International Journal of Cardiology 173 (2014) 139145

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International Journal of Cardiology

journal homepage: www.elsevier.com/locate/ijcard

Review

Hypertonic saline with furosemide for the treatment of acute congestive

heart failure: A systematic review and meta-analysis
Sumeet Gandhi a,b,, Wassim Mosleh c, Robert B.H. Myers b
a
b
c

McMaster University, Division of Cardiology, Hamilton, ON, Canada

Sunnybrook Health Sciences Centre, Division of Cardiology, University of Toronto, ON, Canada
Trinity College, Dublin, Ireland

a r t i c l e

i n f o

Article history:
Received 10 December 2013
Received in revised form 22 February 2014
Accepted 9 March 2014
Available online 14 March 2014
Keywords:
Hypertonic saline
Heart failure
Sodium
Diuretic resistance

a b s t r a c t
Background: Advanced congestive heart failure (CHF) therapies include intravenous inotropic agents, change in
class of diuretics, and venous ultraltration or hemodialysis. These modalities have not been associated with improved prognosis and are limited by availability and cost. Compared to high-dose furosemide alone, concomitant
hypertonic saline solution (HSS) administration has demonstrated improved clinical outcomes with good safety
prole.
Methods: A literature search was conducted for randomized controlled trials that investigated the use of HSS in
patients admitted to hospital with acute CHF.
Results: 1032 patients treated with HSS and 1032 controls, demonstrated decreased all-cause mortality in
patients treat with HSS with RR of 0.56 (95% CI 0.410.76,p = 0.0003). 1012 patients treated with HSS
and 1020 controls, demonstrated decreased heart failure hospital readmission with RR of 0.50 (95% CI
0.330.76,p = 0.001). Patients treated with HSS also demonstrated decreased hospital length of stay
(p = 0.0002), greater weight loss (p b 0.00001), and preservation of renal function (p b 0.00001).
Conclusion: The results of this meta-analysis demonstrate that in patients with advanced CHF concomitant
hypertonic saline administration improved weight loss, preserved renal function, and decreased length of hospitalization, mortality and heart failure rehospitalization. A future adequately powered, multi-centre, placebo controlled, randomized, double dummy, blinded trial is needed to assess the benet of hypertonic saline in patients
with renal dysfunction, in diverse patient populations, as well using a patient population on optimal current heart
failure treatment. Pending further validation, there is promise for hypertonic saline as an advanced therapy for
the management of acute advanced CHF.
2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Therapy for the management of acute congestive heart failure
(CHF) includes loop diuretics such as furosemide (Lasix), with
the goal of relieving pulmonary and systemic vascular congestion
[1]. Diuretic resistance may result from escalating doses of furosemide and is characterized by diuretic ineffectiveness and exposure
of patients to hypotension and acute kidney injury. Diuretic resistance results from a reduction in renal blood ow secondary to
renal afferent arteriolar vasoconstriction, due to activation of the
reninangiotensinaldosterone system (RAAS). Advanced heart

Disclosures: The authors do not believe that they have any conicts of interest with
regards to this research paper. This article represents original work and is not under consideration for publication elsewhere. All authors meet criteria for authorship.
Corresponding author at: A-217, 2075 Bayview Avenue, Toronto, ON M4N 3M5,
Canada. Tel.: +1 416 480 4746; fax: +1 416 480 5251.
E-mail address: Sumeet.gandhi@medportal.ca (S. Gandhi).

http://dx.doi.org/10.1016/j.ijcard.2014.03.020
0167-5273/ 2014 Elsevier Ireland Ltd. All rights reserved.

failure therapies include intravenous inotropic agents, change in

class of diuretics, and venous ultraltration or hemodialysis [2].
Despite short-term benet, these modalities have not been associated with improved prognosis and are limited by availability and cost
[3,4].
2. Diuretic resistance
Diuretic resistance is a reduction in natriuretic response that requires the use of escalating doses and/or combinations of loop and
non-loop diuretics, often at the consequence of worsening renal function [5]. The body's perception of intravascular volume depletion with
rapid diuresis in acute CHF results in activation of the RAAS and sympathetic nervous system [6]. Elevation in central venous pressure in CHF
results in increased renal venous pressure and reduction in glomerular
ltration rate. The response to this is intra-renal vasoconstriction, further reduction in glomerular ltration rate, decreased net ltration of
salt and water, and reduction in renal blood ow. Patients with CHF

