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Acetylcysteine and carbocysteine for acute upper and lower

respiratory tract infections in paediatric patients without


chronic broncho-pulmonary disease (Review)

Duijvestijn YCM, Mourdi N, Smucny J, Pons G, Chalumeau M

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2009, Issue 1
http://www.thecochranelibrary.com

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho-
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 11. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- i
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Acetylcysteine and carbocysteine for acute upper and lower


respiratory tract infections in paediatric patients without
chronic broncho-pulmonary disease

Yvonne CM Duijvestijn1 , Nadjette Mourdi2 , John Smucny3 , Gérard Pons4 , Martin Chalumeau5

1
Department of Paediatrics (119), Medical Centre Alkmaar, Alkmaar, Netherlands. 2 INSERM U149, Epidemiological Research Unit
on Perinatal, Mother and Child Health, Paris, France. 3 Castro Valley Primary Care, Palomares Division, Palo Alto Medical Founda-
tion, Castro Valley, California, USA. 4 Department of Clinical Pharmacology, Cochin-Saint-Vincent-de-Paul Hospital, AP-HP, Paris
Descartes University, Paris, France. 5 Department of Pediatrics, and U149, Saint-Vincent-de-Paul Hospital, AP-HP, Paris Descartes
University, and INSERM U149, Paris, France

Contact address: Yvonne CM Duijvestijn, Department of Paediatrics (119), Medical Centre Alkmaar, Wilhelminalaan 12, Alkmaar,
1815 JD, Netherlands. yvonneduijvestijn@xs4all.nl. duifwart@xs4all.nl.

Editorial group: Cochrane Acute Respiratory Infections Group.


Publication status and date: Edited (no change to conclusions), published in Issue 9, 2010.
Review content assessed as up-to-date: 5 July 2008.

Citation: 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. Art. No.: CD003124. DOI: 10.1002/14651858.CD003124.pub3.

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

Background

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

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, issue 4) which contains the
Acute Respiratory Infections (ARI) Group’s Specialized Register, MEDLINE (1966 to 2008), EMBASE (1980 to 2008); Micromedex
(2008), Pascal (1987 to 2004), and Science Citation Index (1974 to 2008).

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 also used trials comparing the use of acetylcysteine or carbocysteine versus active treatment or no treatment and
case reports.
Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 1
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Data collection and analysis

At least two review authors extracted data and assessed trial quality. We performed a subgroup analysis of children younger than two
years of age.

Main results

Six trials involving 497 participants were included to study efficacy. They showed some benefit from mucolytic agents, although
differences were of little clinical relevance. No conclusion was drawn about the subgroup of infants younger than two years because the
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, 48 cases of paradoxically
increased bronchorrhoea observed in infants were reported to the French pharmacovigilance system.

Authors’ conclusions

The results of this review have to be interpreted with caution because it was 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). Regarding children younger than two years, given concerns
about safety, these drugs should only be used for ARTIs in the context of an RCT.

PLAIN LANGUAGE SUMMARY

Mucolytic drugs to treat acute upper and lower respiratory tract infections in children without chronic broncho-pulmonary
disease

Acetylcysteine and carbocysteine are the most commonly prescribed mucolytic drugs. This systematic review aimed at assessing their
efficacy and safety for treating acute upper and lower respiratory tract infections (ARTIs) in children without chronic broncho-
pulmonary disease. A subgroup analysis among patients younger than two years was performed.

Forty-nine studies met the inclusion criteria. Six trials involving 497 participants were included to study efficacy and compared
acetylcysteine or carbocysteine to placebo. Thirty-four studies including the previous six were eligible to study safety and involved 2064
paediatric patients.

The results of this review suggest actual but limited efficacy of acetylcysteine and carbocysteine and a good overall safety among children
older than two years of age. However, the number of patients included was limited and the methodological quality was questionable.
These results should also take into consideration the fact that acetylcysteine and carbocysteine are prescribed for self-limiting diseases
(e.g., acute cough, bronchitis). Regarding children younger than two years, given concerns about safety, these drugs should only be
used for ARTIs in the context of a randomised controlled trial.

BACKGROUND sputum modification to reduce cough is sought, including cystic


fibrosis, and chronic and acute bronchitis. In adult patients, the
Of the mucolytic drugs available, the cysteine derivatives (that use of cysteine derivatives is associated with a small reduction in
is, acetylcysteine and carbocysteine) are the most commonly acute exacerbations of chronic bronchitis (Poole 1998). In pae-
prescribed in many European countries (Chalumeau 2000; diatric patients with cystic fibrosis, there is no evidence of effec-
Duijvestijn 1997). In vitro, they act by breaking disulphide bridges tiveness of either oral or inhaled administration of acetylcysteine
between macromolecules, which leads to a reduction in mucus (Duijvestijn 1999).
viscosity (Medici 1979). This property led physicians in the 1960s
and 1970s to develop mucolytic drugs for clinical situations where In addition to being used for patients with severe chronic pul-
Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 2
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
monary disease, in some countries cysteine derivatives are also To study safety, we also used trials comparing acetylcysteine and/
widely used to treat previously healthy paediatric patients with or carbocysteine versus active treatment or no treatment and case
acute broncho-pulmonary disease. In the Netherlands, one third of reports.
general practitioners prescribe acetylcysteine for asthmatic bron-
chitis, acute bronchitis, or for productive or dry cough (Duijvestijn
1997). In France, three studies have shown that acetylcysteine and Types of participants
carbocysteine are some of the most prescribed drugs to children, Trials were included regardless of gender and study setting (am-
especially those younger than two years old (Chalumeau 2000; bulatory or hospital-based).
Collet 1991; Horen 2002). In one of these studies, cysteine deriva- Trials were included if the participants met all of the following
tives accounted for 18 to 25% of drug prescriptions for acute criteria:
rhinopharyngitis, acute cough and acute bronchitis (Chalumeau 1. younger than 18 years (when studies involved adults and
2000). The high rate of prescription of cysteine derivatives for children, a minimum of 50% of children was retained as a
acute upper and lower respiratory tract infections in paediatric pa- threshold to include the study);
tients was shown to be unchanged in the last few years in France 2. treated in primary, secondary or tertiary care settings;
(Halna 2005). In Italy, carbocysteine is one of the 20 most pre- 3. physician diagnosis of respiratory tract infection: acute
scribed drugs by family paediatricians (Cazzato 2001). In Spain, pneumonia, acute bronchitis, acute bronchiolitis (secondary to
expectorants are the most prescribed drugs by paediatricians and respiratory syncytial virus or to another virus) or acute cough
general practitioners for the treatment of acute bronchitis and they (including pertussis);
are the second commonest pharmacological group prescribed to 4. duration of symptoms less than four weeks.
children under two years old (Sanz 1988). Trials which included patients with any of the following conditions
were excluded:
To our knowledge, no systematic review has been previously pub- 1. acetaminophen (paracetamol) intoxication;
lished on the efficacy and safety of acetylcysteine and carbocysteine 2. bronchiectasis, cystic fibrosis or broncho-pulmonary
for acute upper and lower respiratory tract infections (ARTIs) in dysplasia;
paediatric patients without chronic broncho-pulmonary disease. 3. underlying immunodeficiency or respiratory tract
anatomical defect;
4. acute respiratory distress requiring mechanical ventilation.
OBJECTIVES Trials which involved patients with underlying asthma or tuber-
culosis (as defined by the investigators) were included.
1. To assess the efficacy of acetylcysteine and carbocysteine as
symptomatic treatments for ARTIs in paediatric patients without
chronic broncho-pulmonary disease. Types of interventions
Trials assessing the systemic use (that is, oral, intramuscular or
2. To evaluate the safety of acetylcysteine and carbocysteine in
intravenous) or inhaled use of acetylcysteine or carbocysteine were
the symptomatic treatment of ARTIs in paediatric patients
included, regardless of the dose regimen.
without chronic broncho-pulmonary disease.
Trials which allowed concurrent use of other treatments (such
3. To establish a benefit-risk ratio for the use of acetylcysteine as antibiotics, corticosteroids, bronchodilators, antitussives, chest
and carbocysteine as symptomatic treatments for ARTIs in physiotherapy, analgesics, or antipyretics) were included to study
paediatric patients without chronic broncho-pulmonary disease. efficacy if they allowed equal access to such medications for pa-
tients in the intervention and control groups.
Trials comparing the use of acetylcysteine or carbocysteine in asso-
METHODS ciation with other treatments (such as antibiotics, corticosteroids,
bronchodilators, antitussives, chest physiotherapy, analgesics, or
antipyretics) versus placebo, active treatment or no treatment, as
well as case reports were included to study the safety of acetylcys-
Criteria for considering studies for this review
teine or carbocysteine in association with other treatments.

