Principles of Diuretic Management in Heart Failure

Consequences of Extracellular Fluid Volume Expansion

Fluid overload causes a number of abnormalities in the heart. Progressive fluid overload and consequent ventricular dilatation cause dilatation of the mitral valve annulus and malcoaptation of the leaflets. As a consequence, mitral regurgitation increases and forward ejection decreases. Ventricular dilatation also increases myocardial wall stress, which increases myocardial oxygen demand and can contribute to myocardial ischemia. Furthermore, progressive volume overload can lead to a leftward shift of the interventricular septum. Septal shift causes a reduction in left ventricular (LV) cavity size, reduced LV filling and thus a reduction in cardiac output.

Fluid overload also can compromise renal function directly. Elevation of right-sided filling pressures (right atrial pressure, central venous pressure) leads to elevation in renal venous pressure. Using isolated dog kidneys perfused by a heart lung apparatus, Winton showed that increases of venous pressure to more than 20 mm Hg caused decreased renal blood flow, increased blood urea nitrogen, decreased urine volume, and decreased urine sodium excretion. Importantly, the lower the mean arterial pressure, the lesser was the increase in venous pressure required to reduce urine volume. Using isolated, perfused rat kidneys, Firth showed that an increase of venous pressure of at least 12.5 mm Hg reduced urine Na excretion, where as a venous pressure of at least 25 mm Hg reduced glomerular filtration rate (GFR). Increased renal venous pressure in intact dogs has been shown to reduce urine sodium excretion. Maxwell showed that increased renal venous pressure was associated with decreased GFR in HF patients. In a study of patients with pulmonary hypertension, right atrial pressure showed a significant negative correlation with GFR. In a study of patients undergoing right heart catheterization, a significant negative correlation was found between central venous pressure (CVP) exceeding 6 mm Hg and estimated GFR. Mullens showed that a higher admission CVP was associated with the development of worsening renal function (WRF) in patients with acute decompensated heart failure.

Increases in intraabdominal pressure sometimes are seen in advanced HF and can affect renal function. Experimental increases in intraabdominal pressure (IAP) to 20 mm Hg reduce the GFR by more than 25%. In a study of patients with acute decompensated heart failure (ADHF), elevated IAP was associated with increased baseline creatinine; there was a significant positive correlation between reductions in intraabdominal pressure and reductions in serum creatinine.

Physiologic Response to Diuretics

The normal physiologic response to a diuretic leads to a decrease in the effect of the diuretic over time. Inhibition of sodium chloride reabsorption in the thick ascending limb of Henle (TALH) by loop diuretics causes a significant increase in the delivery of sodium chloride to the distal convoluted tubule (DCT). Studies have demonstrated a load-dependent increase in DCT sodium reabsorption in response to a bolus of furosemide. Once the tubular diuretic concentration falls below its threshold concentration, a period of sodium retention begins. Mechanisms of postdiuretic sodium retention include extracellular fluid volume (ECFV) depletion, increased TALH sodium reabsorption (caused by increased NKCC transporter number and activity), and increased DCT sodium reabsorption (caused by increased sodium chloride transporter number). Finally, chronic diuretic use leads to progressively less natriuresis for any given diuretic dose. This response has been termed the “braking phenomenon.” ECFV depletion is necessary for the braking phenomenon to occur. Depletion of the ECFV causes stimulation of sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS). SNS stimulation and angiotensin II increase proximal tubular sodium reabsorption as well as increase the filtration fraction. An increase in filtration fraction results in greater proximal tubular fluid reabsorption owing to increases in peritubular capillary oncotic pressure. Norepinephrine and angiotensin II reduce renal blood flow, thus reducing the filtered load and excretion of sodium. Aldosterone causes increases in collecting duct sodium reabsorption, which further reduces urine sodium excretion. Finally, the chronic administration of loop diuretics leads to hypertrophy and hyperplasia of the DCT, which further increases sodium reabsorption and contributes to the braking phenomenon. This DCT hypertrophy depends on increased sodium chloride delivery and increased serum aldosterone.

Influence of Heart Failure on Diuretic Responsiveness

In HF, arterial underfilling causes baroreceptor activation resulting in increased levels of norepinephrine, renin, angiotensin II, and aldosterone. Consequently, there is a reduction in the filtered load of sodium, an increase in the proximal reabsorption of sodium, decreased distal delivery of filtrate to the nephron, and increased distal sodium reabsorption. All of the above events reduce the available sodium to be excreted by diuretics. Furthermore, in more advanced HF, baroreceptor-mediated vasopressin release causes increased water reabsorption by the nephron. As HF progresses, the degree of arterial underfilling worsens, causing progressive increases in norepinephrine, angiotensin II, aldosterone, and vasopressin. The physiologic responses to HF act synergistically with the normal responses to diuretics, potentially leading to diuretic resistance.