TL;DR: The diagnosis and treatment of hyponatremia is discussed, comparing the two guidelines and highlighting recent developments, including fractional uric acid excretion and plasma copeptin concentration, which may further improve the diagnostic approach.
Abstract: Hyponatremia is a common water balance disorder that often poses a diagnostic or therapeutic challenge. Therefore, guidelines were developed by professional organizations, one from within the United States (2013) and one from within Europe (2014). This review discusses the diagnosis and treatment of hyponatremia, comparing the two guidelines and highlighting recent developments. Diagnostically, the initial step is to differentiate hypotonic from nonhypotonic hyponatremia. Hypotonic hyponatremia is further differentiated on the basis of urine osmolality, urine sodium level, and volume status. Recently identified parameters, including fractional uric acid excretion and plasma copeptin concentration, may further improve the diagnostic approach. The treatment for hyponatremia is chosen on the basis of duration and symptoms. For acute or severely symptomatic hyponatremia, both guidelines adopted the approach of giving a bolus of hypertonic saline. Although fluid restriction remains the first-line treatment for most forms of chronic hyponatremia, therapy to increase renal free water excretion is often necessary. Vasopressin receptor antagonists, urea, and loop diuretics serve this purpose, but received different recommendations in the two guidelines. Such discrepancies may relate to different interpretations of the limited evidence or differences in guideline methodology. Nevertheless, the development of guidelines has been important in advancing this evolving field.
TL;DR: In this paper, the authors evaluated the diagnostic utility of three different diagnostic and therapeutic approaches for hyponatremia: inexperienced doctor, intensive care senior physicians acting as Senior Physician, and senior endocrinologist serving as Reference Standard.
Abstract: BACKGROUND
The differential diagnosis of hyponatremia is often challenging because of its association with multiple underlying pathophysiological mechanisms, diseases, and treatment options. Several algorithms are available to guide the diagnostic approach to hyponatremia, but their diagnostic and clinical utility has never been evaluated. We aimed to assess in detail the diagnostic utility as well as the limitations of the existing approaches to hyponatremia.
METHODS
Each of the 121 consecutive subjects presenting with hyponatremia (serum sodium <130 mmoL/L) underwent 3 different and independent diagnostic and therapeutic approaches: inexperienced doctor applying an established Algorithm, intensive care senior physicians acting as Senior Physician, and senior endocrinologist serving as Reference Standard.
RESULTS
The overall diagnostic agreement between Algorithm and Reference Standard was 71% (respective Cohen's kappa and delta values were 0.64 and 0.70), the overall diagnostic agreement between Senior Physician and Reference Standard was 32% (0.20 and 0.19, respectively). Regarding the therapeutic consequences, the diagnostic accuracy of the Algorithm was 86% (0.70 and 0.72, respectively) and of the Senior Physician was 48% (0.01 and 0.04, respectively). In retrospect, by disregarding the patient's extracellular fluid volume and assessing the effective arterial blood volume by determination of the fractional urate excretion, the Algorithm improved its diagnostic accuracy to 95%.
CONCLUSION
Although the Algorithm performed reasonably well, several shortcomings became apparent, rendering it difficult to apply the Algorithm without reservation. Whether some modifications may enhance its diagnostic accuracy and simplify the management of hyponatremia needs to be determined.
TL;DR: Among patients presenting with severe hyponatremia, rapid correction occurred in 41%; nearly all patients with incident osmotic demyelination had a documented episode of rapid correction, and younger age, being a woman, schizophrenia, lower Charlson comorbidity index, lower presentation serum sodium, and urine sodium <30 mEq/L were associated with greater risk of rapid Correction.
