Treatment of severe hyponatremia

Kidney International, Vol. 60 (2001), pp. 2417–2427

NEPHROLOGY FORUM

Treatment of severe hyponatremia Principal discussant: Peter Gross Universita¨tsklinikum Carl Gustav Carus, Dresden, Federal Republic of Germany

CASE PRESENTATION A 31-year-old white woman was admitted to the hospital because of diffuse cramping abdominal pain. The pain was associated with nausea, vomiting, and an inability to eat or hold down fluids. One week prior to admission, the patient had rhinitis. The day of admission coincided with the patient’s onset of menstrual bleeding. Her medical history revealed 30 hospital admissions over the previous six years for acute intermittent porphyria. During previous attacks of porphyria, the physical examination had shown diffuse abdominal tenderness and a diminution or absence of bowel sounds. A neurologist had documented that the patient could not extend the fingers of both hands completely. Otherwise, the physical examination had been unremarkable. Also, the patient’s routine laboratory tests generally had been normal, except that she had elevated excretion of protoporphyrins and porphyrins multiple times, both during exacerbations of the porphyria as well as during remission. Neither cimetidene nor luteinizing hormone-releasing hormone (LHRH) improved the porphyria. Her exacerbations usually were treated with glucose infusions and meperidine. Otherwise, her medical, family, and social histories were unremarkable. Physical examination disclosed that she was in acute distress from severe pain. Her blood pressure was 130/100 mm Hg; pulse rate, 110 beats/min and regular; and temperature, 36.3⬚C. She

The Nephrology Forum is funded in part by grants from Amgen, Incorporated; Merck & Co., Incorporated; Dialysis Clinic, Incorporated; and Bristol-Myers Squibb Co. Key words: porphyria, vasopressin antagonists, cerebral edema, aquaporins, central pontine myelinolysis, blood-brain barrier, aquaresis.

 2001 by the International Society of Nephrology

was awake and fully oriented. Her mental status, cranial nerves, and deep tendon reflexes all were normal. Examination of the heart and lungs was normal. Her abdomen showed tenderness to deep palpation in the right upper quadrant and over the lower quadrants. The skin was normal and showed no obvious signs of dehydration. She had no ankle edema. Laboratory studies revealed: serum sodium concentration, 140 mmol/L; serum creatinine, 147 ␮mol/L (1.7 mg/dL); urea, 14.8 mmol/L; total porphyrin, 0.53 mg/L (normal, ⬍0.3 mg/L); and delta-aminolevulinic acid, 317 ␮mol/L (normal, ⬍220 ␮mol/L). Urinary porphobilinogen was 20.3 mg/24 h (normal, ⬍1.9 h); and deltaamino-levulinic acid, 17.5 mg/24 h (normal, ⬍6.1 mg/24 h). On admission the patient was given 3.6 L of 10% glucose/ day intravenously (IV). These infusions were supplemented with 40 mmol of NaCl/L of infusate, but her pain failed to disappear under this regimen. Her nausea continued and she vomited three to five times per day. Gastroscopy was unremarkable. On the 3rd hospital day, the serum sodium concentration was 132 mmol/L. On the 5th hospital day, the vomiting intensified. She became somnolent and confused. The serum sodium concentration was 115 mmol/L. The creatinine concentration was 133 ␮mol/L (1.5 mg/dL), the urea concentration was 13.9 mmol/L, and the glucose concentration was 9.6 mmol/L. On the 7th hospital day, the patient vomited multiple times. Her regimen of glucose infusions supplemented by NaCl was continued at 3.6 L/day. She was agitated and confused, and she was periodically unable to speak. On the 8th hospital day, the serum sodium concentration had fallen to 97 mmol/L. The patient had a grand mal seizure. A cerebral computed tomography scan (CCT) demonstrated symmetrically small ventricles and “blurring of sulci,” findings suggestive of cerebral edema. An infusion of 10% NaCl corrected the severe hyponatremia from 98 mmol/L to 128 mmol/L within 36 hours (Fig. 1). On the 13th hospital day, a second CCT was unremarkable. After the rapid correction of the hyponatremia, the patient at first continued to be somnolent, unable to communicate, and apparently confused. She had a tremor of her hands. Her attempts at speaking showed a scanning rhythm. The consulting neurologist did not find any cranial nerve disturbances, difficulty swallowing, evidence of pseudobulbar palsy, or abnormalities of the deep tendon reflexes. The intravenous infusions of 10% glucose had been discontinued. No fluid restriction was ordered; the chart documented that daily fluid consumption ranged between 1 and 2 liters. The abdominal pain, the nausea, and the vomiting disappeared between days 10 and 14. From day 14 onwards, she began to communicate somewhat better. An electroencephalogram (EEG) obtained on the 16th hospital day showed generalized changes of moderate severity together with frontotemporal slowing. The patient was given

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Fig. 1. Course of the serum sodium concentration presented over the first 11 days of hospitalization. The horizontal bars at the top of the diagram indicate the treatment given to the patient. The normal range of serum sodium concentration of the laboratory was 136 mmol/L to 149 mmol/L.

