Hyponatremia is an electrolyte abnormality commonly seen in the clinical setting. Defined by a low serum sodium concentration, the potentially life-threatening condition is present in as many as 30% of hospitalized patients, yet no standard treatment algorithm for this condition has been widely accepted.
In recent years, a class of agents has emerged that shows potential as a safe and effective treatment for the condition. This is critical, as hyponatremia is associated with longer hospital stays and increased morbidity, according to a study published in the American Journal of Medicine. What’s more, the condition can result from several common disease states, including cirrhosis, heart failure and syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH). Therefore, it is vital that clinicians have
a solid understanding of how to manage hyponatremia in the hospital setting.
The first step toward effective treatment is in diagnosing hyponatremia in a timely manner. If a patient’s metabolic profile reveals that the serum sodium level is too low (some consider the target to be 130mmol/L, while others argue it is 135mmol/L), he or she is hyponatremic, meaning that there is an increased circulating level of antidiuretic hormone (ADH) that is limiting the kidney’s ability to excrete water, according to Biff Palmer, MD, professor of Internal Medicine, Division of Nephrology at University of Texas Southwestern Medical Center.
At this point, the clinician needs to determine why the ADH is increased. “There are two categories of thought here,” says Palmer. “One is that ADH is raised because of a disturbance within the circulation,” which can present either as total body salt depletion—causing the patient to experience nausea, diarrhea, and vomiting—or salt overload, which is often found in patients with heart failure or cirrhosis. “The other major category is when the circulation is absolutely normal, but ADH is still high, such as in SIADH,” he says.
Addressing an unmet need
In terms of treatment, if the patient has total body salt depletion, “generally that kind of hyponatremia is easy to correct, because all you need to do is replenish the volume with saline,” notes Palmer. However, in patients with heart failure or cirrhosis, this isn’t feasible because it could make the underlying condition worse. The same holds true for SIADH, he says. “If you can identify
the underlying cause, then you try to remove it. But in some circumstances, that’s not so easily done.”
In patients with heart failure, cirrhosis, and SIADH, hyponatremia can be difficult to treat because “you want to restrict their fluid intake, but that’s hard to do”—not just because patients don’t tolerate it well, but also because they are often getting IV fluids for antibiotic administration or other medication. Because of these issues, “there has been a lot of interest in another type of treatment that might enable us to treat those patients in a more efficient manner,” he says.
That’s where the new class of agents—vasopressin V2 receptor antagonists—factors into the equation. In hyponatremia, secretion of vasopressin plays a critical role in the drop of serum sodium; vasopressin V2 receptor antagonists work to block the receptor in the kidney to which ADH is binding. In other words, “they’re targeting the very mechanism that’s causing the defect in the renal water excretion in the first place,” says Palmer. “So in a sense, these V2 receptor antagonists are quite rational and very physiologic at how they approach the problem.”
In that respect, he notes, V2 receptor antagonists address an unmet need. “It’s sometimes hard to correct a hyponatremia in heart failure or cirrhosis, because you’ve already done everything you can to maximize the treatment of their underlying disease, and yet they’re still hyponatremic. V2 receptor blockers are targeting the defect that is present. And because of that, they’re much more effective than fluid restriction.”
Tolvaptan, an oral vasopressin V2 receptor antagonist, has been shown to effectively increase and maintain serum sodium concentrations in hyponatremic patients—both in the short-term (≤30 days), as established in the Study of Ascending Levels of Tolvaptan in Hyponatremia trials (SALT-1 and SALT-2, and during a long-term period (in the SALTWATER trial).
However, while tolvaptan shows promise as an effective treatment for hyponatremia in patients with heart failure, cirrhosis, and SIADH, there are considerations for each disease state that clinicians must be aware of.
• In the elderly population, hyponatremia is often associated with SIADH, which occurs when arginine vasopressin (AVP) is secreted independently of the body’s need to conserve water, usually due to underlying disease processes.
• Treatment methods for hyponatremia in patients with SIADH include saline infusion, fluid restriction, and pharmacologic adjustment of fluid balance. However, while fluid restriction is the most common therapy, it is limited by the slow rate of serum sodium correction, and is associated with poor compliance.
• In a study of patients with SIADH and congestive heart failure, tolvaptan induced rapid free-water elimination.
• In patients with cirrhosis, the development of hyponatremia is a complex process that involves impairment in renal capacity to
eliminate solute-free water. This causes water retention that is disproportionate to the retention of sodium, which in turn leads
• Serum sodium is an important predictor of survival among patients who are candidates for liver transplant; as serum sodium decreases, mortality risk increases.
