Using hypertonic saline to facilitate diuresis seems counterintuitive, paradoxical even. Volume overloaded patients have excess sodium. Why should we give them more? Let’s start by trying to understand the underlying physiology.
hypochloremia may cause renal sodium retention
We generally don’t pay much attention to serum chloride levels. Chloride is often viewed as a leftover, an inert anion that doesn’t actually do anything. Have you ever been paged urgently because a patient had hypochloremia? Probably not.
Hypochloremia is common in patients with advanced heart failure, where it is perhaps best known as a predictor of mortality. We generally discuss this in terms of hypochloremia’s partner, hyponatremia. However, when we fixate on hyponatremia, we are probably focusing on the less important half of this power couple. When the two are directly compared, hypochloremia is actually more predictive of mortality than is hyponatremia.1–3
Hypochloremia isn’t merely a marker of poor prognosis. Rather, hypochloremia can promote sodium retention in several ways:
- Hypochloremia appears to stimulate renin secretion, thereby activating the renin/angiogensin/aldosterone axis.4 Alternatively, hypertonic saline can suppress renin production by the kidney.5,6
- Hypochloremia triggers up-regulation of NaCl channels in the distal convoluted tubule, thereby increasing sodium retention.7
evidentiary support that hypochloremia causes diuretic resistance
Lysine chloride use with mercurial diuretics
In the 1950's it was noted that some patients treated with mercurial diuretics developed hypochloremia, leading to diuretic resistance (“low-salt syndrome”). Several investigators noted that administration of exogenous lysine chloride could improve chloride levels and thereby restore diuretic responsiveness.8,9
Hanberg JS et al. 2016 Hyperchloremia and diuretic resistance in heart failure: Mechanistic insights
This is a two-part study by translational researchers at Yale seeking to clarify the role of hypochloremia in heart failure.10
Part I: Observational study of 162 patients
The first part of the study is an observational study of an outpatient heart failure clinic. As part of patient assessment, 1-3 doses of diuretic were administered in the clinic, with subsequent analysis of urine production.
At baseline, patients with hypochloremia tended to require a higher maintenance furosemide dose (160 mg vs. 80 mg, p<0.001), had lower average GFR (40 vs 52, p=0.01), and had lower average systolic blood pressure (117 mm vs. 126 mm, p=0.005). Overall, patients with hypochloremia were sicker, which is consistent with numerous epidemiological studies.
When challenged with diuretics in the clinic, chloride concentration was related to diuretic resistance in a U-shaped fashion (figure above). Both hypochloremia and hyperchloremia correlated with increased likelihood of diuretic resistance. Multivariable analysis showed that chloride persisted as an independent predictor of diuretic response (even when accounting for other variables including sodium level, bicarbonate level, and several clinical parameters).
Patients with hypochloremia had reduced efficacy of loop diuretics. However, the reabsorption of sodium in the proximal tubule plus ascending loop of Henle was not affected by chloride levels (assessed using the fractional excretion of lithium). Thus, it appears that hypochloremia results in increased sodium reabsorption which occurs after the loop of Henle.
Patients with hypochloremia had higher renin levels. Renin was correlated more closely with hypochloremia than with hyponatremia. In multivariable models, hyperchloremia correlated independently with renin levels (whereas hyponatremia did not).
Part II: Interventional study of oral lysine chloride
The second part of the study involved the administration of oral lysine chloride to stable outpatients with heart failure. Ten patients were selected with >80 mg daily furosemide requirement. Just as in the studies of mercurial diuretics from the 1950s, lysine chloride augmented diuretic efficacy. This was reflected in several indicators of volume loss (decreased weight, decreased brain natriuretic peptide, increased albumin level).
theoretical rationale for hyperdiuresis
Hyperdiuresis involves simultaneous administration of hypertonic saline (e.g. ~150 ml of 3% saline) along with IV furosemide. The rationale for why hypertonic saline could augment loop diuretics is as follows:
- Hypertonic saline could improve chloride levels, thereby reversing the effects of hypochloremia on sodium retention (explored above).
