Syndrome of Inappropriate ADH

Background

SIADH stands for syndrome of inappropriate anti-diuretic hormone. The abnormal production of this hormone ADH, leads to salt wasting, or hyponatremia. The result is a profound metabolic disturbance which may result in coma and death. The pathologist is often called upon to investigate a laboratory abnormality of serum hypo-osmolality, an unexpectedly high urinary specific gravity, an absence of edema or dehydration, hyponatremia, and an elevation of plasma vasopressin. Usually there is normal adrenal, thyroid, and renal function. Occasionally the syndrome is due to head trauma or a tumor. In these cases, the pathologist may be called upon to evaluate a tissue biopsy to confirm the diagnosis.

OUTLINE

Epidemiology Amiodarone
Psychotropic drugs
Vincristine

Disease Associations Head and neck cancer
Lung cancer
Pneumonia

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants Geriatric

Differential Diagnosis Cerebral salt wasting syndrome

Prognosis Central pontine myelinolysis

Treatment Vasopressin Receptor Antagonist

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATION

SYNONYMS Schwartz-Bartter syndrome

INCIDENCE/PREVALENCE Probably more common than reported

AGE

Chronic idiopathic hyponatremia in older people due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) possibly related to aging.

Anpalahan M.

Department of General Medicine, Western Hospital, Melbourne, Australia.
J Am Geriatr Soc 2001 Jun;49(6):788-92 Abstract quote
OBJECTIVE: To determine the prevalence of syndrome of inappropriate antidiuretic hormone secretion (SIADH) among older hyponatremic patients in a subacute geriatric facility, to identify patients with no apparent cause for the SIADH (idiopathic SIADH), and to determine their clinical characteristics.

DESIGN: Prospective analysis of a cohort of older patients over a period of 3 months.

SETTING: Two wards in a geriatric rehabilitation hospital.

PARTICIPANTS: Patients aged 65 and older.

MEASUREMENTS: All patients with hyponatremia (serum sodium <135 mmols/l) were clinically examined and relevant investigations were performed to determine the etiology of hyponatremia. Patients were observed for symptoms of hyponatremia. Hyponatremia was classified into possible SIADH and non-SIADH types. Patients with SIADH type hyponatremia were screened for possible causes. Past medical histories were obtained from the general practitioners.

RESULTS: Of the 172 patients studied, 43 (25%) had hyponatremia. It was symptomatic in only four patients. Twenty-two (51%) had SIADH etiology. In nine (mean age 84 +/- 4), no cause for the SIADH was evident (presumed idiopathic SIADH) and in seven, hyponatremia (128-135 mmols/l) was chronic (12 to 72 months). Further reduction in serum sodium, which was symptomatic, was noted in two of these patients with the onset of pneumonia.

CONCLUSION: Most older hyponatremic patients in a rehabilitation setting seem to have SIADH etiology. This study confirms the presence of a group of older individuals with chronic idiopathic hyponatremia in whom the underlying mechanism may be SIADH related to aging. Hyponatremia is modest in these patients and has little clinical significance. However, they may be at increased risk of developing symptomatic hyponatremia with intercurrent illnesses.

EPIDEMIOLOGIC ASSOCIATIONS

AMIODARONE

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by amiodarone: a report on two cases.

Ikegami H, Shiga T, Tsushima T, Nirei T, Kasanuki H.

Department of Cardiology, The Heart Institute of Japan, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan.
J Cardiovasc Pharmacol Ther 2002 Jan;7(1):25-8 Abstract quote
BACKGROUND: Amiodarone is an effective antiarrhythmic agent for life-threatening arrhythmias but has some noncardiac toxicity. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by amiodarone during long-term therapy seems to be rare among adverse effects.

SUBJECTS AND RESULTS: We report on two elderly cases that developed hyponatremia caused by SIADH occurring during the initial loading period of amiodarone therapy. Both cases improved within 3 weeks after reduction of the dose, although amiodarone was continued.

CONCLUSIONS: Amiodarone-induced SIADH may occur during the initial loading period, and it may be improved by reduction of the dose without discontinuation of the drug.

PSYCHOTROPIC DRUGS

Hyponatraemia and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by psychotropic drugs.

Spigset O, Hedenmalm K.

Division of Clinical Pharmacology, Norrland University Hospital, Umea, Sweden.

Drug Saf 1995 Mar;12(3):209-25 Abstract quote
The use of psychotropic drugs has been associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in a number of case reports. SIADH is characterised by the sustained release of antidiuretic hormone (ADH) from the posterior pituitary.

The patients have a reduced ability to excrete diluted urine, ingested fluid is retained, and the extracellular fluid expands and becomes hypo-osmolar. The cardinal signs are hyponatraemia, serum hypoosmolality and a less than maximally diluted urine. Common symptoms include weakness, lethargy, headache, anorexia and weight gain. These symptoms may be followed by confusion, convulsions, coma and death. The early symptoms are vague and nonspecific, and they may even mimic the symptoms of the psychiatric disorder itself.

For antidepressants, the risk of SIADH seems to be highest during the first weeks of treatment. For antipsychotics, the risk seems to be more spread out in time. The causative role of the drug may sometimes be difficult to estimate, as even drug-free psychiatric patients, mostly those with schizophrenia, develop SIADH on the basis of psychogenic polydipsia. Smoking is another factor associated with the development of SIADH, and the risk may also increase with age. The acute treatment of SIADH induced by a psychotropic drug includes discontinuation of the drug as well as restriction of fluid intake. In cases with significant clinical symptoms, infusion of sodium chloride is recommended. After the acute management, it is useful to evaluate the causative role of the drug by performing a water loading test and/or drug rechallenge.

If continued treatment with an antidepressant or antipsychotic is indicated, a drug with a different pharmacological profile should be chosen, and the serum sodium levels should be monitored closely. If treatment with the drug that caused SIADH must be continued, concomitant treatment with demeclocycline may reduce the tendency of hyponatraemia.

VINCRISTINE

Hyponatremia and syndrome of inappropriate anti-diuretic hormone reported with the use of Vincristine: an over-representation of Asians?
Hammond IW, Ferguson JA, Kwong K, Muniz E, Delisle F.

Pharmacoepidemiol Drug Saf 2002 Apr-May;11(3):229-34 Abstract quote
PURPOSE: This retrospective study used a pharmaceutical company's global safety database to determine the reporting rate of hyponatremia and/or syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) among vincristine-treated patients and to explore the possibility of at-risk population subgroups.

METHOD: We searched the Eli Lilly and Company's computerized adverse event database for all reported cases of hyponatremia and/or SIADH as of 1 November 1999 that had been reported during the use of vincristine.