intensive physical rehabilitation therapy. A neurologic consultation on day 35 disclosed that the patient was occasionally confused, although mostly awake and alert; she communicated frequently. She still exhibited occasional episodes of unfounded agitation. Neurologic consultation on the 60th hospital day revealed a reduced ability to concentrate. An EEG on the 65th hospital day showed only mild irregularities of the alpha rhythm. During the neurologic consultation on the 70th hospital day, the patient complained of difficulty memorizing and concentrating. However, she was generally judged to be stable and improved. On the 80th day of hospitalization, the patient was discharged home. The serum sodium concentration had ranged between 140 to 146 mmol/L from day 10 onwards. The discharge plasma creatinine concentration was 88 ␮mol/L (1.0 mg/dL); urea was 4.7 mmol/L. The urinary excretion rates of delta-amino-levulinic-acid and that of total porphyrin remained elevated.

DISCUSSION Prof. Dr. Peter Gross (Schwerpunkt Professor fu¨r Nephrologie, Medizinische Klinik III und Medizinische Poliklinik, Universita¨tsklinikum Carl Gustav Carus, Dresden, Germany): This patient’s severe symptomatic hyponatremia was related to an attack of acute intermittent porphyria. Although porphyria, vomiting and abdominal pain all cause non-osmotic ADH release [1–4], the overriding stimulus of antidiuretic hormone (ADH) in this patient probably was plasma volume contraction. The hyponatremia was precipitated by voluminous amounts of

Table 1. Signs and symptoms of hyponatremia Mild

Anorexia, nausea, vomiting, weakness, muscle cramps, headache, difficulty in concentrating, impaired memory

Severe

Confusion, hallucinations, obtundation, urinary and fecal incontinence, respiratory insufficiency, coma, decorticate or decerebrate posturing, generalized seizures, respiratory arrest

glucose solution given to treat the porphyria. Her physicians failed to react to the worsening hyponatremia until she had diffuse cerebral edema and a grand mal seizure. The hyponatremia was corrected at a rate of 0.9 mmol/ L/h. A computerized axial tomogram (CT) disclosed no evidence of (central pontine) myelinolysis. The patient had hyponatremic encephalopathy with permanent physical disability resulting from the cerebral edema. Acute severe hyponatremia Severe hyponatremia is arbitrarily defined as a serum sodium concentration ⬍115 mmol/L [5, 6]. The designation “acute” refers to a duration of ⬍36 to 48 hours. This condition commonly occurs after surgery [7]. In that setting, previously asymptomatic patients who receive large amounts of hypotonic fluid (3 to 8 L/12 to 24 h) can develop neurologic signs of increasing severity (Table 1) [8]. If the hyponatremia is progressive, obtundation, confusion, coma, generalized seizures, and respiratory arrest

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Fig. 2. Axial computer tomographic (CT) scans of the brain showing a normal study (A) and brain edema (B). Note the diminution of the size of the ventricles in B; in addition, the sulci of the brain are no longer demonstrable in panel B (CTs were kindly provided by Dr. V. Ha¨nig, U.K.D., Dresden, Germany).

can occur [8]. Imaging studies usually demonstrate brain edema (Fig. 2). Autopsy studies have revealed: diffuse cerebral edema, edema of the brain stem, obliteration of sulci, and herniation of the brain stem into the foramen magnum [9]. This acute hyponatremic syndrome also can occur in psychotic patients with polydipsia, labor and delivery in the presence of high doses of oxytocin given with hypotonic fluids, child abuse involving forced water intake, patients receiving thiazides, and marathon runners [8–14]. The consequences of acute hyponatremia are more serious in young (prepubertal) children and premenopausal women [15–17]. A further aggravating factor is hypoxia; Ayus and Arieff postulated a vicious cycle between hyponatremic brain edema and hypoxia [18, 19]. Progression to death or permanent brain damage is a common event in acute severe hyponatremia left untreated [9, 19]. It is generally agreed that the acute hyponatremic syndrome should be treated rapidly. Ayus and coworkers proposed an hourly correction rate of 1.3 mmol/L, using 5% saline with furosemide while avoiding correction to normo/hypernatremia and an increase of the serum sodium concentration by more than 25 mmol/L in the first 48 hours [20]. According to the literature, this protocol is beneficial and does not cause brain lesions of its own [21–23]. Animal models have been used to gain further insight into cerebral edema in acute hyponatremia. Abrupt hypoosmolality (hyponatremia) of the extracellular space causes an aquaporin-4 (AQP-4)-mediated osmotic water movement into brain cells and swelling. Manley and Verkman presented data at the Third International Conference on the Molecular Biology and Physiology of Water and Solute Transport (Go¨teborg, 2000) indicating

