Urea to Treat Hyponatremia Due to Syndrome of Inappropriate Antidiuretic Hormone Secretion: A Systematic Review and Meta-Analysis.

RATIONALE & OBJECTIVE: The use of urea to treat hyponatremia related to the Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) has not been universally adopted due to questions about effectiveness, safety, and tolerability. This systematic review and meta-analysis of observational studies aimed to address these questions. STUDY DESIGN: This PRISMA-guided study examined published research across four electronic databases. STUDY POPULATIONS: Patients with SIADH-related hyponatremia. SELECTION CRITERIA: Clinical trials and observational studies reporting at least one outcome related to serum sodium concentration, symptom resolution, or adverse effects after oral or nasogastric urea administration. DATA EXTRACTION: Data extraction was performed independently by two reviewers using a standardized form recording study characteristics, participant demographics, intervention details, and treatment outcomes. ANALYTICAL APPROACH: A meta-analysis was conducted using the restricted maximum likelihood method for the random-effects model to assess the effect of urea treatment on serum sodium and serum urea compared to other treatment modalities. Subgroup analyses were conducted based on treatment duration and SIADH severity. RESULTS: Urea treatment significantly increased serum sodium [mean difference (MD) = 9.08 (95%CI 7.64-10.52), p < 0.01] and urea [MD = 31.66 (95%CI 16.05-47.26), p < 0.01] in patients with SIADH albeit with significantly high heterogeneity. Subgroup analysis based on the treatment duration showed a significant rise in the serum sodium level after 24 hours, two, five, seven, and fourteen days, as well as after one year of treatment. Greater increases in serum sodium levels after treatment with urea occurred in patients with severe (<120 mEq/L) [MD = 18.04 (95%CI 13.68-22.39)] than with moderate (120-129 mEq/L [MD = 7.86 (95%CI 6.78-8.94)] or mild (130-135 mEq/L) [MD = 8.00 (95%CI 7.31-8.69)] SIADH induced hyponatremia. Urea treatment was comparable to fluid restriction [MD = 0.81 (95%CI: -0.93-2.55), p = 0.36) and vaptans [MD = -1.96 (95%CI: -4.59-0.66, p = 0.14) but superior to no treatment [MD = 7.99 (95%CI 6.25-9.72), p < 0.01]. Urea was associated with minor adverse events, with poor palatability being most common. LIMITATIONS: As no RCTs investigating urea as a treatment for hyponatremia were identified for inclusion, these analyses were based on observational studies. CONCLUSIONS: Urea is safe and effective for managing SIADH-induced hyponatremia. These finding suggest that urea may be a useful treatment modality in resource-limited settings or when other treatments are contraindicated or poorly tolerated.

Hyponatremia Is Associated with Mortality in Acute Pancreatitis Patients.

BACKGROUND: Disorders of serum sodium are common among general patients and are associated with poor outcomes. The prognostic value of serum sodium disorders in patients with acute pancreatitis (AP) has not been studied. We conducted this retrospective study to explore the association between serum sodium levels and the outcomes of patients with AP. MATERIALS AND METHODS: Patients with AP from the Medical Information Mart for Intensive Care III (MIMIC-III) were screened for this study. The laboratory variables, including serum sodium levels, were obtained by analyzing the first blood sample on the first day after admission. Univariate logistic regression was performed to discover potential factors for mortality of AP. The unadjusted and adjusted association between serum sodium level and mortality of AP was shown by the restricted cubic spline (RCS). The categorical cutoff for the detrimental effect of serum sodium level on the prognosis of AP was also confirmed by stepwise logistic regression after adjusting for con-founding effects of significant factors in the univariate logistic regression. RESULTS: A total of 869 patients with AP in the MIMIC-III were included with a mortality of 13.1%. Unadjusted logistic regression showed that age (p < 0.001), simplified acute physiological score (SAPS) (p < 0.001), systolic blood pressure (p < 0.001), diastolic blood pressure (p < 0.001), hemoglobin (p = 0.040), serum creatinine (p = 0.046), and serum phosphorus (p < 0.001) were significantly associated with the mortality of AP. The RCS showed that the serum sodium level was negatively and linearly associated with mortality of AP after adjusting for confounding effects of significant factors in the univariate logistic regression. Serum sodium < 133 mmol/L, which indicated hyponatremia, was significantly correlated with a higher mortality risk than serum sodium ≥ 133 mmol/L (p = 0.013). CONCLUSIONS: Hyponatremia is widely developed among patients with AP and correlates with a higher mortality risk of AP. Physicians should pay more attention to managing patients with AP with hyponatremia.

