Management of KIAN PENG GOH, M.R.C.P., Alexandra Hospital, Singapore

Hyponatremia is an important abnormality with the potential for significant mor- bidity and mortality. Common causes include and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Hyponatremia can be classified according to the vol- ume status of the patient as hypovolemic, hypervolemic, or euvolemic. Hypervolemic hypona- tremia may be caused by congestive , liver cirrhosis, and renal disease. Differenti- ating between euvolemia and hypovolemia can be clinically difficult, but a useful investigative aid is measurement of plasma osmolality. Hyponatremia with a high plasma osmolality is caused by , while a normal plasma osmolality indicates pseudohyponatremia or the post-transurethral prostatic resection syndrome. The urinary sodium concentration helps in diagnosing patients with low plasma osmolality. High urinary sodium concentration in the presence of low plasma osmolality can be caused by renal disorders, endocrine deficiencies, reset osmostat syndrome, SIADH, and medications. Low urinary sodium concentration is caused by severe burns, gastrointestinal losses, and acute water overload. Management includes instituting immediate treatment in patients with acute severe hyponatremia because of the risk of cerebral edema and hyponatremic encephalopathy. In patients with chronic hyponatremia, fluid restriction is the mainstay of treatment, with therapy reserved for use in persistent cases. Rapid correction should be avoided to reduce the risk of central pontine myelinolysis. Loop are useful in managing edematous hyponatremic states and chronic SIADH. In all instances, identifying the cause of hyponatremia remains an integral part of the treatment plan. (Am Fam Physician 2004;69:2387-94. Copyright© 2004 American Academy of Family Physicians.)

yponatremia generally is defined as a plasma sodium Water and Sodium Balance level of less than 135 mEq Plasma osmolality, a major determinant of per L (135 mmol per L).1,2 total body water homeostasis, is measured by This is the number of solute particles present in 1 kg Hencountered commonly in hospital and of plasma. It is calculated in mmol per L by ambulatory settings.3 The results of one using this formula: prevalence study4 in a nursing home popu- 2 [sodium] + [] + [glucose] lation demonstrated that 18 percent of the Total body sodium is primarily extracellular, residents were in a hyponatremic state, and and any increase results in increased , 53 percent had experienced at least one which stimulates the thirst center and arginine episode of hyponatremia in the previous secretion. Arginine vasopressin 12 months. Acute or symptomatic hypona- then acts on the V2 receptors in the renal tremia can lead to significant rates of mor- tubules, causing increased water reabsorption. bidity and mortality.5-7 Mortality rates as The opposite occurs with decreased extracellu- high as 17.9 percent have been quoted, but lar sodium: a decrease inhibits the thirst center rates this extreme usually occur in the con- and arginine vasopressin secretion, resulting in text of hospitalized patients.8 Morbidity diuresis. In most cases, hyponatremia results also can result from rapid correction of when the elimination of total body water hyponatremia.9,10 Because there are many decreases. The of hypona- causes of hyponatremia and the treatment tremia will be discussed later in this article. differs according to the cause, a logical and Clinical Signs and Symptoms See page 2291 for defi- efficient approach to the evaluation and nitions of strength-of- management of patients with hyponatremia Most patients with hyponatremia are recommendation labels. is imperative. asymptomatic. Symptoms do not usually

Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright© 2004 American Academy of Family Physicians. For the private, noncommercial use of one individual user of the Web site. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests. hypervolemic hyponatremia are congestive The three main causes of hypervolemic hyponatremia are heart failure, liver cirrhosis, and renal dis- congestive heart failure, liver cirrhosis, and renal diseases eases such as renal failure and nephrotic syn- such as renal failure and nephrotic syndrome. drome. These disorders usually are obvious from the clinical history and physical exami- nation alone.

