Hyponatremia: Evolving diagnostics and emerging therapeutics in clinical practice

Abstract

Hyponatremia remains the most common electrolyte disorder in clinical practice, with a wide range of causes ranging from endocrine dysregulation to iatrogenic causes. Recent developments in point-of-care ultrasonography, vasopressin physiology, and osmoregulation have transformed diagnostics by emphasizing accuracy above purely clinical judgment. Although traditional management based on fluid restriction and hypertonic solutions remain the cornerstone of treatment, a careful and cautious monitoring is required to avoid osmotic demyelination and overcorrection. The Furst equation, a validated predictor of response to fluid restriction, should be integrated into routine practice, together with objective tools such as point-of-care ultrasonography, to improve the accuracy of volume assessment and guide more precise therapeutic decisions. Likewise, different therapeutic options have been studied for non-responders to fluid restriction, including urea, desmopressin, and selective vasopressin receptor antagonists (vaptans), showing promising results. Ongoing developments in artificial intelligence and laboratory-based decision support tools are expected to improve personalized management and predictive accuracy, potentially reconciling the disparity between evidence and clinical practice.

Key Words: Hyponatremia; Fluid restriction; Furst equation; Point-of-care ultrasound; Hypertonic saline; Urea; Tolvaptan

Core Tip: Hyponatremia, defined as a low concentration of sodium in the blood, is the most frequent electrolyte disorder in clinical practice. Its causes are diverse and often overlap, from hormonal imbalances to medication effects or underlying heart, liver, and kidney conditions. Effective and safe correction depends on accurately identifying whether the body has too much or too little water, rather than simply restricting fluids. Bedside ultrasound (point-of-care ultrasonography) and simple laboratory tools such as the Furst equation allow clinicians to assess fluid status objectively, predict response to fluid restriction, and guide personalized treatment strategies that reduce complications and improve patient outcomes.

INTRODUCTION

Hyponatremia, classically defined as a serum sodium concentration below 135 mmol/L, represents the most frequent disturbance of fluid and electrolyte balance encountered in clinical practice[1,2]. Rather than a discrete disease entity, it reflects an underlying pathophysiologic alteration in water homeostasis[2]. Dysnatremias in general are among the most common electrolyte disorders presenting in emergency care, with hyponatremia consistently identified as the leading abnormality in the United States[1,3]. Although data is scarce, approximately 3 million to 6 million patients each year are evaluated for hyponatremia, and sodium derangements are present in 12%-20% of individuals admitted through the emergency department[2,4].

The clinical significance of sodium imbalance lies in its role as the predominant extracellular cation and the principal determinant of plasma osmolality[5]. Disruptions in sodium concentration, therefore, have immediate implications for osmotic equilibrium and ion distribution, with potential consequences for organ function, most notably within the central nervous system[2,5].

Given its high prevalence, diagnostic complexity, and potential for severe clinical consequences, hyponatremia remains a condition of significant concern across multiple disciplines[1]. Recent years have witnessed advances in diagnostic tools and the development of novel therapeutic strategies, yet the optimal management of this disorder continues to be debated. This narrative review aims to explore evolving diagnostic approaches and highlight emerging therapeutic interventions, emphasizing their potential implications in everyday clinical practice.

PATHOPHYSIOLOGY OF HYPONATREMIA

In healthy individuals, water balance is tightly regulated, such that plasma osmolality varies by no more than 1%-2% under normal conditions, provided there is unrestricted access to water[5,6]. The preservation of extracellular fluid (ECF) tonicity is crucial for human physiology and is achieved through a complex process of osmoregulation that integrates thirst, fluid intake, and the secretion and action of arginine vasopressin (AVP)[5,7]. In hyponatremia, alterations in these regulatory mechanisms disrupt water and sodium homeostasis, resulting in clinically significant imbalances (Figure 1).

Figure 1 Mechanisms of sodium and water homeostasis. Schematic representation of the physiological regulation of sodium and water balance under conditions of water loss, sodium loss, or water excess. Osmoreceptor activation in the hypothalamus and subsequent vasopressin (antidiuretic hormone) release from the posterior pituitary increase renal water reabsorption via V2 receptors and aquaporin-2 channel insertion, restoring extracellular fluid osmolality and osmotic equilibrium. SIADH: Syndrome of inappropriate antidiuretic hormone; ECF: Extracellular fluid; ADH: Antidiuretic hormone.

Under normal circumstances, plasma osmolality is maintained within a narrow range of 275-295 mmol/kg[2,8]. Variations in water balance independent of solute concentration directly influence osmolality. For instance, water loss from the ECF increases osmolality, driving water movement from the intracellular compartment to the extracellular space[5,9]. Even slight elevations in osmolality activate hypothalamic osmoreceptors, stimulating the thirst center and leading to increased water intake[10,11]. Simultaneously, hypothalamic osmoreceptor activation triggers the release of AVP from the posterior pituitary, thereby enhancing renal water reabsorption[11].

Plasma osmolality is sensed by specialized osmoreceptor neurons in the anterior hypothalamus[11-13]. Fenestrations in the blood-brain barrier allow the circumventricular organs, particularly the subfornical organ and the organum vasculosum lamina terminalis, to be directly exposed to plasma[14,15]. These structures project to hypothalamic nuclei such as the supraoptic nucleus and paraventricular nucleus. An increase in osmolality depolarizes these neurons, leading to the synthesis and secretion of AVP, along with its stable surrogate peptide, copeptin[5,16,17].

