Acute hypernatremia increases functional connectivity of NaCl sensing regions in the human brain: An fMRI pilot study.

Rodent studies demonstrated specialized sodium chloride (NaCl) sensing neurons in the circumventricular organs, which mediate changes in sympathetic nerve activity, arginine vasopressin, thirst, and blood pressure. However, the neural pathways involved in NaCl sensing in the human brain are incompletely understood. The purpose of this pilot study was to determine if acute hypernatremia alters the functional connectivity of NaCl-sensing regions of the brain in healthy young adults. Resting-state fMRI scans were acquired in 13 participants at baseline and during a 30 min hypertonic saline infusion (HSI). We used a seed-based approach to analyze the data, focusing on the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) as regions of interest (ROIs). Blood chemistry and perceived thirst were assessed pre- and post-infusion. As expected, serum sodium increased from pre- to post-infusion in the HSI group. The primary finding of this pilot study was that the functional connectivity between the SFO and a cluster within the OVLT increased from baseline to the late-phase of the HSI. Bidirectional connectivity changes were found with cortical regions, with some regions showing increased connectivity with sodium-sensing regions while others showed decreased connectivity. Furthermore, the functional connectivity between the SFO and the posterior cingulate cortex (a control ROI) did not change from baseline to the late-phase of the HSI. This finding indicates a distinct response within the NaCl sensing network in the human brain specifically related to acute hypernatremia that will need to be replicated in large-scale studies.

Hypernatremia and intercalated disc edema synergistically exacerbate long-QT syndrome type 3 phenotype.

Cardiac voltage-gated sodium channel gain-of-function prolongs repolarization in the long-QT syndrome type 3 (LQT3). Previous studies suggest that narrowing the perinexus within the intercalated disc, leading to rapid sodium depletion, attenuates LQT3-associated action potential duration (APD) prolongation. However, it remains unknown whether extracellular sodium concentration modulates APD prolongation during sodium channel gain-of-function. We hypothesized that elevated extracellular sodium concentration and widened perinexus synergistically prolong APD in LQT3. LQT3 was induced with sea anemone toxin (ATXII) in Langendorff-perfused guinea pig hearts (n = 34). Sodium concentration was increased from 145 to 160 mM. Perinexal expansion was induced with mannitol or the sodium channel ß1-subunit adhesion domain antagonist (ßadp1). Epicardial ventricular action potentials were optically mapped. Individual and combined effects of varying clefts and sodium concentrations were simulated in a computational model. With ATXII, both mannitol and ßadp1 significantly widened the perinexus and prolonged APD, respectively. The elevated sodium concentration alone significantly prolonged APD as well. Importantly, the combination of elevated sodium concentration and perinexal widening synergistically prolonged APD. Computational modeling results were consistent with animal experiments. Concurrently elevating extracellular sodium and increasing intercalated disc edema prolongs repolarization more than the individual interventions alone in LQT3. This synergistic effect suggests an important clinical implication that hypernatremia in the presence of cardiac edema can markedly increase LQT3-associated APD prolongation. Therefore, to our knowledge, this is the first study to provide evidence of a tractable and effective strategy to mitigate LQT3 phenotype by means of managing sodium levels and preventing cardiac edema in patients.NEW & NOTEWORTHY This is the first study to demonstrate that the long-QT syndrome type 3 (LQT3) phenotype can be exacerbated or concealed by regulating extracellular sodium concentrations and/or the intercalated disc separation. The animal experiments and computational modeling in the current study reveal a critically important clinical implication: sodium dysregulation in the presence of edema within the intercalated disc can markedly increase the risk of arrhythmia in LQT3. These findings strongly suggest that maintaining extracellular sodium within normal physiological limits may be an effective and inexpensive therapeutic option for patients with congenital or acquired sodium channel gain-of-function diseases.

Prognostic Impact of Hyponatremia and Hypernatremia in COVID-19 Pneumonia. A HOPE-COVID-19 (Health Outcome Predictive Evaluation for COVID-19) Registry Analysis.

