Volume 342 Number 21 · 1581 Review Article Primary Care PRIMARY CARE H YPONATREMIA H ORACIO J. A DROGUÉ , M.D., AND N ICOLAOS E. M ADIAS , M.D.
From the Department of Medicine, Baylor College of Medicine and Methodist Hospital, and the Renal Section, Department of Veterans Affairs Medical Center, Houston (H.J.A.); and the Department of Medicine, Tufts University School of Medicine, and the Division of Nephrology and Tup- per Research Institute, New England Medical Center, Boston (N.E.M.). Address reprint requests to Dr. Madias at the Division of Nephrology, New England Medical Center, Box 172, 750 Washington St., Boston, MA 02111, or at email@example.com.
©2000, Massachusetts Medical Society. YPONATREMIA is defined as a decrease in the serum sodium concentration to a level below 136 mmol per liter. Whereas hyper- natremia always denotes hypertonicity, hyponatremia can be associated with low, normal, or high tonici- ty.
1,2 Effective osmolality or tonicity refers to the contribution to osmolality of solutes, such as sodi- um and glucose, that cannot move freely across cell membranes, thereby inducing transcellular shifts in water. 3 Dilutional hyponatremia, by far the most com- mon form of the disorder, is caused by water reten- tion. If water intake exceeds the capacity of ... more. less.
the kid- neys to excrete water, dilution of body solutes results, causing hypo-osmolality and hypotonicity (Fig.<br><br> 1B, 1E, 1F, and 1G). Hypotonicity, in turn, can lead to cerebral edema, a potentially life-threatening com- plication. 4 Hypotonic hyponatremia can be associat- ed, however, with normal or even high serum osmo- lality if sufficient amounts of solutes that can permeate cell membranes (e.g., urea and ethanol) have been retained (Fig.<br><br> 1C). Importantly, patients who have hypotonic hyponatremia but normal or high serum osmolality are as subject to the risks of hypotonicity as are patients with hypo-osmolar hyponatremia. The nonhypotonic hyponatremias are hypertonic (or translocational) hyponatremia, isotonic hypona- tremia, and pseudohyponatremia.<br><br> 1,2 Translocational hyponatremia results from a shift of water from cells to the extracellular fluid that is driven by solutes confined in the extracellular compartment (as occurs with hyperglycemia or retention of hypertonic man- nitol); serum osmolality is increased, as is tonicity, the latter causing dehydration of cells (Fig. 1D). Re- H tention in the extracellular space of large volumes of isotonic fluids that do not contain sodium (e.g., man- nitol) generates iso-osmolar and isotonic hypona- tremia but no transcellular shifts of water.<br><br> Pseudo- hyponatremia is a spurious form of iso-osmolar and isotonic hyponatremia identified when severe hyper- triglyceridemia or paraproteinemia increases sub- stantially the solid phase of plasma and the sodium concentration is measured by means of flame pho- tometry. 1,2 The increasing availability of direct meas- urement of serum sodium with the ion-specific elec- trode has all but eliminated this laboratory artifact. 5 A common clinical problem, hyponatremia fre- quently develops in hospitalized patients.<br><br> 6 Although morbidity varies widely in severity, serious compli- cations can arise from the disorder itself as well as from errors in management. In this article, we focus on the treatment of hyponatremia, emphasizing a quantitative approach to its correction. CAUSES Hypotonic (dilutional) hyponatremia represents an excess of water in relation to existing sodium stores, which can be decreased, essentially normal, or in- creased (Fig.<br><br> 1). Retention of water most commonly reflects the presence of conditions that impair renal excretion of water 1,7,8 ; in a minority of cases, it is caused by excessive water intake, with a normal or nearly normal excretory capacity (Table 1). 7 Conditions of impaired renal excretion of water are categorized according to the characteristics of the extracellular-fluid volume, as determined by clin- ical assessment (Table 1).<br><br> 9 With the exception of re- nal failure, these conditions are characterized by high plasma concentrations of arginine vasopressin despite the presence of hypotonicity. 10,11 Depletion of potassium accompanies many of these disorders and contributes to hyponatremia, since the sodium concentration is determined by the ratio of the cexchangeable d (i.e., osmotically active) portions of the body 9s sodium and potassium content to total body water (Fig. 1G).