The syndrome of inappropriate antidiuretic hormone secretion is defined by the hyponatremia, hypo-osmolality of plasma and increases osmolality of urine that results from inappropriate, continued secretion and/or action of antidiuretic hormone despite normal or increased plasma volume.
Hyponatremia is defined as plasma Na+ concentration of less than 135 mEq/L. Syndrome of inappropriate antidiuretic hormone secretion should be differentiated from other causes of hyponatremia. Syndrome of inappropriate antidiuretic hormone secretion is also a leading cause of hyponatremia in children following chemotherapy or stem cell transplantation.
Pathophysiology of Syndrome of inappropriate antidiuretic hormone secretion
Antidiuretic hormone [arginine vasopressin or AVP] promotes the reabsorption of water from the tubular fluid in the collecting duct but does not exert a significant effect on the rate of Na+ reabsorption.
It also causes arteriolar vasoconstriction and a rise in arterial blood pressure.
Arginine vasopressin is synthesized in the cell bodies of neurons of the anterior hypothalamus.
The major stimuli for antidiuretic hormone are secretion are increased in osmolarity and decrease of circulating volume.
These changes are sensed by osmoreceptors [hypothalamus] and baroreceptors [carotid sinus, aortic arch, and left atrium].
Normally, antidiuretic hormone secretion ceases when plasma osmolality falls below 275 mOsm/kg. This decrease causes increased water excretion. When plasma osmolality rises, antidiuretic hormone is secreted, which results in an increase in water reabsorption and an increase in urine osmolality.
Syndrome of inappropriate antidiuretic hormone secretion should be diagnosed when decreased serum sodium, decreased plasma hypo-osmolality and increased osmolality of the urine in a patient who has normal cardiac, renal, adrenal, hepatic, and thyroid function, in the absence of diuretic therapy; and in absence of other factors known to stimulate antidiuretic hormone secretion, such as hypotension, severe pain, nausea, and stress.
The nonphysiological secretion of antidiuretic hormone results in enhanced water reabsorption, leading to dilutional hyponatremia leading to volume expansion.
To counter increased volume, increased loss of sodium and potassium occurs but eventually, a steady state is reached and the amount of Na+ excreted in the urine matches Na intake.
It must be noted that hyponatremia does not occur if water intake is severely restricted.
Persons with this syndrome may also have an inappropriate thirst sensation, which leads to an intake of water that is in excess of free water excreted. This increase in water ingested may contribute to the maintenance of hyponatremia.
Hyponatremia and hypo-osmolality lead to acute edema of the brain cells.
The brain extracellular fluid moves into the CSF to tackle this edema. The brain cells then lose potassium and intracellular organic osmolytes to prevent excessive brain swelling.
Following correction of hyponatremia, electrolytes rapidly reaccumulate in the brain extracellular fluid within 24 hours, resulting in a significant overshoot. Organic osmolytes return to normal brain content very slowly over 5-7 days and is followed by correction of electrolyte brain content.
Irreversible neurologic damage and death may occur when the rate of correction of Na+ exceeds 0.5 mEq/L/h for patients with severe hyponatremia. As osmolytes that have been lost cannot be restored as rapidly when hyponatremia is rapidly corrected. The brain cells are thus subject to osmotic injury, a condition termed osmotic demyelination
Causes of SIADH
SIADH is most often caused by either inappropriate hypersecretion of ADH from its normal hypothalamic source or by ectopic production.