RESULTS: A total of 76 cases of hyponatremia and/or SIADH associated with vincristine use were identified. The overall reporting rate was estimated to be 1.3/100,000 treated patients. The average age of patients was 35.6 +/- 28.3 years, and 62% were males. Approximately 75% of the patients were receiving treatment for leukemia or lymphoma. Among the 39 reports that included information on race, the racial distribution was: 1 Black, 3 Caucasian, and 35 Asian.

CONCLUSION: Our data suggest that Asian patients may be at increased risk of hyponatremia and/or SIADH associated with vincristine use. Although the overall reported rate of SIADH associated with vincristine is very low, physicians caring for Asian oncology patients should be aware of this potential serious but reversible adverse event.

DISEASE ASSOCIATIONS CHARACTERIZATION

HEAD AND NECK CANCERS

Syndrome of inappropriate antidiuretic hormone secretion associated with head neck cancers: review of the literature.

Ferlito A, Rinaldo A, Devaney KO.

Department of Otolaryngology, University of Padua, Italy.

Ann Otol Rhinol Laryngol 1997 Oct;106(10 Pt 1):878-83 Abstract quote
In a minority of patients with malignant tumors, signs and symptoms develop that cannot be explained on the basis of the mass effect produced by the primary tumor or its metastases, or production of a hormone normally associated with the tissue type that has given rise to the malignant tumor; these peculiar symptom complexes are known as paraneoplastic syndromes, and may be divided into endocrinologic, dermatologic, hematologic, neurologic, and osteoarticular manifestations.

In the head and neck region in particular, the syndrome of inappropriate antidiuretic hormone production (SIADH, or Schwartz-Bartter syndrome) is a well-recognized form of paraneoplastic syndrome that may accompany head and neck malignancies. Most of such tumors are squamous carcinomas, with lesser numbers of olfactory neuroblastomas, small cell neuroendocrine carcinomas, adenoid cystic carcinomas, and undifferentiated carcinomas; sarcoma was reported in only a single instance. The lesions associated with the development of SIADH have most often been located in the oral cavity, and less often in the larynx, nasopharynx, hypopharynx, nasal cavity, maxillary sinus, parapharyngeal space, salivary glands, and oropharynx.

Key features of SIADH include serum hypo-osmolality; an unexpectedly high urinary specific gravity; an absence of edema or dehydration; normal adrenal, thyroid, and renal function; hyponatremia; and an elevation of plasma vasopressin.

LUNG CANCERS

Syndrome of inappropriate antidiuretic hormone associated with chemotherapy-induced tumour lysis in small-cell lung cancer: case report and literature review.

Vanhees SL, Paridaens R, Vansteenkiste JF.

Department of Pulmonology, University Hospital Gasthuisberg, Catholic University, Leuven, Belgium.
Ann Oncol 2000 Aug;11(8):1061-5 Abstract quote
A patient with a small-cell lung cancer (SCLC) developed an asymptomatic hyponatremia, with all features of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), two days after the start of his first cycle of chemotherapy with vindesine, ifosfamide and cisplatin. Progression of the tumour with an increase in paraneoplastic SIADH, or drug-induced causes of hyponatremia, could be ruled out by his further clinical course.

The event was interpreted as a consequence of ADH release during the initial tumour cell lysis after effective chemotherapy. The occurrence of hyponatremia during the initial phase of chemotherapy for SCLC should be interpreted with caution. Although it is most commonly due to an increase in paraneoplastic ADH secretion reflecting ineffective therapy, it can also be due to release of ADH from malignant cells in the period of rapid tumour lysis, reflecting effective therapy.

Based on this rare occurrence, a review of the aetiology, clinical findings, diagnosis, prognosis and treatment of SIADH in general is presented.

PNEUMONIA

Hyponatraemia and the inappropriate ADH syndrome in pneumonia.

Dhawan A, Narang A, Singhi S.

Department of Paediatrics, Postgraduate Institute of Medical Education & Research, Chandigarh, India.

Ann Trop Paediatr 1992;12(4):455-62 Abstract quote
We studied serum sodium, plasma osmolality and urinary sodium and osmolality on days 1, 3 and 5 of hospitalization of 100 children aged from 1 month to 12 years admitted with a diagnosis of pneumonia.

Hyponatraemia (serum sodium concentration < or = 130 mmol/l) was found in 31 patients at the time of admission. The probable cause of hyponatraemia in 94% of cases was the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Symptoms and signs indicative of severe pneumonia were two to three times more frequent and the mean duration of tachypnoea, chest-wall retraction and hospital stay about one and a half times longer in children with hyponatraemia.

Four children died (two on day 1, one on day 5 and one on day 8); all four had a serum sodium concentration < or = 125 mmol/l which persisted until death. Of the remaining 27 hyponatraemic children, serum sodium concentrations returned to normal on day 3 in 26, while in one hyponatraemia persisted until day 7. The recovery from hyponatraemia showed a good correlation with improvement in clinical signs of respiratory distress.

The SIADH occurred in about one-third of the children hospitalized for pneumonia, and was associated with a more severe disease and a poorer outcome. Perhaps fluid restriction in these cases may improve the outcome.

LABORATORY/RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION

RADIOLOGIC

LABORATORY MARKERS

GENERAL

Severe hyponatraemia: investigation and management in a district general hospital.

Saeed BO, Beaumont D, Handley GH, Weaver JU.

Department of Clinical Biochemistry, Queen Elizabeth Hospital, Gateshead NE9 6SX, UK.
J Clin Pathol 2002 Dec;55(12):893-6 Abstract quote
AIMS: To study the incidence, investigation, and management of severe hyponatraemia (serum sodium < 120 mmol/litre) over a period of six months in a district general hospital.

METHODS: The laboratory computer was used to identify all inpatients who had a serum sodium concentration of less than 120 mmol/litre over a six month period. The records of these patients were reviewed for the relevant demographic, clinical, and laboratory data, in addition to diagnosis, treatment, and outcome of hospitalisation.

RESULTS: Forty two patients were studied, with a female to male ratio of 2 : 1. Nine patients had central nervous system symptoms, and four of these patients died in hospital. Only 14 patients had their urinary electrolytes and/or osmolality checked. A diagnosis of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was mentioned in eight patients, sometimes without checking their urinary electrolytes or osmolality. Twenty one patients died in hospital. The patients who died did not have lower serum sodium values or a higher rate of correction of hyponatraemia, but they all suffered from advanced medical conditions.

CONCLUSIONS: The possible cause of hyponatraemia should always be sought and that will require an accurate drug history, clinical examination, and assessment of fluid volume, plus the measurement of urinary electrolytes and osmolality in a spot urine sample. The diagnosis of SIADH should not be confirmed without the essential criteria being satisfied. The current or recent use of diuretics is a possible pitfall in the diagnosis of SIADH. The rate of serum sodium correction of less than 10 mmol/day is probably the safest option in most cases.

