European Journal of Cardiovascular Medicine

Hyponatremia, defined as a serum sodium concentration of less than 135 mEq/L, is one of the most frequently encountered electrolyte disturbances in clinical practice, particularly within emergency department settings. Sodium, the principal extracellular cation, plays a pivotal role in maintaining cellular homeostasis, effective osmolality, neuromuscular excitability, and intravascular volume regulation. Its normal serum concentration ranges from 135 to 145 mEq/L, with tight physiological control maintained through the balance of water and sodium via neurohormonal mechanisms. Disruption in this homeostasis may result in hyponatremia, which is primarily a reflection of excess free water relative to sodium in the extracellular compartment [1-3].

Hyponatremia is categorized based on serum sodium levels as mild (130–134 mEq/L), moderate (125–129 mEq/L), and severe (<125 mEq/L). Clinical symptoms correlate more with the acuity of sodium reduction than the absolute value and may range from mild headache and nausea to seizures, coma, and respiratory arrest in cases of profound or rapid onset hyponatremia [4–7]. Importantly, the brain is particularly vulnerable due to osmotic shifts leading to cerebral edema, which underscores the critical nature of prompt recognition and appropriate management of this condition [6,8,9].

The reported incidence of hyponatremia in hospitalized patients varies from 15% to 30%, with severe hyponatremia (<130 mEq/L) occurring in about 1–4% of cases [10]. The most prevalent form is hypotonic hyponatremia, which is further classified by volume status into hypovolemic, euvolemic, and hypervolemic types. Common etiologies include diuretic use, Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), heart failure, cirrhosis, nephrotic syndrome, and gastrointestinal fluid losses [11,12]. Additionally, isotonic and hypertonic forms of hyponatremia, such as pseudohyponatremia and hyponatremia associated with hyperglycemia or mannitol use, must also be considered in differential diagnosis [13,14].

Certain populations, including the elderly, females, and those with low body mass, are more susceptible to hyponatremia. Diuretics—particularly thiazides—are a well-established cause, given their impact on sodium reabsorption at different nephron sites. Thiazide diuretics impair the kidney's diluting capacity without affecting concentrating ability, thereby increasing the risk of dilutional hyponatremia. In contrast, loop diuretics disrupt the medullary concentration gradient, making them relatively safer in this context [15].

Clinical manifestations of hyponatremia largely arise from cerebral edema, and if left unrecognized or mismanaged, may result in devastating outcomes including central pontine myelinolysis due to rapid overcorrection, especially in chronic cases. Moreover, chronic hyponatremia has also been linked to adverse systemic effects such as reduced bone mineral density and an increased risk of fractures [16-19].

Numerous studies have highlighted hyponatremia as a significant prognostic marker associated with increased morbidity and mortality in a range of conditions such as cirrhosis, congestive heart failure, myocardial infarction, pneumonia, AIDS, and malignancies. Specifically, studies have shown that even mild hyponatremia correlates with higher hospital mortality and poorer clinical outcomes, emphasizing the importance of accurate etiological diagnosis and timely intervention [20-21].

The management of hyponatremia requires a nuanced approach that takes into account its chronicity, severity, associated symptoms, and volume status of the patient. Acute symptomatic hyponatremia warrants urgent correction with hypertonic saline to prevent neurological complications, while chronic cases necessitate cautious and controlled correction to avoid osmotic demyelination syndrome. Asymptomatic cases are managed based on volume status through isotonic saline, fluid restriction, loop diuretics, or vasopressin receptor antagonists, depending on the underlying cause. [10]

Despite the high prevalence and potential complications, hyponatremia is often underdiagnosed or inadequately managed in emergency settings. Limited data exist from the Indian subcontinent detailing the clinico-etiological spectrum of hyponatremia in emergency care. Most available literature originates from Western populations, where diuretic use and SIADH have been frequently reported as leading causes. There is variability in findings related to demographics, gender distribution, and underlying etiologies [10,22-24].

Given this context, the present study aims to explore the clinico-etiological profile of hyponatremia among patients presenting to the emergency department of a tertiary care hospital in India. By identifying the predominant types, associated clinical features, and contributing factors, this study seeks to bridge the existing gap in regional data and provide insights that may guide timely diagnosis and management in high-risk patients.

