Hepatology 1991


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Hepatology 1991

  1. 1. Journal of Pediatric Gastroenterology & Nutrition(C) 1999 Lippincott Williams & Wilkins, Inc.----------------------------------------------Volume 29(1) July 1999 pp 12-17----------------------------------------------Propranolol in Prevention of Portal Hypertensive Hemorrhage in Children: APilotStudy[Original Articles]Shashidhar, Harohalli; Langhans, Nancy; Grand, Richard J.Division of Pediatric Gastroenterology and Nutrition, Floating Hospital forChildren at New England Medical Center Hospitals; The Center forGastroenterologyResearch on Absorptive and Secretory Processes (GRASP), and DepartmentofPediatrics, Tufts University School of Medicine, Boston, Massachusetts,U.S.A.Address correspondence and reprint requests to Richard J. Grand, M.D.,Divisionof Pediatric Gastroenterology and Nutrition, The Floating Hospital forChildrenat New England Medical Center, 750 Washington Street, Box 213, Boston, MA02111-1533, U.S.A.Received June 4, 1998; revised November 20, 1998, and January 22, 1999;acceptedJanuary 22, 1999.This article is accompanied by an editorial. Please see Schreiber RA,Propranololand portal hypertension: Should kids be on the block?J Pediatr GastroenterolNutr 1999;29:10-11.----------------------------------------------OutlineABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCESGraphics
  2. 2. Table 1Table 2Table 3Table 4----------------------------------------------ABSTRACTBackground: Data regarding the use of propranolol in the prevention ofportalhypertensive hemorrhage in pediatric patients are limited despite itswidespreaduse in adults with cirrhosis. The purpose of this study was to evaluate safetyand efficacy of propranolol in the management of portal hypertension in thepediatric population. Medical information was retrieved from the records of 21 children withportalhypertension who received propranolol either before or after an episode ofgastrointestinal bleeding. Data collected included diagnosis, type of portalhypertension, age at initiation of therapy, bleeding episodes before andduringpropranolol therapy, degree of reduction of heart rate, adherence, andadverseeffects. Fourteen of 21 patients did not experience portal hypertensive bleedingwhilereceiving propranolol. Of the seven patients who had bleeding episodes, twohadfailed to adhere to the medication regimen, and four were receiving doses ofless than 1 mg/kg per day. Only one of the four patients who experiencedbleeding before initiation of therapy also bled while receiving propranolol,andtwo of the three patients who had a heart rate reduction of less than 25% eachexperienced a bleeding episode. Side effects were minimal and did notnecessitatediscontinuation of therapy in any patient.Conclusions: Propranolol was well tolerated with minimal side effects in ourpatients with portal hypertension. Adherence and adequacy of dosage (>1mg/kgper day, more than twice daily dose frequency) are important determinants ofefficacy. A reduction in heart rate of less than 25% may be associated with
  3. 3. suboptimal efficacy.----------------------------------------------Propranolol and other [beta]-blocking agents have been used for prophylaxisofgastrointestinal bleeding in adults with portal hypertension since the firstpublished report by Lebrec et al. (1). Most experience has been gained withthisusage in patients with chronic liver disease or cirrhosis. Data are limitedregarding the use of propranolol in children with portal hypertension (2,3).Variceal bleeding constitutes the most significant life-threatening clinicalsequela of portal hypertension, and most data on the natural history ofvaricealbleeding are from studies of adults with cirrhosis and portal hypertension.Theprevalence of varices in such patients is variable and is reported to bebetween24% and 69% (4). The estimates of risk of a first variceal bleeding episode inpatients with portal hypertension and liver disease vary from 27% to 48%(5-7).Approximately one third of unselected patients with cirrhosis eventuallybleed(8). The Child-Pugh classification, size of the varices, and red wale markingsare closely linked to the risk of variceal bleeding (5). However, the timing ofthe initial episode of bleeding cannot be accurately predicted, given thecurrent understanding of factors involved. In adults with cirrhosis the initialbleeding carries a mortality of 39% to 54% (9,10), and up to two thirds ofthosewho survive experience rebleeding (8). It has also been shown that the risk ofbleeding from varices is highest within the first 2 years of diagnosis (11).Beta blockade therapy for the prevention of both first and subsequent portalhypertensive bleeding episodes is an attractive alternative, considering themorbidity and mortality rates associated with the hemorrhage and thepotentialfor reducing the need for invasive measures, including sclerotherapy. Theeffects of beta blockade on portal hypertension are achieved by reductions ofboth cardiac output and portal vascular pressure due to decreased portalbloodflow and splanchnic arteriolar resistance, as well as reduction in varicealpressure (12).
