Skip to main content
SpringerLink
Log in

Efficiency of Hypertonic Saline in the Management of Decompensated Heart Failure: A Systematic Review and Meta-Analysis of Clinical Studies

  • Systematic Review
  • Published:
American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

Introduction

Acute decompensated heart failure (ADHF), with an incidence of 1–2%, is a clinical syndrome with significant morbidity and mortality despite therapeutic advancements and ongoing clinical trials. A recent therapeutic approach to patients with ADHF includes combination therapy with hypertonic saline solution (HSS) and furosemide, based on the hypothesis that resistance to loop diuretics occurs because of achievement of plateau in water and sodium excretion in patients receiving long-term loop diuretic therapy.

Objective

Our aim was to conduct a meta-analysis to evaluate the efficiency of combination HSS plus furosemide therapy in patients with ADHF in terms of mortality, readmissions, length of hospital stay, kidney function, urine output, body weight, and B-type natriuretic peptide (BNP).

Methods

A total of 14 studies—four observational and ten randomized studies (total 3398 patients)—were included in the meta-analysis.

Results

Our results demonstrate the superiority of combination HSS plus furosemide therapy over furosemide alone in terms of kidney function preservation (mean creatinine difference − 0.33 mg/dL; P < 0.00001), improved diuresis (mean difference [MD] 581.94 mL/24 h; P < 0.00001) and natriuresis (MD 57.19; P < 0.00001), weight loss (MD 0.99 kg; P < 0.00001), duration of hospital stay (MD − 2.72 days; P < 0.00001), readmissions (relative risk 0.63; P = 0.01), and mortality (relative risk 0.55; P < 0.00001). However, no difference in BNP levels was detected (MD 19.88 pg/mL; P = 0.50).

Conclusion

Despite the heterogeneity and possible risk of bias among the studies, results appear promising on multiple aspects. A clear need exists for future randomized controlled trials investigating the role of combination HSS plus furosemide therapy to clarify these effects and their possible mechanisms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891–975.

  2. Cook C, Cole G, Asaria P, Jabbour R, Francis DP. The annual global economic burden of heart failure. Int J Cardiol. 2014;171(3):368–76.

    Google Scholar 

  3. Cowie M, Mosterd A, Wood D, Deckers J, Poole-Wilson P, Sutton G, et al. The epidemiology of heart failure. Eur Heart J. 1997;18(2):208–25.

    Google Scholar 

  4. Nieminen MS, Brutsaert D, Dickstein K, Drexler H, Follath F, Harjola V-P, et al. EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J. 2006;27(22):2725–36.

    Google Scholar 

  5. Afsar B, Rossignol P, van Heerebeek L, Paulus WJ, Damman K, Heymans S, et al. Heart failure with preserved ejection fraction: a nephrologist-directed primer. Heart Fail Rev. 2017;22(6):765–73.

    Google Scholar 

  6. Afsar B, Ortiz A, Covic A, Solak Y, Goldsmith D, Kanbay M. Focus on renal congestion in heart failure. Clin Kidney J. 2016;9(1):39–47.

    Google Scholar 

  7. Yerlikaya A, Bulbul MC, Afsar B, Dagel T, Aslan G, Voroneanu L, et al. Iron in kidney and heart failure: from theory to practice. Int Urol Nephrol. 2018;50(3):481–93.

    Google Scholar 

  8. Abraham WT, Adams KF, Fonarow GC, Costanzo MR, Berkowitz RL, LeJemtel TH, et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol. 2005;46(1):57–64.

    Google Scholar 

  9. Ahmed A, Allman RM, Fonarow GC, Love TE, Zannad F, Dell’Italia LJ, et al. Incident heart failure hospitalization and subsequent mortality in chronic heart failure: a propensity-matched study. J Cardiac Fail. 2008;14(3):211–8.

    Google Scholar 

  10. Adams KF Jr, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J. 2005;149(2):209–16.

    Google Scholar 

  11. Crespo-Leiro MG, Metra M, Lund LH, Milicic D, Costanzo MR, Filippatos G, et al. Advanced heart failure: a position statement of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2018;20(11):1505–35.

    Google Scholar 

  12. Shah P, Pellicori P, Cuthbert J, Clark AL. Pharmacological and non-pharmacological treatment for decompensated heart failure: what is new? Curr Heart Fail Rep. 2017;14(3):147–57.

    Google Scholar 

  13. Krämer BK, Schweda F, Riegger GA. Diuretic treatment and diuretic resistance in heart failure. Am J Med. 1999;106(1):90–6.