Dysnatremia is associated with increased mortality in patients with community-acquired pneumonia. SARS-COV2 (Severe-acute-respiratory syndrome caused by Coronavirus-type 2) pneumonia can be fatal. The aim of this study was to ascertain whether admittance dysnatremia is associated with mortality, sepsis, or intensive therapy (IT) in patients hospitalized with SARS-COV2 pneumonia. This is a retrospective study of the HOPE-COVID-19 registry, with data collected from January 1th through April 31th, 2020. We selected all hospitalized adult patients with RT-PCR-confirmed SARS-COV2 pneumonia and a registered admission serum sodium level (SNa). Patients were classified as hyponatremic (SNa <135 mmol/L), eunatremic (SNa 135-145 mmol/L), or hypernatremic (SNa >145 mmol/L). Multivariable analyses were performed to elucidate independent relationships of admission hyponatremia and hypernatremia, with mortality, sepsis, or IT during hospitalization. Four thousand six hundred sixty-four patients were analyzed, median age 66 (52-77), 58% males. Death occurred in 988 (21.2%) patients, sepsis was diagnosed in 551 (12%) and IT in 838 (18.4%). Hyponatremia was present in 957/4,664 (20.5%) patients, and hypernatremia in 174/4,664 (3.7%). Both hyponatremia and hypernatremia were associated with mortality and sepsis. Only hyponatremia was associated with IT. In conclusion, hyponatremia and hypernatremia at admission are factors independently associated with mortality and sepsis in patients hospitalized with SARS-COV2 pneumonia. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04334291, NCT04334291.

Tolvaptan-induced hypernatremia related to low serum potassium level accompanying high blood pressure in patients with acute decompensated heart failure.

BACKGROUNDS: Tolvaptan significantly increases urine volume in acute decompensated heart failure (ADHF); serum sodium level increases due to aquaresis in almost all cases. We aimed to elucidate clinical factors associated with hypernatremia in ADHF patients treated with tolvaptan. METHODS: We enrolled 117 ADHF patients treated with tolvaptan in addition to standard therapy. We examined differences in clinical factors at baseline between patients with and without hypernatremia in the initial three days of hospitalization. RESULTS: Systolic (p = 0.045) and diastolic (p = 0.004) blood pressure, serum sodium level (p = 0.002), and negative water balance (p = 0.036) were significantly higher and serum potassium level (p = 0.026) was significantly lower on admission day in patients with hypernatremia (n = 22). In multivariate regression analysis, hypernatremia was associated with low serum potassium level (p = 0.034). Among patients with serum potassium level ≤ 3.8 mEq/L, the cutoff value obtained using receiver operating characteristic curve analysis, those with hypernatremia related to tolvaptan treatment showed significantly higher diastolic blood pressure on admission day (p = 0.004). CONCLUSION: In tolvaptan treatment combined with standard therapy in ADHF patients, serum potassium level ≤ 3.8 mEq/L may be a determinant factor for hypernatremia development. Among hypokalemic patients, those with higher diastolic blood pressure on admission may be carefully managed to prevent hypernatremia.

Approach to Electrolyte Abnormalities, Prerenal Azotemia, and Fluid Balance.

Volume and electrolyte evaluation and management is seen frequently in primary care practices. Some of the most common abnormalities encountered in outpatient practices are prerenal azotemia, dysnatremias, and altered potassium levels. Perturbations in volume or electrolyte concentrations can lead to serious organ dysfunction as well as hemodynamic collapse. This review focuses on the maintenance and regulation of intravascular volume and electrolytes, specifically sodium and potassium.

Progression to Severe Hypernatremia in Hospitalized General Medicine Inpatients: An Observational Study of Hospital-Acquired Hypernatremia.

Background and objectives: Hypernatremia can be community or hospital-acquired, and there may be specific factors unique to the hospital environment, such as intravenous fluid treatment, which contribute to hypernatremia. The aim of this study was to determine the factors associated with the progression from moderate to severe hospital-acquired hypernatremia among patients admitted under general medicine. Materials and Methods: In this retrospective, single-center cohort study (2012 to 2017), we used ICD-10 coding and medical records to identify adult patients who developed moderate hypernatremia and followed them for progression to severe hypernatremia. We profiled the serum biochemistry and the volume and composition of prescribed intravenous fluids. We applied logistic regression to determine the factors associated with the progression to severe hypernatremia, using the patients with moderate hypernatremia as reference. Results: Of the 180 medical inpatients (median age of 81 years) with moderate hospital-acquired hypernatremia, 9.4% progressed to severe hypernatremia. Normal saline comprised 76% of intravenous fluid volume administered prior to onset of moderate hypernatremia. After the onset, 38% of fluid volume prescribed remained normal saline. The factors independently associated with progression to severe hypernatremia included chronic kidney disease stage (odds ratio 2.38, 95% CI: 1.26-4.50, P = 0.008) and serum creatinine increase (per 10 µmol/L, OR 1.29, 95% CI: 1.07-1.57, P = 0.009). Conclusions: Patients with chronic kidney disease and acute kidney injury may have an increased risk of severe hospital-acquired hypernatremia.