The hyponatremic patient: a systematic approach to laboratory diagnosis.

Milionis HJ, Liamis GL, Elisaf MS.

Department of Internal Medicine, University of Ioannina Medical School, Greece.

CMAJ 2002 Apr 16;166(8):1056-62 Abstract quote
Hyponatremia (serum sodium level less than 134 mmol/L) is a common electrolyte disturbance. Its high prevalence and potential neurologic sequelae make a logical and rigorous differential diagnosis mandatory before any therapeutic intervention. A history of concurrent illness and medication use as well as the assessment of extracellular volume status on physical examination may provide useful clues as to the pathogenesis of hyponatremia. Measurement of the effective serum tonicity (serum osmolality less serum urea level) is the first step in the laboratory evaluation. In patients with normal or elevated effective serum osmolality (280 mOsm/kg or greater), pseudohyponatremia should be excluded. In the hypo-osmolar state (serum osmolality less than 280 mOsm/kg), urine osmolality is used to determine whether water excretion is normal or impaired. A urine osmolality value of less than 100 mOsm/kg indicates complete and appropriate suppression of antidiuretic hormone secretion. A urine sodium level less than 20 mmol/L is indicative of hypovolemia, whereas a level greater than 40 mmol/L is suggestive of the syndrome of inappropriate antidiuretic hormone secretion. Levels of hormones (thyroid-stimulating hormone and cortisol) and arterial blood gases should be determined in difficult cases of hyponatremia.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

GENERAL

VARIANTS

GERIATRIC

Chronic idiopathic hyponatremia in older people due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) possibly related to aging.

Anpalahan M.

Department of General Medicine, Western Hospital, Melbourne, Australia.

J Am Geriatr Soc 2001 Jun;49(6):788-92 Abstract quote
OBJECTIVE: To determine the prevalence of syndrome of inappropriate antidiuretic hormone secretion (SIADH) among older hyponatremic patients in a subacute geriatric facility, to identify patients with no apparent cause for the SIADH (idiopathic SIADH), and to determine their clinical characteristics. DESIGN: Prospective analysis of a cohort of older patients over a period of 3 months.

SETTING: Two wards in a geriatric rehabilitation hospital.

PARTICIPANTS: Patients aged 65 and older.

MEASUREMENTS: All patients with hyponatremia (serum sodium <135 mmols/l) were clinically examined and relevant investigations were performed to determine the etiology of hyponatremia. Patients were observed for symptoms of hyponatremia. Hyponatremia was classified into possible SIADH and non-SIADH types. Patients with SIADH type hyponatremia were screened for possible causes. Past medical histories were obtained from the general practitioners.

RESULTS: Of the 172 patients studied, 43 (25%) had hyponatremia. It was symptomatic in only four patients. Twenty-two (51%) had SIADH etiology. In nine (mean age 84 +/- 4), no cause for the SIADH was evident (presumed idiopathic SIADH) and in seven, hyponatremia (128-135 mmols/l) was chronic (12 to 72 months). Further reduction in serum sodium, which was symptomatic, was noted in two of these patients with the onset of pneumonia.

CONCLUSION: Most older hyponatremic patients in a rehabilitation setting seem to have SIADH etiology. This study confirms the presence of a group of older individuals with chronic idiopathic hyponatremia in whom the underlying mechanism may be SIADH related to aging. Hyponatremia is modest in these patients and has little clinical significance. However, they may be at increased risk of developing symptomatic hyponatremia with intercurrent illnesses.

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

CEREBRAL SALT WASTING SYNDROME

Hyponatremia in acute brain disease: the cerebral salt wasting syndrome.

Betjes MG.

Division of Nephrology and Hypertension, Department of Internal Medicine, University Hospital Rotterdam, Dijkzigt, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands
0953-6205 2002 Feb;13(1):9-14 Abstract quote
Hyponatremia in acute brain disease is a common occurrence, especially after an aneurysmal subarachnoid hemorrhage. Originally, excessive natriuresis, called cerebral salt wasting, and later the syndrome of inappropriate antidiuretic hormone secretion (SIADH), were considered to be the causes of hyponatremia.

In recent years, it has become clear that most of these patients are volume-depleted and have a negative sodium balance, consistent with the original description of cerebral salt wasting. Elevated plasma concentrations of atrial or brain natriuretic peptide have been identified as the putative natriuretic factor.

Hyponatremia and volume depletion may aggravate neurological symptoms, and timely treatment with adequate replacement of water and NaCl is essential. The use of fludrocortisone to increase sodium reabsorption by the renal tubules may be an alternative approach.

Hyponatraemia in children with acute CNS disease: SIADH or cerebral salt wasting?

Bussmann C, Bast T, Rating D.

Department of Paediatric Neurology, University of Heidelberg, Germany.
Childs Nerv Syst 2001 Jan;17(1-2):58-62; discussion 63 Abstract quote
Hyponatraemia in patients with an acute central nervous system disease can be caused by two different mechanisms: (1) retention [corrected] of free water, i.e. the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and (2) excessive sodium retention [corrected], i.e., the cerebral salt wasting syndrome (CSW). Although the concept of CSW is well known in adult medicine, it is still not established in child neurology.

We conducted a retrospective analysis of electrolyte disturbances in 195 children with various acute CNS diseases. In 20 children (10.3%) hyponatraemia with plasma sodium below 130 mmol/l was identified. On the basis of clinical and laboratory data 7 of these 20 children were diagnosed as having SIADH, and the other 9 children, as having CSW. Our data suggest that hyponatraemia attributable to CSW is at least as frequent in children as SIADH.

Because of their different pathophysiological mechanisms, which require diametrically opposed therapeutic regimens, early differential diagnosis is mandatory if the correct treatment is to be given.

Cerebral salt wasting in children. The need for recognition and treatment.

Ganong CA, Kappy MS.

St Joseph's Hospital and Medical Center, Department of Pediatric Education, Phoenix, Ariz 85013.

Am J Dis Child 1993 Feb;147(2):167-9 Abstract quote
OBJECTIVES--To describe a salt-wasting syndrome in children with central nervous system (CNS) insults and to differentiate it from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and diabetes insipidus so that it may be more readily diagnosed and treated.

DESIGN--Case reports.

SETTING--Community teaching hospital.

PATIENTS--Two inpatients with CNS insults (closed head trauma in one and seizure disorder, spastic diplegia, mental retardation, and hydrocephalus in the other).

SELECTION CRITERIA--Evidence of hyponatremia accompanied by elevated urine sodium concentration and excessive urine output.

