Treatment of Hyponatremia

□ REVIEW ARTICLE □

Peter Gross

Abstract

Hyponatremia is an electrolyte disorder that is defined by a serum sodium concentration of less than 136 mmol/L. Hyponatremia occurs at a high incidence. It is commonly associated with mild to moderate mental impairment. Hypoosmolar hyponatremia occurs in the setting of plasma volume deficiency (“hypovolemia”, e. g. after gastrointestinal fluid loss), liver cirrhosis and cardiac failure (“hypervolemic” hyponatremia) and syndrome of inappropriate antidiuretic hormone secretion (“euvolemic” hyponatremia). Excessive antidiuretic hormone and continued fluid intake are the pathogenetic causes of these hyponatremias. Whereas hypovolemic hyponatremia is best corrected by isotonic saline, conventional proposals for euvolemic and hypervolemic hyponatremia consist of the following: fluid restriction, lithium carbonate, demeclocycline, urea and loop diuretic. None of these nonspecific treatments is entirely satisfactory. Recently a new class of pharmacological agents―orally available vasopressin antagonists, collectively called vaptans―have been described. A number of clinical trials using vaptans have been performed already. They showed vaptans to be effective, specific and safe in the treatment of euvolemic and hypervolemic hyponatremia.

Key words: hyponatremia, vasopressin receptor antagonist

(Inter Med 47: 885-891, 2008) (DOI: 10.2169/internalmedicine.47.0918)

fied. Clinicians saw hyponatremia primarily as an important Introduction diagnostic marker which indicated the presence of heart failure, liver cirrhosis or neoplastic disease. Clinicians were Hyponatremia is defined by a serum sodium concentration also well aware that acute severe hyponatremia (a serum so- of less than 136 mmol/L (1). It is the most frequent electro- dium concentration <118 mmol/L of a duration <36-48 lyte disorder of patients in the hospital (2) but it is also en- hours) would lead to serious symptoms such as confusion, countered in ambulatory outpatients especially in the elderly unconsciousness, grand mal seizures and even death. Hence, (3). The incidence of hyponatremia has apparently increased it was common to direct therapy at the prevention of pro- over the last 3 decades. Although a prospective study from gression from mild to severe hyponatremia. However mild 1985 reported an incidence of 2.5% from a tertiary care hyponatremia in itself―which is by far the commonest form medical center (4), more recent studies from 2003 (5) and of hyponatremia encountered―was considered oligosympto- 2006 (2) found this number to be between 29 and 42%. Al- matic, exerting little if any impairment of the patient’s well- though hyponatremia in the hospital was not limited to spe- being. There have been several recent changes regarding the cial fields of medical practice, the departments of internal viewpoint of these aspects. medicine, surgery and gynaecology and the areas of inten- There is new evidence that even mild hyponatremia is a sive care, pulmonology and cardiology were those most cause of important symptoms (3). Renneboog et al (3) heavily involved (2). evaluated mental functions in 16 elderly individuals(age 63 ± 15 years) with chronic hyponatremia (126 ± 5 mmol/L) Clincal Relevance of Hyponatremia due to the syndrome of inappropriate ADH secretion (SIADH). The researchers performed tests of balance, di- Until recently the clinical relevance of hyponatremia, es- rected walking, memory, calculation and speed of reactions. pecially in its mild form (130-134 mmol/L) was not clari- Importantly the researchers did one set of tests while the in-

Department of Nephrology, Universitätsklinikum C. G. Carus, Dresden, Germany Received for publication January 14, 2008; Accepted for publication January 23, 2008 Correspondence to Dr. Peter Gross, [email protected]

