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all’ultrafiltrazione in urgenza”

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1 all’ultrafiltrazione in urgenza”
UNIVERSITA’ DEGLI STUDI DI PERUGIA Scuola di Specializzazione in Medicina di Emergenza e Urgenza Direttore Prof. Giancarlo Agnelli SEMINARIO “Lo scompenso cardiaco acuto: dalla terapia diuretica all’ultrafiltrazione in urgenza” Gianfranco Alunni “Area Scompenso” Cardiologia e Fisiopatologia CV Azienda Ospedaliera ed Università PERUGIA

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3 Acute HF: all-cause mortality
IN-HF Outcome Acute HF: all-cause mortality 27.7% 24.0% 19.2% (n. 1855) (n. 1058) (n. 797) Oliva F, Mortara A, Cacciatore G et al EJHF 2012 3

4 Cause di Ricovero in pazienti con SC
50 100 150 200 250 Sodium retention Angina/MI Dysrhythmia Hypertension COPD Infection Bennett et al. Am J Crit Care (1998) 55% 25% 15% 6% No. of patients

5 Il 90% dei pz ricoverati per HF ha congestione
Diuresi inadeguata durante ospedalizzazione N Men kg Women kg ADHERE Registry. 3rd Qtr 2003 National Benchmark Report

6 SCOMPENSO CARDIACO “LA SINDROME”
Disfunzione Cardiaca Attivazione neuroormonale - Bassa Portata - Na-ritenzione

7 IPOPERFUSIONE RENALE CO: PR, = CUORE/SNC Attivazione S.R.A.A.
Secrezione Catecolamine Rilascio Vasopressina PR = 20% PC - 25% IC = - 40% PR IPOPERFUSIONE RENALE MAP<80mm Hg) La PR rappresenta il 20% della PC in condizioni normali. In caso di PC ridotta il flusso viene deviato preferenzialmente verso cuore e SNC, pertanto il rene sarà di gran lunga l’organo più penalizzato, poichè, oltre a perdere la sua quota di base, vede ulteriormente ridurre il suo flusso per la vasocostrizione della arteriole renali afferenti, necessaria alla attuazione della redistribuzione di flusso a favore di cuore e SNC. Il risultato finale è che la PR risulterà di molto inferiore al 20% della portata attuale. La ipoperfusione renale comporta l’attivazione dei sistema neuroormonale….. Activation of angiotensin-II and aldosterone is associated with the stimulation of proinflammatory cytokines, myocardial fibrosis, disease progression, and poor outcomes in HF.8–10,33 It is also possible that the deleterious effects of diuretics are extensions of their common clinical adverse effects such as electrolyte imbalance, hypotension, and worsening kidney function.1

8  Attivazione Neuroormonale  Ritenzione Idrosalina
 IPERVOLEMIA ….si ha quindi una ritenzione idro-elettrolitica, che determina l’espansione della volemia, con conseguente aumento della pressione venosa centrale. PVC

9 Classificazione clinica dello SC
NO SI Congestion Low CO WARM/DRY A low RAP high RBF WARM/WET B high RAP high RBF COLD/DRY D low RAP low RBF COLD/WET C high RAP low RBF Adapted from Stevenson LW et al, Am H. J 1998 D

10 Effetti della Ipertensione Venosa
Congestione viscerale (miocardio compreso) Asinergia diastolica VDx e VSin.  CO Edema, Idrotorace, Ascite P. di perfusione (PA - P.venosa ) Enteropatia proteino-disperdente Epatopatia congestizia, cirrosi cardiaca Ridotta GFR In ultimo ma certamente non da ultimo, una ridotta GFR

