Original Investigation
Efficacy of Furosemide, Oral Sodium Chloride, and Fluid Restriction for Treatment of Syndrome of Inappropriate Antidiuresis (SIAD): An Open-label Randomized Controlled Study (The EFFUSE-FLUID Trial)

https://doi.org/10.1053/j.ajkd.2019.11.012Get rights and content

Rationale & Objective

First-line therapy for syndrome of inappropriate antidiuresis (SIAD) is fluid restriction. Additional treatment for patients who do not respond to fluid restriction are water restriction with furosemide or water restriction with furosemide and salt supplementation. However, the efficacy of these treatments has never been tested in a randomized controlled study. The objective of this study was to investigate whether, combined with fluid restriction, furosemide with or without sodium chloride (NaCl) supplementation was more effective than fluid restriction alone in the treatment of hyponatremia in SIAD.

Study Design

Open-label randomized controlled study.

Setting & Participants

Patients with serum sodium concentrations ([Na+]) ≤ 130 mmol/L due to SIAD.

Intervention(s)

Random assignment to 1 of 3 groups: fluid restriction alone (FR), fluid restriction and furosemide (FR+FM), or fluid restriction, furosemide, and NaCl (FR+FM+NaCl). Strictness of fluid restriction (<1,000 or <500 mL/d) was guided by the urine to serum electrolyte ratio. Furosemide dosage was 20 to 40 mg/d. NaCl supplements were 3 g/d. All treatments were continued for 28 days.

Outcomes

The primary outcome was change in [Na+] at days 4, 7, 14, and 28 after randomization.

Results

92 patients were recruited (FR, n = 31; FR+FM, n = 30; FR+FM+NaCl, n = 31). Baseline [Na+] was 125 ± 4 mmol/L, and there were no significant differences between groups. Mean [Na+] on day 4 in all treatment groups was significantly increased from baseline by 5 mmol/L (P < 0.001); however, the change in [Na+] was not significantly different across groups (P = 0.7). There was no significant difference in percentage of patients or time to reach [Na+] ≥ 130 or ≥135 mmol/L across the 3 groups. Acute kidney injury and hypokalemia (potassium  3.0 mmol/L) were more common in patients receiving furosemide.

Limitations

Open-label treatment.

Conclusions

In patients with SIAD, furosemide with NaCl supplement in combination with fluid restriction did not show benefits in correction of [Na+] compared with treatment with fluid restriction alone. Incidences of acute kidney injury and hypokalemia were increased in patients receiving furosemide.

Funding

None.

Trial Registration

Registered at the Thai Clinical Trial Registry with study number TCTR20170629004.

Section snippets

Study Population

Eligible patients were hospitalized patients who were 18 years or older with a serum [Na+] ≤ 130 mmol/L due to SIAD. For a firm diagnosis of SIAD, all the following criteria had to have been met: (1) serum osmolality < 275 mOsm/kg, (2) urine osmolality > 100 mOsm/kg, (3) clinical euvolemia diagnosed from the history and physical examination, (4) urine [Na+] > 30 mmol/L, and (5) absence of hypothyroidism, glucocorticoid deficiency, estimated glomerular filtration rate < 60 mL/min/1.73 m2 or diagnosed acute

Study Population

A total of 289 patients were screened. Of those, 92 patients underwent randomization (31 in the FR group, 30 in the FR+FM group, and 31 in the FR+FM+NaCl group; Fig 1). Two patients withdrew consent after randomization; however, both were included in outcome analyses. Overall, 66 (72%) patients completed a final visit and 10 (11%) patients died during the follow-up period; 87 (95%) of the participants had data relating to the primary objective. The percentage of patients receiving the trial

Discussion

We conducted this study because to our knowledge there has never been an RCT comparing the efficacy of fluid restriction versus furosemide and/or use of an NaCl supplement in the treatment of patients with SIAD. Our findings have shown that among patients with hyponatremia due to SIAD, there was no evidence that treatments with once-daily furosemide and/or a 3-g NaCl supplement add-on to fluid restriction resulted in a greater change in [Na+] in comparison to fluid restriction alone on day 4

Article Information

Authors’ Full Names and Academic Degrees

Pajaree Krisanapan, MD, Surachet Vongsanim, MD, Pathomporn Pin-on, MD, Chidchanok Ruengorn, PhD, and Kajohnsak Noppakun, MD.

Authors’ Contributions

Research idea and study design: KN, PK; data acquisition: PK; data analysis/interpretation: KN, PK, PP, CR, SV; statistical analysis: KN, CR; supervision or mentorship: KN, CR. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual’s own contributions and to ensure that

References (34)

  • G. Spasovski et al.

    Clinical practice guideline on diagnosis and treatment of hyponatraemia

    Nephrol Dial Transplant

    (2014)
  • E.J. Hoorn et al.

    Mild hyponatremia as a risk factor for fractures: the Rotterdam Study

    J Bone Miner Res

    (2011)
  • S. Kinsella et al.

    Hyponatremia independent of osteoporosis is associated with fracture occurrence

    Clin J Am Soc Nephrol

    (2010)
  • J.G. Verbalis et al.

    Hyponatremia-induced osteoporosis

    J Bone Miner Res

    (2009)
  • B. Renneboog et al.

    Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits

    Am J Med

    (2006)
  • I. Runkle et al.

    Treatment of hyponatremia induced by the syndrome of inappropriate antidiuretic hormone secretion: a multidisciplinary Spanish algorithm

    Nefrologia

    (2014)
  • B.J. Freda et al.

    Evaluation of hyponatremia: a little physiology goes a long way

    Cleve Clin J Med

    (2004)
  • Cited by (0)

    Complete author and article information provided before references.

    View full text