INTERVENTIONS--Volume-for-volume urine replacement with 0.9% and/or 3% sodium chloride. Oral salt supplementation was required for brief periods to maintain normal plasma sodium concentration after discharge from the hospital.

MEASUREMENTS AND MAIN RESULTS--Both patients had hyponatremia, high urine sodium concentrations, hypovolemia, and excessive urine output while receiving maintenance fluids. They also had elevated plasma atrial natriuretic hormone (ANH) concentrations, decreased aldosterone concentrations, and decreased [corrected] plasma renin activity for their degree of hyponatremia and negative fluid balance. Both patients maintained normal serum electrolyte concentrations with appropriate treatment.

CONCLUSIONS--These patients showed true salt wasting associated with acute or chronic CNS injury, with hormonal patterns consistent with "inappropriate" ANH secretion and distinct from the SIADH. It is important to distinguish cerebral salt wasting (CSW) from the two other major disturbances of water metabolism seen following CNS injury (ie, SIADH and diabetes insipidus), because incorrect diagnosis and treatment could greatly increase morbidity in CSW. The etiologic roles of ANH or brain natriuretic peptide in CSW need to be further elucidated.

PROGNOSIS CHARACTERIZATION

CENTRAL PONTINE MYELINOSIS

Prevention of brain demyelination in rats after excessive correction of chronic hyponatremia by serum sodium lowering.

Soupart A, Penninckx R, Crenier L, Stenuit A, Perier O, Decaux G.

Department of Internal Medicine, Erasmus University Hospital, Brussels, Belgium.

Kidney Int 1994 Jan;45(1):193-200 Abstract quote
Brain myelinolysis occurs after correction of chronic hyponatremia in rats when the magnitude of increase in serum sodium (delta SNa) exceeds 20 to 25 mEq/liter/24 hr (the critical threshold for brain). We tested the hypothesis that after a sustained excessive correction, brain lesions (BL) could be prevented by subsequently decreasing the serum sodium below the critical threshold for brain through the administration of hypotonic fluids. After three days of severe (< 115 mEq/liter) chronic (3 days) hyponatremia, 55 rats were submitted to an excessive correction (delta SNa > 25 mEq/liter) by a single i.p. infusion of hypertonic saline (NaCl). This osmotic stress was maintained during 12 hours before the serum sodium decrease was initiated. Thirty-two rats reached the twelfth post-correction hour without symptoms. In group 1 after a large (delta SNa 32 mEq/liter) and sustained (12 hr) osmotic stress, the natremia was rapidly (2 hr) decreased by the administration of oral tap water and, at the end of the first 24 hours, the magnitude of correction was maintained below 20 mEq/liter/24 hr. All the rats fared well in this group and were free of neurologic symptoms. Mild BL were noticed in only 20% of them. On the contrary, in controls (no hypotonic fluids administration at the twelfth hour) whose serum sodium was left overcorrected, all the rats became symptomatic and 57% of them died rapidly. Brain damage developed in 100% of the surviving rats. In group 2, despite hypotonic fluids administration, the serum sodium decreased insufficiently and the correction was > 20 mEq/liter at the end of the first 24 hours (delta SNa 25 mEq/liter).(ABSTRACT TRUNCATED AT 250 WORDS)

Pontine and extrapontine myelinolysis: a neurologic disorder following rapid correction of hyponatremia.

Karp BI, Laureno R.

National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Medicine (Baltimore) 1993 Nov;72(6):359-73 Abstract quote
Neurologic disorders developing after correction of severe, symptomatic hyponatremia were studied in 14 patients. None had a hypoxic event or other identifiable cause for the neurologic illness. Neurologic deterioration began about 3 days after correction and often followed a period of improvement in hyponatremic encephalopathy. Although the symptoms were as mild as transient confusion in 1 patient, they were more severe in the others.

Typically, spastic quadriparesis, pseudobulbar palsy, and impairment in the level of consciousness progressed for up to 7 days. Improvement generally began 2 weeks after correction and continued for up to a year in some patients. Routine spinal fluid analysis was usually normal, but myelin basic protein concentration was elevated in all patients in whom it was measured. Electroencephalograms commonly showed nonfocal slowing. Brainstem auditory evoked potential latencies were prolonged in some patients. Brain imaging was normal in the initial week of illness, while later scans, obtained in 9 patients, showed central pontine and/or symmetric extrapontine lesions. The clinical manifestations and distribution of lesions seen on imaging demonstrate that neurologic illness following correction of hyponatremia is due to myelinolysis. Although this neurologic disorder typically followed an elevation in serum sodium > 18 mEq/L/24 hr, it sometimes followed a rise as slow as 10 mEq/L/24 hr and 21 mEq/L/48 hr.

Whenever possible, the rate of correction of hyponatremia should be kept below these values in order to minimize the risk of myelinolysis.

TREATMENT CHARACTERIZATION

GENERAL

Therapeutic recommendations for management of severe hyponatremia: current concepts on pathogenesis and prevention of neurologic complications.

Soupart A, Decaux G.

Research Unit for the Study of Hydromineral Metabolism, Erasmus University Hospital, Free University of Brussels, Belgium.
Clin Nephrol 1996 Sep;46(3):149-69 Abstract quote
Patients with hyponatremia are exposed to major neurological complications. On the one hand hyponatremia itself produces brain edema, increased intracranial pressure which potentially leads to subsequent neuropathological sequelae or death. On the other hand excessive correction could be followed by development of brain demyelinating lesions (central pontine or extrapontine myelinolysis) with major disability or fatal outcome.

Understanding of brain adaptative mechanisms to changes in osmolality largely contributes to explain these neurological events. When serum sodium decreases, the brain prevents swelling by extruding electrolytes and organic osmolytes, a process almost fully achieved after 48 h. Conversely, during subsequent increase in serum sodium, reestablishment of intracerebral osmolytes occurs but their reuptake is more delayed (+/- 5 days). In both circumstances, these mechanisms can be overwhelmed, leading to brain damage. Acute hyponatremia (< 48 h) is generally hospital-acquired, mainly in the postoperative state and/or after excessive fluid administration. After abrupt fall in serum sodium, seizure, respiratory arrest and coma may develop and these manifestations are sometimes explosive in nature. Recognition of even minor symptoms is crucial and implies prompt correction. There is generally no risk of brain myelinolysis in acute hyponatremia. Some factors are suspected to aggravate the prognosis of hyponatremic encephalopathy, including female gender (menstruant women), hypoxia and young age.

Chronic hyponatremia (> 48 h) usually develops outside the hospital and is generally better tolerated. The risks of brain myelinolysis can be largely reduced by limiting the correction level to < or = 15 mEq/1/24 h. However, if necessary, the initial rate of correction can be rapid provided that the final correction remains < 15 mEq/1/24 h. However, when other recognized risk factors for myelinolysis (hypokalemia, liver disease, poor nutritional state, burns) are present, correction should not exceed 10 mEq/1/24 h. Demyelinization is also observed in hypernatremia but it follows greater (50%) increase in serum sodium than from hyponatremic baseline.