Prognostic value of initial serum sodium level in predicting disease severity in patients with COVID-19: A multicenter retrospective study.

INTRODUCTION: Early prediction of coronavirus disease (COVID-19) severity is crucial. Hyponatremia has been linked to poor outcomes in hospitalized COVID-19 patients, but its association with mild cases is unclear. This study aimed to investigate whether initial serum sodium level is a risk factor for COVID-19 severity in patients with mild-to-moderate disease. METHODS: A multicenter retrospective cohort study was conducted in 10 hospitals in Fukui City, Japan, from July 1, 2020, to October 31, 2021. The study included 1055 adult patients with asymptomatic, mild, or moderate COVID-19 confirmed by a positive RT-PCR test. The primary outcome was the need for oxygen therapy after hospitalization, and the secondary outcome was the composite of in-hospital death and critical care interventions. The association between initial serum sodium level (at the emergency department or on admission) and outcomes was examined, adjusting for age, sex, hypertension, and pneumonia presence. RESULTS: Of the 1267 patients diagnosed with COVID-19 during the study period, 1055 were eligible (median age: 45 years; 54 % male). Hyponatremia was observed in 5.2 % of patients upon admission. A lower initial serum sodium level was associated with an increased risk of the need for oxygen therapy after hospitalization (adjusted odds ratio [OR] per 1 mmol/L lower, 1.12 [95 % confidence interval {CI}, 1.05-1.19]) and the composite of critical care and in-hospital death (adjusted OR per 1 mmol/L lower, 1.09 [95 % CI, 0.99-1.20]). CONCLUSIONS: Among patients with mild COVID-19, lower initial serum sodium level was a risk factor for COVID-19 progression.

Association between serum sodium trajectory and mortality in patients with acute kidney injury: a retrospective cohort study.

INTRODUCTION: Dysnatremia is strongly associated with poor prognosis in acute kidney injury (AKI); however, the impact of sodium trajectories on the prognosis of patients with AKI has not yet been well elucidated. This study aimed to assess the association between sodium trajectories in patients with AKI and mortality at 30-day and 1-year follow-up. METHODS: This retrospective cohort study used data from Medical Information Mart for Intensive Care (MIMIC)-IV database, and patients diagnosed with AKI within 48 h after admission were enrolled. Group-based trajectory models (GBTM) were applied to map the developmental course of the serum sodium fluctuations. Kaplan-Meier survival curve was used to compare differences in mortality in AKI patients with distinct serum sodium trajectories. Hazard ratios (HRs) were calculated to determine the association between trajectories and prognosis using Cox proportional hazard models. RESULTS: A total of 9,314 AKI patients were enrolled. Three distinct sodium trajectories were identified including: (i) stable group (ST, in which the serum sodium levels remained relatively stable, n = 4,935; 53.0%), (ii) descending group (DS, in which the serum sodium levels declined, n = 2,994; 32.15%) and (iii) ascending group (AS, in which the serum sodium levels were elevated, n = 1,383; 14.85%). There was no significant difference in age and gender distribution among the groups. The 30-day mortality rates were 7.9% in ST, 9.5% in DS and 16.6% in AS (p < 0.001). The results of 1-year mortality rates were similar (p < 0.001). In adjusted analysis, patients in the DS (HR = 1.22, 95% confidence interval [CI], 1.04-1.43, p = 0.015) and AS (HR = 1.68, 95% CI, 1.42-2.01, p = 0.013) groups had higher risks of 30-day mortality compared to those in the ST group. CONCLUSION: In patients with AKI, the serum sodium trajectories were independently associated with 30-day and 1-year mortality. Association between serum sodium level trajectories and prognosis in patients with AKI deserve further study.

Changes in serum sodium concentration during hemodialysis is a predictor of mortality and cardio-cerebrovascular event.