- Hypertonic saline could osmotically pull fluid into the intravascular space, thereby promoting diuresis without intravascular volume depletion.
- Increasing the intravascular volume prior to diuresis could temporarily reduce neurohormonal sodium retention (e.g. renin/angiotensin/aldosterone and sympathetic nervous system stimulation), thereby facilitating diuresis.
The combination of hypertonic saline plus furosemide may have synergistically beneficial effects, which cannot be derived from either alone. For example:
- Hypertonic saline alone may decrease renin production and cause some renal vasodilation, thereby facilitating diuresis. However, the increase in chloride levels may also tend to decrease renal blood flow (due to tubuloglomerular feedback).11
- Furosemide blocks tubuloglomerular feedback due to hyperchloremia.12 Thus, the combination of furosemide plus hypertonic saline might retain some beneficial properties (e.g. renin suppression) without triggering tubuloglomerular feedback.
evidentiary basis for hyperdiuresis
Studies by the Di Pasquale et al. group
A group of investigators in Italy has published several studies on hyperdiuresis which are extremely positive. Unfortunately, the validity of these studies has come under question. One meta-analysis coauthored by Di Pasquale was retracted due to concerns regarding duplicated data, which couldn’t be located. A subsequent systematic review on sodium intake excluded all studies by their group (stating “Due to published concerns with the integrity of the data, we did not include any studies from the Di Pasquale group”).13
It’s impossible for me to know the validity of data from the Di Pasquale group. I have no doubt that they have treated many patients with hyperdiuresis, with excellent clinical results. At least some of their data is likely valid (and perhaps all of it is valid). However, to err on the side of being conservative, I’ve excluded data from their group for now.
Mercadante S et al 2009: High-dose furosemide and small-volume hypertonic saline solution infusion for the treatment of leg edema in advanced cancer patients
This is a prospective cohort study in Italy describing 24 patients with advanced malignancy and peripheral edema refractory to conventional diuretic therapy.14 Inclusion criteria required a life expectancy of over one month and a baseline serum sodium <140 mM. Patients were treated twice daily with a regimen of 250 mg furosemide in 180 ml of 3% NaCl over 20 minutes. All patients recorded a subjective improvement in edema, with a diuretic effect of 3.6 liters/day on average. No adverse effects were noted. Following diuresis, patients often experienced improved diuretic sensitivity and were able to be maintained on low doses of oral furosemide. The study is limited by a lack of detail regarding underlying diagnoses and serum chemistries.
Issa VS et al 2013 Hypertonic saline solution for prevention of renal dysfunction in patients with decompensated heart failure
This is a double-blind RCT in Brazil involving 33 patients with decompensated systolic heart failure and creatinine <3 mg/dL.15 Patients were randomized to receive furosemide (in a dose titrated against clinical effect) twice daily, either combined with 100 ml 0.9% NaCl or 100 ml of 7.5% NaCl. Randomization occurred in a ratio of 2:1, with most patients receiving hyperdiuresis.
The primary endpoint was creatinine elevation by 0.3 mg/dL from baseline (which is a common definition of acute kidney injury). Creatinine elevation occurred in 25% of control patients, compared to 10% of hyperdiuresis patients (p=0.01). Creatinine actually tended to increase in the control group, whereas it decreased in the hyperdiuresis group (figure above). Patients in the hyperdiuresis group had a trend towards losing slightly more weight, despite receiving less furosemide (mean 120 mg vs. 160 mg, p<0.001).
Engelmeier et al 2012 Randomized trial of high dose furosemide-hypertonic saline in acute decompensated heart failure with advanced renal disease
This is a blinded RCT in Wisconsin involving 50 patients with acute decompensated heart failure and renal failure (GFR <60 ml/min).16 Patients were randomized to 80 mg of IV furosemide plus 150 ml 0.9% saline (control group) versus 250 mg IV furosemide plus 150 ml 2.4% saline (hyperdiuresis group).