Role of AVP

AVP is a hypothalamic peptide with both antidiuretic and vasopressor properties[5,15]. It mediates its effects through three receptor subtypes, all of which are members of the G protein-coupled receptor family. The V1 receptor, expressed in vascular smooth muscle, activates the Gq/11-phospholipase C pathway, increasing intracellular calcium and producing vasoconstriction, which at higher AVP concentrations translates into a strong vasopressor response[18].

The V2 receptor, localized primarily in the distal nephron and collecting ducts, regulates aquaporin-2 trafficking and thus plays a central role in water reabsorption and urine concentration[5,19]. Once AVP is released into the circulation, it exerts its principal action on the kidney, where binding to V2 receptors on the basolateral membrane of collecting duct cells promotes the insertion of aquaporin-2 water channels into the apical membrane[18]. This increases tubular water permeability, allowing water reabsorption and urine concentration up to approximately 1200 mmol/kg. The osmoregulatory system is highly sensitive, as AVP secretion can change in response to variations in plasma osmolality as small as 1%[12,18].

Finally, the V3 (or V1b) receptor, expressed in anterior pituitary corticotrophs, potentiates adrenocorticotropic hormone release in synergy with corticotropin-releasing hormone, an effect tightly controlled by glucocorticoid feedback[17,18]. Together, these mechanisms maintain plasma osmolality within narrow physiological limits. In hyponatremia, disruption of this finely tuned system, whether due to inappropriate AVP secretion, impaired water excretion, or excessive intake, underpins the pathophysiological basis of the disorder[2,5].

Moreover, understanding AVP’s role has direct therapeutic implications. The development of V2 receptor antagonists, such as tolvaptan and conivaptan, represents a targeted approach to correct water retention and hyponatremia, emphasizing the translation of physiological knowledge into clinical practice[1]. In essence, hyponatremia reflects an excess of water relative to sodium rather than actual sodium depletion. This imbalance results from non-osmotic AVP secretion, impaired renal free-water excretion, or excessive intake, all of which lead to hypotonic plasma. The pathophysiological hallmark is cellular swelling, with the brain being particularly vulnerable, making cerebral edema the critical clinical consequence of hyponatremia.

CLASSIFICATION AND CLINICAL FEATURES

The classification of hyponatremia relies on three main aspects: Volume status, time course, and symptom severity, which collectively guide both diagnosis and treatment decisions[1,2,20]. Volume status remains the cornerstone of etiological classification[2]. In hypovolemic hyponatremia, sodium and water are lost simultaneously, but sodium losses predominate, leading to ECF contraction[5]. Typical extrarenal causes include gastrointestinal fluid losses such as vomiting, diarrhea, or high-output fistulas, as well as excessive sweating or third-spacing in pancreatitis or peritonitis[2,21]. Renal causes include the use of thiazide diuretics, cerebral salt wasting (CSW), mineralocorticoid deficiency, and some forms of tubulointerstitial disease[5]. Clinically, patients often present with orthostatic hypotension, tachycardia, decreased skin turgor, and signs of hypoperfusion[1-4]. A useful diagnostic distinction relies on urinary sodium: Low values suggest extrarenal sodium loss, whereas elevated values indicate renal causes[2,20].

Euvolemic hyponatremia is most frequently due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH; also called syndrome of inappropriate antidiuresis), particularly in hospitalized patients. SIADH can result from pulmonary disorders, central nervous system diseases, malignancies (e.g., small-cell lung carcinoma), or the use of drugs such as selective serotonin reuptake inhibitors, carbamazepine, cyclophosphamide, or vincristine (Table 1)[22,23]. Endocrine disorders such as adrenal insufficiency and hypothyroidism must be excluded, and primary polydipsia remains an additional though less common cause. Importantly, patients with euvolemic hyponatremia usually lack clinical signs of either hypo- or hypervolemia, making laboratory assessment essential[2,5].

Table 1 Medications associated with syndrome of inappropriate antidiuretic hormone or hyponatremia.

Drug class	Examples	Proposed mechanism	Clinical notes
Antidepressants	SSRIs (sertraline, fluoxetine, paroxetine), SNRIs (venlafaxine, duloxetine), tricyclics (amitriptyline), mirtazapine	Enhanced ADH release or potentiation of its renal effect	Most frequent cause in older adults, especially underweight women
Antipsychotics	Haloperidol, risperidone, olanzapine, quetiapine	Dopaminergic and serotonergic modulation of ADH	Risk increases with concomitant antidepressants
Antiepileptics/mood stabilizers	Carbamazepine, oxcarbazepine, valproate, lamotrigine	Increased ADH release and sensitivity at renal V2 receptor	Carbamazepine is a classic cause of chronic SIADH
Chemotherapeutic/oncologic agents	Cyclophosphamide, vincristine, cisplatin, ifosfamide	Direct stimulation of ADH release or renal tubular toxicity	Often transient; risk rises with concomitant nausea or stress
Analgesics	Opioids (morphine, tramadol), NSAIDs	Opioids increase ADH release; NSAIDs potentiate its action by reducing prostaglandin inhibition	Particularly relevant postoperatively
Diuretics	Thiazides (hydrochlorothiazide, indapamide)	Impaired urinary dilution, sodium loss	Responsible for up to 90% of diuretic-induced hyponatremia
Antineoplastic/immunomodulators	Interferon-α, cyclophosphamide, vincristine	Hypothalamic or renal effect on ADH	Usually dose-dependent
Other agents	Desmopressin, chlorpropamide, ecstasy (MDMA)	Direct V2 receptor agonism or ADH secretion	Seen in recreational drug users and hospitalized patients receiving DDAVP

SSRI: Selective serotonin reuptake inhibitor; SNRI: Serotonin-norepinephrine reuptake inhibitor; ADH: Antidiuretic hormone; SIADH: Syndrome of inappropriate antidiuretic hormone secretion; NSAID: Non-steroidal anti-inflammatory drug; MDMA: 3,4-methylenedioxymethamphetamine; DDAVP: 1-deamino-8-D-arginine vasopressin.

