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We studied laboratory parameters of patients with COVID-19 against the background of chronic pathologies (cardiovascular pathologies, obesity, type 2 diabetes melitus, and cardiovascular pathologies with allergy to statins). A decrease in pH and a shift in the electrolyte balance of blood plasma were revealed in all studied groups and were most pronounced in patients with cardiovascular pathologies with allergy to statin. It was found that low pH promotes destruction of lipid components of the erythrocyte membranes in patients with chronic pathologies, which was seen from a decrease in Na + /K + -ATPase activity and significant hyponatrenemia. In patients with cardiovascular pathologies and allergy to statins, erythrocyte membranes were most sensitive to a decrease in pH, while erythrocyte membranes of obese patients showed the greatest resistance to low pH and oxidative stress., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

In patients visiting the emergency department (ED), a potential association between electrolytes disturbance and coronavirus disease 2019 (COVID-19) has not been well studied. We aim to describe electrolyte disturbance and explore risk factors for COVID-19 infection in patients visiting the ED. We carried out a case-control study in three hospitals in France, including adult ED inpatients (≥ 18 years old). A total of 594 ED case patients in whom infection with COVID-19 was confirmed, were matched to 594 non-COVID-19 ED patients (controls) from the same period, according to sex and age. Hyponatremia was defined by a sodium of less than 135 mmol/L (reference range 135-145 mmol/L), hypokalemia by a potassium of less than 3.5 mmol/L (reference range 3.5-5.0 mmol/L), and hypochloremia by a chloride of less than 95 mmol/L (reference range 98-108 mmol/L). Among both case patients and controls, the median (IQR) age was 65 years (IQR 51-76), and 44% were women. Hyponatremia was more common among case patients than among controls, as was hypokalemia and hypochloremia. Based on the results of the multivariate logistic regression, hyponatremia, and hypokalemia were associated with COVID-19 among case patients overall, with an adjusted odds ratio of 1.89 [95% CI 1.24-2.89] for hyponatremia and 1.76 [95% CI 1.20-2.60] for hypokalemia. Hyponatremia and hypokalemia are independently associated with COVID-19 infection in adults visiting the ED, and could act as surrogate biomarkers for the emergency physician in suspected COVID-19 patients., (© 2021. Società Italiana di Medicina Interna (SIMI).)

Old age is a strong independent risk factor for hyponatremia. Dizziness, fatigue, reduced vigilance, cognitive impairment, gait deficits, nausea, vomiting, headache, falls, osteoporosis and fractures, coma and seizures are more frequent and severe than in middle-aged patients. Hyponatremia is mainly caused by the syndrome of inappropriate antidiuretic hormone (SIADH) secretion and also including drugs. Hyponatremia is multifactorial in a significant proportion of older patients. Hyponatremia requires a staged diagnostic approach to identify the underlying cause. The aim of this continuing medical education (CME) report (part I) is to emphasize the special challenges in the diagnostics of hyponatremia, which occur in older patients. Diagnostics should be kept simple. A special algorithm is presented. Part II concerning treatment will follow.

Vasopressin (arginine vasopressin, AVP) plays a crucial role in maintaining body fluid homeostasis. Excessive release of vasopressin can lead to hyponatremia. Changes in cerebral circulation during vasopressin-induced chronic hyponatremia are not elucidated. The present study has been designed to investigate the effect of chronic vasopressin-induced hyponatremia on the regulation of the tone of the middle cerebral artery (MCA) of the rat. Chronic hyponatremia was induced in vivo with the help of vasopressin, released continuously from subcutaneously implanted ALZET mini-osmotic pumps, and a liquid diet. After 3.5 days of chronic hyponatremia, the plasma Na + concentration decreased to 119 ± 3 mM. MCAs were isolated and placed in a MOPS-buffered saline solution containing 121 mM Na + . Chronic hyponatremia did not affect the response of the MCA to increased intravascular pressure, to the administration of acetylcholine (ACh) and nitric oxide (NO) donor (SNAP, S-nitroso-N-acetyl-DL-penicillamine), and to increased K + concentration, but impaired the response of the MCA to increased extravascular H + concentration. Disturbed response of the MCA to acidosis was associated neither with the impairment of K ATP channels nor with the activation of vasopressin V 1 receptor. Correction of hyponatremia did not restore the response of the MCA to acidosis. These results indicate that cerebral blood vessels do not fully adapt to prolonged vasopressin-induced hyponatremia.

