Commentary by Elizabeth Haskins MD, PGY-3
This week’s Grand Rounds was delivered by Dr. Tomas Berl, Chief of the Nephrology Division at the University of Colorado Health Sciences Center in Denver. Dr. Berl’s current research focuses on osmoregulated proteins of the inner medulla.
Hyponatremia, defined as a serum sodium concentration less than 136 mEq/L, is one of the most common electrolyte abnormalities in the hospitalized patient. In one Colorado hospital, the daily incidence of hyponatremia was 1% and the prevalence was 2.5%. The rate of hyponatremia increases with age and time spent in the hospital.
Serum sodium concentration is a function of free water intake and vasopressin release. Vasopressin, which is released from the posterior pituitary gland in response to both increased plasma osmolality and decreased intravascular volume, binds to V2 receptors in the collecting ducts resulting in increased water reabsorption. Thus hyponatremia occurs when vasopressin is released appropriately (as in hypovolemic states or when effective blood volume is low) or inappropriately, as in SIADH (syndrome of inappropriate anti-diuretic hormone).
Symptoms of hyponatremia are caused primarily from cellular water shifts resulting in cerebral edema. In acute (< 48 hours) hyponatremia, seizure, coma, and respiratory arrest can occur, sometimes without warning. Chronic (> 48 hours) hyponatremia tends to be less severe since there is time for adaptation to occur. The most prevalent symptoms are muscle cramps and ataxia, with seizures occurring with only very low serum sodium levels.
The rate of sodium correction is dependent on the acuity of the hyponatremia. Acute symptomatic hyponatremia can usually be corrected rapidly without permanent sequelae, although a rate of 2 mEq/L/hr is recommended. Hypertonic saline at 1-2 ml/kg/hr (or mannitol 0.25-1 gm/kg if hypertonic saline is unavailable), should be administered until cerebral symptoms subside. Lasix should be administered to increase free water excretion.
In chronic hyponatremia, however, rapid correction can result in osmotic demyelination syndrome (ODS) which is a delayed, gradual neurologic deterioration appearing one to several days after rapid correction. The goal is to increase serum sodium by 10% and not exceed 1.5 mEq/L/hr and 12 mEq in 24 hrs. Reversal of over correction with DDAVP or free water is recommended to relower the serum Na concentration and reduce the risk of ODS.
Vasopressin receptor antagonist (“aquaretics”) have recently emerged as a new treatment option for hyponatremia in euvolemic (SIADH) or hypervolemic (cirrhosis, CHF) states. These aquaretics stimulate the excretion of free water into urine with very little or no loss of sodium. Selective nonpeptide V2, receptor antagonists are in various stages of evaluation, including tolvaptan (PO), lixivaptan (PO), satavaptan (PO/), and Conivaptan (IV), a V1/V2 antagonists which is FDA approved for IV use in euvolemic and hypervolemic hyponatremia.
In 2003, Wong et al conducted a small randomized, placebo-controlled study of lixivaptan on 44 hyponatremic hospitalized patients with, cirrhosis, or SIADH. The results showed a significant, dose-related increase in free water clearance as well as serum sodium increase over 1 week. The randomized placebo-controlled clinical trials, SALT I and SALT II (Schrier et al.) demonstrated significant sodium concentration increase during a 30 day period with tolvaptan in 448 patients with euvolemic or hypovolemic hyponatremic, and improvement from baseline in the Mental Component of the Medical Outcomes Health Survey Short Form (SF-12).
Potential complications of aquaretics include ODS and hypotension secondary to the inappropriate use in hypovolemic hyponatremia, as well as unknown affects of blood-brain barrier penetration and CNS side effects. Questions still remain, including the long-term response rate, the role of water restriction, as well as the effects on cognitive function, functional state, overall quality of life, and survival.