Complications and management of hyponatremia

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1 REVIEW C URRENT OPINION Complications and management of hyponatremia Richard H. Sterns and Stephen M. Silver Purpose of review Hyponatremia causes significant morbidity, mortality, and disability. This review considers the literature of the past 18 months to improve understanding of these complications and to identify therapeutic strategies to prevent them. Recent findings Acute hyponatremia causes serious brain swelling that can lead to permanent disability or death. A 4 6 meq/l increase in serum sodium is sufficient to reverse impending herniation. Brain swelling is minimal in chronic hyponatremia, and to avoid osmotic demyelination, correction should not exceed 8 meq/l/day. In high-risk patients, correction should not exceed 4 6 meq/l/day. Inadvertent overcorrection of hyponatremia is common and preventable by controlling unwanted urinary water losses with desmopressin. Even mild chronic hyponatremia is associated with increased mortality, attention deficit, gait instability, osteoporosis, and fractures, but it is not known if the correction of mild hyponatremia improves outcomes. Summary Controlled trials are needed to identify affordable treatments for hyponatremia that reduce the need for hospitalization, decrease hospital length of stay, and decrease morbidity. Such trials could also help answer the question of whether hyponatremia causes excess mortality or whether it is simply a marker for severe, lethal, underlying disease Keywords antidiuretic hormone receptor antagonists, brain, deamino arginine vasopressin, hyponatremia, osteoporosis INTRODUCTION Hyponatremia is associated with significant morbidity, mortality, and disability. Acute hyponatremia causes serious brain swelling that can lead to permanent disability or death. Chronic hyponatremia causes attention deficit, gait instability, and osteoporosis, and it increases the risk of falls and fractures. Overly rapid correction of chronic hyponatremia causes osmotic demyelination, which can lead to irreversible brain damage. Many of these complications can be avoided with proper therapy. This review will highlight the major contributions to our understanding of hyponatremia that have been published in the last 18 months. HYPONATREMIA AND THE BRAIN Brain capillaries, unlike systemic capillaries, are impermeable to sodium, owing to endothelial tight junctions, and astrocyte foot processes that surround brain capillary walls. Hypotonic hyponatremia creates an osmotic force across the blood brain barrier that results in water movement into the brain through aquaporin 4 water channels, expressed on astrocyte membranes [1 ]. Astrocytes play a central role in water handling during hyponatremia [2,3,4 ]. In contrast to neurons, which retain their normal volume, astrocytes swell when confronted with hyponatremia. Brain swelling from acute hyponatremia increases intracranial pressure, impairing cerebral blood flow, leading rarely to fatal herniation. Within 48 h (which defines chronic ), astrocytes adapt to hyponatremia with an adaptive loss of cell solute, most notably organic osmolytes (e.g., glutamate, myoinositol, and taurine), permitting intracellular osmolality to equal plasma osmolality without increasing cell volume [1,2,3,4 ]. Organic osmolytes are intracellular solutes found throughout nature; their concentrations can vary without perturbing cell functions. Hyponatremia results in the release of organic osmolytes through volume-sensitive leak pathways, and down regulates University of Rochester School of Medicine and Dentistry, Nephrology Division, Rochester General Hospital, Rochester, New York, USA Correspondence to Richard H. Sterns, MD, Rochester General Hospital 1425 Portland Ave, Rochester, NY 14621, USA. Tel: ; fax: ; richard.sterns@rochesterregional.org Curr Opin Nephrol Hypertens 2016, 25: DOI: /MNH Volume 25 Number 2 March 2016