that mice deficient in AQP-4 manifest reduced cerebral edema upon hypo-osmotic challenge [24]. Compensation for swelling ensues rapidly, comprising decreased cerebral venous pooling and loss of cerebral spinal fluid from the brain [8, 10]. The finding that young age appears to be a risk factor for brain edema might be explained by the relatively smaller cerebral spinal fluid spaces in young as compared to old brains. Within 5 minutes, cell volumeregulatory ions (Na⫹, K⫹, Cl⫺) are released from brain cells [25]; this efflux can last as long as four hours. Stretch of cell membranes can activate relevant ion channels directly [25]. Work by Fraser et al [26], Arieff et al [27], and Kozniewska et al [28] suggests that the hormonal status in female rats alters the ionic composition of brain cells, which in turn can impair ionic volume regulation and exacerbate brain edema, thereby decreasing brain perfusion, and increasing mortality in female rats. An additional and essential decrease of brain volume can be accomplished within the first two to four days by reducing cellular osmolytes, substances that efficiently transfer osmoles from the intracellular compartment to the extracellular [25]. The osmolytes of brain cells include polyalcohols such as sorbitol and inositol, amino acids, and methylamines [26]. Recent work in patients established the existence of osmolyte regulation in the human brain. In 12 hyponatremic patients, proton magnetic resonance spectroscopy demonstrated decreases of cerebral osmolytes by as much as 50% [29]. In short, an acute lowering of the serum osmolality will cause brain edema until early and late cell volume adaptations have been completed [30]. Because of the rigid skull, cerebral edema can lead to increased intracranial pressure, decreased brain perfusion, and threatened respiratory in-

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sufficiency, and can result in herniation of the brain stem into the foramen magnum [31], permanent brain damage, or death [20]. Rapid correction of an acute hyponatremia is appropriate to avoid hyponatremic brain damage. Rapid correction will restore brain cell volume to normal [32]. In contrast, when chronic hyponatremia is corrected, intracellular ions and osmolytes must reaccumulate to return cell volume to normal. Chronic severe hyponatremia Occasionally, severe hyponatremia is present in a patient for months or even years [33]. Those patients are usually oligosymptomatic or asymptomatic. It is not clear that such patients should be treated. Much more commonly, patients will have had chronic, severe hyponatremia for only a few days, and it will have been associated with drowsiness, nausea, poor memory, or even disorientation [34] (Table 1). The setting generally is thiazide-induced hypokalemic hyponatremia; the syndrome of inappropriate antidiuretic hormone secretion (SIADH); liver cirrhosis, alcoholism, and malnourishment; advanced, diuretic-treated cardiac failure; or protracted vomiting or diarrhea [35]. Physicians usually elect to treat patients with such chronic severe hyponatremia. For instance, it can be important to know whether a patient’s mental changes can be improved by correcting hyponatremia. The physician might be concerned about a worsening of hyponatremia; or the need might exist for large-volume infusions (hyperalimentation). Still, the treatment of chronic severe hyponatremia is controversial because of the alleged possibility of inducing cerebral myelinolysis. In a retrospective study two decades ago, Norenberg and colleagues described autopsy results from 12 patients who had undergone “rapid” correction (20 mmol/L over 1 to 3 days, occasionally reaching hypernatremia) [36]. The correction was followed in 3 to 10 days by central pontine myelinolysis (CPM). Most of the 12 patients also had underlying chronic alcoholism, liver disease (hepatitis, cirrhosis), or both, and these are independent risk factors for CPM. Additional risk factors for myelinolysis include malnutrition, thiazide therapy, hypokalemia, and hyponatremia ⬍105 mmol/L [37–39]. Clinical consequences of CPM in these 12 patients included a sudden disturbance in mental status, flaccid quadriparesis, abnormal conjugate eye movements, and pseudobulbar palsy [36]. When Norenberg et al compared the 12 index patients with 9 others in whom the hyponatremia had been corrected more slowly (Fig. 3), and in whom attainment of normo/hypernatremia had been avoided, they found that none of the 9 had CPM, as shown either by computerized tomography or autopsy. The authors concluded that CPM can be caused by a too rapid or excessive rise in serum sodium from a hyponatremic baseline. The Norenberg study is open to criticism, however,

Fig. 3. Total increase of the serum sodium concentration over the first 7 days of treatment of severe hyponatremia. Symbols are: ( ) 12 patients with CPM; (䊐), 9 patients without CPM. (Reproduced with permission from Williams & Wilkins, [36] Annals of Neurology 11:128–135, 1982.)

