Diagnosis and Management of Disorders of Body Tonicity-Hyponatremia and Hypernatremia: Core Curriculum 2020.

Overall body fluid concentration is regulated within a narrow range by the concerted action of the hypothalamic-pituitary axis to influence water intake through thirst and water excretion via the effect of vasopressin, or antidiuretic hormone, on renal collecting duct water permeability. Sodium is the principal extracellular cation; abnormalities in overall effective body fluid concentration, or tonicity, manifest as disturbances in serum sodium concentration. Depending on its severity and chronicity, hyponatremia can lead to significant symptoms, primarily related to central nervous system function. Failure to correct hyponatremia can lead to permanent neurologic damage, as can over rapid correction. It is thus essential to stay within specific limits for correction, particularly for chronic hyponatremia. Hypernatremia also leads to central nervous system dysfunction, although goals for its correction rate are less well established. This Core Curriculum article discusses the normal regulation of tonicity and serum sodium concentration and the diagnosis and management of hypo- and hypernatremia.

Computational Study of Selected Amine and Lactam N-Oxides Including Comparisons of N-O Bond Dissociation Enthalpies with Those of Pyridine N-Oxides.

A computational study of the structures and energetics of amine N-oxides, including pyridine N-oxides, trimethylamine N-oxide, bridgehead bicyclic amine N-oxides, and lactam N-oxides, allowed comparisons with published experimental data. Most of the computations employed the B3LYP/6-31G* and M06/6-311G+(d,p) models and comparisons were also made between the results of the HF 6-31G*, B3LYP/6-31G**, B3PW91/6-31G*, B3PW91/6-31G**, and the B3PW91/6-311G+(d,p) models. The range of calculated N-O bond dissociation energies (BDE) (actually enthalpies) was about 40 kcal/mol. Of particular interest was the BDE difference between pyridine N-oxide (PNO) and trimethylamine N-oxide (TMAO). Published thermochemical and computational (HF 6-31G*) data suggest that the BDE of PNO was only about 2 kcal/mol greater than that of TMAO. The higher IR frequency for N-O stretch in PNO and its shorter N-O bond length suggest a greater difference in BDE values, predicted at 10-14 kcal/mol in the present work. Determination of the enthalpy of sublimation of TMAO, or at least the enthalpy of fusion and estimation of the enthalpy of vaporization might solve this dichotomy. The "extra" resonance stabilization in pyridine N-oxide relative to pyridine was consistent with the 10-14 kcal/mol increase in BDE, relative to TMAO, and was about half the "extra" stabilization in phenoxide, relative to phenol or benzene. Comparison of pyridine N-oxide with its acyclic model nitrone ("Dewar-Breslow model") indicated aromaticity slightly less than that of pyridine.

Cytochrome P450 Can Epoxidize an Oxepin to a Reactive 2,3-Epoxyoxepin Intermediate: Potential Insights into Metabolic Ring-Opening of Benzene.

Dimethyldioxirane epoxidizes 4,5-benzoxepin to form the reactive 2,3-epoxyoxepin intermediate followed by very rapid ring-opening to an o-xylylene that immediately isomerizes to the stable product 1H-2-benzopyran-1-carboxaldehyde. The present study demonstrates that separate incubations of 4,5-benzoxepin with three cytochrome P450 isoforms (2E1, 1A2, and 3A4) as well as pooled human liver microsomes (pHLM) also produce 1H-2-benzopyran-1-carboxaldehyde as the major product, likely via the 2,3-epoxyoxepin. The reaction of 4,5-benzoxepin with cerium (IV) ammonium nitrate (CAN) yields a dimeric oxidized molecule that is also a lesser product of the P450 oxidation of 4,5-benzoxepin. The observation that P450 enzymes epoxidize 4,5-benzoxepin suggests that the 2,3-epoxidation of oxepin is a major pathway for the ring-opening metabolism of benzene to muconaldehyde.

Predicted Reversal in N-Methylazepine/N-Methyl-7-azanorcaradiene Equilibrium Upon Formation of Their N-Oxides.

