Nephrology

LONG BEACH, CALIF. – If present trends continue, U.S. surgeons will be performing 179,000 more incontinence and prolapse surgeries annually in 2050 than they are today.

The projected increase results primarily from an aging population, Dr. Jennifer Wu said at the annual meeting of the American Urogynecologic Society.

Stress incontinence surgeries are predicted to increase from an estimated 211,000 in 2010 to 310,000 in 2050. Similarly, surgeries for pelvic floor prolapse are predicted to increase from 166,000 this year to 246,000 in 2050.

Dr. Wu of Duke University, Durham, N.C., and her colleagues used three sources of data in making their forecast. The U.S. Census Bureau provided estimates of the female population in various age groups between 2006 and 2050. Data on the number of women undergoing these surgeries, broken down by age group, came from the Nationwide Inpatient Sample of 2007 and the National Survey of Ambulatory Surgery of 2006.

The largest number of surgeries occurred among women aged 40-59 years. During the survey years, 48,050 women in that age group underwent inpatient surgery and 53,790 underwent outpatient surgery for incontinence. Similarly, 49,490 women underwent inpatient surgery and 20,700 underwent outpatient surgery for prolapse.

“One out of every 10 women will undergo surgery for incontinence or prolapse in her lifetime,” Dr. Wu said. “These estimates will provide public health officials and policy makers with important information regarding the future disease burden as well as the economic impact of these procedures.”

Dr. Wu acknowledged that the projections rested on a number of assumptions. For example, the investigators assumed that surgery rates would remain constant. That assumption could be overturned by changes in the incidence of disease, advances in technology and surgical technique, or implementation of successful prevention strategies.

Disclosures: Dr. Wu stated that she had no relevant financial disclosures.

LONG BEACH, CALIF. – If present trends continue, U.S. surgeons will be performing 179,000 more incontinence and prolapse surgeries annually in 2050 than they are today.

The projected increase results primarily from an aging population, Dr. Jennifer Wu said at the annual meeting of the American Urogynecologic Society.

Stress incontinence surgeries are predicted to increase from an estimated 211,000 in 2010 to 310,000 in 2050. Similarly, surgeries for pelvic floor prolapse are predicted to increase from 166,000 this year to 246,000 in 2050.

Dr. Wu of Duke University, Durham, N.C., and her colleagues used three sources of data in making their forecast. The U.S. Census Bureau provided estimates of the female population in various age groups between 2006 and 2050. Data on the number of women undergoing these surgeries, broken down by age group, came from the Nationwide Inpatient Sample of 2007 and the National Survey of Ambulatory Surgery of 2006.

The largest number of surgeries occurred among women aged 40-59 years. During the survey years, 48,050 women in that age group underwent inpatient surgery and 53,790 underwent outpatient surgery for incontinence. Similarly, 49,490 women underwent inpatient surgery and 20,700 underwent outpatient surgery for prolapse.

“One out of every 10 women will undergo surgery for incontinence or prolapse in her lifetime,” Dr. Wu said. “These estimates will provide public health officials and policy makers with important information regarding the future disease burden as well as the economic impact of these procedures.”

Dr. Wu acknowledged that the projections rested on a number of assumptions. For example, the investigators assumed that surgery rates would remain constant. That assumption could be overturned by changes in the incidence of disease, advances in technology and surgical technique, or implementation of successful prevention strategies.

Disclosures: Dr. Wu stated that she had no relevant financial disclosures.

LONG BEACH, CALIF. – If present trends continue, U.S. surgeons will be performing 179,000 more incontinence and prolapse surgeries annually in 2050 than they are today.

The projected increase results primarily from an aging population, Dr. Jennifer Wu said at the annual meeting of the American Urogynecologic Society.

Stress incontinence surgeries are predicted to increase from an estimated 211,000 in 2010 to 310,000 in 2050. Similarly, surgeries for pelvic floor prolapse are predicted to increase from 166,000 this year to 246,000 in 2050.

Dr. Wu of Duke University, Durham, N.C., and her colleagues used three sources of data in making their forecast. The U.S. Census Bureau provided estimates of the female population in various age groups between 2006 and 2050. Data on the number of women undergoing these surgeries, broken down by age group, came from the Nationwide Inpatient Sample of 2007 and the National Survey of Ambulatory Surgery of 2006.

The largest number of surgeries occurred among women aged 40-59 years. During the survey years, 48,050 women in that age group underwent inpatient surgery and 53,790 underwent outpatient surgery for incontinence. Similarly, 49,490 women underwent inpatient surgery and 20,700 underwent outpatient surgery for prolapse.

“One out of every 10 women will undergo surgery for incontinence or prolapse in her lifetime,” Dr. Wu said. “These estimates will provide public health officials and policy makers with important information regarding the future disease burden as well as the economic impact of these procedures.”

Dr. Wu acknowledged that the projections rested on a number of assumptions. For example, the investigators assumed that surgery rates would remain constant. That assumption could be overturned by changes in the incidence of disease, advances in technology and surgical technique, or implementation of successful prevention strategies.

Disclosures: Dr. Wu stated that she had no relevant financial disclosures.

Hyponatremia, defined as a serum sodium concentration below 135 mmol/L, is one of the most frequently encountered electrolyte disorders. In 1981, Flear et al¹ reported that 15% of their hospitalized patients had plasma sodium concentrations lower than 134 mmol/L, the cutoff they were using at that time.

Hyponatremia is sometimes merely a laboratory artifact or a result of improper blood collection. If real, it can be due to excessive water intake or, most often, the inability of the kidney to excrete water coupled with continued water intake. Patients with significant underlying cardiac, hepatic, or renal dysfunction are at greatest risk of developing hyponatremia, secondary to the nonosmotic release of antidiuretic hormone (ADH). Others at risk include postoperative patients (especially menstruating women), older patients on thiazide diuretics, patients with malignant or psychiatric illness, and endurance athletes.

In this article, we review the treatment of acute and chronic hyponatremia, emphasizing the importance of basing the therapy on the severity of symptoms and taking care not to raise the serum sodium level too rapidly, which can cause neurologic dysfunction.

Guidelines for managing hyponatremia² are based mostly on retrospective studies and expert opinion, since few prospective studies have been done. Despite the paucity of evidence-based recommendations, we will attempt to incorporate findings from important human and animal studies and consensus guidelines from expert panels. We will focus initially on the critical diagnostic considerations necessary to initiate treatment.

SYMPTOMATIC VS ASYMPTOMATIC

Subsequent sections will address therapeutic approaches in two clinical settings:

Symptomatic hyponatremia, ie, with severe signs or symptoms of cerebral edema—a medical emergency; and

Asymptomatic hyponatremia, ie, without serious signs or symptoms of cerebral edema.

KEY DIAGNOSTIC STEPS WHEN STARTING TREATMENT

The treatment of hyponatremia begins by confirming a truly hypo-osmolar state, assessing its clinical significance, and determining its cause (Table 1).

The clinical and laboratory evaluations form the foundation of a proper approach to any patient with hyponatremia. The rationale behind making several important diagnostic distinctions will be discussed here briefly and then expanded on in the remaining text. The reader is referred to another review on the diagnostic evaluation of hyponatremia.³

Confirm that the patient truly has hypo-osmolar hyponatremia

The serum osmolality should be measured to confirm that it is low (ie, < 275 mOsm/kg). In addition, the arterial serum sodium concentration can be measured using a blood gas device if pseudohyponatremia (see below) is suspected. This method uses direct potentiometry and bypasses the dilutional step in the processing of venous samples.⁴

Rationale. The clinical consequences of hyponatremia are due to water moving from hypo-osmolar extracellular fluid into the relatively hyperosmolar interior of the cell. This water movement can cause progressive cerebral edema, resulting in a spectrum of signs and symptoms from headache and ataxia to seizures and coma. But significant fluid shifts and cerebral edema occur only if the extracellular fluid is hypo-osmolar relative to the intracellular fluid.

In fact, hyponatremia can occur in several situations in which the extracellular fluid is not hypo-osmolar. An increase in effective plasma osmoles (substances in the extracellular fluid that do not readily move across the plasma membrane) can cause water to move out of cells, resulting in translocational hyponatremia. This may be seen in hyperglycemia or when mannitol or contrast dye has been given. In these situations, the plasma is either isotonic or even hypertonic to the intracellular fluid, resulting in no movement of water into the cells and therefore no clinical consequences relating to the hyponatremia. Importantly, no therapy is required for the hyponatremia.

Other situations in which hyponatremia is present but not associated with true hypotonicity include states of excess protein or lipid in the blood (pseudohyponatremia). Also, if an infusion of hypotonic fluid is running, clinicians must be sure that blood samples are not drawn proximally in the same vein.

Are there significant signs or symptoms of cerebral edema?

Hyponatremia can cause brain swelling within the confined space of the skull as water shifts from the extracellular fluid into the cells. Depending on underlying risk factors (Table 2)⁵ and the severity and duration of hyponatremia (see below), this may result in signs or symptoms of cerebral edema, including visual changes, focal neurologic changes, encephalopathy, respiratory depression, and seizures. Ultimately, brain herniation can occur.

Patients need to be assessed quickly because those with serious neurologic signs or symptoms thought to be related to hyponatremia require urgent treatment with hypertonic saline to increase the serum sodium concentration, regardless of the underlying volume status, the cause of hyponatremia, or the time of onset.

 

 

Determine the duration of hyponatremia

One should try to ascertain when the hyponatremia started, as its duration is important in determining the proper pace of correction.

The brain begins to adapt to hyponatremia within minutes, and the cerebral adaptation is maximal within 2 to 3 days (Figure 1).⁶

At the onset of hyponatremia, water moves from the extracellular fluid into cells, pulled in by osmosis. The brain can decrease the net amount of water entering into the neurons (and thus regulate its volume) by increasing the flow of water from the interstitium into the cerebrospinal fluid via increased interstitial hydraulic pressure.⁷

Over the next several days, inorganic solutes (eg, potassium and sodium salts) and various organic solutes are transported out of the cells. In patients in whom this process has had time to occur, treatment of hyponatremia with hypertonic fluids raises the plasma osmolality faster than the cells can recapture the previously transported osmoles. In this situation, overly rapid correction can cause excessive loss of intracellular water, resulting in cell shrinkage and osmotic demyelination syndrome. Osmotic demyelination usually presents during treatment of hyponatremia after an initial improvement in mental status, with worsening neurologic function and various neurologic signs, including paresis and ultimately even death.⁶

In patients with acute-onset hyponatremia (ie, with onset within the past 48 hours), in whom the above cerebral adaptations have not had time to occur completely, rapid correction is unlikely to result in osmotic demyelination.

In view of the serious risk of osmotic demyelination, if the timing of development of hyponatremia cannot be determined, one should assume it is chronic (> 48 hours) and avoid rapid overcorrection (see discussion below on the rate of correction).

On the other hand, patients who have severe neurologic signs or symptoms initially need their serum sodium increased urgently to safer levels, regardless of the timing of onset (see below for suggested approach). Subsequent treatment of hyponatremia—after the serum sodium level has been raised enough to reverse neurologic symptoms—will be influenced by the duration of the hyponatremia, with careful avoidance of overly rapid correction, especially in patients with chronic hyponatremia.

Assess the patient’s volume status to determine the proper initial treatment

In patients with hypo-osmolar hyponatremia who do not need urgent therapy with hypertonic saline, the initial treatment is based on clinical and laboratory assessment of extracellular fluid volume status, including spot urine sodium measurement (Table 3).³ This will be discussed further below.

Check urine osmolality to assess for hyponatremic states in which urinary dilution is intact

Measuring urine osmolality is useful in ascertaining whether hyponatremic patients are making appropriately dilute urine (< 100 mOsm/kg). If they are, the cause of the hyponatremia may be excessive water intake, a reset osmostat, or low solute intake. In addition, patients with hypovolemic hyponatremia may have appropriately dilute urine soon after treatment with isotonic intravenous fluids.

The serum sodium concentration often returns to normal if the underlying cause is eliminated (eg, if excessive fluid intake is stopped). If there are no serious signs or symptoms, this can usually be accomplished without additional therapy with intravenous fluids or medications, thereby avoiding the risk of overcorrection.

Search for causes of rapidly correctable hyponatremia

If hyponatremia is due to one of several important underlying causes, it may reverse rapidly once the underlying cause has been eliminated (Table 4). Examples: restricting water intake in patients with psychogenic polydipsia, discontinuing thiazide diuretics, replenishing depleted fluid volume, stopping desmopressin (DDAVP), and giving glucocorticoid replacement to those who are glucocorticoid-deficient.

TREATING HYPONATREMIC PATIENTS WITH SERIOUS SIGNS OR SYMPTOMS

Patients with hypo-osmolar hyponatremia and serious signs or symptoms of cerebral edema (lethargy, respiratory depression, seizures) need rapid initial correction of the serum sodium level, as this is a true medical emergency.

Certain patients are at greater risk of developing cerebral edema from hyponatremia (Table 2).

On the other hand, patients with chronic hyponatremia are very unlikely to present with signs or symptoms of cerebral edema. In fact, in a patient with chronic hyponatremia, care must be taken to avoid overcorrection beyond that needed to reverse severe signs and symptoms. In the rare case in which a patient with chronic hyponatremia presents with signs or symptoms of cerebral edema, the hypertonic saline infusion must be stopped as soon as the signs or symptoms have resolved. Further rapid changes in serum sodium must be avoided.

During correction of hyponatremia, some patients are at particularly high risk of osmotic demyelination syndrome secondary to underlying abnormalities in cerebral osmotic regulation. These include patients with alcoholism, malnutrition, hypokalemia, and burns, and elderly women on thiazide diuretics.⁸ These patients should be monitored vigilantly for overly rapid correction during treatment.

INITIAL TREATMENT: REVERSE CEREBRAL EDEMA WITH 3% SALINE

The goal of the initial, rapid phase of correction is to reverse cerebral edema.

Patients with serious signs or symptoms should receive hypertonic (3%) saline at a rate of about 1 mL/kg/hour for the first several hours.⁸ Those with concomitant hypervolemia (as in congestive heart failure) or underlying cardiovascular disease should also receive a loop diuretic to aid in free-water excretion and to prevent volume overload from the saline infusion. This regimen usually raises the serum sodium concentration enough (usually by about 1 mmol/L/hour) to decrease cerebral edema and improve symptoms.

In patients having active seizures or showing signs of brain herniation, 3% saline can be given initially at a higher rate of about 2 to 3 mL/kg/hour over the first few hours. An alternative approach is an initial 50-mL bolus of 3% saline and an additional 200 mL given over the subsequent 4 to 6 hours.⁹

No study has compared the efficacy and safety of these approaches, and clinicians should always monitor extracellular fluid volume status, neurologic status, and serum sodium levels closely in any patient treated with hypertonic saline.

After severe signs and symptoms have resolved, 3% saline is promptly discontinued and appropriate therapy is initiated based on the patient’s volume status and underlying cause of hyponatremia (see discussion below).

 

NEXT, FIND THE APPROPRIATE RATE OF CORRECTION

After the initial serious signs or symptoms have been addressed with hypertonic saline, management should focus on limiting the rate of correction in patients with chronic hyponatremia or hyponatremia of unknown duration.

Animal studies and retrospective human studies have suggested certain guidelines on the appropriate pace and magnitude of correction during treatment of hyponatremia to avoid osmotic demyelination syndrome.²

Clinicians must not attempt to correct the serum sodium to “normal” values. Although patients with acute hyponatremia may tolerate complete correction, there is little evidence that raising the serum sodium concentration acutely by more than 5 to 8 mmol/L is advantageous. Therefore, correction should be judicious in all patients.

Appropriate rates of correction

A recent expert consensus panel suggested that the serum sodium level be raised by no more than 10 to 12 mmol/L during the first 24 hours of treatment, and by less than 18 mmol/L over 48 hours.²

Patients with chronic hyponatremia and signs or symptoms of cerebral edema should have their sodium level raised at an even slower rate—some recommend less than 10 mmol/L in the first 24 hours.¹⁰ Aggressive initial correction at the rate of 1.5 to 2 mmol/hour for the first 3 to 4 hours with 3% saline is indicated until serious symptoms (seizure, obtundation) resolve, but correction beyond 10 to 12 mmol/L in the first 24 hours should be avoided. Hypertonic saline therapy should usually be discontinued well before the serum sodium level has risen this much, to avoid a continuing rise in the sodium level after the infusion has stopped.

While hypertonic saline is being infused, serum sodium levels should be checked every 1 to 2 hours. In a study in 56 patients with severe hyponatremia (serum sodium ≤ 105 mmol/L),¹¹ no neurologic complications were observed in patients with chronic hyponatremia whose serum sodium was corrected by less than 12 mmol/L in 24 hours or by less than 18 mmol/L in 48 hours or in whom the average rate of correction to a serum sodium of 120 mmol/L was less than or equal to 0.55 mmol/L per hour.

