Conivaptan Therapy in an Infant with Severe Hyponatremia and Congestive Heart Failure

Abstract

Conivaptan is a nonspecific arginine vasopressin receptor antagonist that has been used as therapy in adults who have hypervolemic hyponatremia due to congestive heart failure. Its use in children with congestive heart failure has not been reported. We describe the use of conivaptan in a 4-month-old infant girl with severe hypervolemic hyponatremia and heart failure. A therapeutic weight-based dose was extrapolated from the adult dose. Conivaptan therapy was administered for 48 hours, after which the patient recovered from her hyponatremia without untoward effects. Arginine vasopressin receptor antagonists such as conivaptan may be useful as therapy for hyponatremia associated with heart failure. Further studies are required before conivaptan can be recommended for routine use in children.

Hyponatremia is a known complication of congestive heart failure (CHF).¹ Conivaptan hydrochloride is a nonspecific arginine vasopressin receptor (AVPR) antagonist that has been used in adults with euvolemic and hypervolemic hyponatremia in the presence of CHF.² The use of conivaptan in children with CHF has not been reported. We report our use of conivaptan to treat severe hypervolemic hyponatremia in an infant with CHF secondary to left ventricular (LV) noncompaction cardiomyopathy.

Case Report

In June 2011, a 4-month-old, 8.5-kg infant girl with an unremarkable birth, medical, and family medical history was admitted with a 1-day history of dyspnea. Her heart rate was 180 beats/min; respiratory rate, 70 breaths/min; blood pressure, 70/45 mmHg; and oxygen saturation level, 98% on room air. Physical examination revealed a well-nourished, nondysmorphic female infant in severe respiratory distress, with bilateral basilar rales, severe subcostal retractions, an S₃ gallop, a grade 2/6 holosystolic apical murmur consistent with mitral regurgitation, marked hepatomegaly, and moderate generalized edema but normal peripheral perfusion. A neurologic examination revealed no focal deficits, and her muscle tone was appropriate for her age. Laboratory findings were significant for an N-terminal pro-brain natriuretic peptide level of 45,157 pg/mL, a hemoglobin level of 8.8 mg/dL, and a lactate level of 2.3 mMol/L. Preliminary laboratory screening for metabolic and mitochondrial disorders yielded negative results. A chest radiograph showed marked cardiomegaly and pulmonary edema. An echocardiogram revealed features of LV noncompaction cardiomyopathy, severe LV enlargement, severely depressed LV systolic function (ejection fraction, 0.22 by Simpson's biplane method), and moderate mitral valve regurgitation. Cardiac magnetic resonance images confirmed the diagnosis of LV noncompaction cardiomyopathy and did not show features that suggested myocarditis.

Heart failure management was begun, including positive-pressure ventilation, dopamine and milrinone infusions, and therapy with multiple diuretic agents. These agents, administered at various times during the patient's hospital stay, included furosemide, chlorothiazide, spironolactone, acetazolamide, and metolazone. The diuretic therapy helped to improve the general edema; however, the patient's serum sodium level steadily decreased (Fig. 1). Therapy for the hyponatremia involved a combination of fluid restriction, oral sodium chloride supplements, and the discontinuation of metolazone and chlorothiazide. Despite these measures, the hyponatremia continued to worsen, so it was decided to attempt AVPR antagonism with use of conivaptan.

Fig. 1 Graph shows the patient's serum sodium concentrations during the first 16 days of her hospital stay.

On the 10th hospital day, the patient's serum sodium level fell to 119 mEq/L. After an initial intravenous bolus of 2 mEq/kg of sodium chloride, an intravenous bolus dose of 0.3 mg/kg of conivaptan was given over 30 minutes, followed by a continuous infusion of 0.3 mg/kg/d. Eight hours after the start of conivaptan therapy, the patient's serum sodium level increased from 119 to 124 mEq/L. Blood sampling for serum sodium monitoring was performed only once daily because of the patient's low hemoglobin level upon hospitalization and also her parents' Jehovah's Witness beliefs. After 24 hours of the 0.3 mg/kg/d conivaptan dose, the infusion was increased to 0.4 mg/kg/d. The patient's serum sodium levels continued to increase during the next 24 hours. We observed only a minimal increase in the patient's urine output during conivaptan therapy (Fig. 2). This is of note, because increased urine output is expected with AVPR inhibition. After 48 hours of conivaptan infusion, a final 0.2-mg/kg bolus infusion was given over 30 minutes, and the drug was discontinued. The patient did not develop hypotension or hypertension during conivaptan therapy, and no local site irritation occurred, because the conivaptan had been infused through a femoral central venous line. Her serum sodium levels were stable after the discontinuation of conivaptan and slowly returned to normal during the next 3 weeks. She was discharged from the hospital with a normal serum sodium level (135 mEq/L). Furosemide, captopril, and other medications were prescribed for her CHF.

