Elsevier

Journal of Critical Care

Volume 28, Issue 2, April 2013, Pages 219.e1-219.e12
Journal of Critical Care

Hyponatremia in critical care patients: Frequency, outcome, characteristics, and treatment with the vasopressin V2-receptor antagonist tolvaptan

https://doi.org/10.1016/j.jcrc.2012.06.001Get rights and content

Abstract

Hyponatremia is a common problem in critical care patients and is associated with increased duration of hospital stay and increased morbidity and mortality. The prevalence of hyponatremia in the intensive care unit (ICU) has been reported to be as high as 30% to 40%. Recent studies have found hyponatremia at ICU admission in up to 14% of patients in unselected groups; patients with hyponatremia were at elevated risk of mortality vs normonatremic patients. Most cases in the ICU are euvolemic or hypervolemic hyponatremia, with the syndrome of inappropriate secretion of antidiuretic hormone being a predominant cause. The oral selective vasopressin V2-receptor antagonist tolvaptan is effective in treating euvolemic and hypervolemic hyponatremia and may be useful in the management of hyponatremic critical care patients. Tolvaptan treatment increases serum sodium via aquaresis—ie, increased electrolyte-free water excretion—and thus presents an advantage in patients with syndrome of inappropriate secretion of antidiuretic hormone or other euvolemic states or hypervolemic hyponatremia. This article provides a review of hyponatremia and of the potential use of tolvaptan in critical care settings. Case reports provide examples of tolvaptan use in correcting severe hyponatremia and associated abnormal mental status and in resolving hyponatremia prior to surgery.

Introduction

Hyponatremia is common in the critical care population and is associated with significantly increased risk of mortality [1], [2], [3], [4], [5], [6], [7], [8], [9]. Many factors contribute to the high frequency of hyponatremia in critical care settings, including use of hypotonic fluids in patients with compromised ability to maintain water balance, surgery, trauma, numerous medications, and numerous disease states. Hypotonic hyponatremia (excess water relative to solute in extracellular fluid) is of the greatest relevance to the critical care setting, with some data indicating that approximately three quarters of intensive care unit (ICU) hyponatremia cases are hypervolemic or euvolemic hyponatremia [2], [10]. Most patients with hyponatremia have clinical euvolemia, in part because of the large number of diseases associated with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) [11]. SIADH is the most common cause of euvolemic hyponatremia in the critical care setting [10] and is associated with numerous factors, including many commonly used medications, central nervous system (CNS) disorders, carcinomas, and pulmonary disorders [3], [10], [12], [13]. Most hyponatremia is hospital-acquired in association with nonosmotic stimuli for production of arginine vasopressin (AVP; also known as antidiuretic hormone). Because hospitalized patients have numerous stimuli for AVP production, all should be considered at risk for hyponatremia [3].

Tolvaptan is an orally available, selective vasopressin V2-receptor antagonist indicated in the United States for treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium < 125 mEq/L) or less-marked hyponatremia that is symptomatic and resistant to correction by fluid restriction, including patients with SIADH and those with heart failure or cirrhosis. It is not indicated for the treatment of hypovolemic hyponatremia. Vasopressin V2-receptor antagonism acts to increase electrolyte-free water excretion and increase sodium concentration in SIADH and in edema-forming conditions such as heart failure and cirrhosis and is thus an appropriate treatment modality for many cases of hyponatremia in the critical care setting [5].

Section snippets

Prevalence and outcome of hyponatremia in critical care settings

The prevalence of hyponatremia in the ICU can be as high as 30% to 40% [4], [14], [15], and the frequency at admission has been reported at 14% (for serum sodium < 130 mEq/L) in one study [2] and at 13.8%, 2.7% and 1.2% (for serum sodium of 130–134, 125–129, and < 125 mEq/L, respectively) in another [7]. Several studies have shown that mortality is significantly increased in ICU patients with hyponatremia compared with normonatremic patients [2], [6], [7], [8], [9]. Bennani et al, for example,

Benefits of hyponatremia resolution

In a prospective cohort study of 98 411 adults hospitalized between 2000 and 2003 at 2 teaching hospitals in Boston, MA, patients with hyponatremia (serum sodium concentration < 135 mEq/L) had an increased risk of death in hospital (odds ratio, 1.47; 95% CI, 1.33-1.62), at 1 year (hazard ratio, 1.38; 95% CI, 1.32-1.46), and at 5 years (hazard ratio, 1.25; 95% CI, 1.21-1.30) [16]. The increased risk of death was evident even in those with mild hyponatremia (130–134 mEq/L; odds ratio, 1.37; 95% CI,

Characteristics of hyponatremia in critical care

Hyponatremia may be the consequence of chronic heart or liver disease, diuretic use, SIADH, adrenal insufficiency, impaired thyroid function, or cerebral or renal salt wasting. It may reflect increased, decreased, or normal body sodium concentrations, necessitating evaluation of serum osmolality; fluid volume must also be assessed since hypo-osmolar hyponatremia can be hypovolemic, euvolemic, or hypervolemic [12]. AVP secretion appears to be a central component in the reduction of sodium

Management of hyponatremia in critical care

Hyponatremia is particularly difficult to prevent and treat in critical care. Patients frequently have multiorgan system dysfunction in which access to fluids and renal water handling are impaired [3]. Incorporation of fluid management into the management of severe acute and chronic illnesses can be difficult. Further, the most severe cases of hyponatremia (those with CNS involvement) are likely to be managed in the ICU, necessitating prompt diagnosis and treatment.