Purpose: Tolvaptan (TLV) is indicated to treat hyponatremia due to syndrome of inappropriate diuretic hormone (SIADH) in Europe. Treatment is to be initiated at 15 mg QD but post-approval reporting indicates increasing use of 7.5 mg as the starting dose. Physicians believe 7.5 mg is effective and has a lower incidence of overly rapid correction of serum sodium., Methods: Single TLV doses of 3.75, 7.5, and 15 mg were administered to 14 healthy adults in a crossover design and to 29 subjects ≥18 years with SIADH and serum sodium between 120 and 133 mmol/L in a parallel-group design. Pharmacodynamics and TLV plasma concentrations were assessed for 24 h post-dose., Results: In SIADH subjects, corrections of serum sodium (Δ of ≥8 mmol/L in the first 8 h or ≥12 mmol/L in the first 24 h) were observed in one, one, and two subjects in the 3.75-, 7.5-, and 15-mg dose groups. Fluid balance (FB) for 0-6 h post-dose was correlated (r 2  = 0.37) with maximum increases in serum sodium; subjects with large corrections had large (~1 L) negative FB. Compared to healthy adults, subjects with SIADH did not drink in response to their negative FB and had larger increases in serum sodium at 24 h. Median time of maximum increase in healthy adults was 6 h, with no rapid corrections, and FB was near 0 mL by 24 h., Conclusion: Starting titration with 7.5 mg TLV will not eliminate the risk of rapid corrections in serum sodium. Monitoring FB may indicate that a subject is at risk for over correction.

The population of elderly individuals is increasing worldwide. With aging, various hormonal and kidney changes occur, both affecting water homeostasis. Aging is a risk factor for chronic kidney disease (CKD) and many features of CKD are reproduced in the aging kidney. Dehydration and hyperosmolarity can be triggered by diminished thirst perception in this population. Elderly with dementia are especially susceptible to abnormalities of their electrolyte and body water homeostasis and should be (re-)assessed for polypharmacy. Hypo- and hypernatremia can be life threatening and should be diagnosed and treated promptly, following current practice guidelines. In severe cases of acute symptomatic hyponatremia, a rapid bolus of 100 to 150 ml of intravenous 3% hypertonic saline is appropriate to avert catastrophic outcomes; for asymptomatic hyponatremia, a very gradual correction is preferred. In summary, the body sodium (Na+) balance is regulated by a complex interplay of environmental and individual factors. In this review, we attempt to provide an overview on this topic, including dehydration, hyponatremia, hypernatremia, age-related kidney changes, water and sodium balance, and age-related changes in the vasopressin and renin-angiotensin-aldosterone system.

Hip fractures represent a serious health risk in the elderly, causing substantial morbidity and mortality. There is now a considerable volume of literature suggesting that chronic hyponatremia increases the adjusted odds ratio (OR) for both falls and fractures in the elderly. Hyponatremia appears to contribute to falls and fractures by two mechanisms. First, it produces mild cognitive impairment, resulting in unsteady gait and falls; this is probably due to the loss of glutamate (a neurotransmitter involved in gait function) as an osmolyte during brain adaptation to chronic hyponatremia. Second, hyponatremia directly contributes to osteoporosis and increased bone fragility by inducing increased bone resorption to mobilize sodium stores in bone. Low extracellular sodium directly stimulates osteoclastogenesis and bone resorptive activity through decreased cellular uptake of ascorbic acid and the induction of oxidative stress; these effects occur in a sodium level-dependent manner. Hyponatremic patients have elevated circulating arginine-vasopressin (AVP) levels, and AVP acting on two receptors expressed in osteoblasts and osteoclasts, Avpr1α and Avpr2, can increase bone resorption and decrease osteoblastogenesis. Should we be screening for low serum sodium in patients with osteoporosis or assessing bone mineral density (BMD) in patients with hyponatremia? The answers to these questions have not been established. Definitive answers will require randomized controlled studies that allocate elderly individuals with mild hyponatremia to receive either active treatment or no treatment for hyponatremia, to determine whether correction of hyponatremia prevents gait disturbances and changes in BMD, thereby reducing the risk of fractures. Until such studies are conducted, physicians caring for elderly patients must be aware of the association between hyponatremia and bone disorders. As serum sodium is a readily available, simple, and affordable biochemical measurement, clinicians should look for hyponatremia in elderly patients, especially in those receiving medications that can cause hyponatremia. Furthermore, elderly patients with an unsteady gait and/or confusion should be evaluated for the presence of mild hyponatremia, and if present, treatment should be initiated. Finally, elderly patients presenting with an orthopedic injury should have serum sodium checked and hyponatremia corrected, if present.