Abstract: Background and objectives Rapid correction of severe hyponatremia can result in serious neurologic complications, including osmotic demyelination. Few data exist on incidence and risk factors of rapid correction or osmotic demyelination. Design, setting, participants, & measurements In a retrospective cohort of 1490 patients admitted with serum sodium 8 mEq/L at 24 hours. Osmotic demyelination was determined by manual chart review of all available brain magnetic resonance imaging reports. Results Mean age was 66 years old (SD=15), 55% were women, and 67% had prior hyponatremia (last outpatient sodium 8 mEq/L over a 24-hour period before magnetic resonance imaging. Five patients with osmotic demyelination had apparent neurologic recovery. Conclusions Among patients presenting with severe hyponatremia, rapid correction occurred in 41%; nearly all patients with incident osmotic demyelination had a documented episode of rapid correction. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_06_05_CJASNPodcast_18_7_G.mp3
TL;DR: The brain can be affected by the treatment of hyponatremia, which, if not undertaken cautiously, could lead to osmotic demyelination syndrome, a rare demYelinating brain disorder that occurs after rapid correction of severe hypon atremia.
75 citations
Cites background from "Diagnosis and Treatment of Hyponatr..."
...Therefore, prompt correction of hyponatremia should be undertaken in patients who present with severe symptoms, regardless of the chronicity and the magnitude of the decrease in SNa.(68,69) The mainstay of treatment of HNE is the reduction of intracranial pressure by decreasing brain water content....
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...For instance, marathon runners with moderate hyponatremia were reported to experience nausea and vomiting, and sometimes acute confusion, which were treated effectively by correction of SNa.60 The largest series of patients studied with HNE revealed that acute severe hyponatremia might be fatal, with abrupt respiratory arrest in up to 60% of cases, but prompt reversal of the prognosis can occur with correction of SNa.61
Chronic hyponatremia will usually manifest as malaise, weakness, and confusion.62 Until the last decade, it was believed that mild chronic hyponatremia was asymptomatic and carried little neurological dysfunction....
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...Patients with chronic hyponatremia have a much higher risk of falls, which seems to more marked in older adult patients.63,64 Some of thesemanifestations are reversible upon improvement in SNa.63–66 Table 1 shows the manifestations of HNE....
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...Therefore, prompt correction of hyponatremia should be undertaken in patients who present with severe symptoms, regardless of the chronicity and the magnitude of the decrease in SNa.68,69
The mainstay of treatment of HNE is the reduction of intracranial pressure by decreasing brain water content....
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...In patients with salt depletion from renal or extrarenal causes, replacement of salt stock will normalize SNa....
TL;DR: This randomized clinical trial found that both RIB and SIC therapies of hypertonic saline for treating hyponatremia were effective and safe, with no difference in the overcorrection risk.
Abstract: Importance Few high-quality studies have clarified whether hypertonic saline is best administered as slow continuous infusion (SCI) therapy or rapid intermittent bolus (RIB) therapy for symptomatic severe hyponatremia. Objective To compare the risk of overcorrection in RIB and SCI with hypertonic saline in patients with symptomatic hyponatremia. Design, Setting, and Participants This prospective, investigator-initiated, multicenter, open-label, randomized clinical trial enrolled 178 patients older than 18 years with moderately severe to severe hyponatremia and glucose-corrected serum sodium (sNa) levels of 125 mmol/L or less. Recruitment took place from August 24, 2016, until August 21, 2019, across emergency departments and wards of 3 general hospitals in the Republic of Korea. Interventions Either RIB or SCI of hypertonic saline, 3%, for 24 to 48 hours stratified by the severity of clinical symptoms. Main Outcome and Measures The primary outcome was overcorrection at any given period, defined as increase in the sNa level by greater than 12 or 18 mmol/L within 24 or 48 hours, respectively. Secondary and post hoc outcomes included efficacy and safety of the treatment approaches. The sNa concentrations were measured every 6 hours for 2 days. Results The 178 patients (mean [SD] age, 73.1 [12.2] years; 80 (44.9%) male; mean [SD] sNa concentrations, 118.2 [5.0] mmol/L) were randomly assigned to the RIB group (n = 87) or the SCI group (n = 91). Overcorrection occurred in 15 of 87 (17.2%) and 22 of 91 (24.2%) patients in the RIB and SCI groups, respectively (absolute risk difference, −6.9% [95% CI, −18.8% to 4.9%];P = .26). The RIB group showed lower incidence of relowering treatment than the SCI group (36 of 87 [41.4%] vs 52 of 91 [57.1%] patients, respectively; absolute risk difference, −15.8% [95% CI, −30.3% to −1.3%];P = .04; number needed to treat, 6.3). Groups did not differ in terms of efficacy