517 Review Article on Heart Failure Update and Advances in 2021 Page 1 of 8 Optimal diuretic strategies in heart failure Sarabjeet S. Suri, Salpy V. Pamboukian Division of Cardiovascular Diseases, University of Alabama at Birmingham, Birmingham, AL, USA Contributions: (I) Conception and design: SS Suri; (II) Administrative support: SV Pamboukian; (III) Provision of study materials or patients: Both authors; (IV) Collection and assembly of data: Both authors; (V) Data analysis and interpretation: Both authors; (VI) Manuscript writing: Both authors; (VII) Final approval of manuscript: Both authors. Correspondence to: Dr. Sarabjeet S. Suri, MD. University of Alabama at Birmingham, 1900 University Blvd, THT 321, Birmingham, AL 35223, USA. Email: [email protected]. Abstract: Heart failure (HF) is one of the major causes of morbidity and mortality in the world. According to a 2019 American Heart Association report, about 6.2 million American adults had HF between 2013 and 2016, being responsible for almost 1 million admissions. As the population ages, the prevalence of HF is anticipated to increase, with 8 million Americans projected to have HF by 2030, posing a significant public health and financial burden. Acute decompensated HF (ADHF) is a syndrome characterized by volume overload and inadequate cardiac output associated with symptoms including some combination of exertional shortness of breath, orthopnea, paroxysmal nocturnal dyspnea (PND), fatigue, tissue congestion (e.g., peripheral edema) and decreased mentation. The pathology is characterized by hemodynamic abnormalities that result in autonomic imbalance with an increase in sympathetic activity, withdrawal of vagal activity and neurohormonal activation (NA) resulting in increased plasma volume in the setting of decreased sodium excretion, increased water retention and in turn an elevation of filling pressures. These neurohormonal changes are adaptive mechanisms which in the short term are associated with increased contractility of the left ventricular (LV) and improvement in cardiac output. But chronically, the failing heart is unable to overcome the excessive pressure and volume leading to worsening HF. The primary symptomatic management of ADHF includes intravenous (IV) diuresis to help with decongestion and return to euvolemic status. Even though diuretics have not been shown to provide any mortality benefit, they have been clinically proven to be of significant benefit in the acute decompensated phase, as well as in chronic management of HF. Loop diuretics remain the mainstay of therapy for symptomatic management of HF with use of thiazide diuretics for synergistic effect in the setting of diuretic resistance. Poor diuretic efficacy has been linked with higher mortality and increased rehospitalizations. Keywords: Heart failure (HF); diuresis; diuretic resistance Submitted Jun 10, 2020. Accepted for publication Aug 07, 2020. doi: 10.21037/atm-20-4600 View this article at: http://dx.doi.org/10.21037/atm-20-4600 Renal physiology amount of renal plasma flow (RPF) that is filtered across glomerulus (GFR/RPF). It averages about 20%. Extent of Diuretics act on kidneys, and as such, understanding renal chronic kidney disease (CKD) is based on the GFR: stage physiology is pivotal to understanding the role of diuretic 1 GFR>90, stage 2 GFR 60–89, stage 3a 45–59, stage 3b therapy in treating heart failure (HF). Kidneys receive about 30–44, stage 4 15–29, and stage 5 <15. CKD has been 20% of cardiac output which corresponds to about 1 L/minute. demonstrated to be an independent risk factor for poor The glomerular filtration rate (GFR) is the amount of fluid outcomes, morbidity, and mortality in HF (1). filtered from glomeruli into Bowman’s capsule per unit time Kidney autoregulation works to maintain a normal expressed as mL/min/1.73m2. Filtration fraction (FF) is the GFR. Renin-angiotensin-aldosterone system (RAAS) © Annals of Translational Medicine. All rights reserved. Ann Transl Med 2021;9(6):517 | http://dx.doi.org/10.21037/atm-20-4600 Page 2 of 8 Suri and Pamboukian. Optimal diuretic strategies in HF plays an important role through a sequential downstream including biomarkers like elevated brain natriuretic peptide pathway leading to the activation of angiotensin II which (BNP) helps further corroborate an ADHF episode. is responsible for inducing vasoconstriction resulting in Normal natriuretic peptide levels (BNP <100 pg/mL, increased blood pressure, constricting efferent arterioles to N-terminal pro-BNP <300 pg/mL) are helpful in excluding increase FF in the setting of low renal blood flow (RBF), as HF as they carry a high negative predictive value for ADHF well as the releasing aldosterone from the zona glomerulosa (4,5). Imaging evidence of congestion, such