  4. 4. Before the present study, prospective evaluation of beta blockade asprophylactictherapy for portal hypertensive bleeding had not been reported in pediatricpatients. Grading of varices has not customarily been included in studies ofgastrointestinal bleeding in children. In contrast with studies in adults, theChild-Pugh classification of severity of cirrhotic liver disease has not beentested in pediatric patients. (13). Extrahepatic portal hypertension is muchmore frequent in the pediatric age group, ranging from 50% to 70% of cases ofportal hypertension in several published series (14). This may have a bearingonthe severity and frequency of bleeding episodes in children, becauseextrahepaticportal hypertension is generally associated with less severe bleeding, andepisodes tend to decrease in frequency with increasing age, presumablybecauseof development of collateral vessels (15).The purpose of this pilot study was to evaluate the safety and efficacy ofpropranolol in the management of portal hypertensive bleeding in children.PATIENTS AND METHODSPropranolol was first used in our program in 1989. Through 1996, 21consecutivepediatric patients were treated with propranolol, either before or after theinitial portal hypertensive bleeding episode (age range 9 months to 18 years;12male and 9 females). Thus, the study population consisted of patients forwhompropranolol was prescribed after the diagnosis of portal hypertension anddetermination of the presence of esophageal and/or gastric varices but beforethe first portal hypertensive bleeding episode, and those for whom themedication was prescribed after the initial bleeding episode.Medical records were reviewed for patient demography, diagnosis, and typeofportal hypertension (extrahepatic or intrahepatic) based on accepted criteriaand the diagnostic method used to document the presence of varices. Otherdatareviewed included age at initiation of propranolol therapy, source ofgastrointestinalbleeding, mode of intervention to stop the bleeding, maximal and minimaldosageof propranolol used in each patient, and whether heart rate reduction astargeted was achieved. The time to the first bleeding episode after the start of
  5. 5. propranolol therapy was recorded for patients who bled while receivingpropranolol. Particular attention was given to adherence, side effects, and thenecessity for discontinuing the medication. Grading of varices was notroutinelyrecorded.RESULTSThe study population of 21 patients included 19 patients with cirrhosiscomplicated by portal hypertension and two with extrahepatic portalhypertensiondue to portal venous thrombosis in one and portal vein obstruction afterradiation therapy in the other. Most of the patients with cirrhosis had hadextrahepatic biliary atresia and had undergone a Kasai procedure (eightpatients). Other causes of chronic liver disease included autoimmunehepatitis,cystic fibrosis-related liver disease, congenital hepatic fibrosis, sclerosingcholangitis, cryptogenic cirrhosis (two patients each), and cirrhosis secondaryto total parenteral nutrition (one patient; Table 1). The laboratory datapertaining to liver function are shown in Table 2. Of the 21 patients, 55% hadhyperbilirubinemia, 33% had hypoalbuminemia, and 50% had prothrombintimes thatexceeded the upper limits of normal (Table 2).----------------------------------------------TABLE 1. Clinical details of patients receiving propranolol therapy----------------------------------------------
  6. 6. ----------------------------------------------TABLE 2. Liver function profile of patients at the initiation of propranololtherapy----------------------------------------------
  7. 7. Varices were documented in 16 patients with upper gastrointestinalendoscopy andin 5 by gastrointestinal barium series. Esophageal varices alonepredominated,followed by a combination of esophageal and gastric varices (Table 1). Portalhypertensive 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), and5 children had large (grade IV) varices (2 of these underwent upperendoscopywithin a few weeks after medication had been initiated at outside centers).Four patients had experienced at least one episode of gastrointestinal
