Current treatment practice and outcomes. Report of the hyponatremia registry
Authors: Arthur Greenberg, Joseph G. Verbalis, Alpesh N. Amin, Volker R. Burst, Joseph A. Chiodo III, Jun R. Chiong, Joseph F. Dasta, Keith E. Friend, Paul J. Hauptman, Alessandro Peri, Samuel H. Sigal
Journal: Kidney International (2015)

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. 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. Hyponatremia (HN), defined as a serum sodium concentration ([Na+]) below the lower limit of normal, is the most common electrolyte disorder in hospitalized patients, with a prevalence as high as 30–42%.1.Hawkins R.C. Age and gender as risk factors for hyponatremia and hypernatremia.Clin Chim Acta. 2003; 337: 169-172Crossref PubMed Scopus (295) Google Scholar,2.Upadhyay A. Jaber B.L. Madias N.E. Incidence and prevalence of hyponatremia.Am J Med. 2006; 119: S30-S35Abstract Full Text Full Text PDF PubMed Scopus (523) Google Scholar HN is independently associated with mortality in congestive heart failure (CHF), cirrhosis, and hospitalized patients in general3.Gheorghiade M. Abraham W.T. Albert N.M. et al.Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry.Eur Heart J. 2007; 28: 980-988Crossref PubMed Scopus (471) Google Scholar, 4.Ruf A.E. Kremers W.K. Chavez L.L. et al.Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone.Liver Transpl. 2005; 11: 336-343Crossref PubMed Scopus (345) Google Scholar, 5.Kim W.R. Biggins S.W. Kremers W.K. et al.Hyponatremia and mortality among patients on the liver-transplant waiting list.N Engl J Med. 2008; 359: 1018-1026Crossref PubMed Scopus (935) Google Scholar, 6.Wald R. Jaber B.L. Price L.L. et al.Impact of hospital-associated hyponatremia on selected outcomes.Arch Intern Med. 2010; 170: 294-302Crossref PubMed Scopus (388) Google Scholar, 7.Corona G. Giuliani C. Parenti G. et al.Moderate hyponatremia is associated with increased risk of mortality: evidence from a meta-analysis.PLoS One. 2013; 8: e80451Crossref PubMed Scopus (174) Google Scholar and with increased hospital costs and readmission rates.8.Shea A.M. Hammill B.G. Curtis L.H. et al.Medical costs of abnormal serum sodium levels.J Am Soc Nephrol. 2008; 19: 764-770Crossref PubMed Scopus (68) Google Scholar,9.Amin A. Deitelzweig S. Christian R. et al.Evaluation of incremental healthcare resource burden and readmission rates associated with hospitalized hyponatremic patients in the US.J Hosp Med. 2012; 7: 634-639Crossref PubMed Scopus (38) Google Scholar Chronic HN has been linked to impaired gait and balance, increased falls and fracture rates, and osteoporosis.10.Renneboog B. Musch W. Vandemergel X. et al.Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits.Am J Med. 2006; 119: 71-78Abstract Full Text Full Text PDF PubMed Scopus (648) Google Scholar, 11.Kinsella S. Moran S. Sullivan M.O. et al.Hyponatremia independent of osteoporosis is associated with fracture occurrence.Clini J Am Soc Nephrol. 2010; 5: 275-280Crossref PubMed Scopus (219) Google Scholar, 12.Hoorn E.J. Rivadeneira F. van Meurs J.B. et al.Mild hyponatremia as a risk factor for fractures: the Rotterdam Study.J Bone Miner Res. 2011; 26: 1822-1828Crossref PubMed Scopus (201) Google Scholar, 13.Verbalis J.G. Barsony J. Sugimura Y. et al.Hyponatremia-induced osteoporosis.J Bone Miner Res. 2010; 25: 554-563Crossref PubMed Scopus (314) Google Scholar However, a causal role of HN for these associations is largely unproven.14.Hoorn E.J. Zietse R. Hyponatremia and mortality: moving beyond associations.Am J Kidney Dis. 2013; 62: 139-149Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar Correction of severe HN of sudden onset can be genuinely lifesaving,15.Fraser C.L. Arieff A.I. Epidemiology, pathophysiology, and management of hyponatremic encephalopathy.Am J Med. 1997; 102: 67-77Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar, and treatment of chronic HN associated with neurological symptoms is undeniably beneficial. Despite the widespread clinical impression that correction of less severe chronic HN is also worthwhile, evidence-based data demonstrating clinical benefit are limited.10.Renneboog B. Musch W. Vandemergel X. et al.Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits.Am J Med. 2006; 119: 71-78Abstract Full Text Full Text PDF PubMed Scopus (648) Google Scholar, 16.Hauptman P.J. Burnett J. Gheorghiade M. et al.Clinical course of patients with hyponatremia and decompensated systolic heart failure and the effect of vasopressin receptor antagonism with tolvaptan.J Card Fail. 2013; 19: 390-397Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 17.Rossi J. Bayram M. Udelson J.E. et al.Improvement in hyponatremia during hospitalization for worsening heart failure is associated with improved outcomes: insights from the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Chronic Heart Failure (ACTIV in CHF) trial.Acute Card Care. 2007; 9: 82-86Crossref PubMed Scopus (119) Google Scholar, 18.Schrier R.W. Gross P. Gheorghiade M. et al.Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia.N Engl J Med. 2006; 355: 2099-2112Crossref PubMed Scopus (974) Google Scholar Hypovolemic HN responds readily to volume repletion. Until recently, treatment of hypervolemic HN has been limited to fluid restriction (FR) and correction of the underlying disorder. Treatment modalities for euvolemic HN have included FR, hypertonic saline (HS), loop diuretics, demeclocycline, and urea. With the approval of the vasopressin-receptor antagonists conivaptan and tolvaptan, more targeted treatment for euvolemic and hypervolemic HN became available. It remains uncertain how treatment options are employed, and how correction magnitude and incidence of adverse outcomes are affected by the type of therapy. With this background, the multinational HN Registry was initiated to assess the current state of treatment of euvolemic and hypervolemic HN in diverse, real-world hospital settings. Its specific purpose was to determine which diagnostic and treatment modalities are currently employed, how effective they are, and how rapidly and reliably they result in an increase in [Na+]. An additional goal was to determine which treatments posed the greatest risk of overly rapid correction and osmotic demyelination.19.Hauptman P.J. Greenberg A. Verbalis J.G. et al.Design of a prospective, multinational registry to evaluate patients hospitalized with hyponatremia: the HN Registry.Open Access Journal of Clnical Trials. 2013; 5: 93-100Google Scholar A total of 5028 patients were entered (Figure 1) between September 2010 and February 2013. One or more criteria requiring adjudication were met by 2705 patients (54% of those entered), and 1941 of those (72%) failed adjudication. The 764 patients (28%) retained after adjudication and the 2323 (46% of those entered) not requiring adjudication comprise the 3087 individuals of the per-protocol data set. A sensitivity analysis performed with and without the 951 potentially hypovolemic patients excluded because of thiazide use or evidence of volume depletion showed no significant differences in rates of [Na+] change or achievement of [Na+] correction benchmarks. The syndrome of inappropriate antidiuretic hormone (SIADH), CHF, and cirrhosis data sets include patients in whom these diagnoses were made by treating physicians. Patient demographics and baseline characteristics are shown in Table 