Abstract
Rationale & Objective
Euvolemic hyponatremia often occurs due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Vasopressin 2 receptor antagonists may be used to treat SIADH. Several of the major trials used 15 mg of tolvaptan as the lowest effective dose in euvolemic and hypervolemic hyponatremia. However, a recent observational study suggested an elevated risk for serum sodium level overcorrection with 15 mg of tolvaptan in patients with SIADH.
Study Design
A retrospective chart review study comparing outcomes in patients with SIADH treated with 15 versus 7.5 mg of tolvaptan.
Settings & Participants
Patients with SIADH who were treated with a very low dose of tolvaptan (7.5 mg) at a single center compared with patients using a 15-mg dose from patient-level data from the observational study described previously.
Predictors
Tolvaptan dose of 7.5 versus 15 mg daily.
Outcomes
Appropriate response to tolvaptan, defined as an initial increase in serum sodium level > 3 mEq/L, and overcorrection of serum sodium level (>8 mEq/L per day, and >10 mEq/L per day in sensitivity analyses).
Analytical Approach
Descriptive study with additional outcomes compared using t tests and F-tests (Fischer's Exact χ2 Test).
Results
Among 18 patients receiving 7.5 mg of tolvaptan, the mean rate of correction was 5.6 ± 3.1 mEq/L per day and 2 (11.1%) patients corrected their serum sodium levels by >8 mEq/L per day, with 1 of these increasing by >12 mEq/L per day. Of those receiving tolvaptan 7.5 mg, 14 had efficacy, with increases ≥ 3 mEq/L; similar results were seen with the 15-mg dose (21 of 28). There was a statistically significant higher chance of overcorrection with the use of 15 versus 7.5 mg of tolvaptan (11 of 28 vs 2 of 18; P = 0.05; and 10 of 28 vs 1 of 18; P = 0.03, for >8 mEq/L per day and >10 mEq/L per day, respectively).
Limitations
Small sample size, retrospective, and nonrandomized.
Conclusions
Tolvaptan, 7.5 mg, daily corrects hyponatremia with similar efficacy and less risk for overcorrection in patients with SIADH versus 15 mg of tolvaptan.
Index Words: Tolvaptan, SIADH, hyponatremia, osmotic demyelination syndrome
Graphical abstract
Hyponatremia is the most common electrolyte disorder in hospitalized patients.1 Hyponatremia can be caused by fundamentally different physiologic mechanisms that include a discrepancy in water input and output (true hypo-osmolar hyponatremia), transcellular water shifts (true hyperosmolar hyponatremia secondary to hyperglycemia), or changes in the fraction of plasma occupied by water (pseudohyponatremia due to hyperlipidemia and hyperproteinemia).2 In addition to this categorization, hyponatremia is subcategorized by the volume status of patients; that is, hypovolemic, euvolemic, or hypervolemic.3 The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of euvolemic hyponatremia.4
SIADH may be triggered by a variety of conditions, including medications, malignancy, pain, nausea and vomiting, infections, or neurologic/central causes.5 The common finding of patients with SIADH is the increased level of antidiuretic hormone relative to their physiologic needs.5 Patients with SIADH have increased urinary fractional excretion of sodium (Na+), urea, and uric acid6, 7, 8; elevated urine osmolality6; and worsening of hyponatremia with isotonic fluid infusion9 in patients with urinary sodium plus potassium concentration ([Na+ + K+]) > 154 mmol/L.10
Before the development of vasopressin 2 (V2) receptor antagonists (vaptans), treatment of SIADH focused on water restriction, sodium tablets with diuretics, and 3% normal saline solution in cases of severe symptomatic hyponatremia,5 demeclocycline, and urea intake.1 The development of medications such as tolvaptan gave physicians the ability to target the end effect of antidiuretic hormone.11 However, these agents were associated with significant risks, including abnormal liver function test results and the possibility of hyponatremia overcorrection, potentially resulting in osmotic demyelination syndrome12, 13, 14, 15, 16 (Fig S1). Urea, although safer, is poorly palatable.
The risk for hyponatremia overcorrection has been difficult to predict mathematically with existing sodium modeling equations and commonly available inpatient measurements, particularly in dynamic conditions and overextended periods of time.17, 18, 19 Instances of overcorrection were reported particularly in elderly female malnourished patients and patients who had SIADH,12,20 increasing their risk for osmotic demyelination syndrome.15,21 In 2017, Kamgar et al22 suggested evidence of the risk for hyponatremia overcorrection in patients with SIADH on the lowest recommended dose of tolvaptan (15 mg). Accordingly, the authors recommended the use of tolvaptan, 7.5 mg, in patients with SIADH to avoid overcorrection.22 These findings are in contrast to data in the Study of Ascending Levels of Tolvaptan in Hyponatremia 1 (SALT-1), SALT-2, and SALT-3 trials, which included mostly hypervolemic patients receiving 15 mg of tolvaptan who had a low probability of overcorrection.23, 24, 25
Morris et al20 showed that patients with SIADH who received tolvaptan responded differently than volume-overloaded patients with congestive heart failure and hyponatremia. Specifically, 28.6% (8/28) of patients with SIADH receiving 15 mg of tolvaptan had their serum [Na+] increased by >12 mEq/L within a 24-hour period, exceeding the recommended guidelines of 8 to 10 mEq/L per day or less.20 In 39.3% (11/28) of patients, serum [Na+] corrected at a rate > 8 mEq/L within a 24-hour period.26, 27, 28 There were 6 patients reported in supplementary data in that study who received 7.5 mg of tolvaptan, but no statistical analysis of their response was attempted.20 Importantly, this dose is lower than the US Food and Drug Administration’s minimum recommended dose.23
Therefore, in the present study, we performed a retrospective analysis of patients with SIADH receiving low-dose tolvaptan (7.5 mg) in comparison to standard therapy (tolvaptan, 15 mg) to determine the dose-dependent efficacy of correction and risk for overcorrection of serum [Na+] in patients with SIADH.
