Inhaled corticosteroids: effects on growth and adrenal suppression

Abstracts

Este artigo é uma revisão da literatura médica sobre os corticosteróides inalatórios e seus efeitos no crescimento e na supressão adrenal em crianças e adolescentes. Utilizaram-se o Medline e artigos publicados em jornais científicos nacionais e internacionais, principalmente nos últimos cinco anos, para a revisão da literatura. Há controvérsias acerca dos efeitos colaterais dos corticóides inalatórios. Nos 21 estudos sobre crescimento e uso de corticóides inalatórios, notou-se que houve diferença significativa no primeiro ano (retardo de 1 a 1,5 cm) quando se utilizou principalmente beclometasona e budesonida inalatórias, mas não se verificou diferença na altura final adulta quando estudos de mais longa duração foram conduzidos, fazendo-se relação com a altura dos pais. Entretanto, em dez artigos sobre uso de corticóide inalatório e supressão adrenal, foram relatadas hipoglicemia, parada de ganho de peso e altura, e alterações nos exames de cortisol sérico matinal e urinário de 24 h, principalmente com uso de doses altas de corticóide inalatório. Corticóides inalatórios podem diminuir o crescimento no primeiro ano de uso, mas não a altura final adulta. São necessárias mais pesquisas com longo tempo de acompanhamento de crianças em uso de corticóide inalatório para se avaliar o impacto sobre o crescimento final. Monitorar a altura é uma medida para se avaliar eficácia e segurança no uso de corticóide inalatório em crianças. Exames que avaliam o eixo hipotalâmico pituitário adrenal e a insuficiência adrenal devem ser correlacionados com sintomas clínicos ou efeitos colaterais.

Corticosteróides; Administração; Corticosteróides; Estatura; Asma; Asma; Corticotropina; Beclometasona; Budesonida; Hidrocortisona; Testes de função adreno-hipofisária

REVIEW ARTICLE

Inhaled corticosteroids: effects on growth and adrenal suppression^*

Elisete E. Arend^I; Gilberto Bueno Fischer^II; Helena Mocelin^II; Lídia Medeiros^III

^IMasters student in Pediatric Pulmonology at the Universidade Federal do Rio Grande do Sul - UFRGS - Porto Alegre (RS) Brazil

^IIPh.D. Pulmonologist at the Universidade Federal do Rio Grande do Sul - UFRGS - Porto Alegre (RS) Brazil

^IIIDoctoral student in Epidemiology at the Universidade Federal do Rio Grande do Sul - UFRGS - Porto Alegre (RS) Brazil

^{Correspondence}

ABSTRACT

This is a review of the medical literature regarding inhaled corticosteroids and their effects on growth and adrenal suppression in children and adolescents. A review of the literature, principally that published over the last five years, was conducted using Medline and searching indexes of articles published in national and international scientific journals. There is considerable controversy regarding the side effects of inhaled corticosteroids. In 21 studies evaluating the effect that inhaled corticosteroids have on growth, a statistically significant reduction (growth retarded by 1-1.5 cm) was observed within the first year of treatment with Beclomethasone or Budesonide inhalers. However, in studies of longer duration, no significant difference was found between final adult height and adult height of the parents. However, in ten studies of the use of inhaled corticosteroids and their effect on adrenal suppression, hypoglycemia and arrested development (no height or weight gains), as well as changes in morning serum levels and 24-h urinary levels of cortisol, were reported, especially when high doses of inhaled corticosteroids were used. Inhaled corticosteroids can reduce growth during the first year of use but do not affect adult height. However, further long-term studies are needed in order to determine the full impact of inhaled corticosteroids on final adult height. Height measures are a means of evaluating the safety and efficacy of the use of inhaled corticosteroids in children. Tests that evaluate the hypothalamic-pituitary-adrenal axis and adrenal insufficiency should be correlated with clinical symptoms and side effects.

Keywords: Adrenal cortex hormones/therapeutic use; Administration, inhalation; Adrenal cortex hormones/adverse effects; Body height/drug effects; Asthma/drug therapy; Asthma/prevention & control; Corticotropin/diagnostic use; Beclomethasone/therapeutic use; Budesonide/therapeutic use; Hydrocortisone/therapeutic use; Pituitary-adrenal function tests

INTRODUCTION

Since the emergence, two decades ago, of the concept of asthma as a chronic inflammatory disease, inhaled corticosteroids have been used with increasing frequency, and with success, in the management and prevention of moderate and persistent asthma.

