Hyponatremia: Etiology and Management in the High-risk Patient
Presenters: Robert Schrier, MD (University of Colorado) and Mitchell Rosner, MD (University of Virginia)
Sponsor: Otsuka Pharmaceuticals
Schrier starts off the session and will discuss the etiology/pathophysiology of hyponatremia in high-risk patients. He defines high-risk patients (in this presentation) as those with heart failure and advanced liver disease. He starts off with a basic diagnostic algorithm for hyponatremia, focusing on the the changes in total body sodium and total body water to come up with the following classifications: hypovolemic, euvolemic, and hypervolemic hyponatremia.
Schrier mentions a quote from E.H. Starling, in which Starling states that the kidney is intelligently retaining sodium and water in heart failure patients (The Fluids of the Body, The Harter Lectures, 1909). Why would patients with low cardiac output (heart failure) retain sodium and water when patients with high-output cardiac failure (thyrotoxicosis, beriberi) also retain sodium and water? The common notion that a low cardiac output drives salt and water retention is an easy but not universal explanation for the development of hyponatremia.
He shows a slide of the distribution of the body fluid in various compartments. The key point is that 85% of all the body water is on the venous side of the circulation; 15% is on the arterial side. Schrier proposes that the kidney is responding to the fluid balance in the arterial circulation, and not the total body fluid. Arterial underfilling is dependent on cardiac output and systemic vascular tone more so that total body fluid. In thyrotoxicosis (and beriberi), there is a decrease in systemic vascular tone. Sodium and water retention, thus, is a compensatory mechanism to offset the deleterious effects of low cardiac output or decreased vascular tone (or both). This compensatory salt and water retention is mediated by the renin-angiotensin-aldosterone axis, sympathetic nervous system activity, and the non-osmotic release of ADH. Known as hemodynamic congestion, these compensatory mechanisms attempt to normalize cardiac output or vascular tone, but at the expense of developing pulmonary congestion, cerebral edema, and permanent cardiac remodelling (NEJM 1999, p. 577). Hemodynamic congestion is a bad sign for life, and is an explanation for why 50% of hypervolemic hyponatremic patients can present with a normal ejection fraction.
Hyponatremia is common in the heart failure population: about 50% of heart failure patients have serum sodium < 135 meq/L (JASN 2005, p. 16). There is a strong positive correlation (r 0.7) between activity of the renin-angiotensin-aldosterone axis and severity of hyponatremia (Circulation 1986, p. 257). Survival in heart failure is directly related to degree of hyponatremia: 20% survival at 20 months in the presence of low sodium (Circulation 1986, p. 257).
Of course, ADH is elevated in patients with heart failure (NEJM 1981, p. 263). Schrier indicates that measures to improve arterial filling will mitigate salt and water retention. This is the pathophysiologic explanation for why ACE-inhibitors can improve cardiac index (KI 1986, p. 1188). Inhibition of ADH activity can also improve arterial filling (KI 1986, p. 1188 and KI 1990, p. 818 and Am J Physiol Heart Circl Physiol 1994, p. H1713).
ADH has 2 functions: 1) it increases synthesis of and 2) traffics AQP-2 channels to the apical membrane of the principal cells in the collecting ducts. Inhibition of ADH decreases both synthesis and transport of the channel (JASN 1990, p. 2165).
Schrier turns his attention to hyponatremia in cirrhosis. Understanding hyponatremia and hemodynamic congestion in heart failure patients is crucial to understanding hyponatremia in cirrhotics (the mechanisms are very similar). In cirrhotics, there are 2 main hypotheses: 1) underfilling hypothesis: portal hypertension leads to ascites, which causes a decrease in plasma volume and secondary renal sodium and water retention, and 2) overflow hypothesis: a primary renal sodium and water retentive state leads to increased plasma volume, which combined with portal hypertension results in ascites. Schrier believes in the underfilling hypothesis (Annals of Internal Medicine 1990, p. 155).
SALT-1 and SALT-2: looked at heart failure, SIADH, and cirrhosis (all three cause hyponatremia) — after 30 days of tolvaptan use, hyponatremia was corrected, but when discontinued, serum sodium levels dropped to pre-treatment levels (NEJM 2006, p. 2099). ADH-receptor inhibitors work equally well in all three conditions.
