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Meta-Analysis
. 2013 May 31;2013(5):CD003124.
doi: 10.1002/14651858.CD003124.pub4.

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho-pulmonary disease

Martin Chalumeau  1 , Yvonne C M Duijvestijn
Affiliations
Meta-Analysis

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho-pulmonary disease

Martin Chalumeau et al. Cochrane Database Syst Rev. .

Abstract

Background: Acetylcysteine and carbocysteine are the most commonly prescribed mucolytic drugs in Brazil and many European and African countries. To our knowledge, no systematic review has been published on their efficacy and safety for acute upper and lower respiratory tract infections (RTIs) in children without chronic broncho-pulmonary disease.

Objectives: The objective was to assess the efficacy and safety and to establish a benefit-risk ratio of acetylcysteine and carbocysteine as symptomatic treatments for acute upper and lower RTIs in paediatric patients without chronic broncho-pulmonary disease.

Search methods: We searched CENTRAL (2013, Issue 2), MEDLINE (1966 to February week 3, 2013), EMBASE (1980 to March 2013), Micromedex (2010), Pascal (1987 to 2004) and Science Citation Index (1974 to March 2013).

Selection criteria: To study efficacy, we used randomised controlled trials (RCTs) comparing the use of acetylcysteine or carbocysteine versus placebo, either alone or as an add-on therapy. To study safety, we used trials comparing acetylcysteine or carbocysteine versus active treatment or no treatment and case reports.

Data collection and analysis: In this review update two review authors (YD, MC), with help from a colleague, extracted data and assessed trial quality. We performed a subgroup analysis of children younger than two years of age.

Main results: We included six trials involving 497 participants to study efficacy. They showed some benefit (e.g. reduction of cough at day seven) from mucolytic agents, although differences were of little clinical relevance. No conclusion was drawn about the subgroup of infants younger than two years because data were unavailable. Thirty-four studies, including the previous six trials involving 2064 children, were eligible to study safety. Overall safety was good but very few data were available to evaluate safety in infants younger than two years. However, 59 cases of paradoxically increased bronchorrhoea observed in infants were reported to the French pharmacovigilance system.

Authors' conclusions: The results have to be interpreted with caution because they are based on a limited number of participants included in studies whose methodological quality is questionable. Acetylcysteine and carbocysteine seem to have a limited efficacy and appear to be safe in children older than two years. These results should take into consideration the fact that acetylcysteine and carbocysteine are prescribed for self limiting diseases (for example, acute cough, bronchitis). Given strong concerns about safety, these drugs should only be used for acute upper and lower RTIs in the context of a RCT with regards to children younger than two years.

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Conflict of interest statement

No financial conflict of interest.

