- Email: [email protected]
Treatment of Symptomatic Hyponatremia
Treatment of Symptomatic Hyponatremia GUY DECAUX, MD, PHD; ALAIN SOUPART, MD, PHD
ABSTRACT: Inadequate treatment of severe hyponatremia (⬍120 mEq/L) can be associated with severe neurological damage. In acute (⬍48 hours) hyponatremia, usually observed in the postoperative period, prompt treatment with hypertonic saline (3%) can prevent seizures and respiratory arrest. For patients with chronic (⬎48 –72 hours) symptomatic hyponatremia, correction must be rapid during the first few hours (to decrease brain edema) followed by a slow correction limited to 10 mmol/L over 24 hours to avoid the development of osmotic demyelinating syndrome. In patients with
asymptomatic hyponatremia, slow correction is the appropriate approach. When patients are overtreated, neurologic damage can be prevented by relowering the serum sodium (SNa) so that the daily increase in SNa remains below 10 mmol/L/24 hours. Frequent measurements of SNa during the correction phase of SNa are mandatory to avoid overcorrection. The use of urea to treat hyponatremia represents an advantageous alternative to hypertonic saline. KEY INDEXING TERMS: Hyponatremia; Treatment; Demyelination; Urea. [Am J Med Sci 2003;326(1):25–30.]
S
In humans, excess mortality (about 60 times greater) observed in hyponatremic patients is caused mainly by the associated conditions2 and not by hyponatremia itself. In 1986, Arieff5 reported on a series of 15 women with benign operations (eg, cholecystectomy, hysterectomy, etc) who died or developed permanent vegetative state after postoperative hyponatremia (mean SNa, 108 mEq/L). In all of these patients, respiratory arrest was documented before correction. Some of these patients awoke after intubation and correction of hyponatremia, but the neurologic situation deteriorated some days later and the patients lapsed into a vegetative state.5 Hypoxemia caused by respiratory arrest is probably responsible for this sequential clinical evolution. A similar picture is sometimes observed after transitory cardiac arrest, drowning, or carbon monoxide intoxication. The striking feature of these observations is the explosive nature of the symptoms: sometimes patients may walk around and complain of nausea (falsely attributed to the postoperative state, morphines, etc) and headache; thereafter, sudden onset of seizures occur, followed by respiratory arrest (the whole picture lasting no longer than approximately 20 minutes).5 Occasional respiratory arrests are reported with moderate acute hyponatremia (125–128 mEq/L).5,6 Although disputed,4 this complication seems to be more frequent in premenopausal women. There is no doubt that acute (⬍48 hours) hyponatremia requires rapid correction, even if symptoms seem minor. In the late 1970s, the first articles suggesting a relationship between neurologic lesions (central pontine myelinolysis) and rapid correction of chronic hyponatremia were published. Lesions may also be extrapontine and can even occur unrelated to an
erum sodium (SNa) is represented by the following ratio: (exchangeable Na ⫹ exchangeable K)/ total body water. Each modification of any of these parameters will affect SNa. Hyponatremia has a wide range of causes1 in which antidiuretic hormone (ADH) generally plays a key role.2 This article will focus primarily on the treatment of hypotonic hyponatremia. Several animal experiments show that the absence of treatment or an overcorrection of hyponatremia can be deleterious to the brain. In rats for instance, a decrease of SNa by 35 mEq/L in 24 hours is associated with a mortality rate of about 5 to 10%; rapid correction of the hyponatremia substantially reduces the mortality rate.3 However, when the serum sodium is maintained at a level of 105 mEq/L for 3 days and then normalized in 24 hours, the mortality rate is 60 to 80% and the surviving rats develop severe neurologic damage. In hyponatremia of longer duration, the survival rate is 100% without brain lesions when correction is slow.3,4 Since the early 1920s, it has been well known that acute hyponatremia causes brain edema with herniation and that this can be prevented by hypertonic NaCl.4
From the Service de Médecine Interne Générale, Hôpital Universitaire Erasme, Bruxelles, Belgium (GD) and Département de Médecine Interne, Jolimont/Tubize-Nivelles Hospital, Tubize, Belgium (AS). Submitted August 16, 2002; accepted February 11, 2003. Many studies were supported by grants from the “Fonds National de la Recherche Scientifique” (1.5.228.90F/1.5.204.91F/ 1.5.175.94F/1.5.193.96F/1.5.198.97F/1.5.164.98F/1.5.141.00F/ 4574.01). Correspondence: G. Decaux, Médecine Interne Générale, Hôpital Universitaire Erasme, 808 Route de Lennik, 1070 Bruxelles, Belgium (E-mail: [email protected]). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
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Treatment of Symptomatic Hyponatremia
osmotic change. The myelinolysis, sparing the axon, that develops after an osmotic stress is presently called osmotic demyelinating syndrome (ODS).4 In the early 1980s, experiments in animals (rats) established a direct relationship between rapid correction of chronic hyponatremia and myelinolysis.7 In humans, symptoms are typically 2-phased. Generally, this complication involves patients with serum sodium below 120 mEq/L with few or no symptoms (confusion, etc). A few days after the rapid correction of the serum sodium and initial improvement, the neurological status deteriorates. In the most severe cases, progressive quadriparesis occurs with swallowing and speech difficulties and deep coma (central pontine myelinolysis in its most classic expression resembles the “locked-in syndrome” (thrombosis of the arteria basilaris).4 Brain Adaptation to Hyponatremia and Its Treatment Understanding of the most appropriate therapeutic approach in the presence of hyponatremia requires a brief physiopathologic review. When blood tonicity diminishes, the brain will rapidly lower the electrolyte content of its interstitial fluid (Na⫹ and Cl⫺) within minutes; then, intracellular potassium and organic osmolytes such as amino acids (eg, taurine, glutamine, glutamate), polyols (myoinositol), methylamines (creatine, etc) decrease. This prevents excessive cerebral edema,4 which could have serious consequences, because an expansion of 8 to 10% of the brain volume could be fatal. In a hyponatremic rat, after 24 hours, brain water content is almost normalized by solute extrusion.8 When the decrease of serum sodium is too rapid (some argue in humans that this corresponds to a rate of SNa decrease higher than 0.5 mEq/L/hr), the adaptive cerebral mechanisms are overwhelmed with a risk of major cerebral edema. In chronic (⬎48 –72 hours) hyponatremia, the correction induces the reuptake of the different solutes lost during the induction of hyponatremia. The normalization of intracellular solute content is, however, a very slow process lasting for up to 5–7 days, especially for organic osmolytes.8,9 In rats, rapid correction of chronic hyponatremia induces an overshoot of the cerebral content in sodium, chloride, and water at 24 hours, and even much more at 48 hours.8 This excess of electrolyte content of the brain is probably localized partially within cells. This “hyperionization” of the intracellular space is poorly tolerated by the cell, especially with concomitant organic osmolyte depletion, such as for myoinositol, which plays a key role in the homeostasis of the interior milieu.10 When this “hyperionization” lasts too long, several enzymatic dysfunctions occur and may contribute to ODS lesions. Another hypothesis underlying the mechanism inducing ODS implicates neurotoxic factors affecting 26