885 Inter Med 47: 885-891, 2008 DOI: 10.2169/internalmedicine.47.0918 dividuals were in hyponatremia and they performed the same set of tests at another time in normonatremia. It was Pathophysiology of Hyponatremia found that hyponatremia caused: 1) the patients’ balance and gait to be unsteady―predisposing them to falls―,2)made Precise measurements of the serum sodium concentration reaction time significantly longer, and 3) made mental errors became available in 1950 with the introduction of flame significantly more common than was seen in normonatre- photometry into laboratory medicine. Shortly thereafter it mia. In additional tests in normal healthy individuals the was suggested that excessive antidiuretic hormone (ADH, authors quantified the degree of mental impairment by com- vasopressin) was responsible for most cases of hyponatremia parison with the results of drinking alcohol. They found that (11). Leaf and Mamby gave a standard oral water load to a blood alcohol level of 0.6 ± 0.2 g/L lead to the degree of hyponatremic patients (11). The serum sodium concentration mental impairment that had been observed previously at a fell and the urinary flow rate as well as urinary osmolality serum sodium concentration of approximately 126 mmol/L. remained unchanged. A bioassay for the measurement of In another part of the study of Renneboog and colleagues ADH was done and it indicated elevated ADH already at (3), the authors analyzed more specifically the physical con- baseline before the water load. Such a pattern of changes sequences of the dysbalance in hyponatremic patients. They was reminiscent of that observed when a standard oral water studied emergency―room admissions for the incidence of load was given to normal healthy volunteers having received preceding falls. They found that hyponatremic patients had an injection of vasopressin shortly before (12). In laboratory fallen approximately four times more often than their animals hypotonic infusions together with i.v. vasopressin matched normonatremic counterparts in the very recent past. were also shown to bring about hyponatremia (13) whereas Hence, it is most likely that hyponatremia predisposes to either component alone was not effective. As a mirror image bone fractures. Taken together, even mild chronic hyponatre- of the foregoing:when hypophysectomized dogs (14) or va- mia is a cause of important symptoms. sopressin deficient Brattleboro rats (15) were subjected to Furthermore there has been continued interest in the prog- manoeuvers―such as right heart failure or liver cirrhosis― nostic significance of a given hyponatremia. Heumann et al that ordinarily elicit water retention and hyponatremia, this studied 507 cirrhotic patients on the waiting list for liver was no longer observable. transplantation (6). In this cohort of obviously very sick pa- The introduction of the radioimmunoassay for ADH in tients hyponatremia turned out to be an independent predic- 1973 permitted a more rigorous testing of the previous con- tor of survival or premature demise―even when the score cepts. Measurements of ADH have now been made in ex- of severity―the MELD score―was average and not experimental hyponatremic cirrhosis (15), cardiac failure (16), treme (6). In a similar line, hyponatremia at the time of liver glucocorticoid deficiency (17) and several other hyponatre- transplantation was associated with a larger intensity of neu- mic conditions. It was confirmed in all that the hyponatre- rologic disease, renal failure, infectious complications and mic state was associated with stimulated vasopressin, i.e. early posttransplantation demise than normonatremia (7). measurable vasopressin―since osmotically it should be fully These recent publications therefore reinforce previous suppressed and unmeasurable in hypoosmolality. Similar knowledge depicting hyponatremia as a marker of a guarded findings have also been reported from patients with hypona- prognosis; yet they leave the second question unanswered: tremia in the conditions of cardiac failure (18), liver cirrho- does it actively contribute to an adverse prognosis? sis (19), hypothyroidism (20), and SIADH and other set- In chronic cardiac disease hyponatremia is frequently tings. Uniformly all these studies found ADH to be measur- seen. As has been well described several years ago hypona- able, i.e. stimulated and not suppressed. tremia in that setting predicts worsening of the heart failure A surprising feature of the experimental and clinical re- and an unfavourable prognosis (8). It has now been shown ports is the fact that ADH was secreted despite the presence that hyponatremia is also a common finding in acute ST- of hyponatremia, synonymous with hypoosmolality. It was elevation myocardial infarction (9). A recent study of 978 therefore proposed that other stimuli of ADH called “non- acute ST-elevation myocardial infarction patients showed osmotic” would be in operation in hyponatremia. It was that hyponatremia predicted post discharge re-hospitalization later found in many or most settings of hyponatremia that and post discharge demise (9). It is noteworthy that these the non-osmotic stimuli could be traced back to baroreceptor patients did not show cardiac failure at the time of the myo- function in large arterial vessels of the central circulation cardial infarction. Again the data confirm previous knowl- (21). For instance in hyponatremic cardiac failure baroceptor edge of hyponatremia as a marker of an adverse prognosis; afferents from the central arteries and the aortic arch sense they do not answer the question whether hyponatremia in it- the low cardiac output and transmit a vasopressin stimulat- self―or by means of the stimulated vasopressin-contributes ing signal to the hypothalamus;baroceptor denervation pre- to the worsening of the prognosis. However, recently studies vents such vasopressin stimulation (16). A similar chain of using novel vasopressin antagonists have been initiated to events is in operation in hyponatremic liver cirrhosis or ex- test this latter hypothesis (10). tracellular volume depletion. In SIADH paraneoplastic secretion of ADH or direct involvement of the hypothalamus by cerebral changes usually explains the nonosmotic ADH.

