Inappropriate Antidiuresis Research Articles

The Syndrome of Inappropriate Antidiuresis

Abstract The syndrome of inappropriate antidiuresis (SIAD)–the most frequent cause of hypotonic hyponatremia–is mediated by nonosmotic release of arginine vasopressin (AVP), which promotes water retention by activating renal vasopressin type 2 (V2) receptors. There are numerous causes of SIAD, including malignancy, pulmonary and central nervous system diseases and medications. Rare activating mutations of the V2 receptor can also cause SIAD Determination of the etiology of SIAD is important because removal of the stimulus for inappropriate AVP secretion offers the most effective therapy. Treatment of SIAD is guided by symptoms and their severity as well as the level of plasma sodium. In the absence of severe symptoms which require urgent intervention, many clinicians focus on fluid restriction as a first-line treatment. Second-line therapeutic options include loop diuretics and salt tablets, urea, and V2 receptor antagonists.

Oxytocin and the Role of Fluid Restriction in MDMA-Induced Hyponatremia

3,4-Methylenedioxymethamphetamine (MDMA, or ecstasy) is a recreational drug being investigated for the treatment of posttraumatic stress disorder. Acute hyponatremia is a potentially serious complication after even a single dose of MDMA. The assumed etiology has been a vasopressin release inducing the syndrome of inappropriate antidiuresis combined with increased thirst, causing polydipsia and water intoxication. To investigate the incidence and severity of hyponatremia after a single dose of MDMA, underlying neuroendocrine mechanisms of action, and the potential effect of fluid restriction on lowering the incidence of hyponatremia. This ad hoc secondary analysis pooled data from 4 placebo-controlled crossover randomized clinical trials conducted at the University Hospital Basel, Basel, Switzerland. The 96 participants received experimental doses of MDMA between March 1, 2017, and August 31, 2022. A single oral 100- or 125-mg dose of MDMA. Fluid intake was not restricted in 81 participants; it was restricted in 15. Plasma oxytocin, copeptin (marker of vasopressin), and sodium levels were measured repeatedly within 360 minutes after MDMA intake. The association of plasma oxytocin or copeptin levels with plasma sodium level at 180 minutes (peak concentration of MDMA) was determined. Among the 96 participants, the mean (SD) age was 29 (7) years, and 62 (65%) were men. A total of 39 participants (41%) received a 100-mg dose of MDMA, and 57 (59%) received a 125-mg dose. At baseline, the mean (SD) plasma sodium level was 140 (3) mEq/L and decreased in response to MDMA by 3 (3) mEq/L. Hyponatremia occurred in 30 participants (31%) with a mean (SD) sodium level of 133 (2) mEq/L. In 15 participants with restricted fluid intake, no hyponatremia occurred, while in the 81 participants with unrestricted fluid intake, hyponatremia occurred in 30 (37%) (P = .002) with a difference in plasma sodium of 4 (95% CI, 2-5) mEq/L (P < .001) between both groups, suggesting that fluid restriction may mitigate the risk of hyponatremia. At baseline, the mean (SD) plasma oxytocin level was 87 (45) pg/mL and increased in response to MDMA by 388 (297) pg/mL (ie, a mean [SD] 433% [431%] increase at 180 minutes), while the mean (SD) copeptin level was 4.9 (3.8) pmol/L and slightly decreased, by 0.8 (3.0) pmol/L. Change in plasma sodium level from baseline to 180 minutes demonstrated a negative correlation with the changes in oxytocin (R = -0.4; P < .001) and MDMA (R = -0.4; P < .001) levels while showing no correlation with the change in copeptin level. In this secondary analysis of 4 randomized clinical trials, a high incidence of acute hyponatremia was observed in response to MDMA, which may be mitigated by fluid restriction. Hyponatremia was associated with acute oxytocin but not copeptin release. This challenges the current hypothesis of direct vasopressin release and rather indicates that oxytocin mimics the effect of vasopressin in the kidneys due to structural homology.

Efficacy of Low-Dosage Tolvaptan for Treatment of Profound Hyponatremia in Syndrome of Inappropriate Antidiuresis: An Open-Label Randomized Controlled Trial

Efficacy of Low-Dosage Tolvaptan for Treatment of Profound Hyponatremia in Syndrome of Inappropriate Antidiuresis: An Open-Label Randomized Controlled Trial

Syndrome of inappropriate antidiuresis/hyponatremia in COVID-19.