Types of studies Types of outcome measures


To study efficacy, we used randomised controlled trials (RCTs) Trials reporting at least one of the following primary outcome
comparing the systemic or inhaled use of acetylcysteine and/or measures were included:
carbocysteine versus placebo either alone or as an add-on therapy 1. time to resolution of clinical symptoms and/or signs (where
(see ’Types of interventions’). clinical symptoms and signs may include increased respiratory

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 3
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
rate, use of accessory respiratory muscles, abnormal lung #27. bronchitis
examination, cough, sputum production, fever, or activity #28. exp Bronchiolitis/
limitations); #29. bronchiolitis
2. proportions of patients with clinical symptoms and/or signs #30. 10-29 OR
at a designated time; #31. Exp Child/
3. global assessment of improvement by clinicians, patients or #32. child*
their parents at a designated time; #33. paediatric*
4. decreased hospitalisation rates and/or duration of #34. paediatric*
hospitalisation stay; #35. 32-34 OR
5. adverse events reported by the investigators. #36. 9 AND 30 AND 35

Search methods for identification of studies Searching other resources


We handsearched the references of trials obtained to identify other
relevant studies. We contacted trial authors for additional infor-
Electronic searches mation if required, and we requested information on unpublished
We searched the Cochrane Central Register of Controlled Trials trials from drug companies that manufacture acetylcysteine or car-
(CENTRAL) (The Cochrane Library 2007, issue 4) which con- bocysteine in France, the Netherlands and the United States. There
tains the Acute Respiratory Infections (ARI) Group’s Specialized were no language or publication restrictions.
Register, MEDLINE (1966 to March 2008), EMBASE (1980 to
March 2008); Micromedex (April 2008), Pascal (1987 to 2004),
and Science Citation Index (1974 to March 2008). Data collection and analysis
The following search terms were used to search MEDLINE and
CENTRAL. These terms were adapted to search the other elec-
tronic databases. Selection of studies
MEDLINE (PubMed)
#1. Exp Acetylcysteine/ Three review authors (YD, JS, MC) searched titles and abstracts
#2. acetylcysteine to identify potentially relevant articles. Full text versions of these
#3. exp Carbocysteine/ articles, and articles with ambiguous titles or abstracts, were ob-
#4. carbocysteine tained. The same three review authors independently selected arti-
#5. exp Expectorants/ cles which fulfilled the inclusion criteria. Discrepancies regarding
#6. expectorant$ inclusion were resolved by one review author (YD).
#7. exp Mucolytics/
#8. mucolytics
Data extraction and management
#9 1-8 OR
#10. Exp Respiratory Tract Infections/ Three review authors (YD, JS, NM) independently graded the
#11. respiratory tract infections quality of each included study using the Jadad scale (Jadad 1996).
#12. respiratory infections Points were given for method of randomisation (0 to 2), adequacy
#13. exp Rhinitis/ of blinding (0 to 2), and handling of withdrawals (0 to 1), for a
#14. rhinitis total score of 0 to 5 for each study. Disagreements were resolved
#15. exp Common Cold/ by discussion and consensus.
#16. common cold The three review authors independently extracted data from each
#17. exp Influenza/ study.
#18. influenza
#19. exp Pharyngitis/
#20. pharyngitis Unit of analysis issues
#21. exp Sinusitis/ Taking into account differences in populations, inclusion and ex-
#22. sinusitis clusion criteria, interventions and outcome assessment, a quali-
#23. exp Laryngitis/ tative comparison of the studies was undertaken to determine if
#24. laryngitis pooling of the results was reasonable. Primary endpoints were cho-
#25. sore throat sen as the proportion of patients presenting a relevant symptom
#26. exp Bronchitis/ at a common date.

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 4
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
For the dichotomous outcome variables of each individual study, Trastotenojo 1984; Volkl 1992). EMBASE was searched from
risk differences and risk ratios were calculated. The summary 1980 to 2006 and 297 references were identified including 12 po-
weighted risk differences and risk ratios and their 95% confidence tentially relevant studies (Baldini 1989; Banovcin 1992; Camurri
interval (CI) were calculated in Review Manager (version 5) us- 1990; Gusberti 1985; Henocq 1985; Malka 1990; Michael 1986;
ing a fixed-effect model. When risk differences were significant, Nikolic 1980; Rudnik 1980; Santangelo 1985; Szekely 1980;
we calculated the number needed to treat (NNT) using the risk Volkl 1992). Micromedex was searched for acetylcysteine and car-
difference and its CI, and the baseline risk in the control group bocysteine in 1999, 2002 and 2006 and three potentially relevant
thanks to the online calculator Visual Rx (Cates 2003). studies were identified (Malka 1990; Ramenghi 1984; Santangelo
Polytomous outcome variables were recoded in dichotomous vari- 1985). Pascal was searched from 1987 to 2004 and 101 references
ables to enable assessment. For example, an outcome assessed in were identified including one potentially relevant study (Malka
“very good, good, poor, no improvement” was recoded as “actual 1990). From 2005 onward we had no longer access to Pascal. Sci-
improvement versus poor or no improvement”. ence Citation Index was searched from 1974 to March 2008 and
147 references were identified including four potentially relevant
studies (Rudnik 1980; Nikolic 1980; Santangelo 1985; Szekely
Assessment of heterogeneity 1980).
An assessment of possible heterogeneity (the studies did not evalu- The other potentially relevant studies were identified using the
ate the same effect) was carried out for pooled effects using a Bres- references of relevant and non-relevant trials, and the request
low-Day test of heterogeneity. An approach using the I-squared for unpublished trials from drug companies that manufacture
(I²) statistic was used to describe the percentage of total varia- acetylcysteine or carbocysteine in France, the Netherlands and the
tion across studies that is due to heterogeneity rather than chance United States and from authors of relevant and non-relevant stud-
(Higgins 2003). A value above 50% may be considered substantial ies (Anonymous 1987; Amir 1985; Banovcin 1990; Bellomo 1972;
heterogeneity. In case of heterogeneity an analysis using a random- Bellomo 1973; Berger 1978; Caramia 1984; Careddu 1989; Dano
effects model was performed. 1971; Egreteau 1992; Fiocchi 1989; Gaudier 1968; Ginocchi
When studies were combined to evaluate similar (but not exactly 1978; Hofmann 1980; Jean 1982; Leupold 1970; Nakayama
the same) endpoints, we used random-effects models. 1977; Nigam 1981; Olivieri 1979; Poder 1982; Samsygina 1995;
Zanini 1974; Zens 1967).
In summary, we included 49 potentially relevant studies to evaluate
Subgroup analysis and investigation of heterogeneity
the efficacy and safety of acetylcysteine and carbocysteine.
A subgroup analysis of infants younger than two years of age
was performed as recommended by the International Conference
on Harmonisation of Technical Requirements for Registration of Studies included to evaluate efficacy
Pharmaceuticals for Human Use (ICH) topic on the clinical in-
Most of the 49 potentially relevant studies were excluded from
vestigation of medicinal products in the paediatric population be-
the efficacy analysis for one or more reason(s) (see ’Characteris-
cause of different pharmacokinetics and pharmacodynamics in this
tics of excluded studies’ table). Six trials fulfilled the inclusion cri-
age group (EMEA 2001).
teria and none of the exclusion criteria (Bellomo 1972; Biscatti
1972; Fiocchi 1989; Malka 1990; Nakayama 1977; Zanini 1974)
and were eligible to study efficacy (see ’Characteristics of included
studies’ table).
RESULTS
Four of these six trials were written in French and two in Italian.
All six studies were performed more than 17 years ago (median =
Description of studies 32 years). Mucolytics were administrated by oral route in the six
See: Characteristics of included studies; Characteristics of excluded studies.
studies.
CENTRAL Issue 4, 2007 was searched and 159 references were
identified but only one potentially relevant study was found Studies included to evaluate safety
(Zuppi 1984). MEDLINE was searched from 1966 to March Fifteen studies were excluded from the safety analysis because they
2008 and 255 references were retrieved including 17 potentially mainly involved patients with chronic diseases (Amir 1985; Berger
relevant studies (Baldini 1989; Banovcin 1992; Bellomo 1967a; 1978; Egreteau 1992; Hofmann 1980; Nigam 1981; Olivieri
Bellomo 1967b; Berni 1983; Biscatti 1972; Boner 1984; Castello 1979; Plietz 1976; Poder 1982; Ribeiro 1980; Rudnik 1980;
1979; Chalumeau 2002; Henocq 1985; Loscialpo Ramundo Samsygina 1995; Szekely 1980; Volkl 1992; Zens 1967; Zuppi
1968; Mayaud 1980; Plietz 1976; Ribeiro 1980; Santangelo 1985; 1984) (see ’Characteristics of excluded studies’ table).