Methods
A retrospective study was performed to investigate the change in serum [Na+] in patients with SIADH after administration of 7.5 mg of tolvaptan. The project was approved under University of California, Los Angeles (UCLA) Institutional Review Board #17-001783. This work adheres to the Declaration of Helsinki regarding human subject research.
Patient Selection
The UCLA electronic medical record system (EPIC) was queried for the following parameters: serum [Na+], serum [K+], serum urea nitrogen (SUN), serum creatinine, estimated glomerular filtration rate, urine sodium, urine potassium, urine osmolality, serum uric acid, and serum albumin, as well as demographic measures such as weight, height, age, and sex. The diagnosis of SIADH was based on the clinical diagnosis of euvolemic hyponatremia, urine [Na+] > 30 mEq/L, urine osmolality > 300 mOsm/L, low-normal serum uric acid level (if available), and in some instances, a decrease in serum [Na+] following isotonic saline solution infusion.
A total of 195 records were obtained by search with aim to examine records of patients who received 7.5 mg as the first dosing of tolvaptan. There were 71 records excluded due to other concomitant treatments (normal saline solution, salt tablets, and 3% normal saline solution) with tolvaptan use, insufficient dosing information, unclear diagnosis, insufficient laboratory data, outpatient medication administration, or administration of tolvaptan doses at intervals less than 24 hours. A total of 124 records of patients who were treated with only tolvaptan and clearly charted were reviewed in depth. Of those, 30 patients received doses of 30 and 60 mg, 76 patients received a 15-mg dose, and 18 patients received 7.5 mg of tolvaptan. All 18 patients receiving a 7.5-mg dose as treatment were patients with SIADH. Of the selected patients who received 15 mg of tolvaptan, a minority had SIADH, prompting use of Morris et al20 data as a control group (Fig 1). All patients treated with the 7.5-mg tolvaptan dose were treated by one of the authors of this work.
Figure 1.
Patient selection for 7.5-mg tolvaptan cohort. Abbreviations: CHF, congestive heart failure; SIADH, syndrome of inappropriate antidiuretic hormone secretion.
Patients who received 7.5 mg of tolvaptan uniformly had their water restriction liberated and their serum [Na+] monitored at least twice a day. If serum [Na+] increased by >8 mEq/L in the first 24 hours, they were uniformly started on intravenous 5% dextrose in water solution infusion to match water losses to prevent additional correction of serum [Na+]. Eighteen patients were identified who had received tolvaptan, 7.5 mg, daily. Three patients had received tolvaptan serially on more than 1 day until they achieved eunatremia. The causes of SIADH in patients were identified as idiopathic (6), malignancy (3), drug induced (3), pulmonary infections (3), and central nervous system pathology (3; Fig S2).
The raw data from Morris et al20 (courtesy of Dr Juan Carlos Velez) was obtained to enable statistical analysis of the change in sodium values within a specific time frame in comparison with our cohort.
Statistical Analysis
Results are reported as mean ± standard deviation, and the initial and final serum sodium values were compared for statistical significance using paired t test. Baseline characteristics and delta sodium values between cohorts were compared using unpaired t test. The proportion of patients with certain baseline characteristics or achieving certain correction points were compared using Fisher exact χ2 test (F test) with significance defined as P < 0.05. Data were rounded off to a maximum of 1 decimal place.
Results
The total number of patients in our cohort receiving sequential tolvaptan administrations was 3 of 18 patients. Mean age of patients was 72.1 ± 17.5 years. Mean weight was 63.5 ± 20.9 kg, and mean height was 1.6 ± 0.1 m. There were 9 male and 9 female patients. Ethnicities consisted of 11 white patients, 3 Hispanic patients, 2 Asian patients, 1 African American patient, and 1 Middle Eastern patient. Two of 18 patients had a history of congestive heart failure, but they were clinically not in heart failure per charting and their clinical presentations were consistent with euvolemic hyponatremia due to SIADH. One of 18 patients had a diagnosis of nephrotic syndrome (Table 1).
Table 1.