Table 1. Acute Hypotonic Hyponatremia (⬍48 hours) Cerebral edema Generally hospital acquired ● Postoperative (menstruating women, hypoxemia) ● Excessive IV hypotonic fluids with inappropriate antidiuresis ● TURP, endoscopic uterine surgery (glycine irrigant) ● Oxytocin ● Recent thiazide prescription (elderly women) ● Polydipsia (acquired generally outside the hospital; psychiatric patients or beer drinkers) ● Exercise induced (acquired generally outside the hospital) ● Colonoscopy preparation ● Ecstasy
the brain through a leaky blood-brain barrier. The osmotic stress after acute hyponatremia hardly damages the blood-brain barrier; however, this barrier opens more easily when osmotic stress occurs during chronic hyponatremia. Different complement factors seem to be activated through contact with myelin,11 but other hypotheses also exist.4 If the patient presents with acute (⬍48 hours) and severe hyponatremia (⬍120 mEq/L; see below), rapid treatment is required to diminish cerebral edema. If, however, the patient has few or no symptoms, treatment may have deleterious effects. A patient presenting with chronic and symptomatic hyponatremia accumulates risks because of delayed treatment (seizures and respiratory arrest) and overly rapid correction (ODS). The management of these patients is more challenging (see below). Risk Factors for Myelinolysis (ODS) The most important factor is the daily difference in serum sodium level. Furthermore, about 80% of cases of ODS reported in the literature are associated with hypokalemia (often induced by thiazides).12 Most ODS observations were reported in patients presenting with an initial SNa below 120 mEq/L.4 However, in malnourished patients (chronic alcohol abuse, liver cirrhosis, heavy burns, hypocorticism, etc), ODS cases were reported with less severe hyponatremia.13 In animals, there is a good correlation between the daily gradient of serum sodium correction and the degree of neurologic lesions.14,15 The limits of daily difference in sodium levels established in the rat model probably cannot be simply applied to humans. In a retrospective study including 54 patients with hyponatremia ⱕ110 mEq/L, Sterns reported neurologic sequelae in some patients when the change in serum sodium over a 24-hour period was higher than 12 mEq/L/24 hours or 18 mEq/L/48 hours.16 In a more recent retrospective study including 184 patients with chronic hyponatremia ⬎3 days and ⱕ120 mEq/L, Ellis reported cerebral lesions appearing with a daily sodium difference of 9 mEq/L/24 July 2003 Volume 326 Number 1
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Table 2. Treatment of Acute Hyponatremia Prompt correction mandatory ● Hypertonic saline (3% NaCl): 1–2 mL/kg of body weight/hr If severe antidiuresis SNa will increase by about 1–2 mEq/L/ hr and by 2–4 mEq/L/hr if combined with furosemide ● Severe symptoms (seizure, obtundation, or coma): 3% NaCl 4–5 ml/kg of body weight/hr 1 or 2 hours. ● Target: interrupt correction when symptoms regress Rapid normalization of SNa usually safe but rarely necessary. In the beginning it is advisable to measure SNa every 1–2 hours to be sure that SNa is increasing.
hours.17 Some rare cases are even reported at a difference of 8 mEq/L/24 hours! It cannot be excluded, however, that in some of these cases, SNa began to increase spontaneously before first blood measurement in the hospital, leading the clinician to underestimate the absolute gradient of correction. According to these few data, a certain consensus can be obtained from the literature. Treatment of Acute Hyponatremia The circumstances inducing hyponatremia are very important diagnostic clues to recognizing hyponatremia as acute or chronic. Acute hyponatremia occurs generally in hospitalized patients and is most frequently iatrogenic. The main causes are outlined in Table 1. Some symptoms suggest intracranial hypertension: headache, nausea, vomiting, seizures, and deep coma. Sometimes these symptoms may be explosive in nature. Exercise-induced hyponatremia occurs in association with overwhelming physical efforts (eg, marathon races) or sometimes with less intense physical activity.18 The role of excessive sodium losses in sweat is probably marginal. Hyponatremia is mainly dilutional through a combination of excessive water ingestion during exercise and a defect in free water clearance. Nausea, stress, and exercise can also stimulate ADH secretion. Hypoxia, which sometimes complicates acute hyponatremia (either through hypoventilation or noncardiogenic pulmonary edema), interferes with the cerebral mechanism of adaptation to hypotonicity.4 Cerebral anoxia (caused by combined hypoxia and ischemia through edema of the central nervous system that diminishes the loco-regional blood flow) explains why some patients occasionally have 2-phased symptoms: initial awaking of a previously unconscious patient and then neurologic deterioration, as observed in carbon monoxide intoxication. All reported cases did have clinical hypoxemia (intubation, etc). The same observation has been made in an animal model.19 Prompt treatment of acute hyponatremia is summarized in Table 2. NaCl (3%) perfused at rate of 1 to 2 mL/kg/hr will increase the serum sodium by 1 to 2 mEq/L/hr in case of significant antidiuresis. Adding furosemide will increase it THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Table 3. Treatment of Hyponatremia Related to Polydipsia or Beer Drinkers ● Frequently spontaneous rapid correction secondary to high dilute urine output combined with water restriction. ● Often mixed disorder (solute depletion component) and treatment with 1 or 2 L isotonic saline ⫹30 mmol/L KCl over 24 hours is usually sufficient. If severely symptomatic, a few hours’ infusion of NaCl 3% (1–2 ml/kg of body weight/hr) may be necessary. ● If SNa very low (⬍110 mEq/L) likely SNa increase of no more than 10–15 mEq/L/24 hours.