Figures

1
1
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
2
2
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
3
3
Forest plot of comparison: 1 Febrile state (AC vs placebo), outcome: 1.1 Febrile state after 6 days.
4
4
Forest plot of comparison: 4 Cough (AC vs placebo), outcome: 4.1 Cough after 6 to 7 days.
5
5
Forest plot of comparison: 3 Dyspnoea (AC or CC versus placebo), outcome: 3.1 Dyspnoea after 6 to 7 days.
6
6
Forest plot of comparison: 3 Thoracic semeiologic alterations (AC vs placebo), outcome: 3.1 Thoracic semeiologic alterations (after 3 days).
1.1
1.1. Analysis
Comparison 1 Febrile state (AC or CC versus placebo), Outcome 1 Febrile state after 6 days.
1.2
1.2. Analysis
Comparison 1 Febrile state (AC or CC versus placebo), Outcome 2 Febrile state after 6 days.
2.1
2.1. Analysis
Comparison 2 Cough (AC or CC versus placebo), Outcome 1 Cough after 6 to 7 days.
2.2
2.2. Analysis
Comparison 2 Cough (AC or CC versus placebo), Outcome 2 Cough after 6 to 7 days.
2.3
2.3. Analysis
Comparison 2 Cough (AC or CC versus placebo), Outcome 3 Cough at the end of treatment (= 28 days).
2.4
2.4. Analysis
Comparison 2 Cough (AC or CC versus placebo), Outcome 4 Cough at the end of treatment (= 28 days).
3.1
3.1. Analysis
Comparison 3 Dyspnoea (AC or CC versus placebo), Outcome 1 Dyspnoea after 6 to 7 days.
3.2
3.2. Analysis
Comparison 3 Dyspnoea (AC or CC versus placebo), Outcome 2 Dyspnoea after 6 to 7 days.
4.1
4.1. Analysis
Comparison 4 Thoracic semeiologic alterations (AC versus placebo), Outcome 1 Thoracic semeiologic alterations after 5 days.
4.2
4.2. Analysis
Comparison 4 Thoracic semeiologic alterations (AC versus placebo), Outcome 2 Thoracic semeiologic alterations after 5 days.
4.3
4.3. Analysis
Comparison 4 Thoracic semeiologic alterations (AC versus placebo), Outcome 3 Thoracic semeiologic alterations after 5 days.
4.4
4.4. Analysis
Comparison 4 Thoracic semeiologic alterations (AC versus placebo), Outcome 4 Thoracic semeiologic alterations at the end of treatment (= 28 days).
4.5
4.5. Analysis
Comparison 4 Thoracic semeiologic alterations (AC versus placebo), Outcome 5 Thoracic semeiologic alterations at the end of treatment (= 28 days).
5.1
5.1. Analysis
Comparison 5 General condition (CC versus placebo), Outcome 1 Bad general condition after 6 to 7 days.
5.2
5.2. Analysis
Comparison 5 General condition (CC versus placebo), Outcome 2 Bad general condition after 6 to 7 days.
6.1
6.1. Analysis
Comparison 6 Cough productivity (AC versus placebo), Outcome 1 Cough productivity at the end of treatment (= 28 days).
6.2
6.2. Analysis
Comparison 6 Cough productivity (AC versus placebo), Outcome 2 Cough productivity at the end of treatment (= 28 days).
7.1
7.1. Analysis
Comparison 7 Appetite (CC versus placebo), Outcome 1 Appetite trouble at the end of treatment (5 to 9 days).
8.1
8.1. Analysis
Comparison 8 Expectoration (CC versus placebo), Outcome 1 Expectoration at the end of treatment (= 7 days).
8.2
8.2. Analysis
Comparison 8 Expectoration (CC versus placebo), Outcome 2 Expectoration at the end of treatment (= 7 days).
9.1
9.1. Analysis
Comparison 9 Pulmonary function tests (CC versus placebo), Outcome 1 Alteration of the pulmonary function after 3 days.
9.2
9.2. Analysis
Comparison 9 Pulmonary function tests (CC versus placebo), Outcome 2 Alteration of the pulmonary function after 3 days.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Bellomo 1972 {published data only}
    1. Bellomo G, Giudice S. Controlled study on the efficacy of a combination "thiamphenicol‐acetylcysteine" in oral administration in respiratory infections in pediatrics [Studio controllata sull'efficacia della combinazione "tiamfenicolo‐acetilcisteina" per via orale nel trattamento delle infezioni broncopolmonari dell'infanzia]. Clinical Pediatrics 1972;54:30‐51.
Biscatti 1972 {published data only}
    1. Biscatti G, Bruschelli M, Damonte G, Capozzi F. Controlled studies of the clinical effects of acetylcysteine in oral administration in respiratory infections in pediatrics [Ricerca controllata sugli effetti clinici dell'acetilcisteina per via orale nelle infezioni respiratorie in pediatria]. Minerva Pediatrica 1972;24:1075‐84. - PubMed
Fiocchi 1989 {published data only}
    1. Fiocchi A, Vignati B, Sala M, Arancio R, Banderali G, Marangione P, et al. A new n‐acetylcysteine formulation in acute bronchopneumopathy in children [La n‐acetilcisteina nel trattamento delle broncopneumopatie acute in pediatria]. Giornale Italiano delle Malattie del Torace 1989;43:327‐34.
Malka 1990 {published data only}
    1. Malka M, Lablache Combier B. Carbocysteine in the treatment of acute bronchitis in children [Interet d'un mucolytique, la carbocistéine, dans la bronchite aiguë de l'enfant]. Medicina Infantil 1990;97:687‐92.
Nakayama 1977 {published data only}
    1. Nakayama Y, Maeda K, Fuanabashi S, Kubagawa T, Simanugi K, Tateno K, et al. Carbocysteine syrup in pediatrics: a clinical trial [Effets cliniques de s‐carboxymethylcysteine sous forme de sirop en pédiatrie (traduction)]. Japanese Journal of Pediatrics 1977;10:1823.
Zanini 1974 {published data only}
    1. Zanini A, Dodesni G. Lisomucil in pediatrics [Il lisomucil in campo pediatrico]. Clinica Europea 1974;13:1‐12.

