalizationsCostanzo et al. J Am Coll Cardiol. 2005;46:2047-2051.心衰钠水潴留机制和利尿剂的局限性血液超滤治疗心力衰竭（心衰）经历了40年的临床探索，逐渐走向成熟，成为纠正心衰患者水钠滞留和 容量超负荷的金标准，是心衰治疗的重要临床新进展， 受到广泛关注和重视，必将在未來的心衰现代处理上

39、发挥独特的、不可替代甚至不可或缺的作用。2018/10/2UNLOAD研究：超滤减少再住院44%，减少看急诊52%心衰钠水潴留机制和利尿剂的局限性水钠滞留的出现与加重增加了心衰患者的病死率和各种心血管 的发生率，故又是心衰预后的强预测标志。在失代偿的心衰患者中容量负荷促进肾静脉压力增加，导致肾内动脉血管收缩，激活肾素-血管紧张素-醛固酮系统（RAAS），促进近段小管的水钠吸收，加重充血。早期无症状的左室充盈压的增加，即所谓血流动力学的充血， 能预测心衰进展到失代偿状态。使用植入性心腔压力感受器的研究已经表明左室充盈压在急性失代偿心衰患者住院前3-4周已经升高。因此慢性升高的心室充盈压在心肌重抅

40、方面起着决定性的作用，神经内分泌激素的激活，心室壁压力的增加，缺血状态下心肌需氧量的增加，以及二尖瓣返流程度加重均是心肌重构的主要原因。随着水钠潴留的进展，这些情况会导致心脏输出量下降的恶性循环。 水钠滞留也会影响心衰的处理。现代心衰的药物治疗已有巨 大进展，也是卓有成效的，但那些已证实有效的药物如血管 紧张素转換酶抑制剂（ACEI）、受体阻滞剂、醛固酮拮抗剂和血管紧张素受体阻滞剂（ARB）等在应用时，如存在显著浮肿，则疗效往往较差，而不良反应的发生率较高。因此， 有效消除容量超负荷是失代偿性心衰治疗的基础。上世纪九十年代，Agostoni等研究小组进行了血液超滤治疗的系统研究，其结果显示，与

41、药物治疗相比，超滤治疗患者血流动力学、舒张期充盈参数、神经内分泌激素反应和运动耐量均得到改善。同时进行了一个相似的试验研究，但药物治疗更积极。16例轻度心衰患者被随机分入超滤组（500ml/h）和静脉用组（静推后连续平均泵入剂量248mg）。所有患者右心房压降低50%，治疗才停止。结果显示，超滤组能显著改善峰值耗氧量测定的运动耐量，而 组患者没有变化。两组的体重、右房压和肺毛细血管楔压均显著降低。但这些变量在 组快速回到治疗前水平，超滤组仍保持降低状态。对于超滤治疗尿量小于和大于1000ml/24h的心衰患者， 临床研究结果显示，前者出现多尿现象和神经内分泌激素水平下降，后者超滤后神经内分泌激

42、素水平升高， 尿量下降。大多数小型超滤试验均显示住院24内开始超滤治疗是有益的，而在血流动力学指导的治疗失败 之后，应用超滤治疗有着不利的结果。因此，早期出 现的利尿剂抵抗现象，如袢利尿剂治疗后利尿和利钠 反应下降和右心房压力增高，可能预示血液超滤对这 些患者有益。超滤治疗有良好的血流动力学效果，治 疗后预期可产生左室充盈压下降、心脏指数改善、对 利尿剂敏感性恢复等令人鼓舞的结果。超滤是安全的。从2上世纪70年代后期到90年代，血液超滤治疗失代偿性心衰的多个小样本观察性研究，证明了這一结论，并且从不同的角度均显示了对心衰的有效性，如快速缓解呼吸困难等充血症状、充分消除水肿、 降低肺毛细血管楔压

43、、提高心排量、逆转利尿剂抵抗、改善神经内分泌状态等。随访显示单次超滤治疗，疗效可持续3月。1974年，Silverstein等开始将血液超滤用于容量超负荷的慢性透析病人的治疗，操作比透析更加简便，而且不影响电解质和酸碱平衡，理论上可以扩展到顽固心衰或肺水肿的治疗。 与肾功能衰竭不同，心衰有其特殊的病理生理学基础，专用的超滤设备需具备下列条件：（1）体外血流量慢， 不增加心脏额外负荷。通常认为40ml/h血流量对心脏负荷的影响微小；（2）体外循环血液容积小（65ml）， 治疗初始建立体外循环和治疗结束回血时，不会造成容量冲击；（3）小膜面积滤器有助于提高生物相容性，同时满足心衰超滤要求；（4）单

44、纯超滤脱水，不需要肾内科的技术支撑，才能以心内科为主体开展工作。 基于上述认识研发成功的心衰专用超滤治疗设备已开始用于临床。心脏科医生可以在普通病房，依靠设备技术，保障治疗便利性和安全性，降低医护人员劳动强度。這种新的心脏起超滤专用设备在临床实践中证实是有效和安全的( 附表)不过，这些研究使用的是肾功能衰竭患者血液透析装置， 设备使用的难度较大，其操作使用需依赖肾内科医师 和相关专业技术人员的协助，且耗费昂贵。這种状况 限制了心衰治疗中超滤的推广应用。在日常临床实践 中超滤技术使用的比例很低。欧洲统计显示，有容量 超负荷的心衰患者中仅2%采用了超滤治疗。 .心衰超滤专用设备问世和应用 与肾功能

45、衰竭不同，心衰有其特殊的病理生理学基础，专用的超滤设备需具备下列条件：（1）体外血流量慢， 不增加心脏额外负荷。通常认为40ml/h血流量对心脏负荷的影响微小；（2）体外循环血液容积小（65ml）， 治疗初始建立体外循环和治疗结束回血时，不会造成容量冲击；（3）小膜面积滤器有助于提高生物相容性，同时满足心衰超滤要求；（4）单纯超滤脱水，不需要肾内科的技术支撑，才能以心内科为主体开展工作。 基于上述认识研发成功的心衰专用超滤治疗设备已开始用于临床。心脏科医生可以在普通病房，依靠设备技术，保障治疗便利性和安全性，降低医护人员劳动强度。這种新的心脏起超滤专用设备在临床实践中证实是有效和安全的( 附表