as distended of the adrenal gland. It is also responsible for antidiuretic inferior vena cava and B lines in more than 3 lung fields on hormone (ADH) secretion in the posterior pituitary gland bedside ultrasound, can aid in establishing the diagnosis. which stimulates the insertion of the aquaporin channel in A transthoracic echocardiogram to assess left ventricular the collecting duct, responsible for water reabsorption (2). (LV) dysfunction, LV dimension, ejection fraction (6). Right The syndrome of HF decreases RBF as a consequence heart catheterization (RHC) remains the gold standard of increased venous pressure which leads to increased for diagnosis ADHF and to risk stratify the severity of FF resulting in increased protein concentration in the the disease, but given its invasive nature and need for a peritubular capillaries, inadvertently leading to more trained physician to perform the procedure, it is difficult sodium (Na+) and water reabsorption in the nephron to perform on every patient. Furthermore, the Evaluation proximally. Neurohormonal activation in HF, i.e., RAAS Study of Congestive Heart Failure and Pulmonary Artery and sympathetic nervous system activation, occurs as a Catheterization Effectiveness (ESCAPE) trial which compensatory mechanism to maintain hemodynamics via evaluated the role of RHC in ADHF showed that overall salt and water retention and peripheral vasoconstriction. mortality and hospitalization rates were not improved with When these changes in persist in the chronic setting the addition of routine RHC, when compared with physical deleterious effects are induced, leading to further exam alone (7). progression of HF (3). Another dilemma while dealing with ADHF is establishing what euvolemia is. The term first defined in 1979, refers to the dry weight or ideal volume status to which diuresis Defining acute decompensated HF (ADHF) is targeted. Targeting a “dry weight” has been one of the Patients with AHDF can present with a myriad of cornerstone strategies that is employed for measuring presentations from volume overload to cardiogenic shocks congestion relief in ADHF patients, but it actually has a poor requiring inotropic or mechanical circulatory support for correlation with decongestion. Post hoc analysis of Diuretic rescue. Factors leading to exacerbation usually include Optimization Strategy Evaluation Heart Failure (DOSE- dietary indiscretion, medication non-adherence, substance HF) and Cardiorenal Rescue Study in Acute Decompensated abuse, new cardiac disease (e.g., ischemia), arrhythmias, Heart Failure (CARESS-HF) trials has shown that despite and progression of underlying cardiomyopathy. In many aggressive diuresis, 35–40% of patients were still moderately cases, the underlying cause of the exacerbation is unable congested at discharge (8). Hemoconcentration demonstrated to be identified. ADHF further contributes to the disease by elevated hemoglobin/hematocrit or albumin levels during progression through left ventricle remodeling, multi the latter part of the hospitalization has also been studied as organ failure including renal as well as liver dysfunction, another marker of decongestion (9). pulmonary hypertension and right ventricular dysfunction. Salt and fluid restriction has been seen as a non- Currently, we are most reliant on our physical exam, pharmacological way to prevent ADHF. Na+ restriction laboratory data and imaging to confirm an ADHF episode. of less than 2 g/day and fluid restriction <2 L/day are Physical exam findings including S3 gallop, elevated jugular recommended to all patients with congestive HF and are venous pressure (JVP), lung crackles, ascites, and bilateral endorsed by American Heart Association (AHA), Heart pitting edema are seen in HF. Presence of an S3 gallop has Failure Society of America as well as European Society of a high specificity for ADHF. Elevated JVP above 8 cm has Cardiology. These guidelines are based on expert opinion, a 48% sensitivity and 78% specificity to detect congestion. level of evidence C (10). Elevated JVP also correlates well with elevated left-sided filling pressures. Bilateral leg edema has 94% sensitivity but Diuretics only 10% specificity for detecting congestion. Combining the physical exam with laboratory data Any substance that increases micturition and water excretion © Annals of Translational Medicine. All rights reserved. Ann Transl Med 2021;9(6):517 | http://dx.doi.org/10.21037/atm-20-4600 Annals of Translational Medicine, Vol 9, No 6 March 2021 Page 3 of 8 Table 1 Loop diuretic dosing comparison (11,13) Characteristics Furosemide (Lasix) Torsemide Bumetanide Ethacrynic acid Half life (hours) 1.5–2.0 3.0–4.0 1.0–1.5 1.0 Bioavailability (%) 10–100 80–100 80–100 100 Initial oral dosing (mg) 20.0–40.0