Schrier reminds us that the main concern around hyponatremia is cerebral edema. The skull allows for only 8% of edema before herniation occurs. Chronic hyponatremia is often thought of as a condition with minimal (or no) symptoms. Schrier disagrees with this notion. Despite the adaptation by the brain to chronic hyponatremia, careful examination would reveal significant neurologic deficits. There may be no such thing as asymptomatic hyponatremia. He shows a nice graph that illustrates the improvement of gait stability as serum sodium rises in patients labeled as chronic, asymptomatic hyponatremia (Am J Med 2006, Vol 119, p. e1–71). Chronic hyponatremic patients have a 67-fold greater odds of falling than normonatremic controls.
The talk now turns to Rosner who will discuss therapy of hyponatremia in cirrhotics and heart failure patients. Hyponatremia is a strong predictor of mortality in cirrhotic patients (it is included in both the MELD and modified-MELD scores). Pre-transplant patients have a 4–6% likelihood of developing ODS in the post-transplant setting, which is very concerning given the scarcity of allografts. Rosner will discuss each of the following treatments: normal saline, hypertonic saline, fluid restriction, demeclocycline, lasix + NaCl, CRRT, and vasopressin receptor antagonism.
Normal saline is ineffective if volume depletion is not present or if there is any increase in ADH. Hypertonic saline is effective for patients who are acutely symptomatic, but runs the risk of ODS (for which cirrhotic patients are at increased risk already). Fluid restriction is cheap, but very slow to work and hard to comply with. Demeclocycline isn’t approved for hyponatremia treatment and has a degree of nephrotoxicity. Lasix + NaCl is difficult to titrate. CRRT works, and is used in some centers just prior to a liver transplantation, but is expensive and not widely available.
Rosner shows a study that compares fluid restriction (< 1 L/day) versus lixivaptan therapy (Gastroenterology 2003, p. 933). The study showed no change in serum sodium with fluid restriction but increasing sodium concentrations with increasing doses of the vaptan.
Loop diuretics + normal saline produces, in effect, a net water loss of 50% the urine volume. However, it is labor intensive and, as he points out, not always an ideal therapy. Rather, Rosner believes in the primacy of ADH’s role in water retention and should be a target of therapy.
A study of satavaptan showed a rise in serum sodium concentration (by about 5 meq/L) within 24–48 hours, and maintains stability as long as the drug is continued (Hepatology 2008, p. 204).
Vaptan therapy, in conjunction with spironolactone (100 mg), can decrease the number of large volume paracenteses (LVP) needed, regardless of the degree of hyponatremia (J Hepatology 2010, p. 283). 151 patients were randomized to spironolactone versus spironolactone + vaptan therapy, there was a significant decrease in number of LVP’s needed to manage recurrent ascites.
Rosner turns his attention to treatment of hyponatremia in heart failure. He emphasizes the neurohormonal abnormalities in heart failure patients and that therapy must manage all the neurohormonal imbalances. He lists the 4 common treatments: fluid restriction, diuretic therapy, ultrafiltration, and ADH-receptor antagonism.
Fluid restriction hasn’t been studied very well in heart failure patients with hyponatremia. Even with significant restriction (< 1 L per day), there is only 20% patient compliance and no difference in number of diuretics or symptom improvement (J Card Fail 2007, p. 128).
Diuretic therapy can ease congestive symptoms and can improve arterial underfilling if combined with afterload reduction. However, diuretic use is associated with increased mortality and worsens the neurohormonal imbalance (Eur Hear J 2006, p. 1431). Ultrafiltration is safe and effective, but it is expensive and not routinely available (Curr Opin Crit Care 2008, p. 524).
As a result, Rosner believes a strong focus on vaptan therapy is necessary for treatment of hyponatremia in heart failure. Vaptans will increase serum sodium in heart failure patients (Am J Nephrol 2007, p. 447). He shows additional slides from other studies showing improvements in serum sodium with vaptan therapy (Am J Physiol Heart Circ Physiol 1998, p. H176; Am J Physiol Renal Physiol 2006, p. F273; Cleve Clin J Med 2006, p. S24). Rosner admits that mortality in heart failure patients using vaptan therapy does not decrease at 10 months. There is also no difference in heart failure hospitalizations (JAMA 2007, p. 1319). The BALANCE study will look at vaptan effects on all-cause mortality and hospitalization rates (study has concluded, results not released; JACC 2008, p. 1540).