Ultrafiltrazione ed Emofiltrazione nello scompenso cardiaco refrattario. Carlo Guastoni

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1 Ultrafiltrazione ed Emofiltrazione nello scompenso cardiaco refrattario Carlo Guastoni

2 TOPICS Scompenso cardiaco e sindrome cardio-renale La refrattarietà al diuretico L utilizzo dell ultrafiltrazione nello scompenso: i dati della letteratura L Emofiltrazione

3 Arco efferente della regolazione del volume circolante: DUE MECCANISMI NEURO-ORMONALI Attivazione Renina-Angiotensina Aldosterone IPOTALAMO Catecolamine ADH ipovolemia Meccanismi predominanti nell Insufficienza cardiaca VASOCOSTRIZIONE RIASSORBIMENTO RENALE Na e H2O VASODILATAZIONE DIURESI Ipervolemia PEPTIDE NATRIURETICO ATRIALE E VENTRICOLARE

4 Effetto renale dell insufficienza cardiaca: LA SINDROME CARDIORENALE acuta Peggioramento della funzione renale dovuta a: Vasocostrizione renale - riduzione del flusso renale ridotta filtrazione renale da: a) Attivazione neuroormonale Catecolamine RAS Adenosina b) Utilizzo del diuretico macula densa RAS 5702 pts Alterata emodinamica intrarenale da RIDUZIONE DEL egfr GRADIENTE 62±25 PRESSORIO ml/min; A/V RENALE Scr. 1.2 (1-1.6) mg/dl Da aumento PVC da congestione venosa Change in Scr> 0.3 mg/dl Aumento pressione intra-addominale in presenza and di increase ascite >25 % Riduzione della pressione di perfusione renale in 13 (PAM-IAP) %

5 Cardio-Renal Connection: neurohumoral crosstalk in Acute and Chronic dysfunctions Sympathetic Activation Renin Angiotensin System ROS production Via NADPH-oxidase NO-ROS dysbalance Oxidatively modified proteins, carbohydrates and lipids Inflammation Cytokines stimulate Noradrenaline (NA) release NF-kB-mediated FIBROSIS Bogartz L. Eur. H. J Metra M. Eur. H.J. 2012

6 Metra M Eur. H.J. 2012

7 CARDIORENAL Syndrome Combined cardiac and renal dysfunction amplifies progression of failure of the individual organ Two major problem related to CRS: - adverse outcome - diuretic resistance Ronco C. JACC 2008; 52: 1527

8 pts.with ADHF }AKIN stage 1 Circulation 2014; 130:958

9 1855 pts. 455 pts.(24.5 %) with bas.egfr < 40 ml/min

10 Natriuretic response to furosemide in CHF and CRF ++ increased Na+ and fluid adsorption in the proximal tubule ++ renal failure leading to decreased diuretic excretion + increased vasopressin release + hyponatraemia Ellison. Cardiology. 2001;96:

11 Effect of Furosemide 40 mg. i.v. in CHF Group I Moderate CHF: UNa+ 120±36 mmol/l Group II Advanced CHF:UNa+ 68±25 mmol/l All pat. with SCr. < 1.5 mg/dl Nomura A. Clin. Pharmacol. Ther. 1981

12 Effect of neurohormonal activaction on Natriuria BUN (mg/dl) Serum Na (meq/l) Pra (ng/ml/h) Norepinephrine (pg/ml) Furosemide (mg/day) Control 42±28 141±4 0.7± ±48 - A 72±56* 142± ± ±64 135±11 B 120±77*+ 140± ±12*+ 1232± ±112 C 124±53*+ 132±2.9* ±17*+ 1482± ±226 *+ * p<0.01 vs control, + p<0.01 vs. A, p<0.01 vs B Reduction of Sodium concentration in the urine in the 4 groups A B C Marenzi G. Eur.J.Heart Fail. 2002; 4: 597

13 Definizione di resistenza al diuretico mancata riduzione dei sintomi da ritenzione idro-salina a fronte di aumentate dosi di diuretico La sodiuria come marker di inefficacia della terapia diuretica E verosimile che al momento del ricovero valori di sodiuria riflettano una progressiva riduzione avvenuta PRIMA DEL RICOVERO è importante dosarla durante il follow up Non è possibile definire una soglia di sodiuria critica in assoluto, ma ragionevolmente valori < 50 mmol/l possono indicare una soglia critica indicativa di inefficacia della terapia diuretica

14 DOSE study Composite End Point: death, rehospitalization, emergency room visit in 308 ADHF pts. with screat. 1.5±0.5 mg/dl, Na 138± 4 meq/l

15 Ultrafiltration (SCUF) Venous line UF < 500ml/h Filter CONVECTION water and elektrolytes removal at the same concentration as the plasma Ultrafiltrate Peristaltic pump QB 30-60ml/min Arterial line

