Hospital Medicine

Syndrome of inappropriate antidiuretic hormone (SIADH)

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I. What every physician needs to know.

SIADH, more appropriately known as syndrome of inappropriate antidiuresis, is the pathologic state where the kidneys are not appropriately clearing free water. This retention of free water occurs despite the body being at a hypotonic state resulting in euvolemic hyponatremia.

II. Diagnostic Confirmation: Are you sure your patient has SIADH?

Criteria for SIADH require that a patient be intravascularly euvolemic with low serum tonicity (<275mOsm/L) in the setting of high urine osmolality (>100mOsm/L). Urine sodium should be high (>40mEq/L) in a patient taking in normal amounts of water and salt with SIADH.

A. History Part I: Pattern Recognition: Symptoms of SIADH

Symptoms of SIADH are those seen in hyponatremia. Mild hyponatremia can result in occult cognitive slowing and gait abnormalities particularly in the elderly population, along with nonspecific symptoms of headache and nausea. In more severe cases, hyponatremia can lead to seizure, coma and even death. Patients with SIADH are usually clinically euvolemic so symptoms are mostly due to hypotonicity. Rapid change in serum sodium as a result of correction of SIADH related hyponatremia can lead to brain crenation or edema and the symptoms of central pontine myelinolysis (see hyponatremia).

B. History Part 2: Prevalence: Causes of SIADH

SIADH occurs concomitantly with many disease states, drugs and stress states (seeTable I).

Table I

Causes of SAIDH.

Cancers

  • lung cancer- small cell, mesothelioma, bronchogenic carcinoma

  • gastrointestinal cancer - pancreatic, gastric, duodenal

  • genitourinary cancer - bladder, prostate, ureter, endometrium, ovary

  • head and neck cancer - oral, laryngeal, nasopharyngeal

  • endocrine thymomas

  • melanoma

  • lymphoma- Hodgkin's and non-Hodgkins

  • breast cancer

  • central nervous system tumors

  • sarcoma - Ewing's

Pulmonary processes

  • infection-bacterial pneumonia(including abscess), viral pneumonia, fungal pneumonia, tuberculosis

  • chronic obstructive pulmonary disease

  • asthma

  • positive pressure ventilation

  • intrathoracic surgery

  • cystic fibrosis

  • sarcoid

Central nervous system disorders

  • infectious Encephalitis

  • infectious meningitis

  • brain abscess

  • stroke

  • subarachnoid hemorrhage

  • subdural hematoma

  • intracranial surgery

  • hydrocephalus

  • brain tumor

  • cavernous sinus thrombosis

  • vasculitis

  • psychosis

  • delirium tremens

  • Shy-Drager

  • multiple sclerosis

Drugs

  • amiodarone

  • carbamazepine

  • chlorpromazine

  • chlorpropamide

  • clofibrate

  • cyclophosphamide

  • ifosfamide

  • MDMA

  • nicotine

  • narcotics

  • non-steroidal anti-inflammatory drugs

  • oxcarbazepine

  • oxytocin

  • phenothiazines

  • selective serotonin reuptake inhibitors

  • theophylline

  • tricyclic antidepressants

  • vasopressin

  • vincristine

Stress states

  • pain

  • nausea

  • stress

  • excessive exercise

C. History Part 3: Competing diagnoses that can mimic disease SIADH.

Most other causes of hyponatremia can mimic SIADH both clinically and in regards to the lab markers we use to define the syndrome. The initial work-up of SIADH is essentially the work-up of hyponatremia. The most clinically validated algorithm of evaluation of hyponatremia begins with the evaluation of plasma tonicity and then evaluating the patient extracellular volume status (Figure 1).

Figure 1.

Algorithm for the classification of hyponatremia.

SIADH falls into the category of hypotonic euvolemic hyponatremia and the other diagnoses that fit into this category must be ruled out to make the diagnosis of SIADH. Polydipsia and beer potomania can be ruled out by measuring a urine osmolality which should be below 100mOsm/L in these conditions. Adrenal Insufficiency may be associated with hyperkalemia and you can also check a cosyntropin stimulation test to confirm the diagnosis. Severe hypothyroidism can mimic SIADH and can be easily ruled out by checking for an elevated thyroid stimulating hormone level.

Finally, a careful history will rule out the possibility of recent diuretic use or other medications which can cause hyponatremia.

D. Physical Examination Findings.

The spectrum of physical exam findings exhibited in hyponatremia from SIADH vary based on the degree of hyponatremia.

E. What diagnostic tests should be performed?

The most valuable signs on physical exam when evaluating hyponatremia from SIADH is to rule out other causes of hyponatremia. There are no specific signs for SIADH that are independent of the effect of the hypotonicity of hypnatremia. Patients with mild hyponatremia and mean serum sodiums of 131mmol/L have been shown to exhibit a mildly ataxic gait and delayed reaction times.