Demographics of Patients in the Very Low-Dose Tolvaptan Cohort
| Patient ID | History of CHF | History of Cirrhosis | History of NS | Race | Sex | Age, y | Weight, kg | Height, m |
|---|---|---|---|---|---|---|---|---|
| Patient 1, average of 2 administrations | Y | N | N | White | F | 76 | 59.4 | 1.7 |
| Patient 2, average of 3 administrations | N | N | N | White | F | 85 | 53.1 | 1.58 |
| Patient 3, administration 1 | N | N | N | White | M | 78 | 72.1 | 1.82 |
| Patient 4, administration 1 | N | N | N | White | F | 81 | 61 | 1.47 |
| Patient 5, administration 1 | N | N | N | Asian | M | 70 | 67.1 | 1.75 |
| Patient 6, administration 1 | N | N | N | Hispanic | M | 96 | 35.9 | 1.6 |
| Patient 7, administration 1 | N | N | N | White | F | 36 | 71 | 1.6 |
| Patient 8, administration 1 | N | N | Y | Asian | F | 81 | 46.8 | 1.3 |
| Patient 9, administration 1 | N | N | N | White | M | 79 | 80 | 1.78 |
| Patient 10, average of 2 administrations | N | N | N | Middle Eastern | M | 56 | 73.5 | 1.73 |
| Patient 11, administration 1 | N | N | N | White | F | 90 | 55.3 | 1.61 |
| Patient 12, administration 1 | Y | N | N | White | M | 101 | 62.6 | 1.63 |
| Patient 13, administration 1 | N | N | N | African American | M | 52 | 133 | 1.78 |
| Patient 14, administration 1 | N | N | N | White | F | 76 | 48.2 | 1.55 |
| Patient 15, administration 1 | N | N | N | Hispanic | F | 66 | 48.1 | 1.6 |
| Patient 16, administration 1 | N | N | N | White | M | 51 | 52.4 | 1.6 |
| Patient 17, administration 1 | N | N | N | Hispanic | M | 48 | 71.7 | 1.61 |
| Patient 18, administration 1 | N | N | N | White | F | 76 | 51.1 | 1.63 |
| Mean ± SD or n/N (%) | 2/18 (11%) | 0/18 (0%) | 1/18 (6%) | 9/18 (50%) | 72.1 ± 17.5 | 63.5 ± 20.9 | 1.6 ± 0.1 |
Note: Cause of hyponatremia for all patients was syndrome of inappropriate antidiuretic hormone secretion; no history of alcoholism for all patients.
Abbreviations: CHF, congestive heart failure; F, female; M, male; N, no; NS, nephrotic syndrome; SD, standard deviation; Y, yes.
As summarized in Table 2, mean laboratory values were as follows: initial serum [Na+] (sNa+1), 123.7 ± 4.9 mEq/L; serum [K+], 4. ± 0.4 mEq/L; serum SUN, 15.3 ± 7.6 mg/dL; serum creatinine, 0.8 ± 0.5 mg/dL; urine osmolality, 460.6 ± 137.5 mOsm/kg; urine [Na+], 72.7 ± 32.4 mEq/L; urine [K+], 42.1 ± 23.8 mEq/L; and estimated glomerular filtration rate, 83.9 ± 22.3 mL/min/1.73 m2. Mean serum albumin level was 3.5 ± 0.6 g/dL, and mean uric acid level was 3.21 ± 2.1 mg/dL. Twenty-four hours after low-dose (7.5 mg) tolvaptan administration, mean serum [Na+] (sNa+2) had increased significantly to 129.2 ± 4.5 mEq/L. Mean delta [sNa+2 − sNa+1] = 5.6 ± 3.1 mEq/L; P < 0.001. Figure S2 shows delta sodium values in the Hanna et al17 cohort treated with 7.5 mg of tolvaptan and their change over 24 hours (sNa+1 and sNa+2).
Table 2.
Laboratory Values for the Very Low-Dose Tolvaptan Cohort
| Patient ID | Scr, mg/dL | eGFR, mL/min | SUN, mg/dL | sUA, mg/dL | sAlb, g/dL | sK+, mEq/L | sNa+1, mEq/L | sNa+2, mEq/L | uNa+, mEq/L | uK+, mEq/L | Uosm, mOsm/L |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Patient 1, average of 2 administrations | 0.8 | 90 | 17 | 7 | 3.2 | 3.8 | 123.5 | 126 | 44 | 48.5 | 480 |
| Patient 2, average of 3 administrations | 0.7 | 90 | 17 | 2.1 | 3.7 | 4.2 | 127 | 130.33 | 59 | 33.3 | 397 |
| Patient 3, administration 1 | 1.3 | 65 | 22 | 3.8 | 5 | 4.5 | 126 | 134 | 62 | 40.7 | 500 |
| Patient 4, administration 1 | 0.75 | 75 | 17 | 2.5 | 3.3 | 4.2 | 121 | 127 | 36 | 24.4 | 339 |
| Patient 5, administration 1 | 0.6 | 90 | 21 | 2.6 | 4 | 4.9 | 122 | 129 | 40 | 56.3 | 549 |
| Patient 6, administration 1 | 0.4 | 90 | 11 | 1 | 3.3 | 3.7 | 120 | 126 | 150 | 36.3 | 538 |
| Patient 7, administration 1 | 0.5 | 90 | 9 | 1.3 | 2.9 | 4.3 | 122 | 135 | 110 | 111.5 | 713 |
| Patient 8, administration 1 | 1.5 | 33 | 24 | 5.8 | 3.6 | 4.3 | 123 | 127 | 31 | 21.8 | 305 |
| Patient 9, administration 1 | 0.74 | 87 | 14 | 2.5 | 3.9 | 4.4 | 128 | 135 | 65 | 50.8 | 625 |
| Patient 10, average of 2 administrations | 0.63 | 89 | 27 | 3.4 | 3.9 | 134.5 | 136 | 79 | 21 | 278 | |
| Patient 11, administration 1 | 0.69 | 89 | 21 | 3.5 | 4.1 | 121 | 129 | 71 | 338 | ||
| Patient 12, administration 1 | 0.6 | 80 | 10 | 3.1 | 2.9 | 4.2 | 121 | 130 | 67 | 45 | 433 |