Background: Hyponatremia is associated with negative clinical outcomes even when chronic and mild. It is also known that hyponatremia treatment should be appropriately performed, to avoid dramatic consequences possibly leading to death. We have previously demonstrated that chronically low extracellular [Na(+)], independently of reduced osmolality, is associated with signs of neuronal cell distress, possibly involving oxidative stress., Aim: The aim of the present study was to assess whether the return to normal extracellular [Na(+)] is able to revert neuronal cell damage., Methods: After exposing SH-SY5Y and SK-N-AS cells to low [Na(+)] and returning to normal [Na(+)], we analyzed cell viability by MTS assay, ROS accumulation by FASCan and expression of anti-apoptotic genes., Results: We found that the viability of cells was restored upon return to normal [Na(+)]. However, when more subtle signs of cell distress were assessed, such as the expression level of the anti-apoptotic genes Bcl-2 and DHCR24 or of the heme oxygenase 1 gene, a complete return to basal values was not observed, in particular in SK-N-AS, even when [Na(+)] was gradually increased. We also demonstrated that the amount of ROS significantly increased in low [Na(+)], thus confirming that oxidative stress appears to contribute to the effects of low [Na(+)] on cell homeostasis., Conclusions: Overall, this study provided the first demonstration that the correction of chronically low extracellular [Na(+)] may not be able to revert all the cell alterations associated with reduced [Na(+)]. These results suggest that prompt hyponatremia treatment might prevent possible residual abnormalities.

Background: Osmotic demyelination syndrome (ODS) is a complication generally associated with overly rapid correction of hyponatremia. Traditionally, nephrologists have been trained to focus solely on limiting the correction rate. However, there is accumulating evidence to suggest that the prevention of ODS is beyond achieving slow correction rates., Methods: We (1) reviewed the literature for glial intracellular protective alterations during hyperosmolar stress, a state presumed equivalent to the rapid correction of hyponatremia, and (2) analyzed all available hyponatremia-associated ODS cases from PubMed for possible contributing factors including correction rates and concurrent metabolic disturbances involving hypokalemia, hypophosphatemia, hypomagnesemia, and/or hypoglycemia., Results: In response to acute hyperosmolar stress, glial cells undergo immediate extracellular free water shift, followed by active intracellular Na(+), K(+) and amino acid uptake, and eventual idiogenic osmoles synthesis. At minimum, protective mechanisms require K(+), Mg(2+), phosphate, amino acids, and glucose. There were 158 cases of hyponatremia-associated ODS where both correction rates and other metabolic factors were documented. Compared with the rapid correction group (>0.5 mmol/L/h), the slow correction group (≤0.5 mmol/L/h) had a greater number of cases with concurrent hypokalemia (49.4 vs. 33.3 %, p = 0.04), and a greater number of cases with any concurrent metabolic derangements (55.8 vs. 38.3 %, p = 0.03)., Conclusion: Glial cell minimizes volume changes and injury in response to hyperosmolar stress via mobilization and/or utilization of various electrolytes and metabolic factors. The prevention of ODS likely requires both minimization of correction rate and optimization of intracellular response during the correction phase when a sufficient supply of various factors is necessary.