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 5
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
up was documented in two studies (Michael 1986; Trastotenojo
Twenty-eight studies, in addition to the six trials included to study 1984).
efficacy, fulfilled the inclusion criteria and none of the exclusion
criteria to study safety (Table 1).
Effects of interventions
Among these 28 studies, 11 were written in Italian (Baldini
1989; Bellomo 1967a; Bellomo 1967b; Bellomo 1973; Berni
1983; Camurri 1990; Careddu 1989; Castello 1979 ; Ginocchi 1. Efficacy
1978; Gusberti 1985; Loscialpo Ramundo 1968), seven in En-
The six included trials involved 497 participants and compared
glish (Boner 1984; Caramia 1984; Dano 1971; Nikolic 1980;
cysteine derivatives with placebo (Bellomo 1972; Biscatti 1972;
Ramenghi 1984; Santangelo 1985; Trastotenojo 1984), six in
Fiocchi 1989; Malka 1990; Nakayama 1977; Zanini 1974). The
French (Anonymous 1987; Chalumeau 2002; Gaudier 1968;
six trials were blinded but the process of blinding was appropriate
Henocq 1985; Jean 1982; Mayaud 1980), two in German
according to the Jadad scale in only three studies (Biscatti 1972;
(Leupold 1970; Michael 1986) and two in Slovak (Banovcin 1990;
Fiocchi 1989; Nakayama 1977) (Table 2). There was either no
Banovcin 1992). Except for a targeted pharmacovigilance study
loss of follow-up (Bellomo 1972; Biscatti 1972; Nakayama 1977;
(Chalumeau 2002), the studies were at least 15 years old (median
Zanini 1974) or the analyses were based upon an intention-to-
= 23 years). The route of administration was oral in 16 studies,
treat population (Fiocchi 1989; Malka 1990).
intramuscular in six, inhaled in four, and both oral and intramus-
cular in two.
1.a Analysis of included studies with acetylcysteine
Acetylcysteine was tested in three trials (Bellomo 1972; Biscatti
Risk of bias in included studies 1972; Fiocchi 1989) with a total of 209 participants. The first
Because the studies dated mainly from at least 15 to 40 years ago study included 59 patients with acute bronchitis or broncho-pul-
(median = 26 years) we were not successful in obtaining additional monary infections and compared oral administration of the an-
trial data. tibiotic-mucolytic combination (thiamphenicol glycinate acetyl-
cysteinate) (n1 = 30) with thiamphenicol alone (n2 = 29) as an ac-
The Jadad scale of the six studies included to evaluate efficacy var- tive control at the dose of 14 mg/kg/day of acetylcysteine with
ied from 2 to 5 points. Four studies did not report sufficient de- a duration of treatment of six days (Bellomo 1972). There was
tails on randomisation to make meaningful conclusions about the total remission of febrile state, dyspnea, “thoracic semeiologic al-
potential for selection bias (Bellomo 1972; Biscatti 1972; Malka terations” (i.e., “wheezing breathing”, rattling) and cough in both
1990; Zanini 1974). In each of the six studies, the outcome asses- groups. However, there was a statistically significant more rapid
sors were blinded to treatment allocation, but only three studies remission in the group treated with the antibiotic-mucolytic com-
stated the blinding process, which was adequate (Biscatti 1972; bination. For example, there was total remission of febrile state
Fiocchi 1989; Nakayama 1977). Loss to follow up was well doc- in the treated group after six days but it took nine days for the
umented in three studies (Fiocchi 1989; Malka 1990; Nakayama recovery of all the patients in the placebo group (P = 0.03).
1977). Only two studies fulfilled all the quality criteria (Fiocchi The second study included patients with ARTIs and compared
1989; Nakayama 1977) and scored 5 points on the Jadad scale oral administration of acetylcysteine (n1 = 25) and placebo (n2 =
(Table 2). 25) at a daily dose of 100 to 300 mg of acetylcysteine depending
The other 28 studies included to evaluate safety obtained less than on age for six days (Biscatti 1972). All patients received some
2 points on the Jadad scale. Eighteen studies were assessed with kind of antibiotic. The clinical parameters returned to normal in
no points (Anonymous 1987; Banovcin 1990; Bellomo 1967a; a statistically significant shorter time in the acetylcysteine group.
Bellomo 1967b; Boner 1984; Caramia 1984; Castello 1979; For example, by the end of the treatment (six days), the remission
Chalumeau 2002; Dano 1971; Gaudier 1968; Ginocchi 1978; of cough was total in the treated group whereas the cough persisted
Jean 1982; Leupold 1970; Loscialpo Ramundo 1968; Mayaud in 16% of the patients in the placebo group (difference = -16%,
1980; Nikolic 1980; Ramenghi 1984; Santangelo 1985). The CI -31% to -1%) and the risk ratio was 0.11 (0.01 to 1.96).
other 10 studies were also of very poor quality. Seven of them stated The third study compared oral acetylcysteine (n1 = 50) with
the randomisation process (Baldini 1989; Bellomo 1973; Berni placebo (n2 = 50) at a daily dose of 20 mg/kg subdivided into
1983; Camurri 1990; Careddu 1989; Gusberti 1985; Henocq three daily administrations for 28 days in children with bronchitis
1985) which was adequate in two trials (Careddu 1989; Henocq or tracheitis (Fiocchi 1989). Patients received antibiotics if nec-
1985). The outcome assessors were blinded to treatment alloca- essary. Clinical improvement was observed in the four groups by
tion in only two trials and no details were reported on the blind- the end of the trial. In the subgroup of children with bronchi-
ing process (Banovcin 1992; Trastotenojo 1984). Loss to follow tis, statistically significant differences in the clinical parameters

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 6
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(cough score, cough productivity and thoracic semeiologic alter- cally significant in favour of the treatment group but the data were
ations) were recorded favourable for the acetylcysteine treatment. available only for the outcome “overall assessment”. The analysis
For example, the median cough score (range = 0 to 3) decreased of these data showed a risk difference of 17% (3% to 31%) and a
faster in the treated group with a difference before/after of 2.1 NNT of six (4 to 32).
(2.20 to 0.10), whereas in the placebo group the median score The third study included 30 patients with respiratory infections
dropped from 2.20 to 0.50 (P < 0.05). In the subgroup of children (such as bronchitis) and compared oral administration of carbo-
with tracheitis, no statistically significant differences were noted cysteine (n1 = 19) with placebo (n2 = 11) at a dose of 100 to 400
on the various clinical parameters, except a statistically significant mg/day according to age for five to nine days (Zanini 1974) in pa-
improvement of the cough score, with a difference before/after of tients hospitalised for acute respiratory infections. Patients in both
2.00 (2.10 to 0.10) in the acetylcysteine treatment subgroup and groups received antibiotics if necessary. Improvement of clinical
1.60 (2.10 to 0.50) in the placebo group (P < 0.05). A comparison signs (cough, vomiting/dyspnoea, temperature, appetite, general
of the two groups was performed (Analysis 2.3, Analysis 2.4, Anal- condition) was observed in both groups, with significant improve-
ysis 4.4, Analysis 4.5, Analysis 6.1, Analysis 6.2): the treatment ment for cough, vomiting and dyspnoea in both groups, but the
reduced the risk of “thoracic semeiologic alterations” by 83% (risk actual improvement of general condition was better in the placebo
ratio = 0.17, CI 0.03 to 0.99) and the risk difference at the end of group. Though not significant, the risk difference was 12% (-24%
the treatment was statistically significant (-14% (-25% to -3%)). to 49%) in favour of the placebo group.
The NNT was eight (4 to 34). Regarding cough, the risk differ-
ence was -3% (-13% to 7%) and the risk ratio 0.67 (0.16 to 2.76).
At the end of the trial, productive cough was still present in three 1.c Pooled analysis
patients treated with acetylcysteine versus seven patients in the Because we could include very few studies, we have pooled the
placebo group. The risk difference was not statistically significant results of trials involving acetylcysteine and/or carbocysteine. We
though (-8% (-20% to 3%)) and the risk ratio was 0.41 (0.11 to also considered primary endpoints that were similar but not exactly
-1.56). the same, for example, when the endpoint had close but slightly
different dates. As a consequence, we used random-effects models
when both acetylcysteine and carbocysteine were involved and/or
1.b Analysis of included studies with carbocysteine when the primary endpoints were not exactly the same.
Carbocysteine was tested in three of the six included studies (Malka Five major endpoints could be considered for meta-analysis: febrile
1990; Nakayama 1977; Zanini 1974) with a total of 288 partici- state after six days (Analysis 1.1, Analysis 1.2), cough after six to
pants. The first study included 106 patients with acute bronchitis seven days (Analysis 2.1, Analysis 2.2), dyspnea after six to seven
and compared oral administration of carbocysteine (n1 = 49) with days (Analysis 3.1, Analysis 3.2), thoracic semeiologic alterations
placebo (n2 = 57) at a dose of 200 to 300 mg/day depending on age after five days (Analysis 4.1, Analysis 4.2, Analysis 4.3) and general
for seven days (Malka 1990). Both groups received antibiotics if condition after six to seven days (Analysis 5.1, Analysis 5.2).
necessary. The clinical symptoms (cough, expectoration, bronchial Pooled risk differences and when possible, pooled risk ratios were
congestion, dyspnoea) and pulmonary function test abnormalities calculated to assess these outcomes. Febrile state after six days and
diminished in both groups. Significant differences between the cough after six to seven days were evaluated in three trials (Bellomo
two groups were observed for expectoration and pulmonary func- 1972; Biscatti 1972; Zanini 1974). The first two studies involved
tion tests. For example, after four days, expectoration was easier acetylcysteine and the last one, carbocysteine, and the outcome
for 69% of the treated patients versus 49% of the patients of the was not considered at exactly the same date (after six days or after
placebo group (risk difference = 23% (1% to 47%)). an average of six days), so we used a random-effects model. After
The second study included 152 patients with respiratory diseases six days, three patients were still febrile among the patients from
(bronchial asthma or acute bronchitis) and compared oral admin- the placebo group whereas none presented fever in the treated
istration of carbocysteine (n1 = 74) with placebo (n2 = 78) at a group: the pooled risk difference was -5% (-12% to 2%) (Figure
dose of 30 mg/kg/day three to four times daily for seven days 1). Because of cells with zeros, the risk ratio was estimable only for
(Nakayama 1977). Both groups received bronchodilators, antibi- two studies (Bellomo 1972; Biscatti 1972). Then, the risk ratio
otics and antihistamines if previously treated. The author reported was 0.21 (0.02 to 1.77) (Figure 2). Regarding cough, after six to
improvement in clinical symptoms in both groups: global impres- seven days of treatment, the risk difference was -10% (-19% to -
sion, cough, stridor, expectoration. The difference in improve- 1%) (Figure 3) and the NNT was 10 (6 to 101). The risk ratio
ment for overall assessment, stridor and expectoration was statisti- was 0.37 (0.12 to 1.20) (Figure 4).

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 7
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 1. Forest plot of comparison: 1 Febrile state (AC vs Placebo), outcome: 1.1 Febrile state after 6 days.

Figure 2. Forest plot of comparison: 1 Febrile state (AC or CC versus placebo), outcome: 1.2 Febrile state
after 6 days.

Figure 3. Forest plot of comparison: 4 Cough (AC vs Placebo), outcome: 4.1 Cough after 6 to 7 days.

Figure 4. Forest plot of comparison: 2 Cough (AC or CC versus placebo), outcome: 2.2 Cough after 6 to 7
days.

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 8
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
The assessment of the efficacy of acetylcysteine and carbocysteine
to treat dyspnea involved an additional trial (Malka 1990). Six
patients treated complained of dyspnea after 6 to 7 days versus 9
in the placebo group. The risk difference was -3% (-9% to 3%)
(Figure 5) and the risk ratio was 0.66 (0.25 to 1.74) (Figure 6).

Figure 5. Forest plot of comparison: 3 Dyspnoea (AC or CC versus placebo), outcome: 3.1 Dyspnea after 6
to 7 days.

Figure 6. Forest plot of comparison: 2 Dyspnea (AC or CC vs Placebo), outcome: 2.1 Dyspnea after 6 to 7
days.

The data from two studies were pooled to evaluate the efficacy of
acetylcysteine in the treatment of thoracic semeiologic alterations
(Bellomo 1972; Biscatti 1972). After three days, no treated patient
was presenting that symptom versus three in the placebo group,
the risk difference was 6% (-13% to 2%) (Figure 7). However,
there was heterogeneity between the studies. After using a ran-
dom-effects model the risk difference was -5% (-20% to 10%)
(Figure 8). Because of cells with zeros, the pooled risk ratio was
not estimable (Figure 9).