In hypervolemic hyponatremia, there is an increase in both sodium and water content, but with disproportionately greater water retention[1,2]. Although it can occur spontaneously in advanced disease states, it is often exacerbated by iatrogenic factors such as hypotonic fluid administration or aggressive diuretic therapy[2,24]. This imbalance is typically observed in disorders associated with reduced effective arterial blood volume, despite an absolute excess of ECF. Such conditions include advanced heart failure, cirrhosis, and nephrotic syndrome, where decreased perfusion stimulates non-osmotic AVP release, sympathetic activation, and renin-angiotensin-aldosterone system activity. The resulting impaired water excretion aggravates hypotonicity. Clinically, these patients exhibit edema, ascites, and signs of fluid overload[2,20].

The time course of hyponatremia is critical for prognosis and management[2,25]. Acute hyponatremia, defined as a fall in serum sodium within less than 48 hours, carries the highest risk of cerebral edema, seizures, and death due to the lack of sufficient time for osmotic adaptation within neurons[2,4,26]. Chronic hyponatremia (≥ 48 hours or of uncertain duration) tends to present with fewer or subtler symptoms because neurons gradually extrude osmolytes to restore osmotic equilibrium[2,5]. However, this adaptive process renders patients highly vulnerable to osmotic demyelination syndrome (ODS) if serum sodium is corrected too rapidly[1,2,5]. Clinically, the distinction between acute and chronic is often uncertain, and in practice, when the onset is unknown, hyponatremia is assumed to be chronic to minimize treatment-related complications[20,27].

The clinical presentation depends not only on the absolute serum sodium level but also on the rate of decline. Mild-to-moderate hyponatremia often causes nonspecific symptoms such as headache, fatigue, nausea, irritability, dizziness, cognitive impairment, and gait disturbances[1-4,20]. These manifestations may be mistakenly attributed to comorbid conditions, which delays recognition of the electrolyte disorder. Severe or rapidly progressive hyponatremia can precipitate seizures, respiratory depression, coma, or death if untreated[1,2]. Notably, growing evidence highlights that even mild chronic hyponatremia is not benign: Studies have demonstrated associations with increased risk of falls, bone fractures, gait unsteadiness, and impaired attention or memory[28-31].

DIAGNOSTIC STRATEGIES

Advances in diagnostic tools: Urine osmolality, sodium, and emerging biomarkers

Initial assessment of volume and tonicity status in patients with hyponatremia requires a combination of clinical and laboratory data. Traditionally, urinary osmolality and urinary sodium have been used as key diagnostic tools. In the presence of hypotonic hyponatremia, low urinary osmolality (< 100 mOsm/kg) suggests an excess of free water (as in primary polydipsia), while high values (> 100 mOsm/kg) indicate an appropriate renal response to antidiuretic hormone or its inappropriate secretion, as in SIADH or occult hypovolemia[2,32].

Urinary sodium, on the other hand, has been widely used to discriminate hypovolemic causes (usually < 30 mEq/L) from non-hypovolemic causes (usually > 30 mEq/L)[2,20]. However, its interpretation is affected by the use of diuretics, renal failure, and frequent comorbidities in hospitalized patients[2]. Other classic markers, such as blood urea nitrogen/creatinine ratio or sodium excreted fraction, also have limitations in this context and should not be used in isolation[32].

In patients with hypovolemia, typically with sodium and water losses due to gastrointestinal or renal causes, the reduction in effective arterial volume stimulates AVP secretion, perpetuating hyponatremia[5]. In hypervolemic hyponatremia, as in decompensated heart failure or cirrhosis, extracellular volume (ECV) expansion coexists with decreased effective arterial perfusion, again triggering non-osmotic AVP release. In euvolemic hyponatremia, SIADH is the most frequent etiology[10,22,23]. Correct diagnosis requires integrating measurements of urinary osmolality and urinary sodium with the clinical assessment of volume status. However, estimation of ECV by physical examination itself has low sensitivity and specificity, so laboratory parameters are commonly used as surrogates, such as urinary sodium < 30 mmol/L in hypovolemia and > 30 mmol/L in SIADH[2,22]. Despite this, these markers are not exempt from limitations in patients with diuretic use, renal dysfunction, or critical illness[5,21].