Corticosteroids act in the cell, inducing or suppressing various genes involved in the production of cytokines, adhesion molecules and receptors related to inflammation. Inhaled corticosteroids are used for fast relief in crises and for significant reduction of inflammation and improvement of pulmonary function over the course of days or weeks, modifying bronchial hyperreactivity over the course of a few months.

In a study⁽¹⁾ involving 1041 children, budesonide, nedocromil and placebo were used. The authors found that there was a lessening of bronchial hyperreactivity and better asthma control with inhaled budesonide, the use of which resulted in a 43% lower hospitalization rate (p = 0.04), 45% fewer visits to emergency rooms (p = 0.02), a 43% lower rate of prednisone use (p < 0.001), reduced use of albuterol for symptom relief (p < 0.001), fewer symptoms (p = 0.005) and more symptom-free episodes (p = 0.01).

Despite the benefits, it remains in doubt as to whether the prolonged use of inhaled corticosteroids may present the same side effects as their systemic use, especially if used at high doses for more seven days or at conventional doses for 30 days. Neither has it been established whether sudden discontinuity results in suppression of the hypothalamic-hypophyseal-adrenal axis, with cessation of the endogenous production of the corticosteroid hormone and involution of the adrenal gland, resulting in the presence of cushingoid features, growth changes, osteoporosis,⁽³⁾ glaucoma, subcapsular cataract and hypoglycemia.

The focus of this review of the literature was the use of inhaled corticosteroids that affect growth and cause adrenal suppression.

GROWTH AND INHALED CORTICOSTEROIDS

There are studies which demonstrate that, in the first year of use, inhaled corticosteroids, mainly beclomethasone, may decrease growth by 1.1 cm,⁽¹⁾ although final heights are similar at the end of the monitoring period (four to six years). A follow-up study of children over a 9.2-year period showed that they reached an appropriate final height.⁽²⁾ In children, stature is a health indicator that is easy to obtain, is noninvasive and can be used to evaluate the efficiency and safety of the use of inhaled corticosteroids.

Due to the myriad factors that may be involved in growth, the debate regarding evaluation methods and the safety of the prolonged use of inhaled corticosteroids is ongoing. Glucocorticosteroids are potent inhibitors of each component of the growth axis, including insulin factor 1 (the hormone controlling growth, secretion and action), bioactive growth, collagen synthesis and endogenous production.

When evaluating growth, we should be aware of its three phases, which are affected by various influences:⁽³⁾ rapid growth until the age of three (depending on nutritional factors); growth from three years of age up to puberty (regulated by the growth hormone and later decelerating); pubertal growth (characterized by combined acceleration promoted by the growth hormone and by sexual hormones, declining when the pituitary gland halts production). Growth does not occur at a constant rate. There may be intervals of two or more years without growth.

Reductions in the rate of growth over the course of a year may not be accompanied by a decrease in the subsequent year. It has been observed that recording the rate of growth over a three-year period can predict 34% of the variation in the final stature, whereas recording the rate at which the leg grows (knemometry) over a one-month period predicts virtually nothing regarding annual variations in stature.⁽⁴⁾

There is a decrease in the rate of growth prior to puberty. This decrease must be taken into consideration so that this physiological phenomenon is not attributed to the inhaled corticosteroid.

It has also been reported that asthma can retard growth by 0.9 cm per year and may be related to a delay in the onset of puberty, as is the case in other chronic diseases. The frequency of the symptoms and the loss of good control over asthma affect the growth rate and may be confounding factors in studies of growth.

In order to evaluate growth, knemometry,⁽³⁾ a sensitive technique of measuring the short-term growth of the leg, is used in order to compare the effects of various corticosteroids on children.

