心衰超濾治療保定會20141105

1、心力衰竭的血液超濾治療Emerging Therapies for Heart Failure:ULTRAFILTRATION馮新慶中國中醫(yī)科學院西苑醫(yī)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主要治療目標：清除體液液體潴留是心衰患者住院的主要原因利尿劑不能充分解決心衰的液體潴留All Enrolled Discharges in Over 12 Months (01.01.200312.31.2003)Enrolled Discharges (%)50403020107%6%0

4、13%24%30%15%利尿劑無效50%3%2%(10)Change in Weight (lb)Change in Weight From Admission to DischargeADHERE Registry. 2003 National Benchmark Report. 心力衰竭鈉水潴留：機制和后果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心力衰竭時腎功能惡化與CVP, CI, SBP, PCWP的關系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超濾在多個環(huán)節(jié)阻斷心腎惡互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利尿劑治療心衰：兩難的抉擇？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 小膜面積濾器0.1-0.3 m2 低血流速度 (10-50 ml/min) 低體外循環(huán)容積 65 ml (total) 外周淺表靜脈或中心靜脈 不需要透析技術支持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超濾的排鈉能力是利尿劑的2倍P= 0.000025IVD UFmg/dLP= 0.000017P= 0.017鈉鉀鎂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臨床研究方興未艾：正在進行的臨床研究（1）1. Study of Heart Failure Hospitalizations After Aquapheresis Therapy Compared to Intravenous Diuretic Treatment （AVOID-HF）超濾和利尿劑對照的多中心試驗，預計入選810例心衰患者，迄今最大樣本量的隨機對照研究。研究目的是進一步證實和擴展UNLOAD研究的結論：和利尿劑對比，超

22、濾治療能減少心衰發(fā)生率?，F(xiàn)正招募入選病人，預期2016年5月完成。臨床研究方興未艾：正在進行的臨床研究（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檢查評價，與利尿劑對照，研究超濾治療對心衰患者心肌血流和冠脈血流儲備的作用。2018/10/2臨床研究方興未艾：正在進行的臨床研究（3）3. Feasibility Assessment of the Aquadex FlexFlow Ultrafiltration System in Treating Non Hospitalized Heart Fai

24、lure Patients in Dedicated Heart Failure Centers研究超濾在日常門診，不用住院，治療心衰。為在社區(qū)醫(yī)院開展超濾治療，針對心衰進行二級預防，奠定基礎。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心衰處理指南，增加了超濾治療推薦 超濾推薦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.心衰鈉水潴留機制和利尿劑的局限性血液超濾治療心力衰竭（心衰）經(jīng)歷了40年的臨床探索，逐漸走向成熟，成為糾正心衰患者水鈉滯留和 容量超負荷的金標準，是心衰治療的重要臨床新進展， 受到廣泛關注和重視，必將在未來的心衰現(xiàn)代處理上

39、發(fā)揮獨特的、不可替代甚至不可或缺的作用。2018/10/2UNLOAD研究：超濾減少再住院44%，減少看急診52%心衰鈉水潴留機制和利尿劑的局限性水鈉滯留的出現(xiàn)與加重增加了心衰患者的病死率和各種心血管 的發(fā)生率，故又是心衰預后的強預測標志。在失代償?shù)男乃セ颊咧腥萘控摵纱龠M腎靜脈壓力增加，導致腎內(nèi)動脈血管收縮，激活腎素-血管緊張素-醛固酮系統(tǒng)（RAAS），促進近段小管的水鈉吸收，加重充血。早期無癥狀的左室充盈壓的增加，即所謂血流動力學的充血， 能預測心衰進展到失代償狀態(tài)。使用植入性心腔壓力感受器的研究已經(jīng)表明左室充盈壓在急性失代償心衰患者住院前3-4周已經(jīng)升高。因此慢性升高的心室充盈壓在心肌重抅

40、方面起著決定性的作用，神經(jīng)內(nèi)分泌激素的激活，心室壁壓力的增加，缺血狀態(tài)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構的主要原因。隨著水鈉潴留的進展，這些情況會導致心臟輸出量下降的惡性循環(huán)。 水鈉滯留也會影響心衰的處理?，F(xiàn)代心衰的藥物治療已有巨 大進展，也是卓有成效的，但那些已證實有效的藥物如血管 緊張素轉換酶抑制劑（ACEI）、受體阻滯劑、醛固酮拮抗劑和血管緊張素受體阻滯劑（ARB）等在應用時，如存在顯著浮腫，則療效往往較差，而不良反應的發(fā)生率較高。因此， 有效消除容量超負荷是失代償性心衰治療的基礎。上世紀九十年代，Agostoni等研究小組進行了血液超濾治療的系統(tǒng)研究，其結果顯示，與