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S. Gandhi et al. / International Journal of Cardiology 173 (2014) 139145

also have comorbidities that lead to chronic medical renal disease such
as hypertensive nephropathy, diabetic nephropathy, and renal vascular
disease, which over time results in nephron loss and reduction in GFR.
This vulnerable substrate, combined with the activation of the neurohormonal cascade and reduction in glomerular ltration rate, results
in decreased delivery of diuretics to the renal tubules requiring escalating doses of diuretics.
3. Hypertonic saline in CHF
Recent studies have proposed the use of intravenous (IV) hypertonic
saline solution (HSS) in combination with high-dose furosemide for the
management of advanced CHF. HSS alters renal and cardiac hemodynamics by increasing intracellular NaCl concentration, resulting in instantaneous mobilization of extravascular uid into the intravascular
space through the osmotic action of HSS [7]. Through the baroreceptor
reex, plasma volume expansion leads to a reduction in systemic vascular resistance [5]. Through these mechanisms, the small increase in preload and signicant decrease in afterload results in increased cardiac
output, renal blood ow and enhanced organ perfusion. This maintains
a therapeutic furosemide concentration in renal tubules along with the
continued delivery of sodium. Further studies in animal models suggest
that HSS can increase myocardial contractility directly through hypertonicity [8] and decreases inammatory markers such as tumour necrosis
factor- and interleukin-6, which are associated with adverse outcomes
in patients with CHF [8].
Compared to IV high-dose furosemide alone, concomitant HSS administration has demonstrated improved diuresis, preservation of
renal function, improvement in cardiac biomarkers and echocardiographic parameters [911], reduction in length of hospitalization, reduced readmissions to hospital for CHF, and reduced mortality with
good safety prole. We have performed a systematic review of studies
assessing the efcacy of HSS in combination with furosemide for the
treatment of acute advanced CHF.

4.5. Statistical analysis

Meta-analysis was conducted by combining the risk ratios of individual studies into a
pooled risk ratio using a random-effect model. Relative risk ratios are reported with 95%
condence intervals and a p value b0.05 was considered to be statistically signicant. We
tested for heterogeneity using the chi-squared test and the I2 test. The I2 test describes
the percentage of variability in effect estimates that is due to heterogeneity rather than
chance. A value of 25% suggests low variability, 50% suggests moderate variability, and
75% suggests high variability between studies [12]. Mean difference was calculated for continuous variables using a random-effect model, reported with 95% condence intervals.
Comparison of mean difference was calculated using generic inverse variance method. Funnel plots were constructed to assess for publication bias. Analyses were performed with
RevMan 5.1 (Review Manager (RevMan) [Computer program] Version 5.1. Copenhagen:
The Nordic Cochrane Centre, The Cochrane Collaboration, 2011).

5. Results
5.1. Search results
Our search strategy yielded 107 studies, of which 87 were excluded
on review of the title and abstract (Fig. 1). A further 10 studies were excluded after careful review of the full text. Where only partial information on the outcomes of interest was reported, the authors were
contacted and asked to provide additional information. Five review articles were excluded as no new patient data was offered [5,1316]. One
case report of a patient with cardiogenic shock who was administered
10% NaCl hypertonic saline with improvement in dyspnea was also excluded [17]. Ventrella et al. treated patients with cardiorenal syndrome
with intravenous hypertonic saline and high-dose furosemide; this
study was excluded as the authors could not provide an English language translation of their article [18]. Paterna et al. conducted a randomized control trial treating patients with acute heart failure with
hypertonic saline with high dose furosemide compared to hypertonic
saline and torasemide [19]. This study was excluded due to lack of a