<br><br> 12-14 Patients with hyponatre- mia induced by thiazides can present with variable hypovolemia or apparent euvolemia, depending on the magnitude of the sodium loss and water reten- tion. 1,15-17 Excessive water intake can cause hyponatremia by overwhelming normal water excretory capacity (e.g., primary polydipsia) (Table 1). Frequently, however, psychiatric patients with excessive water intake have plasma arginine vasopressin concentrations that are not fully suppressed and urine that is not maximally dilute, thus contributing to water retention.<br><br> 18,19 Downloaded from www.nejm.org on March 24, 2009 . Copyright © 2000 Massachusetts Medical Society. All rights reserved.<br><br> 1582 · May 25, 2000 The New England Journal of Medicine Figure 1. Extracellular-Fluid and Intracellular-Fluid Compartments under Normal Conditions and during States of Hyponatremia. Normally, the extracellular-fluid and intracellular-fluid compartments make up 40 percent and 60 percent of total body water, r e- spectively (Panel A).<br><br> With the syndrome of inappropriate secretion of antidiuretic hormone, the volumes of extracellular fluid and intracellular fluid expand (although a small element of sodium and potassium loss, not shown, occurs during inception of the sy n- drome) (Panel B). Water retention can lead to hypotonic hyponatremia without the anticipated hypo-osmolality in patients who ha ve accumulated ineffective osmoles, such as urea (Panel C). A shift of water from the intracellular-fluid compartment to the extra cel- lular-fluid compartment, driven by solutes confined in the extracellular fluid, results in hypertonic (translocational) hyponat remia (Panel D).<br><br> Sodium depletion (and secondary water retention) usually contracts the volume of extracellular fluid but expands the intracellular-fluid compartment. At times, water retention can be sufficient to restore the volume of extracellular fluid to no rmal or even above-normal levels (Panel E). Hypotonic hyponatremia in sodium-retentive states involves expansion of both compartments, but predominantly the extracellular-fluid compartment (Panel F).<br><br> Gain of sodium and loss of potassium in association with a def ect of water excretion, as they occur in congestive heart failure treated with diuretics, lead to expansion of the extracellular-fl uid com- partment but contraction of the intracellular-fluid compartment (Panel G). In each panel, open circles denote sodium, solid cir cles potassium, large squares impermeable solutes other than sodium, and small squares permeable solutes; the broken line between the two compartments represents the cell membrane, and the shading indicates the intravascular volume. A Normal conditions Extracellular Fluid Intracellular Fluid Hypotonic hyponatremia due to water6 retention in the presence of essentially6 normal sodium stores (e.g., from the6 syndrome of inappropriate secretion of6 antidiuretic hormone) Hypotonic hyponatremia without anticipated6 hypo-osmolality (e.g., from renal failure) Hypertonic hyponatremia due to gain of impermeable6 solutes other than sodium (e.g., from hyperglycemia) Hypotonic hyponatremia due to water6 retention in association with sodium6 depletion (e.g., from diarrhea) Hypotonic hyponatremia due to water6 retention in association with sodium gain6 (e.g., from the nephrotic syndrome) Hypotonic hyponatremia due to water retention in6 association with sodium gain and potassium loss6 (e.g., from congestive heart failure treated with6 diuretics) B C D E G F Downloaded from www.nejm.org on March 24, 2009 .<br><br> Copyright © 2000 Massachusetts Medical Society. All rights reserved. PRIMARY CARE Volume 342 Number 21 · 1583 Hyperglycemia is the most common cause of trans- locational hyponatremia (Fig.<br><br> 1D). An increase of 100 mg per deciliter (5.6 mmol per liter) in the se- rum glucose concentration decreases serum sodium by approximately 1.7 mmol per liter, with the end result a rise in serum osmolality of approximately 2.0 mOsm per kilogram of water. 1 Retention of hy- pertonic mannitol, which occurs in patients with re- nal insufficiency, has the same effect.<br><br> In both condi- tions, the resultant hypertonicity can be aggravated by osmotic diuresis; moderation of hyponatremia or frank hypernatremia can develop, since the total of the sodium and potassium concentrations in the urine falls short of that in serum. 