REVIEW Managing Hyponatremia in Patients With Syndrome of Inappropriate Antidiuretic Hormone Secretion Joseph G. Verbalis, MD Division of Endocrinology and Metabolism, Department of Medicine, Georgetown University Medical Center, Washington DC. J.G. Verbalis received an honorarium funded by an unrestricted educational grant from Otsuka America Pharmaceuticals, Inc., for time and expertise spent in the composition of this article. No editorial assistance was provided. No other conflicts exist. This review will address the management of hyponatremia caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in hospitalized patients. To do so requires an understanding of the pathogenesis and diagnosis of SIADH, as well as currently available treatment options. The review will be structured as responses to a series of questions, followed by a presentation of an algorithm for determining the most appropriate treatments for individual patients with SIADH based on their presenting symptoms. Journal of Hospital Medicine 2010;5:S18–S26. VC 2010 Society of Hospital Medicine. Why is SIADH Important to Hospitalists? What Causes Hyponatremia in Patients with SIADH? Disorders of body fluids, and particularly hyponatremia, are Hyponatremia can be caused by 1 of 2 potential disruptions among the most commonly encountered problems in clinical in fluid balance: dilution from retained water, or depletion medicine, affecting up to 30% of hospitalized patients. In a from electrolyte losses in excess of water. Dilutional hypo- study of 303,577 laboratory samples collected from 120,137 natremias are associated with either a normal (euvolemic) patients, the prevalence of hyponatremia (serum [Naþ] <135 or an increased (hypervolemic) extracellular fluid (ECF) vol- mmol/L) on initial presentation to a healthcare provider was ume, whereas depletional hyponatremias generally are asso- 28.2% among those treated in an acute hospital care setting, ciated with a decreased ECF volume (hypovolemic). Dilu- 21% among those treated in an ambulatory hospital care set- tional hyponatremia can arise from a primary defect in ting, and 7.2% in community care centers.1 Numerous other osmoregulation, such as in SIADH, or as a result of ECF vol- studies have corroborated a high prevalence of hyponatremia ume expansion, as seen in conditions associated with con- in hospitalized patients,2 which reflects the increased vulner- comitant secondary hyperaldosteronism such as heart fail- ability of this patient population to disruptions of body fluid ure, hepatic cirrhosis, or nephrotic syndrome. Among some homeostasis. Recognizing the many possible causes of hypo- hospitalized patient groups, euvolemic hyponatremia is the natremia in hospitalized patients and implementing appro- most common presentation of abnormally low serum [Naþ]. priate treatment strategies therefore are critical steps toward In a study of patients who developed clinically significant optimizing care and improving outcomes in hospitalized postoperative hyponatremia (defined as a serum [Naþ] <130 patients with hyponatremia. mmol/L) in a large teaching hospital, only 8% were hypo- In addition to its frequency, hyponatremia is also impor- volemic, whereas 42% were euvolemic and 21% were tant because it has been associated with worse clinical out- hypervolemic.5 comes across the entire range of inpatient care, from the Euvolemic hyponatremia results from an increase in total general hospital population to those treated in the intensive body water, but with normal or near-normal total body so- care unit (ICU). In a study of 4123 patients age 65 years or dium. As a result, there is an absence of clinical manifesta- older who were admitted to a community hospital, 3.5% tions of ECF volume expansion, such as subcutaneous had clinically significant hyponatremia (serum [Naþ] <130 edema or ascites. It is important to recognize that although mmol/L) at admission. Compared with nonhyponatremic SIADH clearly represents a state of volume expansion due patients, those with hyponatremia were twice as likely to die to water retention, it rarely causes clinically recognizable during their hospital stay (relative risk [RR], 1.95; P < 0.05).3 hypervolemia since the retained water is distributed across In another study of 2188 patients admitted to a medical ICU the intracellular fluid (ICF) as well as the ECF, and because over a 5-year period, 13.7% had hyponatremia. The overall volume regulatory processes act to decrease the actual rate of in-hospital mortality among all ICU patients was high degree of ECF volume expansion.6 Euvolemic hyponatremia at 37.7%. However, severe hyponatremia (serum [Naþ] can accompany a wide variety of pathological processes, <125 mmol/L) more than doubled the risk of in-hospital but