1. Patients with cirrhosis were younger and more likely to be male compared with patients with SIADH or CHF. A prior episode of HN was known to have occurred in 909 patients (29%) and was most likely in patients with cirrhosis and least likely in those with SIADH. Most patients (71%) were under the care of a generalist rather than an internal medicine subspecialist.Table 1Baseline demographic characteristics by comorbidityAll PatientsaIncludes 171 either patients without a diagnosis of SIADH, cirrhosis, or CHF or with multiple comorbidities. (N=3087)SIADH (n=1524)CHF (n=762)Cirrhosis (n=630)Age distribution, n (%)bSIADH versus CHF and cirrhosis, and CHF vs. cirrhosis: P<0.001. ≤50 years479 (16)186 (12)76 (10)190 (30) 51–64 years937 (30)373 (25)164 (22)339 (54) 65–74 years587 (19)339 (22)127 (17)81 (13) ≥75 years1084 (35)626 (41)395 (52)20 (3) Men, n (%)cSIADH versus CHF: P=0.79; and SIADH and CHF versus cirrhosis: P<0.001.1558 (51)695 (46)352 (46)419 (67)Race distribution: US only, n (%)bSIADH versus CHF and cirrhosis, and CHF vs. cirrhosis: P<0.001. White1927 (74)770 (75)575 (76)455 (72) African American309 (12)108 (10)123 (16)58 (9) Asian57 (2)29 (3)10 (1)13 (2) Other154 (6)61 (6)30 (4)53 (9) Unknown149 (6)66 (6)24 (3)51 (8) Median initial [Na+] (IQR), mEq/ldSIADH versus CHF and cirrhosis: P<0.001; CHF versus cirrhosis: P=0.01.125.0 (120.0–128.0)124.0 (119.0–127.0)126.0 (122.0–129.0)125.0 (121.0–128.0) Median initial BUN (IQR), mg/dlbSIADH versus CHF and cirrhosis, and CHF vs. cirrhosis: P<0.001.15.83 (10.0–25.0)12.0 (9.0–17.0)22.0 (14.0–36.0)20.0 (13.0–33.0) Median initial creatinine (IQR), mg/dleSIADH versus CHF and cirrhosis: P<0.001; and CHF versus cirrhosis: P=0.005.0.85 (0.6–1.2)0.70 (0.6–0.9)1.10 (0.8–1.6)1.03 (0.8–1.5) Initial BUN:creatinine ratio (IQR),bSIADH versus CHF and cirrhosis, and CHF vs. cirrhosis: P<0.001.17.8 (13.3–23.4)16.7 (12.2–21.9)20.0 (15.2–26.0)18.2 (14.1–24.0) Median initial blood glucose (IQR), mg/dl112 (97.0–134.0)110 (96.0–130.0)116 (101.0–141.0)109 (95.0–133.0)Prior HN, n (%)bSIADH versus CHF and cirrhosis, and CHF vs. cirrhosis: P<0.001.,fHN during previous hospital admission in prior 12 months. Yes909 (29)407 (27)209 (27)240 (38) No1176 (38)687 (45)253 (33)178 (28) Unknown1001 (32)430 (28)299 (39)212 (34)HN at admission, n (%)gData missing for 24 patients in all, 19 in SIADH and 4 in CHF populations; SIADH versus CHF: P=0.04; SIADH versus cirrhosis: P=0.001; and CHF versus cirrhosis: P<0.001. Yes2532 (82)1252 (82)605 (79)549 (87) No531 (17)253 (17)153 (20)81 (13) Unknown24 (1)19 (1)4 (1)0 (0)Primary physician specialty, n (%) Nephrologist104 (3)82 (5)10 (1)8 (1) Endocrinologist108 (4)106 (7)2 (<1)0 Cardiologist321 (10)49 (3)247 (32)7 (1) Hepatologist260 (8)3 (<1)4 (1)246 (39) Oncologist111 (4)92 (6)5 (1)11 (2) Generalist1844 (60)944 (62)466 (61)315 (50) Other338 (11)247 (16)28 (4)43 (7)HN subspecialist consulted, n (%)hSIADH versus CHF and cirrhosis: P<0.001; and CHF versus cirrhosis: P=0.01.,iHN specialist defined as nephrologist or endocrinologist. No1989 (64)839 (55)530 (70)501 (80) Yes1096 (36)683 (45)232 (30)129 (21)Abbreviations: BUN, blood urea nitrogen; CHF, congestive heart failure; HN, hyponatremia; [Na+], sodium concentration; IQR, interquartile range; SIADH, syndrome of inappropriate antidiuretic hormone secretion.Median (IQR) B-type natriuretic peptide value in the CHF patients was 733.5 pg/ml (1465.0), n=410.a Includes 171 either patients without a diagnosis of SIADH, cirrhosis, or CHF or with multiple comorbidities.b SIADH versus CHF and cirrhosis, and CHF vs. cirrhosis: P<0.001.c SIADH versus CHF: P=0.79; and SIADH and CHF versus cirrhosis: P<0.001.d SIADH versus CHF and cirrhosis: P<0.001; CHF