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Ultrafiltrazione
ed Emofiltrazione
nello scompenso
cardiaco
refrattario
Carlo Guastoni
TOPICS
• Scompenso cardiaco e “sindrome
cardio-renale”
• La refrattarietà al diuretico
• L’utilizzo dell’ultrafiltrazione nello
scompenso: i dati della letteratura
• L’Emofiltrazione
Arco efferente della regolazione del volume
circolante: DUE MECCANISMI NEURO-ORMONALI
Attivazione
Renina-Angiotensina
Aldosterone
Meccanismi predominanti nell’
Insufficienza cardiaca
VASOCOSTRIZIONE
IPOTALAMO
Catecolamine
ADH
ipovolemia
RIASSORBIMENTO
RENALE Na e H2O
VASODILATAZIONE
DIURESI
Ipervolemia
PEPTIDE NATRIURETICO
ATRIALE E
VENTRICOLARE
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:
Attivazione neuroormonale Catecolamine RAS
Adenosina
b)
Utilizzo del diureticomacula densa RAS
5702 pts
62±25PRESSORIO
ml/min; A/V
Alterata emodinamica intrarenale da RIDUZIONE DELeGFR
GRADIENTE
Scr. 1.2 (1-1.6) mg/dl
RENALE
•
Da aumento PVC da congestione venosa
Change in Scr> 0.3 mg/dl
anddiincrease
Aumento pressione intra-addominale in presenza
ascite >25 %
in 13
%
Riduzione della pressione di perfusione renale
(PAM-IAP)
a)
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. 2005
Metra M. Eur. H.J. 2012
Metra M Eur. H.J. 2012
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
pts.with ADHF
}AKIN stage 1
Circulation 2014; 130:958
1855 pts.
455 pts.(24.5 %)
with bas.eGFR
< 40 ml/min
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;96:132-143.
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
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±0.8
218±48
-
A
72±56*
142±3.6
1.5 ±0.9
558±64
135±11
B
120±77*+
140±2.8
17.1±12*+
1232±972
155±112
C
124±53*+
132±2.9*+§
22.4 ±17*+§
1482±1808+
223±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
Marenzi G. Eur.J.Heart Fail. 2002; 4: 597
A B C
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
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
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
Loop diuretics can cause clinical natriuretic failure:
a prescription for volume expansion
15 patients with CHF. GFR 43 ± 17 ml/min (21- 80)
Na+ 137.6± 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
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
– 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
UNLOAD main results
SCUF vs. Standard Care
SCUF
SC
p
Weight loss @ 48 h (Kg)
5.0±3.1
(4.9%)
3.1± 3.5
(3.2%)
0.001
Dyspnoea score
6.4±0.5
6.1±0.7
0.35
Vasoactive @ 48 h (%)
3/99
12/99
0.015
Net fluid loss @ 48 h (L)
4.6±2.6
3.3±2.6
0.001
Length of stay (d)
6.3±4.9
5.8±3.8
0.979
H.F Re-hospital @ 90 days (%)
16/89 (18)
28/87 (32)
0.037
Re-hospital Length of Stay (d)
1.4±4.2
3.8±8.5
0.022
CARRES-HF Study
Bart B. NEJM 2012; 367: 2296
- 188 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 hours after random assignement.
Additional i.v. vasodilators
or inotropic agents were
prohibitted only in the
Ultrafiltration Group
Bart B. NEJM 2012; 367: 2296
CARREESS-HF
96 hours after enrollment
+0.23±0.70 mg/dl
Bart B et al, N Eng J Med, 2012.
CARRES-HF Study
Secondary end points
Bart B. NEJM 2012; 367: 2296
UF
60 days mortality
17 %
Death or HF rehospital. 38 %
Death or any rehospital. 61 %
Pharmacologic therapy
13.8 % (p= 0.47)
35 % (p= 0.96)
48 % (p= 0.12)
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
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.
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.
Main results
* p<0.05
±4.5
*
±3.9 ±5.1
±3.1
5%
*
9%
6%
±5
8.8 %
5%
±3.5
3.2%
Osservazione
48 h
96 h
Dimissione
Main results
* p<0.05
p = 0.08
*
*
90 days
60 days
90 days
1 year
H.F
H.F
any cause
H.F
Mortality
CUORE
CARRESS
UNLOAD
Main differences
Creatinine
mg/dl
Plasma Na
mEq/l
Timing to
treatment
IV diuretics in
UF
Diuresis in
control (L)
1,5
139±5
Within 24h
No
3.3±2.6
48 h
CARRESS
2.09 vs
1.9
N.A.
Within 42 h
No
7.1±4
96 h
CUORE
1.9 vs
1.7
139±4
Within 24h
Yes
Vol, removal
7.9 ±5 at disch.
UNLOAD
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
“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
Algorithm for management of acute pulmonary oedema/congestion
Eur Heart J, 2012, 33, 1787-1847
•
Cardiorenal outcomes after SCUF in refractory
with ADHF
Patients with ADHF andpatients
refractory to standard
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), 1906-12
Fenomeno del refilling plasmatico = “richiamo” (recupero) di
fluido dall’edema tissutale al plasma durante la rimozione
extracorporea
L’entità dipende da:
ESPANSIONE DEL VOLUME
EXTRA CELLULARE (
)
EDEMA
TESSUTI
PLASMA ULTRAFILTRATO
VELOCITA’ DELLA
RIMOZIONE DI FLUIDO (↓ )
H2O
Na
H2O
Na
H2O
Na
CONCENTRAZIONE PROTEICA
PLASMATICA (
)
OSMOLALITA’(Na)
PLASMATICA ()
PRESSIONE IDROST. CAPILLARI
(↓ )
Migliore volemia
efficace
Marenzi G. JACC 2001; 38: 963
Na plasmatico
Bilancio Na
Refilling
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
Venous line
Na+140
Reinfusion
Filter
Ultrafiltrate
Peristaltic pump
Arterial line
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
Rimozione Sodio durante terapia SCUF vs. CVVH post
400,00
350,00
300,00
mmol/24h
250,00
Sodio - 130
200,00
Sodio - 135
Sodio - 140
150,00
100,00
50,00
0,00
SCUF
CVVH post
Ciandrini A. Università di Bologna
SCUF vs. CVVH
Na+paz.=125 mmol/L
deidratazione= 2,5 L/day – reinfusione post 2L/h
Modello di cinetica del Na+ monocompartimentale
Simulazione [Na]
138,00
136,00
134,00
CVVH
132,00
130,00
SCUF
128,00
126,00
124,00
122,00
1431
1378
1325
1272
1219
1166
1113
1060
1007
954
901
848
795
742
689
636
583
530
477
424
371
318
265
212
159
106
53
0
120,00
118,00
tempo (min)
Bilancio Na (SCUF) -312 mmol
Bilancio Na (CVVH) +58 mmol
Ciandrini A. Università di Bologna
Quando è indicato nell’ADHF un trattamento
sostitutivo?
-Mancata riduzione dell’edema
Quale?
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)
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
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