by 2 to 4 mEq/L/hr. In case of severe neurologic symptoms, data from the neurosurgical literature suggest that an osmotic gradient of 10 to 20 mOsmol/kg/H2O is necessary to rapidly diminish cerebral edema. The initial treatment of these symptomatic patients requires larger doses of hypertonic NaCl during the first 1 to 2 hours. Once neurologic symptoms improve, treatment must be stopped, although the serum sodium may be theoretically normalized. Rare cases of ODS-type lesions are observed in patients presenting with acute hyponatremia. These patients probably already started to have some cerebral adaptation to the hypotonicity. In patients with hyponatremia related to polydipsia or “beer drinking,” we frequently observe a spontaneous correction secondary to high dilute urine output combined with water restriction. This state is often a mixed disorder with a solute depletion component.20 Treatment with 1 or 2 L of isotonic saline is usually sufficient (Table 3), but severely symptomatic patients may need brief treatment with hypertonic saline infusion. Treatment of Symptomatic Chronic Hyponatremia (>48 to 72 Hours), Subacute Hyponatremia, or Hyponatremia of Undetermined Duration The clinical context in which hyponatremia develops may be helpful in differentiating acute from chronic hyponatremia. Severe neurologic symptoms often reflect cerebral edema, but this is not always true.21 Extrahospital acquired hyponatremia is generally chronic, except for polydipsia, marathon runners, and ecstasy. Chronic hyponatremia may have a superimposed acute component. Hyponatremia of undetermined duration, especially when it is symptomatic, needs treatment combining rapid decrease of potential brain edema but also avoiding the risks of ODS. A 3% NaCl solution at a rate of 1 to 2 mL/kg/hr for 2 to 3 hours can be infused; then the treatment must be stopped as soon as symptoms improve (it is advisable to measure SNa every 1 to 2 hours to be sure that SNa is increasing). The objective is to maintain the SNa gradient below 10 mEq/ L/24 hours. In case of hyponatremia caused by solute depletion, treatment will be continued by 27
Treatment of Symptomatic Hyponatremia
perfusing a physiologic solution, generally 2 L of 0.9% NaCl/24 hours. As far as hyponatremia secondary to thiazide administration is concerned (frequently responsible for ODS), a slow correction through the intravenous administration of 1 or 2 L of 0.9% NaCl over 24 hours containing 40 mmol/L KCl is generally sufficient in conjunction with stopping the intake of thiazide. The rate of increase in serum sodium must be closely monitored. Relowering of the SNA in Case of Overcorrection of Hyponatremia An excessive rate of correction of hyponatremia may be secondary to the excessive administration of salt (error in calculation of doses to administer), and we have to remember that the administration of potassium in the solution contributes to increase the serum sodium. Most often this is caused by a predictable or unpredictable increase in the excretion of electrolyte free water.22,23 Frequent monitoring of SNa should enable avoidance of this complication. Data obtained in animals suggest that in those patients with a substantial risk for developing ODS (malnutrition, chronic alcoholism, cirrhosis, hypokalemia, hypocorticism) or if the daily increase in serum sodium exceeds 15 mmol/L/24 hours, it is advisable to relower the serum sodium by giving desmopressin acetate and water (water orally or as glucose 5% intravenously). The absolute daily serum sodium difference must stay below 10 mmol/L/24 hours (or 15 if there are no associated risk factors). This preventive measure could prevent neurologic deterioration in patients overcorrected with no or early symptoms24,25 (as has been clearly demonstrated in animal models26,27). Because desmopressin acetate has a long duration of action, fluid administration must be carefully adjusted and SNa monitored to avoid re-establishment of symptomatic hyponatremia. In cases of established ODS, some authors have reported benefits with thyrotropinreleasing hormone, ␥-globulins, corticosteroids, or plasmapheresis.28,29 These data suggest that an immunological component may contribute secondarily to the ODS. In patients with few or no symptoms, a
Table 4. General Recommendations ● Initial rapid correction if severe symptoms. ● Maximum brain volume expansion: 8–10% (rigidity of the skull). Theoretically no need to increase initial SNa by more than 8%. ● Maximum SNa correction ⬍ 10–15 mEq/L/24 hours and lower than 10 mEq/L/24 hours if associated risk factors for myelinolysis: hypokalemia, malnutrition, alcoholism, liver disease, burns, phosphate depletion (?), hypoglycemia (?), hypocorticism (?). Below this upper daily limit of correction the rate of SNa increase is not important. ● Close monitoring of SNa: every 1–2 hours initially, then every 4 hours, particularly if urine output is high (⬎150 mL/hr). ● If SNa increases too rapidly, interrupt the increase by hypotonic fluid administration and/or desmopressin acetate.
slow and generally cause-oriented correction of hyponatremia is required. General Recommendations When hyponatremia is associated with severe neurologic symptoms (vomiting, headaches, seizures, coma, etc), rapid correction of hyponatremia during the first hours is mandatory (Table 4). However, there is no reason to increase SNa by more than 8 to 10%. If the acute nature of hyponatremia is obvious (postoperative, duration ⬍48 hours), normalization of SNa is theoretically possible without inducing cerebral lesions. In those patients in whom the duration of hyponatremia is not definitely established, it is prudent not to correct SNa by more than 10 mmol/L/24 hours, especially when there are predisposing risk factors for ODS. The rate of increase in SNa is not a risk for the brain if the maximal daily limits of correction are respected. It is advisable to measure the serum sodium every 1 to 2 hours in the beginning of the treatment and every 4 hours thereafter, especially when diuresis is high (⬎150 mL/ hour). If the patient has relatively high diuresis, the use of hypertonic saline must be particularly prudent. During saline treatment, one must take the actual urine output volume into account: the formula predicting that 1 mmol/kg/hr of 3% NaCl will
Table 5. Effect of Different Diuresis and Urine Composition on ⌬SNa during 470 mL of 3% NaCl Infusion in a 60-kg Woman with SIADH and a Initial SNa of 110 mEq/L Urinary Na ⫹ K (mEq/L) 75 170 300
Urine Osmolality (mosm/Kg H2O)
24-hour Urine Output (WE) for 468 mL of 3% NaCl (L)
NTBW (L) (TBW ⫹ 0.46 ⫺ WE)
⌬SNa (mEq/L)
220 510 900
240/75 ⫽ 3.21 240/170 ⫽ 1.411 240/300 ⫽ 0.81
27.26 29.05 29.6
11 3.6 1
WE, water excretion; TBW, total body water; NTBW, new total body water.
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Table 6. Use of Urea for Treatment of Symptomatic Hyponatremia ● Rapidly decreases brain edema ● No transient decrease in SNa (as with mannitol) ● Increases SNa by osmotic diuresis and salt retention ● No risk of volume expansion ● No risk of inducing or increasing potassium deficit (as with furosemide) ● Easy to apply (electrolytes monitoring each 4 hours) ● Decreases the risk of myelinolysis Practical use of urea Oral route: Pure crystalline powder (prescribed usually as 30-g doses in small bags). Dissolve in 100 mL of water with antacid (and fruit syrup to improve taste if necessary). Administer after a meal. Intravenous route: 30% (hypertonic) solution of lyophilized powder dissolved in 5% dextrose. Each bottle (135 mL) contains 40 g of urea (Ureaphil; Abbott). Maximum infusion rate: 4 mL/min. Short-term 0.5–1 g/kg BW intravenously over 1 hour, or orally (by gastric tube) will rapidly (1 hr) increase serum administration: osmolality by 15–30 mOsm/kg H2O; eg, 80 g of urea, generally increases SNa concentration by about 15 mEq/L/24 hours when associated with 1 L of isotonic saline (31). Long-term use: Calculate, with the aid of the measured urine osmolality, the daily dose of urea required to obtain the additional volume of urine necessary to maintain normonatraemia; eg, 30 g of urea (500 mOsm) allows excretion of 1 L of free water if urine osmolality is fixed at 500 mOsm/kg H2O. Precautions: -Urea contraindicated if renal failure (creatinine ⬎ 2 mg/100 mL, urea ⬎ 80 mg/100 mL), associated liver disease (bilirubin ⬎ 2 mg/100 mL, hepatic encephalopathy) digestive hemorrhage, or gastric ulcer. -In hyponatremia associated with cerebral haemorrhage: use continuous infusion of urea (IV or by gastric tube) over 24 hours (usually combined with isotonic saline). Reprinted from Decaux G, Musch W, Soupart A. Hyponatremia in the intensive care: from diagnosis to treatment. Acta Clinica Belg 2000;55:68 –78. Copyright 娀 2000 Bruxelles Acta Clinica Belgica. Used with permission.