Density functional calculations and up to five different basis sets have been applied to the exploration of the structural, enthalpy and free energy changes upon conversion of the azepine to the corresponding N-oxide. Although it is well known that azepines are typically much more stable than their 7-azanorcaradiene valence isomers, the stabilities are reversed for the corresponding N-oxides. Structural, thermochemical as well as nucleus-independent chemical shift (NICS) criteria are employed to probe the potential aromaticity, antiaromaticity and nonaromaticity of N-methylazepine, its 7-azanorcaradiene valence isomer. For the sake of comparison, analogous studies are performed on N-methylpyrrole and its N-oxide.

Thiazide-Associated Hyponatremia, Report of the Hyponatremia Registry: An Observational Multicenter International Study.

BACKGROUND: Hyponatremia is a frequent and potentially life-threatening adverse side effect of thiazide diuretics. This sub-analysis of the Hyponatremia Registry database focuses on current management practices of thiazide-associated hyponatremia (TAH) and compares differences between TAH and syndrome of inappropriate antidiuretic hormone secretion (SIADH). METHODS: We analyzed 477 patients from 225 US and EU sites with euvolemic hyponatremia ([Na+] ≤130 mEq/L) who were receiving a thiazide diuretic. Of these, 118 met criteria for true thiazide-induced hyponatremia (TIH). RESULTS: Thiazide was withdrawn immediately after hyponatremia was diagnosed only in 57% of TAH; in these patients, the median rate of [Na+] change (Δdaily[Na+]) was significantly higher than those with continued thiazide treatment (3.8 [interquartile range: 4.0] vs. 1.7 [3.8] mEq/L/day). The most frequently employed therapies were isotonic saline (29.6%), fluid restriction (19.9%), the combination of these two (8.2%), and hypertonic saline (5.2%). Hypertonic saline produced the greatest Δdaily[Na+] (8.0[6.4] mEq/L/day) followed by a combination of fluid restriction and normal saline (4.5 [3.8] mEq/L/day) and normal saline alone (3.6 [3.5] mEq/L/day). Fluid restriction was markedly less effective (2.7 [2.7] mEq/L/day). Overly rapid correction of hyponatremia occurred in 3.1% overall, but in up to 21.4% given hypertonic saline. Although there are highly significant differences in the biochemical profiles between TIH and SIADH, no predictive diagnostic test could be derived. CONCLUSIONS: Despite its high incidence and potential risks, the management of TAH is often poor. Immediate withdrawal of the thiazide is crucial for treatment success. Hypertonic saline is most effective in correcting hyponatremia but associated with a high rate of overly rapid correction. We could not establish a diagnostic laboratory-based test to differentiate TIH from SIADH.

Euvolemic hyponatremia in cancer patients. Report of the Hyponatremia Registry: an observational multicenter international study.

PURPOSE: Hyponatremia secondary to SIADH is frequent in cancer patients and potentially deleterious. The aim of this sub-analysis of the Hyponatremia Registry database is to analyze current diagnostic and therapeutic management practices in cancer patients with SIADH. METHODS: We analyzed 358 cancer patients who had serum sodium concentration ([Na+]) ≤ 130 mEq/L and a clinical diagnosis of SIADH from 225 sites in the USA and EU. RESULTS: Precise diagnostic testing was performed in only 46%. Almost 12% of all patients did not receive any hyponatremia treatment. The most frequent therapies were fluid restriction (20%), isotonic saline (14%), fluid restriction/isotonic saline (7%), tolvaptan (8%), and salt tablets (7%). Hypertonic saline was used in less than 3%. Tolvaptan produced the greatest median rate of [Na+] change (IQR) (3.0 (4.7) mEq/L/day), followed by hypertonic saline (2.0(7.0) mEq/L/day), and fluid restriction/isotonic saline (1.9(3.2) mEq/L/day). Both fluid restriction and isotonic saline monotherapies were significantly less effective (0.8(2.0) mEq/L/day and 1.3(3.0) mEq/L/day, respectively) and were associated with clinically relevant rates of treatment failure. Only 46% of patients were discharged with [Na+] ≥ 130 mEq/L. Overly rapid correction of hyponatremia occurred in 11.7%. CONCLUSIONS: Although essential for successful hyponatremia management, appropriate diagnostic testing is not routinely performed in current practice. The most frequently employed monotherapies were often ineffective and sometimes even aggravated hyponatremia. Tolvaptan was used less often but showed significantly greater effectiveness. Despite clear evidence that hyponatremia is associated with poor outcome in oncology patients, most patients were discharged still hyponatremic. Further studies are needed to assess the beneficial impact of hyponatremia correction with effective therapies.