For symptomatic hyponatremia, rapid correction is usually obtained by hypertonic saline (3%) infusion. Another option consists in administration of intravenous or oral urea. Urea allows a rapid reduction of brain edema and intracranial pressure which is followed by subsequent correction of hyponatremia. Experimental data also suggest that treatment of hyponatremia with urea is associated with a lower incidence of myelinolysis.

In hyponatremic patients without symptoms, there is no need for rapid correction and the treatment should be more conservative. Close monitoring of the serum sodium is indicated initially and if necessary, correction must be stopped and diuresis interrupted with dDAVP. Given recent experimental data, in patients overly corrected (delta SNa > 15 mEq/1/24 h), the risk of myelinolysis could be greatly reduced by rapidly decreasing the serum sodium through hypotonic fluids administration and dDAVP.

VASOPRESSIN RECEPTOR ANTAGONIST

A vasopressin receptor antagonist (VPA-985) improves serum sodium concentration in patients with hyponatremia: A multicenter, randomized, placebo-controlled trial.

Wong F, Blei AT, Blendis LM, Thuluvath PJ.

Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Canada; Department of Medicine, Northwestern University, Chicago, IL; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD.

Hepatology 2003 Jan;37(1):182-91 Abstract quote
Hyponatremia in advanced cirrhosis and ascites or congestive heart failure (CHF) is the result of an inappropriate increase in vasopressin secretion, which acts through activation of specific V(2) receptors in the distal renal nephron to increase water reabsorption.

This study investigates the efficacy and safety of 3 different doses of the V(2) receptor antagonist, VPA-985, in correcting hyponatremia over a 7-day inpatient study period. Forty-four hospitalized patients (33 patients with cirrhosis, 6 with CHF, and 5 with syndrome of inappropriate antidiuretic hormone (SIADH) were studied on a constant sodium intake, with VPA doses of 25, 125, and 250 mg twice daily or placebo. Serum sodium measurements were repeated after every daily dose, and the next dose withheld for excessive serum sodium rises. Fluid intake was adjusted according to previous 24-hour urinary outputs. Adverse events were based on clinical signs of dehydration or encephalopathy. VPA-985 produced a significant overall aquaretic response compared with placebo, with significant dose related increases in free water clearance (P <.05) and serum sodium (P <.05), without significant changes in orthostatic blood pressure or serum creatinine levels. Five patients (50%) on 250 mg twice daily had to have medication withheld on multiple occasions.

End-of-study plasma vasopressin levels increased significantly in the 2 larger dose groups. In conclusion, VPA-985 appears effective and safe in appropriate doses in correcting abnormal renal water handling and hyponatremia in conditions associated with water retention. Higher doses of VPA-985 may produce significant dehydration and will require close monitoring with their use.

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DISEASE ASSOCIATIONS	CHARACTERIZATION
HEAD AND NECK CANCERS
Syndrome of inappropriate antidiuretic hormone secretion associated with head neck cancers: review of the literature. Ferlito A, Rinaldo A, Devaney KO. Department of Otolaryngology, University of Padua, Italy.	Ann Otol Rhinol Laryngol 1997 Oct;106(10 Pt 1):878-83 Abstract quote In a minority of patients with malignant tumors, signs and symptoms develop that cannot be explained on the basis of the mass effect produced by the primary tumor or its metastases, or production of a hormone normally associated with the tissue type that has given rise to the malignant tumor; these peculiar symptom complexes are known as paraneoplastic syndromes, and may be divided into endocrinologic, dermatologic, hematologic, neurologic, and osteoarticular manifestations. In the head and neck region in particular, the syndrome of inappropriate antidiuretic hormone production (SIADH, or Schwartz-Bartter syndrome) is a well-recognized form of paraneoplastic syndrome that may accompany head and neck malignancies. Most of such tumors are squamous carcinomas, with lesser numbers of olfactory neuroblastomas, small cell neuroendocrine carcinomas, adenoid cystic carcinomas, and undifferentiated carcinomas; sarcoma was reported in only a single instance. The lesions associated with the development of SIADH have most often been located in the oral cavity, and less often in the larynx, nasopharynx, hypopharynx, nasal cavity, maxillary sinus, parapharyngeal space, salivary glands, and oropharynx. Key features of SIADH include serum hypo-osmolality; an unexpectedly high urinary specific gravity; an absence of edema or dehydration; normal adrenal, thyroid, and renal function; hyponatremia; and an elevation of plasma vasopressin.
LUNG CANCERS
Syndrome of inappropriate antidiuretic hormone associated with chemotherapy-induced tumour lysis in small-cell lung cancer: case report and literature review. Vanhees SL, Paridaens R, Vansteenkiste JF. Department of Pulmonology, University Hospital Gasthuisberg, Catholic University, Leuven, Belgium.	Ann Oncol 2000 Aug;11(8):1061-5 Abstract quote A patient with a small-cell lung cancer (SCLC) developed an asymptomatic hyponatremia, with all features of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), two days after the start of his first cycle of chemotherapy with vindesine, ifosfamide and cisplatin. Progression of the tumour with an increase in paraneoplastic SIADH, or drug-induced causes of hyponatremia, could be ruled out by his further clinical course. The event was interpreted as a consequence of ADH release during the initial tumour cell lysis after effective chemotherapy. The occurrence of hyponatremia during the initial phase of chemotherapy for SCLC should be interpreted with caution. Although it is most commonly due to an increase in paraneoplastic ADH secretion reflecting ineffective therapy, it can also be due to release of ADH from malignant cells in the period of rapid tumour lysis, reflecting effective therapy. Based on this rare occurrence, a review of the aetiology, clinical findings, diagnosis, prognosis and treatment of SIADH in general is presented.
PNEUMONIA
Hyponatraemia and the inappropriate ADH syndrome in pneumonia. Dhawan A, Narang A, Singhi S. Department of Paediatrics, Postgraduate Institute of Medical Education & Research, Chandigarh, India.	Ann Trop Paediatr 1992;12(4):455-62 Abstract quote We studied serum sodium, plasma osmolality and urinary sodium and osmolality on days 1, 3 and 5 of hospitalization of 100 children aged from 1 month to 12 years admitted with a diagnosis of pneumonia. Hyponatraemia (serum sodium concentration < or = 130 mmol/l) was found in 31 patients at the time of admission. The probable cause of hyponatraemia in 94% of cases was the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Symptoms and signs indicative of severe pneumonia were two to three times more frequent and the mean duration of tachypnoea, chest-wall retraction and hospital stay about one and a half times longer in children with hyponatraemia. Four children died (two on day 1, one on day 5 and one on day 8); all four had a serum sodium concentration < or = 125 mmol/l which persisted until death. Of the remaining 27 hyponatraemic children, serum sodium concentrations returned to normal on day 3 in 26, while in one hyponatraemia persisted until day 7. The recovery from hyponatraemia showed a good correlation with improvement in clinical signs of respiratory distress. The SIADH occurred in about one-third of the children hospitalized for pneumonia, and was associated with a more severe disease and a poorer outcome. Perhaps fluid restriction in these cases may improve the outcome.

