The Effect of Thiazide Diuretics on Urinary Prostaglandin E2 Excretion and Serum Sodium in the General Population.

CONTEXT: Thiazide-induced hyponatremia is one of the most common forms of hyponatremia, but its pathogenesis is incompletely understood. Recent clinical data suggest links with prostaglandin E2 (PGE2) and a single nucleotide polymorphism (SNP) in the prostaglandin transporter gene (SLCO2A1), but it is unknown if these findings also apply to the general population. OBJECTIVE: To study the associations between serum sodium, thiazide diuretics, urinary excretions of PGE2 and its metabolite (PGEM), and the rs34550074 SNP in SLCO2A1 in the general population. DESIGN: Prospective population-based cohort study (Rotterdam Study). SETTING: General population. PARTICIPANTS: 2,178 participants (65% female, age 64 ± 8 years). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum sodium levels. RESULTS: Higher urinary PGE2 excretion was associated with lower serum sodium: difference in serum sodium for each two-fold higher PGE2 -0.19 mmol/l (95%CI -0.31 to -0.06), PGEM -0.29 mmol/l (95%CI -0.41 to -0.17). This association was stronger in thiazide users (per two-fold higher PGE2 -0.73 vs. -0.12 mmol/l and PGEM -0.6 vs. -0.25 mmol/l, p for interaction < 0.05 for both). A propensity score matching analysis of thiazide vs. non-thiazide users yielded similar results. The SNP rs34550074 was not associated with lower serum sodium or higher urinary PGE2 or PGEM excretion in thiazide or non-thiazide users. CONCLUSIONS: Serum sodium is lower in people with higher urinary PGE2 and PGEM excretion and this association is stronger in thiazide users. This suggests that PGE2-mediated water reabsorption regulates serum sodium, which is relevant for the pathogenesis of hyponatremia in general and thiazide-induced hyponatremia in specific.

Hyponatremia is associated with unfavorable outcomes after reperfusion treatment in acute ischemic stroke.

BACKGROUND AND PURPOSE: In patients with acute ischemic stroke, hyponatremia (plasma sodium < 136 mmol/L) is common and associated with unfavorable outcomes. However, data are limited for patients who underwent intravenous thrombolysis (IVT) and/or endovascular thrombectomy (EVT). Therefore, our aim was to assess the impact of hyponatremia on postreperfusion outcomes. METHODS: We analyzed data of consecutive patients who presented with acute ischemic stroke and were treated with IVT and/or EVT at Isala Hospital, the Netherlands, in 2019 and 2020. The primary outcome measure was the adjusted common odds ratio (acOR) for a worse modified Rankin Scale (mRS) score at 3-month follow-up. Secondary outcomes included symptomatic intracranial hemorrhage, in-hospital mortality, infarct core, and penumbra volumes. RESULTS: Of the 680 patients (median age = 73 years, 49% female, median National Institutes of Health Stroke Scale = 5), 430 patients (63%) were treated with IVT, 120 patients (18%) with EVT, and 130 patients (19%) with both. Ninety-two patients (14%) were hyponatremic on admission. Hyponatremia was associated with a worse mRS score at 3 months (acOR = 1.76, 95% confidence interval [CI] = 1.12-2.76) and in-hospital mortality (aOR = 2.39, 95% CI = 1.23-4.67), but not with symptomatic intracranial hemorrhage (OR = 1.17, 95% CI = 0.39-3.47). Hyponatremia was also associated with a larger core (17.2 mL, 95% CI = 2.9-31.5) and core to penumbra ratio (55.0%, 95% CI = 7.1-102.9). CONCLUSIONS: Admission hyponatremia in patients with acute ischemic stroke treated with IVT and/or EVT was independently associated with unfavorable postreperfusion outcomes, a larger infarct core, and a larger core to penumbra ratio. Future studies should address whether correction of hyponatremia improves the prognosis.

Overcorrection and undercorrection with fixed dosing of bolus hypertonic saline for symptomatic hyponatremia.