4. Methods
4.1. Study selection
A systematic search was conducted to retrieve studies that investigated the use of hypertonic saline with furosemide for treatment of acute advanced congestive heart failure.
We identied potential English-language sources from the Pubmed, Medline, EMBASE,
and Cochrane databases from 1950 to November 2013. Keywords used were (hypertonic
saline) and (heart failure). Electronic search of abstracts available online were also
reviewed from the annual congresses of the Canadian Cardiovascular Congress,
European Society of Cardiology, American College of Cardiology, the American Heart Association, and the American Society of Nephrology.
4.2. Inclusion/exclusion criteria
Studies were included if they met the following criteria: (i) subjects included patients
with acute advanced congestive heart failure treated with hypertonic saline and adjuvant
furosemide; (ii) control group included patients with acute advanced heart failure treated
with furosemide; and (iii) published abstract or full article in the English language. Eligibility assessment and data extraction were carried out independently by two investigators
(SG and WM) with discrepancies resolved by consensus in consultation with the senior
author.
4.3. Outcomes of interest
Primary outcomes of interest were the pooled relative risk ratio (RR) of (i) all-cause
mortality and (ii) heart failure hospital readmission in patients. Secondary outcomes
were length of hospitalization, weight loss, and change in serum creatinine.
4.4. Study quality and data extraction
Quality assessment was carried out independently by two investigators (SG and
WM) using the NewcastleOttawa quality assessment scale. We assessed eligibility
by three criteria: the selection of the study groups (04 points), the comparability
of the groups (02 points), and the ascertainment of either the exposure or outcome
of interest (03 points), with a total score of 9. A score 5 was adequate for inclusion
in the meta-analysis. Discrepancies in interpretation of data and inclusion of studies
were resolved in consultation with the senior author.

Fig. 1. Flow diagram of studies included in systematic review.

S. Gandhi et al. / International Journal of Cardiology 173 (2014) 139145

comparable control group with patients treated only with furosemide.

Issa [20] treated 9 patients with acute CHF with hypertonic saline and
furosemide; this study was also excluded due to a lack of comparable
control group. De Vecchis et al. treated patients with acute CHF with furosemide and hypertonic saline and mannitol; this study was also excluded due to a lack of comparable control group [21].
Overall 10 studies were eligible for inclusion in the systematic review. Among these, 5 allowed calculation of RR for mortality, 4 allowed
for calculation of RR for heart failure rehospitalization, 7 studies allowed
for calculation of weighted mean difference (WMD) for length of hospitalization, 8 studies allowed for calculation of WMD for weight loss, and
8 studies allow for calculation of WMD for change in serum creatinine.
5.2. Characteristics of included studies
Characteristics of all eligible studies and patient characteristics are
outlined in Tables 1 and 2. All patients were admitted for acute advanced
CHF, and all studies were randomized control trials. HSS administration
and diuretic dosing are listed in Table 3. All studies reported results from
different patients; there was no overlap in patients between studies. All
studies did not blind the investigators to the treatment assigned. Six
studies [8,9,11,2224] adjusted the concentration of HSS solution

141

based upon serum sodium values to avoid electrolytes disturbances.

Four studies [10,11,22,24] treated the HSS group with a 120 mmol/day
sodium diet compared to the control group which received an
80 mmol/day sodium diet [23]; all patients received a 120 mmol/day
sodium diet [8] and all patients received a b 70 mmol/day sodium diet.
The remaining studies did not disclose the dietary restriction of sodium.
We assessed the quality of included studies using the Newcastle
Ottawa quality assessment scales (Table 1). A score 5 was considered adequate quality for inclusion. Overall, the quality of studies
was high. Six studies [8,10,11,22,24,25] scored 8 points, two studies
[10,26] scored 7 points, and two studies [26,27] scored 6 points.
There was no publication bias detected in comparing mortality and
heart failure hospital readmission in patients treated with hypertonic saline and furosemide compared to furosemide alone respectively,
based on the symmetry of the funnel plots (Figs. 2 and 3).
6. Outcome results
6.1. Mortality
Five randomized control trials studies that assessed all-cause mortality [11,2225] met inclusion criteria with 1032 patients treated

Table 1
Study characteristics.
Study (year)

Study design

Inclusion

Primary study endpoints

Quality
assessment a

Okuhara (2012)
Parrinello (2012)

Randomized, double blind study

Randomized, double blind study

Not identied
Not identied

6
7

Engelmeier (2012)

Randomized, double-dummy study,

enrollment November 2009April 2011
Randomized, double blind study,
enrollment June 2008December 2010

Patients with acute heart failure

Patients with acute heart failure, NYHA III or IV, EF b45%,
BNP N100 pg/mL
Patients with acute heart failure, advanced renal disease
(eGFR b60 mL/min)
N18 years of age, acute heart failure, EF 40%

Not identied

Issa (2011)

Tuttolomondo (2011)

Paterna (2000)

Paterna (2005)