Other studies have shown that the effect of growth retardation by exogenous steroids can be overstated.⁽⁴⁾ Stature is reduced by 1 cm on the same day by the compression of articular cartilage when supporting body weight, and a one-hour rest may mimic a 2-mm increase in the rate of growth, which corresponds to the monthly average leg growth. This generates errors in the long-term evaluation growth.⁽³⁾

The final height observed, in relation to the final height expected, constitutes the only reliable result in the measurement of human growth, taking into account differences in gender and average height of the parents. Therefore, monitoring height with a stadiometer for more than one year would be the best method to determine the effect of inhaled corticosteroids on growth.⁽³⁾

ADRENAL SUPPRESSION

Measurements of baseline serum cortisol, 24-h urinary cortisol and cortisol metabolites are used to determine whether there are systemic effects caused by inhaled corticosteroids. It has been observed that even in the presence of altered levels of cortisol and its metabolites there may not be clinical repercussion.⁽⁵⁾

In order to detect whether there is involution of the adrenal gland resulting from suppression of the hypothalamic-hypophyseal-adrenal axis, other tests would have to be carried out using adrenocorticotropic hormone at microdoses of 0.5 mcg and analyzing the post-stimulus serum cortisol level response.

If morning plasmatic cortisol is less than 10 mcg/dl, an endocrinological evaluation must be performed since it might become necessary to use hydrocortisone in surgical procedures or severe diseases.⁽³⁾

FACTORS THAT INFLUENCE SYSTEMIC ABSORPTION

The systemic concentration of inhaled corticosteroids is the sum of what is topically absorbed by the mouth, lungs and digestive tract, taking into account the hepatic inactivation.

When the spray version is used, only 10% is topically distributed in the lung and 80% in the oropharynx. With the use of spacers, 20% goes to the airways, and 70% to 80% to the oropharynx. Using the Turbohaler^® device, 40% goes to the oropharynx and a greater portion is topically absorbed in the lung, thereby increasing the efficacy of the corticosteroid and potentially decreasing systemic absorption.

Fluticasone has the lowest active percentage of drug available after hepatic inactivation (< 1%), whereas triamcinolone has 10%, budesonide 21% and beclomethasone 41%. Beclomethasone may therefore have a greater systemic effect and present more side effects. The pharmacological industry has been concerned with enhancing topical potency in order to decrease systemic absorption and thereby decrease side effects. The available agents, listed in descending order by potency, are fluticasone, budesonide, beclomethasone, triamcinolone and flunisolide.

Hydrofluoroalkane, rather than chlorofluorocarbon, should be used as a propellant in the sprays since the latter damages the ozone layer of the atmosphere.

It is believed that, in individuals with moderate asthma, the airways are more permeable, the deposition/absorption of the drug is greater, and the adverse effects are more pronounced than in those with severe asthma.

The lipophilic corticosteroids, such as fluticasone, are more easily distributed systemically, and smaller doses should therefore be used.

Chart 1 presents 21 studies of the relationship between inhaled corticosteroids and growth, together with 10 studies that focus on adrenal suppression.

A critical analysis of these articles was carried out according to the guidelines established by Oxford Centre for Evidence-based Medicine:⁽⁶⁾ level of evidence (*); degree of recommendation (+); Excellent levels of evidence = A (1a, 1b or 1c). The conduct is widely recommended = B (2a, 2b or 2c). Level l = evidence that recommends the action. The conclusion is that it is beneficial, and that there is reasonable evidence for the action. Minimum evidence in the analysis of the outcome, benefits and damages do not justify the generalization of the conduct = C (4, 2 or 3). Inconclusive study or opinion of an expert = D.⁽⁵⁾ The meta-analyses were classified according to the quality of reporting of meta-analyses (QUOROM) statement.⁽⁷⁾ In 11 studies, no significant difference was observed regarding growth, whereas in 10 studies there were such differences (1 to 1.5 cm), mainly in the first year of follow-up. This difference was not observed when the patients were monitored for a number of years (until adulthood) or when the growth was calculated according to the height of the parents.

In the 9 studies of adrenal suppression, there were alterations in 24-h urinary cortisol levels, in serum levels of morning cortisol and in the results of the test with adrenocorticotropic hormone to stimulate the adrenal glands. The patients presented hypoglycemia, altered consciousness, arrested development (stunted growth and weight loss), especially when high doses of inhaled corticosteroids were used, although, in some studies,^(28,31-32) there have been alterations even when conventional doses were used. The authors point out that more studies are necessary to check the significance of these exams with the clinical correlation. Some⁽³⁾ call attention to the fact that, in patients with serum cortisol levels of 10 mcg/dl, there must be an endocrinological follow-up, including a test with adrenocorticotropic hormone, in order to detect adrenal insufficiency.