increase SNa by 1 mmol/L/hr is valid if there is no renal excretion. For an intended increase of 8 mEq/L in a 60-kg woman with syndrome of inappropriate ADH secretion (SIADH) and an SNa of 110 mEq/L, we will need to infuse 470 mL 3% NaCl [or total body water (30 L) ⫻ 8 mEq/L ⫽ 240 mEq of Na or 240/513 ⫽ 0.468 L of 3% NaCl]. Nevertheless, hypertonic saline infusion will affect electrolyte free-water excretion, so that the ⌬SNa could be highly variable dependent on urine composition (Table 5) with associated risk of over- or undertreatment. This justifies frequent SNa measurements. When serum sodium increases too rapidly, this increase has to be interrupted by giving desmopressin acetate (Minirin; 4 g subcutaneously) and/or by administrating hypotonic fluids. Urea as Alternative Treatment for Symptomatic Hyponatremia Urea represents a valuable therapeutic alternative in hyponatremia4 (Table 6). This endogenous diuretic is able to rapidly diminish cerebral edema without any risk of volume overload and without the risk of transitory worsening of hyponatremia (as seen with the administration of mannitol, caused by water translocation).30 The osmotic diuresis caused by urea is accompanied by sodium retention that also plays a role in the correction of hyponatremia.31 Urea may also be used as a long-term treatment in SIADH.32 A major feature of urea is its potential protective role against ODS.14,33 In a recent experiment, acute renal insufficiency was induced by administration of HgCl2 in rats with chronic hyponatremia to be able to maintain high plasma urea THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
levels at about 60 mmol/L. The rapid correction of hyponatremia (mean daily sodium difference, 32 mmol/L/24 hours) was particularly well tolerated in these rats, whereas in control rats without renal insufficiency, death or significant cerebral lesions occurred.34 In these uremic rats, treatment of hyponatremia increases, after only 2 hours, the brain organic osmolyte corrects to a level identical to that observed in nonhyponatremic normal rats.35 This property of urea, facilitating brain organic osmolyte accumulation, could explain its protective effects against ODS also in the absence of renal failure.36,37 and probably in humans.38 Even with the use of urea, the daily increase in SNa must remain below 10 to 15 mEq/L. The imminent introduction of oral vasopressin V2 receptor antagonists39 – 41 for clinical use will provide an interesting alternative in the management of hyponatremia. However, by blocking renal ADH receptors, these drugs produce brisk diuresis, which can expose the patient to dangerous levels of serum sodium correction and thus brain damage. References 1. Decaux G, Musch W, Soupart A. Hyponatremia in the intensive care: from diagnosis to treatment. Acta Clinica Belg 2000;55:68 –78. 2. Anderson RJ, Chung HM, Kluge R, et al. Hyponatremia: a prospective analysis of its epidemiology and the pathogenic role of vasopressin. Ann Intern Med 1985;102:164 – 8. 3. Sterns RH. The treatment of hyponatremia: first, do no harm. Am J Med 1990;88:557– 60. 4. Soupart A, Decaux G. Therapeutic recommendations for management of severe hyponatremia: current concepts on
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pathogenesis and prevention of neurologic complications. Clin Nephrol 1996;46:149 – 69. Arieff AI. Hyponatremia, convulsions, respiratory arrest and permanent brain damage after elective surgery in healthy women. N Engl J Med 1986;314:1529 –35. Ayus JC, Wheeler JM, Arieff AI. Postoperative hyponatremic encephalopathy in menstruant women. Ann Intern Med 1992;117:891–7. Kleinschmidt-de Masters BK, Norenberg MD. Rapid correction of hyponatremia causes demyelination: relation to central pontine myelinolysis. Science 1981;211:1068 –70. Verbalis JG, Gullans SR. Rapid correction of hyponatremia produces differential effects on brain osmolyte and electrolyte reaccumulation in rats. Brain Res 1993;106:19 –27. Lien YH. Role of organic osmolytes in myelinolysis. A topographic study in rats after correction of hyponatremia. J Clin Invest 1995;95:1579 – 86. Yancey PH, Clark ME, Hand SC, et al. Living with water stress: evolution of osmolyte systems. Science 1982;217: 1214 –22. Baker EA, Tian Y, Adler S, et al. Blood-brain barrier disruption and complement activation in the brain following rapid correction of chronic hyponatremia. Exp Neurol 2000; 165:221–30. Lohr JW. Osmotic demyelination syndrome following correction of hyponatremia: association with hypokalemia. Am J Med 1994;96:408 –13. Laureno R. Central pontine myelinolysis following rapid correction of hyponatremia. Ann Neurol 1983;13:232– 42. Soupart A, Stenuit A, Perier O, et al. Limits of brain tolerance to daily increments in serum sodium in chronically hyponatremic rats treated with hypertonic saline or urea: advantage of urea. Clin Science 1991;80:77– 84. Soupart A, Penninckx R, Stenuit A, et al. Treatment of chronic hyponatremia in rats by intravenous saline: comparison of rate versus magnitude of correction. Kidney Int 1992; 41:1662–7. Sterns RH. Severe symptomatic hyponatremia: treatment and outcome. A study of 64 cases. Ann Intern Med 1987;107: 656 – 64. Ellis SJ. Severe hyponatremia: complication and treatment. Q J Med 1995;88:905–9. Zelingmer J, Putterman C, Ilan Y, et al. Case series: hyponatremia associated with moderate exercise. Am J Med Sci 1996;311:86 –91. Soupart A, Penninckx R, Stenuit A, et al. Lack of major hypoxia and significant brain damage in rats despite dramatic hyponatremic encephalopathy. J Lab Clin Med 1997; 130:226 –31. Musch W, Xhaet O, Decaux G. Solute loss plays a major role in polydypsia related hyponatremia of both water and beer drinkers. Q J Med 2003;96:421– 6. Decaux G, Szyper M, Grivegnée A. Cerebral ventricular volume during hyponatremia. J Neurol Neurosurg Psych 1983;46:443–5. Rose BD. New approach to disturbances in the plasma sodium concentration. Am J Med 1986;81:1033– 40. Musch W, Decaux G. Treating the syndrome of inappropriate secretion of ADH with isotonic saline. QJM 1998;91:749 – 53.
24. Soupart A, Ngassa M, Decaux G. Therapeutic relowering of the serum sodium in a patient after excessive correction of hyponatremia. Clin Nephrol 1999;51:383– 6. 25. Oya S, Tsutsumi K, Ueki K, et al. Reinduction of hyponatremia to treat central pontine myelinolysis. Neurology 2001; 57:1931–2. 26. Soupart A, Penninckx R, Crenier L, et al. Prevention of brain demyelination in rats after excessive correction of chronic hyponatremia by serum sodium lowering. Kidney Intern 1994;45:193–200. 27. Soupart A, Penninckx R, Stenuit A, et al. Reinduction of hyponatremia improves survival in rats with myelinolysisrelated neurologic symptoms. J Neuropathol Exp Neurol 1996;55:594 – 601. 28. Finsterer J, Engelmayer E, Trnka E, et al. Immunoglobulins are effective in pontine myelinolysis. Clin Nephropharmacol 1999;23:110 –3. 29. Chemaly R, Halaby G, Mohassed G, et al. Extrapontine myelinoysis: treatment with TRH. Rev Neurol 1998;154: 162–5. 30. Porzio P, Halberthal M, Bohn D, et al. Treatment of acute hyponatremia: ensuring the excretion of a predictable amount of electrolyte-free water. Crit Care Med 2000;28: 1905–10. 31. Decaux G, Unger J, Brimouille S, et al. Hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone. Rapid correction with urea, sodium chloride and water restriction. JAMA 1982;247:471– 4. 32. Decaux G, Genette F. Long-term treatment of the syndrome of inappropriate secretion of antidiuretic hormone by urea. Br Med J 1981;283:1081–3. 33. Van Reeth O, Decaux G. Rapid correction of hyponatremia with urea may protect against brain damages in rats. Clin Sci 1989;77:351–5. 34. Soupart A, Penninckx R, Stenuit A, et al. Uremia decreases the risk of brain damage in rats after correction of chronic hyponatremia. Brain Res 2000;852:167–72. 35. Soupart A, Silver S, Schroeder B, et al. Rapid (24-hour) reaccumulation of brain organic osmolytes (particularly myoinositol) in azotemic rats after correction of chronic hyponatremia. J Am Soc Nephrol 2002;13:1433– 41. 36. Soupart A, Penninckx R, Decaux G. Treatment of severe hyponatremia by urea decreases the mortality rate compared to water diuresis in rats [abstract]. J Am Soc Nephrol 2000; 11:110A. 37. Soupart A, Silver S, Schroeder B, et al. Treatment of experimental hyponatremia with exogenous urea promotes rapid reuptake of brain organic osmolytes [abstract]. J Am Soc Nephrol 2001;12:140A. 38. Decaux G, Coffernils M, Brimouille S, et al. In severe acute or chronic hyponatremia treatment with urea is safe for correction of serum sodium of 12–20 mEq/L/24 hr [abstract]. J Am Soc Nephrol 1994;5:366. 39. Gross P, Palm C. The treatment of hyponatremia using vasopressing antagonist. Exp Physiol 2000;855:2535–75. 40. Decaux G. Long term treatment of inappropriate secretion of ADH by the vasopressin receptor antagonist conivaptan, urea or furosemide. Am J Med 2001;110:582– 4. 41. Decaux G. Difference in solute excretion during correction of hyponatremia in patients with cirrhosis or SIADH by oral vasopressin V2 receptor antagonist VPA-985. J Lab Clin Med 2001;138:18 –21.
