title: Hypertonic Saline in Conjunction with High-Dose Furosemide Improves Dose-Response Curves in Worsening Refractory Congestive Heart Failure.
abstract: BACKGROUND
  Diuretic 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.
  
  
  METHODS
  Forty-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.
  
  
  RESULTS
  After 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.
  
  
  CONCLUSIONS
  These results may serve as new pathophysiological basis for HSS use in the treatment of refractory CHF.
authors.affiliation: Dipartimento Biomedico di Medicina Interna e Specialistica (DIBIMIS), AOUP "Paolo Giaccone" Università degli Studi di Palermo, Palermo, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Paterna
authors.affiliation: Dipartimento Biopatologia e Biotecnologie Mediche e Forensi (DiBiMEF), AOUP "Paolo Giaccone" Università degli Studi di Palermo, Palermo, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Di Gaudio
authors.affiliation: Dipartimento Energia, Ingegneria dell'Informazione e Modelli Matematici (DEIM), Università degli Studi di Palermo, Palermo, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: La Rocca
authors.affiliation: Dipartimento Biomedico di Medicina Interna e Specialistica (DIBIMIS), AOUP "Paolo Giaccone" Università degli Studi di Palermo, Palermo, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Balistreri
authors.affiliation: Dipartimento Biopatologia e Biotecnologie Mediche e Forensi (DiBiMEF), AOUP "Paolo Giaccone" Università degli Studi di Palermo, Palermo, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Greco
authors.affiliation: Dipartimento Biomedico di Medicina Interna e Specialistica (DIBIMIS), AOUP "Paolo Giaccone" Università degli Studi di Palermo, Palermo, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Torres
authors.affiliation: Dipartimento Biomedico di Medicina Interna e Specialistica (DIBIMIS), AOUP "Paolo Giaccone" Università degli Studi di Palermo, Palermo, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Lupo
authors.affiliation: UO Medicina D'Urgenza e Pronto Soccorso AOUP "Paolo Giaccone" Università degli Studi di Palermo, Palermo, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Rizzo
authors.affiliation: UO di Cardiologia "Paolo Borsellino", Ospedale GF Ingrassia Palermo, Palermo, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: di Pasquale
authors.affiliation: Dipartimento Biopatologia e Biotecnologie Mediche e Forensi (DiBiMEF), AOUP "Paolo Giaccone" Università degli Studi di Palermo, Palermo, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Indelicato
authors.affiliation: Dipartimento Biomedico di Medicina Interna e Specialistica (DIBIMIS), AOUP "Paolo Giaccone" Università degli Studi di Palermo, Palermo, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cuttitta
authors.affiliation: Cardiology Division, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Javed
authors.initials: J
authors.lastname: Butler
authors.affiliation: Dipartimento Biomedico di Medicina Interna e Specialistica (DIBIMIS), AOUP "Paolo Giaccone" Università degli Studi di Palermo, Palermo, Italy. gaspare.parrinello@unipa.it.
authors.forename: Gaspare
authors.initials: G
authors.lastname: Parrinello
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002908:Chronic Disease; D004232:Diuretics / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004361:Drug Tolerance; D005260:Female; D005665:Furosemide / Q000008:administration & dosage / Q000627:therapeutic use*; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009994:Osmolar Concentration; D012462:Saline Solution, Hypertonic / Q000008:administration & dosage / Q000627:therapeutic use*; D012964:Sodium / Q000652:urine
chemical_list: D004232:Diuretics; D012462:Saline Solution, Hypertonic; D005665:Furosemide; D012964:Sodium
keywords: Dose–response curves; Furosemide; Heart failure; Hypertonic saline; Refractory chronic heart failure