Given these limitations, new biomarkers have been investigated that more closely reflect the activity of the vasopressin-renal axis. Copeptin, a stable peptide derived from the precursor of vasopressin, has been proposed as an indirect marker of antidiuretic hormone secretion[18,33]. Although its plasma concentration is elevated in states of hypovolemia, SIADH, and acute physiological stress, its diagnostic utility has been questioned due to its wide interindividual variability and overlap between hyponatremia subtypes[2,5,33]. In prospective studies, it has been observed that its isolated value does not allow a precise differentiation between hypovolemia, euvolemia, and hypervolemia; however, some authors have suggested that the urinary copeptin/sodium ratio could play a role in distinguishing between SIADH and hypovolemic causes, although with limited clinical utility[2,33-35]. In fact, the Co-MEDy study[34] demonstrated that copeptin levels < 3.9 pmol/L were highly suggestive of primary polydipsia, while values > 84 pmol/L indicated hypovolemia; however, the overlap in intermediate ranges limited its ability to differentiate among the primary etiologies of profound hyponatremia reliably. Similarly, Fenske et al[33] showed that although copeptin levels were elevated across different hyponatremia subtypes, only the copeptin-to-urinary sodium ratio (> 30 pmol/mmol) provided partial discriminatory power between SIADH and hypovolemic hyponatremia.

An emerging biomarker with more promising results is mid-regional pro-atrial natriuretic peptide (MR-proANP)[36]. This marker, released in response to atrial distension, showed a significant association with volume status in the study by Nigro et al[36], where MR-proANP was independently associated with hypovolemia vs euvolemia (odds ratio: 2.45 per SD increase in multivariable models) and provided diagnostic value beyond traditional urine indices. In contrast, N-terminal pro-brain natriuretic peptide, although widely used in the evaluation of heart failure, did not demonstrate discriminative utility for hyponatremia subtypes in this setting[36]. Complementary evidence comes from the CAPNETZ cohort, in which Krüger et al[37] found that both MR-proANP and C-terminal pro-AVP were significantly elevated in patients with community-acquired pneumonia and dysnatremia, and that their combination with serum sodium achieved the highest accuracy for predicting 28-day mortality. Thus, biomarkers such as MR-proANP could complement conventional clinical and laboratory data, particularly when urinalysis is unavailable or yields inconclusive results. However, further validation is needed before systematic incorporation into diagnostic algorithms.

Role of imaging and new assessment techniques in hyponatremia

Accurate assessment of ECV is essential for the differential diagnosis and appropriate treatment of hyponatremia. Traditional tools, such as physical examination, vital signs, and laboratory parameters (e.g., sodium excretion fraction or serum urea nitrogen), have significant limitations, with correct diagnosis rates of less than 50% in some studies[5]. In this context, the use of point-of-care ultrasound (PoCUS) has emerged as a non-invasive, complementary tool that enables a more comprehensive hemodynamic assessment[38].

PoCUS integrates three key components: Lung ultrasound (LUS), venous congestion ultrasound, and focused cardiac ultrasound. This combination enables the estimation of stroke volume, assessment of systemic venous congestion, and detection of pulmonary patterns suggestive of fluid overload or hypovolemia. For example, a pattern with A-lines in LUS, decreased Doppler-measured stroke volume of the left ventricular outflow tract, and a collapsible inferior vena cava suggests hypovolemia[38].

In 2022, Chatterjee and Koratala[39], supported this utility by showing how PoCUS allows the identification of occult hypovolemia in a patient with ambiguous physical findings, since although the examination suggested euvolemia, Doppler showed low stroke volume with a positive response to the passive leg elevation test (increase > 15% in velocity-time integral). This prompted the safe administration of fluids, leading to normalization of both serum sodium and stroke volume, thereby confirming the diagnosis of occult hypovolemia. Such evaluation highlights how PoCUS can guide targeted and safe interventions, resulting in favorable clinical outcomes.

In addition, in 2024, Mazón Ruiz et al[38] suggested incorporating PoCUS early in the diagnostic approach to hyponatremia as a way to improve ECV assessment and to phenotype congestion (non-congestive, congestive, or redistributive), combining LUS, venous congestion ultrasound, and focused cardiac ultrasound to complement clinical and laboratory data. This proposal advances prior guidance, such as the 2014 European Clinical Practice Guideline, which emphasized biochemical and urinary indices while acknowledging the limitations of physical examination in assessing volume status[2]. While innovative, the scheme proposed by Mazón Ruiz et al[38] begins with plasma osmolality as the entry point. In real-world hospitalized or critically ill settings, however, the first abnormality clinicians usually face is the documentation of hyponatremia itself (serum sodium < 135 mmol/L)[1,5]. Using this threshold as the initial step better reflects clinical practice and may streamline subsequent evaluation of tonicity and volume status. Furthermore, incorporating urinary sodium together with PoCUS findings may provide a more precise and pragmatic framework, allowing not only congestion phenotyping but also refinement of the likely etiological diagnoses (Figure 2).

Figure 2 Diagnostic approach and phenotypic classification of hyponatremia. Adapted from Eljazzar et al[38]. Algorithm outlining the stepwise evaluation of hyponatremia based on clinical severity, urine osmolality, and urine sodium concentration. A urinary sodium ≤ 30 mmol/L typically suggests low effective arterial volume; however, this does not always equate to true venous congestion. Differentiating congestive from non-congestive phenotypes requires a comprehensive assessment of volemic status, where point-of-care ultrasound plays a critical role in identifying hemodynamic congestion through evaluation of the inferior vena cava, hepatic, portal, and intrarenal venous flow patterns. IV: Intravenous; VExUS: Venous excess ultrasound; IVC: Inferior vena cava; E/A: Early to late diastolic transmitral flow velocity ratio; E/e’: Eatio of early mitral inflow velocity to early diastolic mitral annular velocity; MAPSE: Mitral annular plane systolic excursion; TAPSE: Tricuspid annular plane systolic excursion; LVOT: Left ventricular outflow tract; VTI: Velocity time integral; HR: Heart rate; ECF: Extracellular fluid; SIAD: Syndrome of inappropriate antidiuresis.