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 9
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 7. Forest plot of comparison: 3 Thoracic semeiologic alterations (AC vs Placebo), outcome: 3.1
Thoracic semeiologic alterations (after 3 days).

Figure 8. Forest plot of comparison: 4 Thoracic semeiologic alterations (AC versus placebo), outcome: 4.4
Thoracic semeiologic alterations after 6 days.

Figure 9. Forest plot of comparison: 4 Thoracic semeiologic alterations (AC versus placebo), outcome: 4.2
Thoracic semeiologic alterations after 6 days.

We also assessed the efficacy on the general condition using the


data of two studies involving carbocysteine (Nakayama 1977;
Zanini 1974). After seven days, 24 children were still presenting
a deteriorated general condition in the treatment group and 32 in
the placebo group. The risk difference was -7% (-35% to 20%)
(Figure 10) and the risk ratio was 0.78 (0.31 to 1.95) (Figure 11).

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 10
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 10. Forest plot of comparison: 7 General condition (CC versus placebo), outcome: 7.1 Bad general
condition after 7 days.

Figure 11. Forest plot of comparison: 5 General condition (CC versus placebo), outcome: 5.2 Bad general
condition after 7 days.

a targeted pharmacovigilance study. The studies reporting adverse


1.d Subgroup analysis of infants under two years
events were not comparable in terms of participants, interventions
Among the studies with acetylcysteine, Bellomo studied 22 chil- or adverse events, so pooling of the results was judged inappropri-
dren under one year of age and 28 children between one to five ate.
years of age and Biscatti studied 29 children under two years of age.
However, it was not possible to obtain more information about
possible differences in results in the different age groups (Bellomo 2.a Analysis of included studies with acetylcysteine
1972; Biscatti 1972).
Twenty studies evaluated acetylcysteine, involving 1080 patients
among which 831 were treated (Baldini 1989; Bellomo 1967a;
Among the studies with carbocysteine, Nakayama studied children
Bellomo 1967b; Bellomo 1972; Bellomo 1973; Biscatti 1972;
in the age of 1 to 14 years old and Zanini studied 18 children
Boner 1984; Camurri 1990; Caramia 1984; Dano 1971; Fiocchi
under one year of age. However, it was not possible to obtain more
1989; Gusberti 1985; Jean 1982; Leupold 1970; Loscialpo
information about possible differences in results in the children
Ramundo 1968; Mayaud 1980; Nikolic 1980; Ramenghi 1984;
under two years of age (Nakayama 1977; Zanini 1974).
Santangelo 1985; Trastotenojo 1984).

Nine of these studies were controlled trials in which the treatment


2. Safety was administered using the oral route except in one study for which
Our search strategy identified 28 studies to evaluate safety, in ad- the route of administration was intramuscular. Control patients
dition to the six trials above (Bellomo 1972; Biscatti 1972; Fiocchi received either placebo (Biscatti 1972; Fiocchi 1989; Trastotenojo
1989; Malka 1990; Nakayama 1977; Zanini 1974). These 34 stud- 1984; Bellomo 1972), an active control treatment (Baldini 1989;
ies involved 2064 paediatric patients. Safety was evaluated using Camurri 1990; Gusberti 1985), or nothing (Bellomo 1967a). If a
clinical, biological, radiographic, or pulmonary function test pa- concomitant treatment was authorised, for example, antibiotics, it
rameters. Among these studies, 17 were controlled trials (includ- was authorised for all patients. The controlled trials studied clinical
ing 14 RCTs), 16 were non-controlled trials, and the last one was or biological tolerance or both. The biological tests consisted usu-
Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 11
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ally of full blood tests (haemoglobin (Hb), red blood count (RBC), test parameters (Malka 1990; Nakayama 1977). Three studies did
white blood count (WBC), and platelets) and the monitoring not document adverse events (Banovcin 1990; Banovcin 1992;
of hepatic (bilirubin, serum glutamate-oxaloacetate transaminase Henocq 1985). The overall clinical safety was good in the other
(SGOT), serum glutamate-pyruvate transaminase (SGPT), alka- trials, with few patients (n = 19; 13%) complaining of gastro-
line phosphatase) and renal function (creatinine). In two studies, intestinal tract disorders (nausea, vomiting, diarrhoea) (Careddu
safety was also evaluated using radiographic (Trastotenojo 1984) 1989; Malka 1990), leading to the withdrawal or dropping out
or pulmonary function test parameters (Fiocchi 1989). The con- of two (1.9%) treated children and one (0.9%) among the con-
trolled trials all showed good clinical safety, except mild gastro- trol patients (Malka 1990). In one of these two studies (Careddu
intestinal tract adverse events (vomiting) in two patients (2%), 1989) the dose used was high (900 mg/day for children weighing
leading to the withdrawal of one of them (Fiocchi 1989). around 25 kg).

In the other trials, the route of administration was oral in one study, The other studies involved 501 paediatric patients. One study
intramuscular in five, inhaled in four, and both oral and intramus- authorised antibiotics for all patients if necessary (Castello 1979),
cular in one. Most of these studies authorised concomitant treat- and another one authorised antibiotics in 33 children (75%) (
ments, mainly antibiotics. All patients had equal access to these Ginocchi 1978). All trials studied clinical tolerance. Biological
treatments, except in one trial (Zanini 1974). Safety was evaluated parameters (Ginocchi 1978) and sputum viscosimetry (Castello
using clinical and typically biological tests. Some studies also eval- 1979) were also used in two trials. Adverse events were observed in
uated safety using radiographic (Boner 1984; Caramia 1984; Jean 13 patients (2.6%). These patients experienced gastro-intestinal
1982; Loscialpo Ramundo 1968; Mayaud 1980; Santangelo 1985) tract disorders (stomach pain, nausea, vomiting, diarrhoea) in two
or pulmonary function test parameters (Dano 1971; Leupold studies (Gaudier 1968; Michael 1986), leading to the withdrawal
1970). In one study, the tolerance was not documented (Nikolic of five patients (1.3%) in one study (Michael 1986).
1980). The main potential adverse event observed was broncho-
constriction induced by inhaled N-acetylcysteine in children older Our search identified only one study designed to evaluate safety
than two years of age (Dano 1971; Leupold 1970). As a conse- (Anonymous 1987). This study was an open uncontrolled trial
quence, 11 children (31%) were withdrawn from one of these that involved 20 patients with ARTIs, including some infants.
studies (Leupold 1970). This side effect was mainly explained by Patients received carbocysteine for six days at a dose of 200 mg
the trial authors by the high concentration (20%) of acetylcys- per day via oral route. No concomitant treatment was allowed,
teine. Whereas in another study, no such effect was reported with except antibiotics in one child. The safety was evaluated clinically
a lower concentration (10%) (Loscialpo Ramundo 1968). In the by questioning parents and children. The only potentially adverse
other uncontrolled trials clinical safety was very good except in event reported (vomiting) occurred after the end of the treatment
one study where 12 patients (11%) complained of gastro-intesti- and involved only the child on antibiotics.
nal tract disorders (nausea, vomiting, diarrhoea), but none were
withdrawn (Mayaud 1980).
2.c Subgroup analysis of infants under two years
Among the 22 studies that provided clear data on patients’ ages,
2.b Analysis of included studies with carbocysteine
only 10 included patients under two years, involving 262 patients
Thirteen studies evaluated carbocysteine, involving 989 patients, (68%) under this age (Banovcin 1992; Bellomo 1967a; Bellomo
among which 755 were treated (Anonymous 1987; Banovcin 1967b; Bellomo 1973; Biscatti 1972; Castello 1979; Chalumeau
1990; Banovcin 1992; Berni 1983; Careddu 1989; Castello 1979; 2002; Ginocchi 1978; Jean 1982; Ramenghi 1984). Among the
Gaudier 1968; Ginocchi 1978; Henocq 1985; Malka 1990; 10 studies, only one was a good quality controlled trial (Biscatti
Michael 1986; Nakayama 1977; Zanini 1974). 1972) and three were low quality controlled trials (Banovcin 1992;
Bellomo 1967a; Bellomo 1973). One hundred and seventy four
The treatment was administrated using the oral route. Eight tri- patients (75%) under two years were included in these four trials;
als were controlled. The control patients received either a placebo 26 were treated with carbocysteine (Banovcin 1992) and 59 with
(Malka 1990; Nakayama 1977; Zanini 1974), or an active treat- acetylcysteine, including 14 in the single good quality controlled
ment (Banovcin 1990; Banovcin 1992; Berni 1983; Careddu trial (Biscatti 1972). None of them had side effects. No side effect
1989) or nothing (Henocq 1985). If a concomitant treatment was was reported in the other six trials.
authorised, for example, antibiotics, it was authorised for all pa-
tients. The controlled trials used clinical and sometimes biologi- Our search strategy also identified a targeted pharmacovigilance
cal parameters to evaluate safety. The biological tests consisted of study (Chalumeau 2002). This study followed the spontaneous re-
blood tests and/or the monitoring of hepatic and renal function. porting to the French pharmarcovigilance system of cases of para-
In two studies, safety was also evaluated using pulmonary function doxically increased bronchorrhea in infants receiving mucolytic

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 12
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
agents. This prospective two-month study was performed in the (n = 46; 2%). Using the data of the two high quality (Jadad 1996)
emergency departments of two paediatric teaching hospitals in RCTs and the 11 medium or low quality RCTs that studied safety,
Paris, France. During this period, six patients were diagnosed as no severe adverse event was identified. These findings should not
having a paradoxically increased bronchorrhea after having re- lead to the conclusion that mucolytic agents are well tolerated in
ceived acetylcysteine (n = 3) or carbocysteine (n = 3) for acute paediatric patients. In fact, (i) the size of the high quality trials was
upper and lower respiratory infections. Patients were aged 2.5 to not sufficient to provide enough statistical power to detect any rare
7.5 months old. The median delay between treatment and the potentially severe adverse event, (ii) many low quality trials did not
diagnosis of paradoxically increased bronchorrhea was 4.5 days. provide detailed descriptions of the severity of adverse events and
The dose was on average 26 mg/kg/d, ranging from 20 to 35 mg/ abnormal laboratory tests or reasons for treatment discontinuation
kg/d. Two children were hospitalised because of their respiratory separately for each intervention group, and (iii) very few children
state. Using the Naranjo scale for causality assessment, the causal- under two years old were involved in the studies. RCTs of adequate
ity between the exposure and the adverse reaction was considered sample size offer the only unbiased approach for assessing the
possible or plausible (Naranjo 1981). frequency and severity of side effects from a given medication,
but when that kind of evidence is lacking, other sources, such as
pharmacovigilance and pharmaco-epidemiology can be helpful.

