Arginine vasopressin plays a major role in preserving water balance, osmolality, and blood volume. Tolvaptan is the first oral arginine vasopressin receptor antagonist for the treatment of hypervolaemic or euvolaemic hyponatraemia, which is associated with cardiac failure, cirrhosis, or syndrome of inappropriate antidiuretic hormone secretion.Reference Zmily, Daifallah and Ghali 1 It is a new therapeutic drug for treating congestive cardiac failure resistant to other diuretics in adults. The result of The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan proved the effectiveness of tolvaptan on congestive cardiac failure in the acute phase.Reference Gheorghiade, Konstam and Burnett 2 However, the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan outcome trial demonstrated that tolvaptan had no effect on long-term mortality or cardiac failure-related morbidity.Reference Konstam, Gheorghiade and Burnett 3 This report presents the case of a 6-year-old boy who recovered from severe congestive cardiac failure with the administration of tolvaptan.
Case report
A 6-year-old boy with restrictive cardiomyopathy had been hospitalised and held for cardiac transplantation. His cardiac failure was initially managed by oral administration of 4.2 mg/kg of furosemide, 4.2 mg/kg of spironolactone, and 0.08 mg/kg of trichlormethiazide per day. However, his cardiac failure worsened after he developed enteritis, and his condition deteriorated. A physical examination revealed facial oedema, jugular vein dilatation, gallop heart sounds, reduced respiratory sounds in the right side of the lung field, abdominal distention, and hepatomegaly with massive ascites. A chest X-ray revealed massive pleural effusion (Fig 1). Although continuous intravenous infusion of furosemide was up-titrated to 0.3 mg/kg/hour, the congestion did not improve. In addition, his body weight increased from 10.9 to 12.3 kg within a few days. Although a large amount of pleural effusion accumulated, we selected medical therapy rather than thoracocentesis in order to eliminate the fluid because the patient demonstrated no respiratory symptoms, and general anaesthesia – or administration of sedative drugs – during thoracocentesis was considered to have a risk of making his cardiac failure worse. His serum sodium concentration decreased to 118 mEq/L. Tolvaptan was started orally 9 days after the initiation of furosemide infusion, at an initial dose of 2 mg (0.17 mg/kg/day). The serum sodium concentration was monitored meticulously to avoid hypernatraemia; it was measured before the administration of tolvaptan, every 6 hours of the 1st day and every 24 hours after that. The dosage of tolvaptan was gradually up-titrated to 5 mg/day (0.42 mg/kg/day). His serum sodium concentration gradually elevated from 121 to 127 mEq/L during the 24 hours after the start of tolvaptan therapy. Tolvaptan helped increase his urine output and his body weight gradually decreased (Fig 1). The pleural effusion had almost disappeared by day 47. Laboratory data at initiation of tolvaptan therapy and at day 47 were: serum sodium concentration, 121 and 133 mEq/L; serum osmolality, 248 and 287 mOsm/kg; and urine osmolality, 246 and 216 mOsm/kg, respectively. There were no significant changes in the concentration of serum creatinine, blood urea nitrogen, and potassium, as well as in the vital signs, during tolvaptan administration (Table 1).
Figure 1 Clinical course – changes in chest X-ray, diuretics, body weight, Na concentration, and urinary volume with time. Chest X-ray: (left) a large pleural effusion was observed before tolvaptan administration and (right) the pleural effusion almost disappeared 40 days after the administration of tolvaptan. CIV = continuous intravenous infusion; Na = sodium.
Table 1 Laboratory and clinical data before and after tolvaptan administration.
mEq/L = milliequivalent per litre; mg/dl = milligram per decilitre; min = minute; mmHg = millimetres of mercury; mOsm/kg H2O = milliosmol per kilogram H2O
Discussion
Tolvaptan, a selective vasopressin V2-receptor antagonist, acts on the distal nephron and causes loss of electrolyte-free water.Reference Goldsmith and Gheorghiade 4 There are no reports on the administration of tolvaptan, not only for cardiac failure but also for other conditions such as cirrhosis and syndrome of inappropriate antidiuretic hormone secretion, in the paediatric field.
As therapeutic drugs for cardiac failure, catecholamines, diuretics, carperitide, and phosphodiesterase type III inhibitors have all been approved for treatment in Japan. In this case, the patient's primary illness, restrictive cardiomyopathy, and the inefficacy of the previous administration of carperitide and phosphodiesterase type III inhibitor prompted us to start tolvaptan administration in addition to loop diuretics.
In Japan, adult patients with cardiac failure are treated with 15 mg of tolvaptan per day. There is no established recommended dosage for administration of the drug in children. The target dose of tolvaptan was set to 5 mg/day in the current patient and was started at a dose of 2 mg, taking his age – 6 years – and body weight (∼10 kg) into consideration. The slow up-titration of the drug could improve his congestive cardiac failure symptoms without side effects such as hypernatraemia. Moreover, the administration of tolvaptan could reduce the dosage of furosemide.
It is reported that high-dose furosemide administration makes the patients’ prognosis worse.Reference Eshaghian, Horwich and Fonarow 5 Reducing the dosage of furosemide by administration of tolvaptan may result in the improvement of the outcome in cardiac failure patients. Although the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan outcome trial demonstrated that tolvaptan had no effect on long-term mortality or cardiac failure-related morbidity, it comprised a very small number of cardiac failure patients with hyponatraemia. In the Multicenter Evaluation of Tolvaptan Effect on Remodeling trial, there was a significantly favourable effect of tolvaptan on the composite of mortality or cardiac failure hospitalisation during the 1-year period.Reference Udelson, McGrew and Flores 6 In the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure trial, the 60-day mortality rate was lower in tolvaptan-treated patients with high blood urea nitrogen levels or severe systemic congestion.Reference Gheorghiade, Gattis and O'Connor 7 However, an analysis carried out on a large cohort of patients to assess the long-term prognosis of tolvaptan treatment is needed for drawing any definitive conclusions.
In our case, the administration of tolvaptan dramatically improved the loop diuretic-resistant congestive cardiac failure in a 6-year-old boy with restrictive cardiomyopathy. Tolvaptan could be a useful and safe drug, even in children with severe congestive cardiac failure. It may improve the long-term outcome in children. However, careful observation is essential during tolvaptan administration, because it is well known that serious side effects, such as hypernatraemia and dehydration, can occur. Moreover, the optimal dosage of tolvaptan has not been postulated in children. Further investigations are needed in order to establish an effective strategy on using tolvaptan for children with congestive cardiac failure.