If the serum sodium concentration has been overcorrected

Desmopressin is effective in preventing and reversing inadvertent overcorrection of hyponatremia. ¹² In one study, desmopressin lowered the sodium concentration by 2 to 9 mmol/L in 14 of 20 patients. None of the patients developed any serious adverse consequences.

In addition, intravenous water (dextrose 5%) can be given alone or in combination with desmopressin to prevent or reverse an excessive increase in serum sodium.¹³ Such therapy may be considered in patients who continue to excrete hypotonic urine and have already reached a serum sodium concentration that meets or exceeds the recommended rate or magnitude of change.

Formulas for estimating the rate of correction

Various formulas have been devised for estimating the change in serum sodium concentration during treatment of hyponatremia.¹⁴

The Adrogué-Madias formula, one of the most commonly used, gives an estimate of how much the serum sodium concentration will rise when 1 L of various intravenous fluids is given (Table 5).¹⁵ This formula also accounts for the increase in serum sodium that takes place during concomitant correction of hypokalemia with potassium. Recently, however, a retrospective study¹⁶ found that this formula underestimated the change in serum sodium in 23 (74.2%) of 31 patients with hyponatremia treated with hypertonic saline.

An alternative is the Barsoum-Levine equation, which takes into account ongoing urinary losses. Although it is more cumbersome to calculate, it may be more precise.¹⁷

Alternatively, in patients without hypovolemia, the clinician can calculate the amount of urinary excretion of free water required to achieve a specific target serum sodium and then measure hourly urinary water excretion during aquaresis induced by furosemide (Lasix).⁸ Although more physiologic, this method can be clinically cumbersome, requiring timely handling of urine specimens, accurate recording of urine output, and rapid reporting of laboratory results.

Ultimately, these methods serve only as estimates of the change in serum sodium and do not replace careful monitoring of electrolytes (every 1 to 2 hours during acute therapy) and fastidious assessment for clinical signs or symptoms of osmotic demyelination syndrome.

PATIENTS WITH HYPONATREMIA AND NO SERIOUS SIGNS OR SYMPTOMS

General approach

Hyponatremic patients without serious signs or symptoms of cerebral edema do not require urgent therapy to raise the serum sodium.

Patients with chronic asymptomatic hyponatremia are commonly encountered in clinical practice. As a result of cerebral adaptation, they can appear to have no symptoms despite serum sodium levels as low as 115 to 120 mmol/L. However, even if they have no serious signs or symptoms of cerebral edema, some patients may complain of fatigue, lethargy, nausea, gait abnormalities, and muscle cramps and have evidence of milder forms of neurocognitive impairment.¹⁸

In a recent case-control study,¹⁸ elderly patients with chronic hyponatremia (mean serum sodium concentration 126 ± 5 mmol/L) were more likely to present to the hospital with falls compared with age-matched controls. Further analysis suggested these patients had marked impairments in gait and attention, which improved in some as the serum sodium increased.

Another recent study¹⁹ reported that mild hyponatremia (mean serum sodium concentration 132 mmol/L) was independently associated with the risk of fracture, even after adjustment for known osteoporotic risk factors.

Even when there is no need for acute therapy to raise the serum sodium level, the clinician should scrutinize the medical regimen and available clinical data to rule out reversible causes of water excess. These may include ongoing administration of hypotonic fluids (eg, parenteral nutrition or dextrose 5% to “keep the vein open”) or of medications that cause inappropriate release of ADH (eg, selective serotonin reuptake inhibitors) or that impair water excretion (eg, nonsteroidal anti-inflammatory drugs). The clinician should also search for an underlying diagnosis that predisposes to water retention, such as hypothyroidism, adrenal insufficiency, congestive heart failure, or hepatic or renal failure. If hyponatremia is due to endocrine disease, correction of hypothyroidism or adrenal insufficiency should result in water excretion and improvement in the serum sodium.

If the cause of the hyponatremia is not immediately apparent, treatment can be started on the basis of assessment of the patient’s extracellular fluid volume status using clinical examination and supplementary laboratory data such as the serum uric acid concentration and urinary sodium concentration.³ Table 3 outlines general treatment options for hypoosmolar hyponatremia according to extracellular fluid volume status.

Of note, physical examination alone has poor sensitivity and specificity in assessing extracellular fluid volume status in patients with hyponatremia.^20,21 This highlights the importance of spot measurements of urine sodium and serum uric acid and, when appropriate, isotonic intravenous saline challenge to detect occult hypovolemia.

In general, patients with euvolemia are treated with fluid restriction, and patients with hypovolemia are given isotonic saline. Patients with hypervolemia can be difficult to treat, but in general they are prescribed both sodium and fluid restriction. Loop diuretics can be given to promote excretion of water and sodium. Thiazide diuretics are avoided, as they impair urinary dilution and worsen hyponatremia. Attempts should be made to optimize the treatment of the underlying hypervolemic disorder (congestive heart failure, cirrhosis, advanced renal failure). Vasopressin receptor antagonists can also be used in selected cases of hypervolemic or euvolemic hyponatremia (see discussion below).

 

 

How to prescribe fluid restriction rationally

Ideally, patients should not ingest any more fluid than they can excrete in urine and insensible losses—otherwise, the serum sodium can continue to decrease.

Water excretion can be estimated from solute intake and urine osmolarity. In theory, a 70-kg person with a typical daily solute intake of about 10 mOsm/kg and intact urinary dilution to a urine osmolarity of 50 mOsm/L can excrete up to 14 L of urine (700 mOsm/50 mOsm/L) per day. However, a patient with the syndrome of inappropriate ADH secretion (SIADH) and a fixed urine osmolality of 700 mOsm/kg would excrete a similar solute load in only 1 L of urine. Thus, any fluid intake in excess of this volume could worsen hyponatremia.

To excrete free water, urinary sodium plus urinary potassium must be less than the serum sodium concentration. In this regard, the necessary degree of fluid restriction can also be estimated made on the basis of the patient’s urinary electrolytes.²²

Increased solute intake to augment water excretion

In patients without hypervolemia, solute intake can be increased to augment water excretion. ²² This can be achieved with salt tablets or oral urea. Although urea can be effective, it is not commonly used because it is not available the United States and it has poor gastrointestinal tolerability. In patients whose nutritional intake is limited and who continue to ingest fluids (such as, for example, an elderly patient subsisting on tea and toast) every effort should be made to increase solute intake with high-protein foods or supplements.

DRUGS TO INHIBIT VASOPRESSIN

Unfortunately, patients often do not adhere to these strategies, as fluid restriction and unpalatable salt tablets or urea can become too burdensome. In such instances, pharmacologic inhibition of vasopressin-mediated water reabsorption can be considered using the following agents.

Demeclocycline (Declomycin) and lithium inhibit the kidney’s response to vasopressin. Because lithium may be nephrotoxic and has unwanted effects on the central nervous system, demeclocycline has become the preferred agent. Given in doses of 300 to 600 mg twice daily, demeclocycline promotes free water excretion, but often takes 1 to 2 weeks of therapy to begin working.

Renal failure due to demeclocycline has been reported in patients with concomitant liver disease.²³ Demeclocycline can also cause photosensitivity and is contraindicated in children and pregnant women due to abnormalities in bone and enamel formation. In addition, it can be expensive and may not be covered fully by some prescription plans.

Vasopressin receptor antagonists (‘vaptans’)

ADH, also called vasopressin, interacts with various receptor subtypes, including V1a (causing vasoconstriction, platelet aggregation, inotropic stimulation, myocardial protein synthesis), V1b (causing secretion of adrenocorticotropic hormone), and V2 (causing water reabsorption and release of von Willebrand factor and factor VIII).

Drugs that block V2 receptors in the renal tubule increase water excretion, making them attractive as therapy for some hyponatremic states (Table 6).^24,25 These drugs exert their aquaretic effect by causing a decrease in transcription and insertion of aquaporin-2 channels (“water pores”) into the apical collecting duct membrane. As a result, the water permeability of the collecting duct is decreased even in the presence of circulating ADH.

Conivaptan (Vaprisol) is a combined V1a-V2 antagonist that has been approved for the treatment of euvolemic and hypervolemic hyponatremia. Conivaptan inhibits the cytochrome P450 3A4 system and thus may interact with other drugs; therefore, its use has been limited to no more than 4 days of intravenous administration in the hospital setting. The recommended dosage is an initial 20-mg infusion over 30 minutes, followed by continuous infusions of 20 to 40 mg/day. Dosing adjustments in renal and hepatic impairment have not been well defined.

Tolvaptan (Samsca) is an oral selective V2 antagonist that has been studied in patients with euvolemic and hypervolemic hyponatremia. ²⁶ Studies have included patients with congestive heart failure, cirrhosis, and SIADH. Although tolvaptan has not been shown to reduce rates of rehospitalization or death in congestive heart failure, it improves serum sodium, overall fluid balance, and congestive symptoms.²⁷ Tolvaptan has recently been approved for the treatment of euvolemic and hypervolemic hyponatremia.

A recent study has confirmed the longterm efficacy of tolvaptan in 111 patients over a mean duration of treatment greater than 700 days.²⁸ While the clinical benefits of chronic tolvaptan therapy have yet to be clearly demonstrated, this study shows that tolvaptan therapy can result in a sustained improvement in serum sodium concentration without an unacceptable increase in adverse events.²⁹

Lixivaptan (VPA-985), another oral selective V2 receptor antagonist, is being studied in patients with euvolemic and hypervolemic hyponatremia.

Current role of vasopressin antagonists

Current studies of vasopressin antagonists in the treatment of hyponatremia are promising, though definite recommendations are needed to ensure slow, careful correction of hyponatremia. Most studies suggest that these agents provide slow, reliable increases in serum sodium. In one large study of patients with congestive heart failure, serum sodium rose by more than 12 mmol/L in 24 hours in fewer than 2% of patients.²⁶

Notably, no cases of osmotic demyelination syndrome have been reported in these studies. However, it should be noted that therapy was started in the hospital with close monitoring of serum sodium levels and discontinuation of fluid restriction; the incidence of overly rapid correction of sodium may be higher outside of carefully done clinical studies. Clinicians should adopt monitoring strategies similar to those used in these rigorous studies.

At present, there is little experience with vasopressin antagonists in hyponatremic patients with serious signs or symptoms of cerebral edema, and most clinicians still view 3% saline as the gold standard for these patients.

Vasopressin antagonists should not be used in patients with hypovolemic hyponatremia, due to concerns about V1a blockade causing hypotension and about V2 blockade producing water excretion and a worsening of the volume-depleted state.

Recent clinical trials have reported that patients often experience increased thirst while taking these agents. This highlights the need to monitor serum sodium during treatment.

These agents are expensive. Tolvaptan costs about $250 per tablet; conivaptan, which is administered intravenously, may cost a little more per treatment course.

 

THERAPY IN SPECIFIC DISEASE STATES

Patients with hyponatremia and cirrhosis

The focus of treatment remains water and salt restriction and judicious use of loop diuretics and aldosterone antagonists such as spironolactone (Aldactone).

Tolvaptan has been effective at raising the serum sodium level in patients with cirrhosis, ²⁶ while conivaptan should be avoided at present because of vasodilation from V1a receptor antagonism and its potential effects on systemic hemodynamics and risk of variceal bleeding.³⁰

As the severity of cirrhosis increases, the only effective treatment of hyponatremia is liver transplantation.

Patients with SIADH

In most cases, water restriction is the mainstay of therapy. Adequate nutritional intake should also be stressed so that enough solute is available for ongoing water excretion. Although fluid restriction is usually effective, many patients cannot adhere to the level of restriction required.

In cases in which fluid restriction is not effective on its own, demeclocyline can be used to antagonize ADH action and increase water excretion. Sodium tablets and loop diuretics can also be used, taking care to avoid hypovolemia from diuretic-induced sodium losses. The use of tolvaptan in patients with SIADH has resulted in short-term increases in serum sodium.²⁶ A recent study has suggested that this effect can be sustained with longer-term treatment,²⁸ but further studies are needed to show a complementary clinical benefit (eg, improved neurocognition) to guide the use of these costly agents in clinical practice.

Patients with diuretic-induced hyponatremia

Thiazide diuretics should be discontinued and hypovolemia and hypokalemia should be corrected with isotonic saline and potassium supplementation. As the hypokalemia is corrected and the diuretic effect and hypovolemic stimulus to ADH dissipates, water excretion can increase rapidly, resulting in a brisk change in serum sodium.

Serum sodium levels should be closely monitored during therapy to avoid overcorrection. For this reason, use of hypertonic saline should generally be avoided. Hypotonic fluid— eg, half-normal (0.45%) or quarter-normal (0.22%) saline or even desmopressin—may become necessary in the later stages of therapy to avoid overly rapid correction.

Patients with exercise-associated hyponatremia

Patients at highest risk of exercise-associated hyponatremia include those who drink too much fluid during a long-distance race, who have low body weight, who are female, who exercise longer than 4 hours, and who use nonsteroidal anti-inflammatory drugs.³¹ The cause of hyponatremia is likely multifactorial, with excessive water intake coupled with sodium losses and impaired renal excretion of water due to ADH action and impaired renal dilution. To prevent exercise-associated hyponatremia, fluid intake should be limited to 400 to 800 mL/hour, with the higher end recommended for larger athletes and hotter climates.

Consensus recommendations suggest that most patients with mild hyponatremia (serum sodium 130 to 135 mmol/L) should be treated with fluid restriction and clinical observation, as spontaneous water diuresis leads to improvement in the serum sodium level. Importantly, the reflex to provide isotonic saline infusions should be avoided unless clear signs of volume depletion are present. Intravenous saline has the potential to worsen hyponatremia in the presence of ADH. In addition, some athletes will have retained water in the gastrointestinal tract that may be mobilized after the race, resulting in worsening of hyponatremia.³²

In athletes with severe hyponatremia (serum sodium < 120 mmol/L) or symptomatic exercise-associated hyponatremia (lethargy, respiratory depression, seizures), hypertonic saline is the treatment of choice. One protocol suggests giving 100 mL of 3% saline over 10 minutes in the field, followed by prompt transportation to hospital.³³

SUMMARY POINTS

• Hyponatremia is a common electrolyte disorder that in its most severe form requires urgent therapy with hypertonic saline to correct cerebral edema.
• In patients without serious signs or symptoms of cerebral edema, recent observations suggest there may be clinically important symptomatology relating to mild neurocognitive dysfunction and an association with risk of bone fracture.
• Multiple treatment strategies are available according to the underlying extracellular fluid volume status and cause of hyponatremia. These include fluid and sodium restriction and augmentation of urinary water excretion with various nutritional and pharmacologic strategies. The most novel therapy includes antagonism of the vasopressin V2 receptor with a class of aquaretic agents known as vaptans.
• There can be serious neurologic injury associated with overly rapid correction of chronic hyponatremia or undercorrection of acute symptomatic hyponatremia.
• Clinicians must be familiar with the details of each of the treatments and have an appreciation of the importance of careful monitoring during treatment.

Hyponatremia, defined as a serum sodium concentration below 135 mmol/L, is one of the most frequently encountered electrolyte disorders. In 1981, Flear et al¹ reported that 15% of their hospitalized patients had plasma sodium concentrations lower than 134 mmol/L, the cutoff they were using at that time.

Hyponatremia is sometimes merely a laboratory artifact or a result of improper blood collection. If real, it can be due to excessive water intake or, most often, the inability of the kidney to excrete water coupled with continued water intake. Patients with significant underlying cardiac, hepatic, or renal dysfunction are at greatest risk of developing hyponatremia, secondary to the nonosmotic release of antidiuretic hormone (ADH). Others at risk include postoperative patients (especially menstruating women), older patients on thiazide diuretics, patients with malignant or psychiatric illness, and endurance athletes.

In this article, we review the treatment of acute and chronic hyponatremia, emphasizing the importance of basing the therapy on the severity of symptoms and taking care not to raise the serum sodium level too rapidly, which can cause neurologic dysfunction.

Guidelines for managing hyponatremia² are based mostly on retrospective studies and expert opinion, since few prospective studies have been done. Despite the paucity of evidence-based recommendations, we will attempt to incorporate findings from important human and animal studies and consensus guidelines from expert panels. We will focus initially on the critical diagnostic considerations necessary to initiate treatment.

SYMPTOMATIC VS ASYMPTOMATIC

Subsequent sections will address therapeutic approaches in two clinical settings:

Symptomatic hyponatremia, ie, with severe signs or symptoms of cerebral edema—a medical emergency; and

Asymptomatic hyponatremia, ie, without serious signs or symptoms of cerebral edema.

KEY DIAGNOSTIC STEPS WHEN STARTING TREATMENT

The treatment of hyponatremia begins by confirming a truly hypo-osmolar state, assessing its clinical significance, and determining its cause (Table 1).

