Presentazione sul tema: "e strategie di trattamento"— Transcript della presentazione:
1e strategie di trattamento Anemia,insufficienza renalee scompenso cardiaco:patogenesi comunee strategie di trattamentoGessica Italiani,Cardiologia Pescia
2Insuff. Ventricolare sx STADI MALATTIA RENALEe CARDIOVASCOLAREInsuff. Renalecronica terminaleScompenso cardiacoStadiofinaleInsuff. RenaleCronica (FG)Eventi/malattia cardiovascolareProgressioneAlbuminuriaProteinuriaInsuff. Ventricolare sxInizioPiù volte è stato sottolineato che la malattia cardiovascolare è molto simile a quella renale cronica nei vari stadi evolutivi.Età, obesitàDiabete Mellito,IpertensioneEtà, obesitàDiabete Mellito,Ipertensione“A rischio”Malattia Renale CronicaMalattia CardiovascolareSarnak MJ & Levey AS, Am J Kidney Dis, 2000
4Alta morbidità e mortalità INSUFFICIENZA CARDIACA e INSUFFICIENZA RENALEAlta prevalenzaAlta morbidità e mortalitàAlti costiSingolarmenteInvecchiamento popolazione> Incidenza diabete, obesità, IA, altri fattori di rischioCause
5PREVALENZA ASSOCIAZIONE IR-IC Registro Scompenso Cardiaco Acuto
7FATTORI di RISCHIO CV TRADIZIONALI CORRELATI A IRC Età avanzata Sesso maschileIpertensioneIpertrofia ventricolare sinistraDislipidemiaDiabete mellitoFumoInattività fisicaMenopausaStoria familiare di CVDSovraccarico volume liquido extracellulare (ECFV)AnemiaAlterato metabolismo Ca/PInfiammazione/MalnutrizioneStress ossidativoIperomocisteinemiaFattori trombogeniciProteinuriaSono elencati i fattori di rischio tradizionali e quelli correlati con l’IRC.Modificato da Am J Kidney Disease 39 (S 1): 2002
10Sindrome Cardiorenale: definizione Section 2: Pathophysiology of Acute Decompensated Heart FailureSindrome Cardiorenale: definizioneInterazione tra RENI ed altri compartimenti circolatoriAumento del volume circolantePeggioramento del compensoAccelerazione della progressione di malattia“Cardiorenal Dysregulation”:la terapia per ridurre la congestione non funziona per ulteriore declino della funzione renale1Cardiorenal syndrome is a general term that is frequently used to describe the often dysfunctional interaction between the heart and the kidney in ADHF. There does not exist a consensus definition of this term, however a recent group of investigators1 led by Lynne Warner Stevenson convened to try and further characterize this interaction. Interactions between the heart and the kidney have been garnering increasing focus because of epidemiological evidence indicating that even a mild deterioration of renal function is an important risk factor for poor outcome in patients with congestive HF.NHLBI Working Group: Cardio-Renal Connections in Heart Failure and Cardiovascular Disease, August 20, 2004Executive SummaryThe National Heart, Lung, and Blood Institute convened a Working Group of investigators on August 20, 2004, in McLean, Virginia, to evaluate the current state of knowledge regarding interactions between the cardiovascular system and the kidney, to identify critical gaps in our knowledge, understanding, and application of research tools, and to develop specific recommendations for NHLBI in cardiorenal interactions related to HF and other cardiovascular diseases such as congenital heart disease.DiscussionThe Working Group focused on cardiorenal connections in which abnormalities of cardiac function were not preceded by a known diagnosis of chronic kidney disease, such that acute and chronic renal responses are due to primary impairment of cardiac function. Among patients hospitalized for decompensated HF, worsening renal function predicts adverse cardiovascular outcomes. Since these patients are routinely excluded, clinical HF trials provide little evidence or information on which to base therapy for HF patients experiencing worsening renal function. As a result, treatment for these patients is largely empirical. The lack of formal interaction across clinical disciplines, with insight into the diverse factors that affect both cardiac and renal function, has also limited our recognition, understanding, and potential therapies for cardiorenal dysregulation in HF. New and effective therapies need to be identified for the treatment and prevention of this challenging syndrome. The deliberations and considerations of this Working Group should broaden the perspective and enhance understanding across traditional specialty boundaries.A working definition of cardiorenal dysregulation was introduced and served as the basis of subsequent discussion and recommendations. In HF, it is the result of interactions between the kidneys and other circulatory compartments that increase circulating volume and symptoms of heart failure and disease progression are exacerbated.Continued on next pageNHLBI Working Group.April 30, 2005.