Current treatment practice and outcomes. Report of the hyponatremia registry.

Current management practices for hyponatremia (HN) are incompletely understood. The HN Registry has recorded diagnostic measures, utilization, efficacy, and outcomes of therapy for eu- or hypervolemic HN. To better understand current practices, we analyzed data from 3087 adjudicated adult patients in the registry with serum sodium concentration of 130 mEq/l or less from 225 sites in the United States and European Union. Common initial monotherapy treatments were fluid restriction (35%), administration of isotonic (15%) or hypertonic saline (2%), and tolvaptan (5%); 17% received no active agent. Median (interquartile range) mEq/l serum sodium increases during the first day were as follows: no treatment, 1.0 (0.0-4.0); fluid restriction, 2.0 (0.0-4.0); isotonic saline, 3.0 (0.0-5.0); hypertonic saline, 5.0 (1.0-9.0); and tolvaptan, 4.0 (2.0-9.0). Adjusting for initial serum sodium concentration with logistic regression, the relative likelihoods for correction by 5 mEq/l or more (referent, fluid restriction) were 1.60 for hypertonic saline and 2.55 for tolvaptan. At discharge, serum sodium concentration was under 135 mEq/l in 78% of patients and 130 mEq/l or less in 49%. Overly rapid correction occurred in 7.9%. Thus, initial HN treatment often uses maneuvers of limited efficacy. Despite an association with poor outcomes and availability of effective therapy, most patients with HN are discharged from hospital still hyponatremic. Studies to assess short- and long-term benefits of correction of HN with effective therapies are needed.

Electrospray ionization (ESI) fragmentations and dimethyldioxirane reactivities of three diverse lactams having full, half, and zero resonance energies.

Three lactams having, respectively, ~20, ~10, and 0 kcal/mol of resonance energy have been subjected to electrospray ionization mass spectrometry (ESI/MS) as well as to attempted reaction with dimethyldioxirane (DMDO). The ESI/MS for all three lactams are consistent with fragmentation from the N-protonated, rather than the O-protonated tautomer. Each exhibits a unique fragmentation pathway. DFT calculations are employed to provide insights concerning these pathways. N-Ethyl-2-pyrrolidinone and 1-azabicyclo[3.3.1]nonan-2-one, the full- and half-resonance lactams, are unreactive with DMDO. The "Kirby lactam" (3,5,7-trimethyl-1-azaadamantan-2-one) has zero resonance energy and reacts rapidly with DMDO to generate a mixture of reaction products. The structure assigned to one of these is the 2,2-dihydroxy-N-oxide, thought to be stabilized by intramolecular hydrogen bonding and buttressing by the methyl substituents. A reasonable pathway to this derivative might involve formation of an extremely labile N-oxide, in a purely formal sense, an example of the hitherto-unknown amide N-oxides, followed by hydration with traces of moisture.

Role of vaptans in the management of hyponatremia.

Hyponatremia, the most commonly encountered electrolyte abnormality, affects as many as 30% of hospitalized patients. It is a powerful predictor of poor outcomes, especially in patients with congestive heart failure or cirrhosis. The failure to excrete electrolyte-free water that results from persistent secretion of antidiuretic hormone despite low serum osmolality usually underlies the development of hyponatremia. Treatment depends on several factors, including the cause, overall volume status of the patient, severity of hyponatremic symptoms, and duration of hyponatremia at presentation. This review focuses on the role of the vasopressin receptor antagonists, or vaptans, in the treatment of hyponatremia. These recently introduced agents have the unique ability to induce an aquaresis, the excretion of electrolyte-free water without accompanying solutes. After a brief historical perspective and discussion of pharmacologic characteristics of vaptans, we review the accumulated experience with vaptans for the treatment of hyponatremia. Vaptans have been shown to increase serum sodium concentrations in patients with euvolemic or hypervolemic hyponatremia in a reproducible manner, but their safe use requires full understanding of their indications and contraindications.