in increasing sNa concentrations nor improving symptoms, but RIB, when compared with SCI, showed better efficacy in achieving target correction rate within 1 hour (intention-to-treat analysis: 28 of 87 (32.2%) vs 16 of 91 (17.6%) patients, respectively; absolute risk difference, 14.6% [95% CI, 2%-27.2%];P = .02; number needed to treat, 6.8; per-protocol analysis: 21 of 72 (29.2%) vs 12 of 73 (16.4%) patients, respectively; absolute risk difference, 12.7% [95% CI, −0.8% to 26.2%];P = .07). The statistical significance of the intention-to-treat and per-protocol analyses were similar for all outcomes except for achieving the target correction rate within 1 hour. Conclusions and Relevance This randomized clinical trial found that both RIB and SIC therapies of hypertonic saline for treating hyponatremia were effective and safe, with no difference in the overcorrection risk. However, RIB had a lower incidence of therapeutic relowering treatment and tended to have a better efficacy in achieving sNa within 1 hour than SCI. RIB could be suggested as the preferred treatment of symptomatic hyponatremia, which is consistent with the current consensus guidelines. Trial Registration ClinicalTrials.org Identifier:NCT02887469
TL;DR: Tolvaptan initiated for acute treatment of patients hospitalized with heart failure had no effect on long-term mortality or heart failure-related morbidity.
Abstract: ContextVasopressin mediates fluid retention in heart failure. Tolvaptan, a vasopressin V2 receptor blocker, shows promise for management of heart failure.ObjectiveTo investigate the effects of tolvaptan initiated in patients hospitalized with heart failure.Design, Setting, and ParticipantsThe 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.InterventionWithin 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.Main Outcome MeasuresDual 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.ResultsDuring 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.ConclusionTolvaptan initiated for acute treatment of patients hospitalized with heart failure had no effect on long-term mortality or heart failure–related morbidity.Trial Registrationclinicaltrials.gov Identifier: NCT00071331Published online March 25, 2007 (doi:10.1001/jama.297.12.1319).
Abstract: CONTEXT
Vasopressin mediates fluid retention in heart failure. Tolvaptan, a vasopressin V2 receptor blocker, shows promise for management of heart failure.
OBJECTIVE
To investigate the effects of tolvaptan initiated in patients hospitalized with heart failure.
DESIGN, SETTING, AND PARTICIPANTS
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.
INTERVENTION
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.
MAIN OUTCOME MEASURES
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.
RESULTS
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.
CONCLUSION
Tolvaptan initiated for acute treatment of patients hospitalized with heart failure had no effect on long-term mortality or heart failure-related morbidity.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT00071331
TL;DR: In patients with euvolemic or hypervolemic hyponatremia, tolvaptan, an oral vasopressin V2-receptor antagonist, was effective in increasing serum sodium concentrations at day 4 and day 30.
Abstract: Background Hyponatremia (serum sodium concentration, <135 mmol per liter) is a predictor of death among patients with chronic heart failure and cirrhosis. At present, therapy for acute and chronic hyponatremia is often ineffective and poorly tolerated. We investigated whether tolvaptan, an orally active vasopressin V 2 -receptor antagonist that promotes aquaresis — excretion of electrolyte-free water — might be of benefit in hyponatremia. Methods In two multicenter, randomized, double-blind, placebo-controlled trials, the efficacy of tolvaptan was evaluated in patients with euvolemic or hypervolemic hyponatremia. Patients were randomly assigned to oral placebo (223 patients) or oral tolvaptan (225) at a dose of 15 mg daily. The dose of tolvaptan was increased to 30 mg daily and then to 60 mg daily, if necessary, on the basis of serum sodium concentrations. The two primary end points for all patients were the change in the average daily area under the curve for the serum sodium concentration from baseline to day 4 and the change from baseline to day 30. Results Serum sodium concentrations increased more in the tolvaptan group than in the placebo group during the first 4 days (P<0.001) and after the full 30 days of therapy (P<0.001). The condition of patients with mild or marked hyponatremia improved (P<0.001 for all comparisons). During the week after discontinuation of tolvaptan on day 30, hyponatremia recurred. Side effects associated with tolvaptan included increased thirst, dry mouth, and increased urination. A planned analysis that combined the two trials showed significant improvement from baseline to day 30 in the tolvaptan group according to scores on the Mental Component of the Medical Outcomes Study 12-item Short-Form General Health Survey. Conclusions In patients with euvolemic or hypervolemic hyponatremia, tolvaptan, an oral vasopressin V 2 -receptor antagonist, was effective in increasing serum sodium concentrations at day 4 and day 30. (ClinicalTrials.gov numbers, NCT00072683 [SALT-1] and NCT00201994 [SALT-2].)