| Patient 13, administration 1 | 2.66 | 31 | 26 | 8.4 | 4.1 | 3.4 | 125 | 131 | 41 | 30 | 336 |
| Patient 14, administration 1 | 0.5 | 120 | 6 | 1.1 | 3.9 | 3.5 | 116 | 122 | 100 | 371 | |
| Patient 15, administration 1 | 0.22 | 100 | 4 | 2.7 | 2.3 | 3.9 | 125 | 125 | 128 | 28 | 651 |
| Patient 16, administration 1 | 0.7 | 107 | 9 | 2.1 | 3.1 | 4 | 114 | 120 | 70 | 286 | |
| Patient 17, administration 1 | 0.65 | 100 | 2 | 3 | 3.2 | 3.6 | 130 | 132 | 67 | 631 | |
| Patient 18, administration 1 | 0.88 | 85 | 18 | 2.3 | 3.7 | 3.7 | 127 | 132 | 88 | 520 | |
| No. of measurements | 18 | 18 | 18 | 16 | 18 | 18 | 18 | 18 | 18 | 13 | 18 |
| Mean ± SD | 0.8 ± 0.5 | 83.9 ± 22.3 | 15.3 ± 7.6 | 3.21 ± 2.1 | 3.5 ± 0.6 | 4 ± 0.4 | 123.7 ± 4.9 | 129.2 ± 4.5 | 72.7 ± 32.4 | 42.1 ± 23.8 | 460.6 ± 137.5 |
Abbreviations: eGFR, estimated glomerular filtration rate (Modification of Diet in Renal Disease Study equation ml/min/1.73m2); sAlb, serum albumin; Scr, serum creatinine; SD, standard deviation; sK+, serum potassium; sNa+1, initial serum sodium; sNa+2, final serum sodium; sUA, serum uric acid; SUN, serum urea nitrogen; uK+, urine potassium; uNa+, urine sodium; uOsm, urine osmolality.
The value of 3 mEq/L per day was previously suggested by Morris et al20 as the threshold for efficacy. Fourteen of 18 patients (78% of the cohort) had a correction of ≥3 mEq/L per day. Two of 18 patients corrected serum [Na+] by >8 mEq/L at any time during the 24 hours after the 7.5-mg tolvaptan administration. These 2 and 4 other patients (6 total) received 5% dextrose in water solution infusion (50-200 mL/h) to match their urine output rate and prevent additional correction. Morris et al20 had 5 total patients treated with 5% dextrose in water solution. One of 18 patients had a serum [Na+] correction of >12 mEq/L per day (total correction of 13 mEq/L in 24 hours), and 2 more corrected at exactly 8 mEq/L per day. The value of 3 mEq/L per day was previously defined by Morris et al20 as the threshold for efficacy. Fourteen of 18 patients (78% of our cohort) thus had a correction of ≥3 mEq/L per day.
The 1 patient who overcorrected by >12 mEq/L per day after the 7.5-mg tolvaptan administration did not respond to 5% dextrose in water solution infusion, and there were no documented neurologic sequelae. As shown in Tables 2 and 3, the percentage of patients with a serum [Na+] change rate of 8 to 10 mEq/L per day was 5.6%, 10 to 12 mEq/L per day was 0%, and >12 mEq/L per day was 5.6% (Tables 2 and 3). Correction of serum [Na+] > 8 mEq/L per day was observed in 11.1% of our cohort. In agreement with the previous report by Morris et al20 with full-dose tolvaptan (15 mg), we observed that patients with SIADH with the lowest baseline SUN values had higher risk for overcorrection with 7.5 mg of tolvaptan (P < 0.05). Similarly, in accord with Morris et al,20 patients with lower serum [Na+] and serum creatinine levels were more likely to exhibit a greater increase in serum [Na+] within 24 hours after administration of very low-dose tolvaptan (7.5 mg; P = 0.01; Fig 2).
Table 3.
Sodium Correction Data for the Very Low-Dose Tolvaptan Cohort
| Patient ID | Delta [Na+], mEq/L per d | D5W needed | Overcorrection >12 mEq/L |
|---|---|---|---|
| Patient 1, average of 2 administrations | 2.5 | N | N |
| Patient 2, average of 3 administrations | 3.33 | N | N |
| Patient 3, administration 1 | 8 | Y | N |
| Patient 4, administration 1 | 6 | Y | N |
| Patient 5, administration 1 | 7 | Y | N |
| Patient 6, administration1 | 6 | N | N |
| Patient 7, administration 1 | 13 | Y | Y |
| Patient 8, administration1 | 4 | N | N |
| Patient 9, administration 1 | 7 | N | N |
| Patient 10, average of 2 administrations | 1.5 | N | N |
| Patient 11, administration 1 | 8 | Y | N |
| Patient 12, administration 1 | 9 | Y | N |
| Patient 13, administration 1 | 6 | N | N |
| Patient 14, administration 1 | 6 | N | N |
| Patient 15, administration 1 | 0 | N | N |
| Patient 16, administration 1 | 6 | N | N |
| Patient 17, administration 1 | 2 | N | N |
| Patient 18, administration 1 | 5 | N | N |
| No. of measurements | 18 | 18 | 18 |
| Mean ± SD or n/N (%) | 5.6 ± 3.1 | 6/18 (33.3%) | 1/18 (5.6%) |
Note: Total number of administrations: 21, total number of patients: 18. Percentages have been rounded to 1 significant digit.