Hyponatremia is the most frequent electrolyte alteration among hospitalized patients and it has been reported in 20-40% of patients with SARS-CoV-2 (COVID-19) infection. Multiple causes of hyponatremia have been hypothesized in these patients. The syndrome of inappropriate antidiuresis (SIAD) has been considered one of the main reasons leading to hyponatremia in this condition. SIAD can be secondary to cytokines release, in particular IL-6. Positive pressure ventilation can be another cause of hyponatremia due to SIAD. Other possible etiologies of hyponatremia in COVID-19 patients can be related to secondary hypocortisolism, nausea, vomiting, heart and kidney damage. Similar to many other clinical conditions, there is strong evidence that hyponatremia is associated with a worse prognosis also in patients with COVID-19 infection. In particular, hyponatremia has been identified as an independent risk of ICU transfer, need of non-invasive ventilation and death. Hyponatremia in COVID-19 patients is in principle acute and symptomatic and should be treated as such, according to the published guidelines. Therefore, patients should be initially treated with i.v. hypertonic saline (3% NaCl) infusion and serum [Na+] should be frequently monitored, in order to remain within a safe rate of correction. There is evidence showing that serum [Na+] correction is associated with a better outcome in different pathologies, including COVID-19 infection.

Duloxetine-Induced Antidiuresis in Rats with Lithium-Induced Nephrogenic Diabetes Insipidus.

Antidepressants, including duloxetine, are a significant cause of drug-induced hyponatremia, which can disrupt the continuation of medication. Tolvaptan is beneficial for correcting hyponatremia caused by the syndrome of inappropriate antidiuresis, but its impact on duloxetine-induced hyponatremia remains unknown. We used male Sprague-Dawley rats to examine the impact of duloxetine treatment on lithium-induced nephrogenic diabetes insipidus (Li-NDI) and to evaluate whether the results were reversed by co-treatment with tolvaptan. To induce Li-NDI, lithium chloride (40 mmol lithium/kg dry food) was administered for 2 weeks. Duloxetine (50 mg/kg/day) and tolvaptan (10 mg/kg/day) were also administered in food to assess their individual effects over the same period. At the end of each animal experiment, kidneys were harvested to measure levels of cAMP, vasopressin-2 receptor (V2R), cAMP-responsive element binding protein 1 (CREB-1), aquaporin-2 (AQP2), and prostaglandin E2 (PGE2). Water diuresis was induced in the Li-NDI rats, and duloxetine treatment reduced polyuria while increasing urine osmolality. Duloxetine treatment prevented the decrease in total AQP2, AQP2 phosphorylation at serine 256, and CREB-1 phosphorylation in Li-NDI rats. The V2R mRNA level was also reduced in Li-NDI rats and restored by duloxetine treatment. In the subsequent experiment, the decreased water diuresis in Li-NDI rats treated with duloxetine was reversed by co-treatment with tolvaptan. Tolvaptan co-treatment also reversed the changes in AQP2 protein and CREB-1 phosphorylation in the renal cortex and medulla. The decreased cAMP levels in Li-NDI rat kidneys were elevated by duloxetine treatment, and this elevation was reversed by co-treatment with tolvaptan. However, the elevated PGE2 levels in Li-NDI rat kidneys were not affected by either duloxetine alone or tolvaptan co-treatment. In conclusion, antidiuresis was induced by duloxetine in Li-NDI and reversed by tolvaptan co-treatment through alterations in the V2R-cAMP-AQP2 pathway. These findings could underlie the mechanism of duloxetine-induced hyponatremia and suggest the potential usefulness of tolvaptan in treating drug-induced hyponatremia.

Clinical factors associated with hyponatremia correction during treatment with oral Urea.