TL;DR: Copeptin is stable for days after blood withdrawal and can be quickly and easily measured, and may be a useful alternative to direct measurement of AVP concentration.
Abstract: Background: Arginine vasopressin (AVP) is a key regulator of water balance, but its instability makes reliable measurement difficult and precludes routine use. We present a method for quantifying AVP release by use of copeptin, a glycopeptide comprising the C-terminal part of the AVP prohormone.
Methods: We measured copeptin in 50-μL serum and plasma samples from healthy individuals and from critically ill patients with sepsis. Our sandwich immunoluminometric assay used 2 polyclonal antibodies to amino acids 132–164 of pre-provasopressin.
Results: The assay yielded results within 3 h. The analytical detection limit was 1.7 pmol/L, and the interlaboratory CV was 2.25 pmol/L. The assay was linear on dilution of the analyte. Ex vivo copeptin stability (<20% loss of analyte) for at least 7 days at room temperature and 14 days at 4 °C was shown for serum and EDTA-, heparin-, and citrate plasma. Copeptin (median, 4.2 pmol/L; range, 1–13.8 pmol/L) was detectable in 97.5% of 359 healthy individuals and was not associated with age. Median concentrations were considerably higher in men than women, increased significantly after exercise, and were influenced by fasting and water load. Copeptin was significantly ( P <0.001) increased in 60 critically ill patients with sepsis (median, 79.5 pmol/L; range, 10.6–228.0 pmol/L). The correlation between copeptin and AVP for 110 samples was r = 0.78 ( P <0.0001).
Conclusions: Copeptin is stable for days after blood withdrawal and can be quickly and easily measured. The copeptin assay may be a useful alternative to direct measurement of AVP concentration.
TL;DR: The Clinical Practice Guideline on the diagnostic approach and treatment of hyponatraemia is developed as a joint venture of three societies representing specialists with a natural interest in hyponatonemia to obtain a common and holistic view.
Abstract: Hyponatraemia, defined as a serum sodium concentration !135 mmol/l, is the most common disorder of body fluid and electrolyte balance encountered in clinical practice. It can lead to a wide spectrum of clinical symptoms, from subtle to severe or even life threatening, and is associated with increased mortality, morbidity and length of hospital stay in patients presenting with a range of conditions. Despite this, the management of patients remains problematic. The prevalence of hyponatraemia in widely different conditions and the fact that hyponatraemia is managed by clinicians with a broad variety of backgrounds have fostered diverse institution- and speciality-based approaches to diagnosis and treatment. To obtain a common and holistic view, the European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE) and the European Renal Association – European Dialysis and Transplant Association (ERA–EDTA), represented by European Renal Best Practice (ERBP), have developed the Clinical Practice Guideline on the diagnostic approach and treatment of hyponatraemia as a joint venture of three societies representing specialists with a natural interest in hyponatraemia. In addition to a rigorous approach to methodology and evaluation, we were keen to ensure that the document focused on patient-important outcomes and included utility for clinicians involved in everyday practice.
The paper discusses the treatment of hyponatremia. The guidelines recommend fluid restriction as the first-line treatment for most forms of chronic hyponatremia. Pharmacologic therapy, such as vasopressin receptor antagonists, urea, and loop diuretics, may also be necessary.