11Fisiopatologia Sindrome Cardiorenale La ritenzione idroelettrolitica compensa la riduzione del “volume ematico efficace” dovuta al deficit di pompa (relazione di Frank Starling).Quando l’espansione di volume non riesce più a sopperire al deficit di pompa si sviluppa congestione sistemica
12Bongartz, L. G. et al. Eur Heart J 2005 26:11-17 GUYTON MODEL
14Scompenso Cardiaco Acuto Section 2: Pathophysiology of Acute Decompensated Heart FailureScompenso Cardiaco AcutoInsultCardiac DysfunctionLV RemodelingNeurohormonalActivationRAASCatecholamineEndothelinHemodynamicDecompensationPreloadAfterloadCardiac OutputThis diagram shows the relationship between the primary myocardial insult and subsequent events that contribute to the clinical syndrome of CHF.1 The pathophysiology of HF involves hemodynamic abnormalities, neurohumoral abnormalities, and myocardial cellular alterations. Left ventricular (LV) dysfunction results from myocardial injury. Neurohumoral activation, which includes activation of the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS), occurs in response to acute hemodynamic alterations and myocardial injury. This neurohumoral activation is counterproductive in patients with HF. Changes occur in cardiac function and peripheral circulation that contribute to the symptoms and drive the progression of HF.Neurohumoral activation results in an excess of vasoconstrictors—those in the SNS and the RAAS, as well as endothelin—which increase afterload and preload by retention of salt and water. Vasodilators—hormones in the endogenous natriuretic peptide system (NPS)—work to unload the left ventricle and promote natriuretic actions, but they are overwhelmed by the excess of vasoconstricting neurohomones. Vasodilators are ultimately beneficial counterregulatory hormones.2-4Neurohumoral activation results in progressive dilation and dysfunction of the left ventricle (remodeling). There are also fundamental abnormalities at the cellular level, including myocyte dysfunction, programmed cell death (apoptosis), fetal gene expression, hypertrophy, and myocardial fibrosis.5 Other circulating proinflammatory cytokines, such as interleukin-6 and TNF-alpha, can lead to a progressive wasting of lean tissue, fat, and bone mass.4 Based on this model, hemodynamic decompensation and neurohormonal activation may give rise to either acute impairment of LV function or chronic progression of disease, or both, in a vicious cycle.References:Colucci WS, Braunwald E. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 5th ed. Philadelphia: Saunders; 1997:Stevenson W. J Am Coll Cardiol. 2005;45:Weber. J Am Coll Cardiol. 2004:44(6):Anker et al. Am J Cardiol. 1999;83:Shah M et al. Rev Cardiovasc Med. 2001;2(suppl 2):S2-S6.Renal Vasoconstriction/Fluid RetentionFluid Overload SymptomsMorbidityDeathColucci WS, Braunwald E. Heart Disease: A Textbook of Cardiovascular Medicine. 5th ed. 1997:394.
15Fisiopatologia Sindrome cardio renale Dal 27% al 45% dei pazienti con scompenso cardiaco in stadio III-IV mostrano peggioramento acuto della funzione renaleIl monitoraggio emodinamico dimostra che la riduzione acuta della funzione renale non dipende da un diminuito output cardiacoAHJ , AGOSTO 1999, J Card Fail SMITH GL et al.