Nervous system disorders
- Acute psychosis
- Acute intermittent porphyria
- Brain abscess
- Cavernous sinus thrombosis
- Cerebellar and cerebral atrophy
- Cerebrovascular accident
- CNS lupus
- Delirium tremens
- Encephalitis (viral or bacterial)
- Guillain-Barré syndrome
- Head trauma
- Herpes zoster (chest wall)
- Hypoxic ischemic encephalopathy
- Meningitis (viral, bacterial, tuberculous, and fungal)
- Midfacial hypoplasia
- Multiple sclerosis
- Perinatal hypoxia
- Rocky Mountain spotted fever
- Shy-Drager syndrome
- Subarachnoid hemorrhage
- Subdural hematoma
- Ventriculoatrial shunt obstruction
- Wernicke encephalopathy
- Pulmonary – Lung carcinoma and mesothelioma
- Gastrointestinal – Carcinomas of the duodenum, pancreas, and colon
- Genitourinary – Adrenocortical carcinoma; carcinomas of cervix, ureter/bladder, and prostate; and ovarian tumors
- Other – Brain tumors, carcinoid tumors, Ewing sarcoma, leukemia, lymphoma, nasopharyngeal carcinoma, neuroblastoma (olfactory), and thymoma
- Acute bronchitis/bronchiolitis
- Acute respiratory failure
- Aspergillosis (cavitary lesions)
- Bacterial pneumonia
- Chronic obstructive lung disease
- Cystic fibrosis
- Pneumonia (viral, bacterial [mycoplasmal], fungal)
- Positive pressure ventilation
- Pulmonary abscess
- Pulmonary fibrosis
- Viral pneumonia
Stimulate Antidiuretic hormone release are as follows:
- Antineoplastic agents
- Adenine arabinoside
- Nicotine (inhaled tobacco)
- Nitrous oxide
- Monoamine oxidase inhibitors
- Tricyclic antidepressants
Potentiate the effects of antidiuretic hormone action
- Hypoglycemic agents
- Vasopressin analogs
Drugs with an uncertain mechanism
- Antineoplastic agents
- Antiepilepsy drugs
- Selective serotonin reuptake inhibitors
- Giant cell arteritis
- HIV infection – Idiopathic
Bartter and Schwartz in criteria for diagnosis of Syndrome of inappropriate antidiuretic hormone secretion.
- Hyponatremia with corresponding hypoosmolality
- Continued renal excretion of Na +
- Urine less than maximally dilute
- Absence of clinical evidence of volume depletion
- Absence of other causes of hyponatremia
- Correction of hyponatremia by fluid restriction
Hyponatremia with concomitant hypo-osmolality (serum osmolality) and high urine osmolality is the hallmark of SIADH.
Serum Na and serum osmolality
Hyponatremia (ie, serum Na+ <135 mmol/L) is a defining feature of SIADH. In SIADH, the hyponatremia is associated with measured serum hypo-osmolality (<280 mOsm/kg).
- Within the reference
- Due to the movement of hydrogen ions into the cells and to increased hydrogen ion excretion by the renal tubules
- Generally remains unchanged.
- Due to movement of potassium from the intracellular space to the extracellular space
- Decreased Potassium and metabolic alkalosis -, consider diuretic therapy or vomiting as the cause of hyponatremia.
- Hyperkalemia and metabolic acidosis – Consider adrenal insufficiency and volume depletion leading to acute kidney injury.
- Secondary to dilution of serum Na+ and chloride, with unaffected bicarbonate (HCO3–).
- Reduced the tubular reabsorption of unmeasured anions.
Urinary Na excretion
- Urinary loss of Na+ occurs despite significant hyponatremia
- A reflection of Na+ intake
- Usually > 20 mmol/L.
- Low when Na+ intake restricted or extrarenal loss may be very low.
- Elevated but not necessarily greater than the corresponding serum osmolality
- Hyponatremic patients without SIADH have a urine that is maximally dilute (ie, 50-100 mOsm/kg)
- In SIADH, the urinary osmolality is usually submaximally dilute (ie, >100 mOsm/kg)..
Blood urea nitrogen levels
Usually low secondary to volume expansion and thus dilution.
- Serum uric acid concentration is decreased
- Fractional excretion of uric acid (FEUA)
- Percentage of urate filtered by glomeruli that is excreted in urine.
- Measured by formula: (Urinary uric acid [mg/mL] × serum creatinine [mg/mL] ÷ (serum uric acid [mg/mL] × urinary creatinine [mg/mL]) × 100% = FEUA
- FEUA rises due to volume expansion and a decrease in distal tubular reabsorption.