    Google Scholar 

  14. Dormans TP, Gerlag PG, Russel FG, Smits P. Combination diuretic therapy in severe congestive heart failure. Drugs. 1998;55(2):165–72.

    Google Scholar 

  15. De Vecchis R, Ciccarelli A, Ariano C, Pucciarelli A, Cioppa C, Giasi A, et al. Renoprotective effect of small volumes of hypertonic saline solution in chronic heart failure patients with marked fluid retention: results of a case-control study. Herz. 2011;36(1):12–7.

    Google Scholar 

  16. Nistor I, Bararu I, Apavaloaie MC, Voroneanu L, Donciu MD, Kanbay M, et al. Vasopressin receptor antagonists for the treatment of heart failure: a systematic review and meta-analysis of randomized controlled trials. Int Urol Nephrol. 2015;47(2):335–44.

    Google Scholar 

  17. Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. http://www.cochrane-handbook.org.

  18. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1–34.

    Google Scholar 

  19. Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane handbook for systematic reviews of interventions. Oxford: Wiley; 2019.

    Google Scholar 

  20. Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res. 2018;27(6):1785–805.

    Google Scholar 

  21. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14(1):135.

    Google Scholar 

  22. DerSimonian R, Kacker R. Random-effects model for meta-analysis of clinical trials: an update. Contemp Clin Trials. 2007;28(2):105–14.

    Google Scholar 

  23. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60.

    Google Scholar 

  24. Griffin M, Soufer A, Goljo E, Colna M, Rao VS, Jeon S, et al. Real world use of hypertonic saline in refractory acute decompensated heart failure: a U.S. center’s experience. JACC Heart Fail. 2020;8(3):199–208.

  25. Lafrenière G, Béliveau P, Bégin JY, Simonyan D, Côté S, Gaudreault V, 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):685–92.

    Google Scholar 

  26. Tuttolomondo A, Pinto A, Di Raimondo D, Corrao S, Di Sciacca R, Scaglione R, et al. Changes in natriuretic peptide and cytokine plasma levels in patients with heart failure, after treatment with high dose of furosemide plus hypertonic saline solution (HSS) and after a saline loading. NMCD. 2011;21(5):372–9.

    Google Scholar 

  27. Okuhara Y, Hirotani S, Ando T, Nishimura K, Orihara Y, Komamura K, et al. Comparison of salt with low-dose furosemide and carperitide for treating acute decompensated heart failure: a single-center retrospective cohort study. Heart Vessels. 2017;32(4):419–27.

    Google Scholar 

  28. Engelmeier RS, Le TT, Kamalay SE, Utecht KN, Nikstad TP, Kaliebe JW, et al. Randomized trial of high dose furosemide-hypertonic saline in acute decompensated heart failure with advanced renal disease. J Am Coll Cardiol. 2012;59(13 Supplement):E958.

    Google Scholar 

  29. Issa VS, Andrade L, Ayub-Ferreira SM, Bacal F, de Bragança AC, Guimarães GV, et al. Hypertonic saline solution for prevention of renal dysfunction in patients with decompensated heart failure. Int J Cardiol. 2013;167(1):34–40.

    Google Scholar 

  30. Licata G, Di Pasquale P, Parrinello G, Cardinale A, Scandurra A, Follone G, et al. Effects of high-dose furosemide and small-volume hypertonic saline solution infusion in comparison with a high dose of furosemide as bolus in refractory congestive heart failure: long-term effects. Am Heart J. 2003;145(3):459–66.

    Google Scholar 

  31. Okuhara Y, Hirotani S, Naito Y, Nakabo A, Iwasaku T, Eguchi A, et al. Intravenous salt supplementation with low-dose furosemide for treatment of acute decompensated heart failure. J Card Fail. 2014;20(5):295–301.

    Google Scholar 

  32. Parrinello G, Paterna S, Di Pasquale P, Torres D, Mezzero M, Cardillo M, et al. Changes in estimating echocardiography pulmonary capillary wedge pressure after hypersaline plus furosemide versus furosemide alone in decompensated heart failure. J Card Fail. 2011;17(4):331–9.

    Google Scholar 

  33. Paterna S, Di Pasquale P, Parrinello G, Amato P, Cardinale A, Follone G, et al. Effects of high-dose furosemide and small-volume hypertonic saline solution infusion in comparison with a high dose of furosemide as a bolus, in refractory congestive heart failure. Eur J Heart Fail. 2000;2(3):305–13.

