Hypertonic Saline in Conjunction with High-Dose Furosemide Improves Dose–Response Curves in Worsening Refractory Congestive Heart Failure

Abstract

IntroductionDiuretic responsiveness in patients with chronic heart failure (CHF) is better assessed by urine production per unit diuretic dose than by the absolute urine output or diuretic dose. Diuretic resistance arises over time when the plateau rate of sodium and water excretion is reached prior to optimal fluid elimination and may be overcome when hypertonic saline solution (HSS) is added to high doses of furosemide.MethodsForty-two consecutively hospitalized patients with refractory CHF were randomized in a 1:1:1 ratio to furosemide doses (125 mg, 250 mg, 500 mg) so that all patients received intravenous furosemide diluted in 150 ml of normal saline (0.9%) in the first step (0–24 h) and the same furosemide dose diluted in 150 ml of HSS (1.4%) in the next step (24–48 h) as to obtain 3 groups as follows: Fourteen patients receiving 125 mg (group 1), fourteen patients receiving 250 mg (group 2), and fourteen patients receiving 500 mg (group 3) of furosemide. Urine samples of all patients were collected at 30, 60, and 90 min, and 3, 4, 5, 6, 8, and 24 h after infusion. Diuresis, sodium excretion, osmolality, and furosemide concentration were evaluated for each urine sample.ResultsAfter randomization, 40 patients completed the study. Two patients, one in group 2 and one in group 3 dropped out. Patients in group 1 (125 mg furosemide) had a mean age of 77 ± 17 years, 43% were male, 6 (43%) had heart failure with a preserved ejection fraction (HFpEF), and 64% were in New York Heart Association (NYHA) class IV; the mean age of patients in group 2 (250 mg furosemide) was 80 ± 8.1 years, 15% were male, 5 (38%) had HFpEF, and 84% were in NYHA class IV; and the mean age of patients in group 3 (500 mg furosemide) was 73 ± 12 years, 54% were male, 6 (46%) had HFpEF, and 69% were in NYHA class IV. HSS added to furosemide increased total urine output, sodium excretion, urinary osmolality, and furosemide urine delivery in all patients and at all time points. The percentage increase was 18,14, and 14% for urine output; 29, 24, and 16% for total sodium excretion; 45, 34, and 20% for urinary osmolarity; and 27, 36, and 32% for total furosemide excretion in groups 1, 2, and 3, respectively. These findings were translated in an improvement in the furosemide dose–response curves in these patients.ConclusionThese results may serve as new pathophysiological basis for HSS use in the treatment of refractory CHF.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-015-0254-9) contains supplementary material, which is available to authorized users.

Effects of intravenous furosemide plus small‐volume hypertonic saline solutions on markers of heart failure

“… 37 Administration of hypertonic saline has been shown to increase intraluminal furosemide concentrations as well as to increase 24 h of diuresis, urinary sodium levels, and urinary osmolarity. 39 Another aspect of reduced renal blood flow is the overactivation of the tubuloglomerular feedback mechanism, which may be defined as a vasomotor response to tubular osmolarity and sodium concentrations detected by macula densa cells. 40 Correction of such a compensatory feedback mechanism by means of hypertonic saline treatment and many other drugs, such as mannitol and dextran, that may attract extravascular volume towards intravascular compartments has been proposed.…”

“…Both exert their cardiac effect by activating cell surface‐associated particulate guanylate cyclase A, which in turn increases the concentration of cGMP in the subsarcolemmal compartment. 39 , 40 The myocardial response to acute stretch represents a fundamental adaptive capacity of the heart. Nevertheless, our findings concerning a lower degree of increase in inflammatory and myocardial stretching markers after an acute saline load could suggest a possible modulatory role of HSS plus a moderate/high dose of furosemide in subjects with HFrEF.…”

Does Accidental Overcorrection of Symptomatic Hyponatremia in Chronic Heart Failure Require Specific Therapeutic Adjustments for Preventing Central Pontine Myelinolysis?

“…In the genesis of hypervolemic hyponatremia, i.e., the one that typically occurs during CHF or liver cirrhosis, a frequent overlap of iatrogenic causes has been demonstrated, primarily consisting of overzealous or excessive use of drastic diuretic therapies, capable of worsening the state of reduced arterial effective circulating volume so as to elicit further secretion of ADH. The generation of a state of relative intravascular volume depletion may be prevented using albumin [ 29 ] or hypertonic saline solution [ 30 ], capable of preserving an adequate vascular refilling rate, subsequently to the depletion of the circulating volume arising from the adoption of high doses of IV loop diuretics.…”

Diuretic Resistance in Cardio-Nephrology: Role of Pharmacokinetics, Hypochloremia, and Kidney Remodeling

“…In fact, an increasing number of studies have recently described an enhanced pharmacological efficacy of furosemide when administered with HSS in HF [53]. Specifically, in 2015 Paterna et al [54] reported the dose-response curve following the intravenous administration of high doses of furosemide diluted in HSS. They observed a significant improvement of both urinary output and sodium excretion rate, corresponding to a shift in the dose-response curve to the left.…”