Modest levels of hyponatremia (<125–135mmol/l) may cause patients to exhibit general lethargy, restlessness, disorientation, muscle spasm, and depressed neural reflexes. Severe symptoms are seizure, coma and cardiopulmonary arrest.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

The inappropriate secretion or effect of ADH results the decreased ability to clear free water. Because of this, the urine should be inappropriately concentrated despite a hypotonic serum. Definedcriteria for SIADH require low serum tonicity (<275mOsm/L) in the setting of high urine osmolality (>100mOsm/L). Urine sodium should be high (>40mEq/L) in a patient taking in normal amounts of water and salt with SIADH.

Since patients who suffer from SIADH are clinically euvolemic, their renin-angiotensin-aldosterone system should be suppressed making them less sodium avid. This assumes there is normal adrenal and thyroid function, which are also part of the criteria for SIADH as well. Finally, the above serum and urine tests must be obtained when a patient has no recent use of diuretics, since this can alter the kidney's handling of sodium and water.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

The diagnosis of SIADH is established based on clinical laboratory data, but the cause of the syndrome may not initially be obvious. Because most pulmonary and central nervous system pathology can result in the inappropriate secretion of ADH (see above), the clinician may want to work-up these conditions with appropriate imaging studies. There are no studies to suggest that routine chest or head imaging changes patient outcomes in SIADH without a known cause, and their necessity should be determined on a case by case basis.

III. Default Management.

SInce the majority of hyponatremia seen in the hospital is due to hypovolemic hyponatremia, the default therapy is to give the patient isotonic intravenous fluids and re-check the serum sodium. SIADH is the one condition where this can be detrimental to the patient since they cannot excrete the free water and will drop their sodium into a potentially dangerous range, and fluid restriction is the default therapy. Studies suggest that the degree of ability to excrete free water can be quickly determined by measuring a urine osmolality, and pateints with a urine concentration of <500 mOsm/L can be safely empirically treated with 2L of 0.9% sodium chloride over 24 hours and not have a significant drop in their serum sodium.

A. Immediate management.

The emergency management of SIADH is essentially the emergency treatment of hyponatremia. Fluid restriction to a tolerated level (usually 1.5L/24hours) should always be initiated since SIADH without fluid intake by the patient will almost never result in clinically significant hyponatremia and always assists in the treatment. The underlying conditions which may cause SIADH have their own emergent treatment strategies in and of themselves.

B. Physical Examination Tips to Guide Management.

In the setting of a sodium less than 125mEq/L and severe symptoms (coma, seizure, severe delirium), the sodium should be corrected regardless of amount under these symptoms resolve. Patients should be monitored in a critical care setting with serum sodiums, monitored at least every hour so that correction can be halted as soon as symptoms resolve in order to prevent over correction.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Following the patient's serum sodium to prevent over correction is a necessity in the management of hyponatremia of any cause. High risk groups for over correction are the elderly, malnurished patients and alcoholics. The rate of serum sodium correction in these groups should be no more than 6-8 mOsm/L in a 24-hour period and no more than 8-10mOsm/L in all other groups although this has not been prospectively studied.

Following a patient's urine sodium and potossium can help you to determine what the patient's free water clearance is using the free water clearance equation (Figure 2). This will estimate the amount of free water that the patient is excreting or retaining for every liter of urine that the patient makes. Maintaining a positive free water excretion is necessary to continue to improve hyponatremia.

Figure 2.

Free Water Clearance Equation

D. Long-term management.

The long-term management of SIADH is to treat the underlying cause. Because some of these conditions such as pulmonary malignancy are not curable, there is the potential necessity for chronic therapy. Very few studies have evaluated the long-term efficacy of available treatments. Newer data on vasopressin receptor antagonists or "vaptans" suggest some potential use for these agents in chronic hyponatremia, although the largest study to date was stopped early due to safety concerns over adverse effects.

E. Common Pitfalls and Side-Effects of Management

Treating hyponatremia empirically with a normal saline infusion prior to measuring a urine osmolarity is a common pitfall that can result in permanent neurologic sequelae for these patients.

IV. Management with Co-Morbidities

N/A

A. Renal Insufficiency.

Renal insufficiency can be both a threat and an asset in the treatment of hyponatremia in SIADH. Patients with renal insufficiency often have difficulty excreting a free water load at baseline. You can only excrete what you filter and patients with renal insufficiency have a decreased glomerular filtration rate by definition. This also limits the effect of the inappropriate ADH that is circulating and the worsening of hyponatremia if the patient is given free water in any form.

The net result is a more modest response, insults and treatments and the patient's volume status should be monitored more closely when using intravenous fluid interventions. The management should not be altered, although these patients are at higher risk for having a baseline low sodium.