versus cirrhosis: P=0.01.e SIADH versus CHF and cirrhosis: P<0.001; and CHF versus cirrhosis: P=0.005.f HN during previous hospital admission in prior 12 months.g Data missing for 24 patients in all, 19 in SIADH and 4 in CHF populations; SIADH versus CHF: P=0.04; SIADH versus cirrhosis: P=0.001; and CHF versus cirrhosis: P<0.001.h SIADH versus CHF and cirrhosis: P<0.001; and CHF versus cirrhosis: P=0.01.i HN specialist defined as nephrologist or endocrinologist. Open table in a new tab Abbreviations: BUN, blood urea nitrogen; CHF, congestive heart failure; HN, hyponatremia; [Na+], sodium concentration; IQR, interquartile range; SIADH, syndrome of inappropriate antidiuretic hormone secretion. Median (IQR) B-type natriuretic peptide value in the CHF patients was 733.5 pg/ml (1465.0), n=410. In the 1524 patients with SIADH, serum osmolality was measured in 66%, urine osmolality in 68%, and urine [Na+] in 63%; all three tests were performed in 47%, and none in 11%. Cortisol was measured in 33% of patients and thyroid-stimulating hormone in 64%. All five of these measurements were made in 21% of patients. As shown in Table 2, 17% of patients received no active HN therapy. Utilization varied with [Na+]. Only 3% of patients with severe HN received no therapy compared with 13% with moderate HN and 25% with mild HN (P<0.001). Stopping a medication that may induce SIADH could also be considered an active treatment; of the 509 patients who received no active HN therapy, 265 (52%) were receiving a potentially HN-inducing medication (see Supplementary Table S1 online for list), which was discontinued in 29 (11%).Table 2Treatment utilization according to diagnosis or severity of HNNumber of therapy episodes or unique therapies employedNo therapy, n (%)1 Episode, n (%)≥2 Episodes, n (%)Median therapy episodes/patient (IQR), nAll patients (n=3087)509 (17)1148 (37)1430 (46)2.0 (1.0–3.0)Comorbidity SIADH (n=1524)170 (11)451 (30)903 (59)2.0 (1.0–3.0) CHF (n=762)176 (23)325 (43)261 (34)1.0 (1.0–3.0) Cirrhosis (n=630)125 (20)298 (47)207 (33)1.0 (1.0–2.0)Starting [Na +], mEq/l <120 mEq/l (n=653)22 (3)207 (32)424 (65)2.0 (1.0–3.0) 120–125 mEq/l (n=1048)139 (13)379 (36)530 (51)2.0 (1.0–3.0) >125–130 mEq/l (n=1386)348 (25)562 (41)476 (34)1.0 (1.0–2.0)Abbreviations: CHF, congestive heart failure; HN, hyponatremia; IQR, interquartile range; [Na+], sodium concentration; SIADH, syndrome of inappropriate antidiuretic hormone secretion.Episode of therapy refers to an interval during which a treatment or combination of treatments was given specifically for HN without interruption. For purposes of this analysis, treatment of CHF patients for congestion was not considered a specific treatment of HN as any patient with CHF would have been so treated.No HN therapy: P<0.001, SIADH versus CHF and cirrhosis; P=0.14, CHF versus cirrhosis; P<0.001, mild versus moderate and severe, and moderate versus severe HN.One episode: P<0.001, SIADH versus CHF and cirrhosis; P=0.09, CHF versus cirrhosis; P=0.08, mild versus severe HN; P=0.03, mild versus moderate HN; P=0.06, moderate versus severe HN.≥2 episodes: P<0.001, SIADH versus CHF and cirrhosis; P=0.58, CHF versus cirrhosis; P<0.001, mild versus moderate and severe, and moderate versus severe HN.Therapy episode/patient: P<0.001, SIADH versus CHF and cirrhosis; P=0.29, CHF versus cirrhosis; P<0.001, mild versus moderate and severe, and moderate versus severe HN. Open table in a new tab Download .ppt (.2 MB) Help with ppt files Supplementary Figure 1 Download .docx (.01 MB) Help with docx files Supplementary Table 1 Abbreviations: CHF, congestive heart failure; HN, hyponatremia; IQR, interquartile range; [Na+], sodium concentration; SIADH, syndrome