Oral urea is being used more commonly to treat hyponatremia, but factors contributing to the correction rate are unknown. We hypothesized that clinically relevant factors can be identified to help guide hyponatremia correction with oral urea. Retrospective study in two university hospitals including hospitalized patients with hyponatremia (plasma sodium < 135mmol/L) treated with oral urea. Linear mixed-effects models were used to identify factors associated with hyponatremia correction. Rates of overcorrection, osmotic demyelination and treatment discontinuation were also assessed. We included 161 urea treatment episodes in 140 patients (median age 69 years, 46% females, 93% syndrome of inappropriate antidiuresis). Oral urea succeeded fluid restriction in 117 treatment episodes (73%), was combined with fluid restriction in 104 treatment episodes (65%) and was given as only treatment in 27 treatment episodes (17%). A median dose of 30 grams/day of urea for 4 days (interquartile range 2-7 days) increased plasma sodium from 127 to 134mmol/L and normalized hyponatremia in 47% of treatment episodes. Older age (ß 0.09, 95%CI 0.02 to 0.16), lower baseline plasma sodium (ß -0.65, 95%CI -0.78 to -0.62), and higher cumulative urea dose (ß 0.03, 95%CI -0.02 to -0.03) were independently associated with a greater rise in plasma sodium. Concurrent fluid restriction was associated with a greater rise in plasma sodium only during the first 48h of treatment (ß 1.81, 95%CI 0.40 to 3.08). Overcorrection occurred in 5 cases (3%), no cases of osmotic demyelination were identified, and oral urea was discontinued in 11 cases (11%) due to side-effects. During treatment with oral urea, older age, higher cumulative dose, lower baseline plasma sodium and initial fluid restriction are associated with a greater correction rate of hyponatremia. These factors may guide clinicians to achieve a gradual correction of hyponatremia with oral urea.

Update on the clinical applications of SGLTis: Insight to benefits beyond hypoglycemic and cardiorenal protection.

Sodium glucose cotransporter inhibitor (SGLTi) drugs have been widely used in clinical practice. In addition to their benefits in hyperglycemia, heart failure (HF), and kidney disease, their effects on obesity, metabolic dysfunction-associated steatotic liver disease (MASLD, formerly named nonalcoholic fatty liver disease [NAFLD]), polycystic ovarian syndrome (PCOS), abnormal lipid metabolism, hyperuricemia, obstructive sleep apnea syndrome (OSAS), anemia, and syndrome of inappropriate antidiuresis (SIAD, formerly named syndrome of inappropriate antidiuretic hormone [SIADH]) have been explored. In this review, we searched the data of clinical randomized controlled trials (RCTs) and meta-analyses of SGLTis in patients with diabetes from the PubMed library between January 1, 2020, and February 1, 2024. According to our review, certain SGLTis exhibit relatively superior clinical safety and effectiveness for treating the abovementioned diseases. Proper utilization of SGLTis in these patients can provide additional medication options for patients with different disease scenarios. However, studies of SGLTis in these diseases are relatively rare, with shortcomings such as small sample sizes and short intervention periods. Therefore, further large-scale, long-term, well-designed studies are needed to clarify the findings.

Chronic Hyponatremia: The Role of Reset Osmostat in Patients with Suspected SIAD.

Background: Hyponatremia is common, particularly among the elderly. Reset osmostat (RO) serves as an alternative diagnosis to the syndrome of inappropriate antidiuresis (SIAD). There is limited information available regarding the prevalence of RO in outpatient clinics and hospital wards. The water-diluting test is considered the gold standard for the diagnosis of RO. The recent identification of copeptin provides an additional diagnostic marker alongside the utilization of fractional uric acid excretion. Methods: This single-center, prospective, observational study involved eight patients undergoing a water-diluting test over a study period of 2 years. Results: Reset osmostat was diagnosed in 50% of cases, while SIAD was confirmed in one patient. The tests were inconclusive for the remaining three patients. Conclusions: Our findings suggest that reset osmostat, despite its rarity, is a plausible diagnosis in chronic hyponatremia. The relevance of copeptin could not be confirmed in this study. Moreover, fractional uric acid excretion might be as effective as the water-diluting test in diagnosing reset osmostat.

Apelin and Copeptin Levels in Patients With Chronic SIAD Treated With Empagliflozin.