Sodium is a necessary dietary macromineral that tended to be sparsely distributed in mankind's environment in the past. Evolutionary selection pressure shaped physiological mechanisms including hormonal systems and neural circuits that serve to promote sodium ingestion. Sodium deficiency triggers the activation of these hormonal systems and neural circuits to engage motivational processes that elicit a craving for salty substances and a state of reward when salty foods are consumed. Sodium deficiency also appears to be associated with aversive psychological states including anhedonia, impaired cognition, and fatigue. Under certain circumstances the psychological processes that promote salt intake can become powerful enough to cause "salt gluttony," or salt intake far in excess of physiological need. The present review discusses three aspects of the biopsychology of salt hunger and sodium deficiency: (1) the psychological processes that promote salt intake during sodium deficiency, (2) the effects of sodium deficiency on mood and cognition, and (3) the sensitization of sodium appetite as a possible cause of salt gluttony.

Sodium disturbances are frequent and serious complications in neurocritically ill patients. Hyponatremia is more common than hypernatremia, which is, however, prognostically worse. The aim of this study was to analyse outcome and frequency of sodium disturbances in relation to measured serum osmolality in neurologic-neurosurgical critically ill patients. A 5-year retrospective collection of patients (pts) and laboratory data were made from the Laboratory Information System database in the Clinical Biochemistry Department. The criteria for patients' inclusion was acute brain disease and serum sodium (SNa(+)) <135 mmol/l (hyponatremia) or SNa(+) >150 mmol/l (hypernatremia). Hypoosmolality was defined as measured serum osmolality (SOsm) <275 mmol/kg, hyperosmolality as SOsm >295 mmol/kg. We performed analysis of differences between hyponatremia and hypernatremia and subanalysis of differences between hypoosmolal hyponatremia and hypernatremia. From 1,440 pts with acute brain diseases there were 251 (17 %) pts with hyponatremia (mean SNa(+) 131.78 ± 2.89 mmol/l, SOsm 279.46 ± 11.84 mmol/kg) and 75 (5 %) pts with hypernatremia (mean SNa(+) 154.38 ± 3.76 mmol/l, SOsm 326.07 ± 15.93 mmol/kg). Hypoosmolal hyponatremia occurred in 50 (20 % of hyponatremic patients) pts (mean SNa(+) 129.62 ± 4.15 mmol/l; mean SOsm 267.35 ± 6.28 mmol/kg). Multiple logistic regression analysis showed that hypernatremia is a significant predictor of mortality during neurologic-neurosurgical intensive care unit (NNICU) stay (OR 5.3, p = 0.002) but not a predictor of bad outcome upon discharge from NNICU, defined as Glasgow Coma Scale 1-3. These results showed that hypernatremia occurred less frequently than all hyponatremias, but more often than hypoosmolal hyponatremia. Hypernatremia was shown to be a significant predictor of NNICU mortality compared to hyponatremia.

Objective: The present study was undertaken to reveal the influence of intracerebroventricular (ICV) benzamil on the dynamics of brain water accumulation in hyponatremic rats. Parameters of brain water homeostasis were continuously monitored, using in vivo magnetic resonance imaging (MRI) methods. The results were compared with those obtained in a previous study by tissue desiccation., Methods: A 3-T MRI instrument was applied to perform serial diffusion-weighted imaging to measure the apparent diffusion coefficient (ADC) and MR spectroscopy to determine water signal. A decrease of ADC is thought to represent an increase of intracellular water, whereas water signal is used to quantify brain water content. Five groups of male Wistar rats were studied as follows: normonatremic, native animals (group NN, n = 7), hyponatremic animals (group HN, n = 8), hyponatremic animals treated with ICV benzamil (group HNB, n = 8), hyponatremic animals treated with ICV saline (group HNS, n = 5) and normonatremic animals treated with ICV benzamil (group NNB, n = 5). Hyponatremia was induced by intraperitoneal administration of 140 mmol/l dextrose solution in a dose of 20% of body weight. Benzamil hydrochloride (4 μg) was injected ICV to the treated animals., Results: During the course of hyponatemia, ADC declined steadily from the baseline (100%) to reach a minimum of 92.32 ± 3.20% at 90 min (p < 0.0005). This process was associated with an increase in water signal to a maximum of 5.95 ± 2.62% at 100 min (p < 0.0005). After pretreatment with benzamil, no consistent changes occurred either in ADC or in water signal., Conclusions: These findings suggest that sodium channel blockade with ICV benzamil has an immediate protective effect against the development of hyponatremic brain edema. Sodium channels, therefore, appear to be intimately involved in the initiation and progression of brain water accumulation in severe hyponatremia.