Regarding the safety of mucolytic agents in paediatric patients,


DISCUSSION attention should be paid to the youngest age group. In a tar-
We found a limited number of studies that evaluated the efficacy geted prospective pharmacovigilance study in two paediatric emer-
of acetylcysteine and carbocysteine as symptomatic treatments for gency departments, six infants (all younger than eight months old)
ARTIs in paediatric patients without chronic broncho-pulmonary were diagnosed with paradoxically increased bronchorrhea during
disease (Bellomo 1972; Biscatti 1972; Fiocchi 1989; Malka 1990; a two month period (Chalumeau 2002) and since then 42 simi-
Nakayama 1977; Zanini 1974). These trials showed some ben- lar cases were reported at the Regional Center for Pharmacovig-
efit from mucolytic agents, although differences were sometimes ilance and Information on Drugs, Paris, France. This paradoxi-
small, not statistically significant and/or of little clinical relevance. cal reaction was also mentioned but not documented with ref-
Considering the pooling of the data, the effect of acetylcysteine erences in some articles (Jean 1982; Harris 1967) and textbooks
or carbocysteine was not statistically significant except for cough (Anonymous 2000a; Anonymous 2000b). The paradoxically in-
after six to seven days. The treatment (acetylcysteine or carbocys- creased bronchorrhea could be explained by the effective action
teine) reduced the risk of cough by 63%. However, the NNT was of mucolytic agents which increase bronchial mucus flow. This
10 with a large CI (6 to 101), suggesting a questionable effect flow may exceed the capacity of spontaneous drainage of the in-
size. Only two of the six trials were considered high quality studies fant which is limited by the small bronchial diameter and neuro-
using the Jadad scale (Fiocchi 1989; Nakayama 1977). However, muscular physiologic immaturity (Wohl 1998). This could also
even if these studies obtained the highest Jadad score, their results be explained by a dose-related effect. No dose-response trial has
may be limited by methodological weaknesses. No main outcome ever been performed for acetylcysteine, leading to a unique dose
was defined a priori in these studies and results are contradictory recommendation of 200 mg per day, whatever the weight of the
depending on the criteria chosen. In the study by Fiocchi (Fiocchi child. According to the WHO standards (WHO 2007), the me-
1989) patients were divided into two groups - bronchitis and tra- dian weight of a one-month-old infant is about 4.5 kg as opposed
cheitis - based on clinical criteria (dry or productive cough, fever to 12.2 kg for a two year old. The recommended dose for the
and respiratory signs). Since the results regarding the efficacy of youngest infants is then three times higher than the dose recom-
acetylcysteine are different for the two groups, the conclusions mended for the oldest (about 45 mg/kg/day versus 16 mg/kg/day).
are questionable. In the trial by Nakayama (Nakayama 1977), an This may lead to dose-related adverse events in very young infants.
overall criterion based on an improvement in global condition was In the same way, no clinical research has been implemented to
used as an outcome but this composite criterion has not been val- support the recommended dose of the marketing authorization
idated and may not be clinically relevant. No statistically signifi- of carbocysteine (200 to 300 mg /day). The evaluation of drug
cant difference was observed regarding most symptoms considered safety should depend on age considering that pharmacokinetics
separately, especially expectoration and cough. and pharmacodynamics in paediatric patients differ greatly from
adults, especially in neonates and infants. Paradoxical side-effects
It was not possible to make any conclusions about the subgroup
are not rare in these age groups (Hughes 1994) but a causal re-
of infants under two years old, because none of the six studies
lationship is difficult to prove when a paradoxical side effect of
included to evaluate efficacy mentioned the results on this age
a drug is suspected because of protopathic bias. The term proto-
group separately.
pathic bias is used if the first symptoms of the outcome of interest
The overall safety of acetylcysteine and carbocysteine was good, are the reasons for use of treatment (Salas 1999). This bias leads
with mainly minor gastro-intestinal tract disorders in few patients people to believe that when symptoms worsen during the course

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 13
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
of a drug that is prescribed for a specific disease it may be related acute cough, bronchitis), and (iii) millions of paediatric patients
to the disease itself and not to the drug (Delgado-Rodriguez 2004; are exposed to these drugs each year in many European countries
Horwitz 1980). The only way to evaluate paradoxical side effects (Cazzato 2001; Chalumeau 2000; Collet 1991; Duijvestijn 1997;
of drugs avoiding protopathic bias would be theoretically to study Horen 2002; Sanz 1988). These mucolytic agents seem to have
them in another unrelated disease. However, this is not possible some benefits on frequency, intensity and duration of symptoms
in the case of mucolytic agents because their only indications are and appear to be safe in children older than two years. Regarding
respiratory tract infections. children younger than two years old, there are current concerns
about the safety of acetylcysteine and carbocysteine. Therefore,
The evaluation of the benefit-risk ratio of mucolytic agents should these drugs should only be used for acute respiratory tract infec-
take into consideration the fact that these medicines are prescribed tions in neonates and infants in the context of a randomised con-
for self-limiting diseases (for example, acute cough, bronchitis). trolled trial.
For example, in the study by Bellomo (Bellomo 1972), remission
for all symptoms was complete in the placebo group within nine Implications for research
days at most. Regarding paediatric patients older than two years,
no serious adverse events were reported in the available studies An adequately powered randomised double-blind placebo con-
included in the present review. These studies suggest that acetyl- trolled trial evaluating the efficacy and safety of acetylcysteine or
cysteine and carbocysteine may reduce frequency, intensity and carbocysteine should be performed in patients under two years
duration of symptoms in ARTIs. For the patient group younger of age. This trial should use a main outcome which is clinically
than two years, no separate data were available so the benefit-risk relevant (for example, cough frequency, intensity and duration).
ratio could not be evaluated. Multicenter targeted pharmacovigilance studies could help to con-
firm the suspicion of paradoxically increased bronchorrhoea in in-
Our review has some implications for drug regulation agencies.
fants exposed to acetylcysteine or carbocysteine that we described
Acetylcysteine and carbocysteine are licensed for use for the treat-
in a study involving two centres.
ment of acute upper and lower respiratory tract infections in pae-
diatric patients in many European countries. According to our re-
view, this license is not supported by strong evidence in children
older than two years of age, and is not supported by any evidence
in children under two, despite some concerns on safety. A re-eval- ACKNOWLEDGEMENTS
uation of the benefit-risk ratio of these drugs by the drug regula- To Gérard Bréart, INSERM U149, for his valuable advises on
tion agencies of the countries where they are licensed is necessary, the protocol, the analyses and the manuscript (Paris, France). To
particularly in the age group younger than two years. Liz Dooley, Cochrane Acute Respiratory Infections Group Review
Group Co-ordinator, for her very comprehensive editorial work.
To Ruth Foxlee and Sarah Thorning, for their help with the elec-
tronic searches. To Bernard and France Drujon-d’Astros (Aix-en-
AUTHORS’ CONCLUSIONS Provence, France), Barbara Duijvestijn (Heiloo, the Netherlands)
Implications for practice and Grace Tjebbes (Heiloo, the Netherlands), for their help for
The results of the present review have to be interpreted with cau- translations from German, Italian and Russian. To Dr Françoise
tion because (i) it was based on a limited number of patients in- Bavoux and Dr Caroline Pecriaux, Regional Center for Pharma-
cluded in studies whose methodological quality was questionable covigilance and Information on Drugs, Paris, France. Finally, the
and which dated mainly from the 1970’s and 1980’s, (ii) these re- review authors wish to thank the following people for comment-
sults should take into consideration the fact that acetylcysteine and ing on the draft review: Anne Lyddiatt, Inge Axelsson, Teresa Nee-
carbocysteine are prescribed for self-limiting diseases (for example, man, and Jenny Doust.