2 Hyponatremia Sterns and Silver KEY POINTS Osmotic demyelination can be avoided by correction of hyponatremia at a rate that does not exceed 8 meq/l/ day and, in high-risk patients, 4 6 meq/l/day. Mild chronic hyponatremia is associated with osteoporosis, fractures, gait disturbances, and increased mortality. Exercise-induced hyponatremia is potentially fatal and requires prompt treatment with hypertonic saline to increase the serum sodium rapidly by 4 6 meq/l. ADH receptor antagonists are effective in maintaining a normal serum sodium concentration but have not been proven to improve outcomes. Treatment of severe chronic hyponatremia with the proactive use of desmopressin to prevent overcorrection of serum sodium appears to be an effective strategy. osmolyte-accumulating transporters. Although this adaptation permits survival, it also may contribute to symptoms; for example, the adaptive loss of glutamate, an excitatory neurotransmitter, may increase the susceptibility to seizures in acute hyponatremia, and depletion of intracellular glutamate, may contribute to some of the neurological findings of chronic hyponatremia [5 ]. In addition, osmolyte depletion makes astrocytes susceptible to injury if chronic hyponatremia is corrected too rapidly. Recovery of lost brain osmolytes may take a week or longer; therefore, rapid correction of hyponatremia is an osmotic stress to astrocytes, resulting in apoptosis and a delayed onset of demyelination that presents clinically as the osmotic demyelination syndrome (ODS) [2,3,4 ]. Patients with ODS have a biphasic course: an initial improvement in hyponatremic symptoms is followed by new findings, which can include seizures, behavioral changes, swallowing and speech dysfunction, paralysis, and movement disorders [4,6 ]. Although ODS can cause permanent disability or death, it is potentially reversible, even in patients who require ventilator support. Experiments in animals indicate that ODS can be prevented by relowering the serum sodium concentration after rapid correction, or by the administration of exogenous myoinositol [4,7]. The treatment of hyponatremia with urea rather than with hypertonic saline or vasopressin antagonists reduces the incidence and severity of ODS in animals [8 ]. However, the initial rate of correction was likely to have been slower after urea, making it difficult to interpret these findings [8,9 ]. High levels of urea may prevent brain dehydration after rapid correction of hyponatremia, but uremia does not provide full protection against dialysis-related ODS [10 ]. Several techniques have been described to prevent a large increase in serum sodium when dialyzing high-risk patients [10,11]. Chronic hyponatremia is common in hepatic cirrhosis; untreated hyponatremia is associated with impaired cognition and poor outcomes, and neurological complications related to rapid correction of hyponatremia often complicate liver transplantation [12 14]. In an uncontrolled open label study, increasing serum sodium from to mmol/l with tolvaptan significantly decreased white mater but not gray matter volume, as determined by MRI, and significantly improved cognitive test performance in 14 cirrhotic patients; a 30% reduction in blood ammonia levels, possibly from decreased ammonia reabsorption caused by increased urine flow, could explain both decreased brain swelling and improved cognitive performance [15 ]. HYPONATREMIA AND BONE Because a large fraction of body sodium is stored in bone, the skeleton can serve as a sodium reservoir that can be mobilized in response to homeostatic stress [4,16,17 ]. Hyponatremia promotes bone loss by increasing the number and activity of osteoclasts and by favoring differentiation of mesenchymal stromal cells into adipocytes (which inhibit bone formation) rather than osteoblasts [16,17 ]. These effects appear to be mediated by a specific extracellular sodium detector and are independent of osmolality. Chronic hyponatremia directly promotes bone loss in experimental animals and is an independent risk factor for osteoporosis and fractures in humans [17,18 22,23 ]. A matched casecontrolled study in more than 2.9 million patients found that hyponatremia lasting for more than a year is associated with a four-fold increase in the odds of having osteoporosis [23 ]. The association was both dose dependent (more severe hyponatremia associated with greater risk) and time dependent (more chronic hyponatremia associated with greater risk). Patients with remote hyponatremia had a lower risk than patients with more recent hyponatremia, consistent with findings of a recent case report suggesting bone mass recovers if hyponatremia is reversed [24 ]. A young man with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) caused by a vasopressin-secreting esthesioneuroblastoma presented with severe osteoporosis complicated by vertebral fracture; bone density improved after surgical excision of the tumor and resolution of hyponatremia Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved

3 Clinical nephrology In addition to its effect on bone mineral, chronic hyponatremia is associated with gait instability and falls in the elderly, contributing to an increased risk of fractures [18,19,21,22]. Depletion of intracellular glutamate, an excitatory neurotransmitter, could be responsible for some of these findings; chronically hyponatremic rats exhibit an ataxic gait and evidence of cognitive impairment, which is associated with elevated extracellular glutamate in the hippocampus [5,25 ]. HYPONATREMIA AND MORTALITY A plasma sodium concentration even slightly outside the normal range is associated with increased mortality; however, deaths from neurological complications of hyponatremia, cerebral edema, and osmotic demyelination are rare [10,26,27, 28,29]. Taurine and myoinositol, organic osmolytes that many cells lose in response to hyponatremia, are normally protective against oxidative injury [4 ]. In addition, a low plasma sodium concentration, independent of osmolality, decreases the activity of the vitamin C transporter an important finding, because ascorbic acid is an essential defense against oxidative stress [2,17 ]. Prolonged chronic hyponatremia in an animal model results in hypogonadism, increased body fat, decreased muscle mass, and cardiomyopathy. It is unclear whether the increased mortality associated with hyponatremia is an effect of hyponatremia itself, or whether it reflects the underlying disorders that cause hyponatremia [26]. If hyponatremia itself were responsible, a dose-response relationship, with lower serum sodium associated with higher mortality, would be expected. Although this may be true between 135 and 125 meq/l (levels often associated with severe underlying illness) it does not hold true for lower serum sodium concentrations, which are often drug induced. A large Danish study confirmed that although in-hospital, 30-day, and 1-year mortality rises as the serum sodium falls to 132 meq/l, there was no further increase in mortality as the serum sodium concentration fell progressively below 132 meq/l [30 ]. TREATMENT OF SEVERE HYPONATREMIA Clinicians should respond promptly to the immediate dangers posed by acute hyponatremia, while remaining mindful of potential iatrogenic injury when more sustained hyponatremia is corrected too rapidly [4,31,32,33]. Exercise-associated hyponatremia is one of the more common causes of acute hyponatremia. Once thought to be a complication of competitive running, symptomatic hyponatremia has been recognized in a wider spectrum of activities, causing fatalities in football players, military recruits, and hikers [34 ]. The common thread is intake of water and sports drinks in excess of body fluid losses [34,35]. A consensus conference recommended that athletes with signs or symptoms of encephalopathy should be treated with up to 300 ml of 3% saline given as repeated 100 ml bolus infusions, enough to rapidly correct hyponatremia by 2 5 meq/l [34 ]. Similar regimens have been recommended for other causes of symptomatic acute hyponatremia, including postoperative hyponatremia, and self-induced water intoxication associated with psychosis and use of the illegal recreational drug, 3,4-methylenedioxymethamphetamine, popularly known as "Ecstasy" [4,31,32,33,36 38]. Larger increases can sometimes be tolerated, but there is no evidence that they are needed. Correction by 4 6 meq/l is sufficient to reverse impending herniation; larger increases offer no advantage and can be harmful to patients with chronic hyponatremia [4,31,33,38,39 ]. Isotonic saline should not be used to treat symptomatic hyponatremia or hyponatremia associated with intracranial disease. If vasopressin levels are high, and the urine is concentrated, all administered sodium can be excreted in a small volume of urine so that the volume of fluid administered exceeds the volume of urine excreted; the resulting net positive water balance exacerbates hyponatremia [4,38]. Such a