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