CONCLUSIONS

After a review of the literature, the authors have come to the conclusion that there is a significant difference in height in the first year of use, principally when inhaled beclomethasone or budesonide are used. In addition, there was no difference in the final adult height when the studies were conducted over the long-term or when a correlation was made between the growth and the height of the parents. Nevertheless, in 10 articles evaluating cases of adrenal suppression, hypoglycemia, arrested development (no height or weight gains) and changes in the morning cortisol serum test results were reported, mainly with the use of high doses of inhaled corticosteroids. Inhaled corticosteroids can limit growth in the first year but not the final adult height.

Regarding the use of inhaled corticosteroids for treating asthma safely and efficaciously, the safest corticosteroid should be selected, and a minimum efficacious dose should be used (a morning dose when prescribed once a day). If the control of asthma is unsatisfactory, a long-term bronchodilator or leukotriene antagonists should be added before doubling the dosage of the inhaled corticosteroid. As accompanying strategies, the family should be informed about the importance of reducing allergens and smoke, and vaccination should be recommended. It is necessary to investigate and treat rhinosinusitis or gastroesophageal reflux and monitor growth at all doses of the inhaled corticosteroids used, as well as vision and bone density when higher doses are used. Finally, in cases of persistent asthma, it should be determined whether other topical (nasal or dermatological) corticosteroids are being used, thereby avoiding dose accumulation.

This review of the literature was limited because only the Medline database, the Cochrane library and article references were used. However, 32 studies were found, most of which with a recommendation level of B. Only 12 studies were categorized as evidence level C by the Oxford Evidence Center.

After reviewing these articles, we concluded that, in order to safely maintain the efficacy of inhaled corticosteroids, children should be monitored, especially in terms of their height. Should high doses be used or growth rate slow, exams evaluating the function of the hypothalamic-hypophyseal-adrenal axis should be carried out in order to detect, and treat if necessary, adrenal insufficiency. Further long-term follow-up studies of children using inhaled corticosteroids are necessary so that their impact on final growth can be evaluated. Monitoring height is a means of evaluating efficacy and safety of the use of inhaled corticosteroids in children. The relevance of exams evaluating the hypothalamic-pituitary-adrenal axis and adrenal insufficiency, as well as the correlation with clinical symptoms or side effects should be further elucidated.

REFERENCES

Submitted: 17 November 2003. Accepted, after review: 20 April 2004.

• 1. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med. 2000;343(15):1054-63.
• 2. Agertoft L, Pedersen S. Effect of long term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med. 2000;343(15):1064-9.
• 3. Allen DB. Safety of inhaled corticosteroids in children. Pediatr Pulmonol. 2002;33(3):208-20.
• 4. Fortkamp E, Brown M A. Corticosteróides inalatórios e crescimento. J Pediatr. 2000;76(4):263-74.
• 5. Grebe SK, Feek CM, Durhan JA, Kijakovic M, Cooke RR. Inhaled beclomethasone dipropionate suppresses the hypothalamo - pituitary - adrenal axis in a dose dependent manner. Clin Endocrinol. 1997;47(3):297-304.
• 6. Centre for Evidence-Based Medicine. Oxford - Centre for Evidence Based Medicine. Background to EBM [text on the Internet]. [cited 2004 Oct 27]. Oxford: Institute of Health Science. Available from: http://www.cebm.net/background.asp
• 7. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Lancet. 1999;354(9193):1896-900.
• 8. Benedictis FM, Teper A, Green R J, Boner AL, Williams L, Medley H. International Study Group. Effects of 2 inhaled corticosteroids on growth: results of a randomized controlled trial. Arch Pediatr Adolesc Med. 2001;155(11):1248-54.
• 9. Visser MJ, Van Aalderen WM, Elliott BM, Odink RJ, Brand PL. Short term growth in asthmatic children using fluticasone propionate. Chest. 1998;113(3):584-6.
• 10. Rao R, Gregson RK, Jones AC, Miles EA, Campbell MJ, Warner JO. Systemic effects of inhaled corticosteroids on growth and bone turnover in childhood asthma: a comparison of fluticasone with beclomethasone. Eur Respir J. 1999;13(1):87-94.
• 11. Sharek PJ, Bergman DA. The effect of inhaled steroids on the linear growth of children with asthma: a meta-analysis. Pediatrics. 2000;106(1):E8.
• 12. Skoner DP, Szefler SJ, Welch M, Walton-Bowen K, Cruz-Rivera M, Smith JA. Longitudinal growth in infants and young children treated with budesonida inhalation suspension for persistent asthma. J Allergy Clin Immunol. 2000;105(2 Pt 1):259-68.
• 13. Allen DB, Bronsky EA, LaForce CF, Nathan RA, Tinkelman DG, Vandewalker ML et al. Growthin asthmatic children treated with fluticonasone propionate. Fluticasone Propianate Asthma Study Group. J Pediatr. 1998;132(3 Pt 1):472-7.
• 14. Shapiro G, Mendelson L, Kraemer MJ, Cruz-Rivera M, Walton-Bowen K, Smith JÁ. Efficacy and safety of budesonide inhalation suspension (Pulmicort Respules) in young children with inhaled steroid dependent, persistent asthma. J Allergy Clin Immunol. 1998;102(5):789-96.
• 15. Efthimiou J, Barnes PJ. Effect of inhaled corticosteroids on bones and growth. Eur Respir J. 1998;11(5):1167-77.
• 16. Verberne AA , Frost C, Roorda R J, Laag H, Kerrebijn KF. One year treatment with salmeterol compared with beclomethasone in children with asthma. The Dutch pediatric asthma study group. Am J Respir Crit Care Med. 1997;156(3 Pt 1):688-95.
• 17. Simons FE. A comparison of beclomethasone, salmeterol and placebo in children with asthma. Canadian Beclomethasone Dipropionate - Salmeterol xinafoate study group. N Engl J Med. 1997;337(23):1659-65.
• 18. Silverstein MD, Yunginger JW, Reed CE, Petterson T, Zimmermann D, Li JT, et al. Attained adult heigth after childhood asthma: effect of glucocorticoid therapy. J Allergy Clin Immunol. 1997;99(4):466-74.
• 19. Visser MJ, Postma DS, Arends LR, Vries TW, Duiverman EJ, Brand PL. One year treatment with different dosing schedules of fluticasone propionate in childhood asthma. Am J Respir Crit Care Med. 2001;164(11):2073-7.
• 20. Doull IJ, Freezer NJ, Holgate ST. Growth of prepubertal children with mild asthma treated with inhaled beclomethasone dipropionate. Am J Respir Crit Care Med. 1995; 151(6):1715-9.
• 21. Allen DB, Mullen M, Mullen B. A meta-analysis of the effect of oral and inhaled corticosteroids on growth. J Allergy Clin Immunol. 1994;93(6):967-76.
• 22. Price JF, Russell G, Hindmarsch PC, Weller P, Heaf DP, Williams J. Growth during one year of treatment with fluticasone propionate or sodium cromoglycate in children with asthma. Pediatr Pulmonol. 1997;24(3):178-86.
• 23. Van Bever HP, Desager KN, Lijssens N, Weyler JJ, Du Caju MV. Does treatment of asthmatic children with inhaled corticosteroids affect their adult height? Pediatr Pulmonol. 1999;27(6):369-75.
• 24. Doull IJ, Campbell MJ, Holgate ST. Duration of growth suppressive effects of regular inhaler corticosteroids. Arch Dis Child. 1998;78(2):l72-3.
• 25. Fitzgerald D, Van Asperen P, Mellis C, Honner M, Smith L, Ambler G. Fluticasone propionate 750mcgh/day versus beclomethasone dipropionate 1500mcg/day: comparison of efficacy and adrenal function in paediatric asthma. Thorax. 1998; 53(8):656-61.
• 26. Saha MT, Laippala P, Lenko HL. Growth of asthmatic children is slower during than before treatment with inhaled glucocorticoids. Acta Paediatr. 1997;86(2):138-42.
• 27. Thomas BC, Stanhope R, Grant DB. Impaired growth in children with asthma during treatment with conventional doses of inhaled corticosteroids. Acta Paediatr. 1994;83(2):196-9.
• 28. Dunlop KA, Carson DJ, Shields MD. Hypoglycemia due to adrenal suppression secondary to high dose nebulized corticosteroid. Pediatr Pulmonol. 2002;34(1):85-6.
• 29. Carrel AL, Somers S, Lemanske RF Jr, Allen DB. Hypoglycemia and cortisol deficiency associated with low dose corticosteroid therapy for asthma. Pediatrics. 1996;97(6 Pt 1):921-4. Erratum in: Pediatrics. 1996;98(4 Pt 1):672.
• 30. Patel L, Wales JK, Kibirige MS, Massarano AA, Couriel JM, Clayton PE. Symptomatic adrenal insufficiency during inhaled corticosteroid treatment. Arch Dis Child. 2001;85(4):330-4.
• 31. Yiallouros PK, Milner AD, Conway E, Honour JW. Adrenal function and high dose inhaled corticosteroids for asthma. Arch Dis Child. 1997;76(5):405-10.
• 32. Lipworth BJ, Clark DJ, McFarlane LC. Adrenocortical activity with repeated twice daily dosing of fluticasone propionate and budesonide given via a large volume spacer to asthmatic school children. Thorax. 1997;52(8):686-9.
• 33. Kannisto S, Korppi M, Remes K, Voutilainen R. Adrenal suppression evaluated by a low dose adrenocorticotropin test, and growth in asthmatic children treated with inhaled steroids. J Clin Endocrinol Metab. 2000;85(2):652-7.
• 34. Broide J, Soferman R, Kivity S, Golander A, Dickstein G, Spirer Z, et al. Low-dose adrenocorticotropin test reveals impaired adrenal function in patients taking inhaled corticosteroids. J Clin Endocrinol Metab. 1995;80(4):1243-6.
• 35. Zimmermann B, Gold M, Wherrett D, Hanna AK . Adrenal suppression in two patients with asthma treated with low doses of the inhaled steroid fluticasone propionate. J Allergy Clin Immunol. 1998;101(3):425-6.
• 36. Zwaan CM, Odink RJ, Delemarre-van de Waal HA, Dankert-Roelse JE, Bokman JA. Acute adrenal insufficiency after discontinuation of inhaled corticosteroid therapy. Lancet. 1992;340(8830):1289-90.
• 37. Landstra AM, Postma DS, Boezen HM, Van Aalderen WM. Role of serum cortisol levels in children with asthma. Am J Respir Crit Care Med. 2002;165(5):708-12.
• 38. Sorkness CA. Establishing a therapeutic index for the inhaled corticosteroids> part II. Comparisons of systemic activity and safety among different inhaled corticosteroids. J Allergy Clin Immunol. 1998;102(4 Pt 2):S52-64.
• 39. Skoner DP. Balancing safety and efficacy in pediatric asthma management. Pediatrics. 2002;109(2):381-91.
• 40. Bisgaard H, Damkjaer Nielsen M, Andersen B, Andersen P, Foged N, Fuglsang G, et al. Adrenal function in a children with bronchial asthma treated with beclomethasone dipropionate or budesonide. J Allergy Clin Immunol. 1988;81(6):1088-95.
• 41. Israel E, Banerger TR, Fitzmaurice GM, Kotlov TV, LaHive K, LeBoff MS. Effects of inhaled glucocorticoids on bone density in premenopausal women. N Engl J Med. 2001;345(13):941-7.
• 42. Skoner DP. Outcome measures in childhood asthma. Pediatrics. 2002:109(2 Suppl):393-8.
• 43. Selroos O, Pietinalho A, Lofroos AB, Riska H. Effect of early vs. late intervention with inhaled corticosteroids in asthma. Chest. 1995;108(5):1228-34.
• 44. Suissa S, Ernest P, Benayoun S, Baltzan M, Cai B. Low dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Méd. 2000;343(5):332-6.
• 45. Chernick and Boat. Disorders of the respiratory tract in children, 6Ş ed W B Saunders. 1998;688-730.
• ⁴⁶
  The Cochrane Library [database on the Internet]. Issue 1, 2003 [cited 2004 Nov 2]. Oxford: Update Software. Disponível em: http://cochrane.bireme.br

*

Study carried out at the Federal University of Rio Grande do Sul - UFRGS - Porto Alegre (RS) Brazil.

Publication Dates

• Publication in this collection
  31 Oct 2005
• Date of issue
  Aug 2005

History

• Accepted
  20 Apr 2004
• Received
  17 Nov 2003