sequence, known as desalination is common in postoperative SIADH and subarachnoid hemorrhage. In these settings, large volumes of isotonic saline are often given and the resulting hypervolemia promotes urinary sodium excretion despite a low serum sodium [4 ]. Desalination associated with subarachnoid hemorrhage is sometimes called cerebral salt wasting, a label implying sodium loss despite hypovolemia, rather than natriuresis because of volume expansion, as occurs in SIADH. With no gold standard to define volume depletion, it is difficult to distinguish between SIADH and cerebral salt wasting [40]. Such a distinction is unnecessary; given the dire consequences of worsening hyponatremia, patients with intracranial disease should corrected with hypertonic saline. This is usually given intravenously (i.v.) as a 3% solution, but a single case report demonstrated that hourly doses of 1 g of NaCl orally, equivalent to 35 ml/h of 3% saline, can be effective [41 ]. A recent prospective study of 100 patients with subarachnoid hemorrhage identified 49 who became hyponatremic; the cause determined by clinical examination, fluid balance, and vasopressin and natriuretic peptide levels, was SIADH in 71.4%, hypotonic fluids in 10.2%, hypovolemia without Volume 25 Number 2 March 2016

4 Hyponatremia Sterns and Silver salt wasting in 10.2%, and no cases of cerebral salt wasting [42 ]. Notably, acute glucocorticoid insufficiency was identified in 8.2% of patients; their hyponatremia rapidly responded to steroid replacement. Most hyponatremia is chronic, developing over 48 h or more, and should be presumed to be chronic when the duration is unknown. Experts agree that large increases in serum sodium (10 meq/l in 24 h or 18 meq/l in 48 h) should be avoided in all chronically hyponatremic patients (some would set the limit at 8 meq/l/day), and, in patients with serum sodium 105 meq/l or less, hypokalemia, alcoholism, liver disease, and malnutrition (conditions increasing the risk of ODS), correction should not exceed 4 6 meq/l/day [4,31,32,33,36 38]. It can be difficult to avoid excessive correction, because the cause of hyponatremia is often reversible, and inadvertent overcorrection is common [33,39,40,43 ]; once the cause is eliminated (by stopping medication, volume repletion, cortisol replacement, or the passage of time), physiological suppression of vasopressin secretion provokes a water diuresis that can correct hyponatremia by more than 2 meq/l/h. In hypokalemic patients, potassium replacement, given orally or as a 400 mm i.v. solution, will also increase the serum sodium. Desmopressin (a synthetic vasopressin analogue) has been used to avoid iatrogenic injury from overcorrection of chronic hyponatremia. Three strategies have been described: proactive, where desmopressin is administered based on the presenting serum sodium (<125 meq/l) and the perceived risk of overcorrection before any correction has occurred; reactive, where desmopressin is administered in response to a change in serum sodium or increase in urine output, indicating that excessive correction is likely to occur; and rescue, where desmopressin is administered after correction has already exceeded accepted limits, or neurological complications of overcorrection have developed, to stabilize or relower the serum sodium [44 ]. Desmopressin-induced hyponatremia is one example of a reversible cause; if desmopressin is discontinued, the resulting water diuresis can cause permanent brain damage if water losses are not replaced [45]. Rather than discontinuing desmopressin, it can be continued to prevent urinary water losses, concurrently administering 3% saline to slowly correct hyponatremia. The same strategy has been shown to be effective for other causes of reversible hyponatremia [4,38,46]. A review of the literature concluded that this proactive strategy is more likely to avoid excessive correction, particularly in patients at high risk of developing ODS [44 ]. MANAGING MILD HYPONATREMIA Because of the many adverse effects associated with hyponatremia, maintenance of a normal serum sodium is a desirable goal in all patients. The availability of vasopressin antagonists, tolvaptan, and conivaptan, now makes it possible to achieve normonatremia in most patients with euvolemic or hypervolemic hyponatremia [47 ]. Their