The clinical and laboratory evaluations form the foundation of a proper approach to any patient with hyponatremia. The rationale behind making several important diagnostic distinctions will be discussed here briefly and then expanded on in the remaining text. The reader is referred to another review on the diagnostic evaluation of hyponatremia.³

Confirm that the patient truly has hypo-osmolar hyponatremia

The serum osmolality should be measured to confirm that it is low (ie, < 275 mOsm/kg). In addition, the arterial serum sodium concentration can be measured using a blood gas device if pseudohyponatremia (see below) is suspected. This method uses direct potentiometry and bypasses the dilutional step in the processing of venous samples.⁴

Rationale. The clinical consequences of hyponatremia are due to water moving from hypo-osmolar extracellular fluid into the relatively hyperosmolar interior of the cell. This water movement can cause progressive cerebral edema, resulting in a spectrum of signs and symptoms from headache and ataxia to seizures and coma. But significant fluid shifts and cerebral edema occur only if the extracellular fluid is hypo-osmolar relative to the intracellular fluid.

In fact, hyponatremia can occur in several situations in which the extracellular fluid is not hypo-osmolar. An increase in effective plasma osmoles (substances in the extracellular fluid that do not readily move across the plasma membrane) can cause water to move out of cells, resulting in translocational hyponatremia. This may be seen in hyperglycemia or when mannitol or contrast dye has been given. In these situations, the plasma is either isotonic or even hypertonic to the intracellular fluid, resulting in no movement of water into the cells and therefore no clinical consequences relating to the hyponatremia. Importantly, no therapy is required for the hyponatremia.

Other situations in which hyponatremia is present but not associated with true hypotonicity include states of excess protein or lipid in the blood (pseudohyponatremia). Also, if an infusion of hypotonic fluid is running, clinicians must be sure that blood samples are not drawn proximally in the same vein.

Are there significant signs or symptoms of cerebral edema?

Hyponatremia can cause brain swelling within the confined space of the skull as water shifts from the extracellular fluid into the cells. Depending on underlying risk factors (Table 2)⁵ and the severity and duration of hyponatremia (see below), this may result in signs or symptoms of cerebral edema, including visual changes, focal neurologic changes, encephalopathy, respiratory depression, and seizures. Ultimately, brain herniation can occur.

Patients need to be assessed quickly because those with serious neurologic signs or symptoms thought to be related to hyponatremia require urgent treatment with hypertonic saline to increase the serum sodium concentration, regardless of the underlying volume status, the cause of hyponatremia, or the time of onset.

 

 

Determine the duration of hyponatremia

One should try to ascertain when the hyponatremia started, as its duration is important in determining the proper pace of correction.

The brain begins to adapt to hyponatremia within minutes, and the cerebral adaptation is maximal within 2 to 3 days (Figure 1).⁶

At the onset of hyponatremia, water moves from the extracellular fluid into cells, pulled in by osmosis. The brain can decrease the net amount of water entering into the neurons (and thus regulate its volume) by increasing the flow of water from the interstitium into the cerebrospinal fluid via increased interstitial hydraulic pressure.⁷

Over the next several days, inorganic solutes (eg, potassium and sodium salts) and various organic solutes are transported out of the cells. In patients in whom this process has had time to occur, treatment of hyponatremia with hypertonic fluids raises the plasma osmolality faster than the cells can recapture the previously transported osmoles. In this situation, overly rapid correction can cause excessive loss of intracellular water, resulting in cell shrinkage and osmotic demyelination syndrome. Osmotic demyelination usually presents during treatment of hyponatremia after an initial improvement in mental status, with worsening neurologic function and various neurologic signs, including paresis and ultimately even death.⁶

In patients with acute-onset hyponatremia (ie, with onset within the past 48 hours), in whom the above cerebral adaptations have not had time to occur completely, rapid correction is unlikely to result in osmotic demyelination.

In view of the serious risk of osmotic demyelination, if the timing of development of hyponatremia cannot be determined, one should assume it is chronic (> 48 hours) and avoid rapid overcorrection (see discussion below on the rate of correction).

On the other hand, patients who have severe neurologic signs or symptoms initially need their serum sodium increased urgently to safer levels, regardless of the timing of onset (see below for suggested approach). Subsequent treatment of hyponatremia—after the serum sodium level has been raised enough to reverse neurologic symptoms—will be influenced by the duration of the hyponatremia, with careful avoidance of overly rapid correction, especially in patients with chronic hyponatremia.

Assess the patient’s volume status to determine the proper initial treatment

In patients with hypo-osmolar hyponatremia who do not need urgent therapy with hypertonic saline, the initial treatment is based on clinical and laboratory assessment of extracellular fluid volume status, including spot urine sodium measurement (Table 3).³ This will be discussed further below.

Check urine osmolality to assess for hyponatremic states in which urinary dilution is intact

Measuring urine osmolality is useful in ascertaining whether hyponatremic patients are making appropriately dilute urine (< 100 mOsm/kg). If they are, the cause of the hyponatremia may be excessive water intake, a reset osmostat, or low solute intake. In addition, patients with hypovolemic hyponatremia may have appropriately dilute urine soon after treatment with isotonic intravenous fluids.

The serum sodium concentration often returns to normal if the underlying cause is eliminated (eg, if excessive fluid intake is stopped). If there are no serious signs or symptoms, this can usually be accomplished without additional therapy with intravenous fluids or medications, thereby avoiding the risk of overcorrection.

Search for causes of rapidly correctable hyponatremia

If hyponatremia is due to one of several important underlying causes, it may reverse rapidly once the underlying cause has been eliminated (Table 4). Examples: restricting water intake in patients with psychogenic polydipsia, discontinuing thiazide diuretics, replenishing depleted fluid volume, stopping desmopressin (DDAVP), and giving glucocorticoid replacement to those who are glucocorticoid-deficient.

TREATING HYPONATREMIC PATIENTS WITH SERIOUS SIGNS OR SYMPTOMS

Patients with hypo-osmolar hyponatremia and serious signs or symptoms of cerebral edema (lethargy, respiratory depression, seizures) need rapid initial correction of the serum sodium level, as this is a true medical emergency.

Certain patients are at greater risk of developing cerebral edema from hyponatremia (Table 2).

On the other hand, patients with chronic hyponatremia are very unlikely to present with signs or symptoms of cerebral edema. In fact, in a patient with chronic hyponatremia, care must be taken to avoid overcorrection beyond that needed to reverse severe signs and symptoms. In the rare case in which a patient with chronic hyponatremia presents with signs or symptoms of cerebral edema, the hypertonic saline infusion must be stopped as soon as the signs or symptoms have resolved. Further rapid changes in serum sodium must be avoided.

During correction of hyponatremia, some patients are at particularly high risk of osmotic demyelination syndrome secondary to underlying abnormalities in cerebral osmotic regulation. These include patients with alcoholism, malnutrition, hypokalemia, and burns, and elderly women on thiazide diuretics.⁸ These patients should be monitored vigilantly for overly rapid correction during treatment.

INITIAL TREATMENT: REVERSE CEREBRAL EDEMA WITH 3% SALINE

The goal of the initial, rapid phase of correction is to reverse cerebral edema.

Patients with serious signs or symptoms should receive hypertonic (3%) saline at a rate of about 1 mL/kg/hour for the first several hours.⁸ Those with concomitant hypervolemia (as in congestive heart failure) or underlying cardiovascular disease should also receive a loop diuretic to aid in free-water excretion and to prevent volume overload from the saline infusion. This regimen usually raises the serum sodium concentration enough (usually by about 1 mmol/L/hour) to decrease cerebral edema and improve symptoms.

In patients having active seizures or showing signs of brain herniation, 3% saline can be given initially at a higher rate of about 2 to 3 mL/kg/hour over the first few hours. An alternative approach is an initial 50-mL bolus of 3% saline and an additional 200 mL given over the subsequent 4 to 6 hours.⁹

No study has compared the efficacy and safety of these approaches, and clinicians should always monitor extracellular fluid volume status, neurologic status, and serum sodium levels closely in any patient treated with hypertonic saline.

After severe signs and symptoms have resolved, 3% saline is promptly discontinued and appropriate therapy is initiated based on the patient’s volume status and underlying cause of hyponatremia (see discussion below).

 

NEXT, FIND THE APPROPRIATE RATE OF CORRECTION

After the initial serious signs or symptoms have been addressed with hypertonic saline, management should focus on limiting the rate of correction in patients with chronic hyponatremia or hyponatremia of unknown duration.

Animal studies and retrospective human studies have suggested certain guidelines on the appropriate pace and magnitude of correction during treatment of hyponatremia to avoid osmotic demyelination syndrome.²

Clinicians must not attempt to correct the serum sodium to “normal” values. Although patients with acute hyponatremia may tolerate complete correction, there is little evidence that raising the serum sodium concentration acutely by more than 5 to 8 mmol/L is advantageous. Therefore, correction should be judicious in all patients.

Appropriate rates of correction

A recent expert consensus panel suggested that the serum sodium level be raised by no more than 10 to 12 mmol/L during the first 24 hours of treatment, and by less than 18 mmol/L over 48 hours.²

Patients with chronic hyponatremia and signs or symptoms of cerebral edema should have their sodium level raised at an even slower rate—some recommend less than 10 mmol/L in the first 24 hours.¹⁰ Aggressive initial correction at the rate of 1.5 to 2 mmol/hour for the first 3 to 4 hours with 3% saline is indicated until serious symptoms (seizure, obtundation) resolve, but correction beyond 10 to 12 mmol/L in the first 24 hours should be avoided. Hypertonic saline therapy should usually be discontinued well before the serum sodium level has risen this much, to avoid a continuing rise in the sodium level after the infusion has stopped.

While hypertonic saline is being infused, serum sodium levels should be checked every 1 to 2 hours. In a study in 56 patients with severe hyponatremia (serum sodium ≤ 105 mmol/L),¹¹ no neurologic complications were observed in patients with chronic hyponatremia whose serum sodium was corrected by less than 12 mmol/L in 24 hours or by less than 18 mmol/L in 48 hours or in whom the average rate of correction to a serum sodium of 120 mmol/L was less than or equal to 0.55 mmol/L per hour.

If the serum sodium concentration has been overcorrected

Desmopressin is effective in preventing and reversing inadvertent overcorrection of hyponatremia. ¹² In one study, desmopressin lowered the sodium concentration by 2 to 9 mmol/L in 14 of 20 patients. None of the patients developed any serious adverse consequences.

In addition, intravenous water (dextrose 5%) can be given alone or in combination with desmopressin to prevent or reverse an excessive increase in serum sodium.¹³ Such therapy may be considered in patients who continue to excrete hypotonic urine and have already reached a serum sodium concentration that meets or exceeds the recommended rate or magnitude of change.

Formulas for estimating the rate of correction

Various formulas have been devised for estimating the change in serum sodium concentration during treatment of hyponatremia.¹⁴

The Adrogué-Madias formula, one of the most commonly used, gives an estimate of how much the serum sodium concentration will rise when 1 L of various intravenous fluids is given (Table 5).¹⁵ This formula also accounts for the increase in serum sodium that takes place during concomitant correction of hypokalemia with potassium. Recently, however, a retrospective study¹⁶ found that this formula underestimated the change in serum sodium in 23 (74.2%) of 31 patients with hyponatremia treated with hypertonic saline.

An alternative is the Barsoum-Levine equation, which takes into account ongoing urinary losses. Although it is more cumbersome to calculate, it may be more precise.¹⁷

Alternatively, in patients without hypovolemia, the clinician can calculate the amount of urinary excretion of free water required to achieve a specific target serum sodium and then measure hourly urinary water excretion during aquaresis induced by furosemide (Lasix).⁸ Although more physiologic, this method can be clinically cumbersome, requiring timely handling of urine specimens, accurate recording of urine output, and rapid reporting of laboratory results.

Ultimately, these methods serve only as estimates of the change in serum sodium and do not replace careful monitoring of electrolytes (every 1 to 2 hours during acute therapy) and fastidious assessment for clinical signs or symptoms of osmotic demyelination syndrome.

PATIENTS WITH HYPONATREMIA AND NO SERIOUS SIGNS OR SYMPTOMS

General approach

Hyponatremic patients without serious signs or symptoms of cerebral edema do not require urgent therapy to raise the serum sodium.

Patients with chronic asymptomatic hyponatremia are commonly encountered in clinical practice. As a result of cerebral adaptation, they can appear to have no symptoms despite serum sodium levels as low as 115 to 120 mmol/L. However, even if they have no serious signs or symptoms of cerebral edema, some patients may complain of fatigue, lethargy, nausea, gait abnormalities, and muscle cramps and have evidence of milder forms of neurocognitive impairment.¹⁸

In a recent case-control study,¹⁸ elderly patients with chronic hyponatremia (mean serum sodium concentration 126 ± 5 mmol/L) were more likely to present to the hospital with falls compared with age-matched controls. Further analysis suggested these patients had marked impairments in gait and attention, which improved in some as the serum sodium increased.

Another recent study¹⁹ reported that mild hyponatremia (mean serum sodium concentration 132 mmol/L) was independently associated with the risk of fracture, even after adjustment for known osteoporotic risk factors.

Even when there is no need for acute therapy to raise the serum sodium level, the clinician should scrutinize the medical regimen and available clinical data to rule out reversible causes of water excess. These may include ongoing administration of hypotonic fluids (eg, parenteral nutrition or dextrose 5% to “keep the vein open”) or of medications that cause inappropriate release of ADH (eg, selective serotonin reuptake inhibitors) or that impair water excretion (eg, nonsteroidal anti-inflammatory drugs). The clinician should also search for an underlying diagnosis that predisposes to water retention, such as hypothyroidism, adrenal insufficiency, congestive heart failure, or hepatic or renal failure. If hyponatremia is due to endocrine disease, correction of hypothyroidism or adrenal insufficiency should result in water excretion and improvement in the serum sodium.

If the cause of the hyponatremia is not immediately apparent, treatment can be started on the basis of assessment of the patient’s extracellular fluid volume status using clinical examination and supplementary laboratory data such as the serum uric acid concentration and urinary sodium concentration.³ Table 3 outlines general treatment options for hypoosmolar hyponatremia according to extracellular fluid volume status.

Of note, physical examination alone has poor sensitivity and specificity in assessing extracellular fluid volume status in patients with hyponatremia.^20,21 This highlights the importance of spot measurements of urine sodium and serum uric acid and, when appropriate, isotonic intravenous saline challenge to detect occult hypovolemia.

In general, patients with euvolemia are treated with fluid restriction, and patients with hypovolemia are given isotonic saline. Patients with hypervolemia can be difficult to treat, but in general they are prescribed both sodium and fluid restriction. Loop diuretics can be given to promote excretion of water and sodium. Thiazide diuretics are avoided, as they impair urinary dilution and worsen hyponatremia. Attempts should be made to optimize the treatment of the underlying hypervolemic disorder (congestive heart failure, cirrhosis, advanced renal failure). Vasopressin receptor antagonists can also be used in selected cases of hypervolemic or euvolemic hyponatremia (see discussion below).

 

 

How to prescribe fluid restriction rationally

Ideally, patients should not ingest any more fluid than they can excrete in urine and insensible losses—otherwise, the serum sodium can continue to decrease.

Water excretion can be estimated from solute intake and urine osmolarity. In theory, a 70-kg person with a typical daily solute intake of about 10 mOsm/kg and intact urinary dilution to a urine osmolarity of 50 mOsm/L can excrete up to 14 L of urine (700 mOsm/50 mOsm/L) per day. However, a patient with the syndrome of inappropriate ADH secretion (SIADH) and a fixed urine osmolality of 700 mOsm/kg would excrete a similar solute load in only 1 L of urine. Thus, any fluid intake in excess of this volume could worsen hyponatremia.

To excrete free water, urinary sodium plus urinary potassium must be less than the serum sodium concentration. In this regard, the necessary degree of fluid restriction can also be estimated made on the basis of the patient’s urinary electrolytes.²²

Increased solute intake to augment water excretion

In patients without hypervolemia, solute intake can be increased to augment water excretion. ²² This can be achieved with salt tablets or oral urea. Although urea can be effective, it is not commonly used because it is not available the United States and it has poor gastrointestinal tolerability. In patients whose nutritional intake is limited and who continue to ingest fluids (such as, for example, an elderly patient subsisting on tea and toast) every effort should be made to increase solute intake with high-protein foods or supplements.

DRUGS TO INHIBIT VASOPRESSIN

Unfortunately, patients often do not adhere to these strategies, as fluid restriction and unpalatable salt tablets or urea can become too burdensome. In such instances, pharmacologic inhibition of vasopressin-mediated water reabsorption can be considered using the following agents.

Demeclocycline (Declomycin) and lithium inhibit the kidney’s response to vasopressin. Because lithium may be nephrotoxic and has unwanted effects on the central nervous system, demeclocycline has become the preferred agent. Given in doses of 300 to 600 mg twice daily, demeclocycline promotes free water excretion, but often takes 1 to 2 weeks of therapy to begin working.