appear until the plasma sodium level drops EUVOLEMIC AND HYPOVOLEMIC below 120 mEq per L (120 mmol per L) and HYPONATREMIA usually are nonspecific (e.g., headache, Hyponatremia in a volume-depleted patient lethargy, nausea).11 In cases of severe hypona- is caused by a deficit in total body sodium and tremia, neurologic and gastrointestinal symp- total body water, with a disproportionately toms predominate.3 The risk of seizures and greater sodium loss, whereas in euvolemic coma increases as the sodium level decreases. hyponatremia, the total body sodium level is The development of clinical signs and symp- normal or near normal. Differentiating toms also depends on the rapidity with which between hypovolemia and euvolemia may be the plasma sodium level decreases. In the clinically difficult, especially if the classic fea- event of a rapid decrease, the patient can be tures of volume depletion such as postural symptomatic even with a plasma sodium level and tachycardia are absent.14 above 120 mEq per L. Poor prognostic factors Laboratory markers of hypovolemia, such for severe hyponatremia in hospitalized as a raised hematocrit level and urea patients include the presence of symptoms, nitrogen (BUN)-to- ratio of more sepsis, and respiratory failure.12 than 20, may not be present. In fact, results of one study15 showed an increased BUN-to- Diagnostic Strategy creatinine ratio in only 68 percent of hypov- Figure 113 shows an algorithm for the olemic patients. Two useful aids for evaluat- assessment of hyponatremia. The identifica- ing euvolemic or hypovolemic patients are tion of hyponatremia must be followed by a measurement of plasma osmolality and uri- clinical assessment of the patient, beginning nary sodium concentration. Plasma osmolal- with a targeted history to elicit the symptoms ity testing places the patient into one of three of hyponatremia and exclude important categories, normal, high, or low plasma causes such as congestive heart failure, liver osmolality, while urinary sodium concentra- or renal impairment, malignancy, hypothy- tion testing is used to refine the diagnosis in roidism, Addison’s disease, gastrointestinal patients who have a low plasma osmolality. losses, psychiatric illness, recent drug inges- tion, surgery, or reception of intravenous flu- Plasma Osmolality Measurement ids. The patient then should be classified into NORMAL PLASMA OSMOLALITY one of the following categories: hyper- The combination of hyponatremia and nor- volemic (edematous), hypovolemic (volume mal plasma osmolality (280 to 300 mOsm per depleted), or euvolemic. kg [280 to 300 mmol per kg]) of water can be caused by pseudohyponatremia or by the post- HYPERVOLEMIC HYPONATREMIA transurethral prostatic resection syndrome. Hyponatremia in the presence of edema The phenomenon of pseudohyponatremia is indicates increased total body sodium and explained by the increased percentage of large water. This increase in total body water is molecular particles, such as proteins and fats in greater than the total body sodium level, the , relative to sodium. These large mol- resulting in edema. The three main causes of ecules do not contribute to plasma osmolality,

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Assessment of Hyponatremia

The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.

FIGURE 1.

resulting in a state in which the relative sodium causes of this condition in patients with concentration is decreased, but the overall pseudohyponatremia. These patients usually osmolality remains unchanged. Severe hyper- are euvolemic. triglyceridemia and hyperproteinemia are two The post-transurethral prostatic resection

MAY 15, 2004 / VOLUME 69, NUMBER 10 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 2389 High Sodium Level. Excess renal so- The main causes of hyponatremia in hypo-osmolar patients dium loss can be confirmed by finding a high with high levels of sodium in the urine are syndrome of inap- urinary sodium concentration (more than 30 mmol per L). In these patients, the main propriate antidiuretic hormone secretion, medications, renal causes of hyponatremia are renal disorders, disorders, endocrine deficiencies, and reset osmostat syndrome. endocrine deficiencies, reset osmostat syn- drome, syndrome of inappropriate antidi- uretic hormone secretion (SIADH), and drugs syndrome consists of hyponatremia with pos- or medications. Because of their prevalence sible neurologic deficits and cardiorespiratory and importance, SIADH and drugs deserve compromise. Although the syndrome has special mention, and the author will elaborate been attributed to the absorption of large vol- on these causes later in the article. umes of hypotonic irrigation fluid intraoper- Renal disorders that cause hyponatremia atively, its pathophysiology and management include sodium-losing nephropathy from remain controversial.16 chronic renal disease (e.g., polycystic , chronic pyelonephritis) and the hyponatremic INCREASED PLASMA OSMOLALITY hypertensive syndrome that frequently occurs Increased plasma osmolality (more than in patients with renal ischemia (e.g., renal 300 mOsm per kg of water) in a patient with artery stenosis or occlusion).17 The combina- hyponatremia is caused by severe hyper- tions of plus (renal glycemia, such as that occurring with diabetic artery stenosis) or hyperkalemia (renal fail- ketoacidosis or a hyperglycemic hyperosmolar ure) are useful clues to this syndrome. state. It is caused by the presence of glucose Endocrine disorders are uncommon causes molecules that exert an osmotic force and of hyponatremia. Diagnosing hypothy- draw water from the intracellular compart- roidism or mineralocorticoid deficiency (i.e., ment into the plasma, with a diluting effect. Addison’s disease) as a cause of hyponatremia Osmotic diuresis from glucose then results in requires a high index of suspicion, because hypovolemia. Fortunately, hyperglycemia can the clinical signs can be quite subtle. In either be diagnosed easily by measuring the bedside case, the serum levels of thyroid-stimulating capillary blood glucose level. hormone (TSH), cortisol, and adrenocorti- cotropic hormone (ACTH) should be mea- DECREASED PLASMA OSMOLALITY sured, because hypothyroidism and hypo- Patients with low plasma osmolality (less adrenalism can coexist as a polyendocrine than 280 mOsm per kg of water) can be hypo- deficiency disorder (i.e., Schmidt’s syn- volemic or euvolemic. The level of urine drome). Treatment of Schmidt’s syndrome sodium is used to further refine the differen- involves steroid replacement before thyroxine