Paterna (2011)

Parrinello (2011)

Licata (2002)

8
Primary outcome:
Increase in serum creatinine
Secondary outcomes:
Difference in serum creatinine,
serum cystatin C, serum NGAL, urine
AQP2, urine NHE3,
8
Randomized double single blind study,
Acute heart failure
Primary outcomes:
enrollment 20052009
Difference in serum ANP, BNP, TNFalpha, IL-1 beta, IL-6, P-selectin IL-10,
ICAM-1, VCAM-1
7
Randomized, single blind study,
EF b35%, NYHA class IV, unresponsive to treatment with Not identied
enrollment January 1996June 1998
oral high doses of furosemide up to 250500 mg/day and
or combinations of diuretics at least 2 weeks before the
randomization and hospitalization
8
Randomized, double blind study,
EF b35%, NYHA class IV, unresponsive to treatment with Not identied
enrollment January 2000January 2002
oral high doses of furosemide up to 250500 mg/day and
or combinations of diuretics at least 2 weeks before the
randomization and hospitalization
8
Randomized, single blind study,
EF b40%, NYHA class III HF
Primary outcomes:
enrollment September 2000August 2007
Death, rst hospitalization for
worsening CHF
Secondary outcomes:
Death from cardiac causes,
hospitalization for cardiac causes,
combined incidence of death from
cardiac causes or hospitalization for
cardiac causes, change in NYHA class
8
Randomized double blind study,
EF b45%, NYHA class IV, unresponsive to treatment with Not identied
enrollment October 2007December 2008 oral high doses of furosemide up to 250500 mg/day and
or combinations of diuretics at least 2 weeks before the
randomization and hospitalization
8
Randomized single blind study,
EF b45%, NYHA class IV, unresponsive to treatment with Not identied
enrollment January 1996December 1999 oral high doses of furosemide up to 250500 mg/day and
or combinations of diuretics at least 2 weeks before the
randomization and hospitalization

ANP, atria natriuretic peptide; AQP2, aquaporin 2; BNP, brain natriuretic peptide; CHF, congestive heart failure; EF, ejection fraction; ICAM1, intracellular adhesion molecule 1; NYHA, New
York Heart Association; NGAL, neutrophil gelatinase-associated lipocalin; NHE3, sodium/hydrogen exchanger 3; PCWP, pulmonary capillary wedge pressure, TNF, tumour necrosis factor;
VCAM-1, vascular cellular adhesion molecule 1;
a
NewcastleOttawa quality assessment scale.

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S. Gandhi et al. / International Journal of Cardiology 173 (2014) 139145

Table 2
Patient characteristics.
Study (year)

Subjects (% female)

Mean age (years)

Mean baseline ejection fraction (%)

Mean baseline renal function

Okuhara (2012)

HSS: 22
Control: 22
HSS: 122 (41%)
Control: 126 (40%)
HSS: 25
Control: 25

HSS: n/a
Control: n/a
HSS: 74.9
Control: 72
HSS: n/a
Control: n/a

HSS: n/a
Control: n/a
HSS: 35.7
Control: 35.5
HSS: n/a
Control: n/a

Issa (2011)

HSS: 20 (5%)
Control: 12 (42%)

HSS: 53.3
Control: 41.5

HSS: 20.8
Control: 26.9

Tuttolomondo (2011)

HSS: 120 (46%)

Control: 30 (47%)

HSS: 64
Control: 66

HSS: 35
Control: 39

Paterna (2000)

HSS: 30 (37%)
Control: 30 (33%)

HSS: 73.57
Control: 74.3

HSS: 30.3
Control: 30.27

Paterna (2005)

HSS: 48 (38%)
Control: 46 (35%)

HSS: 74.7
Control: 74.5

HSS: 30.1
Control: 30.2

Paterna (2011)

HSS: 953 (37%)

Control: 974 (37%)

HSS: 74.7
Control: 73.4

HSS: 33.7
Control: 34.4

Parrinello (2011)

HSS: 66 (36%)
Control: 67 (34%)

HSS: 75.6
Control: 76.3

HSS: 35.7
Control: 35.5

Licata (2002)

HSS: 53 (38%)
Control: 54 (35%)