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ABSTRACT: Inadequate treatment of severe hyponatremia (⬍120 mEq/L) can be associated with severe neurological damage. In acute (⬍48 hours) hyponatremia, usually observed in the postoperative period, prompt treatment with hypertonic saline (3%) can prevent seizures and respiratory arrest. For patients with chronic (⬎48 –72 hours) symptomatic hyponatremia, correction must be rapid during the first few hours (to decrease brain edema) followed by a slow correction limited to 10 mmol/L over 24 hours to avoid the development of osmotic demyelinating syndrome. In patients with
asymptomatic hyponatremia, slow correction is the appropriate approach. When patients are overtreated, neurologic damage can be prevented by relowering the serum sodium (SNa) so that the daily increase in SNa remains below 10 mmol/L/24 hours. Frequent measurements of SNa during the correction phase of SNa are mandatory to avoid overcorrection. The use of urea to treat hyponatremia represents an advantageous alternative to hypertonic saline. KEY INDEXING TERMS: Hyponatremia; Treatment; Demyelination; Urea. [Am J Med Sci 2003;326(1):25–30.]
S
In humans, excess mortality (about 60 times greater) observed in hyponatremic patients is caused mainly by the associated conditions2 and not by hyponatremia itself. In 1986, Arieff5 reported on a series of 15 women with benign operations (eg, cholecystectomy, hysterectomy, etc) who died or developed permanent vegetative state after postoperative hyponatremia (mean SNa, 108 mEq/L). In all of these patients, respiratory arrest was documented before correction. Some of these patients awoke after intubation and correction of hyponatremia, but the neurologic situation deteriorated some days later and the patients lapsed into a vegetative state.5 Hypoxemia caused by respiratory arrest is probably responsible for this sequential clinical evolution. A similar picture is sometimes observed after transitory cardiac arrest, drowning, or carbon monoxide intoxication. The striking feature of these observations is the explosive nature of the symptoms: sometimes patients may walk around and complain of nausea (falsely attributed to the postoperative state, morphines, etc) and headache; thereafter, sudden onset of seizures occur, followed by respiratory arrest (the whole picture lasting no longer than approximately 20 minutes).5 Occasional respiratory arrests are reported with moderate acute hyponatremia (125–128 mEq/L).5,6 Although disputed,4 this complication seems to be more frequent in premenopausal women. There is no doubt that acute (⬍48 hours) hyponatremia requires rapid correction, even if symptoms seem minor. In the late 1970s, the first articles suggesting a relationship between neurologic lesions (central pontine myelinolysis) and rapid correction of chronic hyponatremia were published. Lesions may also be extrapontine and can even occur unrelated to an
erum sodium (SNa) is represented by the following ratio: (exchangeable Na ⫹ exchangeable K)/ total body water. Each modification of any of these parameters will affect SNa. Hyponatremia has a wide range of causes1 in which antidiuretic hormone (ADH) generally plays a key role.2 This article will focus primarily on the treatment of hypotonic hyponatremia. Several animal experiments show that the absence of treatment or an overcorrection of hyponatremia can be deleterious to the brain. In rats for instance, a decrease of SNa by 35 mEq/L in 24 hours is associated with a mortality rate of about 5 to 10%; rapid correction of the hyponatremia substantially reduces the mortality rate.3 However, when the serum sodium is maintained at a level of 105 mEq/L for 3 days and then normalized in 24 hours, the mortality rate is 60 to 80% and the surviving rats develop severe neurologic damage. In hyponatremia of longer duration, the survival rate is 100% without brain lesions when correction is slow.3,4 Since the early 1920s, it has been well known that acute hyponatremia causes brain edema with herniation and that this can be prevented by hypertonic NaCl.4
From the Service de Médecine Interne Générale, Hôpital Universitaire Erasme, Bruxelles, Belgium (GD) and Département de Médecine Interne, Jolimont/Tubize-Nivelles Hospital, Tubize, Belgium (AS). Submitted August 16, 2002; accepted February 11, 2003. Many studies were supported by grants from the “Fonds National de la Recherche Scientifique” (1.5.228.90F/1.5.204.91F/ 1.5.175.94F/1.5.193.96F/1.5.198.97F/1.5.164.98F/1.5.141.00F/ 4574.01). Correspondence: G. Decaux, Médecine Interne Générale, Hôpital Universitaire Erasme, 808 Route de Lennik, 1070 Bruxelles, Belgium (E-mail: [email protected]). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
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Treatment of Symptomatic Hyponatremia
osmotic change. The myelinolysis, sparing the axon, that develops after an osmotic stress is presently called osmotic demyelinating syndrome (ODS).4 In the early 1980s, experiments in animals (rats) established a direct relationship between rapid correction of chronic hyponatremia and myelinolysis.7 In humans, symptoms are typically 2-phased. Generally, this complication involves patients with serum sodium below 120 mEq/L with few or no symptoms (confusion, etc). A few days after the rapid correction of the serum sodium and initial improvement, the neurological status deteriorates. In the most severe cases, progressive quadriparesis occurs with swallowing and speech difficulties and deep coma (central pontine myelinolysis in its most classic expression resembles the “locked-in syndrome” (thrombosis of the arteria basilaris).4 Brain Adaptation to Hyponatremia and Its Treatment Understanding of the most appropriate therapeutic approach in the presence of hyponatremia requires a brief physiopathologic review. When blood tonicity diminishes, the brain will rapidly lower the electrolyte content of its interstitial fluid (Na⫹ and Cl⫺) within minutes; then, intracellular potassium and organic osmolytes such as amino acids (eg, taurine, glutamine, glutamate), polyols (myoinositol), methylamines (creatine, etc) decrease. This prevents excessive cerebral edema,4 which could have serious consequences, because an expansion of 8 to 10% of the brain volume could be fatal. In a hyponatremic rat, after 24 hours, brain water content is almost normalized by solute extrusion.8 When the decrease of serum sodium is too rapid (some argue in humans that this corresponds to a rate of SNa decrease higher than 0.5 mEq/L/hr), the adaptive cerebral mechanisms are overwhelmed with a risk of major cerebral edema. In chronic (⬎48 –72 hours) hyponatremia, the correction induces the reuptake of the different solutes lost during the induction of hyponatremia. The normalization of intracellular solute content is, however, a very slow process lasting for up to 5–7 days, especially for organic osmolytes.8,9 In rats, rapid correction of chronic hyponatremia induces an overshoot of the cerebral content in sodium, chloride, and water at 24 hours, and even much more at 48 hours.8 This excess of electrolyte content of the brain is probably localized partially within cells. This “hyperionization” of the intracellular space is poorly tolerated by the cell, especially with concomitant organic osmolyte depletion, such as for myoinositol, which plays a key role in the homeostasis of the interior milieu.10 When this “hyperionization” lasts too long, several enzymatic dysfunctions occur and may contribute to ODS lesions. Another hypothesis underlying the mechanism inducing ODS implicates neurotoxic factors affecting 26
