3. Pharmacotherapy: Oral Urea

Oral urea is an effective agent that increases renal solute load, thereby promoting free water excretion (aquaresis). While inexpensive and generally effective, its use can be limited by poor palatability and its off-label status for SIADH in some regions.

Mechanism of Action:

Urea acts as an osmotic diuretic. When ingested and absorbed, it is filtered by the glomeruli and poorly reabsorbed in the tubules. This increases the osmolarity of the tubular filtrate, obligating the excretion of water and enhancing electrolyte-free water clearance.

Indications:

Chronic SIADH that is refractory to, or in patients intolerant of, fluid restriction alone. It is particularly useful when urine osmolality is high.

Dosing & Titration:

Start with 15 grams per day, typically administered in divided doses (e.g., 7.5 g twice daily). The dose can be titrated upwards every few days based on serum sodium response, to a usual maintenance dose of 30–45 grams per day. The maximum recommended dose is generally 60 grams per day.

Administration Tips:

• Dissolve urea powder thoroughly in water, juice, or another flavored beverage to improve taste.
• Taking urea with meals may help reduce potential gastrointestinal discomfort.

Monitoring:

Monitor serum sodium every 1–2 weeks during initial titration, then less frequently (e.g., monthly) once stable. Also monitor BUN/creatinine and volume status.

Contraindications:

• Severe hepatic encephalopathy (as urea is metabolized to ammonia).
• Known hypersensitivity to urea.

Advantages:

Low cost, reliable effect on free water excretion, minimal systemic toxicity at therapeutic doses.

Disadvantages:

Poor palatability is the primary drawback. Lack of formal regulatory approval for SIADH in some countries may also be a consideration.

4. Pharmacotherapy: Salt Tablets

Sodium chloride (salt) tablets increase solute intake, which can raise serum osmolality and promote osmotic diuresis, thereby aiding in free water excretion. They are easy to obtain but carry risks, particularly volume overload and hypertension.

Mechanism of Action:

Salt tablets increase the total body sodium and solute load. This increased solute load, when excreted by the kidneys, enhances water clearance, similar to urea but with the added effect of sodium itself.

Indications:

• Mild to moderate chronic SIADH, often as an adjunct to fluid restriction.
• Patients with borderline hyponatremia where a small increase in solute intake may be sufficient.

Dosing:

Typically, 1-gram salt tablets are used. A common dose is 3 grams three times daily (total of approximately 9 grams/day, providing about 154 mEq of sodium). Doses should be spaced out with meals to minimize gastrointestinal upset.

Monitoring:

Monitor serum sodium every 1–2 weeks during titration, then as clinically indicated. Closely monitor blood pressure and for signs of fluid overload (e.g., edema, weight gain, dyspnea).

Contraindications:

• Uncontrolled hypertension.
• Congestive heart failure or other conditions predisposing to volume overload.
• Severe renal impairment where sodium excretion is compromised.

Advantages:

Readily available over-the-counter in many places, inexpensive.

Disadvantages:

Poor taste, potential for inducing or worsening hypertension, risk of peripheral edema and fluid overload.

5. Assessment Prior to Transition to Oral Therapy

A thorough assessment is mandatory to ensure clinical and biochemical stability before switching a patient from intravenous (IV) therapies used in the acute setting (like hypertonic saline) to an oral maintenance regimen.

1. Hemodynamic & Neurologic Stability: The patient must be hemodynamically stable without ongoing signs of severe hyponatremia such as seizures, coma, or significant confusion. Any acute hyponatremic symptoms should have resolved.
2. Sodium Trajectory and Level: The rate of serum sodium correction should have been appropriate (≤8–10 mmol/L per 24 hours to avoid osmotic demyelination syndrome). Serum sodium should be stabilized at a safe level, generally >125 mmol/L, before transitioning.
3. Volume Status: Clinically confirm euvolemia. It’s important to rule out underlying hypovolemia (which might suggest a different diagnosis or contributing factor) or hypervolemia (which might require adjustment of therapies like salt tablets).
4. Organ Function: Evaluate renal and hepatic function. Impaired kidney function can affect the efficacy and safety of urea and salt tablets. Severe liver disease is a contraindication to urea.
5. Medication Reconciliation: Review all medications. Discontinue or adjust any non-essential drugs known to induce or exacerbate SIADH (e.g., certain SSRIs, thiazide diuretics, carbamazepine, antipsychotics) if clinically appropriate.

6. Designing the Oral Maintenance Regimen

The design of an oral maintenance regimen for SIADH must be individualized. It involves selecting and combining therapies appropriately, providing comprehensive patient education, and implementing a structured follow-up plan to ensure long-term safety and efficacy.

A. Therapy Selection & Combination

• First-line: Initiate with fluid restriction, coupled with thorough patient education on adherence strategies and self-monitoring of intake.
• Second-line: If fluid restriction alone is insufficient to maintain target serum sodium, add oral urea or salt tablets. The choice depends on patient tolerance, comorbidities, cost, and availability. Urea is often preferred for its aquaretic effect without significant sodium load if tolerated.
• Adjuncts: Loop diuretics (e.g., furosemide) may be considered cautiously as an adjunct, particularly if urine osmolality is high relative to plasma osmolality or if there is concomitant mild volume overload. They work by impairing the kidney’s concentrating ability. However, they can also cause electrolyte losses.
• Vasopressin Antagonists (Vaptans): Drugs like tolvaptan are generally reserved for select cases of refractory or severe hyponatremia, often in hospitalized settings, due to their cost, need for careful monitoring (risk of overly rapid correction, liver injury), and specific initiation/duration guidelines. They are less commonly used for routine chronic outpatient management.

B. Patient & Family Education

• Demonstrate the proper preparation and administration of urea powder (if prescribed) and explain the dosing schedule for salt tablets.
• Provide clear, written guidelines for fluid restriction, including examples of fluid content in common foods and beverages. Offer tracking tools (logs, apps).
• Educate the patient and family on recognizing early signs and symptoms of hyponatremia recurrence (e.g., headache, nausea, vomiting, confusion, lethargy, muscle cramps) and when to seek medical attention.
• Discuss potential side effects of medications and strategies to manage them.

C. Structured Follow-Up

• Laboratory Monitoring: Schedule regular follow-up for serum sodium monitoring. Initially, this might be every 1–2 weeks while titrating oral therapies, then extended to monthly or every few months once the patient is stable on a maintenance regimen. Also monitor renal function and other relevant labs based on chosen therapies.
• Outpatient Handoff: Ensure a concise and clear summary of the SIADH diagnosis, treatment regimen, monitoring parameters, specific sodium targets, and emergency triggers is communicated to the outpatient primary care physician and any relevant specialists.
• Telehealth or Clinic Visits: Regular check-ins, either via telehealth or in-person clinic visits, can reinforce adherence, allow for early problem-solving, and provide an opportunity to adjust therapy as needed.
• Quality Metrics: Healthcare systems may track quality metrics such as hospital readmission rates for hyponatremia, adherence to SIADH management protocols, and completeness of patient education documentation.

Comparison of Oral Maintenance Therapies for SIADH