BACKGROUND: Previous study consistently showed that lower serum sodium (SNa) was associated with a greater risk of mortality in hemodialysis (HD) patients. However, few studies have focused on the change in SNa (ΔSNa = post-HD SNa - pre-HD SNa) during an HD session. METHODS: In a retrospective cohort of maintenance HD adults, all-cause mortality and cardio-cerebrovascular event (CCVE) were followed up for a medium of 82 months. Baseline pre-HD SNa and ΔSNa were collected; time-averaged pre-HD SNa and ΔSNa were computed as the mean values within 1-year, 2-year and 3-year intervals after enrollment. Cox proportional hazards models were used to evaluate the relationships of pre-HD and ΔSNa with outcomes. RESULTS: Time-averaged pre-HD SNa were associated with all-cause mortality (2-year pre-HD SNa: HR [95% CI] 0.86 [0.74-0.99], p = 0.042) and CCVE (3-year pre-HD SNa: HR [95% CI] 0.83 [0.72-0.96], p = 0.012) with full adjustment. Time-averaged ΔSNa also demonstrated an association with all-cause mortality (3-year ΔSNa: HR [95% CI] 1.26 [1.03-1.55], p = 0.026) as well as with CCVE (3-year ΔSNa: HR [95% CI] 1.51 [1.21-1.88], p = <0.001) when fully adjusted. Baseline pre-HD SNa and ΔSNa didn't exhibit association with both outcomes. CONCLUSIONS: Lower time-averaged pre-HD SNa and higher time-averaged ΔSNa were associated with a greater risk of all-cause mortality and CCVE in HD patients.

Hyponatraemia and fluid overload are associated with higher risk of mortality in dialysis patients.

BACKGROUND: The 5-year mortality rate for haemodialysis patients is over 50%. Acute and chronic disturbances in salt and fluid homeostasis contribute to poor survival and are established as individual mortality risk factors. However, their interaction in relation to mortality is unclear. METHODS: We used the European Clinical Database 5 to investigate in a retrospective cohort analysis the relationship between transient hypo- and hypernatremia, fluid status and mortality risk of 72 163 haemodialysis patients from 25 countries. Incident haemodialysis patients with at least one valid measurement of bioimpedance spectroscopy were followed until death or administrative censoring from 1 January 2010 to 4 December 2019. Fluid overload and depletion were defined as >2.5 L above, and -1.1 L below normal fluid status, respectively. N = 2 272 041 recorded plasma sodium and fluid status measurements were available over a monthly time grid and analysed in a Cox regression model for time-to-death. RESULTS: Mortality risk of hyponatremia (plasma sodium <135 mmol/L) was slightly increased when fluid status was normal [hazard ratio (HR) 1.26, 95% confidence interval (CI) 1.18-1.35], increased by half when patients were fluid depleted (HR 1.56, 95% CI 1.27-1.93) and accelerated during fluid overload (HR 1.97, 95% CI 1.82-2.12). CONCLUSIONS: Plasma sodium and fluid status act independently as risk factors on mortality. Patient surveillance of fluid status is especially important in the high-risk subpopulation of patients with hyponatremia. Prospective patient-level studies should examine the effects of chronic hypo- and hypernatremia, risk determinants, and their outcome risk.

Prognostic Significance of Serum Chloride Level Reduction in Patients with Chronic Heart Failure with Different Ejection Fractions.