of inappropriate antidiuretic hormone secretion. Episode of therapy refers to an interval during which a treatment or combination of treatments was given specifically for HN without interruption. For purposes of this analysis, treatment of CHF patients for congestion was not considered a specific treatment of HN as any patient with CHF would have been so treated. No HN therapy: P<0.001, SIADH versus CHF and cirrhosis; P=0.14, CHF versus cirrhosis; P<0.001, mild versus moderate and severe, and moderate versus severe HN. One episode: P<0.001, SIADH versus CHF and cirrhosis; P=0.09, CHF versus cirrhosis; P=0.08, mild versus severe HN; P=0.03, mild versus moderate HN; P=0.06, moderate versus severe HN. ≥2 episodes: P<0.001, SIADH versus CHF and cirrhosis; P=0.58, CHF versus cirrhosis; P<0.001, mild versus moderate and severe, and moderate versus severe HN. Therapy episode/patient: P<0.001, SIADH versus CHF and cirrhosis; P=0.29, CHF versus cirrhosis; P<0.001, mild versus moderate and severe, and moderate versus severe HN. The therapies utilized, according to underlying diagnosis or severity of HN, are shown in Figures 2 and 3. Overall, 55% of patients were treated with FR or isotonic saline (NS) or both. Treatments more likely to result in an increase in [Na+]—HS or tolvaptan—were used in 7% of patients.Figure 3Choice of initial therapy according to baseline serum sodium concentration: all patients. P-values shown for comparisons where P<0.05; all other intergroup comparisons did not reach statistical significance. Dotted lines indicate P-value comparisons for <120- vs. 126–130-mEq/l groups. FR, fluid restriction; HN, hyponatremia; HS, hypertonic saline; NS, isotonic saline. aNo prescribed therapy specifically targeting HN.View Large Image Figure ViewerDownload (PPT) FR alone was selected most frequently. NS alone or with FR was used significantly more often in patients with SIADH (30%) than with CHF (7%) or cirrhosis (10%). Patients with lower baseline [Na+] were more likely to receive HS. When used as a monotherapy, FR was least effective, although more rigorous FR (≤1000 ml/day) resulted in a more rapid [Na+] increase compared with a lesser degree of FR (Table 3). Addition of FR to the other monotherapies had a small effect, if any. Median (interquartile range) rate of change with NS alone was 2.0 (0.3–4.0) versus 2.4 (1.0–5.0) mEq/l/day with addition of FR (P=0.004), but rate of change, correction rate, or frequency of overly rapid correction did not change significantly with addition of FR to any other monotherapy. Examined categorically (Figure 4), correction of [Na+], defined de minimus as a [Na+] increase >2 mEq/l, was more likely and lack of correction, defined as a final [Na+] within 2 mEq/l of the starting [Na+], less likely with HS or tolvaptan than with FR or NS. [Na+] was also less likely to decrease by >2 mEq/l in patients who received HS or tolvaptan than in patients who received FR or NS as monotherapy. For decrease >2 mEq/l: FR versus HS, P=0.03; FR versus tolvaptan, P<0.01; NS versus HS, P=0.04; NS versus tolvaptan, P=0.01.Table 3Response to therapy for initial monotherapy episodesTreatmentOverly rapid correction, n (%)Patients, nMedian baseline [Na+] (IQR), mEq/lMedian rate of [Na+] change (IQR), mEq/l/dayaCalculated as total increment in [Na+] during the period of treatment utilization/no. of treatment days (interval of HN used for no treatment group).Median first day change (IQR), mEq/l/daybCalculated incremental change during the first 24±12 h window. The actual interval for any individual patient ranged from 12 to 36 h, depending on the timing of the reported laboratory values.Mean duration of Rx (IQR), dayscDuration