Varices were documented in 16 patients with upper gastrointestinal endoscopy and in 5 by gastrointestinal barium series. Esophageal varices alone predominated, followed by a combination of esophageal and gastric varices (Table 1). Portal hypertensive gastropathy was documented at endoscopy in 5 of 16 patients. Varices in 11 of these 16 patients were described as small (grade I or II), and 5 children had large (grade IV) varices (2 of these underwent upper endoscopy within a few weeks after medication had been initiated at outside centers).
Four patients had experienced at least one episode of gastrointestinal bleeding before therapy was initiated (Table 3). None of these had received sclerotherapy. One patient with extrahepatic portal venous thrombosis required a surgical transection procedure to control bleeding. Variceal bleeding was established using endoscopic confirmation, whether or not there had been a change in hemoglobin or occurrence of melena or hematemesis.
The dosage of propranolol was adjusted to achieve a reduction of 25% in resting heart rate (1). Ten patients received between 1.0 and 2.0 mg/kg per day, six patients were receiving less than 1.0 mg/kg per day, and five were receiving more than 2.0 mg/kg per day. Heart rate reduction of 25% was achieved in 17 patients at the start of therapy. Three patients achieved less than 25% reduction in heart rate. Two of these experienced an episode of bleeding while receiving therapy. Two of the three patients had undergone endoscopy and had small esophageal varices at the time the medication was prescribed. Of the two who experienced a bleeding episode, one had a red wale sign at the time of bleeding, whereas the other child did not undergo endoscopy, because the episode of bleeding was managed conservatively at an outside center (Table 1). This patient had evidence of ascites and coagulopathy, both at the time of bleeding and at the start of the medication. Insufficient information was available for one patient to document the effect of treatment on heart rate.
Fourteen patients experienced no variceal bleeding episodes while receiving propranolol. Of the seven patients who bled, two were noncompliant at the time of bleeding, and four were receiving dosages equal to or less than 1.0 mg/kg per day (Table 1). Both patients who had received 1 mg/kg per day had less than a 25% reduction in the heart rate recorded at the beginning of therapy. Five of the seven patients had a twice-daily dose schedule. Six of the seven patients who experienced bleeding had only one such documented episode. Only one of four patients who had bled before receiving propranolol also bled while receiving therapy. This patient, with associated renal hypertension, experienced multiple episodes of bleeding while receiving propranolol at dosages adjusted for control of hypertension. Bleeding occurred within 18 months of prescribing the medication in five of the seven patients in whom the interval could be determined.
The side effects were mild and transient, and no patient required discontinuation of the medication (Table 4). Two patients had reported dizziness and headaches that resolved on changing to a long-acting preparation of propranolol in one and to atenolol in the other.
Experience with the long-term use of propranolol in pediatric patients for prophylaxis of portal hypertensive hemorrhage has not been described, despite similar usage in adults with cirrhosis. A meta-analysis of randomized, placebo-controlled studies in the adult population by Hayes et al. (16) showed reductions both in bleeding episodes (by 44%) and in deaths (by 42%) from variceal bleeding. A similar meta-analysis by Grace (17) showed a significant reduction in initial variceal hemorrhage but no increase in survival. In both studies the duration of follow-up was up to 3 years. Another meta-analysis of studies comparing β-blocker with nonactive treatment (nine trials) in adult patients with cirrhosis showed that β-blockers significantly reduced the incidence of initial bleeding with a trend toward reduced mortality in those with a high risk of bleeding (large varices, red wale sign, and hepatic vein pressure gradient >12 mm Hg) (18). A meta-analysis by D'Amico et al. (19) showed similar significant reduction in the risk of initial variceal bleeding with use of β-blockers.