Little is known regarding the prognostic value of serum chloride in patients with chronic heart failure (CHF) with different ejection fractions. We sought to determine the postdischarge outcomes associated with lower serum chloride between different CHF types.We reviewed the medical records of 1221 consecutive patients with CHF admitted to the First Affiliated Hospital of Kunming Medical University from January 2017 to October 2021. After excluding patients with in-hospital death, missing follow-up data, missing serum chloride level data, or chronic dialysis therapy, 791 patients were included. Of these patients, 343 had heart failure with reduced ejection fraction (HFrEF; i.e., left ventricular ejection fraction (LVEF) < 40%), and 448 had heart failure with preserved ejection fraction (HFpEF) or heart failure with median ejection fraction (HFmrEF; HFpEF plus HFmrEF; i.e., LVEF ≥40%). Over a median follow-up of 750 days, 344 patients (43.5%) had all-cause mortality. In the univariate analysis, serum sodium and chloride were strongly associated with mortality in both HF subgroups (P < 0.0001). A multivariable model including both serum sodium and chloride showed the highly significant association between serum chloride and survival (P < 0.0001), whereas the association between serum sodium and mortality was not reported (HFpEF plus HFmrEF, hazard ratio (HR) 0.975, 95% confidence interval [CI] 0.942-1.010, P = 0.158; HFrEF, HR 1.007, 95% CI 0.966-1.051, P = 0.734). Kaplan-Meier survival curve analysis revealed a significant difference in mortality risk with decreasing chloride levels in all patients with CHF. The optimal cutoff value of chloride in predicting all-cause mortality was 102.95 mmol/L with area under the curve value of 0.76 [HR 0.760, 95% CI 0.727-0.793, P < 0.0001], sensitivity of 60.2%, and specificity of 78.3%.Lower serum chloride is an independent predictor of death in CHF, regardless of heart failure subtype.

Hypertonic Saline for Hyponatremia: Meeting Goals and Avoiding Harm.

Hypertonic saline has been used for the treatment of hyponatremia for nearly a century. There is now general consensus that hypertonic saline should be used in patients with hyponatremia associated with moderate or severe symptoms to prevent neurological complications. However, much less agreement exists among experts regarding other aspects of its use. Should hypertonic saline be administered as a bolus injection or continuous infusion? What is the appropriate dose? Is a central venous line necessary? Should desmopressin be used concomitantly and for how long? This article considers these important questions, briefly explores the historical origins of hypertonic saline use for hyponatremia, and reviews recent evidence behind its indications, dosing, administration modality and route, combined use with desmopressin to prevent rapid correction of serum sodium, and other considerations such as the need and degree for fluid restriction. The authors conclude by offering some practical recommendations for the use of hypertonic saline.

Association of pre-ESKD hyponatremia with post-ESKD outcomes among incident ESKD patients.

BACKGROUND: Hyponatremia is one of the most common electrolyte disturbances in advanced chronic kidney disease (CKD) and end-stage kidney disease (ESKD) patients, and has been shown to be associated with higher mortality risk. However, the relationship between hyponatremia during late-stage CKD and the risk of poor outcomes after ESKD transition is unknown. METHODS: We conducted a retrospective cohort study including 32 257 US veterans transitioning to ESKD from 1 October 2007 to 30 March 2015. We evaluated adjusted associations between the 3-month averaged pre-transition to ESKD serum sodium and all-cause mortality. Secondary outcomes included cardiovascular (CV) mortality, infection-related mortalities and hospitalization rate. RESULTS: Cohort mean ± standard deviation serum sodium was 139 ± 3 mEq/L, mean age was 67 ± 11 years, 98% were male and 28% were African American. Over a median (interquartile range) follow-up of 702 days (296, 1301) there were 17 162 deaths. Compared with the reference of 135 to <144 mEq/L, the lowest serum sodium group (<130 mEq/L) had a 54% higher all-cause mortality risk [hazard ratio 1.54 (95% confidence interval 1.34-1.76)] in the fully adjusted model. Associations were similar for CV and infection-related mortality, and hospitalization outcomes. CONCLUSIONS: Hyponatremia prior to ESKD transition is associated with higher risk of all-cause, CV and infection-related mortalities, and hospitalization rates after ESKD transition. Future studies evaluating management of pre-ESKD hyponatremia may be indicated to improve patient outcomes for those transitioning to ESKD.

Relationship between high fructose corn syrup sweetened drinks, diet soft drinks, and serum sodium: NHANES 2003-2006.