Table 1. Acute Hypotonic Hyponatremia (⬍48 hours) Cerebral edema Generally hospital acquired ● Postoperative (menstruating women, hypoxemia) ● Excessive IV hypotonic fluids with inappropriate antidiuresis ● TURP, endoscopic uterine surgery (glycine irrigant) ● Oxytocin ● Recent thiazide prescription (elderly women) ● Polydipsia (acquired generally outside the hospital; psychiatric patients or beer drinkers) ● Exercise induced (acquired generally outside the hospital) ● Colonoscopy preparation ● Ecstasy
the brain through a leaky blood-brain barrier. The osmotic stress after acute hyponatremia hardly damages the blood-brain barrier; however, this barrier opens more easily when osmotic stress occurs during chronic hyponatremia. Different complement factors seem to be activated through contact with myelin,11 but other hypotheses also exist.4 If the patient presents with acute (⬍48 hours) and severe hyponatremia (⬍120 mEq/L; see below), rapid treatment is required to diminish cerebral edema. If, however, the patient has few or no symptoms, treatment may have deleterious effects. A patient presenting with chronic and symptomatic hyponatremia accumulates risks because of delayed treatment (seizures and respiratory arrest) and overly rapid correction (ODS). The management of these patients is more challenging (see below). Risk Factors for Myelinolysis (ODS) The most important factor is the daily difference in serum sodium level. Furthermore, about 80% of cases of ODS reported in the literature are associated with hypokalemia (often induced by thiazides).12 Most ODS observations were reported in patients presenting with an initial SNa below 120 mEq/L.4 However, in malnourished patients (chronic alcohol abuse, liver cirrhosis, heavy burns, hypocorticism, etc), ODS cases were reported with less severe hyponatremia.13 In animals, there is a good correlation between the daily gradient of serum sodium correction and the degree of neurologic lesions.14,15 The limits of daily difference in sodium levels established in the rat model probably cannot be simply applied to humans. In a retrospective study including 54 patients with hyponatremia ⱕ110 mEq/L, Sterns reported neurologic sequelae in some patients when the change in serum sodium over a 24-hour period was higher than 12 mEq/L/24 hours or 18 mEq/L/48 hours.16 In a more recent retrospective study including 184 patients with chronic hyponatremia ⬎3 days and ⱕ120 mEq/L, Ellis reported cerebral lesions appearing with a daily sodium difference of 9 mEq/L/24 July 2003 Volume 326 Number 1
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Table 2. Treatment of Acute Hyponatremia Prompt correction mandatory ● Hypertonic saline (3% NaCl): 1–2 mL/kg of body weight/hr If severe antidiuresis SNa will increase by about 1–2 mEq/L/ hr and by 2–4 mEq/L/hr if combined with furosemide ● Severe symptoms (seizure, obtundation, or coma): 3% NaCl 4–5 ml/kg of body weight/hr 1 or 2 hours. ● Target: interrupt correction when symptoms regress Rapid normalization of SNa usually safe but rarely necessary. In the beginning it is advisable to measure SNa every 1–2 hours to be sure that SNa is increasing.
hours.17 Some rare cases are even reported at a difference of 8 mEq/L/24 hours! It cannot be excluded, however, that in some of these cases, SNa began to increase spontaneously before first blood measurement in the hospital, leading the clinician to underestimate the absolute gradient of correction. According to these few data, a certain consensus can be obtained from the literature. Treatment of Acute Hyponatremia The circumstances inducing hyponatremia are very important diagnostic clues to recognizing hyponatremia as acute or chronic. Acute hyponatremia occurs generally in hospitalized patients and is most frequently iatrogenic. The main causes are outlined in Table 1. Some symptoms suggest intracranial hypertension: headache, nausea, vomiting, seizures, and deep coma. Sometimes these symptoms may be explosive in nature. Exercise-induced hyponatremia occurs in association with overwhelming physical efforts (eg, marathon races) or sometimes with less intense physical activity.18 The role of excessive sodium losses in sweat is probably marginal. Hyponatremia is mainly dilutional through a combination of excessive water ingestion during exercise and a defect in free water clearance. Nausea, stress, and exercise can also stimulate ADH secretion. Hypoxia, which sometimes complicates acute hyponatremia (either through hypoventilation or noncardiogenic pulmonary edema), interferes with the cerebral mechanism of adaptation to hypotonicity.4 Cerebral anoxia (caused by combined hypoxia and ischemia through edema of the central nervous system that diminishes the loco-regional blood flow) explains why some patients occasionally have 2-phased symptoms: initial awaking of a previously unconscious patient and then neurologic deterioration, as observed in carbon monoxide intoxication. All reported cases did have clinical hypoxemia (intubation, etc). The same observation has been made in an animal model.19 Prompt treatment of acute hyponatremia is summarized in Table 2. NaCl (3%) perfused at rate of 1 to 2 mL/kg/hr will increase the serum sodium by 1 to 2 mEq/L/hr in case of significant antidiuresis. Adding furosemide will increase it THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Table 3. Treatment of Hyponatremia Related to Polydipsia or Beer Drinkers ● Frequently spontaneous rapid correction secondary to high dilute urine output combined with water restriction. ● Often mixed disorder (solute depletion component) and treatment with 1 or 2 L isotonic saline ⫹30 mmol/L KCl over 24 hours is usually sufficient. If severely symptomatic, a few hours’ infusion of NaCl 3% (1–2 ml/kg of body weight/hr) may be necessary. ● If SNa very low (⬍110 mEq/L) likely SNa increase of no more than 10–15 mEq/L/24 hours.