This single-centre, observational study was conducted in the Emergency Department of Index Medical College Hospital and Research Centre, Indore, over a period of one year from April 2023 to March 2024. The study included adult patients aged over 18 years who presented with serum sodium levels below 135 mEq/L and required inpatient care. Written informed consent was obtained from all participants. Patients were excluded if they declined consent, had pseudohyponatremia (due to hyperglycemia >250 mg/dL, hyperlipidemia, hyperproteinemia, or mannitol/IVIG administration), or had alternative diagnoses mimicking hyponatremia.

The sample size was determined using the formula 4PQ/D², based on a prior study by Chatterjee et al. [25] where the proportion of euvolemic hyponatremia was 51%. With P = 0.51, Q = 0.49, and D = 0.12 (20% precision), the minimum required sample size was calculated to be 70.

Methodology

Data were collected prospectively by the primary investigator using a predesigned proforma. In cases with altered mental status, relevant clinical history and consent were obtained from attendants. The assessment included symptoms such as nausea, vomiting, headache, giddiness, confusion, drowsiness, seizures, and coma. Medication history, especially use of diuretics, anticonvulsants, and antidepressants, was recorded. Comorbidities such as diabetes mellitus, hypertension, ischemic heart disease, CKD, cirrhosis, hypothyroidism, CLD, COPD, seizure disorder, depression, and prior cranial surgery were noted. Volume status was evaluated clinically and categorized as hypovolemic, euvolemic, or hypervolemic based on standard signs like dry mucosa, orthostatic hypotension, pedal edema, ascites, and JVP.

Laboratory Investigations

Serum sodium was estimated using the indirect ion-selective electrode (ISE) method. In all patients with serum sodium <135 mEq/L, serum osmolality, urine sodium, and urine osmolality were assessed. Serum osmolality was calculated using the formula: [2 × (PNa + PK)] + (BUN / 2.8) + (Glucose / 18), where values are in mg/dL. Patients were classified based on serum osmolality as hypo-osmolar (<275 mOsm/kg), normo-osmolar (275–290 mOsm/kg), or hyperosmolar (>290 mOsm/kg). Urine sodium was measured using Quick LYTE multisensor technology, and urine osmolality was estimated from specific gravity by multiplying the hundredths and thousandths digits by 35.

Etiological Classification

Each enrolled patient was followed during admission, and the final etiology of hyponatremia was documented. Diagnostic criteria for different causes included:

• SIADH: Euvolemia, serum osmolality <275 mOsm/kg, urine osmolality >200 mOsm/kg, urine sodium >20 mEq/L, normal adrenal, thyroid, cardiac, hepatic, and renal function
• Hypothyroidism: TSH >10 mU/L, urine sodium >40 mEq/L, urine osmolality >100 mOsm/kg, euvolemia
• Diuretic-induced hyponatremia: Use of diuretics, urine sodium >20 mEq/L, urine osmolality >100 mOsm/kg, no edema
• Hypovolemic hyponatremia: Clinical hypovolemia, urine sodium <10 mEq/L, urine osmolality >100 mOsm/kg

Statistical Analysis

Data were entered into Microsoft Excel and analyzed using SPSS version 22.0 and R version 3.2.2. Continuous variables were expressed as mean ± SD for normally distributed data and as median (interquartile range) for non-normally distributed data. Normality was tested using the Kolmogorov–Smirnov test. For comparison among more than two groups, one-way ANOVA was used for normally distributed data and Kruskal-Wallis test for skewed data. Categorical variables were compared using Chi-square or Fisher’s exact test. Mood’s median test was applied to compare medians across groups. A p-value <0.05 was considered statistically significant.

A total of 100 patients presenting with hyponatremia to the emergency department were enrolled in the study. Of these, 59% were male, and the mean age of the study population was 62.5 ± 12.4 years. The distribution of patients by age and gender is depicted in Figure 1.