HSS: 74.7
Control: 74.5

HSS: 30.4
Control: 30.3

HSS: n/a
Control: n/a
HSS: 1.22 mg/dL
Control: 1.18 mg/dL
HSS: 1.78 mg/dL
Control: 1.79 mg/dL
Included patients with eGFR b60 mL/min
HSS: 1.72 mg/dL
Control: 1.58 mg/dL
Excluded patients with serum creatinine N3 mg/dL (265 umol/L)
HSS: 1.1 mg/dL
Control: 1.0 mg/dL
Excluded patients with serum creatinine N2.5 mg/dL (221 umol/L)
HSS: 1.6 mg/dL
Control: 1.65
Excluded patients with serum creatinine N2 mg/dL (176.8 umol/L)
HSS: 1.51 mg/dL
Control: 1.55 mg/dL
Excluded patients with serum creatinine N2 mg/dL (176.8 umol/L)
HSS: 1.65 mg/dL
Control: 1.61 mg/dL
Excluded patients with serum creatinine N2.5 mg/dL (221 umol/L)
HSS: 1.5 mg/dL
Control: 1.4 mg/dL
Excluded patients with serum creatinine N2 mg/dL (176.8 umol/L)
HSS: 1.6 mg/dL
Control: 1.65 mg/dL
Excluded patients with serum creatinine N2 mg/dL (176.8 umol/L)

Parrinello (2012)
Engelmeier (2012)

HSS, hypertonic saline solution.

with hypertonic saline and 1032 controls (Fig. 4). HSS was only administered upon initial study entry, and not during any other further hospital admissions in follow-up. All cause mortality was observed in 151 of
the 1032 in the hypertonic saline group (14.6%) versus 277 of the
1032 (26.8%) controls, with a signicant pooled RR of 0.56 (95% CI
0.410.76, p = 0.0003, I2 = 43%). Sensitivity analysis demonstrated
similar results when each individualized study was removed.
In a study by Licata et al. [22] all-cause mortality was similar in both
groups during the initial 3 months; however, after 6 months mortality

was lower in the HSS group than the control group. After 48 months,
there was a 55% survival rate in the HSS group versus 13% in the control
group (p = 0.001). 10 of the 24 patients (41.7%) in the hypertonic saline
group died from irreversible heart failure compared to 25 of 47 (53.2%)
controls (p b 0.05). Neither group was receiving beta-blockers or
spironolactone, but did receive ACE inhibitors. Issa [25] assessed inhospital mortality in their study with a median follow-up time of
69.5 days. The study was stopped prematurely as the primary endpoint of an increase in creatinine by 0.3 mg/dL (26.52 umol/L) was

Table 3
Hypertonic saline and diuretic administration.
Study (year)

Intervention
Hypertonic Saline

Okuhara, 2012
Parrinello (2012)
Paterna (2011)
Engelmeier (2012)

Diuretics
Control

IV 1.7% NaCl, 500 cc infusion

IV 5% glucose,
500 cc infusion
If sodium b125 mEq/L, given 150 cc IV 4.6% NaCl, if sodium 126135 mEq/L, given 150 cc IV None
3.5% NaCl, if sodium N135 mEq/L, given 150 cc IV 1.4%2.4% NaCl. All patients supplemented
with potassium chloride 2040 mEq/L as necessary. Given twice daily.
IV 2.4% NaCl, 150 cc infusion
IV 0.9% NaCl, 150 cc
infusion

Issa (2011)

IV 7.5% NaCl, 100 cc infusion twice daily

IV 0.9% NaCl, 100 cc

infusion twice daily

Tuttolomondo (2011)

If sodium b125 mEq/L, given IV 15 mL/kg of 4.6% NaCl, if sodium 126135 mEq/L, given
15 mL/kg of IV 3.5% NaCl, if sodium N135 mEq/L, given 15 mL/kg of IV 1.4%2.4% NaCl. All
patients supplemented with potassium chloride 2040 mEq/L as necessary. Given twice daily.
If sodium b125 mEq/L, given IV 150 cc of 4.6% NaCl, if sodium 126135 mEq/L, given 150 cc
of IV 3.5% NaCl, if sodium N135 mEq/L, given 150 cc of IV 1.4%2.4% NaCl. All patients
supplemented with potassium chloride 2040 mEq/L as necessary. Given twice daily.
If sodium b125 mEq/L, given 150 cc of IV 4.6% NaCl, if sodium 126135 mEq/L, given 150 cc
of IV 3.5% NaCl, if sodium N135 mEq/L, given 150 cc of IV 1.4%2.4% NaCl. All patients
supplemented with potassium chloride 2040 mEq/L as necessary. Given twice daily.
IV 3.0% NaCl twice daily, 150 cc infusion twice daily.