Empagliflozin increases sodium levels in patients with a chronic syndrome of inappropriate antidiuresis (SIAD), and dapagliflozin increases apelin levels in patients with diabetes mellitus. Exogenous apelin increases sodium levels in rats with SIAD. We aimed to investigate whether an increase in plasma apelin concentration may contribute to the efficacy of empagliflozin in SIAD. Post hoc secondary analysis of a double-blind, crossover, placebo-controlled trial performed from December 2017 to August 2021 at the University Hospital Basel, Switzerland, investigating the effect of 4-week treatment with empagliflozin 25 mg/day as compared to placebo in 14 outpatients with chronic SIAD (NCT03202667). The objective was to investigate the effect of empagliflozin on plasma apelin and copeptin concentrations and their ratio. Fourteen patients, 50% female, with a median [interquartile range] age of 72 years [65-77] were analyzed. Median apelin concentration was 956 pmol/L [853, 1038] at baseline. Median [interquartile range] apelin relative changes were +11% [0.7, 21] and +8% [-5, 25] (P = .672) at the end of the placebo and empagliflozin phases, respectively. Median copeptin concentration was 2.6 [2.2, 4.5] pmol/L at baseline and had a relative change of +5 [-2. 11]% and +25% [10, 28] (P = .047) over the placebo and empagliflozin phases, respectively. Empagliflozin did not lead to significant changes in apelin or the apelin/copeptin ratio in patients with chronic SIAD but led to an increase in copeptin. This suggests that the efficacy of empagliflozin in SIAD is independent of apelin and is not blunted by the adaptative increase in copeptin.

Copeptin and the syndrome of inappropriate antidiuresis (SIAD) after pituitary transsphenoidal surgery.

This study evaluates the predictive value of copeptin for syndrome of inappropriate antidiuresis (SIAD) postpituitary transsphenoidal surgery (TSS). Data from 133 consecutive patients undergoing TSS (November 2017-October 2022) at Oxford University Hospitals NHS trust are presented in this retrospective study. Logistic regression (LR) and receiver operating characteristic (ROC) curves were performed to evaluate the diagnostic utility of copeptin. The Mann-Whitney U test was used to compare copeptin levels between the SIAD and no SIAD groups. Fourteen patients (10.8%) developed SIAD. Copeptin was available in 121, 53 and 87 patients for Days 1, 241 and 8 post-TSS, respectively. LR for Day 1 copeptin to predict SIAD gave an odds ratio (OR) of 1.0 (95%CI 42 0.84-1.20, p = .99), area under-ROC curve (AUC) was 0.49; Day 2 copeptin OR was 0.65 (95%CI 0.39-1.19, 43 p = .77), AUC was 0.57 LR for Day 1 sodium to predict SIAD gave an odds ratio (OR) of 1.0 (95%CI 0.85-1.21, p = .99), AUC was 0.50. In conclusion, our data provide no evidence for copeptin as a predictive marker for post-TSS SIAD.

Simultaneous Occurrence of Hyponatremia and Hypokalemia in a Patient with Herpes Zoster: A Case Report with a Review of the Literature.

We herein report a patient with herpes zoster (HZ), severe hyponatremia, and hypokalemia. Syndrome of inappropriate antidiuresis (SIAD) leads to euvolemic hyponatremia and hypoosmotic plasma due to inadequate diuresis. Hyponatremia in the current patient was caused by SIAD and associated with HZ of the trigeminal facial nerve (V1). The patient also had hypokalemia, with excessive urinary potassium excretion and elevated cortisol levels. Hypokalemia is caused by hypercortisolemia, which is stimulated by HZ pain. Adequate treatment for HZ and comprehensive pain control play pivotal roles in improving SIAD, cortisol hypersecretion, and the subsequent electrolyte abnormalities.

Urea as a therapeutic option in inadequate antidiuresis syndrome

Syndrome of Inappropriate Antidiuresis (SIAD), is produced by an alteration in the hypothalamus-neurohypophysis axis due to a failure in the osmotic regulatory response or non-osmotic factors, with complications directly related to the degree of hyponatremia and impact on quality of life and patient mortality. Management consists of normalization of natremia, and the search for the underlying etiology. We present the case of an adult patient diagnosed with idiopathic SIAD and associated neurocognitive disorder, with a favorable response to treatment with urea.