41、藥物治療相比，超濾治療患者血流動力學、舒張期充盈參數(shù)、神經(jīng)內(nèi)分泌激素反應和運動耐量均得到改善。同時進行了一個相似的試驗研究，但藥物治療更積極。16例輕度心衰患者被隨機分入超濾組（500ml/h）和靜脈用組（靜推后連續(xù)平均泵入劑量248mg）。所有患者右心房壓降低50%，治療才停止。結果顯示，超濾組能顯著改善峰值耗氧量測定的運動耐量，而 組患者沒有變化。兩組的體重、右房壓和肺毛細血管楔壓均顯著降低。但這些變量在 組快速回到治療前水平，超濾組仍保持降低狀態(tài)。對于超濾治療尿量小于和大于1000ml/24h的心衰患者， 臨床研究結果顯示，前者出現(xiàn)多尿現(xiàn)象和神經(jīng)內(nèi)分泌激素水平下降，后者超濾后神經(jīng)內(nèi)分泌激

42、素水平升高， 尿量下降。大多數(shù)小型超濾試驗均顯示住院24內(nèi)開始超濾治療是有益的，而在血流動力學指導的治療失敗 之后，應用超濾治療有著不利的結果。因此，早期出 現(xiàn)的利尿劑抵抗現(xiàn)象，如袢利尿劑治療后利尿和利鈉 反應下降和右心房壓力增高，可能預示血液超濾對這 些患者有益。超濾治療有良好的血流動力學效果，治 療后預期可產(chǎn)生左室充盈壓下降、心臟指數(shù)改善、對 利尿劑敏感性恢復等令人鼓舞的結果。超濾是安全的。從2上世紀70年代后期到90年代，血液超濾治療失代償性心衰的多個小樣本觀察性研究，證明了這一結論，并且從不同的角度均顯示了對心衰的有效性，如快速緩解呼吸困難等充血癥狀、充分消除水腫、 降低肺毛細血管楔壓

43、、提高心排量、逆轉利尿劑抵抗、改善神經(jīng)內(nèi)分泌狀態(tài)等。隨訪顯示單次超濾治療，療效可持續(xù)3月。1974年，Silverstein等開始將血液超濾用于容量超負荷的慢性透析病人的治療，操作比透析更加簡便，而且不影響電解質(zhì)和酸堿平衡，理論上可以擴展到頑固心衰或肺水腫的治療。 與腎功能衰竭不同，心衰有其特殊的病理生理學基礎，專用的超濾設備需具備下列條件：（1）體外血流量慢， 不增加心臟額外負荷。通常認為40ml/h血流量對心臟負荷的影響微??；（2）體外循環(huán)血液容積?。?5ml）， 治療初始建立體外循環(huán)和治療結束回血時，不會造成容量沖擊；（3）小膜面積濾器有助于提高生物相容性，同時滿足心衰超濾要求；（4）單

44、純超濾脫水，不需要腎內(nèi)科的技術支撐，才能以心內(nèi)科為主體開展工作。 基于上述認識研發(fā)成功的心衰專用超濾治療設備已開始用于臨床。心臟科醫(yī)生可以在普通病房，依靠設備技術，保障治療便利性和安全性，降低醫(yī)護人員勞動強度。這種新的心臟起超濾專用設備在臨床實踐中證實是有效和安全的( 附表)不過，這些研究使用的是腎功能衰竭患者血液透析裝置， 設備使用的難度較大，其操作使用需依賴腎內(nèi)科醫(yī)師 和相關專業(yè)技術人員的協(xié)助，且耗費昂貴。這種狀況 限制了心衰治療中超濾的推廣應用。在日常臨床實踐 中超濾技術使用的比例很低。歐洲統(tǒng)計顯示，有容量 超負荷的心衰患者中僅2%采用了超濾治療。 .心衰超濾專用設備問世和應用 與腎功能

45、衰竭不同，心衰有其特殊的病理生理學基礎，專用的超濾設備需具備下列條件：（1）體外血流量慢， 不增加心臟額外負荷。通常認為40ml/h血流量對心臟負荷的影響微小；（2）體外循環(huán)血液容積?。?5ml）， 治療初始建立體外循環(huán)和治療結束回血時，不會造成容量沖擊；（3）小膜面積濾器有助于提高生物相容性，同時滿足心衰超濾要求；（4）單純超濾脫水，不需要腎內(nèi)科的技術支撐，才能以心內(nèi)科為主體開展工作。 基于上述認識研發(fā)成功的心衰專用超濾治療設備已開始用于臨床。心臟科醫(yī)生可以在普通病房，依靠設備技術，保障治療便利性和安全性，降低醫(yī)護人員勞動強度。這種新的心臟起超濾專用設備在臨床實踐中證實是有效和安全的( 附表