Renal failure due to demeclocycline has been reported in patients with concomitant liver disease.²³ Demeclocycline can also cause photosensitivity and is contraindicated in children and pregnant women due to abnormalities in bone and enamel formation. In addition, it can be expensive and may not be covered fully by some prescription plans.

Vasopressin receptor antagonists (‘vaptans’)

ADH, also called vasopressin, interacts with various receptor subtypes, including V1a (causing vasoconstriction, platelet aggregation, inotropic stimulation, myocardial protein synthesis), V1b (causing secretion of adrenocorticotropic hormone), and V2 (causing water reabsorption and release of von Willebrand factor and factor VIII).

Drugs that block V2 receptors in the renal tubule increase water excretion, making them attractive as therapy for some hyponatremic states (Table 6).^24,25 These drugs exert their aquaretic effect by causing a decrease in transcription and insertion of aquaporin-2 channels (“water pores”) into the apical collecting duct membrane. As a result, the water permeability of the collecting duct is decreased even in the presence of circulating ADH.

Conivaptan (Vaprisol) is a combined V1a-V2 antagonist that has been approved for the treatment of euvolemic and hypervolemic hyponatremia. Conivaptan inhibits the cytochrome P450 3A4 system and thus may interact with other drugs; therefore, its use has been limited to no more than 4 days of intravenous administration in the hospital setting. The recommended dosage is an initial 20-mg infusion over 30 minutes, followed by continuous infusions of 20 to 40 mg/day. Dosing adjustments in renal and hepatic impairment have not been well defined.

Tolvaptan (Samsca) is an oral selective V2 antagonist that has been studied in patients with euvolemic and hypervolemic hyponatremia. ²⁶ Studies have included patients with congestive heart failure, cirrhosis, and SIADH. Although tolvaptan has not been shown to reduce rates of rehospitalization or death in congestive heart failure, it improves serum sodium, overall fluid balance, and congestive symptoms.²⁷ Tolvaptan has recently been approved for the treatment of euvolemic and hypervolemic hyponatremia.

A recent study has confirmed the longterm efficacy of tolvaptan in 111 patients over a mean duration of treatment greater than 700 days.²⁸ While the clinical benefits of chronic tolvaptan therapy have yet to be clearly demonstrated, this study shows that tolvaptan therapy can result in a sustained improvement in serum sodium concentration without an unacceptable increase in adverse events.²⁹

Lixivaptan (VPA-985), another oral selective V2 receptor antagonist, is being studied in patients with euvolemic and hypervolemic hyponatremia.

Current role of vasopressin antagonists

Current studies of vasopressin antagonists in the treatment of hyponatremia are promising, though definite recommendations are needed to ensure slow, careful correction of hyponatremia. Most studies suggest that these agents provide slow, reliable increases in serum sodium. In one large study of patients with congestive heart failure, serum sodium rose by more than 12 mmol/L in 24 hours in fewer than 2% of patients.²⁶

Notably, no cases of osmotic demyelination syndrome have been reported in these studies. However, it should be noted that therapy was started in the hospital with close monitoring of serum sodium levels and discontinuation of fluid restriction; the incidence of overly rapid correction of sodium may be higher outside of carefully done clinical studies. Clinicians should adopt monitoring strategies similar to those used in these rigorous studies.

At present, there is little experience with vasopressin antagonists in hyponatremic patients with serious signs or symptoms of cerebral edema, and most clinicians still view 3% saline as the gold standard for these patients.

Vasopressin antagonists should not be used in patients with hypovolemic hyponatremia, due to concerns about V1a blockade causing hypotension and about V2 blockade producing water excretion and a worsening of the volume-depleted state.

Recent clinical trials have reported that patients often experience increased thirst while taking these agents. This highlights the need to monitor serum sodium during treatment.

These agents are expensive. Tolvaptan costs about $250 per tablet; conivaptan, which is administered intravenously, may cost a little more per treatment course.

 

THERAPY IN SPECIFIC DISEASE STATES

Patients with hyponatremia and cirrhosis

The focus of treatment remains water and salt restriction and judicious use of loop diuretics and aldosterone antagonists such as spironolactone (Aldactone).

Tolvaptan has been effective at raising the serum sodium level in patients with cirrhosis, ²⁶ while conivaptan should be avoided at present because of vasodilation from V1a receptor antagonism and its potential effects on systemic hemodynamics and risk of variceal bleeding.³⁰

As the severity of cirrhosis increases, the only effective treatment of hyponatremia is liver transplantation.

Patients with SIADH

In most cases, water restriction is the mainstay of therapy. Adequate nutritional intake should also be stressed so that enough solute is available for ongoing water excretion. Although fluid restriction is usually effective, many patients cannot adhere to the level of restriction required.

In cases in which fluid restriction is not effective on its own, demeclocyline can be used to antagonize ADH action and increase water excretion. Sodium tablets and loop diuretics can also be used, taking care to avoid hypovolemia from diuretic-induced sodium losses. The use of tolvaptan in patients with SIADH has resulted in short-term increases in serum sodium.²⁶ A recent study has suggested that this effect can be sustained with longer-term treatment,²⁸ but further studies are needed to show a complementary clinical benefit (eg, improved neurocognition) to guide the use of these costly agents in clinical practice.

Patients with diuretic-induced hyponatremia

Thiazide diuretics should be discontinued and hypovolemia and hypokalemia should be corrected with isotonic saline and potassium supplementation. As the hypokalemia is corrected and the diuretic effect and hypovolemic stimulus to ADH dissipates, water excretion can increase rapidly, resulting in a brisk change in serum sodium.

Serum sodium levels should be closely monitored during therapy to avoid overcorrection. For this reason, use of hypertonic saline should generally be avoided. Hypotonic fluid— eg, half-normal (0.45%) or quarter-normal (0.22%) saline or even desmopressin—may become necessary in the later stages of therapy to avoid overly rapid correction.

Patients with exercise-associated hyponatremia

Patients at highest risk of exercise-associated hyponatremia include those who drink too much fluid during a long-distance race, who have low body weight, who are female, who exercise longer than 4 hours, and who use nonsteroidal anti-inflammatory drugs.³¹ The cause of hyponatremia is likely multifactorial, with excessive water intake coupled with sodium losses and impaired renal excretion of water due to ADH action and impaired renal dilution. To prevent exercise-associated hyponatremia, fluid intake should be limited to 400 to 800 mL/hour, with the higher end recommended for larger athletes and hotter climates.

Consensus recommendations suggest that most patients with mild hyponatremia (serum sodium 130 to 135 mmol/L) should be treated with fluid restriction and clinical observation, as spontaneous water diuresis leads to improvement in the serum sodium level. Importantly, the reflex to provide isotonic saline infusions should be avoided unless clear signs of volume depletion are present. Intravenous saline has the potential to worsen hyponatremia in the presence of ADH. In addition, some athletes will have retained water in the gastrointestinal tract that may be mobilized after the race, resulting in worsening of hyponatremia.³²

In athletes with severe hyponatremia (serum sodium < 120 mmol/L) or symptomatic exercise-associated hyponatremia (lethargy, respiratory depression, seizures), hypertonic saline is the treatment of choice. One protocol suggests giving 100 mL of 3% saline over 10 minutes in the field, followed by prompt transportation to hospital.³³

SUMMARY POINTS

• Hyponatremia is a common electrolyte disorder that in its most severe form requires urgent therapy with hypertonic saline to correct cerebral edema.
• In patients without serious signs or symptoms of cerebral edema, recent observations suggest there may be clinically important symptomatology relating to mild neurocognitive dysfunction and an association with risk of bone fracture.
• Multiple treatment strategies are available according to the underlying extracellular fluid volume status and cause of hyponatremia. These include fluid and sodium restriction and augmentation of urinary water excretion with various nutritional and pharmacologic strategies. The most novel therapy includes antagonism of the vasopressin V2 receptor with a class of aquaretic agents known as vaptans.
• There can be serious neurologic injury associated with overly rapid correction of chronic hyponatremia or undercorrection of acute symptomatic hyponatremia.
• Clinicians must be familiar with the details of each of the treatments and have an appreciation of the importance of careful monitoring during treatment.

Hyponatremia, defined as a serum sodium concentration below 135 mmol/L, is one of the most frequently encountered electrolyte disorders. In 1981, Flear et al¹ reported that 15% of their hospitalized patients had plasma sodium concentrations lower than 134 mmol/L, the cutoff they were using at that time.

Hyponatremia is sometimes merely a laboratory artifact or a result of improper blood collection. If real, it can be due to excessive water intake or, most often, the inability of the kidney to excrete water coupled with continued water intake. Patients with significant underlying cardiac, hepatic, or renal dysfunction are at greatest risk of developing hyponatremia, secondary to the nonosmotic release of antidiuretic hormone (ADH). Others at risk include postoperative patients (especially menstruating women), older patients on thiazide diuretics, patients with malignant or psychiatric illness, and endurance athletes.

In this article, we review the treatment of acute and chronic hyponatremia, emphasizing the importance of basing the therapy on the severity of symptoms and taking care not to raise the serum sodium level too rapidly, which can cause neurologic dysfunction.

Guidelines for managing hyponatremia² are based mostly on retrospective studies and expert opinion, since few prospective studies have been done. Despite the paucity of evidence-based recommendations, we will attempt to incorporate findings from important human and animal studies and consensus guidelines from expert panels. We will focus initially on the critical diagnostic considerations necessary to initiate treatment.

SYMPTOMATIC VS ASYMPTOMATIC

Subsequent sections will address therapeutic approaches in two clinical settings:

Symptomatic hyponatremia, ie, with severe signs or symptoms of cerebral edema—a medical emergency; and

Asymptomatic hyponatremia, ie, without serious signs or symptoms of cerebral edema.

KEY DIAGNOSTIC STEPS WHEN STARTING TREATMENT

The treatment of hyponatremia begins by confirming a truly hypo-osmolar state, assessing its clinical significance, and determining its cause (Table 1).

The clinical and laboratory evaluations form the foundation of a proper approach to any patient with hyponatremia. The rationale behind making several important diagnostic distinctions will be discussed here briefly and then expanded on in the remaining text. The reader is referred to another review on the diagnostic evaluation of hyponatremia.³

Confirm that the patient truly has hypo-osmolar hyponatremia

The serum osmolality should be measured to confirm that it is low (ie, < 275 mOsm/kg). In addition, the arterial serum sodium concentration can be measured using a blood gas device if pseudohyponatremia (see below) is suspected. This method uses direct potentiometry and bypasses the dilutional step in the processing of venous samples.⁴

Rationale. The clinical consequences of hyponatremia are due to water moving from hypo-osmolar extracellular fluid into the relatively hyperosmolar interior of the cell. This water movement can cause progressive cerebral edema, resulting in a spectrum of signs and symptoms from headache and ataxia to seizures and coma. But significant fluid shifts and cerebral edema occur only if the extracellular fluid is hypo-osmolar relative to the intracellular fluid.

In fact, hyponatremia can occur in several situations in which the extracellular fluid is not hypo-osmolar. An increase in effective plasma osmoles (substances in the extracellular fluid that do not readily move across the plasma membrane) can cause water to move out of cells, resulting in translocational hyponatremia. This may be seen in hyperglycemia or when mannitol or contrast dye has been given. In these situations, the plasma is either isotonic or even hypertonic to the intracellular fluid, resulting in no movement of water into the cells and therefore no clinical consequences relating to the hyponatremia. Importantly, no therapy is required for the hyponatremia.

Other situations in which hyponatremia is present but not associated with true hypotonicity include states of excess protein or lipid in the blood (pseudohyponatremia). Also, if an infusion of hypotonic fluid is running, clinicians must be sure that blood samples are not drawn proximally in the same vein.

Are there significant signs or symptoms of cerebral edema?

Hyponatremia can cause brain swelling within the confined space of the skull as water shifts from the extracellular fluid into the cells. Depending on underlying risk factors (Table 2)⁵ and the severity and duration of hyponatremia (see below), this may result in signs or symptoms of cerebral edema, including visual changes, focal neurologic changes, encephalopathy, respiratory depression, and seizures. Ultimately, brain herniation can occur.

Patients need to be assessed quickly because those with serious neurologic signs or symptoms thought to be related to hyponatremia require urgent treatment with hypertonic saline to increase the serum sodium concentration, regardless of the underlying volume status, the cause of hyponatremia, or the time of onset.

 

 

Determine the duration of hyponatremia

One should try to ascertain when the hyponatremia started, as its duration is important in determining the proper pace of correction.

The brain begins to adapt to hyponatremia within minutes, and the cerebral adaptation is maximal within 2 to 3 days (Figure 1).⁶

At the onset of hyponatremia, water moves from the extracellular fluid into cells, pulled in by osmosis. The brain can decrease the net amount of water entering into the neurons (and thus regulate its volume) by increasing the flow of water from the interstitium into the cerebrospinal fluid via increased interstitial hydraulic pressure.⁷

Over the next several days, inorganic solutes (eg, potassium and sodium salts) and various organic solutes are transported out of the cells. In patients in whom this process has had time to occur, treatment of hyponatremia with hypertonic fluids raises the plasma osmolality faster than the cells can recapture the previously transported osmoles. In this situation, overly rapid correction can cause excessive loss of intracellular water, resulting in cell shrinkage and osmotic demyelination syndrome. Osmotic demyelination usually presents during treatment of hyponatremia after an initial improvement in mental status, with worsening neurologic function and various neurologic signs, including paresis and ultimately even death.⁶

In patients with acute-onset hyponatremia (ie, with onset within the past 48 hours), in whom the above cerebral adaptations have not had time to occur completely, rapid correction is unlikely to result in osmotic demyelination.

In view of the serious risk of osmotic demyelination, if the timing of development of hyponatremia cannot be determined, one should assume it is chronic (> 48 hours) and avoid rapid overcorrection (see discussion below on the rate of correction).

On the other hand, patients who have severe neurologic signs or symptoms initially need their serum sodium increased urgently to safer levels, regardless of the timing of onset (see below for suggested approach). Subsequent treatment of hyponatremia—after the serum sodium level has been raised enough to reverse neurologic symptoms—will be influenced by the duration of the hyponatremia, with careful avoidance of overly rapid correction, especially in patients with chronic hyponatremia.

Assess the patient’s volume status to determine the proper initial treatment

In patients with hypo-osmolar hyponatremia who do not need urgent therapy with hypertonic saline, the initial treatment is based on clinical and laboratory assessment of extracellular fluid volume status, including spot urine sodium measurement (Table 3).³ This will be discussed further below.

Check urine osmolality to assess for hyponatremic states in which urinary dilution is intact

Measuring urine osmolality is useful in ascertaining whether hyponatremic patients are making appropriately dilute urine (< 100 mOsm/kg). If they are, the cause of the hyponatremia may be excessive water intake, a reset osmostat, or low solute intake. In addition, patients with hypovolemic hyponatremia may have appropriately dilute urine soon after treatment with isotonic intravenous fluids.

The serum sodium concentration often returns to normal if the underlying cause is eliminated (eg, if excessive fluid intake is stopped). If there are no serious signs or symptoms, this can usually be accomplished without additional therapy with intravenous fluids or medications, thereby avoiding the risk of overcorrection.

Search for causes of rapidly correctable hyponatremia

If hyponatremia is due to one of several important underlying causes, it may reverse rapidly once the underlying cause has been eliminated (Table 4). Examples: restricting water intake in patients with psychogenic polydipsia, discontinuing thiazide diuretics, replenishing depleted fluid volume, stopping desmopressin (DDAVP), and giving glucocorticoid replacement to those who are glucocorticoid-deficient.

TREATING HYPONATREMIC PATIENTS WITH SERIOUS SIGNS OR SYMPTOMS

Patients with hypo-osmolar hyponatremia and serious signs or symptoms of cerebral edema (lethargy, respiratory depression, seizures) need rapid initial correction of the serum sodium level, as this is a true medical emergency.

Certain patients are at greater risk of developing cerebral edema from hyponatremia (Table 2).

On the other hand, patients with chronic hyponatremia are very unlikely to present with signs or symptoms of cerebral edema. In fact, in a patient with chronic hyponatremia, care must be taken to avoid overcorrection beyond that needed to reverse severe signs and symptoms. In the rare case in which a patient with chronic hyponatremia presents with signs or symptoms of cerebral edema, the hypertonic saline infusion must be stopped as soon as the signs or symptoms have resolved. Further rapid changes in serum sodium must be avoided.

During correction of hyponatremia, some patients are at particularly high risk of osmotic demyelination syndrome secondary to underlying abnormalities in cerebral osmotic regulation. These include patients with alcoholism, malnutrition, hypokalemia, and burns, and elderly women on thiazide diuretics.⁸ These patients should be monitored vigilantly for overly rapid correction during treatment.