the most common cause by far is SIADH. Normally, mortality (RR, 2.10; P < 0.001).4 In addition to the general increased plasma osmolality activates osmoreceptors hospital population, in virtually every disease ever studied, located in the anterior hypothalamus and stimulates the the presence of hyponatremia has been found to be an inde- secretion of arginine vasopressin (AVP), also called antidiu- pendent risk factor for increased mortality, from congestive retic hormone (ADH), a key neurohormone that regulates heart failure to tuberculosis to liver failure.2 fluid homeostasis. In patients with euvolemic hyponatremia 2010 Society of Hospital Medicine DOI 10.1002/jhm.783 Published online in Wiley InterScience (www.interscience.wiley.com). S18 Journal of Hospital Medicine Vol 5 No 6 Supplement 3 July/August 2010 to understand the full spectrum of hyponatremic symptoms. As the ECF [Naþ] decreases, regardless of whether due to a loss of sodium or a gain of water, there is an obligate move- ment of water into the brain along osmotic gradients. That water shift causes swelling of the brain, or cerebral edema. If the increased brain water reaches approximately 8% in adults, it exceeds the capacity of the skull to accommodate brain expansion, leading to tentorial herniation and death from re- spiratory arrest and/or ischemic brain damage. However, if the patient survives the initial hyponatremia, a very strong volume regulatory process follows, consisting of loss of elec- trolytes and small organic molecules called osmolytes from brain cells into brain ECF, and eventually the peripheral ECF.12,13 As the solute content of the brain decreases, the water content is allowed to normalize, eventually reaching a state in which brain edema is virtually absent, and as a result FIGURE 1. Etiologies of syndrome of inappropriate symptoms are markedly less than with acute hyponatremia. antidiuretic hormone secretion. Although the time required for the brain to acieve a volume- regulated state varies across patients, this process is com- due to SIADH, plasma AVP levels are not suppressed despite pleted within 48 hours in experinmental animal studies, and normal or decreased plasma osmolality.7 This can be a probably follows a similar time course in humans. result of ectopic production of AVP by tumors, or stimula- Despite this powerful adaptation process, chronic hypona- tion of endogenous pituitary AVP secretion as a result of tremia is frequently associated with neurological symptoma- nonosmotic stimuli that also stimulate vasopressinergic tology, albeit milder and more subtle in nature. A recent neurons, which include hypovolemia, hypotension, angio- report found a fairly high incidence of symptoms in 223 tensin II, nausea, hypoxia, hypercarbia, hypoglycemia, patients with chronic hyponatremia as a result of thiazide stress, and physical activity. Nonsuppressed AVP levels have administration: 49% had malaise/lethargy, 47% had dizzy been documented in the majority of hyponatremic patients, spells, 35% had vomiting, 17% had confusion/obtundation, including those with SIADH8 and heart failure.9 17% experienced falls, 6% had headaches, and 0.9% had seiz- 14 SIADH can develop as the result of many different dis- ures. Although dizziness can potentially be attributed to a ease processes that disrupt the normal mechanisms that diuretic-induced hypovolemia, symptoms such as confusion, regulate AVP secretion, including pneumonias and other obtundation and seizures are more consistent with hypona- lung infections, thoracic and extrathoracic tumors, a variety tremic symptomatology. Because thiazide-induced hypona- of different central nervous system disorders, the postopera- tremia can be readily corrected by stopping the thiazide and/ tive state, human immunodeficiency virus (HIV), and many or administering sodium, this represents an ideal situation in different drugs (Figure 1). Given the multiplicity of disorders which to assess improvement in hyponatremia symptomatol- þ and drugs that can cause disrupted AVP secretion, it is not ogy with normalization of the serum [Na ]; in this study, all surprising that hyponatremia is the most common electro- of these symptoms improved with correction of the hypona- lyte abnormality seen in clinical practice. tremia. This represents one of the best examples demonstrat- ing reversal of the symptoms associated with chronic hypo- What Symptoms are Associated With SIADH? natremia by correction of the hyponatremia, because the Symptoms of hyponatremia correlate both with the degree patients in this study did not in general have severe underly- of decrease in the serum [Naþ] and with the chronicity of ing comorbidities that might complicate interpretation of the hyponatremia. Acute hyponatremia, defined