mechanism of action explains why vasopressin antagonists should be reserved for mild hyponatremia in ambulatory patients, or minimally symptomatic hyponatremia in hospitalized patients, and should not be used in hyponatremic emergencies. Vasopressin binds at a superficial site on the vasopressin receptor, located on the blood side of the collecting duct cell membrane, whereas vasopressin antagonists penetrate deeply into the membrane, altering the ability of vasopressin to bind to its receptor in the adjacent loop. The antagonists prevent insertion of water channels into the apical membrane, inhibiting reabsorption of water and generation of concentrated urine, but a maximum aquaresis is delayed by 2 h. In clinical trials, tolvaptan caused only a small increase in serum sodium within 8 h, and 12 h after conivaptan only half the patients had corrected by more than 4 meq/l. Approximately 15% of patients fail to respond, possibly because of high plasma vasopressin levels that cannot be overcome by the competitive antagonist, or because of vasopressin-independent impairments in water excretion. Because vasopressin antagonists can result in overcorrection of hyponatremia [48], the serum sodium concentration should be monitored at 4-h intervals after their administration, and once an increase of 6 8 meq/l has been achieved, urinary water losses should be replaced oral water or i.v. 5% dextrose in water [47 ]. The chief barriers to the use of vasopressin antagonists in ambulatory patients is their high cost, the absence of outcome data showing that an improved serum sodium concentration improves outcomes, and concerns about hepatic toxicity [32,47 ]. A registry of 3087 patients with a serum sodium of less than 130 meq/l from 225 sites in the USA and Europe found that only 4% were treated with tolvaptan [49 ]. After abnormal liver function tests were identified in a clinical trial using high doses of tolvaptan for polycystic kidney disease, the US Food and Drug Administration issued a recommendation limiting the use of tolvaptan to 30 days and advising against its use in patients with liver disease. We endorse the conclusion of a recent review that patients awaiting liver transplantation should be considered an exception to this advice, because hyponatremia increases the risk of osmotic demyelination after transplantation [47 ] Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved

5 Clinical nephrology Citing concerns about outcomes, cost, and toxicity, the European Clinical Practice Guideline recommends against the use of vasopressin antagonists for any indication [32 ]. The European Guideline recommended treatment with oral urea, an agent that increases urinary water excretion by causing an osmotic diuresis [32 ]. Although urea has been shown to be effective in both inpatient and ambulatory settings, it has not been subjected to placebo controlled trials, and it is not available in pharmacies [9,50,51 ]. There is a pressing need for prospective, controlled trials to identify affordable treatments for mild hyponatremia that reduce the need for hospitalization, decrease hospital length of stay, and decrease morbidity. Such trials could also help answer the question of whether hyponatremia causes excess mortality or whether it is simply a marker for severe, lethal, underlying disease [47 ]. CONCLUSION The recent literature on hyponatremia has confirmed the importance of the slow correction of severe chronic hyponatremia to prevent ODS and rapid correction of acute hyponatremia to ameliorate cerebral edema, and it has yielded strategies to achieve these goals. The deleterious effects of chronic mild hyponatremia on bone and neurologic function are being increasingly recognized, as well as osmotic and nonosmotic cellular effects of hyponatremia on bone, brain, and other tissues. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest. REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1. Danziger J, Zeidel ML. Osmotic homeostasis. Clin J Am Soc Nephrol 2015; 10: A superb, comprehensive review of the regulation of the serum sodium concentration. 2. Giuliani C, Peri A. Effects of hyponatremia on the brain. J Clin Med 2014; 3: A clear, comprehensive review with a fascinating perspective on the nonosmotic effects of hyponatremia on the brain. 