Hypouricemia and an elevated FEUA may be seen in either salt-wasting syndromes or SIADH.
In SIADH, both typically resolve after correction of hyponatremia but persist in those with salt-wasting syndromes.
- Values are not usually available quickly
- Co-peptin is a stable C-peptide fragment of the AVP precursor protein which is easier to measure
These studies may help to evaluate the probable causes of the syndrome of inappropriate antidiuretic hormone secretion.
For example, chest radiographs may reveal an underlying pulmonary cause.
In case of the nervous system causes, CT or MRI may be done.
The treatment of the syndrome of inappropriate antidiuretic hormone secretion centers around correction of hyponatremia first followed by treatment of the cause if present.
The correction of the low sodium status depends on
- Degree of hyponatremia
- Whether the patient is symptomatic
- Acute (<48 h) or chronic
- Urine osmolality
- Creatinine clearance
If the patient is asymptomatic, the condition is presumed to be chronic.
In case of severe hyponatremia, correcting hyponatremia too rapidly may result in central pontine myelinolysis with permanent neurologic deficits.
Water, 5% dextrose or desmopressin can be used to slow the rate of correction if the water diuresis is profound
Therefore the correction, even by fluid restriction, should be regulated.
Fluid restriction is the first line of treatment.
Second-line is increasing solute intake.
Drugs are considered if serum Na + is not corrected after 24-48 hr of fluid restriction or if the patient has a low urinary electrolyte free water excretion
Aggressive management of hyponatremia is indicated in patients with severe symptoms like seizures, stupor, coma, and respiratory arrest, regardless of the degree of hyponatremia.
Or those with moderate-to-severe hyponatremia with a documented duration of less than 48 hours.
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. [The fast correction should be avoided to avoid risk of neural complication discussed above]
For correction of sodium 3% hypertonic saline can be administered. Both neurological symptoms and serum Na+ should be monitored frequently to achieve the desired target and to prevent overcorrection.
A more aggressive approach corrects sodium at a rate
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.
Furosemide increases excretion of free water and has been used along with hypertonic saline in severe cases to limit treatment-induced volume expansion.
It results in a faster rate of correction of serum Na and requires that serum Na+ osmolality and change in serum Na+ values should be monitored more frequently.
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.
The patient’s serum Na+ level and clinical status must be monitored often to determine the need for continued aggressive therapy.
Water restriction to about 500-1500 mL/d or lower is usually prescribed.
Vasopressin receptor antagonists
These are agents that competitively block ADH action and increase water excretion.
Conivaptan [continuous infusion or as intermittent boluses] and tolvaptan [oral] are the available drugs. The group drugs is called vaptan.
Furosemide and other loop diuretics can be used to increase the excretion of free water.
Fluid restriction and vaptans are main choices for treatment. Other therapeutic modalities include chronic loop diuretics with increased salt intake, urea p 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 orally], mannitol, and demeclocycline.
Complications of SIADH
The following complications are noted in SIADH:
- Cerebral edema leading to cerebral herniation.
- Noncardiogenic pulmonary edema
- Central pontine myelinolysis is the feared complication of excessive, overly rapid correction of hyponatremia.
- Spastic quadriparesis
- Pseudobulbar palsy
High-risk groups are
- Persons with hepatic failure
- Potassium depletion
- Large burns
- Premenopausal patients undergoing surgery
There is no proven treatment for this disorder.
Even mild hyponatremia can cause significant impairment, such as unsteady gait, and lead to frequent falls
The mortality of patients with hyponatremia (Na+ <130 mEq/L) is increased 60-fold.
When the Na+ concentration drops below 105 mEq/L, there is a higher risk of life-threatening complications.
The prognosis of the syndrome of inappropriate antidiuretic hormone also depends on the underlying cause and severity of hyponatremia and its correction
As noted before, patients whose serum Na+ is rapidly corrected, especially those who are asymptomatic, can also develop permanent neurologic impairment from central pontine myelinolysis (CPM).
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