B. Liver Insufficiency.

Cirrhosis results physiologically in an ineffective circulating volume and an increase in the appropriate release of ADH by the posterior pituitary. Patients with cirrhosis also have resultant activation of their renin-angiotensin-aldosterone system and therefore have a low urine sodium. Because of these processes, a patient with cirrhosis can technically never meet criteria for syndrome of "inappropriate" ADH. Treatment of their hyponatremia from cirrhosis may be more resistent to interventions since they will inherently have a decreased free water clearance at baseline.

C. Systolic and Diastolic Heart Failure

Both systolic and diastolic heart failure result physiologically in an ineffective circulating volume and in the appropriate release of ADH by the posterior pituitary. These patients also have resultant activation of their renin-angiotensin-aldosterone system and therefore have a low urine sodium. Because of these processes, a patient with heart failure can technically never meet criteria for syndrome of "inappropriate" ADH. Treatment with diuretics, which is one of the mainstays of therapy in congestive heart failure, tends to dilute the urine and helps with the treatment of SIADH.

F. Malignancy

Since malignancies are a common underlying cause of SIADH (see above), treatment of the malignancy is the mainstay of long-term treatment of hyponatremia in SIADH for these patients.

H. Primary Lung Disease (COPD, Asthma, ILD)

Since pulmonary pathology is a common underlying causes of SIADH (see above), treatment of these pulmonary diseases is the mainstay of long-term treatment of hyponatremia in SIADH for these patients.

I. Gastrointestinal or Nutrition Issues

Patients with malnutrition are at increased risk for the complications of overcorrection of serum sodium regardless of the cause. There are no randomized controlled trials evaluating this group. Case reports suggest that central pontine myelinolysis can occur even when serum sodium was corrected by only 10m/molL in 24 hours, and so these patients should be corrected by only 6-8m/mol/L in a 24-hour period.

K. Dementia or Psychiatric Illness/Treatment

Since psychiatric illness and its treatments are a common underlying cause of SIADH (see above), treatment of the these processses and discontinuation of these therapies when possible are the maintstay of long-term treatment of hyponatremia in SIADH for these patients.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Signing out a patient to a colleague while treating acute or subacute hyponatremia poses the same risks associated with the treatment of any other cause of hyponatremia.

B. Anticipated Length of Stay.

Given the widely variable causes of SIADH, there are no large studies published on length of stay. In a small study of an elderly cohort with SIADH of variable cause, length of stay was approximately 13 days. This was not altered by the patient's degree of hyponatremia.

C. When is the Patient Ready for Discharge.

The serum sodium level at which patients with SIADH are safe to discharge is not well defined. It is clear that patients should be clear of moderate and severe symptoms of hyponatremia which usually occur at serum sodiums below 125mEq/L. Beyond this, discharge should be based on a patients comorbidities, stability of serum sodium prior to discharge, and follow-up plan for monitoring of sodium after transfer to a facility or home setting.

D. Arranging for Clinic Follow-up

N/A

1. When should clinic follow up be arranged and with whom.

Unless the hyponatremia resulting from SIADH was difficult to treat in hospital, follow up with the patient's primary care physician is sufficient. Prompt follow-up in the week after discharge is usually sufficient for monitoring of their serum sodium if they are discharged with a serum sodium greater than 130mOsm/L although their are no published guidelines. Nephrology should be cosulted for patients with difficulty in controlling hyponatremia while in hospital, and these patients will often need to be seen upon discharge in nephrology clinic as well.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

It is helpful to the outpatient provider, to arrange for the patient to have a serum sodium measured just prior to their clinic visit so that the result is available to make clinical decisions for interventions at the visit.

E. Placement Considerations.

Occult symptoms from hyponatremia are prevalent when physicians have looked more closely. Careful consideration for a functional assessment by occupational therapy and physical therapy to help with decisions about appropriate disposition is warranted in this patient population.

F. Prognosis and Patient Counseling.

Although hyponatremia does portend a poor prognosis in many disease states, it is difficult for studies to evaluate what contribution, if any, comes from SIADH.

VI. Patient Safety and Quality Measures

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Discussion with the patient regarding fluid restriction, medication administration and need for follow-up are necessary to assure a solid transition of care when discharging patients with SIADH.

What's the evidence?

Waikar, SS, Mount, DB, Curhan, GC. "Mortaity after hospitalization with mild, moderate, and severe hyponatremia". Am J Med. vol. 122. 2009. pp. 857-65.

R.W.Schrier. "Body water homeostasis: clinical disorders of urinary dilution and concentration". J Am Soc Nephrol. vol. 17. 2006. pp. 1820-1832.

Ellison, DH, Berl, T. "Clinical practice: The syndrome of inappropriate antidiuresis". N Engl J Med 17. vol. 356. 2007. pp. 2064-72.

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