SIADH, or syndrome of inappropriate antidiuretic hormone secretion, is a condition where there is persistent inappropriate release of antidiuretic hormone from the pituitary or other sources, or continued action at the level of vasopressin receptors. Frederic Bartter and William Schwartz first described the syndrome in 1967 in two patients who had lung cancer. They delineated the classic Bartter and Schwartz basis for diagnosing SIADH, which remains the same even today. SIADH is manifested by a decreased ability to excrete water, with hyponatremia, often concomitant with hypervolemia or euvolemia. 

The occurrence of SIADH rises with age, although recent studies have also revealed an increased incidence in children. Children and the elderly are more prone to developing hyponatremia, especially when the cause of admission is respiratory and infections of CNS, including bronchiolitis, meningitis, or pneumonia. A greater proportion of the post-operative and hospitalized patients also develop SIADH mainly due to hypotonic fluids, some medications, and the stress response. 

ADH, or arginine vasopressin, is synthesized in the hypothalamus but then transported via the pituitary stalk to the posterior pituitary for storage and release. Its primary function is in osmoregulation. When there is a significant decrease in effective blood volume, ADH will adjust its activity to regulate volume, even if it compromises effective plasma osmolality or tonicity. It is important to differentiate between “plasma osmolality” and “plasma tonicity” or “effective plasma osmolality”. The latter two are determined by the effective osmoles in the ECF, which include sodium, all of which cannot cross easily through cell membranes and thus participate in ECF tonicity. While urea and glucose also contribute to plasma osmolality, they act as ineffective osmoles since they easily diffuse beyond the cell membrane and therefore exert no osmotic effect for plasma tonicity maintenance. 

Osmoregulation 

ADH plays a key role in regulating plasma tonicity through control of water balance. Hypothalamic osmoreceptors are sensitive to alterations in the efficacious plasma osmolality and control the output of ADH to regulate water. When plasma tonicity is high, ADH is released and acts on vasopressin V2 receptors found in the luminal cell surface present in collecting tubules. Through its action, aquaporin-2 water channels can be generated, which reabsorb water through the gradient in the direction of gradient water. The aforementioned channels could be eventually disconnected by endocytosis and recycled back to cytoplasm. Osmoreceptors are so sensitive that they can detect changes in plasma tonicity as small as 1%. In humans, the release of ADH is stimulated when the plasma osmolality falls below about 280 to 290 mOsmol/kg. In SIADH, the level of ADH continues to be high despite low or hyponatremic plasma osmolality since excessive water absorption then keeps blood volume normal or high. 

Volume regulation 

A rapid fall in the blood pressure, detected through the “volume receptors” than by “osmoreceptors,” is the stimulus for the release of ADH, as well as renin and epinephrine. The resulting increase in these hormones stimulates the kidneys to absorb large amounts of free water and can cause hyponatremia and a reduction in effective osmolality of extracellular fluid (ECF). In states of rapid or large volume loss, “volume regulation” becomes the predominant response, even at the loss of osmolality. It is well-illustrated in patients with hepatic or cardiac disease where hyponatremia often becomes a direct marker of worse prognosis. 

SIADH is most often a secondary condition resulting due to another disease in the body. Inherited SIADH, also called nephrogenic SIADH, is attributed to a gain of function mutation in the V2 (vasopressin 2) receptors present in kidneys. 

Factors that regularly cause SIADH: 

CNS disturbances: abnormalities in CNS can stimulate excessive release of ADH from pituitary gland, causing SIADH. Such disorders include hemorrhage, trauma, psychosis, stroke, infections, and mental illness. 

Malignancies: SCLC is a frequent tumor associated with ectopic production of ADH. Less commonly, ectopic ADH release can also occur with small cell carcinomas (extrapulmonary), neck and head cancers, and olfactory neuroblastomas. 

Drugs: Other drugs cause SIADH by stimulating the release of ADH or by increasing the sensitivity of target tissues to the action of ADH; these drugs include oxcarbazepine, cyclophosphamide, carbamazepine, chlorpropamide, or the SSRIs. The increased sensitivity to ADH which is associated with chlorpropamide therapy is said to be due to a greater than normal count of V2 receptors in the collecting tubules of the kidney. Cyclophosphamide, when used at high doses to stop hemorrhagic cystitis, may provoke SIADH.  SSRIs may lead to SIADH by a mechanism that is unclear. People over the age of 65 are more affected. Many recreational drugs, like “ecstasy,” are especially associated with ADH secretion and hyponatremia. 