by 2 to 4 mEq/L/hr. In case of severe neurologic symptoms, data from the neurosurgical literature suggest that an osmotic gradient of 10 to 20 mOsmol/kg/H2O is necessary to rapidly diminish cerebral edema. The initial treatment of these symptomatic patients requires larger doses of hypertonic NaCl during the first 1 to 2 hours. Once neurologic symptoms improve, treatment must be stopped, although the serum sodium may be theoretically normalized. Rare cases of ODS-type lesions are observed in patients presenting with acute hyponatremia. These patients probably already started to have some cerebral adaptation to the hypotonicity. In patients with hyponatremia related to polydipsia or “beer drinking,” we frequently observe a spontaneous correction secondary to high dilute urine output combined with water restriction. This state is often a mixed disorder with a solute depletion component.20 Treatment with 1 or 2 L of isotonic saline is usually sufficient (Table 3), but severely symptomatic patients may need brief treatment with hypertonic saline infusion. Treatment of Symptomatic Chronic Hyponatremia (>48 to 72 Hours), Subacute Hyponatremia, or Hyponatremia of Undetermined Duration The clinical context in which hyponatremia develops may be helpful in differentiating acute from chronic hyponatremia. Severe neurologic symptoms often reflect cerebral edema, but this is not always true.21 Extrahospital acquired hyponatremia is generally chronic, except for polydipsia, marathon runners, and ecstasy. Chronic hyponatremia may have a superimposed acute component. Hyponatremia of undetermined duration, especially when it is symptomatic, needs treatment combining rapid decrease of potential brain edema but also avoiding the risks of ODS. A 3% NaCl solution at a rate of 1 to 2 mL/kg/hr for 2 to 3 hours can be infused; then the treatment must be stopped as soon as symptoms improve (it is advisable to measure SNa every 1 to 2 hours to be sure that SNa is increasing). The objective is to maintain the SNa gradient below 10 mEq/ L/24 hours. In case of hyponatremia caused by solute depletion, treatment will be continued by 27
Treatment of Symptomatic Hyponatremia
perfusing a physiologic solution, generally 2 L of 0.9% NaCl/24 hours. As far as hyponatremia secondary to thiazide administration is concerned (frequently responsible for ODS), a slow correction through the intravenous administration of 1 or 2 L of 0.9% NaCl over 24 hours containing 40 mmol/L KCl is generally sufficient in conjunction with stopping the intake of thiazide. The rate of increase in serum sodium must be closely monitored. Relowering of the SNA in Case of Overcorrection of Hyponatremia An excessive rate of correction of hyponatremia may be secondary to the excessive administration of salt (error in calculation of doses to administer), and we have to remember that the administration of potassium in the solution contributes to increase the serum sodium. Most often this is caused by a predictable or unpredictable increase in the excretion of electrolyte free water.22,23 Frequent monitoring of SNa should enable avoidance of this complication. Data obtained in animals suggest that in those patients with a substantial risk for developing ODS (malnutrition, chronic alcoholism, cirrhosis, hypokalemia, hypocorticism) or if the daily increase in serum sodium exceeds 15 mmol/L/24 hours, it is advisable to relower the serum sodium by giving desmopressin acetate and water (water orally or as glucose 5% intravenously). The absolute daily serum sodium difference must stay below 10 mmol/L/24 hours (or 15 if there are no associated risk factors). This preventive measure could prevent neurologic deterioration in patients overcorrected with no or early symptoms24,25 (as has been clearly demonstrated in animal models26,27). Because desmopressin acetate has a long duration of action, fluid administration must be carefully adjusted and SNa monitored to avoid re-establishment of symptomatic hyponatremia. In cases of established ODS, some authors have reported benefits with thyrotropinreleasing hormone, ␥-globulins, corticosteroids, or plasmapheresis.28,29 These data suggest that an immunological component may contribute secondarily to the ODS. In patients with few or no symptoms, a
Table 4. General Recommendations ● Initial rapid correction if severe symptoms. ● Maximum brain volume expansion: 8–10% (rigidity of the skull). Theoretically no need to increase initial SNa by more than 8%. ● Maximum SNa correction ⬍ 10–15 mEq/L/24 hours and lower than 10 mEq/L/24 hours if associated risk factors for myelinolysis: hypokalemia, malnutrition, alcoholism, liver disease, burns, phosphate depletion (?), hypoglycemia (?), hypocorticism (?). Below this upper daily limit of correction the rate of SNa increase is not important. ● Close monitoring of SNa: every 1–2 hours initially, then every 4 hours, particularly if urine output is high (⬎150 mL/hr). ● If SNa increases too rapidly, interrupt the increase by hypotonic fluid administration and/or desmopressin acetate.
slow and generally cause-oriented correction of hyponatremia is required. General Recommendations When hyponatremia is associated with severe neurologic symptoms (vomiting, headaches, seizures, coma, etc), rapid correction of hyponatremia during the first hours is mandatory (Table 4). However, there is no reason to increase SNa by more than 8 to 10%. If the acute nature of hyponatremia is obvious (postoperative, duration ⬍48 hours), normalization of SNa is theoretically possible without inducing cerebral lesions. In those patients in whom the duration of hyponatremia is not definitely established, it is prudent not to correct SNa by more than 10 mmol/L/24 hours, especially when there are predisposing risk factors for ODS. The rate of increase in SNa is not a risk for the brain if the maximal daily limits of correction are respected. It is advisable to measure the serum sodium every 1 to 2 hours in the beginning of the treatment and every 4 hours thereafter, especially when diuresis is high (⬎150 mL/ hour). If the patient has relatively high diuresis, the use of hypertonic saline must be particularly prudent. During saline treatment, one must take the actual urine output volume into account: the formula predicting that 1 mmol/kg/hr of 3% NaCl will
Table 5. Effect of Different Diuresis and Urine Composition on ⌬SNa during 470 mL of 3% NaCl Infusion in a 60-kg Woman with SIADH and a Initial SNa of 110 mEq/L Urinary Na ⫹ K (mEq/L) 75 170 300
Urine Osmolality (mosm/Kg H2O)
24-hour Urine Output (WE) for 468 mL of 3% NaCl (L)
NTBW (L) (TBW ⫹ 0.46 ⫺ WE)
⌬SNa (mEq/L)
220 510 900
240/75 ⫽ 3.21 240/170 ⫽ 1.411 240/300 ⫽ 0.81
27.26 29.05 29.6
11 3.6 1
WE, water excretion; TBW, total body water; NTBW, new total body water.
28
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Table 6. Use of Urea for Treatment of Symptomatic Hyponatremia ● Rapidly decreases brain edema ● No transient decrease in SNa (as with mannitol) ● Increases SNa by osmotic diuresis and salt retention ● No risk of volume expansion ● No risk of inducing or increasing potassium deficit (as with furosemide) ● Easy to apply (electrolytes monitoring each 4 hours) ● Decreases the risk of myelinolysis Practical use of urea Oral route: Pure crystalline powder (prescribed usually as 30-g doses in small bags). Dissolve in 100 mL of water with antacid (and fruit syrup to improve taste if necessary). Administer after a meal. Intravenous route: 30% (hypertonic) solution of lyophilized powder dissolved in 5% dextrose. Each bottle (135 mL) contains 40 g of urea (Ureaphil; Abbott). Maximum infusion rate: 4 mL/min. Short-term 0.5–1 g/kg BW intravenously over 1 hour, or orally (by gastric tube) will rapidly (1 hr) increase serum administration: osmolality by 15–30 mOsm/kg H2O; eg, 80 g of urea, generally increases SNa concentration by about 15 mEq/L/24 hours when associated with 1 L of isotonic saline (31). Long-term use: Calculate, with the aid of the measured urine osmolality, the daily dose of urea required to obtain the additional volume of urine necessary to maintain normonatraemia; eg, 30 g of urea (500 mOsm) allows excretion of 1 L of free water if urine osmolality is fixed at 500 mOsm/kg H2O. Precautions: -Urea contraindicated if renal failure (creatinine ⬎ 2 mg/100 mL, urea ⬎ 80 mg/100 mL), associated liver disease (bilirubin ⬎ 2 mg/100 mL, hepatic encephalopathy) digestive hemorrhage, or gastric ulcer. -In hyponatremia associated with cerebral haemorrhage: use continuous infusion of urea (IV or by gastric tube) over 24 hours (usually combined with isotonic saline). Reprinted from Decaux G, Musch W, Soupart A. Hyponatremia in the intensive care: from diagnosis to treatment. Acta Clinica Belg 2000;55:68 –78. Copyright 娀 2000 Bruxelles Acta Clinica Belgica. Used with permission.