886 Inter Med 47: 885-891, 2008 DOI: 10.2169/internalmedicine.47.0918

tion to approximately 0.8 L/day. Given that obligatory uri- Clinical Settings of Hyponatremia nary excretion plus insensible losses yield > 1 L/day of fluid volume, this kind of a fluid restriction should result in a For the diagnosis and treatment of a given hyponatremia negative fluid balance and hence an increase in the serum the clinical evaluation has to include a careful medical his- sodium. However the improvement will occur at a slow tory, a physical examination with attention to the patient’s pace. Furthermore hyponatremic patients are thirsty patients extracellular fluid volume status and laboratory measure- ―if they were not they would stop drinking and they would ments. The latter should include the plasma-osmolality, - not become hyponatremic in the first place. It is therefore potassium, -uric acid, -urea and-glucose. The urinary osmo- notoriously difficult for hyponatremic patients to adhere to a lality and the urinary sodium concentration are also re- fluid restriction (1) and this measure may not work. quired. The use of pharmacologic agents has been suggested for Hyponatremia in the presence of hyperosmolality is usu- the induction of a nephrogenic diabetes insipidus. This can ally due to hyperglycemia or occasionally to mannitol caus- be expected to correct a hyponatremia (22, 23). Thus, lith- ing a shift of water from the intracellular to the extracellular ium in lithium carbonate is an inhibitor of ADH induced compartment―because the cell membrane is impermeable to adenylate cyclase in the collecting duct principal cell. the glucose in uncontrolled diabetes or the mannitol. This Hence, lithium antagonizes the hydroosmotic effect of ADH hyponatremia is a disorder of water distribution and not one (22). However lithium is potentially nephrotoxic, its plasma of water balance. Hence treatment should be directed to- levels vary and have to be watched closely (24) and the ef- wards hyperglycemia and its correction with insulin in the fects on renal water excretion are not reliable. case of hyperglycemic hyponatremia, but not towards ADH Demeclocycline is an older tetracycline antibotic. One of or water. Hypoosmolar hyponatremia may occur in the pres- its adverse effects was polyuria and nephrogenic diabetes in- ence of advanced renal failure (stages IV or V of renal fail- sipidus. Doses of 600-1,200 mg/day have been given to treat ure). It is then primarily due to the kidney’s inability to fil- hyponatremia (23). Although demeclocycline is more effec- ter and excrete enough water. This hyponatremia also is not tive and more predictable than lithium in the treatment of a disturbance of ADH. hyponatremia (23) demeclocycline may induce azotemia in The remaining entities of hypoosmolar hyponatremia― general and it may be nephrotoxic in liver cirrhosis (25). and the ones to be discussed herein―will be those that are Furthermore demeclocycline is no longer available on the associated with cardiac failure and liver cirrhosis (also called market in most countries. “hypervolemic” hyponatremia because of edema formation), Urea given as a powder or in the form of capsules in SIADH (also called “euvolemic” hyponatremia) and “hy- doses of several gram/day has been used. It induces an os- povolemia” (as occurs after gastrointestinal fluid losses or motic diuresis and an augmented excretion of free water by profuse sweating). SIADH is associated with a unique pat- the kidneys. This has been used successfully by some to tern of laboratory abnormalities:low or even subnormal correct the hyponatremia of SIADH (26); however urea has serum-urea, -creatinine and importantly-uric acid, whereas not met with widespread acceptance by patients and physi- the sodium excretion rate will be high (>40 mmol/L). In the cians. hypervolemic and hypovolemic hyponatremias the laboratory In SIADH high doses of i.v. loop diuretics elicit a volu- measurements are changed in the opposite direction from minous diuresis that has a low sodium content. If the so- the ones just mentioned. The urinary osmolality will be dium excreted is replenished quantitatively by giving hyper- higher than 100 mosm/kg in all conditions. This indicates tonic saline, a negative water balance ensues and hyponatre- the kidney’s inability to excrete maximally dilute urine, one mia can be corrected in this way (27). This treatment is ef- which would correct any hyponatremia. fective and reliable, but it is cumbersome. Therefore it is not used very frequently. Taken together, the conventional ap- Conventional Treatment of Hyponatremia proaches for the treatment of hyponatremia lack specificity, efficiency and ease of application. Therefore scientists have In the entity of hypovolemic hyponatremia infusions of been interested in other means such as vasopressin antago- isotonic saline are the treatment of choice. Such infusions nists to improve the treatment of hyponatremia. will saturate the baroreceptors, terminate the stimuli to ADH secretion and allow the kidneys to excrete excess water, i.e. Vasopressin Antagonists correct any hyponatremia. In euvolemic and hypervolemic hyponatremia saline infusions may occasionally be given as The pathogenetic role of ADH in most types of hypona- an emergency measure―i.e. in grand mal seizures or in very tremia suggested that vasopressin antagonists would be a severe hyponatremia (<110 mmol/L) with major mental suitable approach to treatment. Manning et al were the first changes―but in general this approach is unproductive. In- to describe a large number of peptidic vasopressin antago- stead other measures focusing on reducing total body water nists (28). It was shown that antagonists worked in principle have been recommended in the literature: in animal models with hyponatremia and in human subjects A standard procedure is the prescription of a fluid restric- (29). However the peptidic nature of the agents, the need for