Hypovolemic hyponatremia is

Conivaptan treatment for hyponatremia

Conivaptan is a dual V1A/V2-receptor antagonist that is administered via an IV loading dose over 30 minutes, followed by 24-hour continuous infusion for up to 4 days [33]. The effect of conivaptan on serum sodium was demonstrated in a double-blind, placebo-controlled, randomized, multicenter study involving 84 patients with euvolemic (n = 56) or hypervolemic (n = 28) hyponatremia (serum sodium, 115-130 mEq/L; mean, 123.3 mEq/L) from a variety of underlying causes (malignant or nonmalignant

Tolvaptan treatment for hyponatremia

Tolvaptan is an oral, selective vasopressin V2-receptor antagonist that blocks the effects of AVP, resulting in increased electrolyte-free water excretion and, thus, increased serum sodium concentration. Unlike diuretics, tolvaptan does not significantly affect urinary sodium or potassium excretion or serum potassium concentration. It is currently indicated for treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium < 125 mEq/L) or less-marked hyponatremia that

Potential uses of tolvaptan in critical care settings

Tolvaptan may have significant utility in treating hyponatremia in patients in a critical care setting(as noted previously, IV conivaptan is the preferred option for hospitalized patients who cannot tolerate oral medications; its use, however, is limited to a total of 4 days). In patients requiring surgical procedures that may be impacted due to hyponatremia, correction of the abnormality can potentially reduce length of hospital stay and thereby reduce risk of infection following surgery.

Conclusions

Hyponatremia is common in critical care patients and is associated with a prolonged hospital stay and increased morbidity and mortality. Vigilance for both hyponatremia at ICU admission and hyponatremia acquired during the ICU stay should be high. Hyponatremia should be investigated as a cause of delirium in ICU patients. Euvolemic hyponatremia, and SIADH in particular, may be the most common form of hyponatremia in critically ill patients, with hypervolemic hyponatremia also being quite

Acknowledgments

The authors wish to thank Eric Justice of BioScience Communications, New York, New York, for editorial assistance in the development of this manuscript (supported by Otsuka America Pharmaceutical, Inc, Rockville, MD).

References (46)

  • R.J. Anderson et al.

    Hyponatremia: a prospective analysis of its epidemiology and the pathogenetic role of vasopressin

    Ann Intern Med

    (1985)
  • M.L. Moritz et al.

    Dysnatremias in the critical care setting

    Contrib Nephrol

    (2004)
  • E.J. Hoorn et al.

    Development of severe hyponatremia in hospitalized patients: treatment-related risk factors and inadequate management

    Nephrol Dial Transplant

    (2006)
  • R.W. Schrier et al.

    Diagnosis and management of hyponatremia in acute illness

    Curr Opin Crit Care

    (2008)
  • H.T. Stelfox et al.

    The epidemiology of intensive care unit-acquired hyponatraemia and hypernatraemia in medical-surgical intensive care units

    Crit Care

    (2008)
  • G.C. Funk et al.

    Incidence and prognosis of dysnatremias present on ICU admission

    Intensive Care Med

    (2010)
  • C.C. Jenq et al.

    Serum sodium predicts prognosis in critically ill cirrhotic patients

    J Clin Gastroenterol

    (2010)
  • H.T. Stelfox et al.

    Characterization of intensive care unit acquired hyponatremia and hypernatremia following cardiac surgery

    Can J Anaesth

    (2010)
  • M.D. Kraft et al.

    Treatment of electrolyte disorders in adult patients in the intensive care unit

    Am J HealthSyst Pharm

    (2005)
  • M.S. Buckley et al.

    Electrolyte disturbances associated with commonly prescribed medications in the intensive care unit

    Crit Care Med

    (2010)
  • M.V. DeVita et al.

    Incidence and etiology of hyponatremia in an intensive care unit

    Clin Nephrol

    (1990)
  • R.W. Schrier

    Body water homeostasis: clinical disorders of urinary dilution and concentration

    J Am Soc Nephrol

    (2006)
  • H.J. Adrogué et al.

    Hyponatremia

    N Engl J Med

    (2000)
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    Conflicts of interest: BF is on Speakers' Bureaus for Otsuka America Pharmaceutical, Inc (manufacturer of tolvaptan) and Astellas Pharma US, Inc (manufacturer of conivaptan). JC is an employee of Otsuka America Pharmaceutical, Inc, which manufactures tolvaptan.

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