16Fisiopatologia Sindrome cardio renale Riduzione dell’attività dei peptidi natriuretici:baroreceptor adaptation con ridotta sensibilitàPotenziamento RAASPeggioramento IPONATRIEMIA (concausa i diuretici): fattore prognostico negativo
17Manifestazioni Cliniche e Mortalità IponatriemiaManifestazioni Cliniche e MortalitàCefaleaIrritabilitàNausea e VomitoConfusione mentaleDisorientamentoStupor/ComaConvulsioniArresto Respiratorio
19Admitted Patients and Volume Overload Section 1: Epidemiology and DemographicsAt Hospitalization—ADHERE®1Any dyspnea – 89%Pulmonary congestion (CXR) – 74%Rales – 67%Dyspnea at rest – 34%Peripheral edema – 65%Data from the ADHERE (Acute Decompensated Heart Failure National Registry) study show a high percentage of patients at time of admission have symptoms of both pulmonary congestion and volume overload.1,2References:The ADHERE Registry. First Quarter National Benchmark Registry. Fremont, CA: Scios Inc; 2003.2. Friedman MM. Older adults’ symptoms and their duration before hospitalization for heart failure Heart Lung. 1997;26:The Majority of These Patients Have Failed Treatment With Oral Diuretics2ADHERE Registry. 3rd Qtr 2003 National Benchmark Report.2. Adams et al. Am Heart J. 2005;149:
20TERAPIA: DiureticiRidurre il volume del fluido extracellulare (FEC) incrementando l’eliminazione di urine, in particolare di SODIO, principale determinante del FEC.
21Con i diuretici è rimovibile al massimo il 20% del carico filtrato di SODIO Brater D; Am J Med Sci 2000
22Aumento Neurormoni provoca Diuretico-Resistenza Section 3: Diuretic Therapy in Acute Decompensated Heart FailureGlomeruloNorepinephrine (and endothelin) diminuiscono il flusso renale e GRFTubulo prossimaleAng II aumenta il riassorbimento di sodioThere are 2 types of diuretic resistance—short-term tolerance (“braking”), which may be mediated by activation of angiotensin II (Ang II) or the sympathetic nervous system (SNS), or long-term tolerance, in which sodium that escapes the loop of Henle is reabsorbed at more distal sites, decreasing overall diuresis; this may be overcome with sequential diuretic blockade.1Diuretic insensitivity and resistance are conferred largely by activation of various neurohormonal systems. Ang II and renal nerve stimulation activate receptors on the proximal tubule epithelium,2,3 causing proximal tubular reabsorption of water and sodium, which decreases availability of substrates for loop and thiazide diuretics.Catecholamines (eg, norepinephrine) and endothelin, which mediate some of the renal actions of Ang II, also may decrease renal blood flow and consequently can decrease delivery of diuretics to tubules. Nearly all diuretics must be filtered by the glomeruli to reach their (intraluminal) transport mechanism.4References:1. Brater DC. N Engl J Med. 1998:339:387.2. Riggleman A et al. Hypertension. 2001;38:105.3. Bell-Reuss E et al. Effect of renal sympathetic nerve stimulation on proximal water and sodium reabsorption. J Clin Invest. 1976;57:4. Myers BD et al. Effects of norepinephrine and angiotensin II on the determinants of glomerular ultrafiltration and proximal tubule fluid reabsorption in the rat. Circ Res. 1983;37:Dotto CollettoreAldosterone aumenta il riassorbimento di sodioKrämer et al. Am J Med. 1999;106:90.
23Diuretico-resistenza Section 3: Diuretic Therapy in Acute Decompensated Heart FailureDiuretico-resistenzaRiduzione o perdita della diuresi prima del raggiungimento del goal terapeurico di risoluzione dell’edema120%–30% dei pazienti con SC21. Kramer et al. Nephrol Dial Transplant. 1999;14(suppl 4):39-42.2. Ellison. Cardiology. 2001;96:.CAUSE:Fenomeno del “Braking”Riduzione della risposta diuretica dopo la prima doseTolleranza nel lungo termineIpertrofia tubulare compensatoria alla perdita di saliThere is no consensus definition of diuretic resistance; however, it has been described as a clinical state in which the diuretic response is diminished or lost before the therapeutic goal of relief from edema has been reached. This may be mediated by the “braking” phenomenon.120% to 30% of all patients with HF develop diuretic resistance.2References:Kramer et al. Nephrol Dial Transplant. 1999;14(suppl 4):39-42.Ellison. Cardiology. 2001;96:Brater. N Engl J Med. 1998;339:387.