THERAPEUTIC APPROACHES

Acute symptomatic hyponatremia

The treatment of acute and symptomatic hyponatremia constitutes a medical emergency[1,2]. Current European guidelines recommend the administration of 3% hypertonic saline as repeated intravenous boluses of 150 mL infused over 20 minutes, which may be repeated up to two additional times depending on the clinical response or until serum sodium has risen by approximately 5 mmol/L[2]. Alternatively, a continuous infusion may be administered at a rate of 0.5-2 mL/kg/hour. Nonetheless, bolus therapy is preferred to achieve a more predictable correction[2,20]. In patients with concomitant hypokalemia, potassium supplementation should be initiated, but clinicians must be aware that potassium repletion itself accelerates the rise in serum sodium by driving intracellular sodium shifts[2,5]. Thus, when potassium chloride is infused (either separately or in combination with hypertonic saline), strict monitoring of serum sodium (every 2 hours) is mandatory to prevent inadvertent overcorrection[2,20]. A sudden increase in free water diuresis further amplifies this risk, with osmotic demyelination as the feared complication[2]. For severe chronic hyponatremia (< 120 mmol/L), although randomized trials are lacking, it has been suggested that slow infusions of hypertonic saline (15-30 mL/hour) may be beneficial even in asymptomatic patients, provided that close surveillance is ensured to avoid overly rapid correction[2,20,40].

Chronic asymptomatic hyponatremia

Overall, mild to moderate and asymptomatic cases should be addressed with less aggressive strategies. For this, the first fundamental step in evaluating a patient with hyponatremia is to determine whether the condition is real (hypotonic) or spurious[1,2]. Isotonic or hypertonic hyponatremia results from water shifts caused by osmotically active solutes like glucose or lipids and does not indicate a true sodium deficiency (often called pseudohyponatremia; Figure 2). Treatment should target the underlying condition. Hypotonic hyponatremia, on the other hand, is the most frequent and clinically relevant form, involving a relative excess of free water with respect to the body’s sodium content[1,2].

Rapid vs slow correction

The rate of serum sodium correction is critical to preventing neurologic injury, particularly ODS. Current guidelines recommend aiming for an initial rise of approximately 4-6 mmol/L within the first 6 hours for patients with acute or severely symptomatic hyponatremia, while avoiding increases > 8 mmol/L in any subsequent 24-hour period and > 18 mmol/L within 48 hours[1,2]. Observational data indicate that ODS has occurred most often when serum sodium increased by > 10 mmol/L in the first 24 hours or > 18 mmol/L in 48 hours[1]. Targets should be individualized. In patients at low risk for ODS, many experts accept totals up to 8-10 (occasionally 10-12) mmol/L in 24 hours provided that 48-hour correction remains ≤ 18 mmol/L; conversely, in high-risk patients (chronic and profound hyponatremia, alcoholism, malnutrition, advanced liver disease, or hypokalemia) a more conservative limit of ≤ 6-8 mmol/L per 24 hours (often aiming for 4-6) is advised, with close biochemical monitoring and readiness to halt or re-lower if overcorrection ensues[2,20].

The pathophysiological basis for the strict limits in sodium correction lies in the cerebral adaptation to chronic hypo-osmolality[5]. In hyponatremia of gradual onset, brain cells reduce their content of organic osmolytes (such as taurine, myo-inositol, and creatine) to prevent cerebral edema[2,27]. A rapidly increasing serum sodium level quickly reverses the osmotic gradient, causing cellular dehydration and damage to glial structures[2,5,41]. Current evidence indicates that the initial damage primarily affects astrocytes, which control osmotic balance through aquaporins and connexins; their dysfunction then disrupts the metabolic and osmotic support for oligodendrocytes, leading to myelin rupture and cell death. This process explains the tendency for damage to occur in the pontine and extrapontine areas, resulting in the clinical syndrome of ODS[41].

However, a recent meta-analysis by Ayus et al[42] including more than 11000 patients challenged this paradigm, showing that rapid correction (≥ 8-10 mmol/L per 24 hours) was associated with lower in-hospital and 30-day mortality, as well as shorter hospital stay, without a significant increase in ODS. These findings suggest that excessively slow correction may also be harmful. Nevertheless, as the analysis was based on observational cohort studies with inherent risks of bias and confounding, its results should be interpreted with caution and do not yet justify changes to current guideline recommendations[2,20].

Practical methods for the preparation of 3% hypertonic saline

Hypertonic saline 3% remains the cornerstone of therapy for acute symptomatic hyponatremia, and commercially prepared solutions are readily available in many settings[1,2,43]. However, in middle- and low-income countries or in hospitals where ready-to-use 3% saline is not accessible, it can be safely prepared from more concentrated stock solutions (e.g., 17.7% NaCl) by validated dilution methods using 0.9% saline as a diluent, allowing accurate and reproducible preparation for clinical use[44].

The general formula is:

Where:

V_{(% major)}: Volume to be used of the most concentrated solution (17.7%).

V_t: Total volume desired.

% target: Desired final concentration (3%).

% minor: Diluent solution concentration (0.9%).

% major: Concentration of the available solution (17.7%).