Figure 1: Distribution of Males and Females in Various Age Groups

Systemic hypertension was the most common comorbidity, present in 60% of patients, followed by diabetes mellitus in 17% and hypothyroidism in 15%. The mean serum sodium level among the participants was 120.9 ± 7.0 mEq/L. Based on severity, 7% of patients had mild hyponatremia (130–134 mEq/L), 26% had moderate hyponatremia (125–129 mEq/L), and 67% had severe hyponatremia (<125 mEq/L).

The most frequently reported symptoms were lethargy (78%) and nausea/vomiting (77%). Other symptoms included confusion (24%), drowsiness (22%), headache (20%), giddiness (6%), and seizures (2%). [Table 1]

Regarding overall symptom severity, one patient had only mild symptoms (lethargy), 77 had moderate symptoms (including nausea, vomiting, headache, confusion, or giddiness), and 22 experienced severe symptoms (drowsiness and/or seizures). The median Glasgow Coma Scale (GCS) score for the cohort was 15 (IQR: 14–15). Median GCS remained 15 in mild and moderate hyponatremia but dropped to 15 (IQR: 14–15) in severe cases, showing statistical significance (P = 0.004).

Volume status assessment revealed that 15% of patients were clinically hypovolemic, 71% were euvolemic, and 14% were hypervolemic. Patients with severe symptomatic hyponatremia had significantly lower serum sodium levels compared to those with mild or moderate symptoms (114.6 ± 7.2 mEq/L vs. 122.6 ± 5.8 mEq/L and 128.0 mEq/L respectively, P < 0.001. [Table 2]

Analysis of factors associated with severity of hyponatremia showed that diuretic use and euvolemic volume status were significantly associated with more severe sodium derangements (P = 0.002 and P = 0.018, respectively). Other factors such as age, sex, hypertension, diabetes, and hypothyroidism did not show statistically significant associations. [Table 3]

Interestingly, while a strong association was found between serum sodium levels and symptom severity, severe hyponatremia (<125 mEq/L) was not always associated with severe symptoms (P = 0.012, see Table 4).

Urine and serum biochemical parameters varied with volume status. Serum osmolality was significantly lower in hypervolemic patients (240.22 ± 20.37 mOsm/kg), while urine osmolality and urine sodium were significantly higher in the same group (439.85 ± 170.83 mOsm/kg and 52.67 ± 22.12 mEq/L respectively, P < 0.05, see Table 5).

Among the study population, 56 patients were on diuretics, and 8 patients were taking medications known to induce SIADH (e.g., SSRIs). Of the patients with diuretic-induced hyponatremia, 45 were clinically euvolemic. Diuretic use was significantly associated with euvolemic and hypervolemic states (P = 0.001).

The most common identified etiology of hyponatremia was diuretic-induced hyponatremia, observed in 48% of patients. Other causes included hypovolemic hyponatremia (16%), hypervolemic hyponatremia (12%), SIADH (11%), severe hypothyroidism (9%), adrenal insufficiency (1%), and undetermined causes (3%). [Figure 2]

Figure 2. Etiology of Hyponatremia

The present observational study evaluated the clinico-etiological profile of hyponatremia in 100 patients presenting to the emergency department with serum sodium levels <135 mEq/L. A significant proportion (62%) of these patients belonged to the elderly age group (≥60 years), and the mean age of the study population was 62.5 ± 12.4 years. This aligns with previous findings by Hochman I et al. [26], who also noted an increased prevalence of hyponatremia among the elderly. Age-related physiological changes, such as impaired renal sodium handling and reduced glomerular filtration rate, compounded by multiple comorbidities and polypharmacy, likely contribute to this increased susceptibility.

A male predominance was noted (59%), consistent with studies conducted by Paniker GI et al. [27] (63%), Chatterjee et al. [25] (62.69%), and Mahavir et al. (64.3%) [28]. Conversely, some studies (e.g., Rao MY et al. and Saeed et al.) reported a slight female preponderance, although these differences were not statistically significant [29,30].

In terms of volume status, euvolemic hyponatremia was the most prevalent subtype in the current study, affecting 71% of patients. This was followed by hypovolemic (15%) and hypervolemic (14%) subtypes. This distribution trend mirrors findings from previous studies by Chatterjee et al. [25] (51% euvolemia) and Hochman et al. [26] (50%), although Anderson et al. [31] reported hypovolemia as the most frequent form. The consistency of the pattern (euvolemia > hypovolemia > hypervolemia) highlights the clinical importance of thorough volume status assessment for accurate diagnosis and management.

Hypertension (60%) was the most frequently observed comorbidity in this study, followed by diabetes mellitus (17%) and hypothyroidism (15%). These findings are comparable to those of Rao MY et al., who reported hypertension in 62% and diabetes in 51% of hyponatremic patients [29]. Although hypertension itself may not be directly linked to hyponatremia, the frequent use of antihypertensive medications—particularly diuretics—may contribute significantly to its development [31,33,34].

Symptomatically, lethargy (78%) and nausea/vomiting (77%) were the most common clinical presentations. Neurological manifestations such as confusion, drowsiness, and headache were significantly more common in patients with serum sodium levels <125 mEq/L. Two patients presented with seizures at serum sodium levels ≤110 mEq/L, highlighting the severity of central nervous system involvement in profound hyponatremia. These findings are in agreement with Rao MY et al. [29], who found drowsiness and lethargy in 33% and 29% of their cohort, respectively, and Agarwal SM et al., who reported confusion (41%), headache (40%), and malaise (38.6%) as predominant symptoms [28]. The variability in symptom prevalence across studies can be attributed to differences in diagnostic criteria, population characteristics, and etiology.

Interestingly, in our study, severe hyponatremia was not always associated with severe clinical symptoms. This finding may be explained by the role of chronicity in symptom manifestation. Rapid-onset hyponatremia is more likely to produce neurological symptoms due to acute cerebral edema, whereas in chronic cases, the brain undergoes osmotic adaptation by extruding intracellular electrolytes (Na⁺, K⁺, Cl⁻) over 48 hours, thus mitigating cellular swelling.

From an etiological perspective, diuretic-induced hyponatremia emerged as the leading cause (48%), followed by hypovolemic hyponatremia (16%). Of the 56 patients on diuretics, 45 (80.3%) were clinically euvolemic. This is consistent with earlier research indicating that thiazide diuretics are a major contributor to hyponatremia in the elderly population [Clark BA et al. [31], Chow KM et al. [32] and Ware JS et al. [33]. The pathophysiology involves impaired free water clearance, loss of sodium and potassium, and impaired urine dilution due to inhibition of electrolyte transport at cortical diluting segments. Despite impaired osmolality regulation, patients may still retain water due to decreased GFR and proximal tubular sodium reabsorption, thereby presenting as euvolemic or hypovolemic.

SIADH accounted for 11% of the cases in this study. Among these, 8 patients were found to be using SSRIs, which are known precipitants. This is comparable to the findings of Huda MS et al., who reported a prevalence of 19.8% for SIADH [34]. Additionally, studies such as that by Saeed et al. described renal, hepatic, and cardiac disorders as contributors to hyponatremia through mechanisms involving effective circulatory volume depletion and secondary activation of ADH and other neurohormonal responses [30].

The biochemical analysis revealed that serum osmolality was significantly lower in patients with hypervolemic hyponatremia, while both urine osmolality and urine sodium were significantly elevated in this group. These findings support the diagnosis of dilutional hyponatremia secondary to water retention mechanisms in states of fluid overload, such as heart failure or cirrhosis.

Although the study provides valuable insights into the clinico-etiological profile of hyponatremia, it is limited by a small sample size, absence of a control group, and lack of outcome or treatment analysis. Moreover, exclusion of asymptomatic patients may have underestimated the true burden and spectrum of the condition.

The present study highlights that lethargy and nausea/vomiting are the predominant clinical manifestations of hyponatremia, often overshadowing more severe neurological symptoms. Diuretic-induced hyponatremia was the leading cause, particularly in euvolemic patients, reinforcing the need for cautious diuretic use, especially in the elderly. Notably, the severity of clinical symptoms did not align proportionally with the degree of hyponatremia, suggesting that symptomatology may be more influenced by the rapidity of onset rather than absolute sodium values. Hypertension emerged as the most frequent comorbidity, further linking the widespread use of diuretics to hyponatremia risk. These findings underscore the critical need for clinicians to prioritize symptom-based evaluation and individualized assessment over reliance solely on biochemical thresholds.

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