Abbreviations: D5W, 5% dextrose in water; Delta [Na+], change in serum sodium concentration; N, no; SD, standard deviation; Y, yes.
Figure 2.
Distribution of changes in serum sodium (sNa+) level 24 hours after 7.5-mg dose of tolvaptan in 18 patients with syndrome of inappropriate antidiuretic hormone secretion according to quartiles of baseline values of (A) serum urea nitrogen (SUN) and sNa+ (above and below the median) and (B) serum creatinine (sCr) and sNa+ (above and below the median).
Analyzing the data of Morris et al,20 the SIADH cohort treated with 15 mg of tolvaptan consisted of 28 patients, of whom 24 had data points out to 24 hours and beyond. Four others had terminal serum [Na+] between 8 and 16 hours. Though these points could not be used for mean delta serum [Na+] change over 24 hours (24 of 28 points used), they were used in comparing the risk for overcorrection within the first 24 hours (28 of 28 points used).
Table 4 describes the statistical comparison between baseline characteristics between our cohort that received 7.5 mg of tolvaptan and the prior study of Morris et al20 that received 15 mg of tolvaptan. Baseline characteristics are not statistically significantly different, with the exception that the initial serum [Na+] in our cohort was slightly greater than that in Morris et al.
Table 4.
Baseline Characteristics of Hanna et al and Morris et al Cohorts
| Characteristic | Hanna et al19 UCLA Cohort | Morris et al20 Ochsner Cohort |
Statistical Test Type | P Significance (<0.05) |
|---|---|---|---|---|
| N | 18 | 28 | NA | NA |
| Female sex | 9/18 (50%) | 13/28 (46.4%) | Fisher exact χ2 test | P = 1 |
| Male sex | 9/18 (50%) | 15/28 (53.6%) | Fisher exact χ2 test | P = 1 |
| White | 11/18 (61.1%) | 22/28 (78.6%) | Fisher exact χ2 test | P = 0.3 |
| African American | 1/18 (5.6%) | 6/28 (21.4%) | Fisher exact χ2 test | P = 0.2 |
| Idiopathic SIADH | 6/18 (33%) | 6/28 (21.4%) | Fisher exact χ2 test | P = 0.5 |
| Malignancy SIADH | 3/18 (16.7%) | 13/28 (46.4%) | Fisher exact χ2 test | P = 0.06 |
| Drug-induced SIADH | 3/18 (16.7%) | 2/28 (7.1%) | Fisher exact χ2 test | P = 0.4 |
| Pulmonary SIADHa | 3/18 (16.7%) | 2/28 (7.1%) | Fisher exact χ2 test | P = 0.4 |
| CNS SIADH | 3/18 (16.7%) | 2/28 (7.1%) | Fisher exact χ2 test | P = 0.4 |
| Postoperative SIADH | 0/18 (0%) | 3/28 (10.7%) | Fisher exact χ2 test | P = 0.3 |
| Age, y | 72.1 ± 17.5 | 67.3 ± 15.3 | Unpaired 2-tailed t test | P = 0.3 |
| Weight, kg | 63.5 ± 20.9 | 74 ± 20.3 | Unpaired 2-tailed t test | P = 0.1 |
| Height, m | 1.6 ± 0.1 | ND | ND | NA |
| BMI, kg/m2b | 23.7 ± 5.9 | 25.7 ± 4.8 | Unpaired 2-tailed t test | P = 0.2 |
| Na+1 initial, mEq/L | 123.7 ± 4.9 | 120.6 ± 5.2 | Unpaired 2-tailed t test | P < 0.05 |
| Serum urea nitrogen, mg/dL | 15.3 ± 7.6 | 12.2 ± 7.6 | Unpaired 2-tailed t test | P = 0.2 |
| eGFR (MDRD), mL/minc | 83.9 ± 22.3 | 92.8 ± 26.6 | Unpaired 2-tailed t test | P = 0.2 |
| Serum uric acid, mg/dLd | 3.2 ± 2.1 | 2.8 ± 2.3 | Unpaired 2-tailed t test | P = 0.7 |
| Serum potassium, mEq/L | 4 ± 0.4 | 4.2 ± 0.6 | Unpaired 2-tailed t test | P = 0.2 |
| Urine sodium, mEq/L | 72.7 ± 32.4 | 88.4 ± 37.9 | Unpaired 2-tailed t test | P = 0.2 |
| Urine osmolality, mOsm/L | 460.6 ± 137.5 | 480.6 ± 130.5 | Unpaired 2-tailed t test | P = 0.6 |
Note: Percentages have been rounded to 1 significant digit.
Abbreviations: BMI, body mass index; CNS, central nervous system; MDRD, Modification of Diet in Renal Disease; NA, not applicable; Na+1, initial serum sodium; ND, not done; SD, standard deviation; SIADH, syndrome of inappropriate antidiuretic hormone secretion; UCLA, University of California, Los Angeles.
Nonmalignant pulmonary SIADH.
Calculated from height and weight in our cohort (Table 1).
MDRD Study equation data available for only our cohort.
n=16 for uric acid for Hanna et al and n=10 for uric acid for Morris et al in the SIADH cohorts.