  8. 8. bleedingbefore therapy was initiated (Table 3). None of these had receivedsclerotherapy.One patient with extrahepatic portal venous thrombosis required a surgicaltransection procedure to control bleeding. Variceal bleeding was establishedusing endoscopic confirmation, whether or not there had been a change inhemoglobin or occurrence of melena or hematemesis.----------------------------------------------TABLE 3. Portal hypertensive bleeding before propranolol therapy in each offourpatients----------------------------------------------The dosage of propranolol was adjusted to achieve a reduction of 25% inrestingheart rate (1). Ten patients received between 1.0 and 2.0 mg/kg per day, sixpatients were receiving less than 1.0 mg/kg per day, and five were receivingmore than 2.0 mg/kg per day. Heart rate reduction of 25% was achieved in 17patients at the start of therapy. Three patients achieved less than 25%reduction in heart rate. Two of these experienced an episode of bleedingwhilereceiving therapy. Two of the three patients had undergone endoscopy andhadsmall esophageal varices at the time the medication was prescribed. Of thetwowho experienced a bleeding episode, one had a red wale sign at the time ofbleeding, whereas the other child did not undergo endoscopy, because the
  9. 9. episodeof bleeding was managed conservatively at an outside center (Table 1). Thispatient had evidence of ascites and coagulopathy, both at the time ofbleedingand at the start of the medication. Insufficient information was available forone patient to document the effect of treatment on heart rate.Fourteen patients experienced no variceal bleeding episodes while receivingpropranolol. Of the seven patients who bled, two were noncompliant at thetimeof bleeding, and four were receiving dosages equal to or less than 1.0 mg/kgperday (Table 1). Both patients who had received 1 mg/kg per day had less than a25% reduction in the heart rate recorded at the beginning of therapy. Five ofthe seven patients had a twice-daily dose schedule. Six of the seven patientswho experienced bleeding had only one such documented episode. Only oneof fourpatients who had bled before receiving propranolol also bled while receivingtherapy. This patient, with associated renal hypertension, experiencedmultipleepisodes of bleeding while receiving propranolol at dosages adjusted forcontrolof hypertension. Bleeding occurred within 18 months of prescribing themedication in five of the seven patients in whom the interval could bedetermined.The side effects were mild and transient, and no patient requireddiscontinuationof the medication (Table 4). Two patients had reported dizziness andheadachesthat resolved on changing to a long-acting preparation of propranolol in oneandto atenolol in the other.----------------------------------------------TABLE 4. Adverse effects of propranolol therapy in pediatric patients
  10. 10. DISCUSSIONExperience with the long-term use of propranolol in pediatric patients forprophylaxis of portal hypertensive hemorrhage has not been described,despitesimilar usage in adults with cirrhosis. A meta-analysis of randomized,placebo-controlled studies in the adult population by Hayes et al. (16)showedreductions both in bleeding episodes (by 44%) and in deaths (by 42%) fromvariceal bleeding. A similar meta-analysis by Grace (17) showed a significantreduction in initial variceal hemorrhage but no increase in survival. In bothstudies the duration of follow-up was up to 3 years. Another meta-analysis ofstudies comparing [beta]-blocker with nonactive treatment (nine trials) inadultpatients with cirrhosis showed that [beta]-blockers significantly reduced theincidence of initial bleeding with a trend toward reduced mortality in thosewith a high risk of bleeding (large varices, red wale sign, and hepatic veinpressure gradient >12 mm Hg) (18). A meta-analysis by DAmico et al. (19)showedsimilar significant reduction in the risk of initial variceal bleeding with useof [beta]-blockers.In the present study, we showed the safety and efficacy of propranolol in thetreatment of variceal bleeding in children and adolescents. Of the sevenpatients who bled while receiving propranolol, two were noncompliant, andfourwere receiving less than 1.0 mg/kg propranolol. Five had a twice-daily doseschedule. The one patient who experienced multiple episodes of bleedingbefore
  11. 11. and during propranolol therapy had complicating renal hypertension. The 14patients who never experienced bleeding while receiving propranolol had adoseschedule of three times daily or more. Compliance and adequacy of dosageappearto be important determinants of efficacy, similar to the experience withpropranolol in adults (20,21). It is noteworthy that three of four patients whoexperienced bleeding before the initiation of therapy did not experiencebleeding after they began taking propranolol. This group of patients with apotentially higher risk of rebleeding also seemed to benefit from betablockade.The initial dosage in all patients was adjusted to achieve a reduction inresting heart rate by 25%. This was achieved in all but three patients at thestart of the therapy. Owing to weight gain and a decrease in baseline heartratewith age, establishing and maintaining an effective dose of propranolol forsustained reduction in heart rate