Study Objectives and Hypothesis

To determine the incidence of hyponatremia at TYKS and the factors associated with it.

To assess how rapidly hyponatremia was corrected and how the rate of correction affected patient prognosis.

To evaluate treatment modalities and their impact on patient prognosis, length of hospital stay, and their appropriateness in comparison with national and international treatment guidelines.

To determine the incidence of osmotic demyelination at TYKS and the factors associated with it.

To assess other complications and their clinical significance.

To evaluate the impact of hyponatremia on various endpoints, such as mortality, length of hospital stay, seizures, confusion, and similar outcomes.

Clinical Significance of Hyponatremia (Study Protocol)

Investigators: Tyko Hellsten, Anssi Mustonen, Ilpo Nuotio

Background of the Study General Background

Hyponatremia is a common electrolyte disorder occurring in approximately 15-30% of hospitalized patients (3,4). Most cases are mild and minimally symptomatic. The most clinically significant cases are rapidly developing severe hyponatremia, which may cause neurological emergencies and death, and chronic severe hyponatremia, in which overly rapid correction may lead to permanent neurological injury and, in the most severe cases, death (3,4). Hyponatremia is not an independent disease but a consequence of underlying illnesses, adverse drug effects, inappropriate fluid therapy, or, rarely, lifestyle-related factors.

Hyponatremia is classified as mild when serum sodium is 130-134 (-138) mmol/L. Although mild hyponatremia has been associated with increased hospital visits, prolonged hospital stays, sarcopenia, falls, fractures, and increased mortality, it is not typically an active target of treatment, and there are no reports on the effectiveness of its treatment.

Rapidly developing severe hyponatremia presenting with neurological symptoms, cerebral edema, or seizures requires an initial rapid increase in serum sodium followed by slower correction (1). In chronic severe hyponatremia, correction must be slow from the beginning to avoid neurological complications (1). Since the rate of development is often unknown, practical guidance recommends an initial rapid increase of 5-6 mmol/L in patients with neurological symptoms, while sodium should be corrected slowly in minimally symptomatic patients.

Hyponatremia is also classified according to serum osmolality into pseudo-, hypertonic, isotonic, and hypotonic hyponatremia. Pseudohyponatremia and hypertonic/isotonic hyponatremia are most commonly caused by hyperglycemia or, rarely, by fluids used in operative settings. This study focuses on hypotonic hyponatremia, its prevalence, associated diseases, clinical significance in acute care, and treatment.

Classification, Etiology and Diagnostics

Hyponatremia is classified as:

Mild: 130-134 (-138) mmol/L

Moderate: 120 (-125) to 130 mmol/L

Severe: <120-125 mmol/L (1)

Based on duration:

Acute hyponatremia develops within 48 hours (e.g., postoperative fluid therapy with increased ADH secretion, polydipsia in psychiatric patients or endurance athletes) (1,3,4).

Chronic hyponatremia develops over more than 48 hours, has an unclear duration, or develops outside hospital settings (1,3,4).

Based on volume status, hypotonic hyponatremia is classified as:

Hypovolemic

Euvolemic

Hypervolemic

Hypovolemic hyponatremia presents with clinical signs of dehydration and is caused by gastrointestinal losses or renal losses (e.g., diuretics, mineralocorticoid deficiency) (4).

Euvolemic hyponatremia, the most common type, is often due to SIADH (syndrome of inappropriate antidiuretic hormone secretion), associated with medications, stress, CNS and pulmonary diseases, and malignancies. Other causes include hypothyroidism, adrenal insufficiency, and abnormal dietary habits (4).

Hypervolemic hyponatremia results from decreased effective arterial blood volume, leading to reactive water retention (4), as seen in liver cirrhosis, heart failure, nephrotic syndrome, and polydipsia.

Assessment of vasopressin activity is commonly based on the urine-to-serum osmolality ratio (U-osmolality > S-osmolality or U-osmolality 100-300) (6), since direct vasopressin measurement is unreliable and copeptin is not routinely used.

Treatment and Associated Risks

Treatment depends on the rate of onset, symptom severity, and etiology. Current guidelines are largely consistent.

If there is a high risk of osmotic demyelination syndrome (ODS) (Na <105 mmol/L, alcoholism, hypokalemia, malnutrition, liver disease), correction should not exceed 4-6 mmol/L per 24 hours (3). Otherwise, up to 8 mmol/L in the first 24 hours is considered safe. In confirmed acute cases (<24-48 hours), correction may proceed more rapidly (3).

Rapid-onset hyponatremia causes cerebral edema due to water movement into brain cells (4). Chronic hyponatremia allows osmotic adaptation, reducing cellular swelling (4).

Known intracranial pathology increases herniation risk, and hypertonic 3% saline should be considered early (1). Sodium levels should be monitored every 4-6 hours, or hourly in severe cases (3).

In Finland, national acute care guidelines recommend fluid restriction for slowly developing, mildly symptomatic hyponatremia. Hypertonic 3% saline is reserved for severe neurological symptoms (8).

After acute correction, hyponatremia may not require further specific treatment if the underlying cause has been addressed. SIADH is often chronic; first-line treatment is fluid restriction and correction of underlying causes (4). Tolvaptan is rarely used due to cost and limited reimbursement. Oral sodium chloride may be considered in SIADH if fluid restriction is insufficient (1).

Complications and Prognosis

Hyponatremia is the most common cause of ODS, particularly in chronic cases with overly rapid correction (2). Clinical manifestations include central pontine and extrapontine myelinolysis (2). Symptoms range from dysarthria and dysphagia to spastic tetraparesis and extrapyramidal features.

MRI is essential in diagnosis. Imaging findings do not directly correlate with prognosis (2).

There is no specific treatment for ODS; prevention through cautious correction is key (1,3). Prognosis has improved substantially compared to the 1980s (2).

Study Objectives and Hypotheses

To determine the incidence of hyponatremia and associated factors at TYKS (Turku University Hospital).

To evaluate correction rates and their impact on prognosis.

To assess treatment modalities, hospital length of stay, outcomes, and adherence to guidelines.

To determine the incidence and risk factors of ODS at TYKS.

To identify other complications and their significance.

To evaluate the impact of hyponatremia on mortality, hospital stay, seizures, confusion, and other endpoints.

The first study will assess incidence and associated factors (2016-2020). The second will evaluate sodium levels and mortality across diagnosis groups. The third will assess ODS incidence and associated factors. The fourth will focus on management of severe hyponatremia.

Materials and Methods

A registry-based study will include all patients with hyponatremia and all cases of osmotic demyelination syndrome treated at TYKS between January 1, 2016, and December 31, 2020.

Data will be analyzed using statistical software (SAS, SPSS, R) by study investigators.

Results will be published in international medical journals and presented at national and international conferences.

Significance of the Study

Hyponatremia is a common clinical challenge in emergency and inpatient care. Controlled correction requires monitored care. This study aims to clarify:

At which sodium levels monitored correction is necessary

What constitutes a safe correction rate

The frequency of complications with rapid correction

Whether patients are overtreated

The impact of hyponatremia and comorbidities on prognosis and mortality

The goal is to clarify diagnostic and therapeutic strategies for hyponatremia.

Ethical Considerations

This is a registry-based study. Separate ethical approval is not required. Data will be anonymized before analysis.

Study Timeline

Study planning: from January 1, 2022 Research permits and data retrieval: from May 1, 2022

Inclusion Criteria:

• Two sodium measurements in Tyks laboratories between 12-36 hours.

Exclusion Criteria:

-

The study design was to enroll as general population that are hospitalized as possible. From this population the main focus group of hyponatremia and ODS patients were selected and formed case-control groups.

Current Finnish legislation does not permit the sharing of individual participant data (IPD).