887 Inter Med 47: 885-891, 2008 DOI: 10.2169/internalmedicine.47.0918 parenteral application and the unexpected property of intrin- sic agonistic effects in addition to antagonistic effects pre- cluded any widespread or chronic use in patients. It was therefore a breakthrough that random screening between 1990 and 2000 yielded several non-peptide, orally available novel vasopressin antagonists collectively called vaptans (Fig. 1).

Mozavaptan

OPC 31260 or mozavaptan was described in 1992 (30). It is a benzazepine derivative (Fig. 1) that bound with a high degree of affinity to the renal hydroosmotic V-2 vasopressin receptor but not to the vascular V-1 vasopressin receptor. It did not cause agonistic effects of its own. When given orally to normal human subjects at a dose of 1 mg/kg the urinary flow rate increased eight fold, the urinary osmolality became maximally dilute (63 mosm/kg) but the urinary sodium excretion rate changed only marginally (31). Although mozavaptan was the first agent of the new class of vaptans and hence had paradigmatic importance mozavaptan was not very potent. Mozavaptan eventually met with limited clinical application and subsequent agents have attracted greater interest. Figure 1. Chemical structure of nonpeptide, orally available vasopressin antagonists. All compounds are vasopressin Lixivaptan V-2 receptor antagonists except for conivaptan which is a mixed V-1/V-2 vasopressin receptor antagonist. (Conivaptan VPA 985 or lixivaptan is a potent, V-2 receptor selective, is presently on the market as a parenteral preparation) orally available vasopressin antagonist reported in 1998 (32). Recently, a short term study in 42 heart failure patients receiving lixivaptan was reported (33). When lixivaptan was potassium remained unchanged. There were very few side given in doses as high as 400 mg the urinary excretion rate effects. Primarily patients noted an increase in thirst. There more than doubled, solute-free water excretion was signifi- were no specific serious adverse events. cantly enhanced and the serum sodium concentration increased (33). A prospective randomized study in 112 pa- Conivaptan tients with euvolemic and hypervolemic hyponatremia was also performed. The study extended over 7 days. Patients Conivaptan or YM 087 is the first combined V-1a/V-2 va- were placed on a fluid restriction of 1 L/day. They received sopressin receptor antagonist (35). A few clinical studies 50 or 100 mg of lixivaptan twice a day per os. have been reported using conivaptan as a parenteral prepara- In the placebo control group the serum sodium remained tion (36). [Although originally developed as an oral antago- unchanged (127.3 ± 3 mmol/L at baseline, 127.7 ± 4 at the nist it was later marketed as a parenteral agent only]. The end of the study) however, there was a significant increase studies included patients with SIADH and hyponatremic car- in the high dose lixivaptan group (receiving 200 mg of lixi- diac failure. Conivaptan was given as a continuous i.v. infu- vaptan/day): the serum sodium went from a baseline of sion over 9 days in doses of 40-80 mg/day. Patients were 126.4 ± 4.4 mmol/L to 132.3 ± 6.9 at the end of the study supposed to be on a mild fluid restriction of 2 L/day. Coni- (p <0.05). The increase of the serum sodium occurred vaptan increased the urinary flow rate significantly, diluted within two to three days after the start of lixivaptan treat- the urine, caused a positive free water balance and increased ment. Patients with a diagnosis of SIADH responded better the serum sodium concentration from 125 ± 33 mmol/L to than those with liver cirrhosis or cardiac failure. In fact only 133 ± 3.7(p <0.05). The urinary sodium excretion rate did 55 % of hyponatremic patients with liver cirrhosis re- not charge and the serum potassium concentration remained sponded with an increase of the serum sodium. The causes stable. Thirst, postural hypotension and headache were re- for the apparent unresponsiveness in this many patients have ported as adverse events (36). It appears that conivaptan is not been clarified. However, it is likely that decreased distal an efficient treatment of hyponatremia in the patients that delivery of tubular fluid to the collecting duct is involved. require parenteral medication. The lixivaptan treatment was associated with a slight, 8% decline of the GFR (34). The excretion rates of sodium and