OBJECTIVE: Current guidelines recommend treating symptomatic hyponatremia with rapid bolus-wise infusion of fixed volumes of hypertonic saline regardless of body weight. We hypothesize that this approach is associated with overcorrection and undercorrection in patients with low and high body weight. DESIGN: Single-center, retrospective cohort study. METHODS: Data were collected on patients treated with ≥1 bolus 100 or 150 mL 3% NaCl for symptomatic hyponatremia between 2017 and 2021. Outcomes were overcorrection (plasma sodium rise > 10 mmol/L/24 h, > 18 mmol/L/48 h, or relowering therapy) and undercorrection (plasma sodium rise < 5 mmol/L/24 h). Low body weight and high body weight were defined according to the lowest (≤60 kg) and highest (≥80 kg) quartiles. RESULTS: Hypertonic saline was administered to 180 patients and caused plasma sodium to rise from 120 mmol/L to 126.4 mmol/L (24 h) and 130.4 mmol/L (48 h). Overcorrection occurred in 32 patients (18%) and was independently associated with lower body weight, weight ≤ 60 kg, lower baseline plasma sodium, volume depletion, hypokalemia, and less boluses. In patients without rapidly reversible causes of hyponatremia, overcorrection still occurred more often in patients ≤ 60 kg. Undercorrection occurred in 52 patients (29%) and was not associated with body weight or weight ≥ 80 kg but was associated with weight ≥ 100 kg and lean body weight in patients with obesity. CONCLUSION: Our real-world data suggest that fixed dosing of bolus hypertonic saline may expose patients with low and high body weight to more overcorrection and undercorrection, respectively. Prospective studies are needed to develop and validate individualized dosing models.

Serum sodium, cognition and incident dementia in the general population.

BACKGROUND: Low serum sodium may be associated with cognitive impairment and dementia in the general population, but the data remain inconclusive. Therefore, we aimed to determine the association of low serum sodium with cognitive function and incident dementia in the general population. METHODS: Participants from a prospective population-based cohort were eligible if data on serum sodium (collected between 1997 and 2008), dementia prevalence and dementia incidence were available (follow-up until 2018). Global cognitive function was assessed with the Mini-Mental State Examination (MMSE) and the general cognitive factor (G-factor, derived from principal component analysis of individual tests). Linear regression and Cox proportional-hazards models were used to assess associations of standardised continuous and categorised low serum sodium (mean - 1.96*SD: cut-off of 137 mmol/L) with overall cognitive function and incident dementia, respectively. RESULTS: In all, 8,028 participants free of dementia at baseline (mean age 63.6 years, 57% female, serum sodium 142 ± 2 mmol/L), including 217 participants with low serum sodium, were included. Cross-sectionally, continuous serum sodium and/or low serum sodium were not associated with the MMSE or G-factor. However, participants with low serum sodium performed worse on the Stroop and Purdue Pegboard tests. During a median follow-up of 10.7 years, 758 subjects developed dementia. Continuous serum sodium (hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.92;1.05) and low serum sodium (HR 1.27, 95% CI 0.90;1.79) were not associated with a higher risk of incident dementia. CONCLUSION: We identified no significant associations of low serum sodium with overall cognitive functioning and risk of dementia. However, low serum sodium-including levels above the clinical cut-off for hyponatremia-was associated with impairments in selected cognitive domains including attention and psychomotor function.

Hyponatremia Intervention Trial (HIT): Study Protocol of a Randomized, Controlled, Parallel-Group Trial With Blinded Outcome Assessment.

Background: Hyponatremia is the most common electrolyte disorder with a prevalence of up to 30% in hospitalized patients. In contrast to acute hyponatremia where the need for immediate treatment is well-recognized, chronic hyponatremia is often considered not clinically relevant. This is illustrated by reports showing that appropriate laboratory tests are ordered in <50% of patients and that up to 75% are still hyponatremic at discharge. At the same time, emerging evidence suggests an association between hyponatremia and adverse events including increased risk of mortality and rehospitalization. Methods: This is a randomized (1:1 ratio) controlled, superiority, parallel-group international multi-center trial with blinded outcome assessment. In total 2,278 participants will be enrolled. Participants will be randomly assigned to undergo either targeted correction of plasma sodium levels or standard of care during hospitalization. The primary outcome is the combined risk of death or re-hospitalization within 30 days. Discussion: All data on hyponatremia and mortality are derived from observational studies and often lack methodologic robustness. Consequently, the direct impact of hyponatremia on mortality and rehospitalization risk is still debated, resulting in a clinical equipoise whether in-hospital chronic hyponatremia should be treated or not. Therefore, a randomized controlled trial is required to study whether targeted plasma sodium correction reduces the risk of mortality and rehospitalization associated with hyponatremia. Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03557957.