BACKGROUND: Consumption of high fructose corn syrup sweetened drinks and diet soft drinks has increased in the United States. However, the relationship between the intake of high fructose corn syrup sweetened drinks and diet soft drinks, and serum sodium has been scarcely studied. Our objective is to evaluate the relation between intake of high fructose corn syrup sweetened drinks and diet soft drinks, and serum sodium, and explore the possible effect modifiers in a nationally representative sample of adults from the United States. METHODS: We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey 2003-2006. The study participants included 6989 adults aged ≥18 years. Using survey-weighted generalized linear regression analyses, we investigated the relationship between high fructose corn syrup sweetened drink, diet soft drink consumption, and serum sodium. Consumption of high fructose corn syrup sweetened drinks and diet soft drinks was evaluated through a food-frequency questionnaire. RESULTS: Serum sodium levels increased as high fructose corn syrup sweetened drink intake increased. Serum sodium levels were higher in participants in the highest high fructose corn syrup sweetened drink consumption quantile, compared with those in the lowest high fructose corn syrup sweetened drink intake quantile (p = 0.020). The multivariate betas for serum sodium, according to the corresponding high fructose corn syrup sweetened drink intake quantiles, were 0.16, 0.19, and 0.21, respectively (P for trend = 0.051). We found no relationship between diet soft drink consumption and serum sodium after adjustment of confounding. (multivariate P > 0.05). CONCLUSION: There was a a step-wise increase in serum sodium concentration with increasing consumption of HFCS sweetened beverages. Even moderate HFCS sweetened soft drink intake was associated with an elevated serum sodium level - a risk factor for hypertension.

Perineural invasion, lactate dehydrogenase, globulin, and serum sodium predicting occult metastasis in oral cancer.

OBJECTIVE: This study aimed to develop a nomogram to predict the neck occult metastasis in early (T1-T2 cN0) oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: The nomogram was developed in a training cohort of 336 early OSCC patients and was validated in a validation cohort including 88 patients. Independent predictors were calculated by univariate and multivariate logistic regression analyses. RESULTS: In univariate logistical regression analysis, gender, perineural invasion (PNI), blood vessel invasion, mean corpuscular hemoglobin, aspartate aminotransferase, prealbumin, globulin (GLO), lactate dehydrogenase (LDH), serum sodium (NA), and serum chloride were significant associated with neck occult metastasis. Multivariate logistical regression analysis identified PNI (p < .001), LDH (p = .003), GLO (p = .019), and NA (p = .020) as independent predictors of neck occult metastasis. Cut-off values for LDH, GLO, and NA obtained from AUC were 142.5, 26.35, and 139.5, respectively. The nomogram based on PNI and categorical GLO, LDH, and NA exhibited a strong discrimination, with a C-indexes of 0.748 (95%CI = 0.688 to 0.810) in the training cohort and 0.751 (95%CI = 0.639 to 0.863) in the validation cohort. CONCLUSIONS: A nomogram based on PNI, LDH, GLO, and NA for predicting the risk of neck lymph nodes occult metastasis in OSCC could help surgeons with therapy decision-making.

Psychotropic drug-induced hyponatremia: results from a drug surveillance program-an update.

Hyponatremia (HN) is the most common electrolyte imbalance (defined as a serum sodium concentration Na(S) of  < 130 mmol/l) and often induced by drugs including psychotropic drugs. AMSP (Arzneimittelsicherheit in der Psychiatrie) is a multicenter drug surveillance program that assesses severe or unusual adverse drug reactions (ADRs) occurring during treatment with psychotropic drugs. This study presents data from 462,661 psychiatric inpatients treated in participating hospitals between 1993 and 2016 and serves as an update of a previous contribution by Letmaier et al. (JAMA 15(6):739-748, 2012). A total of 210 cases of HN were observed affecting 0.05% of patients. 57.1% of cases presented symptomatically; 19.0% presented with severe symptoms (e.g., seizures, vomiting). HN occurred after a median of 7 days following the first dose or dose increase. Incidence of HN was highest among the two antiepileptic drugs oxcarbazepine (1.661% of patients treated) and carbamazepine (0.169%), followed by selective serotonin-norepinephrine reuptake inhibitors (SSNRIs, 0.088%) and selective serotonin reuptake inhibitors (0.071%). Antipsychotic drugs, tricyclic antidepressants, and mirtazapine exhibited a significantly lower incidence of HN. The risk of HN was 16-42 times higher among patients concomitantly treated with other potentially HN-inducing drugs such as diuretic drugs, angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers, and proton pump inhibitors. Female SSNRI-users aged  ≥ 65 years concomitantly using other HN-inducing drugs were the population subgroup with the highest risk of developing HN. The identification of high-risk drug combinations and vulnerable patient subgroups represents a significant step in the improvement of drug safety and facilitates the implementation of precautionary measures.