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 14
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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T, Simanugi K, Tateno K, et al.Carbocysteine syrup
efficacy of acetylcysteine by the oral and intramuscular
in pediatrics: a clinical trial [Effets cliniques de
routes in acute respiratory affections in pediatrics [Studio
s–carboxymethylcysteine sous forme de sirop en pédiatrie
comparativo dell’efficacia dell’acetilcisteina per via orale
(traduction)]. Japanese Journal of Pediatrics 1977;10:1823.
ed intramuscolare nelle affezioni respiratorie acute in
Zanini 1974 {published data only} pediatria]. Minerva Pediatrica 1973;25:844–9.
Zanini A, Dodesni G. Lisomucil in pediatrics [Il lisomucil
in campo pediatrico]. Clinica Europea 1974;13:1–12. Berger 1978 {published data only}
Berger von G, Gottschalk B, Leupold W. Initial
References to studies excluded from this review experiences with ultrasonic aerosol therapy at home in
children with bronchiectasis [Erste erfahrungen mit der
Amir 1985 {published data only}
ultraschall–aerosolbehandlung unter heimbedingungen bei
Amir J, Wilunsky E, Zelikovic I, Reisner SH. Acetylcysteine
kindern mit bronchiektasen]. Kinderärztliche Praxis 1978;
for severe atelectasis in premature infants. Clinical pharmacy
46:523–7.
1985;4:255.
Berni 1983 {published data only}
Anonymous 1987 {unpublished data only}
Berni M, Collina A, Zavattini G. Ambroxol in
Anonymous. A study of tolerance of carbocisteine syrup
bronchopulmonary pathology in children [Ambroxol
in children [Etude de la tolérance clinique du sirop
nella patologia broncopolmonare del bambino]. Clinica
carbocistéine chez l’enfant]. Dossier d’autorisation de mise
Terapeutica 1983;106:351–5.
sur le marché, Laboratoires Alpharma, Aubervilliers, France
1987. Boner 1984 {published data only}
Baldini 1989 {published data only} Boner AL, Valletta EA, Stocchero L, Richelli C, Bennati D.
Baldini G, Gucci M, Taro D, Memmini C. Controlled Combined antibiotic plus mucolytic treatment of acute or
clinical study of a new Ambroxol formula in the treatment recurrent pneumonia in children. Drugs Under Experimental
of infantile spastic bronchitis [Studio clinico controllato and Clinical Research 1984;10:627–30.
Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 15
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Camurri 1990 {published data only} Ginocchi 1978 {published data only}
Camurri S, Marenco G. Clinical evaluation of the safety and Ginocchi G. Clinical effects of a mucolytic agent (Pol 65) in
efficacy of a new pharmaceutical formulation of bromhexine a pediatric statistical study [Effeti clinici di un mucoliyico
compared to N-acetylcysteine in pediatric patients with (Pol 65) in una casistica pediatrica]. Settimana Medica
acute bronchitis [Valutazione clinica dell’efficacia e 1978;66:391–408.
della tollerabilita della nuova formulazione farmaceutica Gusberti 1985 {published data only}
bromessina granulare nei confronti dell’N–acetilcisteina Gusberti C, Bellazzi A, Lonati C, Modesti R. Clinical
granulare in piccoli pazienti affetti da bronchite acuta]. evaluation of a new synthetic derivative of acetylcysteine
Gazzetta Medica Italiana 1990;149:45–8. for treating respiratory inflammations in pediatric patients
Caramia 1984 {published data only} [Valutazione clinica di uno nuovo derivato sintetico
Caramia G, Bizzarri V, Compagnoni L, Gregorini S. dell’acido acetilsalicilico nella terapia di flogosi respiratorie
Combined antibiotic plus mucolytic treatment in broncho- di pazienti pediatrici]. Archivio di Medicina Interna 1985;
pulmonary disease: cefuroxime plus acetylcysteine. Current 37:123–9.
Therapeutic Research, Clinical and Experimental 1984;36: Henocq 1985 {published data only}
658–63. Henocq A, Moreau C, Mallet E, Sauger F, Menibus CH de.
Careddu 1989 {published data only} Changes in IgA levels in nasal mucus after upper respiratory
Careddu P, Bernocchi D, Scotti L, Manini G, Mezzopane tract diseases in infants treated with carbocysteine
A. Therapeutic activity and tolerability of a new [Modifications du taux IgA du mucus nasal au décours des
mucoregulating drug called nesosteine in the treatment affections des voies aériennes supérieures du nourrisson
of acute diseases of the respiratory apparatus. Controlled traitées par la carbocistéine]. Annales d’Oto-Laryngologie et
pediatric study vs carbocysteine [Attivita terapeutica de Chirurgie Cervico Faciale 1985;102:373–5.
e tollerabilita di un nuovo farmaco mucoregolatore Hofmann 1980 {published data only}
denominato nesosteina nel trattamento di affezioni acute Hofmann A. Oral acetylcystein in the treatment of
dell’apparato respiratorio studio pediatrico controllato vs bronchial asthma and chronic respiratory tract diseases
carbocisteina]. Giornale Italiano Delle Malattie Del Torace [Orale anwendung von acetylcystein bei der behandlung
1989;43:47–52. von asthma bronchiale und chronischen erkrankungen der
luftwege]. Therapiewoche 1980;30:2040–6.
Castello 1979 {published data only}
Castello D, Costa G, Candussio G de. Modifications Jean 1982 {unpublished data only}
in catarrhal bronchitis secretion in paediatric age Jean R, Gardair F. Efficacy on expectoration of acetylcysteine
following treatment with S-carboxymethyl-cystein nebulization in pediatric patients [Utilisation du Fluimucil
(viscosimetric study) [Modificazioni dell’escreato nella antibiotic 750 en aérosols chez le nourisson et l’enfant son
bronchite catarrale in eta pediatrica dopo trattamento con efficacité d’expectoration]. Laboratoires Zambon, Paris
S–carbossimetilcisteina (indagine viscosimetrica)]. Minerva 1982.
Pediatrica 1979;31:371–80. Leupold 1970 {published data only}
Chalumeau 2002 {published data only} Leupold W von. Lung function in bronchial asthma during
Chalumeau M, Cheron G, assathiany R, Moulin F, Bavoux treatment with Mucosolvin [Die lungenfunktion bei asthma
F, Breart G, et al.Mucolytic agents for acute respiratory bronchiale unter der behandlung mit Mucosolvia]. Das
tract infections in infants: a pharmacoepidemiologic Deutsche Gesundheitswesen 1970;25:1400–2.
problem? [Fluidifiants bronchiques dans les infections Loscialpo Ramundo 1968 {published data only}
respiratoires aiguës du nourrisson: un problème Loscialpo Ramundo D. On the use of the association
pharmacoépidémiologique?]. Archives de Pédiatrie 2002;9: of acetylcysteine and thiamphenicol glycinate in some
1128–36. pediatric pulmonary diseases [Sull’impiego associazone
acetilcisteina–tiamfenicolo glicinato in alcune forme di
Dano 1971 {published data only}
patologia polmonare pediatrica]. Clinical Pediatrics 1968;
Dano G. Bronchospasm caused by acetylcysteine in children
50:43–56.
with bronchial asthma. Acta Allergologica 1971;26:181–90.
Mayaud 1980 {published data only}
Egreteau 1992 {published data only} Mayaud C, Lentschner C, Bouchoucha S, Marsac
Egreteau L, Gaillard D, Jouet JB, Plotkowski L, Zahm J. Thiamphenicol glycinate acetylcysteinate in the
JM, Pierrot D, et al.Effect of carbocisteine on mucus and treatment of acute respiratory infections with mucostasis
respiratory mucosa in children with recurrent bronchitis. [L’acetylcysteinate de thiamphenicol glycinate dans
European Respiratory Journal 1992;Suppl 5:301. le traitement des infections respiratoires aigues avec
Gaudier 1968 {unpublished data only} mucostase]. European Journal of Respiratory Diseases
Gaudier B, Lelong M. Carbocysteine to treat asthma in Supplement 1980;61(111):70–3.
children [L’utilisation de la S–Carboxy Methyl Cystéine (LJ Michael 1986 {published data only}
206) dans l’asthme de l’enfant]. Laboratoires Joullie, Paris Michael P, Haase W. Treatment of acute and chronic
1968. bronchitis. Therapeutic experience with Pulmoclase
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pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Behandlung akuter und chronischer bronchitis. respiratory tract infections in children. International Journal
Therapeutische erfahrungen mit Pulmoclase]. of Clinical Pharmacology, Therapy, and Toxicology 1985;23:
Therapiewoche 1986;36:4440–5. 279–81.
Nigam 1981 {published data only} Szekely 1980 {published data only}
Nigam BK. S-Carboxymethylcysteine (S-CMC) in Szekely E, Farkas E. Treament of chronic bronchitis
bronchography technique. The Indian Journal of Chest with oral acetylcysteine in children. European Journal of
Diseases & Allied Sciences 1981;23:81–4. Respiratory Diseases Supplement 1980;61(111):142.
Nikolic 1980 {published data only} Trastotenojo 1984 {published data only}
Nikolic P, Korac D. The influence of acetylcysteine on Trastotenojo MS, Harsoyo N, Sachro AD, Soemantri AG,
respiratory functions in children with recurrent bronchitis. Said HW. Use of acetyl cysteine in respiratory tract disease
European Journal of Respiratory Diseases Supplement 1980;61 in children. Paediatrica Indonesiana 1984;24:1–10.
(111):141. Volkl 1992 {published data only}
Olivieri 1979 {published data only} Volkl VKP, Schneider B. Treatment of airway diseases with
Olivieri D, Pezza A, Polistina D, D’Agostino F. Clinical N-acetylcystein. An open therapeutic observational study
evaluation of a new pharmacological association in the involving 2512 patients. Fortschritte der Medizin 1992;110:
therapy of acute and chronic bronchitis [Valutazione clinica 346–50.
di una nuova associazione farmacologica nella terapia delle Zens 1967 {published data only}
broncopneumopatie acute e croniche]. Archivio Monaldi per Zens VM. Clinical trial with a mucolytic agent,
la Tisiologia e le Malattie dell’Apparato Respiratorio 1979;34: acetylcysteine, in children with bronchitis [Klinische
29–41. Erfahrungen mit Acetylcystein, einer mukoltytiscen
Plietz 1976 {published data only} Substanz, bei der Bronchitis im Kindesalter]. Fortschritte der
Plietz J. The treatment of bronchitic syndrome Medizin 1967;85:206–7.
using Transbronchin in the practice. Zeitschrift für
Zuppi 1984 {published data only}
Allgemeinmedizin (Stuttgart) 1976;52:1832–4.
Zuppi LJ, Croce J. Effect of oral route acetylcysteine on
Poder 1982 {unpublished data only} the spirometric parameters in children with asthma or
Poder G, Puskas J, Kelemen J, Gegesi Kiss A, Cserhati E. rhinitis [Efeito da acetilcisteina oral sobre os parametros
The effect of long term treatment with N-Acetylcysteine espirometricos em criancas asmaticas ou com rinite]. Folha
in infants with chronic obstructive bronchitis [Die Médica 1984;89:305–8.
Wirkung der Langzeitbehandlung mit N–Acetylcystein
bei chronisch–obstruktiver Bronchitis im Sauglings– und Additional references
Kleinkindalter]. Laboratoires Zambon (Pharmaceutical
company), Paris 1982. Anonymous 2000a
Anonymous. Acetylcysteine. McVoy GK, editor.
Ramenghi 1984 {published data only} American Hospital Formulary System Drug Information.
Ramenghi M, Sabayini G, Mengoni M. Combined Bethesda: American Society of Health-System Pharmacists
antibiotic plus mucolytic treatment for recurrent bronchial Incorporation, 2000:472–4.
diseases in infancy. Current Therapeutic Research 1984;36:
664–7. Anonymous 2000b
Anonymous. Acetylcysteine. In: Anonymous. Drug
Ribeiro 1980 {published data only}
Facts and Comparisons 2000. Saint Louis. Facts and
Ribeiro TM, Cunha LG, Santos M, Frenkiel S. Treatment
Comparisons; 54th edition (November 1999), 2000:677–9.
of bronchial diseases in pediatrics. Results of the use of oral
acetylcysteine in 80 cases. European Journal of Respiratory Cates 2003
Diseases Supplement 1980;61(111):136–8. Cates C. Visual Rx. Online NNT Calculator (http://
www.nntonline.net/).. nntonline, 2003.
Rudnik 1980 {published data only}
Rudnik J, Gawel J, Haluszka J, Kurzawa R, Mielnicka B, Cazzato 2001
Majewska-Zalewska H, et al.Oral acetylcysteine treatment Cazzato T, Pandolfi C, Campi R, Bonati M. Drug
in children with chronic lung diseases. European Journal of prescribing in out-patient children in Southern Italy.
Respiratory Diseases Supplement 1980;61(111):140. European Journal of Clinical Pharmacology 2001;57:611–6.
Samsygina 1995 {published data only} Chalumeau 2000
Samsygina G, Kazyukova T, Vykhristyuk O, Motina Chalumeau M, Treluyer JM, Salanave B, Assathiany R,
A, Tsaregorodtseva L, Dudina T. Acetylcysteine 100 in Cheron G, Crocheton N, et al.Off label and unlicensed
treatment of children with acute and chronic respiratory drug use among French office based paediatricians. Archives
diseases: experience of use. Pediatriya (Moscow) 1995;1:76. of Disease in Childhood 2000;83(6):502–5.
Santangelo 1985 {published data only} Collet 1991
Santangelo G, Lombardo S, Giannotti G. A combination of Collet JP, Bossard N, Floret D, Gillet J, Honegger D, Boissel
cefuroxime and N-acetyl-cysteine for the treatment of lower JP. Drug prescription in young children: results of a survey