16 Loop diuretics can cause clinical natriuretic failure: a prescription for volume expansion 15 patients with CHF. GFR 43 ± 17 ml/min (21-80) Na ± 5.7; K 3.8 ±0.5; Furosemide dose 184 ±78 mg. 134 ± 8 mmol 60± 47 mmol/l 41±23 mmol 3.7 ± 0.6 mmol/l Ali SS. et al. Congest. Heart Fail. 2009

17 Interrelation of Humoral Factors, Hemodynamics, and Fluid and Salt Metabolism in Congestive Heart Failure: Effects of Extracorporeal Ultrafiltration Urine output <1,000 ml/24h Furosemide 369 mg Urine output >1,000 ml/24h Furosemide 254 mg Marenzi G. et al. Am J Med 1993

18 RCT comparing early (<24 h) ultrafiltration (N=100) versus intravenous loop diuretics (N=100). ADHF pts. Mean bas. Screat. 1.5±0.5; mean Nap. 139±5. Mean bas. Body weight (Kg)101±27 (UF) vs 96±29 (Standard) Duration and rate of UF decided by treating physicians(<500ml/h) Primary efficacy end points were: weight loss and patients dyspnea assessment 48 h after randomization. Secondary efficacy end points included: 1) net fluid loss 48 h after randomization; 2) length of index hospitalization; 3) rehospitalizations for heart failure (HF), percentage of patients rehospitalized for HF, days of rehospitalization, and unscheduled office and emergency department visits within 90 days. Costanzo MR, for the UNLOAD invest. JACC 2007

19 UNLOAD main results SCUF vs. Standard Care Weight 48 h (Kg) 5.0±3.1 (4.9%) SCUF SC p 3.1± 3.5 (3.2%) Dyspnoea score 6.4± ± h (%) 3/99 12/ Net fluid 48 h (L) 4.6± ± Length of stay (d) 6.3± ± H.F 90 days (%) 16/89 (18) 28/87 (32) Re-hospital Length of Stay (d) 1.4± ±

20 CARRES-HF Study Bart B. NEJM 2012; 367: pts.with decompensated HF and worsened renal function (SCreat.increase 0.3 mg/dl 12 weeks before or 10 days after admission) Mean 0.45 mg/dl Mean bas. Screat 2.09 mg/dl(standard Ther.) vs 1.9 (UF) -Mean bas. Body weight (kg) 106 (St.) vs 94 (UF) -UF started 8 hours after the random assignement (mean 42 hours) UF rate: 200 ml/hour until the patients symptoms of congestion have been optimized. NO DIURETIC - UF duration: 40 hours (28-67) -Target diuresis in the Control Group (pharmacol.): 3-5 L/day obtained by incremental-additional diuretic dose -Primary efficacy end points were: Bivariate change from baseline serum creatinine and body weight and 96 hoursafter random assignement.

21 Bart B. NEJM 2012; 367: 2296 Additional i.v. vasodilators or inotropic agents were prohibitted only in the Ultrafiltration Group

22 CARREESS-HF 96 hours after enrollment +0.23±0.70 mg/dl Bart B et al, N Eng J Med, 2012.

23 CARRES-HF Study Bart B. NEJM 2012; 367: 2296 Secondary end points UF Pharmacologic therapy 60 days mortality 17 % 13.8 % (p= 0.47) Death or HF rehospital. 38 % 35 % (p= 0.96) Death or any rehospital. 61 % 48 % (p= 0.12)

24 Comments on CARRESS study Costanzo MR. NEJM 2013;368: 1158 Method bias: 200 ml/h may be inappropriate for patients with low blood pressure or right ventricular dysfunction 12% of patients in the pharmacologic-therapy group received inotropic agents, which are prohibited in ultrafiltration; this may have attenuated hypotension-related worsening renal function. 9% of patients in the ultrafiltration group crossed over to alternative therapy, and 30% received intravenous diuretics before the 96-hour assessment, which may have contributed to worsening renal function Patients of the CARRESS-HF study had an acute impairment of renal function before and during the recovery that could lead to negative outcome during the following period

25 J. Cardiac Fail 2014,20:378 Method: Randomized controlled multicentric study Standard Ther. vs UF. 56 patients. Diuretic used in UF group Target population: hospitalized severe (class III-IV NYHA) acute HF pts (ejection fraction < 40%) with fluid overload (above 4 Kg) Mean bas.screat. 1.9±0.7 (St.Ther.) vs. 1.7±0.6 (UF); egfr 41 vs 43 ml/min Mean bas. Nap. 138±4 (St. Ther.) vs. 139±4 (UF) Mean bas. Body weight (kg) 89±17 (St.) vs 83±12 (UF) Fluid removal not exceding 75 % of initial weight increase and HCT automatically monitored during UF (19± 10 hours) (4.2±1.8 L) End point: N. of rehospitalization for H.F. after first hospitalization (one year) Marenzi G, J Cardiac Fail, 20, 2014.

26 C.U.O.R.E.: Primary End Point Rehospitalization for H.F. 4 events. (11%) 11 events (48%) Marenzi G, J Cardiac Fail, 20, 2014.