Hyponatremic encephalopathy is a potentially lethal condition with numerous reports of death or permanent neurological injury. The optimal treatment for hyponatremic encephalopathy remains controversial. We have introduced a unified approach to the treatment of hyponatremic encephalopathy which uses 3% NaCl (513 mEq/L) bolus therapy. Any patient with suspected hyponatremic encephalopathy should receive a 2 cc/kg bolus of 3% NaCl with a maximum of 100 cc, which could be repeated 1-2 times if symptoms persist. The approach results in a controlled and immediate rise in serum sodium with little risk of inadvertent overcorrection.

Hyperammonemia (HA) is a major and commonly observed feature of hepatic encephalopathy. Furthermore, hyponatremia is an important pathogenetic factor in patients with hepatic encephalopathy. Both conditions have some features in common, such as the release of organic osmolytes, which might be an adaptive mechanism against cell swelling. However, the consequence of a possible relationship between osmoregulatory response in hyperammonemia and hyponatremia is not completely understood. This review gives a short introduction into the pathogenesis of hepatic encephalopathy and hyponatremia. For a comparison of both pathological events, some basics on cellular osmo- and volume regulation are explained, in particular as the mechanisms involved in the adaption of the cell to volume changes can be different under both pathological conditions. The role of brain glutamine and organic osmolytes in hyponatremia and hyperammonemia and their combination are discussed based on findings in experimental animal models, and finally on data obtained from primary astrocytes in culture. The observations that the decrease of brain organic osmolytes in astrocytes not adequately compensate for an increased intracellular osmolarity caused by glutamine are consistent with results obtained after chronic hyponatremia in rats, in which the release of osmolytes does not protect from ammonia-induced brain edema. Furthermore, a decrease in intracellular osmolarity is attributed both to the release and a reduced de novo synthesis of amino acids.

Background: It has been recently shown that A6 cells exposed to hyponatraemic stress respond with increased sodium uptake via activation of benzamil-sensitive sodium channels. This study was performed, therefore, to explore the possible involvement of benzamil-sensitive sodium channels and cellular sodium influx in brain oedema formation in hyponatraemic rats., Methods: Four groups of male Wistar rats were studied (n = 13 in each group). Animals in group I with normonatraemia received intracerebroventricular (icv) 0.9% NaCl; animals in group II-IV were made hyponatraemic by intraperitoneal administration of isotonic glucose solution in a dose of 20% per body weight. Rats were pretreated with icv 0.9% NaCl (group II), 120 microg arginine vasopressin (AVP) (group III) or 4 microg benzamil-hydrochloride (group IV). Plasma sodium (ion-selective electrode) plasma osmolality (vapour pressure osmometer) and brain sodium and potassium content (flame photometer) as well as brain water content (desiccation method) were measured after a 2-h hydration period., Results: Plasma sodium, osmolality and tissue sodium and potassium contents were markedly depressed in hyponatraemic rats (group II-IV, p < 0.0005 for each group) irrespective of drug pretreatment. Brain water content, however, responded to hyponatraemia with an increase from 77.55 +/- 1.00% to 78.45 +/- 0.94% (p < 0.01), and it was further augmented to 79.35 +/- 0.80% (p < 0.0005) by icv AVP pretreatment. By contrast, benzamil administration prevented the rise of brain water caused by hyponatraemia (77.61 +/- 1.04%)., Conclusion: Early in the course of hyponatraemia, brain sodium channels may be activated, and the subsequent cellular sodium uptake may generate osmotic gradient to allow passive water flow into the cells. The simultaneous reduction of osmotic water conductivity of brain-specific aquaporin-4 by hyponatraemia, however, may limit water accumulation.