tial diagnosis. T4 therapy to avoid precipitating an addison- ian crisis. The reset osmostat syndrome occurs when the threshold for antidiuretic hormone secre- The Author tion is reset downward. Patients with this con- KIAN PENG GOH, M.R.C.P., is a registrar in the Department of Medicine at Alexandra dition have normal water-load excretion and Hospital, Singapore. He graduated from the Faculty of Medicine at the National Uni- intact urine-diluting ability after an oral versity of Singapore, where he later obtained a master’s degree in family medicine and membership in the United Kingdom’s Royal College of Physicians. water-loading test. The condition is chronic— but stable—hyponatremia.18 It can be caused Address correspondence to Kian Peng Goh, M.R.C.P., Department of Medicine, Alexandra Hospital, 378 Alexandra Rd., 159964, Singapore. Reprints are not available by , quadriplegia, malignancy, mal- from the author. nutrition, or any chronic debilitating disease.

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TABLE 1 SIADH Agents that Cause Hyponatremia SIADH is an important cause of hypona- tremia that occurs when normal bodily con- Diuretics20 trol of antidiuretic hormone secretion is lost Carbamazepine (Tegretol)21 and antidiuretic hormone is secreted indepen- Chlorpromazine (Thorazine)21 dently of the body’s need to conserve water. Vasopressin analogs21 Antidiuretic hormone causes water retention, 22 Indapamide (Natrilix) so hyponatremia then occurs as a result of 23 Selective serotonin reuptake inhibitors inappropriately increased water retention in Theophylline24 the presence of sodium loss. The diagnostic Amiodarone (Cordarone)25 28 Ecstasy (3,4-methylenedioxymethamphetamine)26 criteria for SIADH are listed in Table 2. SIADH is a diagnosis of exclusion and Information from references 20 through 26. should be suspected when hyponatremia is accompanied by urine that is hyperosmolar compared with the plasma. This situation implies the presence of a low plasma osmolal- Low Urine Sodium Level. Patients with ity with an inappropriately high urine osmo- extra-renal sodium loss have a low urinary lality, although the does not sodium concentration (less than 30 mmol per necessarily have to exceed the normal range. L) as the body attempts to conserve sodium. Another suggestive feature is the presence of Causes include severe burns and gastrointesti- caused by increased fractional nal losses from vomiting or diarrhea. Acute excretion of urate.29 Common causes of water overload, which usually is obvious from SIADH are listed in Table 3. the patient’s history, occurs in patients who Any cerebral insult, from tumors to infec- have been hydrated rapidly with hypotonic fluids, as well as in psychiatric patients with psychogenic overdrinking. TABLE 2 therapy, on the other hand, can Diagnostic Criteria for SIADH cause either a low or a high urinary-sodium concentration, depending on the timing of the last diuretic dose administered, but the pres- ence of concomitant hypokalemia is an The rightsholder did not important clue to the use of a diuretic.19 grant rights to reproduce this item in electronic Drug and Use media. For the missing Medications and drugs that cause hypona- tremia are listed in Table 1.20-26 Some of the item, see the original print more common causes of medication-induced version of this publication. hyponatremia are diuretics20 and selective serotonin reuptake inhibitors (SSRIs).27 Most of the medications cause SIADH, resulting in SIADH = syndrome of inappropriate antidiuretic hor- euvolemic hyponatremia. Diuretics cause a mone secretion. hypovolemic hyponatremia. Fortunately, in Adapted with permission from Smith AF, Beckett GJ, most cases, stopping the offending agent is Walker SW, Rae PW. Lecture notes on clinical bio- sufficient to cause spontaneous resolution of chemistry. 6th ed. Oxford: Blackwell Science, 1998:22. the electrolyte imbalance.