Effect of dipyridamole plus aspirin on hemodialysis graft patency.

BACKGROUND: Arteriovenous graft stenosis leading to thrombosis is a major cause of complications in patients undergoing hemodialysis. Procedural interventions may restore patency but are costly. Although there is no proven pharmacologic therapy, dipyridamole may be promising because of its known vascular antiproliferative activity. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of extended-release dipyridamole, at a dose of 200 mg, and aspirin, at a dose of 25 mg, given twice daily after the placement of a new arteriovenous graft until the primary outcome, loss of primary unassisted patency (i.e., patency without thrombosis or requirement for intervention), was reached. Secondary outcomes were cumulative graft failure and death. Primary and secondary outcomes were analyzed with the use of a Cox proportional-hazards regression with adjustment for prespecified covariates. RESULTS: At 13 centers in the United States, 649 patients were randomly assigned to receive dipyridamole plus aspirin (321 patients) or placebo (328 patients) over a period of 4.5 years, with 6 additional months of follow-up. The incidence of primary unassisted patency at 1 year was 23% (95% confidence interval [CI], 18 to 28) in the placebo group and 28% (95% CI, 23 to 34) in the dipyridamole-aspirin group, an absolute difference of 5 percentage points. Treatment with dipyridamole plus aspirin significantly prolonged the duration of primary unassisted patency (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P=0.03) and inhibited stenosis. The incidences of cumulative graft failure, death, the composite of graft failure or death, and serious adverse events (including bleeding) did not differ significantly between study groups. CONCLUSIONS: Treatment with dipyridamole plus aspirin had a significant but modest effect in reducing the risk of stenosis and improving the duration of primary unassisted patency of newly created grafts. (ClinicalTrials.gov number, NCT00067119.)

Hyponatremia and the use of vasopressin receptor antagonists in critically ill patients.

Hyponatremia in critically ill patients is a common and challenging problem. Increased levels of arginine vasopressin almost always contribute to the etiology. Inhibition of the vasopressin receptor with a vasopressin receptor antagonist (vaptan) is a novel approach to the treatment of hyponatremia. Vaptans are well suited to the treatment of chronic hyponatremia associated with syndrome of inappropriate anti-diuretic hormone secretion (SIADH) and hypervolemic states like cirrhosis or congestive heart failure. No data are available on the use of vaptans in acute hyponatremia, and they are not indicated in hypovolemic hyponatremia. The focus of this review is the treatment of critically ill patients with hyponatremia with vaptans and other measures.

Use of aspirin associates with longer primary patency of hemodialysis grafts.

Extended-release dipyridamole plus low-dose aspirin (ERDP/ASA) prolongs primary unassisted graft patency of newly created hemodialysis arteriovenous grafts, but the individual contributions of each component are unknown. Here, we analyzed whether use of aspirin at baseline associated with primary unassisted graft patency among participants in a randomized trial that compared ERDP/ASA and placebo in newly created grafts. We used Cox proportional hazards regression, adjusting for prespecified baseline comorbidities and covariates. Of all participants, 43% reported use of aspirin at baseline; of these, 82% remained on nonstudy aspirin (i.e., excluding ERDP/ASA) at 1 year. After 1 year of follow-up, the incidence of primary unassisted patency among participants using aspirin at baseline was 30% (95% CI: 24 to 35%) and among those not using aspirin was 23% (95% CI: 18 to 27%). Use of aspirin at baseline associated with a dose-dependent prolongation of primary unassisted graft patency that approached statistical significance (adjusted HR, 0.83; 95% CI: 0.68 to 1.01; P=0.06). Use of aspirin at baseline did not associate with prolongation of cumulative graft patency or participant survival. In conclusion, use of aspirin associates with a trend toward longer primary unassisted patency of newly placed hemodialysis grafts similar to that observed for ERDP/ASA.

1-Azabicyclo[3.3.1]nonan-2-one: nitrogen versus oxygen protonation.