Surgery: These surgical procedures frequently lead to ADH hypersecretion likely mediated by pain signals from affected areas. 

Pulmonary disease: Unknown processes can cause SIADH in patients with pulmonary illnesses, including viral or bacterial, or tuberculous pneumonia. Patients experiencing atelectasis, pneumothorax, asthma, and acute respiratory failure have occasionally exhibited a similar reaction. 

Deficiency of hormone: Both hypothyroidism and hypopituitarism can be associated with a SIADH and hyponatremia like presentation, which can be managed and corrected through HRT. 

HIV infection: Hyponatremia often occurs as a laboratory abnormality in HIV infection, whether in the context of AIDS (acquired immune deficiency syndrome) or prior symptomatic HIV disease. Underlying conditions may include volume depletion due to gastrointestinal losses or adrenal insufficiency, while the basis can also be SIADH. Opportunistic infections, such as pneumonia (e.g., Pneumocystis carinii), can also contribute to SIADH. Endogenous Cushing syndrome is another rare etiological factor. 

Hereditary SIADH: A gain of function mutation that occurs in the renal V2 receptor gene located on the X chromosome causes hereditary SIADH.  As a result of this mutation, V2 receptors are constantly active and cause the reabsorption of too much water, leading to hyponatraemia. This form of hyponatraemia cannot be treated with antagonists of vasopressin receptor. 

The prognosis for patients with SIADH, in general, depends on the underlying cause and the severity of hyponatremia but also on the risks associated with overcorrection. In cases of drug-induced SIADH, the prognosis is typically good and includes prompt and full recovery after withdrawal of the offending medication. 

The symptoms of hyponatremia, due to the syndrome of inappropriate antidiuretic hormone secretion, are based on its degree and rapidity of development. Slowly progressive hyponatremia is less symptomatic compared to rapid declines in serum Na+. Moderate, chronic hyponatremia is associated with prolonged reaction times, cognitive slowing, and ataxia, resulting in frequent falls. Acute hyponatremia symptoms do not necessarily follow severity or acuity. Early signs and symptoms include anorexia, nausea, and malaise; further reductions may lead to headache, muscle cramps, irritability, somnolence, confusion, weakness, seizures, and coma. History of SIADH may alter the rate of correction and provide an etiology for the disorder. 

Once hyponatremia has been established, appropriate management is based on the clinically assessed volume status of the patient. In most cases, SIADH patients have normal blood pressure without peripheral or pulmonary edema, with dry mucous membranes, decreased skin turgor, and orthostatic hypotension. If a hyponatremic patient presents with edema, then it may not be due to SIADH but could be due to some other entity, for example, cirrhosis, CKD, or CHF. 

The physical examination findings are generally more pronounced in cases of severe or rapidly developing hyponatremia and may include the following: 

1. Myoclonus 
2. Hyporeflexia 
3. Dysarthria 
4. Cheyene-Stokes respiration 
5. Ataxia 
6. Confusion 
7. Delirium 
8. Disorientation 
9. Generalized seizures 
10. Asterixis 
11. Coma 
12. Tremor 
13. Pathologic reflexes 

Severe complications are: 

1. Memory problems 
2. Tremors 
3. Muscle cramps 
4. Headaches 
5. Depression 

Most potential complications are: 

1. Seizures 
2. Coma 
3. Hallucinations 
4. Respiratory failure 
5. Death 

Approach considerations 

Treatment of syndrome of inappropriate antidiuretic hormone secretion depends on the severity of hyponatremia, symptoms of the patient, and whether it is acute or chronic. Measured urine osmolality and calculated creatinine clearance are also key factors in choosing appropriate therapy. In the absence of an appropriate history, it is often reasonable to assume the condition is chronic. Treatment of the underlying cause of SIADH should be instituted. Patients who are very hyponatremic or have inappropriate treatment will develop severe complications. A nephrologist should be consulted early because the rapid correction of hyponatremia can lead to central pontine myelinolysis with permanent neurological damage. 

European guidelines usually recommend fluid restriction as a first-line measure. In contrast, American Expert Panel recommendations suggest a more nuanced approach to the management: rate of correction should be limited, pharmacologic therapies may be used, fluid intake is not restricted initially, and fluids like desmopressin, 5% dextrose, and water are used for rate control. 