Lower Serum Sodium Levels Are Associated with the Therapeutic Effect of Sorafenib on Hepatocellular Carcinoma.

BACKGROUND AND AIM: Although the serum sodium level has been reported to be a prognostic and predictive marker for the therapeutic effects of lung cancer and renal cell carcinoma treated with molecular targeted therapy, the serum sodium level has not been investigated in hepatocellular carcinoma (HCC) patients treated with sorafenib. The aim of our analysis was to assess the prognostic role of serum sodium levels in these patients. METHODS: We retrospectively analyzed 341 HCC patients treated with sorafenib between 2009 and 2012 in our hospital and other related institutions. RESULTS: A total of 178 patients were enrolled in this study. The median age was 72 years (44-88), and 148 patients (83%) were male. The median overall survival (OS) was 12.9 months, and the median time to progression (TTP) was 3.1 months. Hyponatremia (hazard ratio (HR) 1.78, 95% confidence interval (CI) 1.26-2.52), a lower sodium level (HR 1.57, 95% CI 1.07-2.80), and a high level of α-fetoprotein (AFP) (≥ 200 ng/mL) (HR 1.78, 95% CI 1.26-2.52) were independent prognostic factors for TTP. We also categorized the patients into three groups according to serum sodium and AFP levels: Group A (n = 39) (serum sodium > 140 mEq/L, AFP < 200 ng/mL), Group C (n = 58) (serum sodium ≤ 140 mEq/L, AFP ≥ 200 ng/mL), and Group B (n = 81) (other patients). Significantly longer TTP and OS were observed in the following order: Groups A, C, and B. CONCLUSION: Serum sodium levels are associated with the effectiveness of sorafenib. The serum sodium level can predict the therapeutic effect of sorafenib in advanced HCC patients.

Efficacy and safety of tolvaptan after pediatric congenital heart disease surgery.

It is not clear whether tolvaptan is safe and effective irrespective of various underlying clinical conditions including the functional ventricle morphology, chromosomal abnormalities, and renal function after complex pediatric congenital heart disease surgery. Also, the appropriate dose of tolvaptan in these patients has not been previously identified. We retrospectively assessed the urine volume, body weight, patient clinical characteristics, laboratory data, and vital signs before and on days 1 and 7 of the tolvaptan administration after congenital heart disease surgery. Also, we assessed the relationship between the tolvaptan dose and its effects. A total of 86 patients were included the study. The mean time from the surgery to the tolvaptan administration was 23.5 ± 3.7 days. After administering tolvaptan, the urine volume significantly increased and body weight significantly decreased from baseline by days 1 and 7 (p < 0.0001). The urine volume significantly increased more in the survivors than the deceased. Of the 22 patients who had low serum sodium concentrations at baseline, 20 had an increased serum sodium concentration on day 7. The clinical effect of tolvaptan was not affected by the functional ventricle morphology, chromosomal abnormalities, or renal function. There was a positive correlation between the tolvaptan dose and change in the urine volume until a tolvaptan dose of up to 0.3 mg/kg/day but not at more than 0.3 mg/kg/day. Tolvaptan administration is safe and effective after congenital heart disease surgery irrespective of various underlying clinical conditions. Though the urine volume tends to increase until a tolvaptan dose of up to 0.3 mg/kg/day in pediatric congenital heart disease patients, there was no further benefit with more than 0.3 mg/kg/day.

Serum sodium in relation to various domains of cognitive function in the elderly US population.