Effect of Protein Supplementation on Plasma Sodium Levels and Urinary Urea Excretion in Patients with Chronic Syndrome of Inappropriate Antidiuresis (SIAD): A Monocentric Open-Label Proof-of-Concept Study

Effect of Protein Supplementation on Plasma Sodium Levels and Urinary Urea Excretion in Patients with Chronic Syndrome of Inappropriate Antidiuresis (SIAD): A Monocentric Open-Label Proof-of-Concept Study

Food for Thought: Protein Supplementation for the Treatment of the Syndrome of Inappropriate Antidiuresis.

Food for Thought: Protein Supplementation for the Treatment of the Syndrome of Inappropriate Antidiuresis.

OR2805 Plasma Sodium Increase Is Associated With An Increase In Bone Formation In Outpatients With Chronic SIAD—A Predefined Secondary Analysis Of The SANDx Trial

Abstract Disclosure: S. Monnerat: None. J. Refardt: None. C. Meier: None. M. Christ-Crain: None. INTRODUCTION Hyponatremia is the most common electrolyte disorder encountered in clinical practice and is associated with increased mortality and morbidity, including an increased risk for osteoporosis and fragility fractures. Preclinical studies suggest that hyponatremia upregulates osteoclasts. In a previous analysis of 88 hospitalized patients with a syndrome of inappropriate antidiuresis (SIAD), we observed that hyponatremia normalization after 4 days had a positive impact on osteoblast function. METHODS This is a secondary analysis of a double-blind, crossover, placebo-controlled trial investigating the effect of 4-week treatment with empagliflozin 25mg/day as compared to placebo in 14 outpatients with chronic SIAD (NCT03202667). Two patients with an antiresorptive osteoporosis treatment and 1 patient with recent hip arthroplasty were excluded (n=11). The primary objective was to investigate the relationship between the change in bone formation index (BFI), defined as PINP/CTX, and the change in plasma sodium levels. Secondary objectives included the relationship between the change in the osteoblasts markers procollagen type 1 N (P1NP) and osteocalcin and the osteoclasts markers C-telopeptide crosslink (CTX), and the change in plasma sodium levels over the treatment period. Linear mixed models and Spearman correlation were computed. RESULTS Six out of the 11 outpatients with a chronic SIAD were female (median [IQR] age 73 years [66, 78]). At baseline, median [IQR] CTX concentration was 0.47 ug/L [0.29, 0.65], median [IQR] osteocalcin was 18.00 ug/L [13.95, 25.87] and median [IQR] P1NP was 64.64 ug/L [45.62, 68.45]. The calculated median BFI [IQR] was 131.86 [96.21, 168.73]. A sodium increase of 1 mmol/L was associated with an increase of 5.21 in BFI (95%-CI: 1.41, 9.00, p = 0.013) and with an increase of 1.48 ug/L in P1NP (95%-CI: 0.26, 2.62, p = 0.03). Plasma sodium concentration was not associated with a change in osteocalcin (β = 0.32; 95%-CI: -0.09, 0.72, p = 0.18), nor with a change in CTX (β = 0.003; 95%-CI: -0.008, 0.014, p = 0.324). Empagliflozin was not a significant predictor for the change of any bone markers and there was no interaction between treatment allocation and sodium. Changes in plasma sodium were positively correlated with changes in BFI and P1NP (BFI: ρ = 0.55, p &amp;lt; 0.001; P1NP: ρ = 0.45, p = 0.004) but not with CTX and osteocalcin (CTX: ρ = -0.21, p = 0.184; Osteocalcin: ρ = 0.34, p = 0.149). CONCLUSION An increase in plasma sodium levels in outpatients with chronic SIAD was associated with an increase in bone formation index (P1NP/CTX), which seemed to be triggered by an increase in P1NP, a surrogate marker of osteoblast function. This supports the importance of treating hyponatremia, particularly in older adults in whom chronic hyponatremia is also associated with falls. Presentation: Sunday, June 18, 2023

THU112 Effect Of Protein Supplementation On Plasma Sodium Levels And Urinary Urea Excretion In Patients With Chronic Siad—A Monocentric Open-Label Proof-Of-Concept Study—The Treasure Study