References to studies excluded from this review

Amir 1985 {published data only}
    1. Amir J, Wilunsky E, Zelikovic I, Reisner SH. Acetylcysteine for severe atelectasis in premature infants. Clinical Pharmacy 1985;4:255. - PubMed
Anonymous 1987 {unpublished data only}
    1. Anonymous. A study of tolerance of carbocisteine syrup in children [Etude de la tolérance clinique du sirop carbocistéine chez l'enfant]. Dossier d'autorisation de mise sur le marché, Laboratoires Alpharma, Aubervilliers, France 1987.
Baldini 1989 {published data only}
    1. Baldini G, Gucci M, Taro D, Memmini C. Controlled clinical study of a new Ambroxol formula in the treatment of infantile spastic bronchitis [Studio clinico controllato sull'attivita di una nuova formulazione di Ambroxol nella bronchite asmatiforme del bambino]. Minerva Pediatrica 1989;41:91‐5. - PubMed
Banovcin 1990 {published data only}
    1. Banovcin P. Efficacy of carbocysteine in the treatment of bronchopneumonias in children. Prakticky Lekar 1990;70:885‐7.
Banovcin 1992 {published data only}
    1. Banovcin P, Jakusova L, Rosslerova V, Miklerova M, Pullman R. Carbocysteine in the treatment of recurrent bronchitis in infants [Karbocystein v liecbe recidivujucich bronchitid u dojciat]. Ceskoslovenska Pediatrie 1992;47:543‐6. - PubMed
Bellomo 1967a {published data only}
    1. Bellomo G, Frigerio G, Tirantello G. Controlled study on the use of intramuscular acetylcysteine in acute respiratory infections in pediatrics [Ricerche controllate sull'impiego dell'acetilcisteina per via intramuscolare nelle infezioni respiratorie acute in pediatria]. Clinica Terapeutica 1967;43:437‐58. - PubMed
Bellomo 1967b {published data only}
    1. Bellomo G, Tirantello G, Giudice S. On the use of a combination of acetylcysteine with thiamphenicol glycinate in the systemic treatment of bronchopulmonary infections in children [Sull'uso di una combinazione dell'acetilcysteina con tiamfenicolo glicato nel trattamento sistemico delle infezioni broncopolmonari in eta' pediatrica]. Clinical Pediatrics 1967;49:402‐24. - PubMed
Bellomo 1973 {published data only}
    1. Bellomo G, Giudice S, Ganci C. Comparative study of the efficacy of acetylcysteine by the oral and intramuscular routes in acute respiratory affections in pediatrics [Studio comparativo dell'efficacia dell'acetilcisteina per via orale ed intramuscolare nelle affezioni respiratorie acute in pediatria]. Minerva Pediatrica 1973;25:844‐9. - PubMed
Berger 1978 {published data only}
    1. Berger von G, Gottschalk B, Leupold W. Initial experiences with ultrasonic aerosol therapy at home in children with bronchiectasis [Erste erfahrungen mit der ultraschall‐aerosolbehandlung unter heimbedingungen bei kindern mit bronchiektasen]. Kinderärztliche Praxis 1978;46:523‐7. - PubMed
Berni 1983 {published data only}
    1. Berni M, Collina A, Zavattini G. Ambroxol in bronchopulmonary pathology in children [Ambroxol nella patologia broncopolmonare del bambino]. Clinica Terapeutica 1983;106:351‐5. - PubMed
Boner 1984 {published data only}
    1. Boner AL, Valletta EA, Stocchero L, Richelli C, Bennati D. Combined antibiotic plus mucolytic treatment of acute or recurrent pneumonia in children. Drugs Under Experimental and Clinical Research 1984;10:627‐30.
Camurri 1990 {published data only}
    1. Camurri S, Marenco G. Clinical evaluation of the safety and efficacy of a new pharmaceutical formulation of bromhexine compared to N‐acetylcysteine in pediatric patients with acute bronchitis [Valutazione clinica dell'efficacia e della tollerabilita della nuova formulazione farmaceutica bromessina granulare nei confronti dell'N‐acetilcisteina granulare in piccoli pazienti affetti da bronchite acuta]. Gazzetta Medica Italiana 1990;149:45‐8.
Caramia 1984 {published data only}
    1. Caramia G, Bizzarri V, Compagnoni L, Gregorini S. Combined antibiotic plus mucolytic treatment in broncho‐pulmonary disease: cefuroxime plus acetylcysteine. Current Therapeutic Research, Clinical and Experimental 1984;36:658‐63.
Careddu 1989 {published data only}
    1. Careddu P, Bernocchi D, Scotti L, Manini G, Mezzopane A. Therapeutic activity and tolerability of a new mucoregulating drug called nesosteine in the treatment of acute diseases of the respiratory apparatus. Controlled pediatric study vs carbocysteine [Attivita terapeutica e tollerabilita di un nuovo farmaco mucoregolatore denominato nesosteina nel trattamento di affezioni acute dell'apparato respiratorio studio pediatrico controllato vs carbocisteina]. Giornale Italiano Delle Malattie Del Torace 1989;43:47‐52.
Castello 1979 {published data only}
    1. Castello D, Costa G, Candussio G. Modifications in catarrhal bronchitis secretion in paediatric age following treatment with S‐carboxymethyl‐cystein (viscosimetric study) [Modificazioni dell'escreato nella bronchite catarrale in eta pediatrica dopo trattamento con S‐carbossimetilcisteina (indagine viscosimetrica)]. Minerva Pediatrica 1979;31:371‐80. - PubMed
Chalumeau 2002 {published data only}
    1. Chalumeau M, Cheron G, assathiany R, Moulin F, Bavoux F, Breart G, et al. Mucolytic agents for acute respiratory tract infections in infants: a pharmacoepidemiologic problem? [Fluidifiants bronchiques dans les infections respiratoires aiguës du nourrisson: un problème pharmacoépidémiologique?]. Archives de Pédiatrie 2002;9:1128‐36. - PubMed
Dano 1971 {published data only}
    1. Dano G. Bronchospasm caused by acetylcysteine in children with bronchial asthma. Acta Allergologica 1971;26:181‐90. - PubMed
Egreteau 1992 {published data only}
    1. Egreteau L, Gaillard D, Jouet JB, Plotkowski L, Zahm JM, Pierrot D, et al. Effect of carbocisteine on mucus and respiratory mucosa in children with recurrent bronchitis. European Respiratory Journal 1992;Suppl 5:301. - PubMed
Gaudier 1968 {unpublished data only}
    1. Gaudier B, Lelong M. Carbocysteine to treat asthma in children [L'utilisation de la S‐Carboxy Methyl Cystéine (LJ 206) dans l'asthme de l'enfant]. Laboratoires Joullie, Paris 1968.
Ginocchi 1978 {published data only}
    1. Ginocchi G. Clinical effects of a mucolytic agent (Pol 65) in a pediatric statistical study [Effeti clinici di un mucoliyico (Pol 65) in una casistica pediatrica]. Settimana Medica 1978;66:391‐408.
Gusberti 1985 {published data only}
    1. Gusberti C, Bellazzi A, Lonati C, Modesti R. Clinical evaluation of a new synthetic derivative of acetylcysteine for treating respiratory inflammations in pediatric patients [Valutazione clinica di uno nuovo derivato sintetico dell'acido acetilsalicilico nella terapia di flogosi respiratorie di pazienti pediatrici]. Archivio di Medicina Interna 1985;37:123‐9.
Henocq 1985 {published data only}
    1. Henocq A, Moreau C, Mallet E, Sauger F, Menibus CH de. Changes in IgA levels in nasal mucus after upper respiratory tract diseases in infants treated with carbocysteine [Modifications du taux IgA du mucus nasal au décours des affections des voies aériennes supérieures du nourrisson traitées par la carbocistéine]. Annales d'Oto‐Laryngologie et de Chirurgie Cervico Faciale 1985;102:373‐5. - PubMed
Hofmann 1980 {published data only}
    1. Hofmann A. Oral acetylcystein in the treatment of bronchial asthma and chronic respiratory tract diseases [Orale anwendung von acetylcystein bei der behandlung von asthma bronchiale und chronischen erkrankungen der luftwege]. Therapiewoche 1980;30:2040‐6.
Jean 1982 {unpublished data only}
    1. Jean R, Gardair F. Efficacy on expectoration of acetylcysteine nebulization in pediatric patients [Utilisation du Fluimucil antibiotic 750 en aérosols chez le nourisson et l'enfant son efficacité d'expectoration]. Laboratoires Zambon, Paris 1982.
Leupold 1970 {published data only}
    1. Leupold W von. Lung function in bronchial asthma during treatment with Mucosolvin [Die lungenfunktion bei asthma bronchiale unter der behandlung mit Mucosolvia]. Das Deutsche Gesundheitswesen 1970;25:1400‐2. - PubMed
Loscialpo Ramundo 1968 {published data only}
    1. Loscialpo Ramundo D. On the use of the association of acetylcysteine and thiamphenicol glycinate in some pediatric pulmonary diseases [Sull'impiego associazone acetilcisteina‐tiamfenicolo glicinato in alcune forme di patologia polmonare pediatrica]. Clinical Pediatrics 1968;50:43‐56. - PubMed
Mayaud 1980 {published data only}
    1. Mayaud C, Lentschner C, Bouchoucha S, Marsac J. Thiamphenicol glycinate acetylcysteinate in the treatment of acute respiratory infections with mucostasis [L'acetylcysteinate de thiamphenicol glycinate dans le traitement des infections respiratoires aigues avec mucostase]. European Journal of Respiratory Diseases Supplement 1980;61(111):70‐3. - PubMed
Michael 1986 {published data only}
    1. Michael P, Haase W. Treatment of acute and chronic bronchitis. Therapeutic experience with Pulmoclase [Behandlung akuter und chronischer bronchitis. Therapeutische erfahrungen mit Pulmoclase]. Therapiewoche 1986;36:4440‐5.
Nigam 1981 {published data only}
    1. Nigam BK. S‐Carboxymethylcysteine (S‐CMC) in bronchography technique. Indian Journal of Chest Diseases and Allied Sciences 1981;23:81‐4. - PubMed
Nikolic 1980 {published data only}
    1. Nikolic P, Korac D. The influence of acetylcysteine on respiratory functions in children with recurrent bronchitis. European Journal of Respiratory Diseases Supplement 1980;61(111):141.
Olivieri 1979 {published data only}
    1. Olivieri D, Pezza A, Polistina D, D'Agostino F. Clinical evaluation of a new pharmacological association in the therapy of acute and chronic bronchitis [Valutazione clinica di una nuova associazione farmacologica nella terapia delle broncopneumopatie acute e croniche]. Archivio Monaldi per la Tisiologia e le Malattie dell'Apparato Respiratorio 1979;34:29‐41. - PubMed
Plietz 1976 {published data only}
    1. Plietz J. The treatment of bronchitic syndrome using Transbronchin in the practice. Zeitschrift für Allgemeinmedizin (Stuttgart) 1976;52:1832‐4. - PubMed
Poder 1982 {unpublished data only}
    1. Poder G, Puskas J, Kelemen J, Gegesi Kiss A, Cserhati E. The effect of long term treatment with N‐Acetylcysteine in infants with chronic obstructive bronchitis [Die Wirkung der Langzeitbehandlung mit N‐Acetylcystein bei chronisch‐obstruktiver Bronchitis im Sauglings‐ und Kleinkindalter]. Laboratoires Zambon (Pharmaceutical company), Paris 1982.
Ramenghi 1984 {published data only}
    1. Ramenghi M, Sabayini G, Mengoni M. Combined antibiotic plus mucolytic treatment for recurrent bronchial diseases in infancy. Current Therapeutic Research 1984;36:664‐7.
Ribeiro 1980 {published data only}
    1. Ribeiro TM, Cunha LG, Santos M, Frenkiel S. Treatment of bronchial diseases in pediatrics. Results of the use of oral acetylcysteine in 80 cases. European Journal of Respiratory Diseases Supplement 1980;61(111):136‐8. - PubMed
Rudnik 1980 {published data only}
    1. Rudnik J, Gawel J, Haluszka J, Kurzawa R, Mielnicka B, Majewska‐Zalewska H, et al. Oral acetylcysteine treatment in children with chronic lung diseases. European Journal of Respiratory Diseases Supplement 1980;61(111):140.
Samsygina 1995 {published data only}
    1. Samsygina G, Kazyukova T, Vykhristyuk O, Motina A, Tsaregorodtseva L, Dudina T. Acetylcysteine 100 in treatment of children with acute and chronic respiratory diseases: experience of use. Pediatriya (Moscow) 1995;1:76.
Santangelo 1985 {published data only}
    1. Santangelo G, Lombardo S, Giannotti G. A combination of cefuroxime and N‐acetyl‐cysteine for the treatment of lower respiratory tract infections in children. International Journal of Clinical Pharmacology, Therapy, and Toxicology 1985;23:279‐81. - PubMed
Szekely 1980 {published data only}
    1. Szekely E, Farkas E. Treatment of chronic bronchitis with oral acetylcysteine in children. European Journal of Respiratory Diseases Supplement 1980;61(111):142.
Trastotenojo 1984 {published data only}
    1. Trastotenojo MS, Harsoyo N, Sachro AD, Soemantri AG, Said HW. Use of acetyl cysteine in respiratory tract disease in children. Paediatrica Indonesiana 1984;24:1‐10. - PubMed
Varricchio 2008 {published data only}
    1. Varricchio A, Capasso M, Giocchino M, Ciprandi G. Inhaled thiamphenicol and acetylcysteine in children with acute bacterial rhinopharyngitis. International Journal of Immunopathology & Pharmacology 2008;21:625‐9. - PubMed
Volkl 1992 {published data only}
    1. Volkl VKP, Schneider B. Treatment of airway diseases with N‐acetylcystein. An open therapeutic observational study involving 2512 patients. Fortschritte der Medizin 1992;110:346‐50. - PubMed
Zens 1967 {published data only}
    1. Zens VM. Clinical trial with a mucolytic agent, acetylcysteine, in children with bronchitis [Klinische Erfahrungen mit Acetylcystein, einer mukoltytiscen Substanz, bei der Bronchitis im Kindesalter]. Fortschritte der Medizin 1967;85:206‐7.
Zuppi 1984 {published data only}
    1. Zuppi LJ, Croce J. Effect of oral route acetylcysteine on the spirometric parameters in children with asthma or rhinitis [Efeito da acetilcisteina oral sobre os parametros espirometricos em criancas asmaticas ou com rinite]. Folha Médica 1984;89:305‐8.

Additional references

Anonymous 2000a
    1. Anonymous. Acetylcysteine. In: McVoy GK editor(s). American Hospital Formulary System Drug Information. Bethesda, USA: American Society of Health‐System Pharmacists Incorporation, 2000:472‐4.
Anonymous 2000b
    1. Anonymous. Acetylcysteine. Anonymous. Drug Facts and Comparisons 2000. 4th Edition. Saint Louis, USA: Facts and Comparisons, 2000:677‐9.
Boluyt 2008
    1. Boluyt N, Tjosvold L, Lefebvre C, Klassen TP, Offringa M. Usefulness of systematic review search strategies in finding child health systematic reviews in MEDLINE. Archives of Pediatrics and Adolescent Medicine 2008;162(2):111‐6. - PubMed
Bricks 1996
    1. Bricks LF, Leone C. Use of medicines by children attending nursery schools. Revista de Saúde Pública 1996;30:527‐35. - PubMed
Bücheler 2002
    1. Bücheler R, Schwab M, Mörike K, Kalchthaler B, Mohr H, Schröder H, et al. Off label prescribing to children in primary care in Germany: retrospective cohort study. BMJ 2002;324(7349):1311‐2. - PMC - PubMed
Cano Garcinuño 2013
    1. Cano Garcinuño A, Casares Alonso I, Rodríguez Barbero J, Pérez García I, Blanco Quirós A. Prescription of systemic cold and cough drugs to children 0‐13 years old. An unresolved problem. Anales de Pediatría 2013;78(1):43‐50. - PubMed
Cates 2003 [Computer program]
    1. Cates C. Visual Rx. Online NNT Calculator (http://www.nntonline.net/). nntonline, 2003.
Cazzato 2001
    1. Cazzato T, Pandolfi C, Campi R, Bonati M. Drug prescribing in out‐patient children in Southern Italy. European Journal of Clinical Pharmacology 2001;57:611‐6. - PubMed
Chalumeau 2000
    1. Chalumeau M, Treluyer JM, Salanave B, Assathiany R, Cheron G, Crocheton N, et al. Off label and unlicensed drug use among French office based paediatricians. Archives of Disease in Childhood 2000;83(6):502‐5. - PMC - PubMed
Chang 2006
    1. Chang AB, Glomb WB. Guidelines for evaluating chronic cough in pediatrics. Chest 2006;129(Suppl):260‐83. - PubMed
Collet 1991
    1. Collet JP, Bossard N, Floret D, Gillet J, Honegger D, Boissel JP. Drug prescription in young children: results of a survey in France. European Journal of Clinical Pharmacology 1991;41:489‐91. - PubMed
Cumberland Pharmaceuticals 2008
    1. Cumberland Pharmaceuticals. Acetadote(r) iv injection, acetylcysteine iv injection. Product information 2008.
Delgado‐Rodriguez 2004
    1. Delgado‐Rodriguez M, Llorca J. Bias. Journal of Epidemiology and Community Health 2004;58:635‐41. - PMC - PubMed
Duijvestijn 1997
    1. Duijvestijn YC, Gerritsen J, Brand PL. Acetylcysteine in children with lung disorders prescribed by one‐third of family physicians: no support in the literature. Nederlands Tijdschrift Voor Geneeskunde 1997;141:826‐30. - PubMed
Duijvestijn 1999
    1. Duijvestijn YC, Brand PL. Systematic review of N‐acetylcysteine in cystic fibrosis. Acta Paediatrica 1999;88:38‐41. - PubMed
EMEA 2001
    1. European Agency for the Evaluation of Medicinal Products. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. Clinical investigation of medicinal products in the paediatric population (ICH Topic E11). http://www.emea.europa.eu/pdfs/human/ich/271199en.pdf 2001 (accessed 15 October 2007).
Halna 2005
    1. Halna M, Leblond P, Aissi E, Dumonceaux A, Delepoulle F, Kohen R, et al. Impact of the consensus conference on outpatient treatment of infant bronchiolitis. Presse Médicale 2005;34:277‐81. - PubMed
Harris 1967
    1. Harris RL, Riley HD. Reactions to aerosol medication in infants and children. JAMA 1967;201:953‐5. - PubMed
Higgins 2003
    1. Higgins JPT, Thompson SG, Deeks JD, Altman G. Measuring inconsistency in meta‐analysis. BMJ 2003;327:557‐60. - PMC - PubMed
Horen 2002
    1. Horen B, Montastruc J‐L, Lapeyre‐Mestre M. Adverse drug reactions and off‐label drug use in paediatric outpatients. Journal of Clinical Pharmacology 2002;54:665‐70. - PMC - PubMed
Horwitz 1980
    1. Horwitz RI, Feinstein AR. The problem of "protopathic bias" in case‐control studies. American Journal of Medicine 1980;68:255‐8. - PubMed
Hughes 1994
    1. Hughes J, Gill A, Leach HJ, Nunn AJ, Billingham I, Ratcliffe J, et al. A prospective study of the adverse effects of midazolam on withdrawal in critically ill children. Acta Paediatrica 1994;83:1194‐9. - PubMed
Mallet 2011
    1. Mallet P, Mourdi N, Dubus J‐C, Bavoux F, Boyer‐Gervoise M‐J, Jean‐Pastor M‐J, et al. Respiratory paradoxical adverse drug reactions associated with acetylcysteine and carbocysteine systemic use in paediatric patients: a national survey. PLoS One 2011;6:e22792. - PMC - PubMed
Medici 1979
    1. Medici TC, Radielovic P. Effects of drugs on mucus glycoproteins and water in bronchial secretion. Journal of International Medical Research 1979;7(5):434‐42. - PubMed
Mourdi 2010
    1. Mourdi N, Dubus JC, Bavoux F, Boyer‐Gervoise M, Jean‐Pastor MJ, Chalumeau M. Mucolytic drugs: towards a contraindication in infants. Archives de Pédiatrie 2010;17:735‐6. - PubMed
Naranjo 1981
    1. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clinical Pharmacology and Therapeutics 1981;30:239‐45. [MEDLINE: ] - PubMed
Poole 2012
    1. Poole P, Black PN, Cates CJ. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 8. [DOI: 10.1002/14651858.CD001287.pub4] - DOI - PubMed
RevMan 2012 [Computer program]
    1. The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012.
Salas 1999
    1. Salas M, Hofman A, Strieker BHC. Confounding by indication: an example of variation in the use of epidemiologic terminology. American Journal of Epidemiology 1999;149:981‐3. - PubMed
Sanz 1988
    1. Sanz EJ, Boada JN. Drug utilization by children in Tenerife Island. European Journal of Clinical Pharmacology 1988;34:495‐9. - PubMed
Sen 2011
    1. Sen EF, Verhamme KM, Felisi M, 't Jong GW, Giaquinto C, Picelli G, et al. Effects of safety warnings on prescription rates of cough and cold medicines in children below 2 years of age. British Journal of Clinical Pharmacology 2011;71:943‐50. - PMC - PubMed
Shields 2008
    1. Shields MD, Bush A, Everard ML, McKenzie S, Primhak R, British Thoracic Society Cough Guideline Group. BTS guidelines: recommendations for the assessment and management of cough in children. Thorax 2008;63(Suppl 3):iii1‐15. - PubMed
Smith 2012
    1. Smith SM, Schroeder K, Fahey T. Over‐the‐counter (OTC) medications for acute cough in children and adults in ambulatory settings. Cochrane Database of Systematic Reviews 2012, Issue 8. [DOI: 10.1002/14651858.CD001831.pub4] - DOI - PubMed
WHO 2007
    1. WHO Child Growth Standards. Weight‐for‐age. http://www.who.int/childgrowth/standards/weight_for_age/en/ 2013 (accessed 1 April 2013).
Wohl 1998
    1. Wohl MEB. Developmental physiology of the respiratory system. In: Chernick V, Boat TF editor(s). Kendig’s Disorders of the Respiratory Tract in Children. Vol. 6th, Philadelphia, USA: WB Saunders Company, 1998.

References to other published versions of this review

Duijvestijn 2009
    1. Duijvestijn YCM, Mourdi N, Smucny J, Pons G, Chalumeau M. Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho‐pulmonary disease. Cochrane Database of Systematic Reviews 2009, Issue 1. [DOI: 10.1002/14651858.CD003124.pub3] - DOI - PubMed

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