20 Massive absorption of irrigant solutions that do not contain sodium (e.g., those used during transurethral *Sodium depletion, potassium depletion, stimulation of thirst, and impaired urinary dilution are implicated. Often a mild reduction in the capacity for water excretion is also present.<br><br> !Hyponatremia is not always hypotonic. T ABLE 1. C AUSES OF H YPOTONIC H YPONATREMIA .<br><br> I MPAIRED C APACITY OF R ENAL W ATER E XCRETION Decreased volume of extracellular fluid Renal sodium loss Diuretic agents Osmotic diuresis (glucose, urea, mannitol) Adrenal insufficiency Salt-wasting nephropathy Bicarbonaturia (renal tubular acido- sis, disequilibrium stage of vomiting) Ketonuria Extrarenal sodium loss Diarrhea Vomiting Blood loss Excessive sweating (e.g., in mara- thon runners) Fluid sequestration in cthird space d Bowel obstruction Peritonitis Pancreatitis Muscle trauma Burns Increased volume of extracellular fluid Congestive heart failure Cirrhosis Nephrotic syndrome Renal failure (acute or chronic) Pregnancy Essentially normal volume of extracellular fluid Thiazide diuretics* Hypothyroidism Adrenal insufficiency Syndrome of inappropriate secretion of antidiuretic hormone Cancer Pulmonary tumors Mediastinal tumors Extrathoracic tumors Central nervous system disorders Acute psychosis Mass lesions Inflammatory and demyelinating diseases Stroke Hemorrhage Trauma Drugs Desmopressin Oxytocin Prostaglandin-synthesis inhibitors Nicotine Phenothiazines Tricyclics Serotonin-reuptake inhibitors Opiate derivatives Chlorpropamide Clofibrate Carbamazepine Cyclophosphamide Vincristine Pulmonary conditions Infections Acute respiratory failure Positive-pressure ventilation Miscellaneous Postoperative state Pain Severe nausea Infection with the human immunodeficiency virus Decreased intake of solutes Beer potomania Tea-and-toast diet E XCESSIVE W ATER I NTAKE Primary polydipsia Dilute infant formula Sodium-free irrigant solutions (used in hysteroscopy, laparoscopy, or transurethral resection of the prostate)! Accidental intake of large amounts of water (e.g., during swimming lessons) Multiple tap-water enemas Downloaded from www.nejm.org on March 24, 2009 . Copyright © 2000 Massachusetts Medical Society.<br><br> All rights reserved. 1584 · May 25, 2000 The New England Journal of Medicine prostatectomy) can cause severe and symptomatic hy- ponatremia. Reflecting the composition of the irri- gant, the resultant hyponatremia can be either hypo- tonic (with an irrigant containing 1.5 percent glycine or 3.3 percent sorbitol) or isotonic (with an irrigant containing 5 percent mannitol).<br><br> Whether the symp- toms derive from the presence of retained solutes, the metabolic products of such solutes, hypotonici- ty, or the low serum sodium concentration itself re- mains unclear. 21,22 The most common causes of severe hyponatremia in adults are therapy with thiazides, the postoperative state and other causes of the syndrome of inappro- priate secretion of antidiuretic hormone, polydipsia in psychiatric patients, and transurethral prostatec- tomy. 1,17,23-25 Gastrointestinal fluid loss, ingestion of dilute formula, accidental ingestion of excessive wa- ter, and receipt of multiple tap-water enemas are the main causes of severe hyponatremia in infants and children.<br><br> 17,26 CLINICAL MANIFESTATIONS Just as in hypernatremia, the manifestations of hy- potonic hyponatremia are largely related to dysfunc- tion of the central nervous system, and they are more conspicuous when the decrease in the serum sodium concentration is large or rapid (i.e., occurring within a period of hours). 27 Headache, nausea, vomiting, mus- Figure 2. Effects of Hyponatremia on the Brain and Adaptive Responses.<br><br> Within minutes after the development of hypotonicity, water gain causes swelling of the brain and a decrease in osmolality of t he brain. Partial restoration of brain volume occurs within a few hours as a result of cellular loss of electrolytes (rapid adapta tion). The normalization of brain volume is completed within several days through loss of organic osmolytes from brain cells (slow adapta- tion).<br><br> Low osmolality in the brain persists despite the normalization of brain volume. Proper correction of hypotonicity reesta blishes normal osmolality without risking damage to the brain. Overly aggressive correction of hyponatremia can lead to irreversible br ain damage.