because the 12 index patients had a much lower baseline hyponatremia than did the 9 so-called controls (106 mmol/L vs. 118 mmol/L). Several additional reports have since appeared indicating that myelinolysis occurring after rapid correction of chronic hyponatremia can be pontine or extrapontine [34, 35, 38, 40-42]. In one publication, 8 patients with chronic, severe, and symptomatic hyponatremia had been treated at a correction rate of 0.5 to 1.2 mmol/L/h (“rapid correction”); all developed a syndrome compatible with CPM [34]. Of 55 comparable patients undergoing correction at less than 0.5 mmol/ L/h, however, none had any neurologic sequelae [34]. However, the study was retrospective. Furthermore, 7 of the 8 patients with CPM had thiazide-induced hyponatremia with hypokalemia. Therefore, hypokalemia could have been a precipitating co-factor of CPM. Other potential problems with the interpretation of this study were that 2 of the 8 patients with CPM were alcoholics; the hyponatremia in the 8 patients with CPM apparently was more severe than that in the 55 uncomplicated patients; and proof of demyelination [CT, magnetic resonance tomography (MRT), autopsy] was missing in 4 of 8 patients with clinically diagnosed CPM. In another study, Sterns et al surveyed the total experience with extreme hyponatremia (⬍105 mmol/L) of 4100 U.S. nephrologists [40]. Of the 56 patients reported, 14 had neurologic sequelae, potentially from myelinolysis. This report indicates that severe hyponatremia is rare but that myelinolysis can occur in as many as 25% of such patients. Most [38, 40–42] but not all recent publications (abstract; Arieff, Ayus, J Am Soc Nephrol 10:19A, 1999)

Nephrology Forum: Severe hyponatremia

have indicated that cerebral demyelination is a complication of overly rapid correction of chronic hyponatremia. Like cerebral edema, demyelination also has been probed in animal experiments. Verbalis and Martinez studied a noninvasive rat model of hyponatremia (111 to 114 mmol/L; duration, 2 to 3 weeks) that is based on administering DDAVP, a pure V2-vasopressin agonist (AVP in humans is a V1/V2 agonist) [43]. Correction of the hyponatremia from 118 mmol/L to 138 mmol/L within 48 hours by water restriction alone did not cause myelinolysis. Correction from 111 mmol/L to 143 mmol/L within 8 hours by infusions of hypertonic saline (or by using a vasopressin antagonist) was followed by focal or diffuse demyelination in 90% of the rats. When the normonatremia was reversed rapidly to a serum sodium level of 111 mmol/L, only 45% of rats developed demyelination. Similar findings also have been observed by other laboratories [44]. The potential pathways by which such rapid correction of chronic hyponatremia cause myelinolysis have been studied. Attention has been given to organic osmolytes and their role in “osmotic reloading” of brain cells. Thurston et al studied chronic (4-day) hyponatremia (91 mmol/L) in young mice [45]. When the hyponatremia was corrected to 134 mmol/L by hypertonic saline within 9 hours, the mice manifested dehydration and shrinkage of the brain, normal brain levels of sodium and potassium, but amino acid content below normal. Lien et al demonstrated that in the course of rapid correction of chronic hyponatremia, re-accumulation of sodium and chloride caused elevations of these ions above the normal range in brain cells (“overshoot”) [46]. This occurred at a time that the re-accumulation of organic osmolytes was seriously lagging behind. In another study [47], the re-accumulation of organic osmolytes took as long as 5 days. Exogenous osmolyte supplementation failed to speed up osmolyte re-accumulation [48]. Potentially accounting for this lag, the transport of organic osmolytes depends in part on tonicity-responsive new transcription and expression of genes for osmolyte transporters (abstract; Woo et al, J Am Soc Nephrol 10:60A, 1999). In yet another recent study, Lien found osmolyte re-accumulation to be most seriously delayed in areas where myelinolysis was most pronounced (mid-brain, striatum) [44]. Such work suggests a relationship between demyelination and osmolytes. Hypothetically, the culprit of such effects is the blood-brain barrier (BBB). According to Kinne and others, organic osmolytes are molecules that are compatible with normal structure and function of cellular proteins and lipids, as opposed to high concentrations of inorganic ions [49, 50]. With respect to demyelination, the question appears to be: which cells are likely to be altered by ionic overshoot and/or deficiency of organic osmolytes? One class of cells affected are the cerebral vascular endothelial cells, func-

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tionally described as the major part of the BBB [51]. This specialized endothelium has tight intercellular junctions, most evident close to the luminal surface, where the cell membranes fuse [51]. The vascular endothelium of the BBB is (electrically) much “tighter” than the “leaky” capillary endothelia elsewhere. Astrocyte foot processes also are an integral part of the BBB. In direct contact with the basement membrane of the endothelium, they form a complete envelope around the capillaries. Increases in osmolarity in the form of forced hyperosmolarity have been known to disrupt the BBB [52, 53]. For instance, intracarotid injection of 25% mannitol over 3 minutes increased ipsilateral BBB permeability by more than 100%, and the BBB disruption was proportional to the degree of maximal hyperosmolarity achieved. Kroll and Neuwelt hypothesized that shrinkage of cells of the BBB causes opening of the epithelial “tight” junctions and retraction of astrocyte foot processes, all of which would lead to BBB disruption [53]. Disruption would permit access to the brain tissue, including myelinated neurons, of plasma constituents normally excluded. Myelinolysis would be a consequence of this scenario. Rojiani et al characterized BBB disruption in rats with chronic (4-day) severe hyponatremia, 8 hours after rapid correction. They observed interendothelial gaps, dilation of interendothelial spaces, swelling of astrocyte foot processes, and extravasation of macromolecules such as peroxidase [54]. Later, degenerative changes of dying oligodendrocytes and vesicular disintegration of myelin sheaths occurred [55]. Animal experiments could not detect a similar chain of events when chronic hyponatremia was corrected slowly [43]. Some investigators have claimed that myelinolysis in animals is preventable by glucocorticoid administration [56, 57]. Taken together, the one or more causes of demyelination in patients with severe hyponatremia are not clear. Severe chronic hyponatremia can be a marker for possible development of cerebral demyelination. Given that there are dire consequences when myelinolysis does occur, I therefore recommend using a correction rate of ⬍0.5 mmol/L/day, as suggested [34], and halting further correction when the serum sodium concentration rises to 126 mmol/L to 130 mmol/L. When a grand mal seizure occurs in a patient with a previously oligosymptomatic severe chronic hyponatremia, I recommend an initial correction rate of 1.0 to 1.5 mmol/L/h for the first three hours. One can use urea to correct hyponatremia [58] or one can lower the serum sodium level in the setting of a “correction overshoot” (defined as a serum sodium concentration ⬎148 mmol/L during the first 72 hours of correction), but whether these maneuvers are of demonstrable clinical benefit remains to be proven. Imaging studies such as CT or MRT should be performed approximately 6 to 12 days after correction of hyponatremia to