A complicated chinese herbal medicine nephrotoxicity.

Chinese herbal medicine is widely used globally. In many instances, it is associated with severe adverse outcomes. We report case of a Chinese herbal nephropathy occurring in a 43-year-old woman showing renal impairment, metabolic acidosis, Stokes - Adams syndrome, hypernatremia, and hypokalemia, characteristics not usually encountered in published cases.

Salt Toxicity: A Systematic Review and Case Reports.

INTRODUCTION: Salt toxicity is a rare form of hypernatremia that typically occurs after a single massive ingestion of salt over a short period of time (minutes/hours). It is a dangerous imbalance capable of causing significant neurological injury; quick recognition of salt toxicity is crucial to allow treatment before permanent brain injury occurs. The purpose of this review is to assist emergency nurses in gaining knowledge on the causes, pathophysiology, symptoms, and treatment of salt toxicity. METHODS: A systematic search for case reports of hypernatremia due to salt toxicity was conducted in the PubMed and Scopus electronic databases. The search terms used were salt, sodium, hypernatremia, toxicity, poisoning, case reports, case series, and cases. The following were the inclusion criteria: publication dates between January 1, 2000, and September 30, 2019; evidence of an acute large oral or gastric tube ingestion of salt over a short period of time (minutes/hours); admission for treatment within hours of the event; laboratory verification of hypernatremia; and full-text article available electronically in English. The following were the exclusion criteria: an unclear history, high salt consumption over a period of days, high sodium intake via the intravenous route, and breast feeding. RESULTS: Only 15 cases met the inclusion criteria for the review. Patients described in the case reports ranged in age from 5 days to 73 years. Forty percent of the patients were children less than 15 years old. Of the 14 cases with known outcomes, 50% were fatal. The most frequent causes of salt toxicity were salt water emetics, intentional administration of large quantities of salt to a child by a caregiver, and suicide attempts. Among the other causes were unintentional salt overload in infant formula, an exorcism ritual, and a college prank. DISCUSSION: Findings from this review of 15 case reports in which a large salt load was ingested over a short period of time suggest that salt toxicity is a rare condition associated with high mortality. In addition, salt toxicity can occur in patients of all ages for a variety of reasons; the most frequently identified reasons in this review were use of salt water as an emetic and child abuse by the intentional administration of a high salt load by a caregiver. For patients whose massive exposure to salt is recent (such as minutes to hours), rapidly reducing the serum sodium concentration may prevent irreversible neurological injury.

Colocalized neurotransmitters in the hindbrain cooperate in adaptation to chronic hypernatremia.

Chronic hypernatremia activates the central osmoregulatory mechanisms and inhibits the function of the hypothalamic-pituitary-adrenal (HPA) axis. Noradrenaline (NE) release into the periventricular anteroventral third ventricle region (AV3V), the supraoptic (SON) and hypothalamic paraventricular nuclei (PVN) from efferents of the caudal ventrolateral (cVLM) and dorsomedial (cDMM) medulla has been shown to be essential for the hypernatremia-evoked responses and for the HPA response to acute restraint. Notably, the medullary NE cell groups highly coexpress prolactin-releasing peptide (PrRP) and nesfatin-1/NUCB2 (nesfatin), therefore, we assumed they contributed to the reactions to chronic hypernatremia. To investigate this, we compared two models: homozygous Brattleboro rats with hereditary diabetes insipidus (DI) and Wistar rats subjected to chronic high salt solution (HS) intake. HS rats had higher plasma osmolality than DI rats. PrRP and nesfatin mRNA levels were higher in both models, in both medullary regions compared to controls. Elevated basal tyrosine hydroxylase (TH) expression and impaired restraint-induced TH, PrRP and nesfatin expression elevations in the cVLM were, however, detected only in HS, but not in DI rats. Simultaneously, only HS rats exhibited classical signs of chronic stress and severely blunted hormonal reactions to acute restraint. Data suggest that HPA axis responsiveness to restraint depends on the type of hypernatremia, and on NE capacity in the cVLM. Additionally, NE and PrRP signalization primarily of medullary origin is increased in the SON, PVN and AV3V in HS rats. This suggests a cooperative action in the adaptation responses and designates the AV3V as a new site for PrRP's action in hypernatremia.

Endothelial Glycocalyx.

The endothelial glycocalyx (EG) is the most luminal layer of the blood vessel, growing on and within the vascular wall. Shedding of the EG plays a central role in many critical illnesses. Degradation of the EG is associated with increased morbidity and mortality. Certain illnesses and iatrogenic interventions can cause degradation of the EG. It is not known whether restitution of the EG promotes the survival of the patient. First trials that focus on the reorganization and/or restitution of the EG seem promising. Nevertheless, the step "from bench to bedside" is still a big one.