<br><br> Water gain (low osmolality) Proper therapy (slow correction of the hypotonic state) Immediate effect of hypotonic state Slow adaptation Improper therapy (rapid correction of the hypotonic state) Normal brain (normal osmolality) Loss of organic osmolytes (low osmolality) Osmotic demyelination Loss of sodium, potassium, and chloride (low osmolality) Water Rapid adaptation Downloaded from www.nejm.org on March 24, 2009 . Copyright © 2000 Massachusetts Medical Society. All rights reserved.<br><br> PRIMARY CARE Volume 342 Number 21 · 1585 cle cramps, lethargy, restlessness, disorientation, and depressed reflexes can be observed. Whereas most patients with a serum sodium concentration exceed- ing 125 mmol per liter are asymptomatic, those with lower values may have symptoms, especially if the disorder has developed rapidly. 4 Complications of se- vere and rapidly evolving hyponatremia include sei- zures, coma, permanent brain damage, respiratory arrest, brain-stem herniation, and death.<br><br> These com- plications often occur with excessive water retention in patients who are essentially euvolemic (e.g., those recovering from surgery or those with primary poly- dipsia); menstruating women appear to be at partic- ular risk. 23,28 Hypotonic hyponatremia causes entry of water into the brain, resulting in cerebral edema (Fig. 2).<br><br> Be- cause the surrounding cranium limits expansion of the brain, intracranial hypertension develops, with a risk of brain injury. Fortunately, solutes leave brain tissues within hours, thereby inducing water loss and ameliorating brain swelling. 29,30 This process of adap- tation by the brain accounts for the relatively asymp- tomatic nature of even severe hyponatremia if it de- velops slowly.<br><br> Nevertheless, brain adaptation is also the source of the risk of osmotic demyelination. 31-33 Although rare, osmotic demyelination is serious and can develop one to several days after aggressive treat- ment of hyponatremia by any method, including water restriction alone. 34-36 Shrinkage of the brain triggers demyelination of pontine and extrapontine neurons that can cause neurologic dysfunction, in- cluding quadriplegia, pseudobulbar palsy, seizures, coma, and even death.<br><br> Hepatic failure, potassium de- pletion, and malnutrition increase the risk of this com- plication. 1,37 MANAGEMENT The optimal treatment of hypotonic hyponatremia requires balancing the risks of hypotonicity against those of therapy. 28 The presence of symptoms and their severity largely determine the pace of correction.<br><br> Symptomatic Hypotonic Hyponatremia Patients who have symptomatic hyponatremia with concentrated urine (osmolality, »200 mOsm per kil- ogram of water) and clinical euvolemia or hyper- volemia require infusion of hypertonic saline (Table 2). This treatment can provide rapid but controlled correction of hyponatremia. Hypertonic saline is usu- ally combined with furosemide to limit treatment- induced expansion of the extracellular-fluid volume.<br><br> Because furosemide-induced diuresis is equivalent to a one-half isotonic saline solution, it aids in the cor- rection of hyponatremia, as do ongoing dermal and respiratory fluid losses; anticipation of these losses should temper the pace of infusion of hypertonic sa- line. Obviously, electrolyte-free water intake must be withheld. In addition to hypertonic saline, hormone- *The numerator in formula 1 is a simplification of the expression (infusate Na + ¡serum Na + )¬ 1 liter, with the value yielded by the equation in millimoles per liter.<br><br> 38 The estimated total body water (in liters) is calculated as a fraction of body weight. The fraction is 0.6 in children; 0.6 and 0.5 in nonelderly men and women, respectively; and 0.5 and 0.45 in elderly men and women, respectively. 39 Normally, extracellular and intracellular fluids account for 40 and 60 percent of total body water, respectively.<br><br> 39 In addition to its complete distribution in the extracellular compartment, this infusate induces osmotic removal of water from the intracellular compartment. T ABLE 2. F ORMULAS FOR U SE IN M ANAGING H YPONATREMIA AND C HARACTERISTICS OF I NFUSATES .<br><br> F ORMULA * C LINICAL U SE 1. Change in serum Na + = infusate Na + ¡serum Na + total body water + 1 Estimate the effect of 1 liter of any infusate on serum Na + 2. Change in serum Na + = (infusate Na + +infusate K + )¡serum Na + total body water + 1 Estimate the effect of 1 liter of any infusate containing Na + and K + on serum Na + I NFUSATE I NFUSATE Na + E XTRACELLULAR -F LUID D ISTRIBUTION mmol per liter % 5% Sodium chloride in water 855 100 3% Sodium chloride in water 513 100 0.9% Sodium chloride in water 154 100 Ringer 9s lactate solution 130 97 0.45% Sodium chloride in water 77 73 0.2% Sodium chloride in 5% dextrose in water 34 55 5% Dextrose in water 0 40 Downloaded from www.nejm.org on March 24, 2009 .