Abstract Disclosure: S. Monnerat: None. C. Atila: None. F.E. Baur: None. M. Dickenmann: None. M. Christ-Crain: None. INTRODUCTION The syndrome of inappropriate antidiuresis (SIAD) is the most common cause of euvolemic hyponatremia. Besides fluid restriction, increasing free-water clearance is an effective treatment approach that can be achieved through osmotic diuresis by administering oral urea. However, oral urea has a very peculiar taste that impedes long-term compliance. Dietary proteins are metabolized into soluble excretable urea by the liver. We hypothesized that dietary protein could increase free water clearance through urea-induced osmotic diuresis and therefore aimed to investigate the effect of high-protein supplementation on plasma sodium levels in outpatients with chronic SIAD. METHODS This is an interim analysis of a monocentric open-label proof-of-concept trial conducted at the University Hospital of Basel since October 2021. Adult outpatients with chronic SIAD of any etiology were eligible. Patients received 90g protein daily for 7 days in the form of protein powder dissolved in a maximum of 1L of liquid of choice. After a wash-out period of at least a week, patients received 30g of oral urea daily for 7 days. Patients were asked to keep their baseline fluid intake unchanged throughout the study. The primary endpoint was the increase in sodium levels from baseline to the end of the 7-day protein supplementation. RESULTS Thirteen patients, 10 females and 3 males, with chronic SIAD were included. Median [IQR] age was 63 [61, 80] and the median [IQR] duration of hyponatremia was 33 months [12, 42]. At baseline, median [IQR] plasma sodium concentration was 130 mmol/L [129, 133]. Eight patients had mild hyponatremia (130-134 mmol/L), 4 had moderate hyponatremia (125-129 mmol/L), and 1 patient had profound hyponatremia (&amp;lt;125 mmol/L). After 7 days of 90g daily protein supplementation (n = 13), sodium levels increased by a median [IQR] of 3 mmol/L [0, 5], blood urea nitrogen increased by a median [IQR] of 4.3 mmol/L [1.7, 5.1] and urinary urea corrected for urine creatinine increased by a median [IQR] of 26.0 mmol/mmol [17.1, 32.3]. After 7 days of oral urea (n = 8), sodium levels increased by a median [IQR] of 2 mmol/L [1, 3], blood urea nitrogen increased by a median [IQR] of 8.5 mmol/L [3.8, 10.2] and urinary urea corrected for urine creatinine increased by a median [IQR] of 31 mmol/mmol [21.1, 39.8]. CONCLUSION This interim analysis suggests that high-protein supplementation with protein powder increases plasma sodium levels in patients with chronic SIAD. The increase in urea concentration in both plasma and urine upon protein supplementation is comparable to the increase upon oral urea administration, which supports protein-induced ureagenesis to be the underlying mechanism of action. Presentation: Thursday, June 15, 2023

Effect of protein supplementation on plasma sodium levels in the syndrome of inappropriate antidiuresis - a monocentric open-label proof-of-concept study - the treasure study

Effect of protein supplementation on plasma sodium levels in the syndrome of inappropriate antidiuresis - a monocentric open-label proof-of-concept study - the treasure study

Isolated Third Cranial Nerve Palsy Associated with Sudden Worsening of Hypotonic Hyponatremia Secondary to Ischemic Pituitary Apoplexy

Pituitary apoplexy (PA) is a rare medical emergency. The sudden pressure increase in the sella turcica may determine compression on the surrounding structures determining the classical symptomatology associated, especially visual field impairment and/or ocular palsies and hypopituitarism; hypotonic hyponatremia may occur too, even if it is not common. Although already described in the literature, cases of isolated III cranial nerve palsies are extremely rare events. We report the case of a mid-60-year-old man with a known pituitary adenoma accessing the Emergency Department (ED) for worsening headaches unresponsive to analgesics, with a morphological picture consistent with ischemic PA, despite no dimensional increase of the pituitary lesion; upon ED access, a mild paucisymptomatic hyponatremia was also observed. Dexamethasone and mannitol were empirically introduced upon neurosurgical indication and tramadol and ketorolac were promptly administered as well, but without benefit. In the next days, a severe hypotonic hyponatremia was evidenced and a clear left III cranial nerve palsy developed, but no clear signs of cerebral bleeding or ischemia, nor a significant compression on the homolateral cavernous sinus, were observed. Upon ruling out other possible causes, a likely diagnosis of syndrome of inappropriate antidiuresis (SIAD) was made, confirmed by the quick response to fluid restriction. Overall, the sudden fall in tonicity plasma levels seemed to contribute to the exacerbation of the neurological deficit since the normalization of sodium levels was associated with a rapid and complete reversion of the III cranial nerve palsy.