Table 5 and Figure 3 both describe the statistical comparison of our cohort and Morris et al.20 Efficacy was previously defined as an increase in serum [Na+] by ≥3 mEq/L in a given day of treatment, and 14 of 18 (77.8%) patients in our cohort and 21 of 28 (75%) in the Morris et al study corrected greater than this threshold. This was determined to be statistically not different between cohorts (P>0.991 by F test). The average delta [Na+] in our cohort was 5.6 ± 3.1 mEq/L per day, whereas the average delta [Na+] in Morris et al20 was 8.3 ± 6.3 mEq /L per day (calculated using 24 of 28 points with a 24-hour serum sodium). Both our cohort and that of Morris et al had a highly significant paired 2-tailed t test for Na+1 ≠ Na+2 (P < 0.0001). An unpaired 2-tailed t test of the average delta [Na+] per 24 hours of our cohort versus the delta [Na+] per 24 hours of Morris et al (the 24 points with appropriate values) was not statistically significant at P = 0.1. The need for 5% dextrose in water solution when serum [Na+] correction was >8 mEq/L was not statistically significant between our cohort of 6 of 18 (33.3%) patients and Morris et al of 5 of 28 (17.9%) patients (P = 0.3; F test).
Table 5.
Analysis of Summary Statistics
| Characteristic | Hanna et al | Morris et al | Statistical Test Type | P Significance (*<0.05) |
|---|---|---|---|---|
| n | 18 | 28 | NA | NA |
| Na+1 ≠ Na+2 | Paired 2-tailed t test | P < 0.001 for both cohortsa | ||
| Delta Na+ (Na+2 − Na+1) over 24 ha,b | 5.6 ± 3.1 | 8.3 ± 6.3 | Unpaired 2-tailed t test | P = 0.1 |
| % needing D5W | (6/18) 33.3% | (5/28) 17.9% | Fisher exact χ2 test | P = 0.3 |
| % efficacy (≥3 mEq/L increase in 1 d) | 14/18 (77.8%) | 21/28 (75%) | Fisher exact χ2 test | P > 0.99 |
| % correcting >8 mEq/L in 1 d | 2/18 (11.1%) | 11/28 (39.3%) | Fisher exact χ2 test | P = 0.049 |
| % correcting 10 mEq/L in 1 d | 1/18 (5.6%) | 10/28 (35.7%) | Fisher exact χ2 test | P = 0.03 |
| % correcting 12 mEq/L in 1 d | 1/18 (5.6%) | 8/28 (28.6%) | Fisher exact χ2 test | P = 0.07 |
Note: Percentages have been rounded to 1 significant digit.
Abbreviations: D5W, 5% dextrose water; Na+1, initial sodium; Na+2, final sodium (in 24 hours); NA, not applicable.
Value = Na+2 [sodium at 24 hours] − Na+1 [initial sodium], in Morris et al.
Only n=24 patients qualified for this because 4 points had terminal values at less than 24 hours.
Figure 3.
Comparison of delta sodium concentration ranges per day with 7.5-mg versus 15-mg tolvaptan administration in Hanna et al19 (University of California at Los Angeles cohort) and Morris et al20 (Ochsner cohort) in mEq/L per day. ** indicates significant P value.
For an increase in [Na+] of 8 and 10 mEq/L, there was a statistically greater likelihood that the 28 patients with SIADH given 15 mg of tolvaptan in Morris et al20 would overcorrect compared with the 18 patients with SIADH given 7.5 mg of tolvaptan in our cohort (>8 points, P = 0.049; >10 points, P = 0.03, both meeting P < 0.05, respectively; F tests). In the Morris et al cohort, percentages of patients who overcorrected were 28.6% at >12 mEq/L, 35.7% at >10 mEq/L, and 39.3% at >8 mEq/L per day compared with our cohort, in which the percentage of patients overcorrecting was 5.6% at >12 mEq/L, 5.6% at >10 mEq/L, and 11.1% at >8 mEq/L The delta [Na+] of 12 mEq/L within a day was trending toward significance among the cohorts at P = 0.07. Figure S3 shows delta [Na+] values in our cohort in graphical form.
Discussion
Our study indicates that 7.5 mg of tolvaptan is effective in correcting hyponatremia in patients with SIADH to the recommended level within current clinical guidelines. The study also shows that there is a statistically significantly decreased tendency for overcorrection at 8 mEq/L within a day compared with the data of Morris et al,20 who administered 15 mg per day, with a trend toward significance at [Na+] of 12 mEq/L within a day. This equates to a difference in overcorrection between 5.5% at >12 mEq/L, 5.5% at >10 mEq/L, 11.1% at >8 mEq/L in our cohort, and 28.6% at >12 mEq/L, 35.7% at >10 mEq/L, and 39.3% at >8 mEq/L per day in the Morris et al cohort. It is important to note that the slightly higher starting sNa+1 in our cohort versus Morris et al may have contributed to the lower rate of overcorrection observed.
In addition to the study of Morris et al,20 overcorrection with SIADH has been established as a concern. In Verbalis et al,29 overcorrection was found to occur in 10.2% of patients with SIADH who were treated with diverse therapies. Park et al30 recently reproduced the overcorrection with use of tolvaptan on the first day of therapy in patients with SIADH as compared with patients with congestive heart failure. However, the SIADH cohort was treated with a variable dose as compared with Morris et al.20
Strict water restriction may increase the risk for overcorrection with V2 antagonist therapy, and serum [Na+] should be checked frequently depending on risk for overcorrection. In low-risk cases, every 8 to 12 hours is generally acceptable, more frequently in cases at higher risk for osmotic demyelination syndrome or overcorrection with vaptan therapy.22 We have previously recommended that patients who receive 7.5 mg of tolvaptan should have urine osmolality and serum [Na+] checked.22 If a sufficient response is noted, laboratory test results should be monitored. If an insufficient response is noted with urine osmolality remaining >300 mOsm, a repeat dosing of 7.5 mg of tolvaptan can be used.22 It is our recommendation that in patients with SIADH, 7.5 mg of tolvaptan should be used as the starting dose for therapy with V2 antagonists, particularly in patients with high risk factors for osmotic demyelination syndrome and/or rapid overcorrection.