of HN therapy is defined as the last day of initial HN therapy episode minus the start of the initial HN therapy episode+1.24 or 48 hdDefined as increment in [Na+] >12 mEq/l in 24 h or 18 mEq/l in 48 h.24 HourseDefined as increment in [Na+] >12 mEq/l in 24 h.No treatment507127.0 (125.0–129.0)0.4 (0.0–1.0)1.0 (0.0–4.0)6.0 (4.0–9.0)7 (1.4)7 (1.4)Fluid restriction992125.0 (121.0–127.0)1.0 (0.0–2.0)2.0 (0.0–4.0)4.0 (2.0–7.0)15 (1.4)13 (1.2) ≤1000 ml399123.0 (120.0–126.0)1.2 (0.3–2.5)2.0 (0.0–4.0)3.0 (1.0–5.0)4 (1.0)4 (1.0) >1000 ml529126.0 (122.0–128.0)0.7 (0.0–2.0)2.0 (0.0–4.0)4.0 (2.0–7.0)7 (1.3)6 (1.1) Normal saline428123.0 (119.0–127.0)2.0 (0.3–4.0)3.0 (0.0–5.0)1.0 (1.0–2.0)13 (2.9)10 (2.2) Hypertonic saline72118.5 (114.5–124.0)3.1 (1.7–7.8)5.0 (1.0–9.0)2.0 (1.0–3.0)12 (16.0)11 (14.7) Tolvaptan131124.0 (120.0–128.0)3.3 (1.4–7.0)4.0 (2.0–9.0)2.0 (1.0–4.0)16 (11.6)12 (8.7)Abbreviations: HN, hyponatremia; [Na+], sodium concentration; IQR, interquartile range; Rx, treatment.Table comprises results of the first treatment given specifically to treat HN if only a single modality was used.a Calculated as total increment in [Na+] during the period of treatment utilization/no. of treatment days (interval of HN used for no treatment group).b Calculated incremental change during the first 24±12 h window. The actual interval for any individual patient ranged from 12 to 36 h, depending on the timing of the reported laboratory values.c Duration of HN therapy is defined as the last day of initial HN therapy episode minus the start of the initial HN therapy episode+1.d Defined as increment in [Na+] >12 mEq/l in 24 h or 18 mEq/l in 48 h.e Defined as increment in [Na+] >12 mEq/l in 24 h. Open table in a new tab Abbreviations: HN, hyponatremia; [Na+], sodium concentration; IQR, interquartile range; Rx, treatment. Table comprises results of the first treatment given specifically to treat HN if only a single modality was used. Overall success in reaching various correction benchmarks is shown in Table 4 for initial monotherapy episodes. Overall, 22% of patients reached a normal [Na+] ≥135 mEq/l. Rate of correction by ≥5 mEq/l with HS was similar to that of tolvaptan in the unadjusted analysis. However, the utilization of various treatments varied with baseline [Na+] (Figure 3). When achievement of [Na+] change benchmarks was adjusted for starting [Na+] using logistic regression (Table 4), only tolvaptan produced a consistently higher rate of success in reaching all three benchmarks. Compared with FR, NS was worse in two of three benchmarks. HS was more likely to result in a [Na+] ≥5 mEq/l. When the [Na+] interaction was examined categorically rather than continuously (Supplementary Table S2 online), the relative likelihood of reaching any of the three benchmarks for HS compared with FR was not different from unity for mild, moderate, or severe HN. In a similar categorical analysis comparing tolvaptan with FR, the relative likelihood of correction to [Na+] >130 mEq/l was 3.131 (1.7324–5.658) with mild HN, 2.106 (1.435–3.092) with moderate HN, and 1.410 (1.007–1.974) with severe HN. The relative likelihood of correction >5 mEq/l was 2.202 (1.446–3.353) with mild HN and 3.533 (1.772–7.044) for moderate HN. The relative likelihood of correction to [Na+] >135 mEq/l was 1.817 (1.340–2.464) for mild HN and 1.200 (1.021–1.409) for moderate HN. The relative likelihoods for other benchmarks or starting [Na+] values did not differ from unity. In some categories, the number of cases was quite small.Table 4Achievement of correction benchmarks[Na +] >130 mEq/lΔ[Na +] ≥5 mEq/l[Na +] >135 mEq/lBy diagnosis Diagnosis, n (%)aAchievement of correction benchmark determined at discharge