888 Inter Med 47: 885-891, 2008 DOI: 10.2169/internalmedicine.47.0918

the treatment phase lasted up to 27 days. The dose of Satavaptan tolvaptan was 60 mg per day. The serum sodium concentration increased from 129 ± 3 mmol/L to 134.7 ± 3.2 in the Satavaptan or SR 121 463 is a potent, specific orally treatment group, but it remained at 129.7 ± 3 in the placebo available vasopressin V-2 receptor antagonist first described group．―In a large trial of 4,133 patients with heart failure in 1996 (37). Clinical phase III studies have been conducted 30 mg of tolvaptan or placebo was given over 9.9 months in SIADH (38). Thirty-four hyponatremic patient received (42). Tolvaptan improved dyspnoea, body weight and 25 or 50 mg orally once a day of satavaptan for 5 to 23 edema. In patients with hyponatremia the serum sodium in- days, or placebo in a double-blind, randomized fashion (38). creased. The most frequently observed adverse events were Patients maintained a fluid restriction of 1.5 L/day. In this thirst and dry mouth. However considering the large number study satavaptan increased the urinary flow rate from 1.5 to of participating subjects and the long duration of observa- 2.5 L/day over the first 5 days of the protocol. The urinary tion it is very important that tolvaptan turned out to be a osmolality decreased by more than 50%, the free-water safe agent (42)．―Another recent large trial―SALT I+II clearance became positive and the hyponatremia corrected (Study of Ascending Levels of Tolvaptan in Hyponatre- from 127 ± 5 mmol/L to 140 ± 6 (38). In the treated pa- mia)― with a total of 448 patients was primarily directed tients there were no significant changes of the urinary excre- at hyponatremia (43). Patients with euvolemic or hypervo- tion rats of sodium or potassium. Despite the increased urine lemic hyponatremia (128.8 ± 4.1 mmol/L) received tolvap- flow patients failed to lose weight. While this lack of a tan 30-60 mg orally once a day or placebo in a randomized, weight loss has been seen in several long term clinical stud- double blind fashion. Patients were not under a fluid restric- ies of vaptans in the satavaptan study (38) it implies that tion. The study was conducted over 30 days on therapy fol- several patients did not comply with the fluid restriction. In- lowed by 1 week of observation after discontinuation of deed thirst was reported as an adverse event. In view of the therapy. It was observed that tolvaptan―but not placebo― brisk initial diuresis it is not surprising that 10% of treated corrected the hyponatremia in all diagnostic categories and patients showed an overly rapid correction rate of their hy- groups of severity of hyponatremia (43) (Fig. 2). After dis- ponatremia, i.e. > 12 mmol/L/day. No osmotic demyelisation continuation of tolvaptan hyponatremia recurred. In the pa- syndrome was observed. In one arm of the protocol satavap- tients receiving tolvaptan the correction of hyponatremia tan was given for a duration of 1 year. In this part of the was associated with a significant improvement of the mental study satavaptan maintained the normonatremia and was health status as measured by the SF-12 questionnaire. Sur- judged to be safe. The evidence suggests that satavaptan will prisingly body weight did not change. The most frequently become an efficient oral agent for the treatment of euvo- encountered adverse events were: thirst, dry mouth, consti- lemic and hypervolemic hyponatremia. pation and weakness. Overly rapid correction of a hyponatremia was not seen and there was no therapeutic overshoot Tolvaptan into the hypernatremic rage. This outpatient study for the first time demonstrated the feasibility―and the benefits―of Tolvaptan or OPC 41061 is an orally available, potent se- long term treatment of hyponatremia with an oral vaso- lective vasopressin-V-2 antagonist (39). In addition to ex- pressin antagonist. perimental work, several phase II-III clinical studies have been conducted already. In the Activ trial (Acute and The Treatment of Hyponatremia Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure) (40) 319 patients admitted to hos- What are the implications of the data discussed in the pital in NYHA classes III and IV for worsening of conges- foregoing sections for the treatment of hyponatremia? tion received tolvaptan (30-90 mg q.d.) or placebo orally in Several principles are straightforward:Hyperosmolar and addition to diuretic therapy for up to 60 days. Tolvaptan in- normoosmolar hyponatremia suggest the presence of hyper- creased urine output from 2.3 to 4 L/day in the initial days glycemia or mannitol and action should be directed at these of the study, lowered the body weight by approximately 2 components. Hyponatremia in the presence of stage IV or V kg, improved signs and symptoms of heart failure and it renal failure is probably the result of fluid intake in excess normalized the serum sodium concentration in the 68 par- of 3 L/day and stopping the polydipsia will cure the hy- ticipants who had hyponatremia. There were no changes of ponatremia. Hyponatremia in hypovolemic states―i.e. after vital signs, serum potassium, blood urea nitrogen or serum gastrointestinal fluid losses―is best treated by infusions of creatinine, although “renal failure” occurred in 5 treated pa- isotonic saline. Such infusions will suppress ADH and en- tients and resulted in discontinuation of tolvaptan. Thirst and able the kidneys to excrete the excess water rapidly. polyuria were the most frequently reported adverse events. However, hyponatremia of euvolemic and hypervolemic In another study of tolvaptan the efficiency of the agent in states is the area in which future changes are imminent. The correcting a hyponatremia was compared with that of a fluid vasopressin antagonist conivaptan is already on the market; restriction at 1,200 cc/day (41). The study incorporated 28 other agents are expected to follow soon. How should vaso- patients with euvolemic or hypervolemic hyponatremia and pressin antagonists be used to treat hyponatremia? What will