remains a difficult problem in the pediatricage group. Of the seven patients who bled, initial reduction in heart rate(REFERENCES1. Lebrec D, Poynard T, Hillon P, Benhamou JP. Propranolol for prevention ofrecurrent gastrointestinal bleeding in patients with cirrhosis. N Engl J Med1981;305:1371-4. Bibliographic Links2. Ozsoylu S, Kocak N, Yuce A. Propranolol for portal hypertension inchildren.J Pediatr 1985;106:317-20. Bibliographic Links3. Hassall E. Nonsurgical treatments for portal hypertension in children.Gastrointest Endosc Clin N Am 1994;4:223-58.4. Pascal JP, Cales P, Desmorat H. Natural history of esophageal varices. In:Bosch J, Rodes J, eds. Recent advances in the pathophysiology and therapy ofportal hypertension. Rome: Ares-Sorono Symposia, 1989:127.5. The North Italian Endoscopic Club for the Study and Treatment ofEsophagealVarices. Prediction of the first variceal hemorrhage in patients with cirrhosisof the liver and esophageal varices: A prospective multicenter study. N Engl JMed 1991;324:1779-84.6. Kleber G, Sauerbruch T, Ansari H, Paumgartner G. Prediction of varicealhemorrhage in cirrhosis: A prospective follow-up study. Gastroenterology1991:100:1332-7. Bibliographic Links
  12. 12. 7. Gores GJ, Weisner RH, Dickson ER, Zinsmeister AR, Jorgensen RA,Langworthy A.Prospective evaluation of esophageal varices in primary biliary cirrhosis:Development, natural history and influence on survival. Gastroenterology1989;96:1552-9. Bibliographic Links8. de Franchis R, Primignani M. Why do varices bleed? Gastroenterol Clin NAm1992;21:85-101. Bibliographic Links9. Hislop IG, Waters TE, Kellock TD, Swynnerton B. The natural history ofhemorrhage from esophageal varices. Lancet 1966;1:945-8. BibliographicLinks10. Graham DY, Smith JL. The course of patients after variceal hemorrhage.Gastroenterology 1981;80:800-9. Bibliographic Links11. Baker LA, Smith C, Lieberman G. The natural history of esophagealvarices. Astudy of 115 cirrhotic patients in whom varices were diagnosed prior tobleeding. Am J Med 1959;26:228-37.12. Feu F, Bordas JM, Luca A, et al. Reduction of variceal pressure bypropranolol: Comparison of the effects on portal pressure and azygos bloodflowin patients with cirrhosis. Hepatology 1993;18:1082-9.13. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R.Transection ofthe oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-9.Bibliographic Links14. Shneider BL, Groszman RJ. Portal hypertension. In: Suchy FJ, Ed. Liverdisease in children. St. Louis: Mosby, 1994:249-66.15. Webb LJ, Sherlock S. The aetiology, presentation and natural history ofextra-hepatic portal venous obstruction. Q J Med 1979;192:627-39.16. Hayes PC, Davis JM, Lewis JA, Bouchier IAD. Meta-analysis of the valueofpropranolol in prevention of variceal hemorrhage. Lancet 1990;336:153-6.Bibliographic Links17. Grace ND. Prevention of initial variceal hemorrhage. Gastroenterol Clin
  13. 13. N Am1992;21:149-61. Bibliographic Links18. Pagliaro L, DAmico G, Sorenson TIA, et al. Prevention of first bleeding incirrhosis. A meta-analysis of randomised trials of non-surgical treatment.AnnIntern Med 1992;117:59-70.19. DAmico G, Pagliaro L, Bosch J. The treatment of portal hypertension: Ameta-analytic review. Hepatology 1995:22:332-54.20. Conn HO, Grace ND, Bosch J, et al. Propranolol in the prevention of thefirst hemorrhage from esophagogastric varices: A multicenter, randomizedclinical trial. The Boston-New Haven-Barcelona Portal Hypertension StudyGroup.Hepatology 1991;13:902-12. Bibliographic Links21. Poynard T, Lebrec D, Hillon P, et al. Propranolol for prevention ofrecurrent gastrointestinal bleeding in patients with cirrhosis: A prospectivestudy of factors associated with rebleeding. Hepatology 1987;7:447-51.Bibliographic Links22. Belle SH, Beringer KC, Detre KM. An update on liver transplantation intheUnited States: Recipient characteristics and outcome. In: Cecka JM, TerasakiPI,Eds. Clinical transplants. Los Angeles: UCLA Tissue Typing Laboratory,1995:19-23.23. Artman M. Pharmacotherapy In: Emmanoulides GC, Allen HD,Riemenschneider TA,Gutgessel HP, Eds. Moss Adams heart disease in infants, children andadolescentsincluding the fetus and young adult. Baltimore: Williams and Wilkins,1995:375-98.24. The Italian Multicenter Project for Propranolol in Prevention of Bleeding.Propranolol prevents first gastrointestinal bleeding in non-ascitic cirrhoticpatients. J Hepatol 1989;9:75-83. Bibliographic Links25. Pascal JP, Cales P, and a Multicenter Study Group. Propranolol in theprevention of first upper gastrointestinal tract hemorrhage in patients withcirrhosis of the liver and esophageal varices. N Engl J Med 1987;317:856-61.
  14. 14. Key Words: Gastrointestinal bleeding; Portal hypertension; Prophylaxis;Propranolol; Varices