Protonation of typical unstrained amides and lactams is heavily favored at oxygen. In contrast, protonation of the highly distorted lactam 1-azabicyclo[2.2.2]octan-2-one is heavily favored at nitrogen. What structures occupy "crossover boundaries" where N- and O-protonation are nearly equienergetic? Density function theory calculations at the B3LYP/6-31G* level, as well as QCISD(T)/6-31G* calculations, predict that 1-azabicyclo[3.3.1]nonan-2-one favors N-protonation at nitrogen only very slightly (<2.0 kcal/mol; "gas phase") over O-protonation. (1)H and (13)C NMR as well as ultraviolet (UV) studies of this lactam, in its combination with sulfuric acid, confirm predominant protonation at nitrogen. Although the calculations very slightly favor the N-protonated chair-chair conformation, experimental spectra clearly support the N-protonated boat-chair. Broadened resonances in the (13)C NMR spectrum suggest an exchange phenomenon. Variable-temperature studies of the (13)C NMR spectra support dynamic exchange between the major tautomer (N-protonated) and the minor tautomer (O-protonated) in a roughly 4:1 mixture. The findings also support the published prediction that a twisted bridgehead lactam with the nitrogen lone pair (n(N)) as HOMO will protonate at nitrogen.

Insights into the formation and isomerization of the benzene metabolite muconaldehyde and related molecules: comparison of computational and experimental studies of simple, benzo-annelated, and bridged 2,3-epoxyoxepins.

2,8-Dioxabicyclo[5.1.0]octa-3,5-diene ("2,3-epoxyoxepin") has been postulated as an intermediate in ring-opening metabolism of benzene. Density functional theory (B3LYP/6-31G*) is employed to study the activation and reaction energies for ring-opening isomerization of 2,3-epoxyoxepin, its 4,5-benzo derivative, and its 3,6-hexamethylene derivative. The results are compared with published experimental data. The markedly different fates of these three molecules suggest a means for testing the postulated metabolic pathway.

When is it appropriate to use vasopressin receptor antagonists?

Hyponatremia is a common and challenging disorder. The mainstays of treatment until recently were water restriction and hypertonic saline. The first nonpeptide vasopressin receptor antagonist (VRA) is now approved by the US Food and Drug Administration for use in patients with euvolemic and hypervolemic hyponatremia. VRA induce urinary dilution with an aquaresis that leads to an increase in serum sodium concentration. In patients with heart failure, VRA modestly improve congestive symptoms but have no effect on short- or long-term mortality. Long-term effects have not been extensively studied, but serious adverse effects of VRA are rare, and the rate of rise in serum sodium that they produce seems unlikely to lead to osmotic demyelination. Beneficial effects beyond changing serum tonicity and alternative uses, such as in polycystic kidney disease, need further exploration. This commentary discusses the current and potential indications for use of VRA.

Hypovolemic Hyponatremia.

The etiology of hyponatremia is often multifactorial. The most common causes include hypovolemia from gastrointestinal (GI) or other fluid losses, thiazide diuretics, and SIAD [1]. In this chapter, we will discuss hypovolemic hyponatremia, as well as the clinical parameters that help distinguish between hypovolemic and euvolemic states. These include not only the urine [Na+] concentration but also the fractional uric acid excretion, a parameter that can be employed even when diuretics have been prescribed [2,3,4,5,6,7]. Among the common causes of hypovolemic hyponatremia are GI fluid loss, a range of endocrinopathies [7], and thiazide-induced hyponatremia, which is best considered as a distinct entity, in particular because recent data suggest that it has a genetic predisposition. Also, the discontinuation of thiazide is a key step in treatment [2,7]. The management of hypovolemic hyponatremia starts with confirming its presence and determining the underlying cause. Correction focuses on the appropriate use of isotonic fluid to effect volume repletion while avoiding an overly rapid rise in serum [Na+] concentration.

Effect of clopidogrel on early failure of arteriovenous fistulas for hemodialysis: a randomized controlled trial.