Example 1: To prepare 1000 mL of 3% sodium chloride (NaCl) using a 17.7% solution:

125 mL of 17.7% NaCl should be mixed with 875 mL of 0.9% sodium saline normal. Since commercial presentations of 17.7% NaCl in Mexico typically come in 10 mL ampoules, this equates to 12.5 ampoules. It is important to note that the calculated volume of concentrated solution must be removed from the total volume of the base solution (gauged) to maintain the desired final concentration.

Example 2: To prepare 500 mL of 3% NaCl:

62.5 mL of 17.7% NaCl should be mixed with 437.5 mL of 0.9% sodium saline normal, which corresponds to 6.25 ampoules of 10 mL. This method is practical, reproducible, and clinically safe (when performed under aseptic conditions) for medical practice.

Fluid restriction

Fluid restriction remains the recommended first-line therapy for chronic euvolemic hyponatremia (commonly seen in SIADH), typically prescribing 800-1000 mL/day, as it is simple, inexpensive, and generally safe[45-47]. Nonetheless, its efficacy is often limited, with up to 40%-50% of patients failing to achieve a meaningful rise in serum sodium[48]. Likewise, data from a randomized controlled trial found that fluid restriction to 1 L/day produced a slight early increase in plasma sodium (median + 3 mmol/L at 3 days) with little additional correction by 30 days[47]. Additionally, observational studies have identified predictors of nonresponse, such as high urine osmolality or elevated urinary sodium, reflecting impaired electrolyte-free water clearance[48].

Unfortunately, in practice, particularly among hospitalized or critically ill patients, it is often challenging to predict who may benefit from fluid restriction based merely on measures. To address this challenge, the Furst equation (also called the Furst index) has been proposed as a simple and practical bedside tool (Figure 3). The Furst equation is calculated as (urinary Na⁺ + K⁺)/plasma Na⁺[45]. Values > 1 indicate concentrated urine and might predict a low likelihood of response to fluid restriction, whereas values < 1 suggest a higher probability of success[45,46]. In a recent study by Chienwichai et al[45], a cutoff of 0.86 optimally identified nonresponders; however, its performance remained modest (AUC: Approximately 0.65). Although studies evaluating the utility and accuracy of the Furst equation in clinical practice are limited, its use needs further validation and opens the door for future research into practical bedside tools for predicting fluid restriction response.

Figure 3 Furst equation and fluid restriction strategy in euvolemic hyponatremia. The Furst equation provides a practical estimation of urine tonicity relative to plasma sodium concentration and helps anticipate the likelihood of response to fluid restriction (FR). A value < 0.5 indicates maximally dilute urine and high probability of correction with standard FR (approximately 800-1000 mL/day). Intermediate values (0.5-1.0) suggest partial concentration and warrant a stricter trial of FR (approximately 500 mL/day) under close monitoring. Ratios > 1.0 reflect concentrated urine (surrogate for urine osmolality > 100 mOsm/kg), indicating poor response to FR and the need for early consideration of second-line therapies (urea or vasopressin receptor antagonists). U_na: Urinary sodium concentration; U_k: Urinary potassium concentration; FR: Fluid restriction.

Beyond predictive formulas such as the Furst equation, calculating daily free water excretion provides additional insight into a patient’s ability to eliminate solute-free water and anticipate response to fluid restriction[5]. This parameter can be estimated using the electrolyte-free water clearance formula: C_h2O_e = V × [1 - (U_na + U_k)/P_na].

Where V is the urine volume, U_na and U_k are urinary sodium and potassium concentrations, and P_na is plasma sodium concentration[1,5]. A daily electrolyte-free water clearance greater than 500-800 mL generally predicts adequate renal water excretion and a favorable response to fluid restriction, whereas lower or negative values indicate impaired clearance and the potential need for adjunctive therapies such as urea or loop diuretics. Although conceptually useful, its application in routine clinical practice remains limited by the need for serial urine studies and laboratory data[1,2,5].

Role of vaptans, urea, and alternative agents in the management of refractory hyponatremia

In patients with persistent hyponatremia despite fluid restriction (mainly in SIADH), various pharmacological options have been proposed[1,49,50]. Among these, vasopressin receptor V2 antagonists (vaptans), such as tolvaptan, and the use of urea, an osmotic agent with a more conservative correction profile, stand out[50].

Tolvaptan, licensed in the United States for euvolemic and hypervolemic hyponatremia, has shown efficacy in rapidly increasing serum sodium, but the potential risk of overcorrection and ODS might limit its use[1,51,52]. In a retrospective multicenter study[49], tolvaptan generated an increase of 5.05 mmol/L at 12 hours compared to 1.10 mmol/L with urea (P = 0.001), although the differences at 24 hours and 48 hours were not significant. However, the risk of overcorrection was 43% with tolvaptan compared to 9% with urea. Regarding the doses used, tolvaptan was administered mostly in schedules of 7.5 mg/day to 15 mg/day, while urea was used in average doses of 18.6 g/day, often in combination with other measures such as water restriction or diuretics[49]. However, tolvaptan achieved a faster correction in the short term, hospital duration, normalization rate, and overall safety favored urea.