<br><br> Copyright © 2000 Massachusetts Medical Society. All rights reserved. 1586 · May 25, 2000 The New England Journal of Medicine replacement therapy should be given to patients with suspected hypothyroidism or adrenal insufficiency after blood samples are obtained for diagnostic testing.<br><br> 7,17 On the other hand, most patients with hypovolemia can be treated successfully with isotonic saline. Pa- tients with seizures also require immediate anticon- vulsant-drug therapy and adequate ventilation. 40 Patients with symptomatic hyponatremia and dilute urine (osmolality, <200 mOsm per kilogram of wa- ter) but with less serious symptoms usually require only water restriction and close observation.<br><br> Severe symptoms (e.g., seizures or coma) call for infusion of hypertonic saline. There is no consensus about the optimal treatment of symptomatic hyponatremia. 28,40-49 Nevertheless, cor- rection should be of a sufficient pace and magnitude to reverse the manifestations of hypotonicity but not be so rapid and large as to pose a risk of the devel- opment of osmotic demyelination.<br><br> Physiologic con- siderations indicate that a relatively small increase in the serum sodium concentration, on the order of 5 percent, should substantially reduce cerebral ede- ma. 9,50 Even seizures induced by hyponatremia can be stopped by rapid increases in the serum sodium concentration that average only 3 to 7 mmol per liter. 51,52 Most reported cases of osmotic demyelina- tion occurred after rates of correction that exceeded 12 mmol per liter per day were used, but isolated cases occurred after corrections of only 9 to 10 mmol per liter in 24 hours or 19 mmol per liter in 48 hours.<br><br> 34,35,40,48,53-56 After weighing the available evi- dence and the all-too-real risk of overshooting the mark, we recommend a targeted rate of correction that does not exceed 8 mmol per liter on any day of treatment. Remaining within this target, the initial rate of correction can still be 1 to 2 mmol per liter per hour for several hours in patients with severe symptoms. Should severe symptoms not respond to correction according to the specified target, we sug- gest that this limit be cautiously exceeded, since the imminent risks of hypotonicity override the poten- tial risk of osmotic demyelination.<br><br> Recommended in- dications for stopping the rapid correction of symp- tomatic hyponatremia (regardless of the method used) are the cessation of life-threatening manifestations, moderation of other symptoms, or the achievement of a serum sodium concentration of 125 to 130 mmol per liter (or even lower if the base-line serum sodium concentration is below 100 mmol per li- ter). 28,40 Long-term management of hyponatremia (described below) should then be initiated. Although faster rates of correction can be tolerated safely by most patients with acute symptomatic hyponatremia, there is no evidence that such an approach is bene- ficial.<br><br> 40,57 Moreover, ascertaining the duration of hy- ponatremia is usually difficult. How can the physician determine what the rate of infusion of the selected solution should be? This rate can be derived expediently by applying formula 1 in Table 2, the same formula used for managing hyper- natremia, which projects the change in serum sodi- um elicited by the retention of 1 liter of any infu- sate.<br><br> 38 Dividing the change in serum sodium targeted for a given treatment period by the output of this formula determines the volume of infusate required, and hence the rate of infusion. Table 2 also presents the sodium concentrations of commonly used infu- sates, their fractional distribution in the extracellular fluid, and clinical estimates of total body water. 39 We do not recommend use of the conventional formula for the correction of hyponatremia, as follows: sodium requirement=total body water¬(desired serum sodium concentration¡current sodium concentration).