None

Paterna (2000)
Licata (2002)
Paterna (2005)

Parinello (2011)

IV furosemide bolus 40 mg daily

IV furosemide bolus 250 mg twice
daily
Intervention: IV furosemide bolus
250 mg daily
Control: IV furosemide bolus 80 mg
daily
Furosemide dosing was estimated
based upon previous dose
administered.
IV furosemide bolus 1251000 mg
twice daily

None

IV furosemide infusion 5001000 mg

daily

None

IV furosemide bolus 5001000 mg

twice daily

IV 0.9% NaCl twice

daily

IV furosemide infusion 250 mg daily

S. Gandhi et al. / International Journal of Cardiology 173 (2014) 139145

143

6.2. Heart failure hospital readmission

Fig. 2. Funnel plot for assessment of publication bias in comparison of mortality.

Four randomized control trials [11,2224] that assessed heart failure

hospital readmission met inclusion criteria with 1012 patients treated
with hypertonic saline and 1020 controls (Fig. 5). HSS was only administered upon initial study entry, and not during any other further hospital admissions in follow-up. Heart failure hospital readmission was
observed in 188 of the 1012 in the hypertonic saline group (18.6%) versus 372 of the 1020 (36.5%) controls, with a signicant pooled RR of 0.50
(95% CI 0.330.76, p = 0.001, I2 = 61%). Sensitivity analysis demonstrated that removal of the subjects from Licata et al. [22] decreased
the RR to 0.13 (95% 0.021.19, p = 0.07) and removal of the subjects
from Paternal (2011) [24] decreased the RR to 0.12 (95% CI 0.012.12,
p = 0.15). Licata et al. had mean follow-up of 31 months, Paterna
(2000) [23] followed up patients for 612 months, Paterna (2005)
[11] used a 30-day double-blind follow-up period, and Paterna (2011)
[24] used a mean follow-up of 57 months.
6.3. Hospitalization length of stay
Seven randomized control trials [811,2224] that assessed hospitalization length of stay met inclusion criteria with 1392 patients treated with hypertonic saline and 1327 controls (Fig. 6). Mean difference in
hospital length of stay between patients treated with hypertonic saline
and controls was 3.13 days (95% CI (4.23)(2.03), p b 0.00001).
Sensitivity analysis demonstrated similar results when each individualized study was removed.
6.4. Weight loss

Fig. 3. Funnel plot for assessment of publication bias in comparison of heart failure hospital
readmissions.

reached. Paterna (2000) [23] followed patients for up to 15 months

after discharge from hospital. No patients in the hypertonic saline
group died from cardiac causes and 7 of the 11 (64%) patients who
died in the control group suffered irreversible heart failure. Neither
group was receiving beta-blockers or spironolactone, but both were receiving ACE inhibitors. Paterna (2005) [11] conducted a second 30-day
double-blind follow-up period for patients. No patients in the hypertonic saline group that died during this period and 1 of the 3 patients in the
control group died from irreversible heart failure. Paterna (2011) [24]
provided further follow up for a mean of 57 months. In the hypertonic
saline group 69 of 881 (7.8%) died from irreversible heart failure compared to 149 of the 890 (16.7%) controls (p b 0.0001).

Eight randomized control trials [911,2226] that assessed

weight loss met inclusion criteria with 1317 patients treated with
hypertonic saline and 1334 controls. In patients treated with hypertonic saline, WMD for weight from initial study entry to discharge
was 9.78 kg (95% CI ( 10.57)( 8.99), p b 0.00001). In the control group, WMD for weight from initial study entry to discharge was
7.74 kg (95% CI ( 8.62)( 6.86), p b 0.00001). Sensitivity analysis demonstrated similar results when each individualized study was
removed. The difference in weight loss between both groups was
statistically signicant (p = 0.0002).
6.5. Renal function
Eight randomized control trials [911,2226] that assessed change in
serum creatinine met inclusion criteria with 1317 patients treated with
hypertonic saline and 1334 controls. Most patients had renal dysfunction
at study entry. In patients treated with hypertonic saline, WMD in serum
creatinine from initial study entry to discharge was 0.20 mg/dL
(17.68 umol/L) (95% CI ( 0.20)( 0.19), p b 0.00001). In the control group, mean difference in serum creatinine was 0.30 mg/dL
(26.52 umol/L) (95% CI 0.300.31, p b 0.00001) demonstrating in

Fig. 4. Forrest plot for comparison of mortality.