Even though there has been an increasing recommendation for vaptan use because of their pharmacological effects, they should not be used as first-line therapy because of their cost-benefit profile and the fact that we still don’t know how they will affect people in the long term, especially those with mild to moderate hyponatremia[49-51]. Randomized studies have not shown any improvements in mortality, quality of life, or clinically significant outcomes, and the exorbitant cost makes it even less likely that this will be used regularly[53]. Even at modest dosages (< 15 mg), tolvaptan might represent a significant risk of overcorrection, remarking the need for meticulous monitoring and judicious application[54]. Urea, on the other hand, is a safe, cheap, and widely available alternative that works by osmotic diuresis and slowly raising sodium levels without a high risk of overcorrection/ODS[54,55]. It is usually administered as oral powder dissolved in water or juice (15-30 g/day), allowing a gradual and controlled increase in serum sodium concentration with minimal adverse effects. When given per os or enterally at a dose of 15 g to 30 g per day, urea has been found to be equally effective as vaptans but safer[1,55]. Demeclocycline and lithium are currently mostly not used anymore because they are toxic. Loop diuretics mixed with isotonic saline may only be used in cases of hypervolemia[20,52]. Overall, treatment for refractory hyponatremia should be tailored to each patient[1]. Urea is a practical second-line option once fluid restriction has failed, while vaptans should only be used in particular situations, with risk, expense, and clinical context carefully considered[55].

Another alternative well-known agent for treating severe hyponatremia is desmopressin [1-deamino-8-D-arginine vasopressin (DDAVP)], a synthetic vasopressin analogue that acts on V2 receptors in the renal collecting duct, thereby promoting water reabsorption and suppressing free-water diuresis[56-59]. Its rationale in hyponatremia is counterintuitive, as it deliberately induces antidiuresis. Nevertheless, this strategy is useful to prevent or reverse overly rapid correction of serum sodium, one of the main risk factors for ODS[57].

Different strategies of DDAVP administration have been described. Proactive (given early to tightly control correction), reactive (administered when an unexpectedly brisk rise in sodium or urine output is observed), and rescue (used once correction limits are exceeded)[57,58]. Observational data from large cohorts show that the reactive approach is most common, and while DDAVP effectively slows the rate of correction, it has been associated with longer hospital stay and lower rates of “safe correction” when used late, largely due to overcorrection occurring before its initiation[58]. In contrast, a proactive strategy has been linked with more predictable sodium trajectories, albeit sometimes at the expense of slower normalization[58,59].

Moreover, Sood et al[59] evaluated the combination of hypertonic saline with scheduled DDAVP to achieve controlled correction. In a quality improvement series, this regimen produced steady sodium increases (approximately 5-6 mmol/L at 24 hours) without cases of excessive correction or ODS, highlighting its utility in critically ill or high-risk patients.

Overall, the role of DDAVP in hyponatremia management is not to raise sodium directly, but rather to act as a “brake” that prevents uncontrolled aquaresis once the underlying cause of hyponatremia begins to resolve[60]. Current data suggest that its judicious use, particularly in patients at high risk of ODS (very low baseline sodium, malnutrition, alcoholism, hypokalemia, or liver disease), might improve safety. Nevertheless, the evidence remains observational mainly, and prospective studies are still needed to clarify its optimal timing, dosing, and impact on hard outcomes[58-60]. In clinical practice, DDAVP may be administered to prevent or reverse overly rapid correction of serum sodium levels[60]. Typical regimens include 1-2 μg intravenously or subcutaneously every 6-8 hours, or 10-20 μg intranasally every 8-12 hours, with frequent monitoring of serum sodium and urine output. In cases where overcorrection has already occurred, DDAVP can be combined with intravenous dextrose 5% solution to safely re-lower sodium levels, maintaining correction rates below 8-10 mmol/L per 24 hours. This proactive “DDAVP clamp” strategy has been increasingly adopted to stabilize sodium trajectories and reduce the risk of osmotic demyelination[58-60].

For certain patients with chronic or difficult-to-treat euvolemic hyponatremia, additional osmotic strategies might help support the correction process. For instance, oral salt tablets can be used to increase solute intake and boost free water clearance, especially if fluid restriction alone isn’t enough[1,2]. Similarly, a low-dose oral furosemide combined with oral sodium supplementation can promote the excretion of excess water by lowering medullary osmolarity[2]. Eating a high-protein diet can also raise urea production and promote osmotic diuresis, which can help improve serum sodium levels without needing medication. It’s important to carefully implement these measures under proper medical and biochemical supervision to prevent too rapid correction or volume depletion[1,2].

Evidence supporting the use of fludrocortisone in hyponatremia is limited to specific conditions such as CSW[1,2,61]. In a randomized controlled trial of 42 patients with hyponatremia following subarachnoid hemorrhage, Misra et al[61] demonstrated that fludrocortisone (0.1-0.4 mg daily) significantly shortened the time to normalization of serum sodium compared with standard therapy alone, with minimal adverse effects. These findings suggest that mineralocorticoid supplementation might be partially safe and effective as an adjunct in selected cases of hypovolemic hyponatremia due to renal sodium loss. Although mineralocorticoid therapy has been proposed in various contexts, it is not recommended in SIADH[1,2,22]. European guidelines[2] restrict fludrocortisone to selected cases of CSW, where it may accelerate sodium correction, but evidence remains limited, and it should not be used in euvolemic or hypervolemic hyponatremia. Thus, the management of SIADH should rely on fluid restriction, oral sodium supplementation combined with loop diuretics, or urea and vasopressin receptor antagonists in refractory cases[1,2,22].

CSW AND RESET OSMOSTAT: ARE THEY REAL?