    Google Scholar 

  34. Parrinello G, Di Pasquale P, Torres D, Cardillo M, Schimmenti C, Lupo U, et al. Troponin I release after intravenous treatment with high furosemide doses plus hypertonic saline solution in decompensated heart failure trial (Tra-HSS-Fur). Am Heart J. 2012;164(3):351–7.

    Google Scholar 

  35. Paterna S, Fasullo S, Parrinello G, Cannizzaro S, Basile I, Vitrano G, et al. Short-term effects of hypertonic saline solution in acute heart failure and long-term effects of a moderate sodium restriction in patients with compensated heart failure with New York Heart Association class III (Class C) (SMAC-HF Study). Am J Med Sci. 2011;342(1):27–37.

    Google Scholar 

  36. Yayla Ç, Akyel A, Canpolat U, Gayretli Yayla K, Eyiol A, Akboğa MK, et al. Comparison of three diuretic treatment strategies for patients with acute decompensated heart failure. Herz. 2015;40(8):1115–20.

    Google Scholar 

  37. Wan Y, Li L, Niu H, Ma X, Yang J, Yuan C, et al. Impact of compound hypertonic saline solution on decompensated heart failure. Int Heart J. 2017;58(4):601–7.

    Google Scholar 

  38. Harjola VP, Mullens W, Banaszewski M, Bauersachs J, Brunner-La Rocca HP, Chioncel O, et al. Organ dysfunction, injury and failure in acute heart failure: from pathophysiology to diagnosis and management. A review on behalf of the Acute Heart Failure Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur J Heart Fail. 2017;19(7):821–36.

  39. Paterna S, Di Gaudio F, La Rocca V, Balistreri F, Greco M, Torres D, et al. Hypertonic saline in conjunction with high-dose furosemide improves dose-response curves in worsening refractory congestive heart failure. Adv Ther. 2015;32(10):971–82.

    Google Scholar 

  40. De Vecchis R, Esposito C, Ariano C, Cantatrione S. Hypertonic saline plus iv furosemide improve renal safety profile and clinical outcomes in acute decompensated heart failure. Herz. 2015;40(3):423–35.

    Google Scholar 

  41. Maningas PA, Mattox KL, Pepe PE, Jones RL, Feliciano DV, Burch JM. Hypertonic saline-dextran solutions for the prehospital management of traumatic hypotension. Am J Surg. 1989;157(5):528–33.

    Google Scholar 

  42. Redfors B, Swärd K, Sellgren J, Ricksten S-E. Effects of mannitol alone and mannitol plus furosemide on renal oxygen consumption, blood flow and glomerular filtration after cardiac surgery. Intensive Care Med. 2009;35(1):115–22.

    Google Scholar 

  43. Riegel JA. Comparative physiology of renal excretion. New York: Hafner Publisher; 1972.

    Google Scholar 

  44. Sjöquist M, Göransson A, Hansell P, Isaksson B, Ulfendahl H. Redistribution of glomerular filtration and renal plasma flow in CNS-induced natriuresis. Acta Physiol Scand. 1986;127(4):491–7.

    Google Scholar 

  45. Kimura T, Abe K, Ota K, Omata K, Shoji M, Kudo K, et al. Effects of acute water load, hypertonic saline infusion, and furosemide administration on atrial natriuretic peptide and vasopressin release in humans. J Clin Endocrinol Metabol. 1986;62(5):1003–10.

    Google Scholar 

  46. Kien ND, Reitan JA, White DA, Wu CH, Eisele JH. Cardiac contractility and blood flow distribution following resuscitation with 7.5% hypertonic saline in anesthetized dogs. Circ Shock. 1991;35(2):109–16.

  47. Wang YL, Lam KK, Cheng PY, Kung CW, Chen SY, Chao CC, et al. The cardioprotective effect of hypertonic saline is associated with inhibitory effect on macrophage migration inhibitory factor in sepsis. Biomed Res Int. 2013;2013:201614.

    Google Scholar 

  48. Pascual JL, Khwaja KA, Ferri LE, Giannias B, Evans DC, Razek T, et al. Hypertonic saline resuscitation attenuates neutrophil lung sequestration and transmigration by diminishing leukocyte-endothelial interactions in a two-hit model of hemorrhagic shock and infection. J Trauma. 2003;54(1):121–30 (discussion 30–2).

  49. Shih CC, Chen SJ, Chen A, Wu JY, Liaw WJ, Wu CC. Therapeutic effects of hypertonic saline on peritonitis-induced septic shock with multiple organ dysfunction syndrome in rats. Crit Care Med. 2008;36(6):1864–72.