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in France. European Journal of Clinical Pharmacology 1991; Hughes 1994
41:489–91. Hughes J, Gill A, Leach HJ, Nunn AJ, Billingham I,
Delgado-Rodriguez 2004 Ratcliffe J, et al.A prospective study of the adverse effects
Delgado-Rodriguez M, Llorca J. Bias. Journal of of midazolam on withdrawal in critically ill children. Acta
Epidemiology and Community Health 2004;58:635–41. Paediatrica 1994;83:1194–9.
Duijvestijn 1997 Jadad 1996
Duijvestijn YC, Gerritsen J, Brand PL. Acetylcysteine in Jadad AR, Moore A, Carroll D, Jenkinson C, Reynolds
children with lung disorders prescribed by one-third of JM, Gavaghan DJ, et al.Assessing the quality of reports of
family physicians: no support in the literature. Nederlands randomized clinical trials: is blinding necessary?. Controlled
Tijdschrift Voor Geneeskunde 1997;141:826–30. Clinical Trials 1996;17:1–12.

Duijvestijn 1999 Medici 1979


Duijvestijn YC, Brand PL. Systematic review of N- Medici TC, Radielovic P. Effects of drugs on mucus
acetylcysteine in cystic fibrosis. Acta Paediatrica 1999;88: glycoproteins and water in bronchial secretion. The Journal
38–41. of International Medical Research 1979;7(5):434–42.
EMEA 2001 Naranjo 1981
European Agency for the Evaluation of Medicinal Products. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts
International Conference on Harmonisation of Technical EA, et al.A method for estimating the probability of adverse
Requirements for Registration of Pharmaceuticals for drug reactions. Clinical Pharmacology and Therapeutics
Human Use. Clinical investigation of medicinal products 1981;30:239–45. [MEDLINE: 7249508]
in the paediatric population (ICH Topic E11). http:/ Poole 1998
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(Accessed October 15, 2007) 2001. or chronic obstructive pulmonary disease. Cochrane
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El Kohen R, Hue V, Martinot A. Impact of the consensus Salas 1999
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in infants and children. Journal of the American Medical Sanz 1988
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Higgins 2003 Island. European Journal of Clinical Pharmacology 1988;34:
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reactions and off-label drug use in paediatric outpatients. Wohl 1998
Journal of Clinical Pharmacology 2002;54:665–70. Wohl MEB. Developmental physiology of the respiratory
Horwitz 1980 system. In: Chernick V, Boat TF editor(s). Kendig’s
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Medicine 1980;68:255–8. ∗
Indicates the major publication for the study

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 18
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Bellomo 1972

Methods RCT
All patients received thiamphenicol with or without acetylcysteine

Participants 59 paediatric outpatients (22 < 1 year; 28 1 to 5 years; 9 > 5 years) seen for acute bronchitis or broncho-
pulmonary infections

Interventions Oral acetylcysteine


13.8 mg/kg/day 2-4 times a day for 6 to 7 days average (maximum 14 days)

Outcomes Clinical: duration of febrile state, dyspnoea, thoracic semeiologic alterations, cough

Notes Italian
Jadad score: 2

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Biscatti 1972

Methods RCT
All patients received some kind of antibiotic

Participants 50 children (29 < 2 years; 21 > 2 years) hospitalised for acute respiratory infections

Interventions Oral acetylcysteine 100 mg/day under 2 years


200 mg/day between 2 and 4 years
300 mg/day above 4 years for 6 days

Outcomes Clinical: cough, dyspnoea, thoracic semeiologic alteration, temperature reading


Biological: ESR and leucocyte count

Notes Italian
Possibly not comparable treatment because various antibiotics were used
Jadad score: 3

Risk of bias

Item Authors’ judgement Description

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 19
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Biscatti 1972 (Continued)

Allocation concealment? Unclear B - Unclear

Fiocchi 1989

Methods RCT
All patients received antibiotics if necessary

Participants 100 paediatric ambulatory patients (all > 2 years) seen in a paediatric department for acute lower respiratory
infections

Interventions Oral acetylcysteine 20 mg/kg/day 3 times daily for 28 days

Outcomes Clinical: cough, cough productivity and thoracic semeilogic alteration


PFT

Notes Italian
side effects: 2 patients vomiting in the acetylcysteine group, with 1 dropout;
Jadad score: 5

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Malka 1990

Methods RCT
All patients received antibiotics if necessary

Participants 106 paediatric ambulatory patients (2-12 years) seen in general practice for acute bronchitis

Interventions Oral carbocysteine for 7 days: 200 mg/day under 5 years. 300 mg/day above 5 years

Outcomes Clinical: cough, expectoration, bronchial congestion, dyspnoea


PFT

Notes French
9 patients with side effects (in the carbocysteine group: 2 nausea, 3 diarrhoea, 1 stomach pain; in the
placebo group: 1 nausea, 2 stomach pain)
Jadad score: 3

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 20
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Nakayama 1977

Methods RCT
Patients received bronchodilators, antibiotics, antihistamine if previously treated

Participants 152 paediatric outpatients (0 to 18 years) bronchial asthma or acute bronchitis

Interventions Oral carbocysteine 30 mg/kg/day (administered in 3 or 4 doses) for 7 days

Outcomes Clinical: overall assessment, cough, stridor, expectoration


PFT

Notes French
Jadad score: 5
Results tables were not available

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Yes A - Adequate

Zanini 1974

Methods RCT
In treatment group: 15 children received antibiotics; 4 received inhaled AC;
in control group: 8 children received antibiotics

Participants 30 children (18 < 1 year; 12 > 1 year) hospitalised for acute respiratory infections

Interventions Oral carbocysteine from 100 to 400 mg/day depending on age for 5 to 9 days

Outcomes Clinical: cough, dyspnoea, temperature level, appetite, general condition

Notes Italian
Jadad score: 2

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

RCT: randomised controlled trial


ESR: erythrocyte sedimentation rate
PFT: pulmonary function tests
Gastralgia: localised stomach ache

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 21
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Amir 1985 No control group; chronic disease

Anonymous 1987 No control group

Baldini 1989 Active control treatment

Banovcin 1990 Non-randomised; active control treatment

Banovcin 1992 Non-randomised; active control treatment

Bellomo 1967a Non-randomised

Bellomo 1967b No control group

Bellomo 1973 Active control treatment

Berger 1978 No control group; chronic disease

Berni 1983 Active control treatment

Boner 1984 No control group

Camurri 1990 Active control treatment

Caramia 1984 No control group

Careddu 1989 Active control treatment

Castello 1979 No control group

Chalumeau 2002 No control group

Dano 1971 No control group

Egreteau 1992 Chronic disease

Gaudier 1968 No control group

Ginocchi 1978 No control group

Gusberti 1985 Active control treatment

Henocq 1985 No placebo


Type of outcome measures

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 22
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

Hofmann 1980 No placebo


Chronic disease

Jean 1982 No placebo

Leupold 1970 No placebo

Loscialpo Ramundo 1968 No control group

Mayaud 1980 No placebo

Michael 1986 No placebo

Nigam 1981 No placebo


Chronic disease

Nikolic 1980 No placebo

Olivieri 1979 Chronic diseases


No control group

Plietz 1976 Chronic diseases


No control group

Poder 1982 Chronic diseases


No control group

Ramenghi 1984 No control group

Ribeiro 1980 Chronic diseases


No control group

Rudnik 1980 Chronic diseases


No control group

Samsygina 1995 Chronic disease


No randomisation
Active control treatment

Santangelo 1985 No control group

Szekely 1980 Chronic diseases


No control group

Trastotenojo 1984 No randomisation

Volkl 1992 No control group

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 23
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