The distinction between CSW and SIADH remains controversial and clinically challenging (Table 2)[2,20]. Both entities may present with hyponatremia, high urinary sodium, and elevated urine osmolality, yet differ in ECV status and therapeutic approach[5,20]. Current guidelines acknowledge that reliable clinical or biochemical differentiation is difficult, as assessment of volume status is often inaccurate and markers such as serum uric acid or natriuretic peptides have limited diagnostic specificity[2,5,20]. Persistent hypouricemia and increased fractional excretion of urate after sodium correction may suggest CSW, but these findings are not pathognomonic[62]. European and American guidelines therefore recommend focusing on careful clinical evaluation and response to isotonic saline rather than rigid classification of these entities[2,20].

Table 2 Comparison of syndrome of inappropriate antidiuretic hormone, cerebral salt wasting, and reset osmostat.

Feature	SIADH	Cerebral salt wasting	Reset osmostat
Volume status	Euvolemic	Hypovolemic (true salt loss)	Euvolemic
Plasma sodium	Low	Low	Mildly low but stable
Urine sodium	> 30 mmol/L	> 30 mmol/L	Variable
Urine osmolality	> 100 mOsm/kg	> 100 mOsm/kg	Normal dilution capacity maintained
Serum uric acid	Low	Low	Normal or low-normal
Fractional excretion of uric acid	Elevated during hyponatremia (> 12%), normalizes after correction	Remains elevated after correction	Normal (< 11%)
Fractional excretion of sodium	> 0.5%-1% (inappropriately high for euvolemia)	> 1%-2% (due to true renal salt loss)	Normal or slightly increased
Fractional excretion of urea	> 55%-60%	> 60%-70%	Normal (< 35%)
Response to isotonic saline	No improvement or worsens hyponatremia	Improves serum sodium and volume	No major change
ADH secretion pattern	Inappropriate, independent of osmolality	Appropriate (secondary to hypovolemia)	Reset to a lower threshold
Volume markers (BUN, hematocrit)	Normal	Elevated (due to hypovolemia)	Normal
Treatment approach	Fluid restriction, salt tablets, urea, vaptans	Volume and salt repletion ± fludrocortisone	Usually none; avoid overcorrection
Typical setting	Pulmonary disorders, malignancy, CNS disease, drugs	CNS injury, subarachnoid hemorrhage, neurosurgery	Chronic illness, elderly, pregnancy, tuberculosis, carcinoma

ADH: Antidiuretic hormone; BUN: Blood urea nitrogen; CNS: Central nervous system.

Similarly, reset osmostat represents a mild, stable form of euvolemic hyponatremia in which the hypothalamic threshold for vasopressin release is chronically lowered, resulting in a new steady-state at a reduced plasma sodium concentration[63]. Recent prospective data support its recognition as a distinct clinical entity rather than a subtype of SIADH, characterized by preserved renal water-diluting capacity and stable sodium balance[63]. The water-diluting test remains the gold standard for diagnosis, with ≥ 80% free-water excretion favoring a reset osmostat over SIADH, whereas excretion usually remains < 40%. Fractional uric acid excretion below 11% may serve as a practical surrogate, whereas copeptin has not demonstrated reliable diagnostic accuracy[63]. Recognizing this entity prevents unnecessary fluid restriction and highlights that CSW, SIADH, and reset osmostat likely represent a physiological continuum rather than discrete categories[5,20,63].

FUTURE DIRECTIONS

Recent advances in artificial intelligence and healthcare information technology are bringing in a new era for the personalized management of hyponatremia[64-66]. Conventional methods depend significantly on clinician interpretation and fixed laboratory thresholds. However, novel models utilize machine learning and decision support systems to dynamically forecast sodium changes and direct customized therapies[65]. A large cohort study in Germany showed that a laboratory-based clinical decision support system indicated that prompt follow-up of sodium measurements (within 12 hours) could markedly enhance correction rates and discharge outcomes. This suggests the potential for automated alerts to improve patient safety and adherence to guideline-based care[66].

Moreover, modern deep learning models have attained enhanced accuracy in forecasting serum sodium variations and recommending personalized therapeutic modifications for critically ill patients[65]. In the future, artificial intelligence-driven prediction, precise monitoring, and customized suggestions could help healthcare providers maintain natremia within a safe range with greater accuracy than ever before. This reflects personalized care, where treatment strength, speed, and tactics are tailored to each patient’s risk and response. At the bedside, this integration can help reduce medical errors, shorten hospital stays, and keep vulnerable groups safer when treatment adjustments are needed.

CONCLUSION

A serum sodium < 135 mmol/L is only the top of the iceberg. Its approach and management might be challenging in some refractory scenarios and in limited-resource settings. Advances in biomarkers, imaging, and physiologic understanding have refined the diagnostic process, while therapeutic strategies continue to evolve toward safer and more tailored correction. Fluid restriction remains the cornerstone of initial therapy, complemented by tools such as the Furst equation to anticipate response. Importantly, the evaluation of volemia in hyponatremia solely on clinical examination is becoming insufficient in modern times. PoCUS should be a routine extension of the physical exam, providing real-time, objective, and reproducible insights into intravascular volume status. For refractory cases, urea and DDAVP offer safe and practical alternatives, whereas vaptans should be reserved for carefully selected patients under close monitoring. Looking ahead, the integration of artificial intelligence and decision-support systems promises to personalize further and refine the management of hyponatremia, translating evidence-based insights into better patient outcomes at the bedside.

ACKNOWLEDGEMENTS

We would like to thank all the medical staff from the internal medicine department at Hospital General Dr. Manuel Gea Gonzalez. Use this review to continue improving residents’ learning.