Propranolol and other β-blocking agents have been used for prophylaxis of gastrointestinal bleeding in adults with portal hypertension since the first published report by Lebrec et al. (1). Most experience has been gained with this usage in patients with chronic liver disease or cirrhosis. Data are limited regarding the use of propranolol in children with portal hypertension (2,3).
Variceal bleeding constitutes the most significant life-threatening clinical sequela of portal hypertension, and most data on the natural history of variceal bleeding are from studies of adults with cirrhosis and portal hypertension. The prevalence of varices in such patients is variable and is reported to be between 24% and 69% (4). The estimates of risk of a first variceal bleeding episode in patients with portal hypertension and liver disease vary from 27% to 48% (5-7).
Approximately one third of unselected patients with cirrhosis eventually bleed (8). The Child-Pugh classification, size of the varices, and red wale markings are closely linked to the risk of variceal bleeding (5). However, the timing of the initial episode of bleeding cannot be accurately predicted, given the current understanding of factors involved. In adults with cirrhosis the initial bleeding carries a mortality of 39% to 54% (9,10), and up to two thirds of those who survive experience rebleeding (8). It has also been shown that the risk of bleeding from varices is highest within the first 2 years of diagnosis (11).
Beta blockade therapy for the prevention of both first and subsequent portal hypertensive bleeding episodes is an attractive alternative, considering the morbidity and mortality rates associated with the hemorrhage and the potential for reducing the need for invasive measures, including sclerotherapy. The effects of beta blockade on portal hypertension are achieved by reductions of both cardiac output and portal vascular pressure due to decreased portal blood flow and splanchnic arteriolar resistance, as well as reduction in variceal pressure (12).
Before the present study, prospective evaluation of beta blockade as prophylactic therapy for portal hypertensive bleeding had not been reported in pediatric patients. Grading of varices has not customarily been included in studies of gastrointestinal bleeding in children. In contrast with studies in adults, the Child-Pugh classification of severity of cirrhotic liver disease has not been tested in pediatric patients. (13). Extrahepatic portal hypertension is much more frequent in the pediatric age group, ranging from 50% to 70% of cases of portal hypertension in several published series (14). This may have a bearing on the severity and frequency of bleeding episodes in children, because extrahepatic portal hypertension is generally associated with less severe bleeding, and episodes tend to decrease in frequency with increasing age, presumably because of development of collateral vessels (15).
The purpose of this pilot study was to evaluate the safety and efficacy of propranolol in the management of portal hypertensive bleeding in children.
PATIENTS AND METHODS
Propranolol was first used in our program in 1989. Through 1996, 21 consecutive pediatric patients were treated with propranolol, either before or after the initial portal hypertensive bleeding episode (age range 9 months to 18 years; 12 male and 9 females). Thus, the study population consisted of patients for whom propranolol was prescribed after the diagnosis of portal hypertension and determination of the presence of esophageal and/or gastric varices but before the first portal hypertensive bleeding episode, and those for whom the medication was prescribed after the initial bleeding episode.
Medical records were reviewed for patient demography, diagnosis, and type of portal hypertension (extrahepatic or intrahepatic) based on accepted criteria and the diagnostic method used to document the presence of varices. Other data reviewed included age at initiation of propranolol therapy, source of gastrointestinal bleeding, mode of intervention to stop the bleeding, maximal and minimal dosage of propranolol used in each patient, and whether heart rate reduction as targeted was achieved. The time to the first bleeding episode after the start of propranolol therapy was recorded for patients who bled while receiving propranolol. Particular attention was given to adherence, side effects, and the necessity for discontinuing the medication. Grading of varices was not routinely recorded.
The study population of 21 patients included 19 patients with cirrhosis complicated by portal hypertension and two with extrahepatic portal hypertension due to portal venous thrombosis in one and portal vein obstruction after radiation therapy in the other. Most of the patients with cirrhosis had had extrahepatic biliary atresia and had undergone a Kasai procedure (eight patients). Other causes of chronic liver disease included autoimmune hepatitis, cystic fibrosis-related liver disease, congenital hepatic fibrosis, sclerosing cholangitis, cryptogenic cirrhosis (two patients each), and cirrhosis secondary to total parenteral nutrition (one patient; Table 1). The laboratory data pertaining to liver function are shown in Table 2. Of the 21 patients, 55% had hyperbilirubinemia, 33% had hypoalbuminemia, and 50% had prothrombin times that exceeded the upper limits of normal (Table 2).
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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