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Fig. 4. Left: Saggital T2-weighted nuclear magnetic resonance (NMR) section showing an oval-shaped region of discrete hyperintensity in the center of the pons 9 days after onset of clinical symptoms following correction of hyponatremia. Right: follow-up examination 23 days after onset of clinical symptoms revealing a distinct rise in signal intensity. (Reproduced with permission from Springer-Verlag, [38] Eur Radiol 6:177–183, 1996.)

determine whether suspected CPM is present (Fig. 4) [38, 41]. The clinical presentation of myelinolysis is unreliable and occasionally takes an apparently asymptomatic course [38]. Severe hyponatremia of uncertain duration Sometimes a patient will have severe hyponatremia of uncertain duration accompanied by symptoms and findings possibly resulting from hyponatremia. In such ambiguous cases, it is impossible to know whether the risks of fast correction (myelinolysis) exceed those from slow correction (brain edema and damage). In this situation, which has not been well studied, I suggest the following: If the patient is in a stable condition with mild to moderate symptoms, I would consider an imaging study (CT, MRT) to search for brain edema and/or cerebral abnormalities; thereafter I would determine the rate of correction accordingly. If the patient is unstable and/or presented advanced symptoms or signs, or if the patient is a symptomatic prepubescent child or a premenopausal woman, I would chose a correction rate of 1 to 2 mmol/ L/h for three or four hours. I then would immediately perform an imaging study to direct subsequent treatment. Admittedly, these suggestions are based on my personal observations only. Vasopressin antagonists Oral vasopressin antagonists are effective and potentially useful in the treatment of hyponatremia. These agents might allow better predictability and better finetuning of treatment. Appropriate use of vasopressin antagonists will require an understanding of the role of vasopressin in hyponatremia. Hyponatremia is primarily a disorder of vasopressin

excess coupled with continued fluid (hypotonic) intake [59]. The excess vasopressin causes increased water reabsorption by the kidney; thus, a fluid intake higher than minimal (that is, 600 to 800 cc/day) leads to water retention, dilution of all fluid compartments, and hyponatremia. The hyponatremia of volume contraction and that of advanced renal insufficiency, which are related to different pathogenetic mechanisms, will not be among the future indications for vasopressin antagonists. Several oral, non-peptidic vasopressin antagonists are currently being studied (Table 2) (abstracts; Kuhn et al, Kidney Blood Press Res 21:183, 1998; Abraham et al, World Cong Neurohypophyseal Hormone, Montreal, 1997, #183; Coupet et al, ibid, #181) [60, 61]. In cardiac failure, vasopressin antagonists increase renal water excretion (“aquaresis”) and improve hypo-osmolality and hyponatremia (abstracts; Abraham et al, ibid; Naitoh et al, ibid, #187) [62, 63]. In addition, a V2 antagonist improved cardiac failure in the dog [63, 64]. In moderately advanced liver cirrhosis, V2 antagonists have induced aquaresis in animals [65] and in humans [61, 66]. When Inoue and colleagues gave OPC-31260 to 8 patients with biopsy-proven cirrhosis, a hypotonic diuresis ensued and urinary flow rate approximately tripled [66]. However, renal function had to be watched closely for signs of potential deterioration in cirrhotic patients given another V2 antagonist [60]. Similarly, the hyponatremia of SIADH was improved by V2 antagonists in animals [67, 68] and humans [69]. None of the studies has reported an effect of oral vasopressin antagonists on thirst in humans. The treatment of hyponatremia can be expected to change when the new vasopressin antagonists become available. However, the principles and guidelines concerning the rate of correction and its potential dangers, as discussed here, probably will not.