BACKGROUND: Recent evidence suggests that sodium imbalances may be associated with cognitive impairment; however, the association between specific domains of cognition remains unclear. This study examines the association between serum sodium levels and immediate and delayed verbal memory as measured by the CERAD Word Learning Test (CERAD WLT), executive function as measured by the Animal Fluency test (AFT), and sustained attention, working memory, and processing speed as measured by the Digit Symbol Substitution test (DSST) in the elderly population of the US aged 60 and older who participated in the 2011-2014 National Health and Nutrition Examination Surveys (n = 2,541). METHODS: Cognitive function tests were performed by trained interviewers and sodium levels were measured using indirect ion selective electrode methodology. RESULTS: After adjusting for all covariates, quintiles of CERAD WLT scores showed significant positive associations with log-transformed sodium levels (Immediate recall (IR) ß = 4.25 (SE = 1.83, p-value 0.027); Delayed recall (DR) ß = 6.54 (SE = 1.82, p-value 0.001)). Compared to normal sodium levels, hyponatremia was significantly associated with lower CERAD WLT-IR (ß = -0.34, SE = 0.15, p-value 0.035) and CERAD WLT-DR scores (ß -0.48, SE = 0.10, p-value < 0.001) and showed borderline significance with AFT scores (ß = = -0.38, SE = 0.19, p-value 0.052). Hypernatremia did not show any significant relationships with cognitive test scores, compared to normal sodium levels. CONCLUSIONS: Our cross-sectional study showed that lower sodium levels were associated with cognitive change, especially regarding memory and executive function.

Short-term water deprivation does not increase blood pressure variability or impair neurovascular function in healthy young adults.

High dietary salt increases arterial blood pressure variability (BPV) in salt-resistant, normotensive rodents and is thought to result from elevated plasma [Na+] sensitizing central sympathetic networks. Our purpose was to test the hypothesis that water deprivation (WD)-induced elevations in serum [Na+] augment BPV via changes in baroreflex function and sympathetic vascular transduction in humans. In a randomized crossover fashion, 35 adults [17 female/18 male, age: 25 ± 4 yr, systolic/diastolic blood pressure (BP): 107 ± 11/60 ± 7 mmHg, body mass index: 23 ± 3 kg/m2] completed two hydration protocols: a euhydration control condition (CON) and a stepwise reduction in water intake over 3 days, concluding with 16 h of WD. We assessed blood and urine electrolyte concentrations and osmolality, resting muscle sympathetic nerve activity (MSNA; peroneal microneurography; 18 paired recordings), beat-to-beat BP (photoplethysmography), common femoral artery blood flow (Doppler ultrasound), and heart rate (single-lead ECG). A subset of participants (n = 25) underwent ambulatory BP monitoring during day 3 of each protocol. We calculated average real variability as an index of BPV. WD increased serum [Na+] (141.0 ± 2.3 vs. 142.1 ± 1.7 mmol/L, P < 0.01) and plasma osmolality (288 ± 4 vs. 292 ± 5 mosmol/kg H2O, P < 0.01). However, WD did not increase beat-to-beat (1.9 ± 0.4 vs. 1.8 ± 0.4 mmHg, P = 0.24) or ambulatory daytime (9.6 ± 2.1 vs. 9.4 ± 3.3 mmHg, P = 0.76) systolic BPV. Additionally, sympathetic baroreflex sensitivity (P = 0.20) and sympathetic vascular transduction were not different after WD (P = 0.17 for peak Δmean BP following spontaneous MSNA bursts). These findings suggest that, despite modestly increasing serum [Na+], WD does not affect BPV, arterial baroreflex function, or sympathetic vascular transduction in healthy young adults.

Efficacy of Furosemide, Oral Sodium Chloride, and Fluid Restriction for Treatment of Syndrome of Inappropriate Antidiuresis (SIAD): An Open-label Randomized Controlled Study (The EFFUSE-FLUID Trial).