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S. Gandhi et al. / International Journal of Cardiology 173 (2014) 139145

Fig. 5. Forrest plot for comparison of heart failure hospital readmission.

overall increase in serum creatinine. Sensitivity analysis demonstrated

similar results when each individualized study was removed. The difference in serum creatinine between both groups was statistically signicant (p b 0.00001).
7. Discussion
The results of this meta-analysis demonstrate that in patients with
acute advanced CHF concomitant hypertonic saline administration improved weight loss, preserved renal function, and decreased length of
hospitalization, mortality and heart failure rehospitalization.
Although the results of our analysis show a signicant benet of HSS
across all outcomes, there are several limitations to this meta-analysis
which is attributed to signicant limitations of the studies discussed.
The study by Paterna et al. (2011) [24] included over 2000 patients,
which represents a large portion of the patients accounted for in this
meta-analysis. Furthermore, the studies discussed were not doubleblinded, which allows introduction of bias, specically in assessing impact of HSS on length of hospital stay. For the primary outcome measures of mortality and heart failure readmissions, only four and ve
studies were included respectively, limiting study power and the ability
to detect statistically signicant ndings. Several studies included in this
meta-analysis enrolled patients in the 1990s, and patients were less
likely to receive beta-blockers, ACE inhibitors, and aldosterone blockers.
This may result in overestimation of the current therapeutic benet of
hypertonic saline. The follow-up for mortality and heart failure hospital
readmission varied from 30 days to more than 1 year. Most signicantly, the authors of several studies have suggested that the administration
of HSS during a single admission resulted in long-term mortality benet; we cannot endorse these ndings, as there is no physiological explanation of this claim given by the authors.
Several studies excluded patients with renal dysfunction. Although
the HSS group demonstrated improvement in serum creatinine, this analysis does not take into account patients with baseline renal dysfunction,
particularly patients with serum creatinine N3 mg/dL (265.2 umol/L).
The treatment regimen and enrollment criteria differed across studies
with a wide range of HSS concentrations with variable treatment

protocols and furosemide dosing. The variation in treatment protocols

makes it difcult to establish a dose and effect relationship with HSS. Several studies used variable total salt intake between the HSS and control
group, which further skews the results of this analysis. A high salt versus
low salt diet in itself is a separate intervention, and therefore it is not possible to differentiate if the treatment effect demonstrated was due to the
HSS or the diet intervention. No studies reported major adverse effects in
the hypertonic saline group requiring cessation of hypertonic saline. Due
to the close monitoring in a clinical trial setting with many studies using
graded hypertonic saline concentration according to serum sodium
values, hypernatremia, hypokalemia, and other metabolic disturbances
were avoided. Lastly, it appears that the majority of these trials were conducted by a core group of authors in the same centre, which limits the
benet of a meta-analysis.
In the era of emergence of novel therapies for acute advanced CHF,
concomitant hypertonic saline administration still needs to be explored
on a larger stage. Although our analysis shows signicant benet, we
cannot endorse the use of HSS for acute advanced CHF at this time.
However, there are potential benets to this therapy. The benet of
such therapy includes a cost-effective alternative with decreased side
effect prole compared to inotropic agents, and reducing invasive procedures such as venous ultraltration or hemodialysis. The administration of hypertonic saline does not require an increased level of patient
monitoring in an intensive care setting, leaving this a viable option for
physicians and patients who are not in a tertiary care centre. A future
adequately powered, multi-centre, placebo controlled, randomized,
double dummy, blinded trial is needed to assess the benet of hypertonic saline in patients with renal dysfunction, in diverse patient populations, as well using a patient population on optimal current heart
failure treatment. Pending further validation, there is promise for
hypertonic saline as an advanced therapy for the management of
acute advanced CHF.

Funding
None.

Fig. 6. Forrest plot for comparison of length of hospitalization (days).

S. Gandhi et al. / International Journal of Cardiology 173 (2014) 139145

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