MAY 15, 2004 / VOLUME 69, NUMBER 10 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 2391 risk of cerebral edema and hyponatremic TABLE 3 encephalopathy.32 The initial correction rate Common Causes of SIADH with hypertonic saline should not exceed 1 to 2 mmol per L per hour, and normo/hyperna- Amiodarone (Cordarone) tremia should be avoided in the first 48 Carbamazepine (Tegretol) hours.33-35 Cerebral disorders (e.g., tumor, meningitis) In patients with chronic hyponatremia, Chest disorders (e.g., pneumonia, empyema) overzealous and rapid correction should be Chlorpromazine (Thorazine) avoided because it can lead to central pontine Ectopic antidiuretic hormone secretion myelinolysis.9,10 In central pontine myelinoly- Selective serotonin reuptake inhibitors sis, neurologic symptoms usually occur one to Theophylline six days after correction and often are irre- versible.19 In most cases of chronic asympto- SIADH = syndrome of inappropriate antidiuretic hor- mone secretion. matic hyponatremia, removing the underlying cause of the hyponatremia suffices.9 Other- wise, fluid restriction (less than 1 to 1.5 L per day) is the mainstay of treatment and the pre- tions, can cause SIADH. Pneumonia and ferred mode of treatment for mild to moder- empyema are well-known pulmonary causes, ate SIADH.20 The combination of loop diuret- with legionnaires’ disease being a classic ics with a high-sodium diet may be required example.30 Another pulmonary cause is bron- to achieve an adequate response in patients chogenic carcinoma and, in particular, small- with chronic SIADH. cell carcinoma, which is also the most com- In patients who have difficulty adhering to mon cause of ectopic antidiuretic hormone fluid restriction or who have persistent severe secretion.31 Drug-induced SIADH is relatively hyponatremia despite the above measures, common. Less common causes include acute demeclocycline (Declomycin) in a dosage of intermittent porphyria, multiple sclerosis, and 600 to 1,200 mg daily can be used to induce a Guillain-Barré syndrome. negative free-water balance by causing nephrogenic diabetes insipidus.19,36 This med- Treatment ication should be used with caution in The treatment of hyponatremia can be patients with hepatic or renal insufficiency.37 divided into two steps. First, the physician In patients with hypervolemic hypona- must decide whether immediate treatment is tremia, fluid and sodium restriction is the pre- required. This decision is based on the pres- ferred treatment. Loop diuretics can be used ence of symptoms, the degree of hypona- in severe cases.38 Hemodialysis is an alterna- tremia, whether the condition is acute (arbi- tive in patients with renal impairment. trarily defined as a duration of less than 48 Newer agents such as the arginine vaso- hours) or chronic, and the presence of any pressin receptor antagonists have shown degree of hypotension. The second step is to promising results39 and may be useful in determine the most appropriate method of patients with chronic hyponatremia.40 correcting the hyponatremia. Shock resulting In all patients with hyponatremia, the cause from volume depletion should be treated with should be identified and treated. Some causes, intravenous isotonic saline. such as congestive heart failure or use of Acute severe hyponatremia (i.e., less than diuretics, are obvious. Other causes, such as 125 mmol per L) usually is associated with SIADH and endocrine deficiencies, usually neurologic symptoms such as seizures and require further evaluation before identifica- should be treated urgently because of the high tion and appropriate treatment.