• Short-term treatment with vaptans is associated with an increase in renal solute-free water excretion and improvement of hyponatremia in patients with cirrhosis, while longterm use has shown to be effective in maintaining the serum sodium levels.
• Heart failure results in 1.1 million hospitalizations every year, according to the American Heart Association.
• Hyponatremia is an indicator of poor prognosis in heart failure patients, adversely affecting mortality and hospital readmission rates.
• Given vasopressin’s role in fluid balance, vasopress in receptor agonists offer an alternate strategy for the management of hyponatremia. Use of AVP antagonists directly targets excessive stimulation of the V2 receptors, a key imbalance driving hyponatremia in heart failure patients.
• In patients with heart failure, tolvaptan appears to decrease body weight and edema and increase serum sodium concentrations without adversely affecting serum electrolyte levels, vital signs, or renal function.
In each of these patient groups, vasopressin receptor antagonists have been shown to work to directly target the underlying cause of hyponatremia. And tolvaptan has been shown to increase serum sodium levels, and continues to be safe and effective over a long-term period.
However, while vasopressin receptor antagonists offer promise as a viable treatment for hyponatremia, their use still needs to be closely monitored to ensure that they don’t work too quickly. According to Palmer, in patients with hyponatremia that has been present for more than 48 hours, “you never want to correct it more than 10-12 milliequivalents in any one 24-hour period; you always want to stay underneath that. The obvious concern with blockers is that they would cause the serum sodium to rise too rapidly.” However, this has not been the case. In fact, “in the SALT trial, the amount of correction in the first 24-36 hours was in the ballpark of 4-5 milliequivalents per 24 hours.” Why? Because, says Palmer, “as you block the receptor and as water excretion starts to go up and the serum sodium starts to improve, patients actually start to get thirsty and they drink more.” And that increased water intake provides somewhat of a safety valve while helping to minimize the chances of overcorrection. Therefore, water intake should not be restricted in patients who take tolvaptan. “If people feel thirsty, allow them to drink,” he says. “It’s important to make people aware of that.”
SIDEBAR: Managing Hyponatremia in Patients with Heart Failure
Paul Hauptman, MD, Professor of Internal Medicine and Director of the Heart Failure and Transplant Program at St. Louis University School of Medicine, was also an investigator in the tolvaptan drug development program, discusses some of the key considerations in managing hyponatremia in patients with heart failure.
The need for a ‘shift in thinking’
“Up to now, cardiologists really haven’t seen hyponatremia as a specific target for treatment. It’s more often seen as something that makes standard treatment more difficult, because it may limit your diuretic use, and everyone knows that fluid restriction isn’t particularly effective. But to say, ‘There’s a low sodium, let me go treat it, is a shift in thinking for the cardiologist. For endocrinologists, I think it’s something they’re comfortable with, because they see patients with SIADH and they know they have to treat the hyponatremia.”
Hyponatremia as a prognostic indicator
“I think there’s not as much recognition as there should be about what hyponatremia means in terms of clinical outcomes, particularly length of stay. “When a cirrhotic patient is being listed for transplant, their place on the list is determined by the MELD
(Model for End-stage Liver Disease) score, which is very helpful in ranking risk. Serum sodium is not part of that score, but at least one study indicates that the MELD score is even more prognostically significant with serum sodium. So I think this is beginning to permeate through the literature and hopefully to clinicians: serum sodium is something you do have to pay attention to, because at the very least, it is a very powerful predictor of prognosis in cirrhosis and heart failure. I think the ultimate challenge is going to be in proving that correcting serum sodium and using sodium as a therapeutic target will change outcomes.”
Considerations with use of diuretics
“In the majority of cases with heart failure patients, diuretics are used. When someone is hyponatremic, even in heart failure, there’s a differential diagnosis that you have to go through—fluid restriction may be more or less successful in different patients. It’s hard to predict.
But if the patient is fluid-overloaded, clinicians will still find themselves selecting diuretics, which at times can potentially exacerbate hyponatremia… and thus, until you can get the serum sodium corrected, clinicians may believe that they are limited in terms of treatment options for congestion. It’s a key question here: will tolvaptan prove to be loop diuretic sparing and/or a facilitator of diuresis in the hyponatremic patient?
“We should never forget that standard of care also requires a clinician to look for precipitants of the exacerbation of heart failure. Is the patient infected? Is it dietary noncompliance? Is it medical noncompliance? Is it a new arrhythmia like atrial fibrillation? One always has to think: why, on this date, did this patient have a worsening?”
SIDEBAR: Hyponatremia Online Resources