11 High Central Venous Presssure
Impatto della Congestione Venosa sulla Pressione di Filtrazione Glomerulare High Central Venous Presssure Reduced GFR Mod. da K. Damman Eu J of HF;9 (2007) 872–878 La pressione di filtrazione è la risultante di gradiente pressorio fra il polo arterioso afferente e quello venoso efferente dei capillari glomerulari, sottratta della pressione oncotica e della pressione all’interno della capsula di Bowman. Se aumenta la pressione venosa si riduce la pressione netta di filtrazione e quindi la velocità di filtrazione glomerulare (VFG), che tenderà ad aggravare il grado di congestione. RIDOTTA VFG Jessup and Costanzo JACC 2009 Vol. 53, No. 7, 597–9

12 Classificazione clinica dello SC
NO SI Congestion Low CO WARM/DRY A low RAP high RBF WARM/WET B high RAP high RBF COLD/DRY D low RAP low RBF COLD/WET C high RAP low RBF Adapted from Stevenson LW et al, Am H. J 1998 D

13 Flusso renale PVC e VFG K. Damman et al. European Journal of Heart Failure 9 (2007) 872–878

14 La congestione peggiora la prognosi
No congestion 1-2 congestion 3-5 congestion Re-assessed at 4-6 weeks Lucas C, Am H J 2000;140:840

15 Diuretici Migliorano: Riducono: Ipervolemia e preload
I più usati… i meno studiati Farmaci EBM per SC “ON TOP” di terapia diuretica Migliorano: Riducono: Ipervolemia e preload - distensibilità arteriosa - sintomi congestizi Se con l’uso dei diuretici viene rimossa la congestione, ciò che rimane è solo l’effetto di attivare il sistema neuroormonale, che non è certo un fatto positivo nello SC

16 An example nephron from Ernst ME, Moser M NEJM 2009;36:2153–64

17 Farmacocinetica dei diuretici dell’ansa
Biodisponibilità 10: dose x 1 = 10 volte superiore Biodisponibilità 100: dose x 1 = stessa dose

18 ESC GL for the diagnosis and treatment of HF 2012
Relation between dose of loop diuretics (LD) and outcomes in HF: Results of the ESCAPE Trial Dose was NOT a significant predictor of Weight Loss Dose of LD and outcomes in HF(ESCAPE Trial) Median Weight Loss : 2.8 kg (0.7, 6.1); Weight Loss and maximum in-H dose were correlated (p=0.0007). Baseline Weight and BNP, Length of stay were significant predictors of Weight Loss After adjusting for these, dose was NOT a significant predictor of Weight Loss Background: We examined the relation of maximal in-hospital diuretic dose to weight loss, changes in renal function, and mortality in hospitalised heart failure (HF) patients. Methods: In ESCAPE, 395 patients received diuretics in-hospital. Weight was measured at baseline, discharge, and every other day before discharge. Weight loss was defined as the difference between baseline and last in-hospital weight. Mortality was assessed using a log-logistic model with non-zero background. Results: Median weight loss: 2.8 kg (0.7, 6.1); mean: 3.7 kg (22% of values b0). Weight loss and maximum in-hospital dose were correlated (p=0.0007). Baseline weight, length of stay, and baseline brain natriuretic peptide were significant predictors of weight loss. After adjusting for these, dose was not a significant predictor of weight loss. A strong relation between dose and mortality was seen (p=0.003), especially at N300 mg/day. Dose remained a significant predictor of mortality after adjusting for baseline variables that significantly predicted mortality. Correlation between maximal dose and creatinine level change was not significant (r=0.043; p=0.412) Conclusions: High diuretic doses during HF hospitalisation are associated with increased mortality and poor 6-month outcome. Vic Hasselblad European Journal of Heart Failure 9 (2007) 1064–1069