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
LABORATORY MARKERS
GENERAL
Severe hyponatraemia: investigation and management in a district general hospital. Saeed BO, Beaumont D, Handley GH, Weaver JU. Department of Clinical Biochemistry, Queen Elizabeth Hospital, Gateshead NE9 6SX, UK.	J Clin Pathol 2002 Dec;55(12):893-6 Abstract quote AIMS: To study the incidence, investigation, and management of severe hyponatraemia (serum sodium < 120 mmol/litre) over a period of six months in a district general hospital. METHODS: The laboratory computer was used to identify all inpatients who had a serum sodium concentration of less than 120 mmol/litre over a six month period. The records of these patients were reviewed for the relevant demographic, clinical, and laboratory data, in addition to diagnosis, treatment, and outcome of hospitalisation. RESULTS: Forty two patients were studied, with a female to male ratio of 2 : 1. Nine patients had central nervous system symptoms, and four of these patients died in hospital. Only 14 patients had their urinary electrolytes and/or osmolality checked. A diagnosis of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was mentioned in eight patients, sometimes without checking their urinary electrolytes or osmolality. Twenty one patients died in hospital. The patients who died did not have lower serum sodium values or a higher rate of correction of hyponatraemia, but they all suffered from advanced medical conditions. CONCLUSIONS: The possible cause of hyponatraemia should always be sought and that will require an accurate drug history, clinical examination, and assessment of fluid volume, plus the measurement of urinary electrolytes and osmolality in a spot urine sample. The diagnosis of SIADH should not be confirmed without the essential criteria being satisfied. The current or recent use of diuretics is a possible pitfall in the diagnosis of SIADH. The rate of serum sodium correction of less than 10 mmol/day is probably the safest option in most cases.
The hyponatremic patient: a systematic approach to laboratory diagnosis. Milionis HJ, Liamis GL, Elisaf MS. Department of Internal Medicine, University of Ioannina Medical School, Greece.	CMAJ 2002 Apr 16;166(8):1056-62 Abstract quote Hyponatremia (serum sodium level less than 134 mmol/L) is a common electrolyte disturbance. Its high prevalence and potential neurologic sequelae make a logical and rigorous differential diagnosis mandatory before any therapeutic intervention. A history of concurrent illness and medication use as well as the assessment of extracellular volume status on physical examination may provide useful clues as to the pathogenesis of hyponatremia. Measurement of the effective serum tonicity (serum osmolality less serum urea level) is the first step in the laboratory evaluation. In patients with normal or elevated effective serum osmolality (280 mOsm/kg or greater), pseudohyponatremia should be excluded. In the hypo-osmolar state (serum osmolality less than 280 mOsm/kg), urine osmolality is used to determine whether water excretion is normal or impaired. A urine osmolality value of less than 100 mOsm/kg indicates complete and appropriate suppression of antidiuretic hormone secretion. A urine sodium level less than 20 mmol/L is indicative of hypovolemia, whereas a level greater than 40 mmol/L is suggestive of the syndrome of inappropriate antidiuretic hormone secretion. Levels of hormones (thyroid-stimulating hormone and cortisol) and arterial blood gases should be determined in difficult cases of hyponatremia.

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
CEREBRAL SALT WASTING SYNDROME
Hyponatremia in acute brain disease: the cerebral salt wasting syndrome. Betjes MG. Division of Nephrology and Hypertension, Department of Internal Medicine, University Hospital Rotterdam, Dijkzigt, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands	0953-6205 2002 Feb;13(1):9-14 Abstract quote Hyponatremia in acute brain disease is a common occurrence, especially after an aneurysmal subarachnoid hemorrhage. Originally, excessive natriuresis, called cerebral salt wasting, and later the syndrome of inappropriate antidiuretic hormone secretion (SIADH), were considered to be the causes of hyponatremia. In recent years, it has become clear that most of these patients are volume-depleted and have a negative sodium balance, consistent with the original description of cerebral salt wasting. Elevated plasma concentrations of atrial or brain natriuretic peptide have been identified as the putative natriuretic factor. Hyponatremia and volume depletion may aggravate neurological symptoms, and timely treatment with adequate replacement of water and NaCl is essential. The use of fludrocortisone to increase sodium reabsorption by the renal tubules may be an alternative approach.
Hyponatraemia in children with acute CNS disease: SIADH or cerebral salt wasting? Bussmann C, Bast T, Rating D. Department of Paediatric Neurology, University of Heidelberg, Germany.	Childs Nerv Syst 2001 Jan;17(1-2):58-62; discussion 63 Abstract quote Hyponatraemia in patients with an acute central nervous system disease can be caused by two different mechanisms: (1) retention [corrected] of free water, i.e. the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and (2) excessive sodium retention [corrected], i.e., the cerebral salt wasting syndrome (CSW). Although the concept of CSW is well known in adult medicine, it is still not established in child neurology. We conducted a retrospective analysis of electrolyte disturbances in 195 children with various acute CNS diseases. In 20 children (10.3%) hyponatraemia with plasma sodium below 130 mmol/l was identified. On the basis of clinical and laboratory data 7 of these 20 children were diagnosed as having SIADH, and the other 9 children, as having CSW. Our data suggest that hyponatraemia attributable to CSW is at least as frequent in children as SIADH. Because of their different pathophysiological mechanisms, which require diametrically opposed therapeutic regimens, early differential diagnosis is mandatory if the correct treatment is to be given.
Cerebral salt wasting in children. The need for recognition and treatment. Ganong CA, Kappy MS. St Joseph's Hospital and Medical Center, Department of Pediatric Education, Phoenix, Ariz 85013.	Am J Dis Child 1993 Feb;147(2):167-9 Abstract quote OBJECTIVES--To describe a salt-wasting syndrome in children with central nervous system (CNS) insults and to differentiate it from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and diabetes insipidus so that it may be more readily diagnosed and treated. DESIGN--Case reports. SETTING--Community teaching hospital. PATIENTS--Two inpatients with CNS insults (closed head trauma in one and seizure disorder, spastic diplegia, mental retardation, and hydrocephalus in the other). SELECTION CRITERIA--Evidence of hyponatremia accompanied by elevated urine sodium concentration and excessive urine output. INTERVENTIONS--Volume-for-volume urine replacement with 0.9% and/or 3% sodium chloride. Oral salt supplementation was required for brief periods to maintain normal plasma sodium concentration after discharge from the hospital. MEASUREMENTS AND MAIN RESULTS--Both patients had hyponatremia, high urine sodium concentrations, hypovolemia, and excessive urine output while receiving maintenance fluids. They also had elevated plasma atrial natriuretic hormone (ANH) concentrations, decreased aldosterone concentrations, and decreased [corrected] plasma renin activity for their degree of hyponatremia and negative fluid balance. Both patients maintained normal serum electrolyte concentrations with appropriate treatment. CONCLUSIONS--These patients showed true salt wasting associated with acute or chronic CNS injury, with hormonal patterns consistent with "inappropriate" ANH secretion and distinct from the SIADH. It is important to distinguish cerebral salt wasting (CSW) from the two other major disturbances of water metabolism seen following CNS injury (ie, SIADH and diabetes insipidus), because incorrect diagnosis and treatment could greatly increase morbidity in CSW. The etiologic roles of ANH or brain natriuretic peptide in CSW need to be further elucidated.