Patients treated with hyperdiuresis experienced a trend towards more weight loss (table below). The hyperdiuresis group experienced a slight elevation in blood urea nitrogen, with no change in creatinine or estimated GFR.
Unfortunately, this study has only been published in abstract form, so it is difficult to fully appreciate all nuances. The study might weakly support the efficacy of hyperdiuresis, but differences in furosemide doses between the groups make this murky.
Yayla C et al. 2015 Comparison of three diuretic treatment strategies for patients with acute decompensated heart failure
This is a single-center RCT in Turkey investigating 43 patients with acute heart failure (excluding patients with creatinine >2 mg/dL, hypotension, or patients on vasodilators/inotropes)(baseline characteristics above).17 All patients were normonatremic at baseline. Patients were randomized into three different treatment arms for 48 hours:
- Bolus group (bl) = furosemide 80 mg IV boluses, twice daily
- Continuous group (cIv) = IV furosemide 160 mg/day, given as a continuous infusion over 16 hours
- Hyperdiuresis group (HSS) = 160 mg IV furosemide plus 150 ml of 2% NaCl, twice daily infused over 30 minutes
Patients in the hyperdiuresis group had shorter hospital length of stay (table below). There were no differences in the change in creatinine over time.
Patients in the hyperdiuresis group trended towards a greater weight loss. This wasn’t significant, (but if expressed as weight change per hospital day, it almost certainly would have been).
Wan et al 2017: Impact of compound hypertonic saline solution on decompensated heart failure
This is a single-center unblinded RCT in China involving 264 patients with systolic heart failure and refractory volume overload.18 Patients were randomized to receive 100 mg IV furosemide twice daily, with or without 100 ml of compound hypertonic saline solution (2.8% NaCl with 0.2% KCl and 0.9% MgSO4). Patients in the hypertonic saline group experienced more effective diuresis, shorter hospital stays, and a reduced rate of re-admission:
LaFreniere G 2017: Effects of hypertonic saline solution on body weight and serum creatinine in patient with acute decompensated heart failure
This is a prospective cohort study describing 47 patients with refractory acute decompensated heart failure treated with hyperdiuresis at Quebec University Hospital Centre.19 Patients were included if they failed to respond to conventional therapy. Subsequently, patients received a combination of 150 ml 3% NaCl plus 250 mg IV furosemide twice daily. Changes in weight and creatinine were compared before and after institution of hyperdiuresis.
Inclusion in the study was made at the discretion of the treating cardiologists. The following eligibility criteria were used:
Baseline characteristics are shown below. Notably, only 25% of patients had hyponatremia at baseline.
Patients were treated with hyperdiuresis for a mean duration of 2.3 days, consistent with the suggested treatment protocol above. Hyperdiuresis was more effective at reducing weight than conventional therapy (-0.4 kg/day vs. -1.4 kg/day on average, p = 0.02). This was especially true in a sub-group of 15 patients who were actively deteriorating on conventional therapy (within this subgroup, conventional therapy caused a weight gain of 0.25 kg/day, whereas hyperdiuresis resulted in a loss of 1.2 kg/day; p=0.003). 81% of patients were reported to experience a clinical improvement in congestion. The mean serum sodium increased by 2.4 mM. Neither therapy caused a significant change in serum creatinine.
No major adverse events were observed (particularly, no pulmonary congestion or neurologic sequelae were reported). Hyperdiuresis did need to be discontinued prematurely in two patients (in one case due to a rise in sodium from 120 mM to 128 mM, in another patient due to hypertension).
A major limitation to this study is that the mean dose of IV furosemide prior to hyperdiuresis was 100 mg. Thus, clinical improvement might simply reflect an increase in furosemide dosage (from 100 mg to 500 mg daily).
