Pediatric Drugs

, Volume 4, Issue 12, pp 771–778 | Cite as

Should β-Blockers be Used for the Treatment of Pediatric Patients with Chronic Heart Failure?

Leading Article


In multiple clinical trials, β-blockers have been shown to significantly improve morbidity and mortality in adults with chronic congestive heart failure, but there is little reported experience with their use in children. Heart failure involves activation of the adrenergic nervous system and other neurohumoral systems in order to maintain cardiovascular homeostasis. These compensatory mechanisms have been shown to cause myocardial damage with chronic activation, which has been hypothesized to be a major contributing factor to the clinical deterioration of adults with heart failure. Studies have demonstrated inhibition of this neurohumoral response and concomitant clinical benefits with β-blockers. Consequently, β-blockers have evolved to become an important part of comprehensive medical therapy for congestive heart failure in adults.

Pediatric heart failure represents an entirely different spectrum of disease, caused more commonly by congenital heart disease than cardiomyopathy. Surgical palliation and correction are important components of pediatric heart failure therapy, and residual, postsurgical cardiac lesions can lead to chronic heart failure. Although neurohumoral activation in children is similar to that in adults with heart failure, there are important differences from adults in physiology and developmental changes that are especially observed in infants.

Current published clinical experience with β-blocker use in children with heart failure is limited to case series with relatively small numbers of patients. Nevertheless, these series show consistent symptomatic improvement, and improvement in ventricular systolic function in patients with cardiomyopathies and congenital heart disease, similar to findings in adults. Adverse effects were common and many patients in these studies had adverse outcomes (death and/or need for transplantation). One study has noted differences in pharmacokinetics in children compared with adults. However, a multicenter, randomized controlled trial to evaluate carvedilol in pediatric heart failure from systolic ventricular dysfunction is currently ongoing and should help to clarify the efficacy and tolerability of carvedilol in children.


Heart Failure Digoxin Chronic Heart Failure Metoprolol Carvedilol 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors have provided no information on sources of funding or on conflicts of interest directly relevant to the content of this review.