889 Inter Med 47: 885-891, 2008 DOI: 10.2169/internalmedicine.47.0918

Figure 2. Course of the serum sodium concentration after the start of tolvaptan on day 1 (circles; n=95 patients) or placebo (squares; n=91). Therapy with tolvaptan was discontinued on day 30. Pa tients had chronic euvolemic or hypervolemic hyponatremia. It is demonstrated that the vaptan corrected hyponatremia into the normal range of serum sodium concentrations. (With permission from the New England Journal of Medicine). be the advantages for the patients? serum-sodium in the normal range over the first 3 weeks. It is likely that physicians will begin to utilize vaptans in Should a vaptan therapy be required over months and years chronic mild to moderate hyponatremia because this is the specific controls of the serum-sodium should be done during area in which experience has accumulated from previous episodes of fluid stress such as in the context of intercurrent studies. In the treatment of chronic hyponatremia a slow diarrhea, vomiting or during heat waves. correction rate of <12 mmol/L/day will be the intended pro- What advantages may patients expect from vaptan treat- cedure. Treatment should be decelerated or stopped when a ment? It is likely that patients will be satisfied to be able to serum―sodium of approximately 134 mmol/L―i.e. the discontinue fluid restrictions. It is also to be expected that minimally hyponatremic range―has been reached. These correction of hyponatremia by vaptan treatment will be fol- precautions should be observed to avoid the risk of osmotic lowed by improvement of patients’ neural status. Further- demyelination. In the future physicians may continue to rec- more in patients with chronic forms of hyponatremia vap- ommend fluid restrictions―but this measure will no longer tans should prove useful in preventing occasional precipitous be strictly required. In choosing a starting dose of any given decreases in the serum-sodium concentration that happen vaptan it shall be advisable to begin with a small dose, es- unpredictably, especially during times of fluid stress. Finally, piecially in patients with SIADH, to avoid an overly rapid vaptans are likely to make any treatment of hyponatremia correction rate. It is foreseeable that the physician will have more specific and better titratable for the physician. Hence to control the serum sodium concentration repeatedly, per- these novel agents should turn out to be interesting thera- haps daily in the first 3 days to titrate the dosage of the vap- peutic tools. tan;thereafter weekly checking may suffice to keep the

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