INITIAL TREATMENT: REVERSE CEREBRAL EDEMA WITH 3% SALINE

The goal of the initial, rapid phase of correction is to reverse cerebral edema.

Patients with serious signs or symptoms should receive hypertonic (3%) saline at a rate of about 1 mL/kg/hour for the first several hours.⁸ Those with concomitant hypervolemia (as in congestive heart failure) or underlying cardiovascular disease should also receive a loop diuretic to aid in free-water excretion and to prevent volume overload from the saline infusion. This regimen usually raises the serum sodium concentration enough (usually by about 1 mmol/L/hour) to decrease cerebral edema and improve symptoms.

In patients having active seizures or showing signs of brain herniation, 3% saline can be given initially at a higher rate of about 2 to 3 mL/kg/hour over the first few hours. An alternative approach is an initial 50-mL bolus of 3% saline and an additional 200 mL given over the subsequent 4 to 6 hours.⁹

No study has compared the efficacy and safety of these approaches, and clinicians should always monitor extracellular fluid volume status, neurologic status, and serum sodium levels closely in any patient treated with hypertonic saline.

After severe signs and symptoms have resolved, 3% saline is promptly discontinued and appropriate therapy is initiated based on the patient’s volume status and underlying cause of hyponatremia (see discussion below).

 

NEXT, FIND THE APPROPRIATE RATE OF CORRECTION

After the initial serious signs or symptoms have been addressed with hypertonic saline, management should focus on limiting the rate of correction in patients with chronic hyponatremia or hyponatremia of unknown duration.

Animal studies and retrospective human studies have suggested certain guidelines on the appropriate pace and magnitude of correction during treatment of hyponatremia to avoid osmotic demyelination syndrome.²

Clinicians must not attempt to correct the serum sodium to “normal” values. Although patients with acute hyponatremia may tolerate complete correction, there is little evidence that raising the serum sodium concentration acutely by more than 5 to 8 mmol/L is advantageous. Therefore, correction should be judicious in all patients.

Appropriate rates of correction

A recent expert consensus panel suggested that the serum sodium level be raised by no more than 10 to 12 mmol/L during the first 24 hours of treatment, and by less than 18 mmol/L over 48 hours.²

Patients with chronic hyponatremia and signs or symptoms of cerebral edema should have their sodium level raised at an even slower rate—some recommend less than 10 mmol/L in the first 24 hours.¹⁰ Aggressive initial correction at the rate of 1.5 to 2 mmol/hour for the first 3 to 4 hours with 3% saline is indicated until serious symptoms (seizure, obtundation) resolve, but correction beyond 10 to 12 mmol/L in the first 24 hours should be avoided. Hypertonic saline therapy should usually be discontinued well before the serum sodium level has risen this much, to avoid a continuing rise in the sodium level after the infusion has stopped.

While hypertonic saline is being infused, serum sodium levels should be checked every 1 to 2 hours. In a study in 56 patients with severe hyponatremia (serum sodium ≤ 105 mmol/L),¹¹ no neurologic complications were observed in patients with chronic hyponatremia whose serum sodium was corrected by less than 12 mmol/L in 24 hours or by less than 18 mmol/L in 48 hours or in whom the average rate of correction to a serum sodium of 120 mmol/L was less than or equal to 0.55 mmol/L per hour.

If the serum sodium concentration has been overcorrected

Desmopressin is effective in preventing and reversing inadvertent overcorrection of hyponatremia. ¹² In one study, desmopressin lowered the sodium concentration by 2 to 9 mmol/L in 14 of 20 patients. None of the patients developed any serious adverse consequences.

In addition, intravenous water (dextrose 5%) can be given alone or in combination with desmopressin to prevent or reverse an excessive increase in serum sodium.¹³ Such therapy may be considered in patients who continue to excrete hypotonic urine and have already reached a serum sodium concentration that meets or exceeds the recommended rate or magnitude of change.

Formulas for estimating the rate of correction

Various formulas have been devised for estimating the change in serum sodium concentration during treatment of hyponatremia.¹⁴

The Adrogué-Madias formula, one of the most commonly used, gives an estimate of how much the serum sodium concentration will rise when 1 L of various intravenous fluids is given (Table 5).¹⁵ This formula also accounts for the increase in serum sodium that takes place during concomitant correction of hypokalemia with potassium. Recently, however, a retrospective study¹⁶ found that this formula underestimated the change in serum sodium in 23 (74.2%) of 31 patients with hyponatremia treated with hypertonic saline.

An alternative is the Barsoum-Levine equation, which takes into account ongoing urinary losses. Although it is more cumbersome to calculate, it may be more precise.¹⁷

Alternatively, in patients without hypovolemia, the clinician can calculate the amount of urinary excretion of free water required to achieve a specific target serum sodium and then measure hourly urinary water excretion during aquaresis induced by furosemide (Lasix).⁸ Although more physiologic, this method can be clinically cumbersome, requiring timely handling of urine specimens, accurate recording of urine output, and rapid reporting of laboratory results.

Ultimately, these methods serve only as estimates of the change in serum sodium and do not replace careful monitoring of electrolytes (every 1 to 2 hours during acute therapy) and fastidious assessment for clinical signs or symptoms of osmotic demyelination syndrome.

PATIENTS WITH HYPONATREMIA AND NO SERIOUS SIGNS OR SYMPTOMS

General approach

Hyponatremic patients without serious signs or symptoms of cerebral edema do not require urgent therapy to raise the serum sodium.

Patients with chronic asymptomatic hyponatremia are commonly encountered in clinical practice. As a result of cerebral adaptation, they can appear to have no symptoms despite serum sodium levels as low as 115 to 120 mmol/L. However, even if they have no serious signs or symptoms of cerebral edema, some patients may complain of fatigue, lethargy, nausea, gait abnormalities, and muscle cramps and have evidence of milder forms of neurocognitive impairment.¹⁸

In a recent case-control study,¹⁸ elderly patients with chronic hyponatremia (mean serum sodium concentration 126 ± 5 mmol/L) were more likely to present to the hospital with falls compared with age-matched controls. Further analysis suggested these patients had marked impairments in gait and attention, which improved in some as the serum sodium increased.

Another recent study¹⁹ reported that mild hyponatremia (mean serum sodium concentration 132 mmol/L) was independently associated with the risk of fracture, even after adjustment for known osteoporotic risk factors.

Even when there is no need for acute therapy to raise the serum sodium level, the clinician should scrutinize the medical regimen and available clinical data to rule out reversible causes of water excess. These may include ongoing administration of hypotonic fluids (eg, parenteral nutrition or dextrose 5% to “keep the vein open”) or of medications that cause inappropriate release of ADH (eg, selective serotonin reuptake inhibitors) or that impair water excretion (eg, nonsteroidal anti-inflammatory drugs). The clinician should also search for an underlying diagnosis that predisposes to water retention, such as hypothyroidism, adrenal insufficiency, congestive heart failure, or hepatic or renal failure. If hyponatremia is due to endocrine disease, correction of hypothyroidism or adrenal insufficiency should result in water excretion and improvement in the serum sodium.

If the cause of the hyponatremia is not immediately apparent, treatment can be started on the basis of assessment of the patient’s extracellular fluid volume status using clinical examination and supplementary laboratory data such as the serum uric acid concentration and urinary sodium concentration.³ Table 3 outlines general treatment options for hypoosmolar hyponatremia according to extracellular fluid volume status.

Of note, physical examination alone has poor sensitivity and specificity in assessing extracellular fluid volume status in patients with hyponatremia.^20,21 This highlights the importance of spot measurements of urine sodium and serum uric acid and, when appropriate, isotonic intravenous saline challenge to detect occult hypovolemia.

In general, patients with euvolemia are treated with fluid restriction, and patients with hypovolemia are given isotonic saline. Patients with hypervolemia can be difficult to treat, but in general they are prescribed both sodium and fluid restriction. Loop diuretics can be given to promote excretion of water and sodium. Thiazide diuretics are avoided, as they impair urinary dilution and worsen hyponatremia. Attempts should be made to optimize the treatment of the underlying hypervolemic disorder (congestive heart failure, cirrhosis, advanced renal failure). Vasopressin receptor antagonists can also be used in selected cases of hypervolemic or euvolemic hyponatremia (see discussion below).

 

 

How to prescribe fluid restriction rationally

Ideally, patients should not ingest any more fluid than they can excrete in urine and insensible losses—otherwise, the serum sodium can continue to decrease.

Water excretion can be estimated from solute intake and urine osmolarity. In theory, a 70-kg person with a typical daily solute intake of about 10 mOsm/kg and intact urinary dilution to a urine osmolarity of 50 mOsm/L can excrete up to 14 L of urine (700 mOsm/50 mOsm/L) per day. However, a patient with the syndrome of inappropriate ADH secretion (SIADH) and a fixed urine osmolality of 700 mOsm/kg would excrete a similar solute load in only 1 L of urine. Thus, any fluid intake in excess of this volume could worsen hyponatremia.

To excrete free water, urinary sodium plus urinary potassium must be less than the serum sodium concentration. In this regard, the necessary degree of fluid restriction can also be estimated made on the basis of the patient’s urinary electrolytes.²²

Increased solute intake to augment water excretion

In patients without hypervolemia, solute intake can be increased to augment water excretion. ²² This can be achieved with salt tablets or oral urea. Although urea can be effective, it is not commonly used because it is not available the United States and it has poor gastrointestinal tolerability. In patients whose nutritional intake is limited and who continue to ingest fluids (such as, for example, an elderly patient subsisting on tea and toast) every effort should be made to increase solute intake with high-protein foods or supplements.

DRUGS TO INHIBIT VASOPRESSIN

Unfortunately, patients often do not adhere to these strategies, as fluid restriction and unpalatable salt tablets or urea can become too burdensome. In such instances, pharmacologic inhibition of vasopressin-mediated water reabsorption can be considered using the following agents.

Demeclocycline (Declomycin) and lithium inhibit the kidney’s response to vasopressin. Because lithium may be nephrotoxic and has unwanted effects on the central nervous system, demeclocycline has become the preferred agent. Given in doses of 300 to 600 mg twice daily, demeclocycline promotes free water excretion, but often takes 1 to 2 weeks of therapy to begin working.

Renal failure due to demeclocycline has been reported in patients with concomitant liver disease.²³ Demeclocycline can also cause photosensitivity and is contraindicated in children and pregnant women due to abnormalities in bone and enamel formation. In addition, it can be expensive and may not be covered fully by some prescription plans.

Vasopressin receptor antagonists (‘vaptans’)

ADH, also called vasopressin, interacts with various receptor subtypes, including V1a (causing vasoconstriction, platelet aggregation, inotropic stimulation, myocardial protein synthesis), V1b (causing secretion of adrenocorticotropic hormone), and V2 (causing water reabsorption and release of von Willebrand factor and factor VIII).

Drugs that block V2 receptors in the renal tubule increase water excretion, making them attractive as therapy for some hyponatremic states (Table 6).^24,25 These drugs exert their aquaretic effect by causing a decrease in transcription and insertion of aquaporin-2 channels (“water pores”) into the apical collecting duct membrane. As a result, the water permeability of the collecting duct is decreased even in the presence of circulating ADH.

Conivaptan (Vaprisol) is a combined V1a-V2 antagonist that has been approved for the treatment of euvolemic and hypervolemic hyponatremia. Conivaptan inhibits the cytochrome P450 3A4 system and thus may interact with other drugs; therefore, its use has been limited to no more than 4 days of intravenous administration in the hospital setting. The recommended dosage is an initial 20-mg infusion over 30 minutes, followed by continuous infusions of 20 to 40 mg/day. Dosing adjustments in renal and hepatic impairment have not been well defined.

Tolvaptan (Samsca) is an oral selective V2 antagonist that has been studied in patients with euvolemic and hypervolemic hyponatremia. ²⁶ Studies have included patients with congestive heart failure, cirrhosis, and SIADH. Although tolvaptan has not been shown to reduce rates of rehospitalization or death in congestive heart failure, it improves serum sodium, overall fluid balance, and congestive symptoms.²⁷ Tolvaptan has recently been approved for the treatment of euvolemic and hypervolemic hyponatremia.

A recent study has confirmed the longterm efficacy of tolvaptan in 111 patients over a mean duration of treatment greater than 700 days.²⁸ While the clinical benefits of chronic tolvaptan therapy have yet to be clearly demonstrated, this study shows that tolvaptan therapy can result in a sustained improvement in serum sodium concentration without an unacceptable increase in adverse events.²⁹

Lixivaptan (VPA-985), another oral selective V2 receptor antagonist, is being studied in patients with euvolemic and hypervolemic hyponatremia.

Current role of vasopressin antagonists

Current studies of vasopressin antagonists in the treatment of hyponatremia are promising, though definite recommendations are needed to ensure slow, careful correction of hyponatremia. Most studies suggest that these agents provide slow, reliable increases in serum sodium. In one large study of patients with congestive heart failure, serum sodium rose by more than 12 mmol/L in 24 hours in fewer than 2% of patients.²⁶

Notably, no cases of osmotic demyelination syndrome have been reported in these studies. However, it should be noted that therapy was started in the hospital with close monitoring of serum sodium levels and discontinuation of fluid restriction; the incidence of overly rapid correction of sodium may be higher outside of carefully done clinical studies. Clinicians should adopt monitoring strategies similar to those used in these rigorous studies.

At present, there is little experience with vasopressin antagonists in hyponatremic patients with serious signs or symptoms of cerebral edema, and most clinicians still view 3% saline as the gold standard for these patients.

Vasopressin antagonists should not be used in patients with hypovolemic hyponatremia, due to concerns about V1a blockade causing hypotension and about V2 blockade producing water excretion and a worsening of the volume-depleted state.

Recent clinical trials have reported that patients often experience increased thirst while taking these agents. This highlights the need to monitor serum sodium during treatment.

These agents are expensive. Tolvaptan costs about $250 per tablet; conivaptan, which is administered intravenously, may cost a little more per treatment course.

 

THERAPY IN SPECIFIC DISEASE STATES

Patients with hyponatremia and cirrhosis

The focus of treatment remains water and salt restriction and judicious use of loop diuretics and aldosterone antagonists such as spironolactone (Aldactone).

Tolvaptan has been effective at raising the serum sodium level in patients with cirrhosis, ²⁶ while conivaptan should be avoided at present because of vasodilation from V1a receptor antagonism and its potential effects on systemic hemodynamics and risk of variceal bleeding.³⁰

As the severity of cirrhosis increases, the only effective treatment of hyponatremia is liver transplantation.

Patients with SIADH

In most cases, water restriction is the mainstay of therapy. Adequate nutritional intake should also be stressed so that enough solute is available for ongoing water excretion. Although fluid restriction is usually effective, many patients cannot adhere to the level of restriction required.

In cases in which fluid restriction is not effective on its own, demeclocyline can be used to antagonize ADH action and increase water excretion. Sodium tablets and loop diuretics can also be used, taking care to avoid hypovolemia from diuretic-induced sodium losses. The use of tolvaptan in patients with SIADH has resulted in short-term increases in serum sodium.²⁶ A recent study has suggested that this effect can be sustained with longer-term treatment,²⁸ but further studies are needed to show a complementary clinical benefit (eg, improved neurocognition) to guide the use of these costly agents in clinical practice.

Patients with diuretic-induced hyponatremia

Thiazide diuretics should be discontinued and hypovolemia and hypokalemia should be corrected with isotonic saline and potassium supplementation. As the hypokalemia is corrected and the diuretic effect and hypovolemic stimulus to ADH dissipates, water excretion can increase rapidly, resulting in a brisk change in serum sodium.

Serum sodium levels should be closely monitored during therapy to avoid overcorrection. For this reason, use of hypertonic saline should generally be avoided. Hypotonic fluid— eg, half-normal (0.45%) or quarter-normal (0.22%) saline or even desmopressin—may become necessary in the later stages of therapy to avoid overly rapid correction.

Patients with exercise-associated hyponatremia

Patients at highest risk of exercise-associated hyponatremia include those who drink too much fluid during a long-distance race, who have low body weight, who are female, who exercise longer than 4 hours, and who use nonsteroidal anti-inflammatory drugs.³¹ The cause of hyponatremia is likely multifactorial, with excessive water intake coupled with sodium losses and impaired renal excretion of water due to ADH action and impaired renal dilution. To prevent exercise-associated hyponatremia, fluid intake should be limited to 400 to 800 mL/hour, with the higher end recommended for larger athletes and hotter climates.