  1. 1.
    Hunt SA, Baker DW, Hein MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary and recommendations. J Am Coll Cardiol 2001; 38: 2101–13PubMedCrossRefGoogle Scholar
  2. 2.
    Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001; 22: 1527–60PubMedCrossRefGoogle Scholar
  3. 3.
    Lipshultz SE, Sleeper LA, Towbin JA, et al. The incidence of pediatric cardiomyopathy: the prospective pediatric cardiomyopathy registry. J Am Coll Cardiol 2001; 37: 465–466ACrossRefGoogle Scholar
  4. 4.
    Kay JD, Colan SD, Graham TP. Congestive heart failure in pediatric patients. Am Heart J 2001; 142: 923–8PubMedCrossRefGoogle Scholar
  5. 5.
    Colucci WS, Braunwald E. Pathophysiology of heart failure. In: Braunwald A, editor. Textbook of cardiovascular medicine. 6th ed. Philadelphia (PA): WB Saunders Company, 2001: 503–33Google Scholar
  6. 6.
    Packer M. Pathophysiology of chronic heart failure. Lancet 1992; 340: 88–91PubMedCrossRefGoogle Scholar
  7. 7.
    Dreyer, WJ, Fisher DJ. Clinical recognition and management of chronic congestive cardiac failure. In: Garson A, Bricker JT, Fisher DJ, et al., editors. The science and practice of pediatric cardiology. Baltimore (MD): Williams and Wilkins, 1998: 2309–25Google Scholar
  8. 8.
    Auslender M. Pathophysiology of pediatric heart failure. Prog Pediatr Cardiol 2000; 11: 175–84PubMedCrossRefGoogle Scholar
  9. 9.
    Abraham WT, Singh B. Ischemic and nonischemic heart failure do not require different treatment strategies. J Cardiovasc Pharmacol 1999; 33Suppl. 3: S1–7PubMedGoogle Scholar
  10. 10.
    Packer M, Bristow MR, Cohn JN, et al., for the US Carvedilol Study Group. The effect of carvedilol on morbidy and mortality in patients with chronic heart failure. N Engl J Med 1996; 334: 1349–55PubMedCrossRefGoogle Scholar
  11. 11.
    Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium: fibrosis and renin-angiotensin-aldosterone system. Circulation 1991; 83: 1849–65PubMedCrossRefGoogle Scholar
  12. 12.
    Weber KT. Aldosterone in congestive heart failure. N Engl J Med 2001; 345: 1689–97PubMedCrossRefGoogle Scholar
  13. 13.
    Walsh EP, Rockernmaher S, Keane JF, et al. Late results in patients with tetralogy of fallot repaired during infancy. Circulation 1988; 77: 1062–7PubMedCrossRefGoogle Scholar
  14. 14.
    Graham TP. Ventricular performance in congenital heart disease. Circulation 1991; 84: 2259–74PubMedCrossRefGoogle Scholar
  15. 15.
    Ross RD, Daniels SR, Schwartz DC, et al. Plasma norepinephrine levels in infants and children with congestive failure. Am J Cardiol 1987; 59: 911–4PubMedCrossRefGoogle Scholar
  16. 16.
    Ross RD, Daniels SR, Schwartz DC, et al. Return of plasma norepinephrine to normal after resolution of congestive heart failure in congenital heart disease. Am J Cardiol 1987; 60: 1411–3PubMedCrossRefGoogle Scholar
  17. 17.
    Wu JR, Chang HR, Chen SS. Circulating noradrenaline and beta-adrenergic receptors in children with congestive heart failure. Acta Paediatr 1996; 85: 923–7PubMedCrossRefGoogle Scholar
  18. 18.
    Wu JR, Chang HR, Huang TY. Reduction in lymphocyte beta-adrenergic receptor density in infants and children with heart failure secondary to congenital heart disease. Am J Cardiol 1996; 77: 170–4PubMedCrossRefGoogle Scholar
  19. 19.
    Kozlik R, Kramer HH, Wicht H, et al. Myocardial β-adenoreceptor density and the distribution of β1- and β2-adenoreceptor subpopulations in children with congenital heart disease. Eur J Pediatr 1991; 150: 388–94PubMedCrossRefGoogle Scholar
  20. 20.
    Dreyer WJ. Perinatal maturation of the cardiomyocyte: an integrated view of the molecular basis of the perinatal maturation of cardiac function. In: Garson A, Bricker JT, Fisher DJ, et al., editors. The science and practice of pediatric cardiology. Baltimore (MD): Williams and Wilkins, 1998: 201–30Google Scholar