<br><br> The conventional formula requires a complicated pro- cedure to convert the amount of sodium required to raise the sodium concentration to an infusion rate for the selected solution. The cases described below illustrate the various forms of symptomatic hyponatremia and their man- agement. Hyponatremia in the Postoperative State A previously healthy 32-year-old woman has three grand mal seizures two days after an appendectomy.<br><br> She receives 20 mg of diazepam and 250 mg of phen- ytoin intravenously and undergoes laryngeal intuba- tion with mechanical ventilation. Three liters of 5 per- cent dextrose in water had been infused during the first day after surgery, and the patient subsequently drank an unknown but substantial amount of water. Clinically, she is euvolemic, and she weighs 46 kg.<br><br> She is stuporous and responds to pain but not to commands. The serum sodium concentration is 112 mmol per liter, the serum potassium concentration is 4.1 mmol per liter, serum osmolality is 228 mOsm per kilogram of water, and urine osmolality is 510 mOsm per kilogram of water. Hypotonic hyponatre- mia in this patient is a result of water retention caused by the impaired excretion of water that is associated with the postoperative state.<br><br> Planned treatment in- cludes the withholding of water, the infusion of 3 per- cent sodium chloride, and the intravenous adminis- tration of 20 mg of furosemide. The estimated volume of total body water is 23 liters (0.5¬46). According to formula 1 of Table 2, it is estimated that the retention of 1 liter of 3 percent sodium chloride will increase the serum sodium concentra- tion by 16.7 mmol per liter ([513¡112]÷[23+1] =16.7).<br><br> Given the seriousness of the patient 9s symp- toms, the initial goal is to raise the serum sodium concentration by 3 mmol per liter over the next three hours; thus, 0.18 liter of hypertonic sodium chloride (3÷16.7), or 60 ml per hour, is required. Frequent monitoring of the serum sodium concentration, ini- tially every two to three hours, is necessary in order Downloaded from www.nejm.org on March 24, 2009 . Copyright © 2000 Massachusetts Medical Society.<br><br> All rights reserved. PRIMARY CARE Volume 342 Number 21 · 1587 to make further adjustments in the amount of fluid administered. Although measuring urinary electro- lytes can occasionally assist with management, it is generally unnecessary, and we do not recommend the routine use of this procedure.<br><br> Three hours later, the patient 9s serum sodium con- centration is 115 mmol per liter. There have been no further seizures, but the level of responsiveness re- mains unchanged. The new goal is to increase the se- rum sodium concentration by an additional 3 mmol per liter over a period of six hours with the use of 3 percent sodium chloride; thus, the infusion rate is adjusted to 30 ml per hour.<br><br> Nine hours after admis- sion, the serum sodium concentration is 119 mmol per liter. There has been no seizure activity, and the patient now responds to simple commands. Hyper- tonic saline is discontinued, but close monitoring of the patient 9s clinical status and serum sodium con- centration remains in effect.<br><br> If the rate of correction is estimated to exceed the targeted rate, hypotonic solution should be administered. 58 Hyponatremia in an Essentially Euvolemic State A 58-year-old man with small-cell lung carcinoma presents with severe confusion and lethargy. Clini- cally, he is euvolemic, and he weighs 60 kg.<br><br> The se- rum sodium concentration is 108 mmol per liter, the serum potassium concentration is 3.9 mmol per li- ter, serum osmolality is 220 mOsm per kilogram of water, the serum urea nitrogen concentration is 5 mg per deciliter (1.8 mmol per liter), the serum creati- nine concentration is 0.5 mg per deciliter (44.2 µmol per liter), and urine osmolality is 600 mOsm per kil- ogram of water. The physician makes a provisional diagnosis of the tumor-induced syndrome of inap- propriate secretion of antidiuretic hormone on the basis of the presence of hypotonic hyponatremia and concentrated urine in a euvolemic patient, the ab- sence of a history of diuretic use, and the absence of clinical evidence of hypothyroidism or hypoadrenal- ism. The treatment plan includes water restriction, the infusion of 3 percent sodium chloride, and the intravenous administration of 20 mg of furosemide.<br><br> The estimated volume of total body water is 36 liters (0.60¬60). According to formula 1 of Table 2, the retention of 1 liter of 3 percent sodium chloride is estimated to increase the serum sodium concentration by 10.9 mmol per liter ([513¡108]÷[36+1]=10.9). The initial goal is to increase the serum sodium concen- tration by 5 mmol per liter over the next 12 hours.