Concentration and Volume: Understanding Sodium and Water in the Body.

Nurses need to have a firm grasp of normal and pathophysiological mechanisms of sodium and water balance to fully understand assessment findings and establish a rationale for a patient's plan of care. While multiple mechanisms control sodium and water balance, antidiuretic hormone and aldosterone are the most important hormonal influences. This article, the first in a new series designed to improve nurses' understanding of the physiological abnormalities underlying many disorders, reviews the common etiologies and symptoms of hyponatremia and hypernatremia, as well as the role of nursing care in patients with imbalances of sodium and water. Case studies guide the reader through relevant medical history and examination findings to an understanding of both the nursing and medical plans of care.

Donor hypernatremia and smoking addiction contribute to primary graft failure in heart transplantation.

INTRODUCTION: Primary graft failure (PGF) is an important contributor to early mortality, accounting for 41% of deaths within the first 30 days after heart transplantation (HT). Donor hypernatremia has been associated with PGF development. However, controversial data exist regarding the impact of sodium deregulation in patient survival after HT. This study aimed to assess the influence of donor hypernatremia on PGF development and to determine the serum sodium level threshold to assist in decision-making for organ procurement. METHODS: The medical record from 200 HT patients and organ donors were retrospectively assessed and categorized by PGF occurrence. Donor sodium levels were compared and cut-off points obtained by receiver operating characteristic (ROC) curve. A multiple logistic regression model was applied to assess the effects of factors and covariates that influence PGF development. RESULTS: Sodium levels of donors were significantly higher in recipients who developed PGF than those who did not develop PGF (162 vs. 153 mmol/L, P = .001). The sodium cut-off value determined by the ROC curve was 159 mmol/L. The group who received organs from donors with a serum sodium concentration ≥159 mmol/L had a higher incidence of PGF (63.3% vs 32.4%, P < .001). Furthermore, donor sodium levels ≥159 mmol/L increased the likelihood of recipients developing PGF by 3.4 times. It is also observed that the incidence of donor smoking addiction was significantly higher in the PGF group (28.6% vs. 11.5%, P = .004) and donor smoking addiction increased the risk of developing PGF by 2.8 times. CONCLUSION: Smoking addiction and the application of suboptimal organs from donors with hypernatremia contribute to primary graft failure in heart transplantation.

Hypernatremic Hydrophobic Transient Adipsia Without Organic or Severe Psychiatric Disorder.

CONTEXT: Psychogenic adipsic hypernatremia is an exceedingly rare and life-threatening condition, occurring in those with severe psychiatric disorders. Its diagnosis requires exclusion of congenital or acquired hypothalamic pathologic entities. We present the case of a patient who experienced transient severe hypernatremia without evidence of brain pathologic features or known psychiatric disease. In our patient, the transient adipsic hypernatremia had resulted from an episode of mild depression that resolved spontaneously. CASE DESCRIPTION: A 46-year-old healthy woman who had had three recurrent admissions within 1 month had presented for evaluation of intractable nausea and vomiting with a history of a recent episode of a depressive mood change. Each admission had shown substantial hypernatremia (maximum plasma sodium, 166 mEq/L) accompanied by a strong aversion to consuming water. The findings from the diagnostic evaluation showed elevated serum osmolality and lower than expected urine osmolality (urine osmolality range, 474-501 mOsm/kg). This finding, along with an MRI scan showing the presence of a normal posterior pituitary bright spot, suggested that the osmoregulation of her thirst and arginine vasopressin (AVP) secretion were both defective during the attack. The patient was evaluated by psychiatry. Mild depression was diagnosed, and the patient started treatment with mirtazapine, which she only took for a few days. The patient's hypernatremia had completely recovered with resolution of her depression within 2 months. CONCLUSION: A mild mood disorder can cause transient dysregulation of the thirst mechanism and AVP secretion through not yet identified mechanisms.

Podocyte Injury Augments Intrarenal Angiotensin II Generation and Sodium Retention in a Megalin-Dependent Manner.