27 Main results *p<0.05 ±3.1 5 % * ±3.5 ±3.9 ±5.1 6% 5% * ±4.5 ± 5 9 % 8.8 % 3.2% Osservazione 48 h 96 h Dimissione

28 Main results *p<0.05 * p = 0.08 * 90 days H.F 60 days H.F 90 days any cause 1 year H.F

29 Mortality CUORE CARRESS UNLOAD

30 Main differences Creatinine mg/dl Plasma Na meq/l Timing to treatment IV diuretics in UF Diuresis in control (L) UNLOAD 1,5 139±5 Within 24h No 3.3± h CARRESS 2.09 vs 1.9 N.A. Within 42 h No 7.1±4 96 h CUORE 1.9 vs ±4 Within 24h Yes Vol, removal 7.9 ±5 at disch. Inoltre nel CUORE la rimozione aveva un target preciso e controllato, nell UNLOAD era lasciata a discrezione del clinico, nel CARRESS HF era 200 ml/h fino al miglioramento dei sintomi da overload

31 Sintesi sui trials in SCUF E difficile trovare evidenze dai tre studi Le maggiori differenze metodologiche consistono nella modalità di deidratazione e nel timing di inizio e nella sospensione o mantenimento del diuretico La mortalità non è influenzata dal trattamento Due studi sono di confronto tra diuretico e SCUF **Tutti gli studi considerano pazienti senza refrattarietà al diuretico

32 Algorithm for management of acute pulmonary oedema/congestion Eur Heart J, 2012, 33,

33 Cardiorenal outcomes after SCUF in refractory Patients with ADHF and patients refractory to standard with ADHF medical therapy 63 pts (median age 58, median weight 98) scr 2.2±0.9, Na 131± 7 Mean time between admission to SCUF 8 days SCUF removal from 100 to 400 ml/h adjusted by hemodynamics goals, without loop diuretics (majority) Mean SCUF duration 3±2 days Weight loss from 100 Kg to 89 Kg (p<0.001) and negative fluid balance 5.7±3.8 L after 48 h 37 pts. (59 %) switched to hemodialysis and 9 (25 %) became dependent on dialysis from discharge Patarroyo, JACC, 2012, 60 (1),

34 Fenomeno del refilling plasmatico = richiamo (recupero) di fluido dall edema tissutale al plasma durante la rimozione extracorporea EDEMA TESSUTI L entità dipende da: ESPANSIONE DEL VOLUME EXTRA CELLULARE ( ) PLASMA ULTRAFILTRATO VELOCITA DELLA RIMOZIONE DI FLUIDO ( ) H2O Na CONCENTRAZIONE PROTEICA PLASMATICA ( ) H2O Na H2O Na OSMOLALITA (Na) PLASMATICA ( ) PRESSIONE IDROST. CAPILLARI ( )

35 Migliore volemia efficace Na plasmatico Bilancio Na Refilling Marenzi G. JACC 2001; 38: 963

36 Venous line IUF-SCUF Fluid removal (1-4 L) related to volume overload Filter Ultrafiltrate Peristaltic pump Arterial line CVVH Fluid removal (20-50 L) with replacement need: negative balance related to volume overload Utilized as CRRT for depurative treatment In AKI Na+140 Reinfusion Ultrafiltrate Filter Venous line Peristaltic pump Arterial line

37 Bilancio di sodio con UF isolata vs. CVVH post diluizione (deidratazione 2.5 L; Na+ inf. 140 mmol/l ; 2 L /ora per 24 ore). Modello di cinetica del Na+ monocompartimentale 400,00 Rimozione Sodio durante terapia SCUF vs. CVVH post 350,00 300,00 250,00 mmol/24h 200,00 150,00 Sodio Sodio Sodio ,00 50,00 0,00 SCUF CVVH post Ciandrini A. Università di Bologna

38 SCUF vs. CVVH Na+paz.=125 mmol/l deidratazione= 2,5 L/day reinfusione post 2L/h Modello di cinetica del Na+ monocompartimentale 138,00 136,00 134,00 132,00 130,00 128,00 126,00 124,00 122,00 120,00 118,00 CVVH SCUF Simulazione [Na] tempo (min) Bilancio Na (SCUF) -312 mmol Ciandrini A. Università di Bologna Bilancio Na (CVVH) +58 mmol

39 Quando è indicato nell ADHF un trattamento sostitutivo? Quale? -Mancata riduzione dell edema dopo aumento della dose di diuretico -UNa+ < 50 mmol/l RESISTENZA AL DIURETICO pna+ > 130 mmol/l *No AKI SCUF pna+ < 130 mmo/l *AKI CVVH *Incremento di creatinina 200 % e/o riduzione diuresi (< 0.5 ml/kg per 12 ore) (AKIN stage 2)

40 48 pazienti con egfr 21± 10 ml/min 30 uno scambio/die con ICODESTRINA 5 due scambi/die 13 automatizzata notturna 2-4 gg/settimana