RATIONALE & OBJECTIVE: First-line therapy for syndrome of inappropriate antidiuresis (SIAD) is fluid restriction. Additional treatment for patients who do not respond to fluid restriction are water restriction with furosemide or water restriction with furosemide and salt supplementation. However, the efficacy of these treatments has never been tested in a randomized controlled study. The objective of this study was to investigate whether, combined with fluid restriction, furosemide with or without sodium chloride (NaCl) supplementation was more effective than fluid restriction alone in the treatment of hyponatremia in SIAD. STUDY DESIGN: Open-label randomized controlled study. SETTING & PARTICIPANTS: Patients with serum sodium concentrations ([Na+]) ≤ 130mmol/L due to SIAD. INTERVENTION(S): Random assignment to 1 of 3 groups: fluid restriction alone (FR), fluid restriction and furosemide (FR+FM), or fluid restriction, furosemide, and NaCl (FR+FM+NaCl). Strictness of fluid restriction (<1,000 or<500mL/d) was guided by the urine to serum electrolyte ratio. Furosemide dosage was 20 to 40mg/d. NaCl supplements were 3g/d. All treatments were continued for 28 days. OUTCOMES: The primary outcome was change in [Na+] at days 4, 7, 14, and 28 after randomization. RESULTS: 92 patients were recruited (FR, n=31; FR+FM, n=30; FR+FM+NaCl, n=31). Baseline [Na+] was 125±4mmol/L, and there were no significant differences between groups. Mean [Na+] on day 4 in all treatment groups was significantly increased from baseline by 5mmol/L (P<0.001); however, the change in [Na+] was not significantly different across groups (P=0.7). There was no significant difference in percentage of patients or time to reach [Na+] ≥ 130 or≥135mmol/L across the 3 groups. Acute kidney injury and hypokalemia (potassium≤3.0mmol/L) were more common in patients receiving furosemide. LIMITATIONS: Open-label treatment. CONCLUSIONS: In patients with SIAD, furosemide with NaCl supplement in combination with fluid restriction did not show benefits in correction of [Na+] compared with treatment with fluid restriction alone. Incidences of acute kidney injury and hypokalemia were increased in patients receiving furosemide. FUNDING: None. TRIAL REGISTRATION: Registered at the Thai Clinical Trial Registry with study number TCTR20170629004.

Thiazide-Associated Hyponatremia: Clinical Manifestations and Pathophysiology.

Hyponatremia can complicate thiazide use in a minority of susceptible individuals and can result in significant morbidity and even mortality. Risk factors for thiazide-associated hyponatremia include age, female sex, and possibly low body mass. A genetic susceptibility has recently been uncovered. Although frequently developing early after thiazide treatment initiation, many cases of hyponatremia present after months or years of use. Many cases are asymptomatic or have mild symptoms, but seizures and/or coma may develop, especially in those with acute onset. The pathophysiology is incompletely understood and includes some combination of excessive fluid intake, cation (sodium and potassium) depletion, osmotic inactivation of sodium, and reduced ability to excrete free water. Reduced distal delivery of filtrate, reduced solute load (urea), direct inhibition of the sodium-chloride cotransporter, and increased collecting duct permeability to water mediated by some combination of antidiuretic hormone, prostaglandins, and thiazides themselves may contribute to this diluting defect. The predominant pathophysiologic mechanism(s) varies from patient to patient. The cornerstone of therapy is cessation of thiazide use, cation repletion, and oral fluid restriction. If severely symptomatic, 3% saline solution may be indicated. Overly rapid correction of chronic hyponatremia must be avoided in all cases.

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.

Prognostic value of hypochloremia versus hyponatremia among patients with chronic kidney disease-a retrospective cohort study.

BACKGROUND: Serum chloride (Cl) levels confer better prognostic value than serum sodium (Na) levels among patients with heart failure. Little is known about the relationship between serum Cl levels and clinical outcomes among patients with chronic kidney disease (CKD). METHODS: This was a retrospective cohort study enrolling patients with Stages G3-G5 CKD who visited the nephrology outpatient department of Osaka University Hospital from April 2005 to December 2014. The main exposure was time-varying serum Cl levels categorized as quartiles. The study outcome was a composite of all-cause death and cardiovascular events. RESULTS: A total of 2661 patients with CKD were included in the analysis. During a median follow-up of 4.0 years, 284 deaths and 416 cardiovascular events occurred. Compared with patients in the third Cl quartile, those in the first Cl quartile showed a significantly higher risk of the outcome after adjustment for demographics and clinical factors including time-varying serum Na, serum albumin and bicarbonate levels, and use of diuretics and sodium bicarbonate [hazard ratio (HR) 2.13; 95% confidence interval (CI) 1.20-3.81; P = 0.01] and, additionally, anion gap (HR 2.13; 95% CI 1.26-3.57; P = 0.004). Adding serum Cl levels, but not serum Na levels, to the multivariable model significantly improved net reclassification index (0.335; P < 0.001) and integrated discrimination improvement (0.0113; P = 0.01). CONCLUSIONS: Lower serum Cl levels are an independent predictor of death and cardiovascular events. The incremental prognostic value of Cl was superior to that of Na in patients with CKD.