for diagnoses. All (N=2948)1494 (51)1790 (61)635 (22) SIADH (n=1422)809 (57)981 (69)361 (25) CHF (n=742)357 (48)395 (53)139 (19) Cirrhosis (n=618)239 (39)316 (51)100 (16)By initial monotherapy episode, unadjusted for baseline sodium concentration Initial treatment, n (%)bAchievement of correction benchmark determined at the end of initial therapy episode. No treatment (n=507)210 (41)195 (39)93 (18) Fluid restriction (n=922)269 (29)402 (44)93 (10) ≤1000 ml (n=386)93 (24)180 (47)31 (8) >1000 ml (n=474)137 (29)185 (39)46 (10) Normal saline (n=397)66 (17)162 (41)17 (4) Hypertonic saline (n=71)18 (25)46 (65)7 (10) Tolvaptan (n=122)80 (66)95 (78)41 (34)By initial monotherapy episode, baseline sodium concentration ≤120 Initial treatment, n (%)bAchievement of correction benchmark determined at the end of initial therapy episode. No treatment (n=22)12 (55)21 (95)6 (27) Fluid restriction (n=189)42 (22)122 (65)16 (8) Normal saline (n=116)6 (5)78 (67)3 (3) Hypertonic saline (n=37)5 (14)29 (78)1 (3) Tolvaptan (n=29)13 (45)24 (83)6 (21)By initial monotherapy episode, baseline sodium concentration 120–125 Initial treatment, n (%)bAchievement of correction benchmark determined at the end of initial therapy episode. No treatment (n=138)47 (34)81 (59)25 (18) Fluid restriction (n=382)91 (24)181 (47)31 (8) Normal saline (n=170)20 (12)63 (37)6 (4) Hypertonic saline (n=25)9 (36)14 (56)4 (16) Tolvaptan (n=47)30 (64)40 (85)11 (23)By initial monotherapy episode, baseline sodium concentration >125–130 Initial treatment, n (%)bAchievement of correction benchmark determined at the end of initial therapy episode. No treatment (n=347)151 (44)93 (27)62 (18) Fluid restriction (n=351)136 (39)99 (28)46 (13) Normal saline (n=111)40 (36)21 (19)8 (7) Hypertonic saline (n=9)4 (44)3 (33)2 (22) Tolvaptan (n=46)37 (80)31 (67)24 (52) By initial monotherapy episode, relative likelihood of correction, referent, fluid restrictioncLogistic regression to control for baseline [Na+], relative likelihood (95% confidence interval). Normal saline0.849 (0.800–0.902)0.953 (0.863–1.052)0.939 (0.912–0.968) Hypertonic saline0.949 (0.823–1.093)1.602 (1.162–2.207)0.997 (0.921–1.080) Tolvaptan2.057 (1.605–2.637)2.548 (1.818–3.572)1.354 (1.191–1.539)Abbreviations: CHF, congestive heart failure; [Na+], sodium concentration; SIADH, syndrome of inappropriate antidiuretic hormone secretion.a Achievement of correction benchmark determined at discharge for diagnoses.b Achievement of correction benchmark determined at the end of initial therapy episode.c Logistic regression to control for baseline [Na+], relative likelihood (95% confidence interval). Open table in a new tab Download .docx (.02 MB) Help with docx files Supplementary Table 2 Abbreviations: CHF, congestive heart failure; [Na+], sodium concentration; SIADH, syndrome of inappropriate antidiuretic hormone secretion. As FR was the most frequently prescribed initial therapy, we separately analyzed the course of patients after FR. A total of 922 patients (30%) with a baseline [Na+] <130 mEq/l were treated with FR initially (Figure 5). The majority did not correct [Na+] by an increment ≥5 mEq/l and the majority of those patients received no additional treatment. Overly rapid correction of [Na+] occurred in 7.9% of patients overall (Table 5) and was most likely in patients with SIADH (10.7%) and least likely with cirrhosis (3.6%; P<0.001, SIADH vs. cirrhosis). Of patients who received no active therapy, 1.4% experienced overly rapid correction. Compared with no therapy, the relative risk (95% confidence interval) for overly rapid correction was 1.6 (0.70–3.57) for FR, 2.35 (0.97–5.65) for NS, 12.01 (5.14–28.04) for HS, and 8.57 (3.84–19.12) for tolvaptan.