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Strength of Recommendations

Strength of Key clinical recommendation recommendation References

Poor prognostic factors for severe hyponatremia in B 12 hospitalized patients include the presence of symptoms, sepsis, and respiratory failure. The initial rate of sodium correction with hypertonic saline B 33 should not exceed 1 to 2 mmol per L per hour. Overzealous correction of chronic hyponatremia can lead to B 9, 10 central pontine myelinolysis. Demeclocycline (Declomycin) in a dosage of 600 to 1,200 mg C 19, 36 daily is effective in patients with refractory hyponatremia. Loop diuretics can be used in patients with volume overload. C 38 Arginine vasopressin receptor antagonists may be useful in C 40 patients with chronic hyponatremia.

The author thanks Evelyn Koay, S.C., associate pro- hyponatremia: a multicenter perspective. J Am Soc fessor in the Department of Pathology, National Uni- Nephrol 1994;4:1522-30. versity of Singapore, and director of the Molecular 10. Sterns RH, Riggs JE, Schochet SS Jr. Osmotic Diagnosis Center, National University Hospital, Sin- demyelination syndrome following correction of hyponatremia. N Engl J Med 1986;314:1535-42. gapore, for review of the manuscript. 11. Walmsley RN, Watkinson LR, Koay ES. Cases in chemical pathology: a diagnostic approach. 3d ed. The author indicates that he does not have any con- Singapore: World Scientific, 1992:22. flicts of interest. Sources of funding: none reported. 12. Nzerue CM, Baffoe-Bonnie H, You W, Falana B, Dai S. Predictors of outcome in hospitalized patients REFERENCES with severe hyponatremia. J Natl Med Assoc 2003; 95:335-43. 1. DeVita MV, Gardenswartz MH, Konecky A, 13. Koay ES, Walmsley RN. A primer of chemical Zabetakis PM. Incidence and etiology of hypona- pathology. Singapore: World Scientific, 1996:20. tremia in an intensive care unit. Clin Nephrol 14. McGee S, Abernethy WB 3d, Simel DL. The rational 1990;34:163-6. clinical examination. Is this patient hypovolemic? 2. Kleinfeld M, Casimir M, Borra S. Hyponatremia as JAMA 1999;281:1022-9. observed in a chronic disease facility. J Am Geriatr 15. Thomas DR, Tariq SH, Makhdomm S, Haddad R, Soc 1979;27:156-61. Moinuddin A. Physician misdiagnosis of 3. Kumar S, Berl T. Sodium. Lancet 1998;352:220-8. in older adults. J Am Med Dir Assoc 2003;4:251-4. 4. Miller M, Morley JE, Rubenstein LZ. Hyponatremia 16. Agarwal R, Emmett M. The post-transurethral in a nursing home population. J Am Geriatr Soc resection of prostate syndrome: therapeutic pro- 1995;43:1410-3. posals. Am J Kidney Dis 1994;24:108-11. 5. Arieff AI. Hyponatremia, convulsions, respiratory 17. Agarwal M, Lynn KL, Richards AM, Nicholls MG. arrest, and permanent brain damage after elective Hyponatremic-hypertensive syndrome with renal surgery in healthy women. N Engl J Med 1986; ischemia: an underrecognized disorder. Hyperten- 314:1529-35. sion 1999;33:1020-4. 6. Arieff AI, Ayus JC, Fraser CL. Hyponatraemia and 18. Milionis HJ, Liamis GL, Elisaf MS. The hyponatremic death or permanent brain damage in healthy chil- patient: a systematic approach to laboratory diag- dren. BMJ 1992;304:1218-22. nosis. CMAJ 2002;166:1056-62. 7. Ayus JC, Wheeler JM, Arieff AI. Postoperative 19. Janicic N, Verbalis JG. Evaluation and management hyponatremic encephalopathy in menstruant of hypo-osmolality in hospitalized patients. women. Ann Intern Med 1992;117:891-7. Endocrinol Metab Clin North Am 2003;32:459-81. 8. Lee CT, Guo HR, Chen JB. Hyponatremia in the 20. Spital A. Diuretic-induced hyponatremia. Am J emergency department. Am J Emerg Med 2000; Nephrol 1999;19:447-52. 18:264-8. 21. Chan TY. Drug-induced syndrome of inappropriate 9. Sterns RH, Cappuccio JD, Silver SM, Cohen EP. antidiuretic hormone secretion. Causes, diagnosis Neurologic sequelae after treatment of severe and management. Drugs Aging 1997;11:27-44.