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Nephrology Forum: Severe hyponatremia Table 2. Properties of V2 receptor antagonistsa OPC 31260 Route of application Ki in rats nmol/L Ki in humans nmol/L Selectivity index (Ki-V1a/Ki-V2) Urine volume Urine osmolality Na⫹ excretion/24 h K⫹ excretion/24 h Serum [Na⫹] response Agonistic activity Manufacturer

SR 121463A

YM 087b

VPA-985

oral 21.7 25.4

oral 1.42 4.1

oral 0.48 1.12

oral 3.0 1.1

10 ↑ (DD) ↓ (DD) unchanged unchanged ↑ none Otsuka, Japan

112 ↑ (DD) ↓ (DD) unchanged unchanged ↑ none Sanofi, France

not determined ↑ (DD) ↓ (DD) unchanged at LD unchanged at LD ↑ none Wyeth-Ayerst, USA

0.1 ↑ (DD) ↓ (DD) unchanged (↑ at HD) unchanged (↑ at HD) ↑ none Parke-Davis/Yamanouchi, USA/Japan

a Abbreviations are: Ki-inhibition constant (concentration of antagonist required to inhibit 50% of maximal V2 effect of vasopressin; DD, dose dependent; LD, low dose; HD, high dose b YM 087 is a nonspecific vasopressin receptor antagonist

QUESTIONS AND ANSWERS Dr. Nicolaos E. Madias (Executive Academic Dean, Tufts University School of Medicine, Boston, Massachusetts, USA): Rapid correction of hyponatremia can occur in other circumstances, such as water restriction in primary polydipsia, volume repletion of volume-depleted patients, dialysis against a bath with a sodium concentration substantially higher than that of the patient, and cortisol replacement of adrenal insufficiency. Could you please comment on the magnitude of the risk for CPM in these settings and measures that can limit the risk? Dr. Gross: The literature does contain some limited information on psychogenic polydipsia [70–75]. Also, Sterns and coworkers mention rare patients with psychosis-, ethanol-, or Addison’s disease-induced severe, possibly chronic, hyponatremia (94 mmol/L to 100 mmol/L) that was corrected at ⬎0.5 mmol/L/h and who then suffered coma, other neurologic sequelae, or death [34]. Brunner et al reported a single patient with Addison’s disease and CPM after correction [41], as did Shoji et al in a patient with Sheehan’s syndrome [76]. The risk in these groups is probably small if the guidelines presented here are heeded. Soupart and colleagues have postulated that uremia confers protection from the risk of brain damage [77]. I would propose guiding therapy in any such patients according to the chronicity of the hyponatremia, as I discussed previously. Dr. Madias: Could you comment on thiazide-induced hyponatremia in this context? Dr. Gross: Thiazide-induced severe hyponatremia has been reported frequently [12, 78, 79], including its association with CPM (Fig. 4) [34, 35, 41, 42]. Usually, such patients are elderly women who have taken the thiazide for less than 2 weeks for hypertension [78]. Reportedly there are signs of mild volume depletion upon presentation. With respect to the mechanism(s) of this hyponatremia, metolazone, a thiazide, was shown to turn a positive free-water clearance into a negative one [78].

I believe that the accompanying hypokalemia—a risk factor for CPM—deserves mentioning. Overall, the risk for CPM appears to be greater with thiazide-induced hyponatremia than with other hyponatremic circumstances. One is usually dealing with a chronic form of severe hyponatremia. In that setting, the electrolyte disorder should be corrected slowly. My bias is that potassium replacement is also important in such patients. Dr. Madias: Considering the patient’s very severe hyponatremia, could you please address our current understanding of the signal for vasopressin escape? Are there situations in which failure of vasopressin escape might occur? Dr. Gross: Escape from vasopressin is a term used to describe the return of urinary osmolality to its baseline low levels despite continued elevation of vasopressin in plasma. Vasopressin escape has only been studied in experimental animals. Using a DDAVP-induced model of SIADH in the rat, we found the signal for vasopressin escape to be related to the degree of the hyponatremia and/or the accompanying plasma volume expansion but not to vasopressin itself [80, 81]. In terms of potential mechanisms of escape, changes in PGE2 and aquaporin-2 might contribute early in mild hyponatremia [80, 81]. Hemodynamic changes such as increases of renal plasma flow and glomerular filtration rate (GFR) were mediators of the escape later in the setting of severe hyponatremia [80, 81]. Escape in other disorders such as cardiac failure, hepatic cirrhosis, and volume depletion states has not been studied. I would expect vasopressin escape to be impaired in those disorders, even to the extent of escape failure, because GFR often is reduced and distal delivery of tubular fluid also is often decreased. Dr. Madias: I would like to ask several questions with respect to vasopressin antagonists. Is the therapeutic efficacy of AVP V2-receptor antagonists similar in hyponatremic patients with SIADH compared to those with edematous disorders? Is the risk of developing hyper-