Emergent care 

Immediate intervention with aggressive treatment regimens is indicated in patients with severe symptoms like seizures, stupor, coma, and respiratory arrest. This, however, is also indicated in patients with moderate to severe hyponatraemia if a documented history of the condition is within 48 hours. The goal of treatment is to cautiously normalize the hyponatraemia level without causing neurological complications, for example, increasing the serum Na stable upon presentation by 0.5-1 mEq/h and not exceed 10-12 mEq/L in the first day. The rule of sixes recommends 6 mEq/L over 24 hours to be safe; some authors recommend initial correction of 1-2 mEq/L/h until resolution of the symptoms. However, total correction over the initial 24 hours should not exceed 10-12 mEq. CPM has been reported in patients when the initial correction was over 12 mEq and even when the target was set lower at 8 mEq/24 hours. Formulas for dose and rate calculation of hypertonic saline still have not been prospectively studied and, therefore, retesting of serum Na+ concentration is still clinically required very often. 

Nephrology

Fluid restriction 

Low fluid is a major way to treat the disease by maintaining it in patients. Sticking to prescribed fluid restrictions enables patients to reduce water retention levels and fight against hyponatremia at the same time. 

Medication management 

If appropriate, modification of the patient’s medication course to include vasopressin receptor antagonists or other pharmacologic agents is indicated. Assurance that medications are appropriately managed and administered can obviate complications and facilitate desired treatment goals. 

Patient education 

The fluid restriction, symptoms of hyponatremia, and importance of compliance with the treatment plan should be explained and communicated to the patient. Adequate instructions with proper emotional support make it easier for the patient to understand and follow the set regimen. 

Environmental controls 

Modification of the patient’s environment to decrease stressors that might increase SIADH can be helpful, such as maintaining a noise free, calm, and comfortable setting. In some cases, there are occasions when stress reduction does contribute to overall effectiveness in a treatment plan. 

Nephrology

Conivaptan: It is a non-selective antagonist of vasopressin receptor that is administered parenterally. It is employed in treating euvolemic hyponatremia in patients who are hospitalized. 

Tolvaptan: It is a selective antagonist of V2-vasopressin receptor given orally. It is employed in the treatment of euvolemic and hypervolemic hyponatremia. 

Nephrology

Furosemide: It enhances the elimination of water by inhibiting the transporter of Na+, 2Cl-, K+ in the ascending Henle’s loop. This inhibition reduces the reabsorption of sodium and chloride leading to increased distal reabsorption of Na+. Consequently, the urine becomes hypo-osmolar compared to serum.  

Nephrology

Mannitol: This induces a rapid free-water diuresis by increasing the osmolarity of the glomerular filtrate, which inhibits the reabsorption of water in the tubules. While it also promotes the excretion of sodium and chloride, this effect is less pronounced compared to water excretion. It is usually administered as a 15-20% solution that can be administered intravenously. 

Nephrology

Demeclocycline: This is a derivative of the tetracycline, causes diabetes insipidus through its interference with the generation and action of cAMP, which interferes with the action of AVP in the collecting ducts. Its onset of action may be delayed by more than a week, so its use is inappropriate for urgent symptomatic hyponatremia. 

Nephrology

SIADH stands for Syndrome of Inappropriate Antidiuretic Hormone Secretion. It is hyponatremic syndrome. On the other hand, there are multiple phases involved in the management of SIADH: initial evaluation and diagnosis, treatment, fluid management, and sodium level correction. This can be associated with such symptoms as confusion, headaches, nausea, and seizures. Diagnosis assesses symptoms, confirms diagnosis, and afterwards volume status is evaluated. 

Underlying causes identified and treated, that is, infections, malignancies, medication effects. Medications are modified. Fluid restriction is often the first line of treatment. The fluid balance is monitored regularly. Gradual sodium correction to avoid some major complications like central pontine myelinolysis. 

Pharmacological treatment includes Vasopressin Receptor Antagonists, demeclocycline, and regular follow-up. Patients were instructed to compliance with fluid restriction and signs and symptoms that alerted them to hyponatremia. Special considerations will include consultation with subspecialists for further management and care of potential complications. Each phase should be individualized according to the patient’s needs and characteristics of SIADH.