Background: We developed a new method that diagnoses when either Na or water alone are altered during electrolyte abnormalities. The aim of this study is to describe the preliminary report of an original method which can give exact or useful calculations even in mixed disorders., Methods: when NaCl is lost, the plasma Cl (PCl) to plasma Na (PNa) ratio falls from 0.75 (the normal value) toward zero, the ratio of plasma anions other than Cl (POAN) to PNa rises toward unity and POAN/PPCl toward infinity. With subscript 0 or normal values and subscript 1 for those during derangement, PCl1/PCl0 falls below unity, while POAN 1 /POAN 0 rises above unity in these hyponatremic disorders. Based on these changes, we developed exact mathematical formulas to compute alterations in solvent and solutes. The boundary conditions of applicability were computer modeled., Results: regression coefficients between true data fed oo the computer and those calculated with our formulas were 1.00 when the boundary conditions were entirely met (R2=1.00, <0.0001) and 0.93-0.96 (R2>0.94<0.99, <0.001) when the boundary conditions were allowed to extend beyond their limits of exclusive mathematical validity. The method was extended to patients whose data satisfied the boundary conditions. The results show that the computations satisfactorily predict the exact measurements obtained by the change in body weight (R2=0.61, <0.001)., Conclusions: This new method represents useful adjunct in evaluating and treating hyponatremias. Although its validity is limited to rather strict boundary conditions, it represents an original way to evaluate mixed solvent/solute derangements.

It is well known that changes in the mass balance of K+ can lead to an alteration in the plasma water sodium concentration ([Na+]pw). We have recently shown that based on the Edelman equation, the [Na+]pw is determined by the total exchangeable Na+ (Nae), total exchangeable K+ (Ke), total body water (TBW), osmotically inactive Nae and Ke, plasma water [K+], intracellular and extracellular osmotically active non-Na+ and non-K+ osmoles, and plasma osmotically active non-Na+ and non-K+ osmoles. In light of these findings, a re-analysis of the role of K+ in modulating the [Na+]pw is required in understanding the pathophysiology of hypokalemia-induced hyponatremia. In this article, we characterize the complex role of K+ in the pathogenesis of hypokalemia-induced hyponatremia using a three-compartment model and the known parameters in the Edelman equation. Our analysis indicates that K+ modulates the [Na+]pw by changing Ke in addition to the parameters in the y-intercept of the Edelman equation. Moreover, the magnitude of potassium-induced changes in the [Na+]pw is determined by the pathophysiologic mechanisms by which changes in Ke occur.

A prospective observational study of the pathophysiology of sodium and water disorders in patients with pituitary region tumours after surgical excision was carried out in 20 patients. Serial pre-operative and post-operative fluid and sodium balance, plasma and urine elctrolyte biochemistry and their derived parameters, and circulating hormones associated with fluid balance, atrial natriureic peptide (ANP) and antidiuretic hormone (ADH) were documented to correlate with the patients' clinical conditions. Ten out of these twenty cases developed diabetes insipidus (DI) requiring ADH replacement therapy, although in the majority (6 cases), this way only a transient event. Of the nine patients who developed hyponatraemia, six had symptoms such as impaired consciousness and convulsions. Four patients developed alternating hypoatraemia and hypernatraemia, which constituted a difficult group, where appropriate sodium and fluid management, and ADH replacement therapy were based upon twice daily plasma and urine biochemistry and their derived parameters. Whilst DI in this group of patients was the result of a low circulating ADH level, hyponatraemia was not associated with an exaggerated ADH activity (6.0 +/- 2.3 vs 7.4 +/- 2.3 pmol/ml, mean +/- SEM). Rather, hyponatraemia was strongly associated with an elevated circulating ANP concentration (82.4 +/- 10.5 vs 30.0 +/- 3.1 pmol/ml, mean +/- SEM, p < 0.001), resulting in salt wasting and hypovolaemia.

Brain cortical water spaces were determined in rat brain following an intraperitoneal infusion of distilled water (15% of body weight). Total water content was determined by gravimetric methods while the size of the interstitial space and the interstitial ion concentrations were measured by ion-selective microelectrodes. Ion content of brain gray matter and plasma were determined by standard methods. During 2 h the plasma osmolarity changed from 301 to 251 mosmol/l while cortical water content increased from 4.04 ml/g dry weight (gdw) to 4.42 ml/gdw. It was observed that the size of the interstitial space remained stable during the two hours of osmotic challenge. Although the brain showed a volume regulatory response by an outward transport of ions, it was not sufficient since there was an increase of brain volume of 10%. The accumulated water was distributed in the interstitial and intracellular compartments according to their individual sizes. It is concluded that cells in brain gray matter are not able to regulate their volume in cytotoxic brain oedema.