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natremia while taking these medications more substantial in elderly patients with hypodipsia, who depend on others for ensuring their water requirements? Have you encountered hypernatremia in your studies of vasopressin antagonists? Finally, since the abundance of vasopressin receptors seems to change in relation to the chronicity of the hyponatremia, have any studies in animal models tested whether the effectiveness of vasopressin antagonists is a function of the duration of hyponatremia? Dr. Gross: In the study involving VPA-985, the V2 antagonist was more effective in the hyponatremia of SIADH than that of liver cirrhosis or heart failure [60]. We have not encountered hypernatremia in either of two investigations with vasopressin antagonists so far. Vasopressin antagonists, however, could produce hypernatremia were their effects not monitored closely. Precautions such as frequent measurement of the serum sodium concentration are indicated, especially in patients in whom the vasopressin antagonist is followed by a large aquaresis. Your last question regarding a possible relation between vasopressin V2-receptor density and chronicity of the hyponatremia is difficult to answer; to the best of my knowledge, it has not been studied. Dr. Vladimir Teplan (Professor of Medicine and Nephrology, Institute of Clinical Experimental Medicine, Prague, Czech Republic): Disorders of the serum sodium concentration present problems in cadaveric organ donors with brain death. In this situation, we usually observe hypernatremia, sometimes up to 180 mmol/L. In a minority of donors, however, we observe hyponatremia, which can be very difficult to treat. What are your explanations for these two situations? Dr. Gross: Hypernatremia in a potential organ donor is indeed not uncommon. It is reportedly caused by central diabetes insipidus from brain death [82–84]. Your remark concerning hyponatremia in brain-dead potential organ donors is very intriguing. One report attributes such hyponatremia to the administration of vasopressin and epinephrine [82]. In patients in whom the posterior pituitary is working, adrenal insufficiency, severe hypothyroidism, cardiac failure, or liver cirrhosis occasionally causes hyponatremia. Dr. Kai-Uwe Eckardt (Associate Professor, Department of Nephrology and Intensive Care, Humboldt-Universita¨t, Berlin, Germany): The patient you presented today was a young lady. You mentioned several times that data indicate an increased risk in premenopausal females for developing neurologic complications. What is the mechanism of this phenomenon? Dr. Gross: The work by Ayus and Arieff has shown two pathogenetic mechanisms: inhibition of cerebral Na⫹,K⫹-ATPase activity by estrogens with an impaired ability of brain cells to extrude Na⫹ in the initial cell volume defense, and increased vasoconstriction of cere-

bral blood vessels by vasopressin, causing a decrease of brain perfusion in female but not in male rats [85]. Dr. Eckardt: My other question relates to the pathophysiology of the neurologic complications. Some data indicate that vasopressin has direct effects on the brain. Is it possible that the inappropriate elevation of vasopressin in hyponatremia has itself effects on the brain beyond those of hyponatremia? Could this have future implications for therapies with vasopressin antagonists? Dr. Gross: Ayus and Arieff point out that there are at least four separate direct effects of vasopressin on the brain: (1) water movement into the brain; (2) decline in brain synthesis of ATP; (3) decreased brain blood flow; and (4) impairment of sodium efflux during hyponatremia [10]. Whether these effects might have any bearing on treatment of hyponatremia with vasopressin antagonists has not been studied. It is conceivable that you might well be right. Dr. Eckardt: The ability to excrete water does not depend merely on the kidney’s diluting capacity; it also depends on the amount of solute to be excreted. The case you presented reminds me of beer potomania. In such patients the caloric intake consists primarily of carbohydrates. Those patients are not eating protein, so they do not excrete any sizable amounts of solute. Like your patient, these people live on carbohydrates. In retrospect, what would you have recommended in today’s patient? Dr. Gross: The patients described by Fenves et al were binge-drinking alcoholics [79]. Reported daily volumes of beer were in the range of 4 to 5 L. Nonetheless, those patients presented with dry mucous membranes, low arterial blood pressure, tachycardia, very low urinary sodium excretion rate, and hyponatremia. In one patient, the urinary osmolality was reportedly 50 mOsm/kg, that is, maximally dilute. Vasopressin levels were not reported. The authors explained the syndrome by excessive daily intake of beer with minimal concurrent intake of solute. They recommended “salting the beer.” I find it difficult to follow their interpretation. I wonder whether in such patients nausea, vomiting, diarrhea, or cirrhosis contribute to the hyponatremia. To answer your question: I would have stopped the glucose and switched to heme therapy. Heme administration, (heme arginate, 3 mg/kg body weight IV once daily for 4 days) suppresses the activity of hepatic ␦-aminolevulinic acid synthase. Also, I would have interrupted the vomiting by medication. I do not see a compelling reason to supply protein or amino acids with respect to the hyponatremia. Dr. Eckhart Bu¨ssemaker (Nephrologist, Universita¨tsklinikum C. G. Carus): You indicated that vasopressin is important in generating hyponatremia. However, in the patient presented, it appeared that you did not measure the plasma vasopressin concentration. Dr. Gross: Surprisingly, measurements of the plasma