Article Information
Authors’ Full Names and Academic Degrees
Ramy M. Hanna, MD, Juan Carlos Velez, MD, Anjay Rastogi, MD, PhD, Minhtri K. Nguyen, MD, Mohammad K. Kamgar, MD, Kyaw Moe, MD, Farid Arman, MD, Huma Hasnain, MD, Niloofar Nobakht, MD, Umut Selamet, MD, and Ira Kurtz, MD.
Authors’ Contributions
Research idea and study design: RMH, JCV, MK, KM, FA, HH; data acquisition: RMH, JCV, MK, FA, HH, NN, US; data analysis and interpretation: RMH, JCV, AR, MN, MK, FA, NN, US, IK; statistical analysis: RMH, JCV, MK, FA; supervision/mentorship: JCV, AR, MN, IK. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.
Support
Clinical and Translational Science Institute (CTSI) data gathering was supported for 10 hours under National Institutes of Health (NIH)/National Center for Advancing Translational Sciences grant UL1TR001881. Dr Ira Kurtz is supported in part by funds from the NIH (R01-DK077162), the Allan Smidt Charitable Fund, the Factor Family Foundation, and the Ralph Block Family Foundation. The funders had no role in study design, data collection, or writing of the manuscript.
Financial Disclosure
Dr Nguyen is a member of the Speaker’s Bureau and consultant for Otsuka Pharmaceuticals for tolvaptan and received speaker and consulting fees. Dr Velez is a member of the Speaker’s Bureau for Otsuka Pharmaceuticals for tolvaptan and received speaker and consulting fees. Dr Kamgar is a speaker for Otsuka Pharmaceuticals for tolvaptan and received speaker and consulting fees. Dr Rastogi is a speaker and consultant for Otsuka for jynarque and received speaker and consulting fees. Dr Hanna was the principal investigator for the Otsuka Reprise open-label extension study. The remaining authors declare that they have no relevant financial interests.
Acknowledgements
The authors acknowledge the UCLA CTSI for aid in accessing chart data regarding tolvaptan use in UCLA between 2015 and 2018 and the UCLA Biostatistics Department and Ms Lena Ghobry for biostatistical analysis and reviewing the statistical parameters of the work.
Peer Review
Received February 16, 2019. Evaluated by 2 external peer reviewers, with direct editorial input from the Statistical Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form September 1, 2019.
Footnotes
Complete author and article information provided before references.
Figure S1: Risk factors for osmotic demyelination and serum sodium concentration overcorrection.
Figure S2: Causes of syndrome of inappropriate diuresis/SIADH in very low-dose tolvaptan cohort.
Figure S3: Na+1 and Na+2 (initial and terminal sodium concentrations) in Hanna et al cohort treated with 7.5 mg of tolvaptan.
Supplementary Material
Figures S1-S3.
References
- 1.Siragy H.M. Hyponatremia, fluid-electrolyte disorders, and the syndrome of inappropriate antidiuretic hormone secretion: diagnosis and treatment options. Endocr Pract. 2006;12(4):446–457. doi: 10.4158/EP.12.4.446. [DOI] [PubMed] [Google Scholar]
- 2.Kim G.H. Pseudohyponatremia: does it matter in current clinical practice? Electrolyte Blood Press. 2006;4(2):77–82. doi: 10.5049/EBP.2006.4.2.77. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Milionis H.J., Liamis G.L., Elisaf M.S. The hyponatremic patient: a systematic approach to laboratory diagnosis. CMAJ. 2002;166(8):1056–1062. [PMC free article] [PubMed] [Google Scholar]
- 4.Pillai B.P., Unnikrishnan A.G., Pavithran P.V. Syndrome of inappropriate antidiuretic hormone secretion: revisiting a classical endocrine disorder. Indian J Endocrinol Metab. 2011;15(suppl 3):S208–S215. doi: 10.4103/2230-8210.84870. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Gross P. Clinical management of SIADH. Ther Adv Endocrinol Metab. 2012;3(2):61–73. doi: 10.1177/2042018812437561. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Decaux G., Musch W. Clinical laboratory evaluation of the syndrome of inappropriate secretion of antidiuretic hormone. Clin J Am Soc Nephrol. 2008;3(4):1175–1184. doi: 10.2215/CJN.04431007. [DOI] [PubMed] [Google Scholar]
- 7.Frey F.J. [Serum concentration of uric acid, a diagnostic 'must' in patients with hyponatremia] Ther Umsch. 2004;61(9):583–587. doi: 10.1024/0040-5930.61.9.583. [DOI] [PubMed] [Google Scholar]
- 8.Sonnenblick M., Rosin A.J. Significance of the measurement of uric acid fractional clearance in diuretic induced hyponatraemia. Postgrad Med J. 1986;62(728):449–452. doi: 10.1136/pgmj.62.728.449. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Onitilo A.A., Kio E., Doi S.A. Tumor-related hyponatremia. Clin Med Res. 2007;5(4):228–237. doi: 10.3121/cmr.2007.762. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Musch W., Decaux G. Treating the syndrome of inappropriate ADH secretion with isotonic saline. QJM. 1998;91(11):749–753. doi: 10.1093/qjmed/91.11.749. [DOI] [PubMed] [Google Scholar]