<br><br> Therefore, 0.46 liter of 3 percent sodium chloride (5÷10.9), or 38 ml per hour, is required. Twelve hours after admission, the serum sodium concentration is 114 mmol per liter. The patient is mildly lethargic but easily arousable.<br><br> Hypertonic sa- line is stopped, but fluid restriction and close mon- itoring continue. The new goal is to increase the se- rum sodium concentration by 2 mmol per liter over the next 12 hours. Twenty-four hours after admis- sion, the serum sodium concentration is 115 mmol per liter and the patient is alert.<br><br> Long-term manage- ment of hyponatremia is instituted. Hyponatremia in a Hypovolemic State A 68-year-old woman is brought to the hospital because of progressive drowsiness and syncope. She is being treated with a low-sodium diet and 25 mg of hydrochlorothiazide daily for essential hyperten- sion; she has had diarrhea for the past three days.<br><br> She is lethargic but has no focal neurologic deficits. She weighs 60 kg. Her blood pressure while in a su- pine position is 96/56 mm Hg, and the pulse is 110 beats per minute.<br><br> The jugular veins are flat, and skin turgor is decreased. The serum sodium concentra- tion is 106 mmol per liter, the serum potassium con- centration is 2.2 mmol per liter, the serum bicarbon- ate concentration is 26 mmol per liter, the serum urea nitrogen concentration is 46 mg per deciliter (16.4 mmol per liter), the serum creatinine concen- tration is 1.4 mg per deciliter (123.8 µmol per liter), serum osmolality is 232 mOsm per kilogram of wa- ter, and urine osmolality is 650 mOsm per kilogram of water. Hypotonic hyponatremia caused by thia- zide therapy, gastrointestinal losses of sodium, and an associated depletion of potassium are diagnosed.<br><br> Hydrochlorothiazide and water are withheld, and in- fusion of a 0.9 percent sodium chloride solution con- taining 30 mmol of potassium chloride per liter is initiated. The estimated volume of total body water is 27 liters (0.45¬60). According to formula 2 of Table 2 (a simple de- rivative of formula 1), it is projected that the retention of 1 liter of this infusate will increase the serum so- dium concentration by 2.8 mmol per liter ([154+30] ¡106÷[27+1]=2.8).<br><br> Considering the patient 9s he- modynamic status, the physician prescribes 1 liter of infusate per hour for the next two hours. At the end of this period, the blood pressure is 128/72 mm Hg, mental status is substantially improved, the serum sodium concentration is 112 mmol per liter, and the serum potassium concentration is 3.0 mmol per li- ter. The physician recognizes that as soon as the pa- tient 9s extracellular-fluid volume nears restoration, the nonosmotic stimulus to arginine vasopressin release will cease, thereby fostering rapid excretion of dilute urine and correction of the hyponatremia at an over- ly rapid pace.<br><br> Therefore, the prescription is switched to 0.45 percent sodium chloride containing 30 mmol of potassium chloride per liter infused at 100 ml per hour. Despite the estimate that retention of 1 liter of this infusate will have no measurable effect on the serum sodium concentration (i.e., [77+30]¡112 ÷[27+1]=¡0.2), the anticipated production of urine with lower sodium and potassium concentra- tions than those of the infusate will promote correc- Downloaded from www.nejm.org on March 24, 2009 . Copyright © 2000 Massachusetts Medical Society.<br><br> All rights reserved. 1588 · May 25, 2000 The New England Journal of Medicine tion of the hyponatremia. Twelve hours after admis- sion, the patient 9s condition continues to improve; the serum sodium concentration is 114 mmol per li- ter, and the serum potassium concentration is 3.2 mmol per liter.<br><br> To slow down further correction over the next 12 hours, an infusion of 5 percent dex- trose in water containing 30 mmol of potassium chloride per liter is started at a rate matching urinary output. Subsequently, long-term management of hy- ponatremia should be pursued. Asymptomatic Hypotonic Hyponatremia For certain patients with asymptomatic hyponatre- mia, the main risk of complications occurs during the correction phase.<br><br> This is true of patients who stopped drinking large amounts of water 36 and those who underwent repair of a water-excretion defect (e.g., repletion of extracellular-fluid volume and dis- continuation of drugs that cause the condition). If excessive diuresis occurs and the projected rate of spontaneous correction exceeds that recommended for patients with symptomatic hyponatremia, hypo- tonic fluids or desmopressin can be administered. 