Nephrology Forum: Severe hyponatremia

vasopressin concentration usually are not helpful in the ordinary clinical management of severe hyponatremia. The reasons for this are: (1) results are not available on the same day; (2) in a study of 200 patients with hyponatremia (⬍134 mmol/L) we showed that almost all had “elevated” vasopressin [59]; and (3) the interpretation of vasopressin measurements is usually a source of confusion. Physicians tend to forget about the relation between vasopressin and osmolality. In hypo-osmolar hyponatremia, vasopressin is biologically suppressed, that is, unmeasurable. Thus, if vasopressin can be measured, as in almost all patients with hyponatremia, it is elevated in the context of the prevailing hypo-osmolality, even if the level looks low for a normal plasma osmolality. Therefore, indeed, it is not necessary to measure the plasma ADH concentration in the routine management of severe hyponatremia. Dr. Jana Henschkowski (Physician, Universita¨tsklinikum C. G. Carus): In your study using vasopressin antagonists in patients, you were unable to predict the initial aquaretic response to the antagonist. Could you speculate as to the causes of this failure? Dr. Gross: As you implied, there was indeed no correlation between initial plasma vasopressin concentration and subsequent aquaretic response. The only exception to this was observed in the group of cirrhotic patients. The degree of severity of hyponatremia also did not correlate with aquaresis. There could be several explanations for this. The plasma vasopressin concentration is not constant in a given hyponatremic patient; rather, it varies by as much as 50% within 24 hours. Also, fluid intake, which differs among patients, affects the degree of hyponatremia. Finally, factors such as GFR, distal delivery of filtrate, and abnormalities of collecting duct function influence water balance too. Dr. Madias: For a number of reasons, one can overshoot the mark of intended correction of severe hyponatremia. Do data support the usefulness of returning serum sodium to a lower level by administering hypotonic fluids in this setting? Dr. Gross: Studies in laboratory animals indicate that re-induction of a hyponatremia is beneficial after correction overshoot [43, 77]. There are no comparable data in humans. Dr. Madias: Although most reported cases of CPM indeed have occurred following correction of serum sodium by ⬎12 mmol/L/day, cases have been reported following corrections of as little as 9 to 10 mmol/L/24 h or 19 mmol/L in 48 h. Furthermore, physiologic considerations indicate that increases in serum sodium on the order of 5% should substantially decrease cerebral edema and serious symptoms of hyponatremia. Even seizures can be terminated by increasing serum sodium by only a few mmol/L. Ascertaining the duration of hyponatremia is a daunting task. Therefore, I would suggest that it is more

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prudent to aim for a correction that does not exceed 8 mmol/L on any day of treatment. Depending on the severity of the symptoms, the rate of correction can be 1 to 2 mmol/L/h for several hours with subsequent slowing of the pace of correction. Of course, if severe symptoms persist, one is obligated to exceed the targeted range of correction, the imminent risks of cerebral edema outweighing the potential risk of CPM. Dr. Gross: As far as I know, all authors are in agreement that cerebral edema deserves rapid correction of hyponatremia. Arieff and Ayus recently presented an analysis of 270 patients with acute severe hyponatremia (110 mmol/L). They noted an hourly correction rate of 1.3 mmol/L, reaching 132 ⫾ 7 mmol by 31 hours of correction. There was no detectable relation between the rate of correction and outcome (abstract; Arieff, Ayus, J Am Soc Nephrol 10:119A, 1999). Your next point was a total daily correction rate not to exceed 8 mmol/L in chronic oligosymptomatic hyponatremia. As far as I know, no prospective data in the literature clearly support such a suggestion. In fact, we might never be in a position to test whether there is a difference between your proposed correction rate and the standard rate (⬍0.5 mmol/L/h) with respect to CPM because CPM occurring after correction of hyponatremia is a very rare event. For instance, Sterns et al had to evaluate responses from 4100 participating nephrologists to be able to find 14 cases with “neurologic sequelae” after treatment of severe hyponatremia [35]. In addition, it is never possible in such reports to fully exclude other underlying brain pathologies and other clinical risk factors as causes of “neurologic sequelae.” Thus, the usefulness of 0.3 mmol/ L/h—as opposed to 0.5 mmol/L/h—will be very difficult to confirm in randomized studies of chronic oligosymptomatic severe hyponatremia in the future. As far as severe symptomatic hyponatremia of uncertain duration is concerned, I suggest an imaging study. The study often can reveal the presence (or absence) of brain edema, which in turn could guide the corrective therapy. Reprint requests to Dr. P. Gross, Nephrology, Medizinische Klinik III, Universita¨tsklinikum Carl Gustav Carus, Fetscherstrasse 76, D-01307 Dresden, Germany. E-mail: [email protected]

ACKNOWLEDGMENTS Dr. Gross’ research on hyponatremia was funded by grants from the Deutsche Forschungsgemeinschaft: Gr 605,3-1 and 3-2; Gr 605, 5-1; Gr 605, 8-1. The multicenter VPA-985 study was sponsored by WYETH-AYERST, Paris, France. The author is indebted to Dr. M. Damian, Dresden, for his expert assistance in analyzing neurologic problems; to Dr. V. Ha¨nig, Dresden, for the CT studies; to Drs. J. Passauer and T. Franz, and to Ms. Ingrid Gross for their help in the preparation of the manuscript.

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