19 Mean Change in Creatinine Level
Diuretic Strategies in Pts with ADHF: DOSE study Dose x1 o x 2.5 Bolo x 2 o Infusione (n. 308) Composite End Point of Death Rehospitalization, or ED visit. Mean Change in Creatinine Level Diuretics Most patients with dyspnoea caused by pulmonary oedema obtain rapid symptomatic relief from administration of an i.v. diuretic, as a result of both an immediate venodilator action and subsequent removal of fluid. The optimum dose and route of administration (bolus or continuous infusion) are uncertain. A recent, small, prospective RCT compared 12-hourly bolus injection with continuous infusion and low-dose (equal to pre-existing oral dose) with highdose (×2.5 times previous oral dose) using a 2 × 2 factorial design.213 There was no difference between either of the treatment comparisons for the co-primary endpoints (patient global assessment of symptoms and change in serum creatinine). Compared with the low-dose strategy, the high-dose strategy was, however, associated with greater improvement in a number of secondary outcomes (including dyspnoea) but at the expense of more transient worsening of renal function. Il recente studio randomizzato Diuretic Optimization Strategies Evaluation (DOSE) trial18 non ha osservato differenze significative nel miglioramento dei sintomi (a sinistra) o della funzione renale (a destra) a 72 ore tra infusione intermittente (bolo ogni 12 ore) oppure continua sia a bassa che alta dose. Figura a sinistra: Patients’ Global Assessment of Symptoms during the 72-Hour Study-Treatment Period. Patients’ global assessment of symptoms was measured with the use of a visual-analogue scale and quantified as the area under the curve (AUC) of serial assessments from baseline to 72 hours. Mean (―SD) AUCs are shown for the group that received boluses every 12 hours as compared with the group that received a continuous infusion (Panel A) and for the group that received a low dose of the diuretic (equivalent to the patients’ previous oral dose) as compared with the group that received a high dose (2.5 times the previous oral dose) (Panel B). Plus–minus values are means }SD. Figura a destra: The mean change in the serum creatinine level over the course of the 72-hour study-treatment period is shown for the group that received boluses every 12 hours as compared with the group that received a continuous infusion and for the group that received a low dose of the diuretic (equivalent to the patients’ previous oral dose) as compared with the group that received a high dose (2.5 times the previous oral dose). To convert the values for creatinine to micromoles per liter, multiply by 88.4. ABSTRACT: Background: Loop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use. Methods In a prospective, double-blind, randomized trial, we assigned 308 patients with acute decompensated heart failure to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient’s previous oral dose) or a high dose (2.5 times the previous oral dose). The protocol allowed specified dose adjustments after 48 hours. The coprimary end points were patients’ global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours. Results In the comparison of bolus with continuous infusion, there was no significant difference in patients’ global assessment of symptoms (mean AUC, 4236±1440 and 4373±1404, respectively; P = 0.47) or in the mean change in the creatinine level (0.05±0.3 mg per deciliter [4.4±26.5 μmol per liter] and 0.07±0.3 mg per deciliter [6.2±26.5 μmol per liter], respectively; P = 0.45). In the comparison of the high-dose strategy with the low-dose strategy, there was a nonsignificant trend toward greater improvement in patients’ global assessment of symptoms in the high-dose group (mean AUC, 4430±1401 vs. 4171±1436; P = 0.06). There was no significant difference between these groups in the mean change in the creatinine level (0.08±0.3 mg per deciliter [7.1±26.5 μmol per liter] with the high-dose strategy and 0.04±0.3 mg per deciliter [3.5±26.5 μmol per liter] with the low-dose strategy, P = 0.21). The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function. Conclusions Among patients with acute decompensated heart failure, there were no significant differences in patients’ global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT ) Felker et al. N Engl J Med 2011;364:

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21 Diuretic response There were no interactions between diuretic response and renal function Mattia A. E. Valente1, Adriaan A. Voors1*, European Heart Journal (2014) 35, 1284–1293 Mattia A. E. Valente1, Adriaan A. Voors1*, Eu Heart Journal (2014) 35, 1284–1293