Consensus recommendations suggest that most patients with mild hyponatremia (serum sodium 130 to 135 mmol/L) should be treated with fluid restriction and clinical observation, as spontaneous water diuresis leads to improvement in the serum sodium level. Importantly, the reflex to provide isotonic saline infusions should be avoided unless clear signs of volume depletion are present. Intravenous saline has the potential to worsen hyponatremia in the presence of ADH. In addition, some athletes will have retained water in the gastrointestinal tract that may be mobilized after the race, resulting in worsening of hyponatremia.³²

In athletes with severe hyponatremia (serum sodium < 120 mmol/L) or symptomatic exercise-associated hyponatremia (lethargy, respiratory depression, seizures), hypertonic saline is the treatment of choice. One protocol suggests giving 100 mL of 3% saline over 10 minutes in the field, followed by prompt transportation to hospital.³³

SUMMARY POINTS

• Hyponatremia is a common electrolyte disorder that in its most severe form requires urgent therapy with hypertonic saline to correct cerebral edema.
• In patients without serious signs or symptoms of cerebral edema, recent observations suggest there may be clinically important symptomatology relating to mild neurocognitive dysfunction and an association with risk of bone fracture.
• Multiple treatment strategies are available according to the underlying extracellular fluid volume status and cause of hyponatremia. These include fluid and sodium restriction and augmentation of urinary water excretion with various nutritional and pharmacologic strategies. The most novel therapy includes antagonism of the vasopressin V2 receptor with a class of aquaretic agents known as vaptans.
• There can be serious neurologic injury associated with overly rapid correction of chronic hyponatremia or undercorrection of acute symptomatic hyponatremia.
• Clinicians must be familiar with the details of each of the treatments and have an appreciation of the importance of careful monitoring during treatment.

ST. LOUIS – Treatment of urinary incontinence by means of a pubic bone stabilization sling – a suburethral sling that is anchored to the pubic bone using titanium screws – is highly effective and is not associated with an increased risk of osteomyelitis, according to findings from the largest prospective observational study to date.

Although concerns that the procedure could cause osseous complications have been circulating for years and have discouraged some surgeons from using the pubic bone stabilization sling, only 1 case occurred in the 2,331 patients in the study, for an incidence of 0.000043%, Dr. S. Robert Kovac reported at the 19th International Pelvic Reconstructive and Vaginal Surgery Conference, which was sponsored by the Society of Pelvic Reconstructive Surgeons.

Patients were treated for intrinsic sphincter dysfunction (ISD) and/or stress urinary incontinence (SUI), and were followed for a mean of 13 years, and up to 17 years at four different institutions, said Dr. Kovac, the John D. Thompson Distinguished Professor of Gynecologic Surgery and director of the center for pelvic reconstructive surgery and urogynecology at Emory University, Atlanta. His associates are Dr. P.D. Dietz, Dr. M. Muniz, and Dr. S.H. Cruikshank.

Follow-up was done by exams, questionnaires, and telephone conversations.

The cure rate for those with ISD and/or SUI who had total dryness was 92%.

In a prospective study published in 2004, the incidence of osteomyelitis was 0.08% in 1,228 patients who underwent transvaginal bone anchor fixation in female pelvic reconstructive surgery, Dr. Kovac noted (Urology 2004; 64:669-74).

By comparison, abdominal sacrocolpopexy is associated with an osteomyelitis incidence of 11%, according to reports in the literature, Dr. Kovac said.

“I think we got off on the wrong track,” he said of the unfounded fears regarding osteomyelitis in patients undergoing pubic bone stabilization (PBS) sling procedures.

Dr. Kovac, who developed the PBS sling procedure more than 20 years ago, said that more than 350,000 have been performed worldwide, and that in all that time he hasn’t seen a single case of osteomyelitis or osteitis pubis in any of his patients who underwent the procedure.

Furthermore, the PBS sling has the lowest complication rate and the best long-term outcomes of the various suburethral slings currently used for urinary incontinence, he said.

Currently, the procedure is performed transvaginally by placing a suburethral sling of Biodesign Surgisis over the midurethra, and securing it with titanium bone screws to the posterior-inferior pubis to restore proper anatomy for continence.

In addition to the high cure rate and low complication rate, the approach has several other advantages, Dr. Kovac said, including the following:

• It is a totally vaginal, unified approach; all defects can be treated during one procedure.

• There is efficacy for both urethral hypermobility and ISD-related SUI.

• It functions as a retropubic procedure, a vaginal Marshall-Marchetti-Krantz (MMK) operation without the need for an abdominal incision.

• It is easy to learn and teach.

• There is low or no pain.

• There is rapid return to normal voiding postoperatively.

• There is no need for blindly placed trocars.

• Surgical time is less than 30 minutes.

• There is no need for mesh, so there are no mesh-related complications.

• There is no voiding dysfunction; it is truly tension free.

The procedure also has little reliance on cystoscopy, although Dr. Kovac said that he recommends cystoscoping all patients to avoid potential bladder-related hazards.

Dr. Kovac disclosed that he is a consultant for Cook Medical Inc. and Ethicon-Endo Surgery Inc., but he sold his patent on the PBS sling to American Medical Systems and has no financial interest in the procedure.

ST. LOUIS – Treatment of urinary incontinence by means of a pubic bone stabilization sling – a suburethral sling that is anchored to the pubic bone using titanium screws – is highly effective and is not associated with an increased risk of osteomyelitis, according to findings from the largest prospective observational study to date.

Although concerns that the procedure could cause osseous complications have been circulating for years and have discouraged some surgeons from using the pubic bone stabilization sling, only 1 case occurred in the 2,331 patients in the study, for an incidence of 0.000043%, Dr. S. Robert Kovac reported at the 19th International Pelvic Reconstructive and Vaginal Surgery Conference, which was sponsored by the Society of Pelvic Reconstructive Surgeons.

Patients were treated for intrinsic sphincter dysfunction (ISD) and/or stress urinary incontinence (SUI), and were followed for a mean of 13 years, and up to 17 years at four different institutions, said Dr. Kovac, the John D. Thompson Distinguished Professor of Gynecologic Surgery and director of the center for pelvic reconstructive surgery and urogynecology at Emory University, Atlanta. His associates are Dr. P.D. Dietz, Dr. M. Muniz, and Dr. S.H. Cruikshank.

Follow-up was done by exams, questionnaires, and telephone conversations.

The cure rate for those with ISD and/or SUI who had total dryness was 92%.

In a prospective study published in 2004, the incidence of osteomyelitis was 0.08% in 1,228 patients who underwent transvaginal bone anchor fixation in female pelvic reconstructive surgery, Dr. Kovac noted (Urology 2004; 64:669-74).

By comparison, abdominal sacrocolpopexy is associated with an osteomyelitis incidence of 11%, according to reports in the literature, Dr. Kovac said.

“I think we got off on the wrong track,” he said of the unfounded fears regarding osteomyelitis in patients undergoing pubic bone stabilization (PBS) sling procedures.

Dr. Kovac, who developed the PBS sling procedure more than 20 years ago, said that more than 350,000 have been performed worldwide, and that in all that time he hasn’t seen a single case of osteomyelitis or osteitis pubis in any of his patients who underwent the procedure.

Furthermore, the PBS sling has the lowest complication rate and the best long-term outcomes of the various suburethral slings currently used for urinary incontinence, he said.

Currently, the procedure is performed transvaginally by placing a suburethral sling of Biodesign Surgisis over the midurethra, and securing it with titanium bone screws to the posterior-inferior pubis to restore proper anatomy for continence.

In addition to the high cure rate and low complication rate, the approach has several other advantages, Dr. Kovac said, including the following:

• It is a totally vaginal, unified approach; all defects can be treated during one procedure.

• There is efficacy for both urethral hypermobility and ISD-related SUI.

• It functions as a retropubic procedure, a vaginal Marshall-Marchetti-Krantz (MMK) operation without the need for an abdominal incision.

• It is easy to learn and teach.

• There is low or no pain.

• There is rapid return to normal voiding postoperatively.

• There is no need for blindly placed trocars.

• Surgical time is less than 30 minutes.

• There is no need for mesh, so there are no mesh-related complications.

• There is no voiding dysfunction; it is truly tension free.

The procedure also has little reliance on cystoscopy, although Dr. Kovac said that he recommends cystoscoping all patients to avoid potential bladder-related hazards.

Dr. Kovac disclosed that he is a consultant for Cook Medical Inc. and Ethicon-Endo Surgery Inc., but he sold his patent on the PBS sling to American Medical Systems and has no financial interest in the procedure.

ST. LOUIS – Treatment of urinary incontinence by means of a pubic bone stabilization sling – a suburethral sling that is anchored to the pubic bone using titanium screws – is highly effective and is not associated with an increased risk of osteomyelitis, according to findings from the largest prospective observational study to date.

Although concerns that the procedure could cause osseous complications have been circulating for years and have discouraged some surgeons from using the pubic bone stabilization sling, only 1 case occurred in the 2,331 patients in the study, for an incidence of 0.000043%, Dr. S. Robert Kovac reported at the 19th International Pelvic Reconstructive and Vaginal Surgery Conference, which was sponsored by the Society of Pelvic Reconstructive Surgeons.

Patients were treated for intrinsic sphincter dysfunction (ISD) and/or stress urinary incontinence (SUI), and were followed for a mean of 13 years, and up to 17 years at four different institutions, said Dr. Kovac, the John D. Thompson Distinguished Professor of Gynecologic Surgery and director of the center for pelvic reconstructive surgery and urogynecology at Emory University, Atlanta. His associates are Dr. P.D. Dietz, Dr. M. Muniz, and Dr. S.H. Cruikshank.

Follow-up was done by exams, questionnaires, and telephone conversations.

The cure rate for those with ISD and/or SUI who had total dryness was 92%.

In a prospective study published in 2004, the incidence of osteomyelitis was 0.08% in 1,228 patients who underwent transvaginal bone anchor fixation in female pelvic reconstructive surgery, Dr. Kovac noted (Urology 2004; 64:669-74).

By comparison, abdominal sacrocolpopexy is associated with an osteomyelitis incidence of 11%, according to reports in the literature, Dr. Kovac said.

“I think we got off on the wrong track,” he said of the unfounded fears regarding osteomyelitis in patients undergoing pubic bone stabilization (PBS) sling procedures.

Dr. Kovac, who developed the PBS sling procedure more than 20 years ago, said that more than 350,000 have been performed worldwide, and that in all that time he hasn’t seen a single case of osteomyelitis or osteitis pubis in any of his patients who underwent the procedure.

Furthermore, the PBS sling has the lowest complication rate and the best long-term outcomes of the various suburethral slings currently used for urinary incontinence, he said.

Currently, the procedure is performed transvaginally by placing a suburethral sling of Biodesign Surgisis over the midurethra, and securing it with titanium bone screws to the posterior-inferior pubis to restore proper anatomy for continence.

In addition to the high cure rate and low complication rate, the approach has several other advantages, Dr. Kovac said, including the following:

• It is a totally vaginal, unified approach; all defects can be treated during one procedure.

• There is efficacy for both urethral hypermobility and ISD-related SUI.

• It functions as a retropubic procedure, a vaginal Marshall-Marchetti-Krantz (MMK) operation without the need for an abdominal incision.

• It is easy to learn and teach.

• There is low or no pain.

• There is rapid return to normal voiding postoperatively.

• There is no need for blindly placed trocars.

• Surgical time is less than 30 minutes.

• There is no need for mesh, so there are no mesh-related complications.

• There is no voiding dysfunction; it is truly tension free.

The procedure also has little reliance on cystoscopy, although Dr. Kovac said that he recommends cystoscoping all patients to avoid potential bladder-related hazards.

Dr. Kovac disclosed that he is a consultant for Cook Medical Inc. and Ethicon-Endo Surgery Inc., but he sold his patent on the PBS sling to American Medical Systems and has no financial interest in the procedure.

The Food and Drug Administration on Sept. 9 required manufacturers of five gadolinium contrast agents to strengthen boxed warnings on their products to minimize the risk of nephrogenic systemic fibrosis in some patients with kidney dysfunction.

Three of the agents – Magnevist (gadopentetate dimeglumine), Omniscan (gadodiamide), and Optimark (gadoversetamide) – are now contraindicated in patients with acute kidney injury (AKI) or chronic, severe kidney disease. Severe kidney disease is marked by a glomerular filtration rate of less than 30 mL/min/1.73m².

In addition, the revised labeling recommends that healthcare professionals screen all patients being considered for any gadolinium-based contrast agent (GBCA) for AKI or chronic, severe kidney disease. GBCAs also should be avoided in patients suspected or known to have impaired drug elimination unless the diagnostic information obtained is essential and cannot be acquired without the use of a contrast agent.

It’s been known since at least 2006 that patients with AKI or chronic, severe kidney disease are at increased risk of developing nephrogenic systemic fibrosis (NSF). In 2007 the FDA issued its first boxed warning about the risk of NSF associated with GBCA use. That warning stated only that healthcare professionals should be aware of the possibility that some patients might develop NSF. The new warning adds the absolute contraindication for the use of the three agents in patients with AKI and chronic, severe kidney disease.

The earlier boxed warning appears to have had the effect of reducing the incidence of NSF, according to one FDA official. Late last year, at a joint meeting of the FDA’s Cardiovascular and Renal Drugs and Drug Safety and Risk Management advisory committees, Dr. James Kaiser of the agency’s office of surveillance and epidemiology noted that in 2006 there were 194 cases of NSF associated with GBCAs. That number decreased to 128 cases in 2007, 55 in 2008, and 6 in 2009 (through September).

While three GBCAs had been associated with numerous cases of NSF, the other two – MultiHance (gadobenate dimeglumine) and ProHance (gadoteridol) ‑ have not. As of September 2009, a total of 382 reports of NSF had been associated with Omniscan (GE HealthCare), 195 with Magnevist (Bayer HealthCare), 35 with OptiMARK (Covidien), 1 with MultiHance (Bracco Diagnostics), and 0 with ProHance (Bracco Diagnostics). At last year’s meeting a majority of advisory committee members recommended that Omniscan and OptiMARK be contraindicated in patients with serious kidney dysfunction. There was less agreement on whether Magnevist should also be contraindicated.

The Food and Drug Administration on Sept. 9 required manufacturers of five gadolinium contrast agents to strengthen boxed warnings on their products to minimize the risk of nephrogenic systemic fibrosis in some patients with kidney dysfunction.

Three of the agents – Magnevist (gadopentetate dimeglumine), Omniscan (gadodiamide), and Optimark (gadoversetamide) – are now contraindicated in patients with acute kidney injury (AKI) or chronic, severe kidney disease. Severe kidney disease is marked by a glomerular filtration rate of less than 30 mL/min/1.73m².

In addition, the revised labeling recommends that healthcare professionals screen all patients being considered for any gadolinium-based contrast agent (GBCA) for AKI or chronic, severe kidney disease. GBCAs also should be avoided in patients suspected or known to have impaired drug elimination unless the diagnostic information obtained is essential and cannot be acquired without the use of a contrast agent.

It’s been known since at least 2006 that patients with AKI or chronic, severe kidney disease are at increased risk of developing nephrogenic systemic fibrosis (NSF). In 2007 the FDA issued its first boxed warning about the risk of NSF associated with GBCA use. That warning stated only that healthcare professionals should be aware of the possibility that some patients might develop NSF. The new warning adds the absolute contraindication for the use of the three agents in patients with AKI and chronic, severe kidney disease.

The earlier boxed warning appears to have had the effect of reducing the incidence of NSF, according to one FDA official. Late last year, at a joint meeting of the FDA’s Cardiovascular and Renal Drugs and Drug Safety and Risk Management advisory committees, Dr. James Kaiser of the agency’s office of surveillance and epidemiology noted that in 2006 there were 194 cases of NSF associated with GBCAs. That number decreased to 128 cases in 2007, 55 in 2008, and 6 in 2009 (through September).

While three GBCAs had been associated with numerous cases of NSF, the other two – MultiHance (gadobenate dimeglumine) and ProHance (gadoteridol) ‑ have not. As of September 2009, a total of 382 reports of NSF had been associated with Omniscan (GE HealthCare), 195 with Magnevist (Bayer HealthCare), 35 with OptiMARK (Covidien), 1 with MultiHance (Bracco Diagnostics), and 0 with ProHance (Bracco Diagnostics). At last year’s meeting a majority of advisory committee members recommended that Omniscan and OptiMARK be contraindicated in patients with serious kidney dysfunction. There was less agreement on whether Magnevist should also be contraindicated.

The Food and Drug Administration on Sept. 9 required manufacturers of five gadolinium contrast agents to strengthen boxed warnings on their products to minimize the risk of nephrogenic systemic fibrosis in some patients with kidney dysfunction.

Three of the agents – Magnevist (gadopentetate dimeglumine), Omniscan (gadodiamide), and Optimark (gadoversetamide) – are now contraindicated in patients with acute kidney injury (AKI) or chronic, severe kidney disease. Severe kidney disease is marked by a glomerular filtration rate of less than 30 mL/min/1.73m².

In addition, the revised labeling recommends that healthcare professionals screen all patients being considered for any gadolinium-based contrast agent (GBCA) for AKI or chronic, severe kidney disease. GBCAs also should be avoided in patients suspected or known to have impaired drug elimination unless the diagnostic information obtained is essential and cannot be acquired without the use of a contrast agent.