3. Podesta MA, Faravelli I, Cucchiari D, et al. Neurological counterparts of hyponatremia: pathological mechanisms and clinical manifestations. Curr Neurol Neurosci Rep 2015; 15: Sterns RH. Disorders of plasma sodium: causes, consequences, and correction. N Engl J Med 2015; 372: Review of the pathophysiology of hyponatremia and the rationale for current therapeutic recommendations. 5. Fujisawa H, Sugimura Y, Takagi H, et al. Chronic hyponatremia causes neurologic and psychologic impairments. J Am Soc Nephrol 2015; doi: /ASN [Epub ahead of print] An important study of the neurological manifestations of chronic hyponatremia in an experimental model, supporting clinical observations that apparently asymptomatic hyponatremia can cause gait and cognitive abnormalities. 6. Singh TD, Fugate JE, Rabinstein AA. Central pontine and extrapontine myelinolysis: a systematic review. Eur J Neurol 2014; 21: A complete review that highlights the potential for improvement of neurologic function in ODS. 7. Changal KH, Raina H, Wani IY. Osmotic demyelination syndrome; treated with re lowering of serum sodium. Acta Neurol Taiwan 2014; 23: Gankam Kengne F, Couturier BS, Soupart A, Decaux G. Urea minimizes brain complications following rapid correction of chronic hyponatremia compared with vasopressin antagonist or hypertonic saline. Kidney Int 2015; 87: An important study of the pathogenesis of osmotic demyelination syndrome in an experimental model with the provocative observation that treatment with urea is less likely to cause neurological complications than other modalities. As pointed out in an accompanying editorial, this observation needs to be confirmed with models that assure that the rate of correction from urea is comparable with that resulting from hypertonic saline or vasopressin antagonists. 9. Sterns RH, Silver SM, Hix JK. Urea for hyponatremia? Kidney Int 2015; 87: A concise review of the advantages and limitations of urea as a treatment of hyponatremia. 10. Combs S, Berl T. Dysnatremias in patients with kidney disease. Am J Kidney Dis 2014; 63: An excellent review of the association of hyponatremia with adverse outcomes in patients with kidney disease. Includes a helpful discussion of how to manage hyponatremic patients who require dialysis. 11. Yessayan L, Yee J, Frinak S, Szamosfalvi B. Treatment of severe hyponatremia in patients with kidney failure: role of continuous venovenous hemofiltration with low-sodium replacement fluid. Am J Kidney Dis 2014; 64: Cardenas A, Riggio O. Correction of hyponatraemia in cirrhosis: treating more than a number! J Hepatol 2015; 62: CardenasA,SolaE,RodriguezE,et al. Hyponatremia influences the outcome of patients with acute-on-chronic liver failure: an analysis of the CANONIC study. Crit Care 2014; 18:700. doi: /s Crivellin C, Cagnin A, Manara R, et al. Risk factors for central pontine and extrapontine myelinolysis after liver transplantation: a single-center study. Transplantation 2015; 99: Ahluwalia V, Heuman DM, Feldman G, et al. Correction of hyponatraemia improves cognition, quality of life, and brain oedema in cirrhosis. J Hepatol 2015; 62: Careful, but uncontrolled study showing improvements in standardized cognitive tests and brain white matter edema after correction of moderately severe hyponatremia in cirrhotic patients. It is one of the few studies to make such measurements before and after correction of hyponatremia and will hopefully lead to additional studies in other populations using appropriate controls. 16. Fibbi B, Benvenuti S, Giuliani C, et al. Low extracellular sodium promotes adipogenic commitment of human mesenchymal stromal cells: a novel mechanism for chronic hyponatremia-induced bone loss. Endocrine 2015; doi: /s [Epub ahead of print] A study of the nonosmotic effects of a low sodium concentration on precursor cells for bone and fat. 17. Hannon MJ, Verbalis JG. Sodium homeostasis and bone. Curr Opin Nephrol Hypertens 2014; 23: Excellent review of the effect of hyponatremia on bone. 18. Cumming K, Hoyle GE, Hutchison JD, Soiza RL. Prevalence, incidence and etiology of hyponatremia in elderly patients with fragility fractures. PLoS One 2014; 9:e Ganguli A, Mascarenhas RC, Jamshed N, et al. Hyponatremia: incidence, risk factors, and consequences in the elderly in a home-based primary care program. Clin Nephrol 