22 Diuretic response in ADHF: W. Loss/40 mg furosemide
1745 hospitalized acute heart failure patients from the PROTECT trial. Adjusted hazard ratio for 180-day mortality for diuretic response. Adjusted for model 3 covariates (Table 4). Legend: dark blue: hazard function, fitted using a penalized spline, light blue: 95% CI; grey: density plot. Mattia A. E. Valente1, Adriaan A. Voors1*, European Heart Journal (2014) 35, 1284–1293

23 Consistent survival benefit for a better diuretic response (log-rank P , 0.001)
Mattia A. E. Valente1, Adriaan A. Voors1*, European Heart Journal (2014) 35, 1284–1293

24 Diuretic response in acute HF:
Clinical characteristics and prognostic significance Predictors of diuretic response Aim Diminished diuretic response is common in patients with acute heart failure, although a clinically useful definition is lacking. Our aim was to investigate a practical, workable metric for diuretic response, examine associated patient characteristics and relationships with outcome. Methods and results We examined diuretic response (defined as D weight kg/40 mg furosemide) in 1745 hospitalized acute heart failure patients from the PROTECT trial. Day 4 responsewas used to allow maximum differentiation in responsiveness and tailoring of diuretic doses to clinical response, following sensitivity analyses.We investigated predictors of diuretic response and relationships with outcome. The median diuretic responsewas20.38 (20.80 to 20.13) kg/40 mg furosemide. Poor diuretic response was independently associated with low systolic blood pressure, high blood urea nitrogen, diabetes, and atherosclerotic disease (all P , 0.05). Worse diuretic response independently predicted 180-day mortality (HR: 1.42; 95% CI: 1.11–1.81, P ¼ 0.005), 60-day death or renal or cardiovascular rehospitalization (HR: 1.34; 95% CI: 1.14–1.59, P , 0.001) and 60-day HF rehospitalization (HR: 1.57; 95% CI: 1.24–2.01, P , 0.001) in multivariable models. The proposed metric—weight loss indexed to diuretic dose—better captures a dose–response relationship. Model diagnostics showed diuretic response provided essentially the same or slightly better prognostic information compared with its individual components (weight loss and diuretic dose) in this population, while providing a less biased, more easily interpreted signal. Conclusions Worse diuretic response was associated with more advanced heart failure, renal impairment, diabetes, atherosclerotic disease and in-hospital worsening heart failure, and predicts mortality and heart failure rehospitalization in this post hoc, hypothesis-generating study. Low SBP, low serum K, high BUN, atherosclerotic disease and diabetes, associated with poor diuretic response. Mattia A. E. Valente1, Adriaan A. Voors1*, European Heart Journal (2014) 35, 1284–1293

25 Diuretic resistance Definition: failure to diurese (or decongest) in response to escalating doses of diuretics Diuretic absorption and efficacy is reduced in HF patients and response is blunted further in AHF WRF and cardiorenal syndromes, all highly prevalent in AHF. Distal tubule hypertrophy Hyponatremia We did note that patients who developed worsening diuretic response over time had a greater risk of rehospitalization outcomes in particular; while the initial diuretic response after 1 day of treatment is already predictive of outcome, responsiveness at a later time provides more accurate prognostic information Diuretic resistance … is a dynamic process, not a static one.. Mattia A. E. Valente1, Adriaan A. Voors1*, European Heart Journal (2014) 35, 1284–1293

26 The data come from a series of clinical trials and registries
The data come from a series of clinical trials and registries. You'll notice some difference in these figures, but on the average about 20% of patients who come into the hospital with decompensated heart failure have hyponatremia, defined as a serum sodium of less than 135 mEq/L. What you might notice is that the EVEREST trial, the largest clinical trial looking at patients with a vaptan, had the lowest incidence of hyponatremia in the population. This is probably reflective of the entry criteria into the trial.