Inappropriate therapy of euvolemic hyponatremia, the most frequent type of hyponatremia in SARS-CoV-2 infection, is associated with increased mortality in COVID-19 patients.

Admission hyponatremia, frequent in patients hospitalized for COVID-19, has been associated with increased mortality. However, although euvolemic hyponatremia secondary to the Syndrome of Inappropriate Antidiuresis (SIAD) is the single most common cause of hyponatremia in community-acquired pneumonia (CAP), a thorough and rigorous assessment of the volemia of hyponatremic COVID-19 subjects has yet to be described. We sought to identify factors contributing to mortality and hospital length-of-stay (LOS) in hospitalized COVID-19 patients admitted with hyponatremia, taking volemia into account. Retrospective study of 247 patients admitted with COVID-19 to a tertiary hospital in Madrid, Spain from March 1st through March 30th, 2020, with a glycemia-corrected serum sodium level (SNa) < 135 mmol/L. Variables were collected at admission, at 2nd-3rd day of hospitalization, and ensuing days when hyponatremia persisted. Admission volemia (based on both physical and analytical parameters), therapy, and its adequacy as a function of volemia, were determined. Age: 68 years [56-81]; 39.9% were female. Median admission SNa was 133 mmol/L [131- 134]. Hyponatremia was mild (SNa 131-134 mmol/L) in 188/247 (76%). Volemia was available in 208/247 patients; 57.2% were euvolemic and the rest (42.8%) hypovolemic. Hyponatremia was left untreated in 154/247 (62.3%) patients. Admission therapy was not concordant with volemia in 43/84 (51.2%). In fact, the majority of treated euvolemic patients received incorrect therapy with isotonic saline (37/41, 90.2%), whereas hypovolemics did not (p=0.001). The latter showed higher mortality rates than those receiving adequate or no therapy (36.7% vs. 19% respectively, p=0.023). The administration of isotonic saline to euvolemic hyponatremic subjects was independently associated with an elevation of in-hospital mortality (Odds Ratio: 3.877, 95%; Confidence Interval: 1.25-12.03). Hyponatremia in COVID-19 is predominantly euvolemic. Isotonic saline infusion therapy in euvolemic hyponatremic COVID-19 patients can lead to an increased mortality rate. Thus, an exhaustive and precise volemic assessment of the hyponatremic patient with CAP, particularly when due to COVID-19, is mandatory before instauration of therapy, even when hyponatremia is mild.

Severe hyponatremia with consciousness disturbance after receiving SARS-CoV-2 mRNA vaccination.

There are very few reports of syndrome of inappropriate antidiuresis hormone secretion (SIADH) after receiving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine. Herein, we present the case of an 84-year-old woman who developed severe hyponatremia following the second administration of the SARS-CoV-2 mRNA vaccine. The patient presented with nausea, vomiting, and headache. Laboratory tests showed a plasma sodium level of 119 mmol/L. After receiving 500 mL of intravenous saline over a 2-h period, her plasma sodium level raised to 121 mmol/L, but her symptoms persisted. Considering that rapid plasma sodium correction was necessary, we started 3% saline solution overnight. Her plasma sodium level raised to 132 mmol/L and her symptoms completely resolved. Clinical and laboratory findings were consistent with a diagnosis of SIADH. In the absence of any other triggering factors, we concluded that the condition was likely associated with the vaccination. Clinicians should be aware of the potential for hyponatremia, particularly SIADH, associated with SARS-CoV-2 mRNA vaccination. Reports of syndrome of inappropriate antidiuresis hormone secretion after receiving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination are limited. If nausea, headache, and confusion are observed immediately after SARS-CoV-2 vaccination, clinicians should consider the presence of hyponatremia. As similar case reports to date have presented with severe hyponatremia, prompt treatment may be required.