Fig. 2 Graph shows the patient's urine output during the first 16 days of her hospital stay. A small increase in urine output was observed after conivaptan therapy was begun.

Discussion

Hyponatremia, a known sequela of CHF, is considered to be a strong predictor of poor outcome in hospitalized adults.¹ The pathogenesis of hyponatremia in CHF is multifactorial. Likely causes include increased extracellular fluid volume, disproportionate secretion of arginine vasopressin, and overuse of diuretics. Treatments include fluid restriction, withdrawal of diuretic therapy, and neurohormonal blockade; however, the efficacy of these methods is poorly documented.³

Plasma levels of arginine vasopressin are inappropriately elevated in both acute and chronic heart failure.⁴ Activation of one receptor, AVPR_1a, results in the constriction of smooth muscle and has a positive inotropic effect in cardiac muscle. Activation of another, AVPR₂, increases the permeability of water in the renal collecting tubular cells, resulting in water retention. Blocking the effects of AVPR₂ produces aquaresis, the electrolyte-sparing excretion of water—an ideal approach to correcting hypervolemic hyponatremia.⁵

Arginine vasopressin receptor antagonists include conivaptan, tolvaptan, lixivaptan, and satavaptan, and their clinical use in adults has been reviewed by Oghlakian and Klapholz⁶ and by others.⁷ These AVPR antagonists are a relatively new class of medications that have been given to adults who have hyponatremia secondary to CHF. However, because no long-term benefit was found in randomized controlled trials, this class of medications has not been approved for the treatment of CHF.^7,8 Conivaptan is approved by the United States Food and Drug Administration as therapy for euvolemic and hypervolemic hyponatremia in adults, and in clinical practice it is most often given to patients who have syndrome of inappropriate secretion of antidiuretic hormone (SIADH). However, AVPR antagonists have not been studied in children.

To our knowledge, conivaptan therapy in children with CHF has not been reported. One report in the pediatric medical literature described the use of conivaptan in a 13-year-old boy who had metastatic large-cell lymphoma with hyponatremia due to SIADH.⁹ Conivaptan therapy enabled adequate intravenous hydration before the induction of chemotherapy. In that 49-kg child, a loading dose of 10 mg (0.2 mg/kg) was followed by the infusion of 10 mg/d (0.2 mg/kg/d). The patient's serum sodium level did not increase sufficiently after 6 hours of conivaptan infusion, so the infusion dose was increased to 30 mg/d (0.6 mg/kg/d). The patient's serum sodium level then increased during the next 18 hours; his urine output increased and urine osmolality decreased, indicating the induction of free water clearance by conivaptan. The conivaptan therapy was tapered and discontinued after 4 days, and no side effects were reported.⁹

When conivaptan is used as therapy for euvolemic and hypervolemic hyponatremia in adults, the recommended dose is a 20-mg intravenous bolus infused over 30 minutes followed by infusion of 20 to 40 mg/d for a maximum period of 4 days.¹⁰ The dose for children has not been established. For our infant patient, we extrapolated a weight-based pediatric dose from the adult dosage guidelines. Initially, the 20-mg bolus—based on that for a 70-kg adult—was converted to a bolus of 0.3 mg/kg. The 40-mg maximum daily adult dose was converted to a maximum daily dose of 0.6 mg/kg. In our patient, after the initial 0.3-mg/kg bolus, we started the infusion at 0.3 mg/kg/d. When the dose was increased on day 2 of therapy, we chose a gradual increase to 0.4 mg/kg/d instead of a maximum dose of 0.6 mg/kg. We observed a gradual increase in the patient's serum sodium level without any rapid changes in fluid balance. Her urine output increased only minimally during conivaptan therapy. We attribute this unexpected finding to the discontinuation of other potent diuretic agents, including metolazone and chlorothiazide, immediately before the conivaptan therapy was begun. The patient's serum levels of blood urea nitrogen (18 mg/dL) and creatinine (0.5 mg/dL) were normal before conivaptan therapy and did not change significantly during conivaptan infusion, suggesting that her renal function was not impaired by that medication. Because of the steady improvement in serum sodium levels, we limited the duration of conivaptan therapy to 48 hours, consistent with the suggested 1- to 4-day duration of therapy in adults. After the therapy was discontinued, the patient showed no signs of rebound hyponatremia, which is a sequela that has been reported.⁸

At conivaptan doses extrapolated from the recommended adult doses, our patient's hyponatremia improved over 48 hours without adverse effects. Our experience suggests the potential use of conivaptan as therapy for severe hyponatremia in pediatric patients with CHF; however, further studies are needed to determine the safety and efficacy of conivaptan and its optimal dosage in children.