27 This next slide looks at the relationship between the admitting serum sodium level in patients who come into the hospital with decompensated heart failure and mortality. The distribution and the curve here is quite interesting. It shows that when patients have a normal serum sodium level, they have the lowest risk for mortality during the hospitalization. If their serum sodium is above this normal range, there's a slight increase in mortality. But look what happens with lower levels of serum sodium. There's a stepwise and progressive increase in mortality during the hospitalization. And when patients get down to serum sodium levels below 130 mEq/L, there's a substantial increase in mortality. This goes up even further as serum sodium levels get lower.

28 The mechanisms of hyponatremia in heart failure are varied and multiple. They include the nonosmotic release of arginine vasopressin due to low cardiac output, decreased renal blood flow, and baroreceptor stimulation mediated by low blood pressure. Potent thirst stimulation mediated by both low cardiac output and angiotensin II plays a role. Diuretics, including thiazides, spironolactone, and loop diuretics, rid the body of salt and water and are also involved. Then finally, and it's important that we remember this in the population that gets admitted to the hospital with decompensated heart failure, many of these patients are taking other drugs and some of them may affect serum sodium levels. The drugs that I think about are the nonsteroidal anti-inflammatory drugs (NSAIDs) and the selective serotonin reuptake inhibitors (SSRIs).

29 What are the treatments that are available for hyponatremia in patients with heart failure? One method is to improve hemodynamics. Although there are no clinical trials that specifically address this, my own clinical experience is that improving hemodynamics in a patient population with decompensated heart failure and hyponatremia is associated with an improvement in outcomes. I mentioned before that the patients who come in with decompensated heart failure often are taking other drugs, some of which may promote hyponatremia. Clearly discontinuing these agents would be an important modality to correct the hyponatremia. Fluid restriction is the standard way. The problem with fluid restriction is that it's poorly tolerated and only minimally effective. Although we should attempt this in our patients, it's important that we be aware of the difficulties associated with fluid restriction. In general if I have a patient who comes in with hyponatremia, I will restrict their fluid to either 1 L or 1500 cc per day. I'll see how effective this is, but in general I'll usually have to do more in this patient population. Another therapy that people have looked at is the use of hypertonic saline, and in point of fact, there are some data from some clinical trials that were done in Italy suggesting that one can improve serum sodium levels and accomplish this safely by giving hypertonic saline. I want to caution the audience that this is an experimental approach and should only be done in the context of a clinical trial because the data are still emerging about whether this is a safe and effective modality for treating hyponatremia. Demeclocycline is a drug that is used that can correct hyponatremia. The results here are variable. There's nephrotoxicity. In general, heart failure experts are reluctant to use this in a heart failure population with hyponatremia particularly because of the adverse impact on renal function, which often is already an issue in this patient population. Then finally we have the new kid on the block. These are the vasopressin receptor antagonists. They have been recently approved by the FDA for the treatment of symptomatic hyponatremia and we'll talk a little bit about them as we go on in the course of this talk.

30 The use of tolvaptan in heart failure with hypervolemic hyponatremia is outlined in this slide. Tolvaptan is indicated in patients with dilutional hyponatremia with a serum sodium less than 125 mEq/L or in patients who are symptomatic with a serum sodium that's between 125 mEq/L and 135 mEq/L. These are patients who have not responded to fluid restriction alone.