PROGNOSIS	CHARACTERIZATION
CENTRAL PONTINE MYELINOSIS
Prevention of brain demyelination in rats after excessive correction of chronic hyponatremia by serum sodium lowering. Soupart A, Penninckx R, Crenier L, Stenuit A, Perier O, Decaux G. Department of Internal Medicine, Erasmus University Hospital, Brussels, Belgium.	Kidney Int 1994 Jan;45(1):193-200 Abstract quote Brain myelinolysis occurs after correction of chronic hyponatremia in rats when the magnitude of increase in serum sodium (delta SNa) exceeds 20 to 25 mEq/liter/24 hr (the critical threshold for brain). We tested the hypothesis that after a sustained excessive correction, brain lesions (BL) could be prevented by subsequently decreasing the serum sodium below the critical threshold for brain through the administration of hypotonic fluids. After three days of severe (< 115 mEq/liter) chronic (3 days) hyponatremia, 55 rats were submitted to an excessive correction (delta SNa > 25 mEq/liter) by a single i.p. infusion of hypertonic saline (NaCl). This osmotic stress was maintained during 12 hours before the serum sodium decrease was initiated. Thirty-two rats reached the twelfth post-correction hour without symptoms. In group 1 after a large (delta SNa 32 mEq/liter) and sustained (12 hr) osmotic stress, the natremia was rapidly (2 hr) decreased by the administration of oral tap water and, at the end of the first 24 hours, the magnitude of correction was maintained below 20 mEq/liter/24 hr. All the rats fared well in this group and were free of neurologic symptoms. Mild BL were noticed in only 20% of them. On the contrary, in controls (no hypotonic fluids administration at the twelfth hour) whose serum sodium was left overcorrected, all the rats became symptomatic and 57% of them died rapidly. Brain damage developed in 100% of the surviving rats. In group 2, despite hypotonic fluids administration, the serum sodium decreased insufficiently and the correction was > 20 mEq/liter at the end of the first 24 hours (delta SNa 25 mEq/liter).(ABSTRACT TRUNCATED AT 250 WORDS)
Pontine and extrapontine myelinolysis: a neurologic disorder following rapid correction of hyponatremia. Karp BI, Laureno R. National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.	Medicine (Baltimore) 1993 Nov;72(6):359-73 Abstract quote Neurologic disorders developing after correction of severe, symptomatic hyponatremia were studied in 14 patients. None had a hypoxic event or other identifiable cause for the neurologic illness. Neurologic deterioration began about 3 days after correction and often followed a period of improvement in hyponatremic encephalopathy. Although the symptoms were as mild as transient confusion in 1 patient, they were more severe in the others. Typically, spastic quadriparesis, pseudobulbar palsy, and impairment in the level of consciousness progressed for up to 7 days. Improvement generally began 2 weeks after correction and continued for up to a year in some patients. Routine spinal fluid analysis was usually normal, but myelin basic protein concentration was elevated in all patients in whom it was measured. Electroencephalograms commonly showed nonfocal slowing. Brainstem auditory evoked potential latencies were prolonged in some patients. Brain imaging was normal in the initial week of illness, while later scans, obtained in 9 patients, showed central pontine and/or symmetric extrapontine lesions. The clinical manifestations and distribution of lesions seen on imaging demonstrate that neurologic illness following correction of hyponatremia is due to myelinolysis. Although this neurologic disorder typically followed an elevation in serum sodium > 18 mEq/L/24 hr, it sometimes followed a rise as slow as 10 mEq/L/24 hr and 21 mEq/L/48 hr. Whenever possible, the rate of correction of hyponatremia should be kept below these values in order to minimize the risk of myelinolysis.