It’s been known since at least 2006 that patients with AKI or chronic, severe kidney disease are at increased risk of developing nephrogenic systemic fibrosis (NSF). In 2007 the FDA issued its first boxed warning about the risk of NSF associated with GBCA use. That warning stated only that healthcare professionals should be aware of the possibility that some patients might develop NSF. The new warning adds the absolute contraindication for the use of the three agents in patients with AKI and chronic, severe kidney disease.

The earlier boxed warning appears to have had the effect of reducing the incidence of NSF, according to one FDA official. Late last year, at a joint meeting of the FDA’s Cardiovascular and Renal Drugs and Drug Safety and Risk Management advisory committees, Dr. James Kaiser of the agency’s office of surveillance and epidemiology noted that in 2006 there were 194 cases of NSF associated with GBCAs. That number decreased to 128 cases in 2007, 55 in 2008, and 6 in 2009 (through September).

While three GBCAs had been associated with numerous cases of NSF, the other two – MultiHance (gadobenate dimeglumine) and ProHance (gadoteridol) ‑ have not. As of September 2009, a total of 382 reports of NSF had been associated with Omniscan (GE HealthCare), 195 with Magnevist (Bayer HealthCare), 35 with OptiMARK (Covidien), 1 with MultiHance (Bracco Diagnostics), and 0 with ProHance (Bracco Diagnostics). At last year’s meeting a majority of advisory committee members recommended that Omniscan and OptiMARK be contraindicated in patients with serious kidney dysfunction. There was less agreement on whether Magnevist should also be contraindicated.

The Food and Drug Administration on Sept. 9 required manufacturers of five gadolinium contrast agents to strengthen boxed warnings on their products to minimize the risk of nephrogenic systemic fibrosis in some patients with kidney dysfunction.

Three of the agents – Magnevist (gadopentetate dimeglumine), Omniscan (gadodiamide), and Optimark (gadoversetamide) – are now contraindicated in patients with acute kidney injury (AKI) or chronic, severe kidney disease. Severe kidney disease is marked by a glomerular filtration rate of less than 30 mL/min/1.73m².

In addition, the revised labeling recommends that healthcare professionals screen all patients being considered for any gadolinium-based contrast agent (GBCA) for AKI or chronic, severe kidney disease. GBCAs also should be avoided in patients suspected or known to have impaired drug elimination unless the diagnostic information obtained is essential and cannot be acquired without the use of a contrast agent.

It’s been known since at least 2006 that patients with AKI or chronic, severe kidney disease are at increased risk of developing nephrogenic systemic fibrosis (NSF). In 2007 the FDA issued its first boxed warning about the risk of NSF associated with GBCA use. That warning stated only that healthcare professionals should be aware of the possibility that some patients might develop NSF. The new warning adds the absolute contraindication for the use of the three agents in patients with AKI and chronic, severe kidney disease.

The earlier boxed warning appears to have had the effect of reducing the incidence of NSF, according to one FDA official. Late last year, at a joint meeting of the FDA’s Cardiovascular and Renal Drugs and Drug Safety and Risk Management advisory committees, Dr. James Kaiser of the agency’s office of surveillance and epidemiology noted that in 2006 there were 194 cases of NSF associated with GBCAs. That number decreased to 128 cases in 2007, 55 in 2008, and 6 in 2009 (through September).

While three GBCAs had been associated with numerous cases of NSF, the other two – MultiHance (gadobenate dimeglumine) and ProHance (gadoteridol) ‑ have not. As of September 2009, a total of 382 reports of NSF had been associated with Omniscan (GE HealthCare), 195 with Magnevist (Bayer HealthCare), 35 with OptiMARK (Covidien), 1 with MultiHance (Bracco Diagnostics), and 0 with ProHance (Bracco Diagnostics). At last year’s meeting a majority of advisory committee members recommended that Omniscan and OptiMARK be contraindicated in patients with serious kidney dysfunction. There was less agreement on whether Magnevist should also be contraindicated.

The Food and Drug Administration on Sept. 9 required manufacturers of five gadolinium contrast agents to strengthen boxed warnings on their products to minimize the risk of nephrogenic systemic fibrosis in some patients with kidney dysfunction.

Three of the agents – Magnevist (gadopentetate dimeglumine), Omniscan (gadodiamide), and Optimark (gadoversetamide) – are now contraindicated in patients with acute kidney injury (AKI) or chronic, severe kidney disease. Severe kidney disease is marked by a glomerular filtration rate of less than 30 mL/min/1.73m².

In addition, the revised labeling recommends that healthcare professionals screen all patients being considered for any gadolinium-based contrast agent (GBCA) for AKI or chronic, severe kidney disease. GBCAs also should be avoided in patients suspected or known to have impaired drug elimination unless the diagnostic information obtained is essential and cannot be acquired without the use of a contrast agent.

It’s been known since at least 2006 that patients with AKI or chronic, severe kidney disease are at increased risk of developing nephrogenic systemic fibrosis (NSF). In 2007 the FDA issued its first boxed warning about the risk of NSF associated with GBCA use. That warning stated only that healthcare professionals should be aware of the possibility that some patients might develop NSF. The new warning adds the absolute contraindication for the use of the three agents in patients with AKI and chronic, severe kidney disease.

The earlier boxed warning appears to have had the effect of reducing the incidence of NSF, according to one FDA official. Late last year, at a joint meeting of the FDA’s Cardiovascular and Renal Drugs and Drug Safety and Risk Management advisory committees, Dr. James Kaiser of the agency’s office of surveillance and epidemiology noted that in 2006 there were 194 cases of NSF associated with GBCAs. That number decreased to 128 cases in 2007, 55 in 2008, and 6 in 2009 (through September).

While three GBCAs had been associated with numerous cases of NSF, the other two – MultiHance (gadobenate dimeglumine) and ProHance (gadoteridol) ‑ have not. As of September 2009, a total of 382 reports of NSF had been associated with Omniscan (GE HealthCare), 195 with Magnevist (Bayer HealthCare), 35 with OptiMARK (Covidien), 1 with MultiHance (Bracco Diagnostics), and 0 with ProHance (Bracco Diagnostics). At last year’s meeting a majority of advisory committee members recommended that Omniscan and OptiMARK be contraindicated in patients with serious kidney dysfunction. There was less agreement on whether Magnevist should also be contraindicated.

The Food and Drug Administration on Sept. 9 required manufacturers of five gadolinium contrast agents to strengthen boxed warnings on their products to minimize the risk of nephrogenic systemic fibrosis in some patients with kidney dysfunction.

Three of the agents – Magnevist (gadopentetate dimeglumine), Omniscan (gadodiamide), and Optimark (gadoversetamide) – are now contraindicated in patients with acute kidney injury (AKI) or chronic, severe kidney disease. Severe kidney disease is marked by a glomerular filtration rate of less than 30 mL/min/1.73m².

In addition, the revised labeling recommends that healthcare professionals screen all patients being considered for any gadolinium-based contrast agent (GBCA) for AKI or chronic, severe kidney disease. GBCAs also should be avoided in patients suspected or known to have impaired drug elimination unless the diagnostic information obtained is essential and cannot be acquired without the use of a contrast agent.

It’s been known since at least 2006 that patients with AKI or chronic, severe kidney disease are at increased risk of developing nephrogenic systemic fibrosis (NSF). In 2007 the FDA issued its first boxed warning about the risk of NSF associated with GBCA use. That warning stated only that healthcare professionals should be aware of the possibility that some patients might develop NSF. The new warning adds the absolute contraindication for the use of the three agents in patients with AKI and chronic, severe kidney disease.

The earlier boxed warning appears to have had the effect of reducing the incidence of NSF, according to one FDA official. Late last year, at a joint meeting of the FDA’s Cardiovascular and Renal Drugs and Drug Safety and Risk Management advisory committees, Dr. James Kaiser of the agency’s office of surveillance and epidemiology noted that in 2006 there were 194 cases of NSF associated with GBCAs. That number decreased to 128 cases in 2007, 55 in 2008, and 6 in 2009 (through September).

While three GBCAs had been associated with numerous cases of NSF, the other two – MultiHance (gadobenate dimeglumine) and ProHance (gadoteridol) ‑ have not. As of September 2009, a total of 382 reports of NSF had been associated with Omniscan (GE HealthCare), 195 with Magnevist (Bayer HealthCare), 35 with OptiMARK (Covidien), 1 with MultiHance (Bracco Diagnostics), and 0 with ProHance (Bracco Diagnostics). At last year’s meeting a majority of advisory committee members recommended that Omniscan and OptiMARK be contraindicated in patients with serious kidney dysfunction. There was less agreement on whether Magnevist should also be contraindicated.

Intensive blood pressure control doesn’t slow the progression of chronic kidney disease any better than standard blood pressure control in most patients, according to a report in the Sept. 2 New England Journal of Medicine.

It appears that the more intensive approach may benefit only patients who have proteinuria with a protein:creatinine ratio greater than 0.22, a value that is compatible with the widely accepted threshold of 300 mg/day for absolute urinary protein excretion, said Dr. Lawrence J. Appel of Johns Hopkins University, Baltimore, and his associates in the AASK (African-American Study of Kidney Disease and Hypertension) Collaborative Research Group.

Until now, “few trials have tested the effects of intensive blood pressure control [compared with conventional control] on the progression of chronic kidney disease, and the findings from such trials have been inconsistent. Despite a lack of compelling evidence, numerous guidelines recommend a reduced blood pressure target in patients with CKD,” they wrote.

Previous studies have rarely followed patients beyond 5 years, even though it typically takes longer than that for end-stage renal disease (ESRD) to develop in patients with CKD.

The AASK study compared outcomes between the two approaches to BP control in 1,094 black adults with mild to moderate hypertensive chronic kidney disease (defined as diastolic BP greater than 95 mm Hg and a glomerular filtration rate of 20-65 mL/min) but without marked proteinuria. Patients with diabetes were excluded from the trial.

In the first phase of the AASK investigation, patients were randomly assigned to either intensive BP control with a target of 92 mm Hg or lower mean arterial pressure (that is, lower than the usual target of 130/80 mm Hg recommended for CKD patients) or to conventional BP control with a target of 102-107 mm Hg mean arterial pressure (which corresponds to the conventional BP target of 140/90 mm Hg).

Throughout this initial phase of the trial, which lasted approximately 4 years, mean blood pressure was significantly lower in the intensive-control group (130/78 mm Hg) than in the standard-control group (141/86 mm Hg), yet there was no significant difference in the primary outcome of progression of kidney disease, development of ESRD, or death. Likewise, there was no significant difference between the two approaches in secondary or clinical outcomes.

In the second phase of the AASK investigation, patients who had not yet developed ESRD were invited to continue in a cohort portion of the trial, in which the BP target was 140/90 mm Hg. In 2004, when national guidelines were changed, this target was amended to lower than 130/80 mm Hg.

After a cumulative follow-up of 8-12 years, there still was no significant difference in primary or secondary outcomes between those who were initially assigned to the intensive-control and the standard-control groups. More intensive BP control did not slow the rate of progression of CKD, Dr. Appel and his associates reported (N. Engl. J. Med. 2010;363:918-29).

However, the intensive-control approach did benefit one subgroup of patients with proteinuria: those who had a protein:creatinine ratio of more than 0.22 at baseline. These patients showed a significant reduction in the primary outcome of progression of kidney disease, development of ESRD, or death, as well as in secondary and clinical outcomes.

The reason for this discrepancy is not known. “Overall, it is hard to develop a coherent, biologically plausible argument for a qualitative interaction between harm in patients without proteinuria and benefit in those with proteinuria,” the researchers said.

In an accompanying editorial, Dr. Julie R. Ingelfinger, chief of pediatric nephrology at Massachusetts General Hospital, Boston, and a deputy editor of the New England Journal of Medicine, wrote that the study lends hope to the concept that intensive treatment will improve renal outcomes in at least some patients with hypertension, chronic kidney disease, and microalbuminuria (N. Engl. J. Med. 2010;363:974-6). She noted that the Modification of Diet in Renal Disease trial showed that intensive BP control, compared with standard control, benefited patients who had more than 1 g of proteinuria at baseline. The ESCAPE trial (Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of Chronic Renal Failure in Pediatric Patients) also demonstrated that intensive BP control with a fixed dose of an ACE inhibitor significantly slowed the progression of renal disease, with the largest effects seen in children who had substantial proteinuria, hypertension, and a reduced GFR at baseline. And intensive BP control was beneficial in a recent study of adults in Italy who had idiopathic glomerular diseases associated with hypertension and proteinuria, Dr. Ingelfinger wrote.

 

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the Office of Research in Minority Health, and the National Institutes of Health. King Pharmaceuticals provided financial support and donated antihypertensive medications to each clinical center. Pfizer, AstraZeneca, GlaxoSmithKline, Forest Laboratories, Pharmacia, and Upjohn also donated antihypertensive drugs. None of these companies had any role in the design of the study, the accrual or analysis of data, or the preparation of the manuscript. Some of the investigators reported being in consultant and/or advisory board roles or receiving funds from numerous companies including Daiichi-Sankyo, Novartis, Amgen, King Pharmaceuticals, Abbott, Boehringer-Ingelheim, Litholink, Eli Lilly, Takeda, Merck, and Watson. Dr. Ingelfinger reported having no conflicts of interest.

Intensive blood pressure control doesn’t slow the progression of chronic kidney disease any better than standard blood pressure control in most patients, according to a report in the Sept. 2 New England Journal of Medicine.

It appears that the more intensive approach may benefit only patients who have proteinuria with a protein:creatinine ratio greater than 0.22, a value that is compatible with the widely accepted threshold of 300 mg/day for absolute urinary protein excretion, said Dr. Lawrence J. Appel of Johns Hopkins University, Baltimore, and his associates in the AASK (African-American Study of Kidney Disease and Hypertension) Collaborative Research Group.

Until now, “few trials have tested the effects of intensive blood pressure control [compared with conventional control] on the progression of chronic kidney disease, and the findings from such trials have been inconsistent. Despite a lack of compelling evidence, numerous guidelines recommend a reduced blood pressure target in patients with CKD,” they wrote.

Previous studies have rarely followed patients beyond 5 years, even though it typically takes longer than that for end-stage renal disease (ESRD) to develop in patients with CKD.

The AASK study compared outcomes between the two approaches to BP control in 1,094 black adults with mild to moderate hypertensive chronic kidney disease (defined as diastolic BP greater than 95 mm Hg and a glomerular filtration rate of 20-65 mL/min) but without marked proteinuria. Patients with diabetes were excluded from the trial.

In the first phase of the AASK investigation, patients were randomly assigned to either intensive BP control with a target of 92 mm Hg or lower mean arterial pressure (that is, lower than the usual target of 130/80 mm Hg recommended for CKD patients) or to conventional BP control with a target of 102-107 mm Hg mean arterial pressure (which corresponds to the conventional BP target of 140/90 mm Hg).

Throughout this initial phase of the trial, which lasted approximately 4 years, mean blood pressure was significantly lower in the intensive-control group (130/78 mm Hg) than in the standard-control group (141/86 mm Hg), yet there was no significant difference in the primary outcome of progression of kidney disease, development of ESRD, or death. Likewise, there was no significant difference between the two approaches in secondary or clinical outcomes.

In the second phase of the AASK investigation, patients who had not yet developed ESRD were invited to continue in a cohort portion of the trial, in which the BP target was 140/90 mm Hg. In 2004, when national guidelines were changed, this target was amended to lower than 130/80 mm Hg.

After a cumulative follow-up of 8-12 years, there still was no significant difference in primary or secondary outcomes between those who were initially assigned to the intensive-control and the standard-control groups. More intensive BP control did not slow the rate of progression of CKD, Dr. Appel and his associates reported (N. Engl. J. Med. 2010;363:918-29).

However, the intensive-control approach did benefit one subgroup of patients with proteinuria: those who had a protein:creatinine ratio of more than 0.22 at baseline. These patients showed a significant reduction in the primary outcome of progression of kidney disease, development of ESRD, or death, as well as in secondary and clinical outcomes.

The reason for this discrepancy is not known. “Overall, it is hard to develop a coherent, biologically plausible argument for a qualitative interaction between harm in patients without proteinuria and benefit in those with proteinuria,” the researchers said.

In an accompanying editorial, Dr. Julie R. Ingelfinger, chief of pediatric nephrology at Massachusetts General Hospital, Boston, and a deputy editor of the New England Journal of Medicine, wrote that the study lends hope to the concept that intensive treatment will improve renal outcomes in at least some patients with hypertension, chronic kidney disease, and microalbuminuria (N. Engl. J. Med. 2010;363:974-6). She noted that the Modification of Diet in Renal Disease trial showed that intensive BP control, compared with standard control, benefited patients who had more than 1 g of proteinuria at baseline. The ESCAPE trial (Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of Chronic Renal Failure in Pediatric Patients) also demonstrated that intensive BP control with a fixed dose of an ACE inhibitor significantly slowed the progression of renal disease, with the largest effects seen in children who had substantial proteinuria, hypertension, and a reduced GFR at baseline. And intensive BP control was beneficial in a recent study of adults in Italy who had idiopathic glomerular diseases associated with hypertension and proteinuria, Dr. Ingelfinger wrote.