increase SNa by 1 mmol/L/hr is valid if there is no renal excretion. For an intended increase of 8 mEq/L in a 60-kg woman with syndrome of inappropriate ADH secretion (SIADH) and an SNa of 110 mEq/L, we will need to infuse 470 mL 3% NaCl [or total body water (30 L) ⫻ 8 mEq/L ⫽ 240 mEq of Na or 240/513 ⫽ 0.468 L of 3% NaCl]. Nevertheless, hypertonic saline infusion will affect electrolyte free-water excretion, so that the ⌬SNa could be highly variable dependent on urine composition (Table 5) with associated risk of over- or undertreatment. This justifies frequent SNa measurements. When serum sodium increases too rapidly, this increase has to be interrupted by giving desmopressin acetate (Minirin; 4 g subcutaneously) and/or by administrating hypotonic fluids. Urea as Alternative Treatment for Symptomatic Hyponatremia Urea represents a valuable therapeutic alternative in hyponatremia4 (Table 6). This endogenous diuretic is able to rapidly diminish cerebral edema without any risk of volume overload and without the risk of transitory worsening of hyponatremia (as seen with the administration of mannitol, caused by water translocation).30 The osmotic diuresis caused by urea is accompanied by sodium retention that also plays a role in the correction of hyponatremia.31 Urea may also be used as a long-term treatment in SIADH.32 A major feature of urea is its potential protective role against ODS.14,33 In a recent experiment, acute renal insufficiency was induced by administration of HgCl2 in rats with chronic hyponatremia to be able to maintain high plasma urea THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
levels at about 60 mmol/L. The rapid correction of hyponatremia (mean daily sodium difference, 32 mmol/L/24 hours) was particularly well tolerated in these rats, whereas in control rats without renal insufficiency, death or significant cerebral lesions occurred.34 In these uremic rats, treatment of hyponatremia increases, after only 2 hours, the brain organic osmolyte corrects to a level identical to that observed in nonhyponatremic normal rats.35 This property of urea, facilitating brain organic osmolyte accumulation, could explain its protective effects against ODS also in the absence of renal failure.36,37 and probably in humans.38 Even with the use of urea, the daily increase in SNa must remain below 10 to 15 mEq/L. The imminent introduction of oral vasopressin V2 receptor antagonists39 – 41 for clinical use will provide an interesting alternative in the management of hyponatremia. However, by blocking renal ADH receptors, these drugs produce brisk diuresis, which can expose the patient to dangerous levels of serum sodium correction and thus brain damage. References 1. Decaux G, Musch W, Soupart A. Hyponatremia in the intensive care: from diagnosis to treatment. Acta Clinica Belg 2000;55:68 –78. 2. Anderson RJ, Chung HM, Kluge R, et al. Hyponatremia: a prospective analysis of its epidemiology and the pathogenic role of vasopressin. Ann Intern Med 1985;102:164 – 8. 3. Sterns RH. The treatment of hyponatremia: first, do no harm. Am J Med 1990;88:557– 60. 4. Soupart A, Decaux G. Therapeutic recommendations for management of severe hyponatremia: current concepts on
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24. Soupart A, Ngassa M, Decaux G. Therapeutic relowering of the serum sodium in a patient after excessive correction of hyponatremia. Clin Nephrol 1999;51:383– 6. 25. Oya S, Tsutsumi K, Ueki K, et al. Reinduction of hyponatremia to treat central pontine myelinolysis. Neurology 2001; 57:1931–2. 26. Soupart A, Penninckx R, Crenier L, et al. Prevention of brain demyelination in rats after excessive correction of chronic hyponatremia by serum sodium lowering. Kidney Intern 1994;45:193–200. 27. Soupart A, Penninckx R, Stenuit A, et al. Reinduction of hyponatremia improves survival in rats with myelinolysisrelated neurologic symptoms. J Neuropathol Exp Neurol 1996;55:594 – 601. 28. Finsterer J, Engelmayer E, Trnka E, et al. Immunoglobulins are effective in pontine myelinolysis. Clin Nephropharmacol 1999;23:110 –3. 29. Chemaly R, Halaby G, Mohassed G, et al. Extrapontine myelinoysis: treatment with TRH. Rev Neurol 1998;154: 162–5. 30. Porzio P, Halberthal M, Bohn D, et al. Treatment of acute hyponatremia: ensuring the excretion of a predictable amount of electrolyte-free water. Crit Care Med 2000;28: 1905–10. 31. Decaux G, Unger J, Brimouille S, et al. Hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone. Rapid correction with urea, sodium chloride and water restriction. JAMA 1982;247:471– 4. 32. Decaux G, Genette F. Long-term treatment of the syndrome of inappropriate secretion of antidiuretic hormone by urea. Br Med J 1981;283:1081–3. 33. Van Reeth O, Decaux G. Rapid correction of hyponatremia with urea may protect against brain damages in rats. Clin Sci 1989;77:351–5. 34. Soupart A, Penninckx R, Stenuit A, et al. Uremia decreases the risk of brain damage in rats after correction of chronic hyponatremia. Brain Res 2000;852:167–72. 35. Soupart A, Silver S, Schroeder B, et al. Rapid (24-hour) reaccumulation of brain organic osmolytes (particularly myoinositol) in azotemic rats after correction of chronic hyponatremia. J Am Soc Nephrol 2002;13:1433– 41. 36. Soupart A, Penninckx R, Decaux G. Treatment of severe hyponatremia by urea decreases the mortality rate compared to water diuresis in rats [abstract]. J Am Soc Nephrol 2000; 11:110A. 37. Soupart A, Silver S, Schroeder B, et al. Treatment of experimental hyponatremia with exogenous urea promotes rapid reuptake of brain organic osmolytes [abstract]. J Am Soc Nephrol 2001;12:140A. 38. Decaux G, Coffernils M, Brimouille S, et al. In severe acute or chronic hyponatremia treatment with urea is safe for correction of serum sodium of 12–20 mEq/L/24 hr [abstract]. J Am Soc Nephrol 1994;5:366. 39. Gross P, Palm C. The treatment of hyponatremia using vasopressing antagonist. Exp Physiol 2000;855:2535–75. 40. Decaux G. Long term treatment of inappropriate secretion of ADH by the vasopressin receptor antagonist conivaptan, urea or furosemide. Am J Med 2001;110:582– 4. 41. Decaux G. Difference in solute excretion during correction of hyponatremia in patients with cirrhosis or SIADH by oral vasopressin V2 receptor antagonist VPA-985. J Lab Clin Med 2001;138:18 –21.
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