Epidemiology	Amiodarone Psychotropic drugs Vincristine
Disease Associations	Head and neck cancer Lung cancer Pneumonia
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants	Geriatric
Differential Diagnosis	Cerebral salt wasting syndrome
Prognosis	Central pontine myelinolysis
Treatment	Vasopressin Receptor Antagonist
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	Schwartz-Bartter syndrome
INCIDENCE/PREVALENCE	Probably more common than reported
AGE
Chronic idiopathic hyponatremia in older people due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) possibly related to aging. Anpalahan M. Department of General Medicine, Western Hospital, Melbourne, Australia.	J Am Geriatr Soc 2001 Jun;49(6):788-92 Abstract quote OBJECTIVE: To determine the prevalence of syndrome of inappropriate antidiuretic hormone secretion (SIADH) among older hyponatremic patients in a subacute geriatric facility, to identify patients with no apparent cause for the SIADH (idiopathic SIADH), and to determine their clinical characteristics. DESIGN: Prospective analysis of a cohort of older patients over a period of 3 months. SETTING: Two wards in a geriatric rehabilitation hospital. PARTICIPANTS: Patients aged 65 and older. MEASUREMENTS: All patients with hyponatremia (serum sodium <135 mmols/l) were clinically examined and relevant investigations were performed to determine the etiology of hyponatremia. Patients were observed for symptoms of hyponatremia. Hyponatremia was classified into possible SIADH and non-SIADH types. Patients with SIADH type hyponatremia were screened for possible causes. Past medical histories were obtained from the general practitioners. RESULTS: Of the 172 patients studied, 43 (25%) had hyponatremia. It was symptomatic in only four patients. Twenty-two (51%) had SIADH etiology. In nine (mean age 84 +/- 4), no cause for the SIADH was evident (presumed idiopathic SIADH) and in seven, hyponatremia (128-135 mmols/l) was chronic (12 to 72 months). Further reduction in serum sodium, which was symptomatic, was noted in two of these patients with the onset of pneumonia. CONCLUSION: Most older hyponatremic patients in a rehabilitation setting seem to have SIADH etiology. This study confirms the presence of a group of older individuals with chronic idiopathic hyponatremia in whom the underlying mechanism may be SIADH related to aging. Hyponatremia is modest in these patients and has little clinical significance. However, they may be at increased risk of developing symptomatic hyponatremia with intercurrent illnesses.
EPIDEMIOLOGIC ASSOCIATIONS
AMIODARONE
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by amiodarone: a report on two cases. Ikegami H, Shiga T, Tsushima T, Nirei T, Kasanuki H. Department of Cardiology, The Heart Institute of Japan, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan.	J Cardiovasc Pharmacol Ther 2002 Jan;7(1):25-8 Abstract quote BACKGROUND: Amiodarone is an effective antiarrhythmic agent for life-threatening arrhythmias but has some noncardiac toxicity. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by amiodarone during long-term therapy seems to be rare among adverse effects. SUBJECTS AND RESULTS: We report on two elderly cases that developed hyponatremia caused by SIADH occurring during the initial loading period of amiodarone therapy. Both cases improved within 3 weeks after reduction of the dose, although amiodarone was continued. CONCLUSIONS: Amiodarone-induced SIADH may occur during the initial loading period, and it may be improved by reduction of the dose without discontinuation of the drug.
PSYCHOTROPIC DRUGS
Hyponatraemia and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by psychotropic drugs. Spigset O, Hedenmalm K. Division of Clinical Pharmacology, Norrland University Hospital, Umea, Sweden.	Drug Saf 1995 Mar;12(3):209-25 Abstract quote The use of psychotropic drugs has been associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in a number of case reports. SIADH is characterised by the sustained release of antidiuretic hormone (ADH) from the posterior pituitary. The patients have a reduced ability to excrete diluted urine, ingested fluid is retained, and the extracellular fluid expands and becomes hypo-osmolar. The cardinal signs are hyponatraemia, serum hypoosmolality and a less than maximally diluted urine. Common symptoms include weakness, lethargy, headache, anorexia and weight gain. These symptoms may be followed by confusion, convulsions, coma and death. The early symptoms are vague and nonspecific, and they may even mimic the symptoms of the psychiatric disorder itself. For antidepressants, the risk of SIADH seems to be highest during the first weeks of treatment. For antipsychotics, the risk seems to be more spread out in time. The causative role of the drug may sometimes be difficult to estimate, as even drug-free psychiatric patients, mostly those with schizophrenia, develop SIADH on the basis of psychogenic polydipsia. Smoking is another factor associated with the development of SIADH, and the risk may also increase with age. The acute treatment of SIADH induced by a psychotropic drug includes discontinuation of the drug as well as restriction of fluid intake. In cases with significant clinical symptoms, infusion of sodium chloride is recommended. After the acute management, it is useful to evaluate the causative role of the drug by performing a water loading test and/or drug rechallenge. If continued treatment with an antidepressant or antipsychotic is indicated, a drug with a different pharmacological profile should be chosen, and the serum sodium levels should be monitored closely. If treatment with the drug that caused SIADH must be continued, concomitant treatment with demeclocycline may reduce the tendency of hyponatraemia.
VINCRISTINE
Hyponatremia and syndrome of inappropriate anti-diuretic hormone reported with the use of Vincristine: an over-representation of Asians? Hammond IW, Ferguson JA, Kwong K, Muniz E, Delisle F.	Pharmacoepidemiol Drug Saf 2002 Apr-May;11(3):229-34 Abstract quote PURPOSE: This retrospective study used a pharmaceutical company's global safety database to determine the reporting rate of hyponatremia and/or syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) among vincristine-treated patients and to explore the possibility of at-risk population subgroups. METHOD: We searched the Eli Lilly and Company's computerized adverse event database for all reported cases of hyponatremia and/or SIADH as of 1 November 1999 that had been reported during the use of vincristine. RESULTS: A total of 76 cases of hyponatremia and/or SIADH associated with vincristine use were identified. The overall reporting rate was estimated to be 1.3/100,000 treated patients. The average age of patients was 35.6 +/- 28.3 years, and 62% were males. Approximately 75% of the patients were receiving treatment for leukemia or lymphoma. Among the 39 reports that included information on race, the racial distribution was: 1 Black, 3 Caucasian, and 35 Asian. CONCLUSION: Our data suggest that Asian patients may be at increased risk of hyponatremia and/or SIADH associated with vincristine use. Although the overall reported rate of SIADH associated with vincristine is very low, physicians caring for Asian oncology patients should be aware of this potential serious but reversible adverse event.

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
VARIANTS
GERIATRIC
Chronic idiopathic hyponatremia in older people due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) possibly related to aging. Anpalahan M. Department of General Medicine, Western Hospital, Melbourne, Australia.	J Am Geriatr Soc 2001 Jun;49(6):788-92 Abstract quote OBJECTIVE: To determine the prevalence of syndrome of inappropriate antidiuretic hormone secretion (SIADH) among older hyponatremic patients in a subacute geriatric facility, to identify patients with no apparent cause for the SIADH (idiopathic SIADH), and to determine their clinical characteristics. DESIGN: Prospective analysis of a cohort of older patients over a period of 3 months. SETTING: Two wards in a geriatric rehabilitation hospital. PARTICIPANTS: Patients aged 65 and older. MEASUREMENTS: All patients with hyponatremia (serum sodium <135 mmols/l) were clinically examined and relevant investigations were performed to determine the etiology of hyponatremia. Patients were observed for symptoms of hyponatremia. Hyponatremia was classified into possible SIADH and non-SIADH types. Patients with SIADH type hyponatremia were screened for possible causes. Past medical histories were obtained from the general practitioners. RESULTS: Of the 172 patients studied, 43 (25%) had hyponatremia. It was symptomatic in only four patients. Twenty-two (51%) had SIADH etiology. In nine (mean age 84 +/- 4), no cause for the SIADH was evident (presumed idiopathic SIADH) and in seven, hyponatremia (128-135 mmols/l) was chronic (12 to 72 months). Further reduction in serum sodium, which was symptomatic, was noted in two of these patients with the onset of pneumonia. CONCLUSION: Most older hyponatremic patients in a rehabilitation setting seem to have SIADH etiology. This study confirms the presence of a group of older individuals with chronic idiopathic hyponatremia in whom the underlying mechanism may be SIADH related to aging. Hyponatremia is modest in these patients and has little clinical significance. However, they may be at increased risk of developing symptomatic hyponatremia with intercurrent illnesses.