 

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the Office of Research in Minority Health, and the National Institutes of Health. King Pharmaceuticals provided financial support and donated antihypertensive medications to each clinical center. Pfizer, AstraZeneca, GlaxoSmithKline, Forest Laboratories, Pharmacia, and Upjohn also donated antihypertensive drugs. None of these companies had any role in the design of the study, the accrual or analysis of data, or the preparation of the manuscript. Some of the investigators reported being in consultant and/or advisory board roles or receiving funds from numerous companies including Daiichi-Sankyo, Novartis, Amgen, King Pharmaceuticals, Abbott, Boehringer-Ingelheim, Litholink, Eli Lilly, Takeda, Merck, and Watson. Dr. Ingelfinger reported having no conflicts of interest.

Intensive blood pressure control doesn’t slow the progression of chronic kidney disease any better than standard blood pressure control in most patients, according to a report in the Sept. 2 New England Journal of Medicine.

It appears that the more intensive approach may benefit only patients who have proteinuria with a protein:creatinine ratio greater than 0.22, a value that is compatible with the widely accepted threshold of 300 mg/day for absolute urinary protein excretion, said Dr. Lawrence J. Appel of Johns Hopkins University, Baltimore, and his associates in the AASK (African-American Study of Kidney Disease and Hypertension) Collaborative Research Group.

Until now, “few trials have tested the effects of intensive blood pressure control [compared with conventional control] on the progression of chronic kidney disease, and the findings from such trials have been inconsistent. Despite a lack of compelling evidence, numerous guidelines recommend a reduced blood pressure target in patients with CKD,” they wrote.

Previous studies have rarely followed patients beyond 5 years, even though it typically takes longer than that for end-stage renal disease (ESRD) to develop in patients with CKD.

The AASK study compared outcomes between the two approaches to BP control in 1,094 black adults with mild to moderate hypertensive chronic kidney disease (defined as diastolic BP greater than 95 mm Hg and a glomerular filtration rate of 20-65 mL/min) but without marked proteinuria. Patients with diabetes were excluded from the trial.

In the first phase of the AASK investigation, patients were randomly assigned to either intensive BP control with a target of 92 mm Hg or lower mean arterial pressure (that is, lower than the usual target of 130/80 mm Hg recommended for CKD patients) or to conventional BP control with a target of 102-107 mm Hg mean arterial pressure (which corresponds to the conventional BP target of 140/90 mm Hg).

Throughout this initial phase of the trial, which lasted approximately 4 years, mean blood pressure was significantly lower in the intensive-control group (130/78 mm Hg) than in the standard-control group (141/86 mm Hg), yet there was no significant difference in the primary outcome of progression of kidney disease, development of ESRD, or death. Likewise, there was no significant difference between the two approaches in secondary or clinical outcomes.

In the second phase of the AASK investigation, patients who had not yet developed ESRD were invited to continue in a cohort portion of the trial, in which the BP target was 140/90 mm Hg. In 2004, when national guidelines were changed, this target was amended to lower than 130/80 mm Hg.

After a cumulative follow-up of 8-12 years, there still was no significant difference in primary or secondary outcomes between those who were initially assigned to the intensive-control and the standard-control groups. More intensive BP control did not slow the rate of progression of CKD, Dr. Appel and his associates reported (N. Engl. J. Med. 2010;363:918-29).

However, the intensive-control approach did benefit one subgroup of patients with proteinuria: those who had a protein:creatinine ratio of more than 0.22 at baseline. These patients showed a significant reduction in the primary outcome of progression of kidney disease, development of ESRD, or death, as well as in secondary and clinical outcomes.

The reason for this discrepancy is not known. “Overall, it is hard to develop a coherent, biologically plausible argument for a qualitative interaction between harm in patients without proteinuria and benefit in those with proteinuria,” the researchers said.

In an accompanying editorial, Dr. Julie R. Ingelfinger, chief of pediatric nephrology at Massachusetts General Hospital, Boston, and a deputy editor of the New England Journal of Medicine, wrote that the study lends hope to the concept that intensive treatment will improve renal outcomes in at least some patients with hypertension, chronic kidney disease, and microalbuminuria (N. Engl. J. Med. 2010;363:974-6). She noted that the Modification of Diet in Renal Disease trial showed that intensive BP control, compared with standard control, benefited patients who had more than 1 g of proteinuria at baseline. The ESCAPE trial (Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of Chronic Renal Failure in Pediatric Patients) also demonstrated that intensive BP control with a fixed dose of an ACE inhibitor significantly slowed the progression of renal disease, with the largest effects seen in children who had substantial proteinuria, hypertension, and a reduced GFR at baseline. And intensive BP control was beneficial in a recent study of adults in Italy who had idiopathic glomerular diseases associated with hypertension and proteinuria, Dr. Ingelfinger wrote.

 

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the Office of Research in Minority Health, and the National Institutes of Health. King Pharmaceuticals provided financial support and donated antihypertensive medications to each clinical center. Pfizer, AstraZeneca, GlaxoSmithKline, Forest Laboratories, Pharmacia, and Upjohn also donated antihypertensive drugs. None of these companies had any role in the design of the study, the accrual or analysis of data, or the preparation of the manuscript. Some of the investigators reported being in consultant and/or advisory board roles or receiving funds from numerous companies including Daiichi-Sankyo, Novartis, Amgen, King Pharmaceuticals, Abbott, Boehringer-Ingelheim, Litholink, Eli Lilly, Takeda, Merck, and Watson. Dr. Ingelfinger reported having no conflicts of interest.

Intensive blood pressure control doesn’t slow the progression of chronic kidney disease any better than standard blood pressure control in most patients, according to a report in the Sept. 2 New England Journal of Medicine.

It appears that the more intensive approach may benefit only patients who have proteinuria with a protein:creatinine ratio greater than 0.22, a value that is compatible with the widely accepted threshold of 300 mg/day for absolute urinary protein excretion, said Dr. Lawrence J. Appel of Johns Hopkins University, Baltimore, and his associates in the AASK (African-American Study of Kidney Disease and Hypertension) Collaborative Research Group.

Until now, “few trials have tested the effects of intensive blood pressure control [compared with conventional control] on the progression of chronic kidney disease, and the findings from such trials have been inconsistent. Despite a lack of compelling evidence, numerous guidelines recommend a reduced blood pressure target in patients with CKD,” they wrote.

Previous studies have rarely followed patients beyond 5 years, even though it typically takes longer than that for end-stage renal disease (ESRD) to develop in patients with CKD.

The AASK study compared outcomes between the two approaches to BP control in 1,094 black adults with mild to moderate hypertensive chronic kidney disease (defined as diastolic BP greater than 95 mm Hg and a glomerular filtration rate of 20-65 mL/min) but without marked proteinuria. Patients with diabetes were excluded from the trial.

In the first phase of the AASK investigation, patients were randomly assigned to either intensive BP control with a target of 92 mm Hg or lower mean arterial pressure (that is, lower than the usual target of 130/80 mm Hg recommended for CKD patients) or to conventional BP control with a target of 102-107 mm Hg mean arterial pressure (which corresponds to the conventional BP target of 140/90 mm Hg).

Throughout this initial phase of the trial, which lasted approximately 4 years, mean blood pressure was significantly lower in the intensive-control group (130/78 mm Hg) than in the standard-control group (141/86 mm Hg), yet there was no significant difference in the primary outcome of progression of kidney disease, development of ESRD, or death. Likewise, there was no significant difference between the two approaches in secondary or clinical outcomes.

In the second phase of the AASK investigation, patients who had not yet developed ESRD were invited to continue in a cohort portion of the trial, in which the BP target was 140/90 mm Hg. In 2004, when national guidelines were changed, this target was amended to lower than 130/80 mm Hg.

After a cumulative follow-up of 8-12 years, there still was no significant difference in primary or secondary outcomes between those who were initially assigned to the intensive-control and the standard-control groups. More intensive BP control did not slow the rate of progression of CKD, Dr. Appel and his associates reported (N. Engl. J. Med. 2010;363:918-29).

However, the intensive-control approach did benefit one subgroup of patients with proteinuria: those who had a protein:creatinine ratio of more than 0.22 at baseline. These patients showed a significant reduction in the primary outcome of progression of kidney disease, development of ESRD, or death, as well as in secondary and clinical outcomes.

The reason for this discrepancy is not known. “Overall, it is hard to develop a coherent, biologically plausible argument for a qualitative interaction between harm in patients without proteinuria and benefit in those with proteinuria,” the researchers said.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the Office of Research in Minority Health, and the National Institutes of Health. King Pharmaceuticals provided financial support and donated antihypertensive medications to each clinical center. Pfizer, AstraZeneca, GlaxoSmithKline, Forest Laboratories, Pharmacia, and Upjohn also donated antihypertensive drugs. None of these companies had any role in the design of the study, the accrual or analysis of data, or the preparation of the manuscript. Some of the investigators reported being in consultant and/or advisory board roles or receiving funds from numerous companies including Daiichi-Sankyo, Novartis, Amgen, King Pharmaceuticals, Abbott, Boehringer-Ingelheim, Litholink, Eli Lilly, Takeda, Merck, and Watson. Dr. Ingelfinger reported having no conflicts of interest.

Intensive blood pressure control doesn’t slow the progression of chronic kidney disease any better than standard blood pressure control in most patients, according to a report in the Sept. 2 New England Journal of Medicine.

It appears that the more intensive approach may benefit only patients who have proteinuria with a protein:creatinine ratio greater than 0.22, a value that is compatible with the widely accepted threshold of 300 mg/day for absolute urinary protein excretion, said Dr. Lawrence J. Appel of Johns Hopkins University, Baltimore, and his associates in the AASK (African-American Study of Kidney Disease and Hypertension) Collaborative Research Group.

Until now, “few trials have tested the effects of intensive blood pressure control [compared with conventional control] on the progression of chronic kidney disease, and the findings from such trials have been inconsistent. Despite a lack of compelling evidence, numerous guidelines recommend a reduced blood pressure target in patients with CKD,” they wrote.

Previous studies have rarely followed patients beyond 5 years, even though it typically takes longer than that for end-stage renal disease (ESRD) to develop in patients with CKD.

The AASK study compared outcomes between the two approaches to BP control in 1,094 black adults with mild to moderate hypertensive chronic kidney disease (defined as diastolic BP greater than 95 mm Hg and a glomerular filtration rate of 20-65 mL/min) but without marked proteinuria. Patients with diabetes were excluded from the trial.

In the first phase of the AASK investigation, patients were randomly assigned to either intensive BP control with a target of 92 mm Hg or lower mean arterial pressure (that is, lower than the usual target of 130/80 mm Hg recommended for CKD patients) or to conventional BP control with a target of 102-107 mm Hg mean arterial pressure (which corresponds to the conventional BP target of 140/90 mm Hg).

Throughout this initial phase of the trial, which lasted approximately 4 years, mean blood pressure was significantly lower in the intensive-control group (130/78 mm Hg) than in the standard-control group (141/86 mm Hg), yet there was no significant difference in the primary outcome of progression of kidney disease, development of ESRD, or death. Likewise, there was no significant difference between the two approaches in secondary or clinical outcomes.

In the second phase of the AASK investigation, patients who had not yet developed ESRD were invited to continue in a cohort portion of the trial, in which the BP target was 140/90 mm Hg. In 2004, when national guidelines were changed, this target was amended to lower than 130/80 mm Hg.

After a cumulative follow-up of 8-12 years, there still was no significant difference in primary or secondary outcomes between those who were initially assigned to the intensive-control and the standard-control groups. More intensive BP control did not slow the rate of progression of CKD, Dr. Appel and his associates reported (N. Engl. J. Med. 2010;363:918-29).

However, the intensive-control approach did benefit one subgroup of patients with proteinuria: those who had a protein:creatinine ratio of more than 0.22 at baseline. These patients showed a significant reduction in the primary outcome of progression of kidney disease, development of ESRD, or death, as well as in secondary and clinical outcomes.

The reason for this discrepancy is not known. “Overall, it is hard to develop a coherent, biologically plausible argument for a qualitative interaction between harm in patients without proteinuria and benefit in those with proteinuria,” the researchers said.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the Office of Research in Minority Health, and the National Institutes of Health. King Pharmaceuticals provided financial support and donated antihypertensive medications to each clinical center. Pfizer, AstraZeneca, GlaxoSmithKline, Forest Laboratories, Pharmacia, and Upjohn also donated antihypertensive drugs. None of these companies had any role in the design of the study, the accrual or analysis of data, or the preparation of the manuscript. Some of the investigators reported being in consultant and/or advisory board roles or receiving funds from numerous companies including Daiichi-Sankyo, Novartis, Amgen, King Pharmaceuticals, Abbott, Boehringer-Ingelheim, Litholink, Eli Lilly, Takeda, Merck, and Watson. Dr. Ingelfinger reported having no conflicts of interest.

Intensive blood pressure control doesn’t slow the progression of chronic kidney disease any better than standard blood pressure control in most patients, according to a report in the Sept. 2 New England Journal of Medicine.

It appears that the more intensive approach may benefit only patients who have proteinuria with a protein:creatinine ratio greater than 0.22, a value that is compatible with the widely accepted threshold of 300 mg/day for absolute urinary protein excretion, said Dr. Lawrence J. Appel of Johns Hopkins University, Baltimore, and his associates in the AASK (African-American Study of Kidney Disease and Hypertension) Collaborative Research Group.

Until now, “few trials have tested the effects of intensive blood pressure control [compared with conventional control] on the progression of chronic kidney disease, and the findings from such trials have been inconsistent. Despite a lack of compelling evidence, numerous guidelines recommend a reduced blood pressure target in patients with CKD,” they wrote.

Previous studies have rarely followed patients beyond 5 years, even though it typically takes longer than that for end-stage renal disease (ESRD) to develop in patients with CKD.

The AASK study compared outcomes between the two approaches to BP control in 1,094 black adults with mild to moderate hypertensive chronic kidney disease (defined as diastolic BP greater than 95 mm Hg and a glomerular filtration rate of 20-65 mL/min) but without marked proteinuria. Patients with diabetes were excluded from the trial.

In the first phase of the AASK investigation, patients were randomly assigned to either intensive BP control with a target of 92 mm Hg or lower mean arterial pressure (that is, lower than the usual target of 130/80 mm Hg recommended for CKD patients) or to conventional BP control with a target of 102-107 mm Hg mean arterial pressure (which corresponds to the conventional BP target of 140/90 mm Hg).

Throughout this initial phase of the trial, which lasted approximately 4 years, mean blood pressure was significantly lower in the intensive-control group (130/78 mm Hg) than in the standard-control group (141/86 mm Hg), yet there was no significant difference in the primary outcome of progression of kidney disease, development of ESRD, or death. Likewise, there was no significant difference between the two approaches in secondary or clinical outcomes.

In the second phase of the AASK investigation, patients who had not yet developed ESRD were invited to continue in a cohort portion of the trial, in which the BP target was 140/90 mm Hg. In 2004, when national guidelines were changed, this target was amended to lower than 130/80 mm Hg.

After a cumulative follow-up of 8-12 years, there still was no significant difference in primary or secondary outcomes between those who were initially assigned to the intensive-control and the standard-control groups. More intensive BP control did not slow the rate of progression of CKD, Dr. Appel and his associates reported (N. Engl. J. Med. 2010;363:918-29).

However, the intensive-control approach did benefit one subgroup of patients with proteinuria: those who had a protein:creatinine ratio of more than 0.22 at baseline. These patients showed a significant reduction in the primary outcome of progression of kidney disease, development of ESRD, or death, as well as in secondary and clinical outcomes.

The reason for this discrepancy is not known. “Overall, it is hard to develop a coherent, biologically plausible argument for a qualitative interaction between harm in patients without proteinuria and benefit in those with proteinuria,” the researchers said.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the Office of Research in Minority Health, and the National Institutes of Health. King Pharmaceuticals provided financial support and donated antihypertensive medications to each clinical center. Pfizer, AstraZeneca, GlaxoSmithKline, Forest Laboratories, Pharmacia, and Upjohn also donated antihypertensive drugs. None of these companies had any role in the design of the study, the accrual or analysis of data, or the preparation of the manuscript. Some of the investigators reported being in consultant and/or advisory board roles or receiving funds from numerous companies including Daiichi-Sankyo, Novartis, Amgen, King Pharmaceuticals, Abbott, Boehringer-Ingelheim, Litholink, Eli Lilly, Takeda, Merck, and Watson. Dr. Ingelfinger reported having no conflicts of interest.