MAY 15, 2004 / VOLUME 69, NUMBER 10 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 2393 Hyponatremia

22. Chapman MD, Hanrahan R, McEwen J, Marley JE. 32. Arieff AI, Llach F, Massry SG. Neurological manifes- Hyponatraemia and hypokalaemia due to inda- tations and morbidity of hyponatremia: correlation pamide. Med J Aust 2002;176:219-21. with brain water and . Medicine [Balti- 23. Wilkinson TJ, Begg EJ, Winter AC, Sainsbury R. more] 1976;55:121-9. Incidence and risk factors for hyponatraemia fol- 33. Ayus JC, Krothapalli RK, Arieff AI. Treatment of lowing treatment with fluoxetine or paroxetine in symptomatic hyponatremia and its relation to brain elderly people. Br J Clin Pharmacol 1999;47:211-7. damage. A prospective study. N Engl J Med 1987; 24. Liberopoulos EN, Alexandridis GH, Christidis DS, 317:1190-5. Elisaf MS. SIADH and hyponatremia with theo- 34. Gross P. Treatment of severe hyponatremia. Kidney phylline. Ann Pharmacother 2002;36:1180-2. Int 2001;60:2417-27. 25. Patel GP, Kasiar JB. Syndrome of inappropriate anti- 35. Lauriat SM, Berl T. The hyponatremic patient: prac- diuretic hormone-induced hyponatremia associ- tical focus on therapy. J Am Soc Nephrol 1997;8: ated with amiodarone. Pharmacotherapy 2002; 1599-607. 22:649-51. 36. Forrest JN Jr, Cox M, Hong C, Morrison G, Bia M, 26. Hartung TK, Schofield E, Short AI, Parr MJ, Henry Singer I. Superiority of demeclocycline over lithium JA. Hyponatraemic states following 3,4-methyl- in the treatment of chronic syndrome of inappro- enedioxymethamphetamine (MDMA, ‘ecstasy’) priate secretion of antidiuretic hormone. N Engl J ingestion. QJM 2002;95:431-7. Med 1978;298:173-7. 27. Woo MH, Smythe MA. Association of SIADH with 37. Curtis NJ, van Heyningen C, Turner JJ. Irreversible selective serotonin reuptake inhibitors. Ann Phar- nephrotoxicity from demeclocycline in the treat- macother 1997;31:108-10. ment of hyponatremia. Age Ageing 2002;31: 28. Smith AF, Beckett GJ, Walker SW, Rae PW. Lecture 151-2. notes on clinical biochemistry. 6th ed. Oxford: 38. Szatalowicz VL, Miller PD, Lacher JW, Gordon JA, Blackwell Science, 1998:22. Schrier RW. Comparative effect of diuretics on 29. Beck LH. Hypouricemia in the syndrome of inap- renal water excretion in hyponatremic oedematous propriate secretion of antidiuretic hormone. N Engl disorders. Clin Sci [Lond] 1982;62:235-8. J Med 1979;301:528-30. 39. Saito T, Ishikawa S, Abe K, Kamoi K, Yamada K, 30. Fernandez JA, Lopez P, Orozco D, Merino J. Clinical Shimizu K, et al. Acute aquaresis by the nonpep- study of an outbreak of Legionnaire’s disease in tide arginine vasopressin (AVP) antagonist OPC- Alcoy, Southeastern Spain. Eur J Clin Microbiol 31260 improves hyponatremia in patients with Infect Dis 2002;21:729-35. syndrome of inappropriate secretion of antidiuretic 31. Johnson BE, Damodaran A, Rushin J, Gross A, Le hormone (SIADH). J Clin Endocrinol Metab 1997; PT, Chen HC, et al. Ectopic production and pro- 82:1054-7. cessing of atrial natriuretic peptide in a small cell 40. Wong LL, Verbalis JG. Vasopressin V2 receptor lung carcinoma cell line and tumor from a patient antagonists. Cardiovasc Res 2001;51:391-402. with hyponatremia. Cancer 1997;79:35-44.

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