We have previously shown that podocyte injury increases the glomerular filtration of liver-derived Agt (angiotensinogen) and the generation of intrarenal Ang II (angiotensin II) and that the filtered Agt is reabsorbed by proximal tubules in a manner dependent on megalin. In the present study, we aimed to study the role of megalin in the generation of renal Ang II and sodium handling during nephrotic syndrome. We generated proximal tubule-specific megalin KO (knockout) mice and crossed these animals with NEP25 mice, in which podocyte-specific injury can be induced by injection of the immunotoxin LMB2. Without podocyte injury, renal Agt staining was markedly diminished and urinary Agt increased in KO mice. However, renal Ang II was similar between KO and control mice on average: 117 (95% CI, 101-134) versus 101 (95% CI, 68-133) fmol/g tissue. We next tested the effect of megalin KO on intrarenal Ang II generation with podocyte injury. Control NEP25 mice showed markedly increased renal Agt staining and renal Ang II levels: 450 (336-565) fmol/g tissue. Megalin KO/NEP25 mice showed markedly diminished Agt reabsorption and attenuated renal Ang II: 199 (156-242) fmol/g tissue (P<0.001). Compared with control NEP25 mice, megalin KO/NEP25 mice excreted 5-fold more sodium in the urine. Western blot analysis showed that megalin KO decreased NHE3 and the cleaved α and γ forms of Epithelial Na Channel. These data indicate that Agt reabsorbed by proximal tubules via megalin in nephrotic syndrome is converted to Ang II, which may contribute to sodium retention and edema formation by activating NHE3 and Epithelial Na Channel.

Neonatal Hypernatremic Dehydration.

Hypernatremic dehydration in exclusively breast-fed neonates is associated with a free water deficit secondary to inadequate fluid intake. It is a common but underrecognized problem in the primary care setting, as the degree of dehydration can be underestimated due to fluid shifts. Neonates of primiparous mothers and those who experience greater weight loss in the first week of life are at higher risk of developing hypernatremic dehydration and most often present for care between 6 and 10 days of life. No consensus treatment guidelines exist, but most experts recommend a goal reduction rate of serum sodium levels of 0.5 mEq/L per hour with correction over 48 hours. Serum sodium level greater than 160 mEq/L is a risk factor for morbidity and mortality. Complications of hypernatremic dehydration, with seizure being most common, usually occur during improper correction. Several small studies have documented varying degrees of neurodevelopmental delay on long-term follow-up of patients admitted for hypernatremic dehydration treatment as a neonate. [Pediatr Ann. 2019;48(5):e197-e200.].

Acute Dysnatremias - a dangerous and overlooked clinical problem.

BACKGROUND: Dysnatremias are common electrolyte disturbances with significant morbidity and mortality. In chronic dysnatremias a slow correction rate (<10 mmol/L/24 h) is indicated to avoid neurological complications. In acute dysnatremias (occurring <48 h) a rapid correction rate may be indicated. Most guidelines do not differ between acute and chronic dysnatremias. In this review, we focus on the evidence-based treatment of acute dysnatremias. METHODS: A literary search in PubMed and Embase. A total of 72 articles containing 79 cases were included, of which 12 cases were excluded due to lack of information. RESULTS: Of 67 patients (70% women) with acute dysnatremia, 60 had hypo- and 7 had hypernatremia. All patients with hyper- and 88% with hyponatremia had a rapid correction rate (> 10 mmol/L/24 h). The median time of correction was 1 day in patients with hypo- and 2.5 days in patients with hypernatremia. The mortality was 7% in patients with hypo- and 29% in patients with hypernatremia. INTERPRETATION: Severe acute dysnatremias have significant mortality and require immediate treatment. A rapid correction rate may be lifesaving and is not associated with neurological complications. Chronic dysnatremias, on the other hand, are often compensated and thus less severe. In these cases a rapid correction rate may lead to severe cerebral complications.

Hypodipsic-hypernatremia syndrome in an adult with polycythemia: a case report.

BACKGROUND: Hypernatremia is a very common electrolyte disorder and is frequently encountered in out-patient as well as in-hospital settings. We describe an adult who was found to have unexplained relative polycythemia and episodic hypernatremia. A diagnosis of idiopathic hypodipsic-hypernatremia syndrome was made and the patient was managed with a water-drinking schedule. CASE PRESENTATION: A 24-year-old South African-Indian man was found to have polycythemia in association with episodes of hypernatremia. Investigations indicated that he had relative polycythemia. He experienced no thirst at a time when his serum sodium concentration was found to be 151 mmol/L. Further testing indicated that his renal response to arginine vasopressin was intact and magnetic resonance imaging of his brain revealed no hypothalamic lesions. A diagnosis of idiopathic hypodipsic-hypernatremia syndrome was made and he was managed with a water-drinking schedule that corrected his hypernatremia. CONCLUSION: Hypodipsia should always be considered when a patient without physical or cognitive disability presents with unexplained episodic hypernatremia or with relative polycythemia.