2015; 84: Gefen S, Joffe E, Mayan H, Justo D. Recurrent hospitalizations with moderate to severe hyponatremia in older adults and its associated mortality. Eur J Intern Med 2014; 25: Jamal SA, Arampatzis S, Harrison SL, et al. Hyponatremia and fractures: findings from the MrOS study. J Bone Miner Res 2015; 30: Kruse C, Eiken P, Vestergaard P. Hyponatremia and osteoporosis: insights from the Danish National Patient Registry. Osteoporos Int 2015; 26: Usala RL, Fernandez SJ, Mete M, et al. Hyponatremia is associated with increased osteoporosis and bone fractures in a large US health system population. J Clin Endocrinol Metab 2015; 100: Careful analysis of the association of osteoporosis with hyponatremia in a population of over million patients Volume 25 Number 2 March 2016

6 Hyponatremia Sterns and Silver 24. Sejling AS, Thorsteinsson AL, Pedersen-Bjergaard U, Eiken P. Recovery from SIADH-associated osteoporosis: a case report. J Clin Endocrinol Metab 2014; 99: An important case report of a young patient with severe osteoporosis associated with long-standing hyponatremia caused by ectopic ADH secretion from a sinus tumor. Bone density improved after resection of the tumor, indicating that hyponatremia-associated bone loss is reversible. 25. Cohen DM. Modeling the neurologic and cognitive effects of hyponatremia. J Am Soc Nephrol 2015; doi: /ASN [Epub ahead of print] Accompanying editorial to reference [5 ] that is a useful guide to the state of the art. 26. Chawla A, Sterns RH, Nigwekar SU, Cappuccio JD. Mortality and serum sodium: do patients die from or with hyponatremia? Clin J Am Soc Nephrol 2011; 6: Corona G, Giuliani C, Verbalis JG, et al. Hyponatremia improvement is associated with a reduced risk of mortality: evidence from a meta-analysis. PLoS One 2015; 10:e A formal meta-analysis of the existing literature on the association of hyponatremia and mortality, addressing the important question of whether raising the serum sodium concentration improves outcomes. The analysis cannot, unfortunately, provide a definitive answer to the question because one cannot tell from retrospective data if greater correction of hyponatremia is more likely to occur in patients whose underlying disease improves. 28. Bavishi C, Ather S, Bambhroliya A, et al. Prognostic significance of hyponatremia among ambulatory patients with heart failure and preserved and reduced ejection fractions. Am J Cardiol 2014; 113: Dasta J, Waikar SS, Xie L, et al. Patterns of treatment and correction of hyponatremia in intensive care unit patients. J Crit Care 2015; 30: Holland-Bill L, Christiansen CF, Heide-Jorgensen U, et al. Hyponatremia and mortality risk: a Danish cohort study of acutely hospitalized patients. Eur J Endocrinol 2015; 173: The most rigorous analysis of mortality associated with hyponatremia in a large cohort. The findings confirm that very mild hyponatremia (serum sodium meq/l) is associated with increased mortality, but mortality rates among patients with lower serum sodium concentrations, including those with levels less than 120 meq/l, were not higher. 31. Adrogue HJ, Madias NE. Diagnosis and treatment of hyponatremia. Am J Kidney Dis 2014; 64: Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrol Dial Transplant 2014; 29 (Suppl 2):i1 i39. European guidelines from a panel of experts from several disciplines. 33. Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med 2013; 126:S Hew-Butler T, Rosner MH, Fowkes-Godek S, et al. Statement of the Third International Exercise-Associated Hyponatremia Consensus Development Conference, Carlsbad, California, Clin J Sport Med 2015; 25: An excellent review on all aspects of this potentially fatal condition, emphasizing aggressive use of hypertonic saline. 