CONTEXT: The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas. OBJECTIVE: To determine whether clopidogrel reduces early failure of hemodialysis fistulas. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003-2007. Eight hundred seventy-seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later. INTERVENTION: Participants were randomly assigned to receive clopidogrel (300-mg loading dose followed by daily dose of 75 mg; n = 441) or placebo (n = 436) for 6 weeks starting within 1 day after fistula creation. MAIN OUTCOME MEASURES: The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/min or more during 8 of 12 dialysis sessions. RESULTS: Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46-0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94-1.17; P = .40). CONCLUSION: Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis. Trial Registration clinicaltrials.gov Identifier: NCT00067119.

Postinfectious glomerulonephritis in renal allograft recipients.

Postinfectious glomerulonephritis (PIGN) is a rare etiology of de novo glomerulonephritis following kidney transplantation. To date, there have only been eight cases reported in the literature. We report an additional three patients transplanted at our institution between January 2000 and October 2004 who had clinical and pathologic findings consistent with posttransplant PIGN. All three patients were type 1 diabetics. One had received a cadaveric kidney transplant, one a simultaneous kidney-pancreas transplant, and the third a living related kidney transplant followed by a pancreas transplant. All patients were on triple immunosuppressive therapy with tacrolimus, mycophenolate mofetil, and prednisone. In each case, an acute decline in allograft function developed in association with a known or suspected infectious process, and renal biopsies revealed an immune complex glomerulonephritis with features of PIGN. All regained renal function with treatment of their known or suspected infections and without specific therapies for their glomerulonephritis, including corticosteroids.

Diagnosing and Treating the Syndrome of Inappropriate Antidiuretic Hormone Secretion.

BACKGROUND: The syndrome of inappropriate antidiuretic hormone secretion is the most common cause of hyponatremia in clinical practice, but current management of hyponatremia and outcomes in patients with syndrome of inappropriate antidiuretic hormone secretion are not well understood. The objective of the Hyponatremia Registry was to assess the current state of management of hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion in diverse hospital settings, specifically which diagnostic and treatment modalities are currently used and how rapidly and reliably they result in an increase in serum sodium concentration ([Na(+)]). A secondary objective was to determine whether treatment choices and outcomes differ across the United States and the European Union. METHODS: The Hyponatremia Registry recorded selected diagnostic measures and use, efficacy, and outcomes of therapy for euvolemic hyponatremia diagnosed clinically as syndrome of inappropriate antidiuretic hormone secretion in 1524 adult patients with [Na(+)] ≤130 mEq/L (1034 from 146 US sites and 490 from 79 EU sites). A subgroup of patients with more rigorously defined syndrome of inappropriate antidiuretic hormone secretion via measurement of relevant laboratory parameters was also analyzed. RESULTS: The most common monotherapy treatments for hyponatremia in syndrome of inappropriate antidiuretic hormone secretion were fluid restriction (48%), isotonic (27%) or hypertonic (6%) saline, and tolvaptan (13%); 11% received no active agent. The mean rate of [Na(+)] change (mEq/L/d) was greater for all active therapies than no active treatment. Hypertonic saline and tolvaptan produced the greatest mean rate of [Na(+)] change (interquartile range, both 3.0 [6.0] mEq/L/d) compared with lower interquartile range rates of [Na(+)] change for isotonic saline (1.5 [3.0] mEq/L/d) and fluid restriction (1.0 [2.3] mEq/L/d). The general pattern of responses was similar in both the US and EU cohorts. At discharge, [Na(+)] was <135 mEq/L in 75% of patients and ≤130 mEq/L in 43% of patients. Overly rapid correction occurred in 10.2% of patients. CONCLUSIONS: Current treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion often uses therapies with limited efficacy; the most commonly chosen monotherapy treatments, fluid restriction and isotonic saline, failed to increase the serum [Na(+)] by ≥5 mEq/L in 55% and 64% of monotherapy treatment episodes, respectively. Appropriate laboratory tests to diagnose syndrome of inappropriate antidiuretic hormone secretion were obtained in <50% of patients; success rates in correcting hyponatremia were significantly higher when such tests were obtained. Few outcome differences were found between the United States and the European Union. A notable exception was hospital length of stay; use of tolvaptan was associated with significantly shorter length of stay in the European Union but not in the United States. Despite the availability of effective therapies, most patients with syndrome of inappropriate antidiuretic hormone secretion were discharged from the hospital still hyponatremic.