- 11.Watkins P.B., Lewis J.H., Kaplowitz N. Clinical pattern of tolvaptan-associated liver injury in subjects with autosomal dominant polycystic kidney disease: analysis of clinical trials database. Drug Saf. 2015;38(11):1103–1113. doi: 10.1007/s40264-015-0327-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Malhotra I., Gopinath S., Janga K.C., Greenberg S., Sharma S.K., Tarkovsky R. Unpredictable nature of tolvaptan in treatment of hypervolemic hyponatremia: case review on role of vaptans. Case Rep Endocrinol. 2014;2014:807054. doi: 10.1155/2014/807054. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Gharaibeh K.A., Brewer J.M., 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(2):170–175. doi: 10.1097/MAJ.0000000000000324. [DOI] [PubMed] [Google Scholar]
- 14.Humayun M.A., Cranston I.C. In-patient tolvaptan use in SIADH: care audit, therapy observation and outcome analysis. BMC Endocr Disord. 2017;17(1):69. doi: 10.1186/s12902-017-0214-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Lin S.H., Hsu Y.J., Chiu J.S., Chu S.J., Davids M.R., Halperin M.L. Osmotic demyelination syndrome: a potentially avoidable disaster. QJM. 2003;96(12):935–947. doi: 10.1093/qjmed/hcg159. [DOI] [PubMed] [Google Scholar]
- 16.Peters M.A., van der Hoeven J., Hoedemaekers C. Risk factors for poor outcome in patients with osmotic demyelination syndrome. Crit Care. 2012;16(suppl 1):P143. [Google Scholar]
- 17.Hanna R.M., Yang W.T., Lopez E.A., Riad J.N., Wilson J. The utility and accuracy of four equations in predicting sodium levels in dysnatremic patients. Clin Kidney J. 2016;9(4):530–539. doi: 10.1093/ckj/sfw034. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Lindner G., Schwarz C., Kneidinger N., Kramer L., Oberbauer R., Druml W. Can we really predict the change in serum sodium levels? An analysis of currently proposed formulae in hypernatraemic patients. Nephrol Dial Transplant. 2008;23(11):3501–3508. doi: 10.1093/ndt/gfn476. [DOI] [PubMed] [Google Scholar]
- 19.Sterns R.H. Formulas for fixing serum sodium: curb your enthusiasm. Clin Kidney J. 2016;9(4):527–529. doi: 10.1093/ckj/sfw050. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Morris J.H., Bohm N.M., Nemecek B.D. Rapidity of correction of hyponatremia due to syndrome of inappropriate secretion of antidiuretic hormone following tolvaptan. Am J Kidney Dis. 2018;71(6):772–782. doi: 10.1053/j.ajkd.2017.12.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Martin R.J. Central pontine and extrapontine myelinolysis: the osmotic demyelination syndromes. J Neurol Neurosurg Psychiatry. 2004;75(suppl 3):iii22–iii28. doi: 10.1136/jnnp.2004.045906. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Kamgar M., Hanna R.M., Hasnain H., Khalil D., Wilson J.M. Risk of serum sodium overcorrection with V2 antagonists in SIADH and other high risk patients. J Onconephrol. 2017;1(3):143–146. [Google Scholar]
- 23.Berl T., Quittnat-Pelletier F., Verbalis J.G. Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol. 2010;21(4):705–712. doi: 10.1681/ASN.2009080857. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Ireland R. Hyponatremia: prolonged use of the vasopressin antagonist tolvaptan is a safe and effective treatment for hyponatremia. Nat Rev Nephrol. 2010;6(6):315. doi: 10.1038/nrneph.2010.61. [DOI] [PubMed] [Google Scholar]
- 25.Schrier R.W., Gross P., Gheorghiade M. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006;355(20):2099–2112. doi: 10.1056/NEJMoa065181. [DOI] [PubMed] [Google Scholar]
- 26.Sterns R.H., Cappuccio J.D., Silver S.M., Cohen E.P. Neurologic sequelae after treatment of severe hyponatremia: a multicenter perspective. J Am Soc Nephrol. 1994;4(8):1522–1530. doi: 10.1681/ASN.V481522. [DOI] [PubMed] [Google Scholar]
- 27.Sterns R.H. Treatment of severe hyponatremia. Clin J Am Soc Nephrol. 2018;13(4):641–649. doi: 10.2215/CJN.10440917. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Sterns R.H. Severe symptomatic hyponatremia: treatment and outcome. A study of 64 cases. Ann Intern Med. 1987;107(5):656–664. doi: 10.7326/0003-4819-107-5-656. [DOI] [PubMed] [Google Scholar]
- 29.Verbalis J.G., Greenberg A., Burst V. Diagnosing and treating the syndrome of inappropriate antidiuretic hormone secretion. Am J Med. 2016;129(5):537 e9–537 e23. doi: 10.1016/j.amjmed.2015.11.005. [DOI] [PubMed] [Google Scholar]
- 30.Park G.H., Lee C.M., Song J.W. Comparison of tolvaptan treatment between patients with the SIADH and congestive heart failure: a single-center experience. Korean J Intern Med. 2018;33(3):561–567. doi: 10.3904/kjim.2016.155. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figures S1-S3.