35. Hoffman MD, Stuempfle KJ. Sodium supplementation and exercise-associated hyponatremia during prolonged exercise. Med Sci Sports Exerc 2015; 47: Maxwell AP. Diagnosis and management of hyponatraemia: AGREEing the guidelines. BMC Med 2015; 13:31. doi: /s Nagler EV, Vanmassenhove J, van der Veer SN, et al. Diagnosis and treatment of hyponatremia: a systematic review of clinical practice guidelines and consensus statements. BMC Med 2014; 12:1. doi: /s Sterns RH, Hix JK, Silver SM. Management of hyponatremia in the ICU. Chest 2013; 144: Geoghegan P, Harrison AM, Thongprayoon C, et al. Sodium correction practice and clinical outcomes in profound hyponatremia. Mayo Clin Proc 2015; 90: A study of 412 patients with serum sodium concentrations of 120mEq/l or less, one of the largest cohorts studied to date. Correction was suboptimal in about half the patients. However, there were no neurological complications among87 patients who were corrected too slowly (defined as <5 meq/l), and only one case of ODS among 114 patients who were corrected too fast (defined as >10 meq/l). The low incidence of complications after rapid correction should not be taken to mean that measures to avoid overcorrection are unnecessary. Patients in this series who were corrected too rapidly experienced rates of correction that were only slightly outside of recommended limits. In addition, it is not known how many of the overcorrected patients had serum sodium concentrations between 116 and 120 meq/l, levels that are at much lower risk of developing ODS. By confirming that extremely slow correction rarely leads to complications, these findings support the suggestion that there is no advantage to correction by more than 4 6 meq/l/day. 40. Sterns RH, Silver SM. Cerebral salt wasting versus SIADH: what difference? J Am Soc Nephrol 2008; 19: Kerns E, Patel S, Cohen DM. Hourly oral sodium chloride for the rapid and predictable treatment of hyponatremia. Clin Nephrol 2014; 82: With no hypertonic saline available, resourceful clinicians successfully used salt tablets to rapidly correct acute hyponatremia. 42. Hannon MJ, Behan LA, O Brien MM, et al. Hyponatremia following mild/moderate subarachnoid hemorrhage is due to SIAD and glucocorticoid deficiency and not cerebral salt wasting. J Clin Endocrinol Metab 2014; 99: The most carefully done study of hyponatremia after subarachnoid hemorrhage published to date. The findings indicate that cerebral salt wasting is very rare and that unsuspected glucocorticoid deficiency is a surprisingly common cause of hyponatremia in this population. 43. Gharaibeh KA, Brewer JM, Agarwal M, Fulop T. Risk factors, complication and measures to prevent or reverse catastrophic sodium overcorrection in chronic hyponatremia. Am J Med Sci 2015; 349: A useful review of the problem of overcorrection of hyponatremia. 44. MacMillan TE, Tang T, Cavalcanti RB. Desmopressin to prevent rapid sodium correction in severe hyponatremia: a systematic review. Am J Med 2015; 128:1362; e15 e24. A review of the use of the vasopressin analogue, desmopressin, to prevent unintentional rapid correction of hyponatremia. 45. Achinger SG, Arieff AI, Kalantar-Zadeh K, Ayus JC. Desmopressin acetate (DDAVP)-associated hyponatremia and brain damage: a case series. Nephrol Dial Transplant 2014; 29: Sood L, Sterns RH, Hix JK, et al. Hypertonic saline and desmopressin: a simple strategy for safe correction of severe hyponatremia. Am J Kidney Dis 2013; 61: Berl T. Vasopressin antagonists. N Engl J Med 2015; 372: A comprehensive, informative review of vasopressin antagonists that includes a discussion of their pharmacology and a thoughtful discussion of how they should and should not be used in the management of hyponatremia. 48. Tzoulis P, Waung JA, Bagkeris E, et al. Real-life experience of tolvaptan use in the treatment of severe hyponatraemia due to syndrome of inappropriate antidiuretic hormone secretion. Clin Endocrinol (Oxf) 2015; doi: / cen [Epub ahead of print] 49. Greenberg A, Verbalis JG, Amin AN, et al. Current treatment practice and outcomes. Report of the hyponatremia registry. Kidney Int 2015; 88: Findings of a large multicenter hyponatremia registry indicating that 3% saline and desmopressin were rarely used to treat patients with a serum sodium less than 130 meq/l. Data were based on voluntary submissions and it is not known how representative the findings are. 50. de Sola-Morales O, Riera M. Urea for management of the syndrome of inappropriate secretion of ADH: a systematic review. Endocrinol Nutr 2014; 61: Decaux G, Gankam Kengne F, Couturier B, et al. Actual therapeutic indication of an old drug: urea for treatment of severely symptomatic and mild chronic hyponatremia related to SIADH. J Clin Med 2014; 3: A review of the use of urea to treat hyponatremia by the group that first suggested this therapy Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved