Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) Treatment & Management

Treatment of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and the rapidity of correction of hyponatremia depend on the degree of hyponatremia, on whether the patient is symptomatic, and on whether it is acute (< 48 h) or chronic. The urine osmolality and creatinine clearance also must be considered when choosing the type of therapy. If no history is available to determine the duration of hyponatremia and if the patient is asymptomatic, it is reasonable to presume the condition is chronic. Diagnosis and treatment of the underlying cause of SIADH is also important.

Extreme hyponatremia and an inappropriate approach to its treatment can both have disastrous consequences; consultation with a nephrologist should be sought early in difficult cases. Correcting hyponatremia too rapidly may result in central pontine myelinolysis (CPM) with permanent neurologic deficits. It is important to remember that even severe hyponatremia can correct rapidly with just fluid restriction if the hyponatremia is associated with absent ADH secretion (eg, psychogenic polydipsia).

European guidelines for the treatment of syndrome of inappropriate antidiuresis include the following recommendations for management of moderate or profound hyponatremia ^[31] :

• Restrict fluid intake as first-line treatment
• Second-line treatments include increasing solute intake with 0.25–0.50 g/kg per day of urea or a combination of low-dose loop diuretics and oral sodium chloride
• Use of lithium, demeclocycline, or vasopressin receptor antagonists is not recommended

Recommendations on the treatment of SIADH from an American Expert Panel included the following ^[32] :

• If chronic, limit rate of correction
• Fluid restriction should generally be first-line therapy
• Consider pharmacologic therapies if serum Na ⁺ is not corrected after 24-48 hr of fluid restriction or if patient has a low urinary electrolye free water excretion
• Patients being treated with vaptans should not be on a fluid restriction initially
• Water, 5% dextrose or desmopressin can be used to slow the rate of correction if the water diuresis is profound

Aggressive treatment of hyponatremia should always be weighed against the risk of inducing CPM. A rare but serious complication, CPM can develop 1 to several days after aggressive treatment of hyponatremia. Aggressive management of hyponatremia is indicated in patients with severe symptoms such as seizures, stupor, coma, and respiratory arrest, regardless of the degree of hyponatremia. Emergent treatment should also be strongly considered for those with moderate-to-severe hyponatremia with a documented duration of less than 48 hours.

The goal is to correct hyponatremia at a rate that does not cause neurologic complications. The objective is to raise serum Na⁺ levels by 0.5-1 mEq/h, and not more than 10-12 mEq in the first 24 hours, to bring the Na⁺ value to a maximum level of 125 -130 mEq/L. Administration of 3% hypertonic saline should be restricted to these emergent circumstances, and both neurological symptoms and serum Na⁺ should be monitored frequently to achieve the desired target and to prevent overcorrection.

Correction of serum Na⁺ levels by 6 mEq/L in 24 hours has been dubbed the "rule of sixes." The rule states that, "Six a day makes sense for safety; 6 in 6 hours for severe symptoms and stop." ^[33]

Other authors have recommended a rate of initial correction of 1-2 mEq/L/h in severely symptomatic patients until symptoms resolve (or for the first 3-4 h). However, total correction in the first 24 hours must not exceed 10-12 mEq. CPM has been reported in cases in which the initial correction exceeded 12 mEq and even in cases in which the correction was 9-10 mEq/24 h. This has led some authors to recommend a lower target of 8 mEq in 24 hours. In the special situation of exercise-induced hyponatremia with neurological symptoms, some authors recommend an immediate bolus of 100 mL of 3% hypertonic saline repeated every 10 minutes until symptoms resolve. ^[23]

Formulas for the dose and rate of hypertonic saline have been proposed based on a Na⁺ deficit to calculate the rate of administration of hypertonic fluids. ^{[18, 34]} However, they have not been prospectively studied. Despite the correct use of these formulas, hyponatremia is often corrected too rapidly. Therefore, these formulas should serve only as guidelines. Patients still require frequent retesting of their serum Na⁺ concentration. ^[21]

The approximate Na⁺ deficit can be estimated by using the following formula (0.5 L/kg for females):

• Na⁺ Deficit (mEq) = (Desired Na⁺ - Measured Na⁺) x 0.6 L/kg x Weight (kg)

Three-percent hypertonic saline has 513 mEq/L each of Na⁺ and Cl^- and has an osmolality of 1026 mOsm/L. The volume of hypertonic saline needed to correct that deficit can be calculated as follows:

• Volume of 3% Saline = (Na⁺ Deficit)/513 mEq/L Na⁺

Assuming a rate of correction of chronic hyponatremia of 0.5 mEq/L per hour, the amount of time needed to correct a given degree of hyponatremia is as follows:

• Time Needed for Correction = (Desired Na⁺ - Measured Na⁺)/0.5 mEq/L per hour

The rate of infusion of hypertonic saline is as follows:

• Rate = (Volume of 3% Saline)/(Time Needed for Correction)

Furosemide increases excretion of free water and has been used along with hypertonic saline in severe cases to limit treatment-induced volume expansion. The diuresis induced by furosemide has a urine solute concentration roughly equivalent to half-normal saline; thus, excretion of free water occurs. Electrolyte free water intake can be restricted. Combining furosemide with hypertonic saline and water restriction may lead to a faster rate of correction of serum Na and requires that serum Na⁺ osmolality and urine osmolality be checked frequently to monitor the change in serum Na⁺ values and to prevent overcorrection. Attention should also be paid to the prevention of severe hypokalemia in conjunction with treatment of hyponatremia.

In the acute setting (ie, < 48 h since onset) with moderate symptoms such as confusion, delirium, disorientation, nausea, and vomiting, the treatment options for the hyponatremia include 3% hypertonic saline (513 mEq/L), loop diuretics with saline, vasopressin-2 receptor antagonists (aquaretics), and water restriction.

Depending on the rate of development of hyponatremia, the approach to correction varies. If an acute onset and moderate neurologic symptoms have occurred, the use of hypertonic saline may be warranted (discussed under Emergent Care). If symptoms are less severe (headache, irritability, inability to concentrate, altered mood) or absent, then vasopressin-2 receptor antagonists (aquaretics) or water restriction are both options. The patient's serum Na⁺ level and clinical status must be monitored often to determine the need for continued aggressive therapy.

Water restriction

The degree of water restriction depends on the prior water intake, the expected ongoing fluid losses, and the degree of hyponatremia. Water restriction to about 500-1500 mL/d (or even lower in some cases) is usually prescribed. Although easier to maintain in the hospital setting, this becomes difficult for patients to follow in an outpatient setting. 

One of the functions of the kidneys is to excrete solutes in varying amounts of water. In persons with SIADH, urine osmolality is fixed at a certain value; for the kidneys to eliminate an "X" amount of solutes, a certain volume of water must be excreted. If water intake is lowered below total obligatory fluid losses (insensible losses plus volume of urine required to excrete the osmolar load), then serum osmolality rises because a net loss of water occurs. The insensible losses of relatively hypotonic fluids also contribute to net water loss. The key is sufficient restriction of water intake so that the excretion of free water from all sources is in excess of that taken in.

For example, consider a patient who has a net solute load of 900 mOsm/kg/day that must be excreted, and, because of SIADH, his or her urine osmolality is fixed at 600 mOsm/kg. This patient then excretes the solute load in 1.5 L of urine. On the other hand, if the urine osmolarity is fixed at 300 mOsm/kg, then 3 L of urine is required to excrete the same osmolar load. When water intake is restricted, the body mobilizes the free water already present to excrete this load. Thus, if urine output (plus insensible losses) exceeds water intake, a net water loss occurs and the serum Na⁺ level returns towards normal.  For that reason when the sum of urinary Na⁺ and K⁺ is greater than serum Na+ concentration, fluid restriction alone is unlikely to be effective. ^[32]

Vasopressin receptor antagonists

Inhibition of the AVP V2 receptor reduces the number of aquaporin-2 water channels in the renal collecting duct and decreases the water permeability of the collecting duct. Collectively, agents that competitively block ADH action and increase water excretion are called aquaretics, and they are useful in the treatment of the hyponatremia in SIADH. The term "vaptan" has been coined to officially name all the members of this new class of drugs. ^[6]

Two aquaretics are currently approved by the US Food and Drug Administration (FDA). Conivaptan is a parenteral nonpeptide dual AVP V1a- and V2-receptor antagonist, which is approved for use in hospitalized patients with euvolemic (dilutional) and hypervolemic hyponatremia. The drug is given as a 20-mg loading dose followed by a continuous infusion or as intermittent boluses, but it should not be used for more than 4 days. The pivotal studies in euvolemic hyponatremia showed that compared with fluid restriction alone, conivaptan together with a 2 L fluid restriction over 4 days increased serum Na by 6 mEq/L, with a median increase of 4 mEq/L by 23 hours. ^[35]

Tolvaptan is a selective oral V2 receptor antagonist also approved for use in hospitalized patients for hypervolemia and euvolemic hyponatremia. ^[36] The drug is started at 15 mg once daily and titrated up to 60 mg daily as required, and it is best to avoid fluid restriction during the dose-finding phase. In the pivotal studies, which included patients with heart failure, cirrhosis, and SIADH, tolvaptan compared with fluid restriction alone increased serum Na by 8 mEq/L over 30 days, although with withdrawal of the drug, serum Na⁺ falls back to that seen in the placebo group. ^[37]

This is a useful drug to consider in a patient in whom serum Na⁺ does not rise by 2 mEq in the first 24 hrs after a 1000-mL fluid restriction. Once the drug is initiated, the patient can be discharged in 24-48 hours if neurological symptoms have resolved or the patient was asymptomatic at presentation. If the underlying cause of SIADH has resolved, the drug can be withdrawn after 2-4 weeks, while carefully monitoring serum Na⁺ daily for the next 5 days. If the serum Na⁺ falls again and if is less than 125 for more than 48 hours, the patient may need to be admitted again before reinitiating tolvaptan. Tolvaptan can also be considered for long-term therapy of chronic hyponatremia. ^[38]

Results of a study by Morris et al suggest that low baseline serum Na⁺ and serum urea nitrogen (SUN) values can identify patients with SIADH who are likely to experience rapid correction of hyponatremia with tolvaptan, and who are thus at risk of overcorrection. In their study, which included 28 patients with SIADH treated with tolvaptan, the rate of increase in serum Na⁺ concentration was significantly greater (mean 24-hour increase of 15.4 mEq/L) in patients with baseline serum Na⁺ of 121 mEq/L or less and baseline SUN of 10 mg/dL or less, than it was in patients with higher baseline Na⁺ and SUN concentrations. ^[39]

The vaptans can have a profound effect on serum Na and they should be used by physicians experienced in the management of hyponatremia. These drugs should be avoided in hypovolemic hyponatremia. The vaptans are more likely to be effective compared with fluid restriction alone in patients in whom the sum of urinary potassium and Na⁺ concentration is greater than the plasma concentration. They offer the benefit of prompt correction of serum Na⁺, producing water excretion without electrolyte excretion and eliminating the need for fluid restriction. The primary risk of using these drugs is an excessively rapid rate of correction of the serum sodium concentration.

Furosemide

Furosemide and other loop diuretics can be used to increase the excretion of free water. Excess water that must be removed to correct the hyponatremia can be calculated using total body water (TBW). TBW equals body weight in kg multiplied by 0.6, assuming that the total body solute or water has not changed. The diuresis induced by furosemide has a urine solute concentration roughly equivalent to half-normal saline; thus, excretion of free water occurs. The excreted Na⁺ is replaced with 3% hypertonic saline or with normal saline (NaCl 154 mEq/L), thus avoiding a net Na⁺ loss while effecting a loss of free water.

Other sources of free water intake should be restricted as well. If the measured sum of urinary potassium and Na⁺ with furosemide is greater than the plasma Na, then hypertonic saline rather than normal saline should be used to replace excreted Na. Serum Na⁺ and osmolality and urine osmolality should be checked frequently to monitor the change in serum Na⁺ and the rate of correction.

Asymptomatic patients with chronic SIADH, the principal options are fluid restriction and V2 receptor antagonists (see Acute Setting). If V2 receptor antagonists are not available or if local experience with these agents is very limited, other therapeutic modalities include chronic loop diuretics with increased salt intake, urea, mannitol, and demeclocycline.

Urea

Urea is a solute that must be excreted by the kidneys. Because urine osmolality is fixed in persons with SIADH, the obligatory urine volume can be increased by increasing the osmotic or solute load. Increased urinary loss of water decreases free water retention. This therapy can be used in chronic and acute settings if the urine osmolality is low and can increase the serum Na⁺ by up to 5 mEq/L/day. Urea is a relatively nontoxic compound and, as opposed to sodium chloride treatment, does not cause edema or increase body weight.

Urea can be administered on a long-term basis (0.5 g/kg body weight) without major adverse effects. Urea is available as a powder, which is dissolved in water and taken orally during or after meals. To avoid gastric upset, it can be taken with an antacid. Urea can also be used continuously in patients with cerebral hemorrhage via a gastric tube or intravenously to prevent a rapid fall in intracranial pressure.

Urea should be used with great care in patients with serum creatinine of 2 mg/dL or more, BUN 80 mg/dL or more, or bilirubin of 2 mg/dL or more, to avoid progressive azotemia, hyperammonemia, and hepatic encephalopathy. Hypernatremia and dehydration may occur if the patient does not have free access to water.