44 By contrast, there is no such risk associated with the asymptomatic hyponatremia that accompanies edematous states or the persistent syndrome of inap- propriate secretion of antidiuretic hormone because of the prevailing defect of water excretion.<br><br> Water re- striction (to <800 ml per day) is the mainstay of long- term management, with the goal being induction of negative water balance. 43,44 In severe cardiac failure, optimization of hemodynamics by several measures, including the use of angiotensin-converting 3enzyme inhibitors, can increase excretion of electrolyte-free water and moderate hyponatremia. Loop, but not thi- azide, diuretics reduce urine concentration and aug- ment excretion of electrolyte-free water, thereby per- mitting relaxation of fluid restriction.<br><br> In the syndrome of inappropriate secretion of antidiuretic hormone, but not in edematous disorders, loop diuretics should be combined with plentiful sodium intake (in the form of dietary sodium or salt tablets), a treatment that augments water loss. If these measures fail, 600 to 1200 mg of demeclocycline per day can help by inducing nephrogenic diabetes insipidus. 44 Monitor- ing of renal function is required, because demeclocy- cline has nephrotoxic effects, especially in patients with cirrhosis.<br><br> Moreover, the drug imposes the risk of hypernatremia in patients who do not take in suf- ficient water. Management of chronic hyponatremia will be helped by the anticipated introduction of promising oral agents that antagonize the effect of arginine vasopressin on the V 2 receptor. 59,60 Nonhypotonic Hyponatremia Corrective measures for nonhypotonic hyponatre- mia are directed at the underlying disorder rather than at the hyponatremia itself.<br><br> Administration of insulin is the basis of treatment for uncontrolled di- abetes, but deficits of water, sodium, and potassium should also be corrected. Furosemide hastens the re- covery of patients who absorb irrigant solutions; if renal function is impaired, hemodialysis is the pre- ferred option. 22 Common Errors in Management Although water restriction will ameliorate all forms of hyponatremia, it is not the optimal therapy in all cases.<br><br> Hyponatremias associated with the depletion of extracellular-fluid volume (Table 1) require cor- rection of the prevailing sodium deficit. On the oth- er hand, isotonic saline is unsuitable for correcting the hyponatremia of the syndrome of inappropriate secretion of antidiuretic hormone; if administered, the resulting rise in serum sodium is both small and transient, with the infused salt being excreted in concentrated urine and thereby causing a net reten- tion of water and worsening of the hyponatremia. 38 Although uncertainty about the diagnosis might oc- casionally justify a limited trial of isotonic saline, at- tentive follow-up is needed to confirm the diagnosis before substantial deterioration occurs.<br><br> Great vigi- lance is required in order to recognize and diagnose hypothyroidism and adrenal insufficiency, since these disorders tend to masquerade as cases of the syn- drome of inappropriate secretion of antidiuretic hor- mone. The presence of hyperkalemia should always alert the physician to the possibility of adrenal insuf- ficiency. Whereas patients with persistent asymptomatic hy- ponatremia require slow-paced management, those with symptomatic hyponatremia must receive rapid but controlled correction.<br><br> Prudent use of hyperton- ic saline can be lifesaving, but failure to follow the recommendations for treatment can cause devastat- ing and even lethal consequences. Hyponatremia that is acquired in the hospital is largely preventable. 6 A defect of water excretion can be present on admission, or it can worsen or develop during the course of hospitalization as a result of several antidiuretic influences (e.g., medications, or- gan failure, and the postoperative state).<br><br> The presence of such a defect notwithstanding, hyponatremia will not develop as long as the intake of electrolyte-free water does not exceed the capacity for water excre- tion plus insensible losses. Thus, hypotonic fluids must be supplied carefully to hospitalized patients. 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