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      Vaptans and Hyponatremia in Critical Patients

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          Abstract

          Hyponatremia is the most frequent fluid and electrolyte disorder in hospitalized patients (20%), particularly in ICU, associated with an increase in morbility and mortality. While hypovolaemic hyponatremia needs to be corrected with the replacement of the lost extracellular fluid by isotonic saline, euvolaemic (SIADH) and hypervolaemic hyponatremia (oedematous states like decompensated heart failure, liver cirrhosis, i.e.) are treated by restriction of fluid intake, loop diuretics and hypertonic saline. A novel approach consists in use of vaptans, non-peptide arginine vasopressin (AVP) receptor antagonists. Vaptans cause “aquaresis”, which results in the correction of plasma osmolality and serum sodium levels, without activation of the renin-angiotensin-aldosterone system or changes in blood pressure and renal function. In this paper we critically reviewed the results of the available randomized controlled critical trials, discussing the effectiveness and safety of vaptans in treating hypervolaemic and euvolaemic hyponatremia in critical patients.

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          Most cited references44

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          Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial.

          Vasopressin mediates fluid retention in heart failure. Tolvaptan, a vasopressin V2 receptor blocker, shows promise for management of heart failure. To investigate the effects of tolvaptan initiated in patients hospitalized with heart failure. The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST), an event-driven, randomized, double-blind, placebo-controlled study. The outcome trial comprised 4133 patients within 2 short-term clinical status studies, who were hospitalized with heart failure, randomized at 359 North American, South American, and European sites between October 7, 2003, and February 3, 2006, and followed up during long-term treatment. Within 48 hours of admission, patients were randomly assigned to receive oral tolvaptan, 30 mg once per day (n = 2072), or placebo (n = 2061) for a minimum of 60 days, in addition to standard therapy. Dual primary end points were all-cause mortality (superiority and noninferiority) and cardiovascular death or hospitalization for heart failure (superiority only). Secondary end points included changes in dyspnea, body weight, and edema. During a median follow-up of 9.9 months, 537 patients (25.9%) in the tolvaptan group and 543 (26.3%) in the placebo group died (hazard ratio, 0.98; 95% confidence interval [CI], 0.87-1.11; P = .68). The upper confidence limit for the mortality difference was within the prespecified noninferiority margin of 1.25 (P<.001). The composite of cardiovascular death or hospitalization for heart failure occurred in 871 tolvaptan group patients (42.0%) and 829 placebo group patients (40.2%; hazard ratio, 1.04; 95% CI, 0.95-1.14; P = .55). Secondary end points of cardiovascular mortality, cardiovascular death or hospitalization, and worsening heart failure were also not different. Tolvaptan significantly improved secondary end points of day 1 patient-assessed dyspnea, day 1 body weight, and day 7 edema. In patients with hyponatremia, serum sodium levels significantly increased. The Kansas City Cardiomyopathy Questionnaire overall summary score was not improved at outpatient week 1, but body weight and serum sodium effects persisted long after discharge. Tolvaptan caused increased thirst and dry mouth, but frequencies of major adverse events were similar in the 2 groups. Tolvaptan initiated for acute treatment of patients hospitalized with heart failure had no effect on long-term mortality or heart failure-related morbidity. clinicaltrials.gov Identifier: NCT00071331
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            Aquaporins in the kidney: from molecules to medicine.

            The discovery of aquaporin-1 (AQP1) answered the long-standing biophysical question of how water specifically crosses biological membranes. In the kidney, at least seven aquaporins are expressed at distinct sites. AQP1 is extremely abundant in the proximal tubule and descending thin limb and is essential for urinary concentration. AQP2 is exclusively expressed in the principal cells of the connecting tubule and collecting duct and is the predominant vasopressin-regulated water channel. AQP3 and AQP4 are both present in the basolateral plasma membrane of collecting duct principal cells and represent exit pathways for water reabsorbed apically via AQP2. Studies in patients and transgenic mice have demonstrated that both AQP2 and AQP3 are essential for urinary concentration. Three additional aquaporins are present in the kidney. AQP6 is present in intracellular vesicles in collecting duct intercalated cells, and AQP8 is present intracellularly at low abundance in proximal tubules and collecting duct principal cells, but the physiological function of these two channels remains undefined. AQP7 is abundant in the brush border of proximal tubule cells and is likely to be involved in proximal tubule water reabsorption. Body water balance is tightly regulated by vasopressin, and multiple studies now have underscored the essential roles of AQP2 in this. Vasopressin regulates acutely the water permeability of the kidney collecting duct by trafficking of AQP2 from intracellular vesicles to the apical plasma membrane. The long-term adaptational changes in body water balance are controlled in part by regulated changes in AQP2 and AQP3 expression levels. Lack of functional AQP2 is seen in primary forms of diabetes insipidus, and reduced expression and targeting are seen in several diseases associated with urinary concentrating defects such as acquired nephrogenic diabetes insipidus, postobstructive polyuria, as well as acute and chronic renal failure. In contrast, in conditions with water retention such as severe congestive heart failure, pregnancy, and syndrome of inappropriate antidiuretic hormone secretion, both AQP2 expression levels and apical plasma membrane targetting are increased, suggesting a role for AQP2 in the development of water retention. Continued analysis of the aquaporins is providing detailed molecular insight into the fundamental physiology and pathophysiology of water balance and water balance disorders.
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              Age and gender as risk factors for hyponatremia and hypernatremia.

              This study assesses gender and age as independent risk factors for hypo- and hypernatremia and describes the prevalence of hypo- and hypernatremia in different population groups. Details of all serum Na results with accompanying patient demographics for 2 years were downloaded from the laboratory database into Microsoft Access for multiple logistic regression analysis using SPSS. Female gender and age 145, and >165 mmol/l were for acute hospital care patients: 28.2%, 0.49%, 1.43%, and 0.06%; ambulatory hospital care: 21%, 0.17%, 0.53%, and 0.01%; community care: 7.2%, 0.03%, 0.72%, and 145 and >165 mmol/l, respectively) for age >81 years. Male gender was a mild risk factor for Na<136 mmol/l and was otherwise unimportant. Hyponatremia is a common but generally mild condition while hypernatremia is uncommon. Increasing age is a strong independent risk factor for both hypo- and hypernatremia. Gender is not an important risk factor for disturbances of serum Na concentration.
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                Author and article information

                Journal
                Transl Med UniSa
                Transl Med UniSa
                Translational Medicine @ UniSa
                Università di Salerno
                2239-9747
                2239-9747
                30 April 2012
                May-Aug 2012
                : 3
                : 1-14
                Affiliations
                [1 ]Department of Anesthesia and Intensive Care, Federico II University, Napoli, Italy
                [2 ]Department of Medicine, University of Salerno, Salerno, Italy
                Article
                tm-03-01
                3728787
                23905047
                3bdc2ec2-8a1b-4165-820c-44bcb72135fe
                Copyright @ 2012

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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                Categories
                Review

                avp receptor antagonists,hyponatremia,vaptans,vasopressin

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