  21. 21.
    Artman M, Henry G, Coetzee WA. Cellular basis for age-related differences in cardiac excitation-contraction coupling. Prog Pediatr Cardiol 2000; 11: 185–94PubMedCrossRefGoogle Scholar
  22. 22.
    Price KM, Littler WA, Cummins P. Human atrial and ventricular myosin light-chain subunits in adults and during development. Biochem J 1980; 191: 571–80PubMedGoogle Scholar
  23. 23.
    Mahdavi V, Izumo S, Nadal-Ginard B. Developmental and hormonal regulation of sarcomeric myosin heavy chain gene family. Circ Res 1987; 60: 804–14PubMedCrossRefGoogle Scholar
  24. 24.
    Lucchesi PA, Sweadner KJ. Postnatal changes in Na-K ATPase isoform expression in rat cardiac ventricle: conservation of biphasic ouabain affinity. Biol Chem 1991; 266: 9327–31Google Scholar
  25. 25.
    Khatter JC. Mechanisms of age-related differences in the cardiotoxic action of digitalis. J Cardiovasc Pharm 1985; 7: 258–61CrossRefGoogle Scholar
  26. 26.
    Lowrie L. Diuretic therapy of heart failure in infants and children. Prog Pediatr Cardiol 2000; 12: 45–55PubMedCrossRefGoogle Scholar
  27. 27.
    Packer M. Treatment of chronic heart failure. Lancet 1992; 340: 92–5PubMedCrossRefGoogle Scholar
  28. 28.
    Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancet 1990; 336: 1–6CrossRefGoogle Scholar
  29. 29.
    Packer M, Carver JB, Rodefeller RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 1991; 325: 1468–75PubMedCrossRefGoogle Scholar
  30. 30.
    Frishman WH. Carvedilol. N Engl J Med 1998; 339: 1759–65PubMedCrossRefGoogle Scholar
  31. 31.
    McKelvie RS, Benedict CR, Yusuf S. Evidence based cardiology: prevention of congestive heart failure and management of asymptomatic left ventricular dysfunction. BMJ 1999; 318: 1400–2PubMedCrossRefGoogle Scholar
  32. 32.
    Brown NJ, Vaughan DE. Angiotensin-converting enzyme inhibitors. Circulation 1998; 97: 1411–20PubMedCrossRefGoogle Scholar
  33. 33.
    Grenier MA, Fioravanti J, Truesdell SC. Angiotensin-converting enzyme inhibitor therapy for ventricular dysfunction in infants, children and adolescents: a review. Prog Pediatr Cardiol 2000; 12: 91–111PubMedCrossRefGoogle Scholar
  34. 34.
    Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341: 709–17PubMedCrossRefGoogle Scholar
  35. 35.
    MacFadyen RJ, Barr CS, Struthers AD. Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients. Cardiovasc Res 1997; 35: 30–4PubMedCrossRefGoogle Scholar
  36. 36.
    Newton GE, Tong JH, Schofield AM, et al. Digoxin reduces cardiac sympathetic activity in severe congestive heart failure. J Am Coll Cardiol 1996; 28: 155–61PubMedCrossRefGoogle Scholar
  37. 37.
    Hauptman PJ, Kelly RA. Digitalis. Circulation 1999; 99: 1265–70PubMedCrossRefGoogle Scholar
  38. 38.
    The Digitalis Intervention Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336: 525–33CrossRefGoogle Scholar
  39. 39.
    Cleland JG, McGowan J, Cowburn PJ. Beta-blockers for chronic heart failure: from prejudice to enlightenment. J Cardiovasc Pharmacol 1998; 32Suppl. 1: S52–60PubMedGoogle Scholar
  40. 40.
    Franciosa JA. Beta-adrenergic blocking agents: past, present, and future perspectives. Coronary Art Dis 1999; 10: 369–76CrossRefGoogle Scholar
  41. 41.
    Lechat P, Packer M, Chalon S, et al. Clinical effects of beta-adrenergic blockade in chronic heart failure: a meta-analysis of double-blind, placebo-controlled, randomized trials. Circulation 1998; 98: 1184–91PubMedCrossRefGoogle Scholar
  42. 42.
    Bristow MR, Gilbert EM, Abraham WT, et al., for the MOCHA Investigators. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation 1996; 94: 2807–16PubMedCrossRefGoogle Scholar
  43. 43.
    Krum H. Beta-blockers in heart failure: the ‘new wave’ of clinical trials. Drugs 1999; 58: 203–10PubMedCrossRefGoogle Scholar