In the present study, we showed the safety and efficacy of propranolol in the treatment of variceal bleeding in children and adolescents. Of the seven patients who bled while receiving propranolol, two were noncompliant, and four were receiving less than 1.0 mg/kg propranolol. Five had a twice-daily dose schedule. The one patient who experienced multiple episodes of bleeding before and during propranolol therapy had complicating renal hypertension. The 14 patients who never experienced bleeding while receiving propranolol had a dose schedule of three times daily or more. Compliance and adequacy of dosage appear to be important determinants of efficacy, similar to the experience with propranolol in adults (20,21). It is noteworthy that three of four patients who experienced bleeding before the initiation of therapy did not experience bleeding after they began taking propranolol. This group of patients with a potentially higher risk of rebleeding also seemed to benefit from beta blockade.
The initial dosage in all patients was adjusted to achieve a reduction in resting heart rate by 25%. This was achieved in all but three patients at the start of the therapy. Owing to weight gain and a decrease in baseline heart rate with age, establishing and maintaining an effective dose of propranolol for sustained reduction in heart rate remains a difficult problem in the pediatric age group. Of the seven patients who bled, initial reduction in heart rate (<25%) was achieved at the start of therapy in five of the patients. However, two were noncompliant at the time of bleeding. Reduction in cardiac output accounts only partially for reduction in portal venous pressure. Direct effects on the portal and splanchnic vascular systems may act to reduce variceal pressure in addition to the negative chronotropic effect. This may account for the difference in efficacy at different dosages and dose frequencies, despite successful reduction in heart rate. Other noninvasive means of determining an effective dose should thus include not only cardiac kinetics by echocardiography but also Doppler assessment of portal venous flow. These methods will help in further understanding the adequacy of dosage and may provide an additional method to document efficacy of beta blockade in reducing portal hypertension in children.
Liver transplantation is established as the treatment of choice for most progressive chronic liver disorders in children; the severity and progression of portal hypertension may also influence the timing of liver transplantation. Approximately half of pediatric liver transplant recipients are outside the hospital awaiting transplantation and therefore have a relatively stable clinical status before receiving new livers (22). Beta blockade offers the possibility of reducing the prevalence of variceal bleeding as a comorbid factor in this ambulatory population.
Propranolol has been used in other clinical settings in the pediatric age group including supraventricular tachyarrhythmia, hypertension, and migraine headache with an excellent safety profile (23). Concern regarding the usage of propranolol in children with portal hypertension has centered on possible excessive suppression of beta-sympathomimetic activity, hypoglycemia, potentially impaired compensatory vascular response in the face of blood loss, and reduced long-term school performance. In our experience with this medication, adverse effects were mild, transient, and when present, mostly caused by known systemic effects of beta blockade. Hypoglycemia was not encountered in any of our young patients.
In studies in adults with cirrhosis and portal hypertension, the response to beta blockade has been characterized in terms of variceal grading (24,25). Although varices have not been routinely graded in previous studies in children, data from this study indicate that in the future grading of varices is needed to achieve uniformity in reporting results and identifying subgroups of patients who could benefit from beta blockade therapy.
The present study has some inherent limitations: It was nonrandomized and had no routine grading of varices before and during propranolol therapy. The study population was not stratified according to severity and stage of liver disease. However, in this first long-term study in a pediatric population, the results strongly indicate efficacy of beta blockade therapy in the treatment of portal hypertension, and highlight the necessity for future prospective studies to examine these issues.
In general, in this patient population with portal hypertension, propranolol was well tolerated, was associated with minimal side effects, and appeared to be effective in reducing the frequency of both first and subsequent bleeding episodes. Adherence and dosage greater than 1 mg/kg per day given in at least three divided doses are important determinants of efficacy. Heart rate reduction of less than 25% may be associated with inadequate protection. Prospective, multicenter trials that enable patient recruitment in larger numbers are necessary to determine the factors influencing efficacy of propranolol in the prevention of variceal bleeding in children. Applicability of Child-Pugh classification and variceal grading, as well as measures of effective and adequate beta blockade, are other factors that should be investigated in future studies evaluating medical therapy for portal hypertension in the pediatric age group.
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Keywords:© 1999 Lippincott Williams & Wilkins, Inc.
Gastrointestinal bleeding; Portal hypertension; Prophylaxis; Propranolol; Varices