31 An example nephron from Ernst ME, Moser M NEJM 2009;36:2153–64

32

33 Ridotta funzione renale
Precarico, Portata Cardiaca e Diuretici Portata Cardiaca (L/min) Pressione di riempimento ventricolare sinistra (mm Hg) Normale Insuff. Cardiaca Ridotta funzione renale Ridotta Congestione 15 30 5.0 2.5 Nel caso in cui oltre al decongestionamento si verifica un eccessivo calo del precarico con l’uso dei diuretici, per l’ulteriore calo della PC, si passa facilmente ad una condizione di insufficienza renale, che sappiamo influenza notevolmente la prognosi. Il rene riceve il 20% della portata cardiaca in condizioni normali. In caso di bassa portata, si verifica una rididstribuzione del flusso a favore di cuore e cervello. Da ciò risulta evidente come sia il rene l’organo che più di ogni altro ne fa le spese; infatti vedrà crollare la sua quota di portata cardiaca, ben al di sotto del 20%. A queste condizioni, l’eccessiva riduzione della pressione di riempimento VS, determina un ulteriore abbassamento della portata cardiaca e la conseguente ulteriore sofferenza renale. Hypotension may be an important physiologic mechanism of diuretic resistance in severe CHF, which is independent of renal function Background: Diuretic resistance and systemic hypotension are common in chronic heart failure (CHF), however, the two have not been associated. Aims: Since blood pressure (BP) might be an important determinant of sodium excretion, we searched for an association between BP and diuretic dosage in severe CHF. Methods: Our heart failure database was retrospectively reviewed for patients with severe left ventricular systolic dysfunction. The 54-patient cohort was divided on the basis of frusemide dosage (high-dose z250 mg daily, n=26). Results: Patients taking high-dose frusemide had higher serum creatinine, and lower systolic and diastolic BP. On logistic regression analysis, increased serum creatinine and reduced diastolic BP were independent predictors of the use of high-dose frusemide. Grouping these variables into tertiles, the odds ratio for the use of high-dose frusemide was 4.0 as diastolic BP decreased ( p<0.01), and 6.8 as serum creatinine increased ( p<0.001). Conclusions: We have found an association between hypotension and the use of high-dose frusemide in severe CHF, which is independent of renal function, and which may be an important physiologic mechanism of diuretic resistance in severe CHF. Ipovolemia!! Robert W. Schrier, MD Circ Heart Fail. 2008;1:2-5 modificata

34 Diuretici e Deplezione di Volume
Ipovolemia Rilascio Renina Angiotensina II Vasocostrizione Selettiva Arteriola Efferente Mantenimento Fraz. di Filtrazione ESC Expert Consensus Document on ACE-I, European Heart Journal (2004) 25,

35 The clinical presentation of hyponatremia is outlined on this slide
The clinical presentation of hyponatremia is outlined on this slide. The clinical manifestations are largely due to central nervous system dysfunction secondary to cerebral edema. Depending on the rapidity and severity of hyponatremia, these symptoms may vary from headache and nausea, vomiting, disorientation, seizures, and coma all the way onward to death when hyponatremia develops very rapidly. Usually in patients with decompensated heart failure, it's a slower process, and gastrointestinal symptoms and disorientation are the most common symptoms in the heart failure population.

36 The reason for this is that the vaptans work by helping the kidneys to get rid of free water. With the reduction in free water, there's a reduction in pulmonary artery wedge pressure.

37 Let me talk a little bit about some of the common side effects with tolvaptan. These include thirst, polydipsia, polyuria, dry mouth, and frequent daytime urination. These are perhaps not surprising given the mechanism of action of this drug.

38 So for management when patients come in hyponatremic, we exert fall precautions during the early period in the hospital. If we start a vaptan, we'll measure electrolytes initially 3 times a day for the first day or 2 and then we'll switch back to twice daily during the duration that the vaptan is being used.

39 Let me summarize then some of the clinical implications and approaches to managing patients with hyponatremia. Hyponatremia is common in patients with decompensated heart failure and, looking at the available data, occurs in about 20% of the population. There is good evidence that low serum sodium is associated with cognitive and neuromuscular impairment and also increased mortality. What we don't know is whether or not improving serum sodium levels enhances outcomes and improves morbidity and mortality figures. That's a question that remains unanswered at least at this time. Vaptans increase serum sodium levels in patients with hypovolemia and hyponatremia. Vaptans can improve cognitive function, enhance diuresis, and improve hemodynamics. These agents are generally well tolerated with a low side effect profile. The effects on survival and other outcomes in hyponatremic heart failure patients are uncertain and we await the results of future clinical trials.


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