  44. 44.
    Richards AM, Doughty R, Nicholls MG. Neurohumoral prediction of benefit from carvedilol in ischemic left ventricular dysfunction. Circulation 1999; 99: 786–92PubMedCrossRefGoogle Scholar
  45. 45.
    van Campen LC, Visser FC, Visser CA. Ejection fraction improvement by beta-blocker treatment in patients with heart failure: an analysis of studies published in the literature. J Cardiovasc Pharmacol 1998; 32Suppl. 1: S31–5PubMedGoogle Scholar
  46. 46.
    Ruffolo Jr RR, Feuerstein GZ. Neurohormonal activation, oxygen free radicals, and apoptosis in the pathogenesis of congestive heart failure. J Cardiovasc Pharmacol 1998; 32Suppl. 1: S22–30PubMedGoogle Scholar
  47. 47.
    Lowes BD, Gill EA, Abraham WT, et al. Effects of carvedilol on left ventricular mass, chamber geometry, and mitral regurgitation in chronic heart failure. Am J Cardiol 1999; 83: 1201–5PubMedCrossRefGoogle Scholar
  48. 48.
    Kukin ML, Kalman J, Charney RH, et al. Prospective, randomized comparison of effect of long-term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart failure. Circulation 1999; 99: 2645–51PubMedCrossRefGoogle Scholar
  49. 49.
    Bristow MR. β-Adrenergic receptor blockade in chronic heart failure. Circulation 2000; 101: 558–69PubMedCrossRefGoogle Scholar
  50. 50.
    Bristow MR. Changes in myocardial and vascular receptors in heart failure. J Am Coll Cardiol 1993; 22Suppl. A: 61–71ACrossRefGoogle Scholar
  51. 51.
    Tan LB, Benjamin IJ, Clark WA. β-adrenergic receptor densensitization may serve a cardioprotective role. Cardiovasc Res 1992; 26: 608–14PubMedCrossRefGoogle Scholar
  52. 52.
    Fowler MB, Bristow MR. Rationale for beta-adrenergic blocking drugs in cardiomyopathy. Am J Cardiol 1985; 55: D120–4CrossRefGoogle Scholar
  53. 53.
    Flesch M, Maack C, Cremers B, et al. Effect of beta-blockers on free radical-induced cardiac contractile dysfunction. Circulation 1999; 100: 346–53PubMedCrossRefGoogle Scholar
  54. 54.
    Eichhorn EJ, Heesch CM, Barnett JH, et al. Effect of metoprolol on myocardial function and energetics in patients with nonischemic dilated cardiomyopathy: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 1994; 24: 1310–20PubMedCrossRefGoogle Scholar
  55. 55.
    Senior R, Muller-Beckmann B, DasGupta P, et al. Effects of carvedilol on ventricular arrhythmias. J Cardiovasc Pharmacol 1992; 19Suppl. 1: S117–21PubMedCrossRefGoogle Scholar
  56. 56.
    Lowes BD, Gilbert EM, Abraham WT, et al. Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents. N Engl J Med 2002; 346: 1357–65PubMedCrossRefGoogle Scholar
  57. 57.
    Yue TL, Cheng HY, Lysko PG, et al. Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and free radical scavenger. J Pharmacol Exp Therap 1992; 263: 92–8Google Scholar
  58. 58.
    Bristow MR, Larrabee P, Muller-Beckmann B, et al. Effects of carvedilol on adrenergic receptor pharmacology in human ventricular myocardium and lymphocytes. Clin Inv 1992; 70Suppl. 1: S105–13Google Scholar
  59. 59.
    MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure. Lancet 1999; 353: 2001–7CrossRefGoogle Scholar
  60. 60.
    CIBIS Investigators. A randomized trial of beta-blockade in heart failure: the Cardiac Insufficiency Bisoprolol study. Circulation 1994; 90: 1765–73CrossRefGoogle Scholar
  61. 61.
    CIBIS II Investigators and Committees. The Cardiac Insufficiency Bisoprolol study (CIBIS-II): a randomized trial. Lancet 1999; 353: 9–13CrossRefGoogle Scholar
  62. 62.
    Buchhorn R, Bartmus D, Siekmeyer W, et al. Beta-blocker therapy of severe congestive heart failure in infants with left to right shunts. Am J Cardiol 1998; 81: 1366–8PubMedCrossRefGoogle Scholar
  63. 63.