    Google Scholar 

  50. Hogue B, Chagnon F, Lesur O. Resuscitation fluids and endotoxin-induced myocardial dysfunction: is selection a load-independent differential issue? Shock. 2012;38(3):307–13.

    Google Scholar 

  51. Bielecka-Dabrowa A, Godoy B, Schefold JC, Koziolek M, Banach M, von Haehling S. Decompensated heart failure and renal failure: what is the current evidence? Curr Heart Fail Rep. 2018;15(4):224–38.

    Google Scholar 

  52. Ando T, Okuhara Y, Orihara Y, Nishimura K, Yamamoto K, Masuyama T, et al. Urinary composition predicts diuretic efficiency of hypertonic saline solution with furosemide therapy and heart failure prognosis. Heart Vessels. 2018;33(9):1029–36.

    Google Scholar 

  53. Griffin M, Soufer A, Goljo E, Colna M, Rao VS, Jeon S, et al. Real world use of hypertonic saline in refractory acute decompensated heart failure: a US center’s experience. JACC Heart Fail. 2020;8(3):199–208.

  54. Tuttolomondo A, Pinto A, Di Raimondo D, Corrao S, Di Sciacca R, Scaglione R, et al. Changes in natriuretic peptide and cytokine plasma levels in patients with heart failure, after treatment with high dose of furosemide plus hypertonic saline solution (HSS) and after a saline loading. Nutr Metab Cardiovasc Dis. 2011;21(5):372–9.

    Google Scholar 

  55. Gandhi S, Mosleh W, Myers RB. Hypertonic saline with furosemide for the treatment of acute congestive heart failure: a systematic review and meta-analysis. Int J Cardiol. 2014;173(2):139–45.

    Google Scholar 

Download references

Acknowledgements

MK gratefully acknowledges use of the services and facilities of the Koc University Research Center for Translational Medicine (KUTTAM), funded by the Presidency of Turkey, Presidency of Strategy and Budget. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Presidency of Strategy and Budget.

Author information

Authors and Affiliations

  1. Department of Nephrology, Grigore T. Popa’ University of Medicine and Pharmacy, Iasi, Romania

    Adrian Covic, Dimitrie Siriopol & Ionut Nistor

  2. Department of Medicine, Koc University School of Medicine, Istanbul, Turkey

    Sidar Copur

  3. Cardiovascular Diseases Institute, Gr. T. Popa” University of Medicine and Pharmacy, Iasi, Romania

    Laura Tapoi & Carina Ureche

  4. Department of Medicine, Division of Nephrology, Suleyman Demirel University School of Medicine, Isparta, Turkey

    Baris Afsar

  5. Nephrology Clinic, Dialysis and Renal Transplant Centre, “Dr C. I. Parhon” Hospital, Iasi, Romania

    Ionut Nistor

  6. Evidence Based Medicine and Research Methodology Center, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania

    Ionut Nistor

  7. Division of Nephrology, Department of Medicine, Koc University School of Medicine, 34010, Istanbul, Turkey

    Mehmet Kanbay

Authors
  1. Adrian Covic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sidar Copur
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laura Tapoi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Baris Afsar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carina Ureche
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dimitrie Siriopol
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ionut Nistor
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mehmet Kanbay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mehmet Kanbay.

Ethics declarations

Funding

No external funding was used in the preparation of manuscript.

Conflicts of interest

Adrian Covic, Sidar Copur, Laura Tapoi, Baris Afsar, Carina Ureche, Dimitrie Siriopol, Ionut Nistor, and Mehmet Kanbay have no conflicts of interest that are directly relevant to the content of this article.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and material

Not applicable.

Code availability

Not applicable.

Author contributions

Adrian Covic, Sidar Copur, Carina Ureche, Dimitrie Siriopol, Laura Tapoi, and Mehmet Kanbay contributed substantially to the conception or design of the work or the acquisition, analysis, or interpretation of data for the work. Baris Afsar, Ionut Nistor, Adrian Covic, and Mehmet Kanbay drafted the work or revised it critically for important intellectual content. Mehmet Kanbay, Adrian Covic, and Ionut Nistor approved the final version to be published.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 2675 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Covic, A., Copur, S., Tapoi, L. et al. Efficiency of Hypertonic Saline in the Management of Decompensated Heart Failure: A Systematic Review and Meta-Analysis of Clinical Studies. Am J Cardiovasc Drugs 21, 331–347 (2021). https://doi.org/10.1007/s40256-020-00453-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40256-020-00453-7

Search

Navigation