- Hyperdiuresis involves the combination of large doses of furosemide plus hypertonic saline to facilitate diuresis. Theoretically, the two agents may function synergistically to achieve decongestion while preserving renal function.
- Hyperdiuresis remains a counterintuitive and controversial therapy. However, it is supported by a moderate amount of clinical evidence. Studies reviewed above suggest that hyperdiuresis is safe and effective across a variety of different contexts.
- Additional evidence is needed to clarify the value of this therapy. In the interim, attempting hyperdiuresis may be reasonable for patients who have failed conventional therapies and don't have other great treatment options (e.g. hyperdiuresis versus ultrafiltration/hemodialysis versus palliative care). If hyperdiuresis is attempted, it must be monitored carefully and discontinued if patients don't respond favorably.
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- 7.Elfar A, Sambandam K. The Basic Metabolic Profile in Heart Failure-Marker and Modifier. Curr Heart Fail Rep. 2017;14(4):311-320. doi:10.1007/s11897-017-0344-x
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- 9.RUBIN A, SPRITZ N, MEAD A, HERRMANN R, BRAVEMAN W, LUCKEY E. The use of L-lysine monomydrochloride in combination with mercurial diuretics in the treatment of refractory fluid retention. Circulation. 1960;21:332-336. doi:10.1161/01.cir.21.3.332
- 10.Hanberg J, Rao V, Ter M, et al. Hypochloremia and Diuretic Resistance in Heart Failure: Mechanistic Insights. Circ Heart Fail. 2016;9(8). doi:10.1161/CIRCHEARTFAILURE.116.003180
- 11.Liszkowski M, Nohria A. Rubbing salt into wounds: hypertonic saline to assist with volume removal in heart failure. Curr Heart Fail Rep. 2010;7(3):134-139. doi:10.1007/s11897-010-0018-4
- 12.He X, Greenberg S, Briggs J, Schnermann J. Effects of furosemide and verapamil on the NaCl dependency of macula densa-mediated renin secretion. Hypertension. 1995;26(1):137-142. doi:10.1161/01.hyp.26.1.137
- 13.Mahtani K, Heneghan C, Onakpoya I, et al. Reduced Salt Intake for Heart Failure: A Systematic Review. JAMA Intern Med. 2018;178(12):1693-1700. doi:10.1001/jamainternmed.2018.4673
- 14.Mercadante S, Villari P, Ferrera P, David F, Intravaia G. High-dose furosemide and small-volume hypertonic saline solution infusion for the treatment of leg edema in advanced cancer patients. J Pain Symptom Manage. 2009;37(3):419-423. doi:10.1016/j.jpainsymman.2008.03.019
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- 16.Engelmeier RS, Le TT, Kamalay SE, et al. RANDOMIZED TRIAL OF HIGH DOSE FUROSEMIDE-HYPERTONIC SALINE IN ACUTE DECOMPENSATED HEART FAILURE WITH ADVANCED RENAL DISEASE. Journal of the American College of Cardiology. March 2012:E958. doi:10.1016/s0735-1097(12)60959-0
- 17.Yayla Ç, Akyel A, Canpolat U, et al. Comparison of three diuretic treatment strategies for patients with acute decompensated heart failure. Herz. 2015;40(8):1115-1120. doi:10.1007/s00059-015-4327-y
- 18.Wan Y, Li L, Niu H, et al. Impact of Compound Hypertonic Saline Solution on Decompensated Heart Failure. Int Heart J. 2017;58(4):601-607. doi:10.1536/ihj.16-313
- 19.Lafrenière G, Béliveau P, Bégin J, et al. Effects of hypertonic saline solution on body weight and serum creatinine in patients with acute decompensated heart failure. World J Cardiol. 2017;9(8):685-692. doi:10.4330/wjc.v9.i8.685
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