25METODICHE DIALITICHE CONTINUE (CRRT) Le CRRT sono tutti i trattamenti extracorporei intesi a sostituire la funzione renale insufficiente per un periodo di almeno 24 ore.“DIALISI”: movimenti di soluti in concentrazioni diverse, per depurare ed eliminare fluidi in eccesso utilizzando una membrana semipermeabile.I principi chimico – fisici in gioco nelle CRRT sono:Differenza di concentrazione delle sostanze ai due lati della membrana (DIFFUSIONE)Pressione idrostatica del liquido da filtrare (ULTRAFILTRAZIONE/CONVEZIONE)
27Storia dell’Ultrafiltrazione Section 4: Ultrafiltration History and PhysiologyStoria dell’Ultrafiltrazione1974: Silverstein described solitary ultrafiltration on 5 ESRD patients via a modified dialysis circuit31949: Schneierson proposed intermittent peritoneal dialysis for refractive ADHF1194019501960197019801954: Kolff noted that ultrafiltration could be used for a “reduction of intractable edema”21979: Paganini and others reported the practical application of ultrafiltration in a volume-overloaded patient4Ultrafiltration in its many forms (ie, peritoneal, isolated ultrafiltration via a dialysis model) as a therapeutic option for refractory ADHF has been historically evident for over 50 years. A literature review1 counted 115 published case reports that gathered patients with or without concurrent renal failure who were treated with peritoneal dialysis for refractory ADHF. Several other examples exist, as described in this slide, of isolated ultrafiltration administered in the edematous patient. Ensuing slides list various references of over 50 studies where ultrafiltration has been used in patients with refractory edema.In 1949, Schneierson proposed that peritoneal dialysis be used in a patient with refractory congestive HF. Regression of congestive HF was noted, followed by the observation of enhanced response to diuretics.22. “The concept of the extracorporeal removal of fluid with UF has been reported for over 50 years” and can be used for the “reduction of otherwise intractable edema by dialysis or filtration.” This was opined by Willem Kolff—who to some is considered the father of dialysis—who developed the first artificial kidney in Dr Kolff went on to design the heart–lung machine that made open-heart surgery possible. He has pioneered artificial eyes, ears, and arms, and for 25 years led the effort to develop the artificial heart. In 1982, a heart designed under his supervision was successfully implanted in Barney Clark, an event that captured the imagination of the world. 3,43. Silverstein described, for the first time, the use of solitary ultrafiltration in 5 current patients with end-stage renal disease (ESRD). He noted that a certain subset of patients would continue to have persistent edema despite being treated with fluid and dietary salt restriction. Ultrafiltration was completed utilizing a modified circuit with applied transmembrane pressure of 200 mmHG, with ultrafiltration rates of between 200 to 800 mL. He further observed that this was a safe procedure and that the ultrafiltrate components were identical to plasma; thus electrolyte imbalances from diuretic therapy such as hypokalemia, hypocalcemia, hyperuricemia, or contraction metabolic alkalosis would be avoided.5Continued on next page1. Schneierson SJ. Am J Med Soc. 1949;298.2. Kolff et al. Cleve Clin Q. 1954;21.3. Silverstein et al. N Engl J Med. 1974;291:4. Paganini et al. Adv Ren Replace Ther. 1996;3:
28Utilizzo in Cardiologia SCUF: Ultrafiltrazione lenta continuaRimozione di quantità elevate di liquidi dove non siano richieste necessità di depurazione. Rimuove liquido ISOTONICO rispetto al plasma (Es: SE RIMUOVO 2 LITRI DI ACQUA IN UN PAZIENTE CON NA+ DI 130 MEQ/L RIMUOVERÒ 130X2 MEQ DI SODIO)CVVHDF: Emodiafiltrazione veno-venosa continuaUtilizza DIFFUSIONE E CONVEZIONE. Rimuove piccole e medie molecole dal sangue. E’ la tecnica più utilizzata.Rimozione indipendente di sodio e acqua(Esempio: POSSO RIMUOVERE 10 LITRI DI ACQUA SENZA DOVER RIMUOVERE 130X10 MEQ DI NA+)
29Effetti Emodinamici dell’UF nello SC Section 4: Ultrafiltration History and PhysiologyEffetti Emodinamici dell’UF nello SCCO (L/m)SV (mL)5.0 –4.0 –3.0 –2.0 –70 –60 –50 –40 –30 –BeforeUF1liter2liter3liter4literAfterUF24h afterUFBeforeUF1liter2liter3liter4literAfterUF24h afterUFRAP (mmHg)PWP (mmHg)This study by Marenzi et al (brief description below) demonstrates that ultrafiltration of more than 4 L of plasma water over approximately 9 h reduced mean arterial pressures and pulmonary wedge pressure (PWP).1 Cardiac output increased at the end of the session and was shown to decrease further 24 h after ultrafiltration was completed. Moreover during treatment, heart rate, systemic arterial pressure, cardiac output, and systemic vascular resistances did not change.Further details: The goal of the study was to investigate the hemodynamic and circulatory adjustments to extracorporeal ultrafiltration in refractory congestive HF. Twenty-four patients (18 men and 6 women)—Class IV ADHF, with signs and symptoms of volume overload, >5 kg weight gain within 1 month—were allowed to continue on digoxin, diuretics (24 of 24 patients), and angiotensin-converting enzyme inhibitors (15 of 24 patients). A continuous renal replacement therapy (CRRT) device was utilized to remove fluid, and hemodynamic measurements were taken after 1 L, 2 L, 3 L, and 4 L ultrafiltration, and then 24 h after ultrafiltration had ceased. The mean duration of ultrafiltration was 9 ± 3 h, and total volume removed was 4880 L ± 896 mL. Urine output and NYHA association class improved. Response to diuretics improved from 380 ± 157 mg/day to 112 ± 70 mg/day beginning the day after ultrafiltration started.Reference:1. Marenzi et al. Circulatory response to fluid overload by extracoporeal ultrafiltration in refractory congestive heart failure. J Am Coll Cardiol. 2001;38:25 –20 –15 –10 –5 –0 -30 –25 –20 –15 –10 -BeforeUF1liter2liter3liter4literAfterUF24h afterUFBeforeUF1liter2liter3liter4literAfterUF24h afterUFMarenzi et al. J Am Coll Cardiol. 2001;38:
30Costanzo et al. J Am Coll Cardiol. 2005;46:2047-2051. The EUPHORIA Trial: Early Ultrafiltration in Patients With Decompensated HF and Observed Resistance to Intervention With Diuretic AgentsSection 5: Ultrafiltration Clinical TrialsStudio di EFFICACIA e SICUREZZAMedia dei cicli di 8: 2.6 ± 1.2Volume rimosso dall’UF: 8653 ± 4314 mLCostanzo et al. J Am Coll Cardiol. 2005;46:
31Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683. Section 5: Ultrafiltration Clinical TrialsCostanzo MR et al. J Am Coll Cardiol. 2007;49:
32Adverse Events Ultrafiltration Standard Care P Value Catheter/Needle 3 Section 5: Ultrafiltration Clinical TrialsUltrafiltrationStandard CareP ValueCatheter/Needle3.156Filter5NA.154InfectionCatheter related1.315Other49.202Bleeding7.032Hypotension2210.113Anemia.080DialysisWorsening HF3963.094Myocardial infarction2.988Arrhythmias.968Cardiac arrest6.987Neurological15.070Costanzo MR et al. J Am Coll Cardiol. 2007;49:
33Section 5: Ultrafiltration Clinical Trials ConclusioniLa precoce UF produce una perdita di peso > dei diuretici EV, senza peggioramento della funzione renaleLa strategia di UF, nel follow up a 90 giorni, RIDUCE:% di paz. reospedalizzatiNumero di ospedalizzazioni per SCGiorni di reospedalizzazione per SCVisite Emergenza o non programmateCostanzo MR et al. J Am Coll Cardiol. 2007;49:
34Ultrafiltrazione vs Terapia Diuretica Section 4: Ultrafiltration History and PhysiologyUltrafiltrazione vs Terapia DiureticaUltrafiltrato ISOTONICOMaggior rimozione di SodioNon ci sono turbe elettroliticheMaggior riduzione del volume extracellulare rispetto ad equivalente perdita di peso da diureticiPoint 2: Ultrafiltration removes more sodium than diuretics for a similar given volume. Approximately 3 g of sodium per liter of ultrafiltrate.1Point 4: Since sodium and its anion are the major determinants of extracelllular fluid (ECF) volume, ultrafiltration decreases ECF volume more than a comparable volume induced by diuretics. Therefore, it follows that ultrafiltration decreases more ECF volume than diuretics.1Reference:1. Schrier R. Role of diminished renal function in cardiovascular mortality. J Am Coll Cardiol ;47:1-8.Schrier. J Am Coll Cardiol. 2006;47:1-8.1
35ACC/AHA Guidelines 4.4.1. Management of Fluid Status Section 6: Current Therapies and Guidelines in ADHFACC/AHA GuidelinesManagement of Fluid StatusIn general, patients should not be discharged from the hospital until a stable and effective diuretic regimen is established, and ideally, not until euvolemia is achievedPatients who are sent home before these goals are reached are at high risk of recurrence of fluid retention and early readmission because unresolved edema may itself attenuate the response to diureticsHunt et al. ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult. American College of Cardiology and the American Heart Association, Inc
36Section 6: Current Therapies and Guidelines in ADHF HFSA 2006 Guidelines12.11When congestion fails to improve in response to diuretic therapy, the following options should be considered:Sodium fluid restrictionIncreasing doses of loop diureticContinuous infusion of loop diureticAddition of a second type of diuretic orally (metolazone or spironolactone) or intravenously (chlorothiazide)A fifth option, ultrafiltration, may be considered (strength of evidence:c)
37Scompenso Cardiaco ed Anemia Lo studio Framingham ha dimostrato che la presenza di anemia costituisce un fattore di rischio indipendente per lo sviluppo di Scompenso Cardiaco.Lo studio SOLVD ne ha evidenziato l’importanza come fattore prognostico negativo in pazienti già affetti da Scompenso Cardiaco.
38ANEMIA CAUSA DI SCOMPENSO CARDIACO Ipossia tessutaleVasodilatazione perifericaPressione arteriosaAttività simpaticaFlusso ematico renaleRenina angiotensina aldosterone ADHRitenzione liquidiVolume plasmaticoDiametro ventricolareIVS e infine morte cellulareScompenso cardiacoL’anemia nell’IRC attraverso vari meccanismi può essere causa di scompenso cardiaco.
58Intravenous Iron Reduces NT-Pro-Brain Natriuretic Peptide in Anemic Patients With Chronic Heart Failure and Renal InsufficiencyJorge Eduardo Toblli, MD et al, J Am Coll Cardiol, 2007; 50:Am Heart J Dec;152(6):1096.e9-15Erythropoietin improves anemia exercise tolerance and renal function and reduces B-type natriuretic peptide and hospitalization in patients with heart failure and anemia.Palazzuoli A, Silverberg DAm Heart J Oct;154(4):645.e LinksEffects of beta-erythropoietin treatment on left ventricular remodeling, systolic function, and B-type natriuretic peptide levels in patients with the cardiorenal anemia syndrome.Palazzuoli A, Silverberg DS, et al SienaJ Cardiovasc Med (Hagerstown) Nov;8(11):Prognostic value of reduced kidney function and anemia in patients with chronic heart failure.Petretta M et al Napoli (NO ANEMIA!!!)IRON - HF