    Buchhorn R, Hulpke-Wette M, Hilgers R, et al. Propranolol treatment of congestive heart failure in infants with congenital heart disease: The CHF-PRO-INFANT Trial. Int J Cardiol 2001; 79: 167–73PubMedCrossRefGoogle Scholar
  64. 64.
    Shaddy RE, Olsen SL, Bristow MR, et al. Efficacy and safety of metoprolol in the treatment of doxorubicin-induced cardiomyopathy in pediatric patients. Am Heart J 1995; 139: 197–9CrossRefGoogle Scholar
  65. 65.
    Shaddy RE, Tani LY, Gidding SS, et al. Beta-blocker treatment of dilated cardiomyopathy with congestive heart failure in children: a multi-institutional experience. J Heart Lung Transplant 1999; 18: 269–74PubMedCrossRefGoogle Scholar
  66. 66.
    Ishikawa Y, Bach JR, Minami R. Cardioprotection for Duchenne’s muscular dystrophy. Am Heart J 1999; 137: 895–902PubMedCrossRefGoogle Scholar
  67. 67.
    Bruns LA, Kichuk-Chrisant M, Lamour JM, et al. Carvedilol as therapy in pediatric heart failure: an initial multicenter experience. J Pediatr 2001; 138: 505–11PubMedCrossRefGoogle Scholar
  68. 68.
    Liler S, Mit TS, Behn F, et al. Carvedilol therapy in pediatric patients with congestive heart failure: a study investigating clinical and pharmacokinetic parameters. Am Heart J 2002; 143: 916–22CrossRefGoogle Scholar
  69. 69.
    Rusconi P, Redha E, Marin JR, et al. Carvedilol for the treatment of congestive heart failure in children with cardiomyopathy [abstract]. J Am Coll Cardiol 2002; 39: 399ACrossRefGoogle Scholar
  70. 70.
    Newton GE, Parker JD. Acute effects of β1-selective and nonselective β-adrenergic receptor blockade on cardiac sympathetic activity in congestive heart failure. Circulation 1996; 94: 353–8PubMedCrossRefGoogle Scholar
  71. 71.
    Gaffney TE, Braunwald MD. Importance of the adrenergic nervous system in the support of circulatory function in patients with congestive heart failure. Am J Med 1963; 34: 320–4PubMedCrossRefGoogle Scholar
  72. 72.
    Haber HL, Christopher LS, Gimple LW, et al. Why do patients with congestive heart failure tolerate the initiation of β-blocker therapy. Circulation 1993; 88: 1610–9PubMedCrossRefGoogle Scholar
  73. 73.
    Talwar KK, Bhargava B, Upasani PT, et al. Hemodynamic predictors of early intolerance and long-term effects of propranolol in dilated cardiomyopathy. J Card Fail 1996; 2: 273–7PubMedCrossRefGoogle Scholar
  74. 74.
    Bristow MR, Roden RL, Lowes BD, et al. The role of third generation β-blocking agents in chronic heart failure. Clin Cardiol 1998; 21: 317–25CrossRefGoogle Scholar
  75. 75.
    Eichhorn EJ, Bristow MR. Practical guidelines for initiation of beta-adrenergic blockade in patients with chronic heart failure. Am J Cardiol 1997; 79: 794–8PubMedCrossRefGoogle Scholar
  76. 76.
    DeMey C, Brendel E, Enterling D. Carvedilol increases the systemic bioavailability of oral digoxin. Br J Clin Pharmacol 1990; 29: 486–90CrossRefGoogle Scholar
  77. 77.
    Auslender M, Artman M. Overview of the management of pediatric heart failure. Prog Pediatr Cardiol 2000; 11: 231–41PubMedCrossRefGoogle Scholar
  78. 78.
    Lewis AB, Chabot M. The effect of treatment with angiotensin-converting enzyme inhibitors on survival of pediatric patients with dilated cardiomyopathy. Pediatr Cardiol 1993; 14: 9–12PubMedGoogle Scholar
  79. 79.
    Shaddy RE, Curtin EL, Sower B, et al. The Pediatric Randomized Carvedilol Trial in children with heart failure: rationale and design. Am Heart J 2002; 144(3): 383–9PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  1. 1.Department of Pediatrics, Division of Pediatric Cardiology, St John’s Mercy Medical CenterChildren’s Heart Center of St LouisSt LouisUSA
  2. 2.Department of Pediatrics, Division of Pediatric Cardiology, 3S-30, St Louis Children’s HospitalWashington University in St Louis School of MedicineSt LouisUSA

Personalised recommendations