Zens 1967 Chronic diseases


No control group

Zuppi 1984 Chronic diseases

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 24
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DATA AND ANALYSES

Comparison 1. Febrile state (AC or CC versus placebo)

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Febrile state after six days 3 139 Risk Difference (M-H, Random, 95% CI) -0.05 [-0.12, 0.02]
2 Febrile state after six days 3 139 Risk Ratio (M-H, Random, 95% CI) 0.21 [0.02, 1.77]

Comparison 2. Cough (AC or CC versus placebo)

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Cough after six to seven days 3 139 Risk Difference (M-H, Random, 95% CI) -0.10 [-0.19, -0.01]
2 Cough after six to seven days 3 139 Risk Ratio (M-H, Random, 95% CI) 0.37 [0.12, 1.20]
3 Cough at the end of treatment 1 100 Risk Difference (M-H, Fixed, 95% CI) -0.03 [-0.13, 0.07]
(= 28 days)
3.1 Subgroup = bronchitis 1 48 Risk Difference (M-H, Fixed, 95% CI) -0.07 [-0.25, 0.11]
3.2 Subgroup = tracheitis 1 52 Risk Difference (M-H, Fixed, 95% CI) 0.01 [-0.10, 0.12]
4 Cough at the end of treatment 1 100 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.16, 2.76]
(= 28 days)
4.1 Subgroup = bronchitis 1 48 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.10, 2.83]
4.2 Subgroup = tracheitis 1 52 Risk Ratio (M-H, Fixed, 95% CI) 1.26 [0.08, 19.09]

Comparison 3. Dyspnoea (AC or CC versus placebo)

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Dyspnea after six to seven days 4 245 Risk Difference (M-H, Random, 95% CI) -0.03 [-0.09, 0.03]
2 Dyspnea after six to seven days 4 245 Risk Ratio (M-H, Random, 95% CI) 0.66 [0.25, 1.74]

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 25
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Comparison 4. Thoracic semeiologic alterations (AC versus placebo)

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Thoracic semeiologic alterations 2 109 Risk Difference (M-H, Fixed, 95% CI) -0.06 [-0.13, 0.02]
after five days
2 Thoracic semeiologic alterations 2 109 Risk Difference (M-H, Random, 95% CI) -0.05 [-0.20, 0.10]
after five days
3 Thoracic semeiologic alterations 2 109 Risk Ratio (M-H, Fixed, 95% CI) 0.14 [0.01, 2.63]
after five days
4 Thoracic semeiologic alterations 1 100 Risk Difference (M-H, Fixed, 95% CI) -0.14 [-0.25, -0.03]
at the end of treatment (= 28
days)
4.1 Subgroup = bronchitis 1 48 Risk Difference (M-H, Fixed, 95% CI) -0.11 [-0.27, 0.06]
4.2 Subgroup = tracheitis 1 52 Risk Difference (M-H, Fixed, 95% CI) -0.17 [-0.32, -0.02]
5 Thoracic semeiologic alterations 1 100 Risk Ratio (M-H, Fixed, 95% CI) 0.17 [0.03, 0.99]
at the end of treatment (= 28
days)
5.1 Subgroup = bronchitis 1 48 Risk Ratio (M-H, Fixed, 95% CI) 0.26 [0.03, 2.32]
5.2 Subgroup = tracheitis 1 52 Risk Ratio (M-H, Fixed, 95% CI) 0.11 [0.01, 1.95]

Comparison 5. General condition (CC versus placebo)

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Bad general condition after six 2 182 Risk Difference (M-H, Random, 95% CI) -0.07 [-0.35, 0.20]
to seven days
2 Bad general condition after six 2 182 Risk Ratio (M-H, Random, 95% CI) 0.78 [0.31, 1.95]
to seven days

Comparison 6. Cough productivity (AC versus placebo)

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Cough productivity at the end 1 100 Risk Difference (M-H, Fixed, 95% CI) -0.08 [-0.20, 0.03]
of treatment (= 28 days)
1.1 Subgroup = bronchitis 1 48 Risk Difference (M-H, Fixed, 95% CI) -0.07 [-0.25, 0.11]
1.2 Subgroup = tracheitis 1 52 Risk Difference (M-H, Fixed, 95% CI) -0.09 [-0.25, 0.06]
2 Cough productivity at the end 1 100 Risk Ratio (M-H, Fixed, 95% CI) 0.41 [0.11, 1.56]
of treatment (= 28 days)
2.1 Subgroup = bronchitis 1 48 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.10, 2.83]
2.2 Subgroup = tracheitis 1 52 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.04, 2.63]

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 26
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Comparison 7. Appetite (CC versus placebo)

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Appetite trouble at the end of 1 30 Risk Difference (M-H, Fixed, 95% CI) -0.09 [-0.29, 0.11]
treatment (five to nine days)

Comparison 8. Expectoration (CC versus placebo)

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Expectoration at the end of 1 106 Risk Difference (M-H, Fixed, 95% CI) -0.15 [-0.31, 0.01]
treatment (= seven days)
2 Expectoration at the end of 1 106 Risk Ratio (M-H, Fixed, 95% CI) 0.55 [0.27, 1.10]
treatment (= seven days)

Comparison 9. Pulmonary function tests (CC versus placebo)

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Alteration of the pulmonary 1 106 Risk Difference (M-H, Fixed, 95% CI) 0.05 [-0.14, 0.24]
function after three days
2 Alteration of the pulmonary 1 106 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [0.75, 1.66]
function after three days

ADDITIONAL TABLES
Table 1. Characteristics of studies included to evaluate safety

Study Methods Participants Intervention Outcomes Notes Allocat°


concealment

Anonymous Case report 20 children (1 - Oral Clin- French Not used


1987 14 years) carbocysteine ical: cough fre-
300 mg/day quency and in-
above 5 years tensity, spu-
200 mg/day un- tum quality and
der 5 years quantity
2 - 3 times daily
for 6 days (except

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 27
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Characteristics of studies included to evaluate safety (Continued)

1: 3 days)

Baldini 1989 RCT 28 children older Oral Clinical: expec- Italian Unclear
Active treatment than 2 years old acetylcysteine toration, sputum Jadad score: 1
(ambroxol); 300 mg/day viscosity, dysp-
patients received above 5 years noea, cough, dif-
antibiotics if 200 mg/day un- ficulty of expec-
necessary der 5 years; toration;
for 10 days Biological: blood
exam, monitor-
ing of hepatic
and renal func-
tion

Banovcin 1990 Controlled trial 18 children (6 - Oral PFT Slovak Unclear


Active treatment 15 years) carbocysteine Jadad score: 0
(Ipeca syrup); 250 mg three
antibiotics times a day
and vitamins for
all patients

Banovcin 1992 RCT 51 children (6 - Oral Clinical Slovak Unclear


Active treatment 24 months) carbocysteine score: lung aus- Jadad score: 1
(Ipeca syrup); 50 - 62.5 mg cultation, fever,
antibiotics for all three times a day cough;
patients Biological: blood
exam

Bellomo 1967a Controlled trial 81 children (< 8 Intramuscular Clinical: cough, Italian Unclear
Control patients years) acetylcysteine dyspnoea, tho- Jadad score: 0
received no treat- 25 - 50 mg/kg/ racic semeilogic
ment day alteration, fever

Bellomo 1967b Uncontrolled 39 children (16: Intramuscular Clinical: cough, Italian Unclear
trial < 2 years) acetylcysteine dyspnoea, tho- Jadad score: 0
Thiamphenicol 10 - 18 mg/kg/ racic semeilogic
for all patients day alteration, fever;
Biological: blood
exam;
X-ray

Bellomo 1972 RCT 59 children (22: Oral Clinical: du- Italian Unclear
All < 1 year; 28: 1 acetylcysteine ration of febrile Jadad score: 2
patients received - 5 years; 9: > 5 13.8 mg/kg/day state, dyspnoea,
thiamphenicol years) 2 - 4 times daily thoracic semeio-
with or without for 6 - 7 days av- logic alterations,
acetylcysteine erage (maximum cough
14 days)

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 28
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Characteristics of studies included to evaluate safety (Continued)

Bellomo 1973 RCT 50 children (35: Oral and intra- Clinical: cough, Italian Unclear
Oral and intra- < 2 years) muscular acetyl- dyspnoea, tho- Jadad score: 1
muscular acetyl- cysteine racic semeilogic
cysteine; 300 mg/day un- alteration, fever
thiamphenicol der 2 years;
for all patients 600 mg/day
above

Berni 1983 RCT 30 children (2 - 8 Oral Clinical: cough, Italian Unclear


Antibiotics if years) carbocysteine dyspnoea, expec- Jadad score: 1
necessary 200 - 300 mg toration

Biscatti 1972 RCT 50 children (29: Oral Clinical: cough, Italian Unclear
All patients re- < 2 years; 21: > 2 acetylcysteine dyspnoea, tho- Pos-
ceived some kind years) 100 mg/day un- racic semeilogic sibly not compa-
of antibiotic der 2 years; alteration, tem- rable treatment
200 mg/day be- perature level; because various
tween 2 and 4 Bio- antibiotics were
years; logical: ESR and used
300 mg/day leucocyte count Jadad score: 3
above 4 years for
6 days

Boner 1984 Uncontrolled 60 children (4 - Intramuscular Clini- English Unclear


trial 12 years) acetylcysteine cal: temperature, Jadad score: 0
Cefuroxime for 15 - 30 mg/kg/ cough, chest and
all patients day abdomen
pain, dyspnoea,
wheezing;
Bacteriological:
respiratory secre-
tion cultures;
X-ray

Camurri 1990 RCT 32 children (2 - Oral Clinical: cough, Italian Unclear


Active treatment 11 years) acetylcysteine dyspnoea, expec- Jadad score: 1
(bromhexine) 300 mg/day toration
(difficulty, quan-
tity and quality)

Caramia 1984 Uncontrolled 40 chil- Intramuscular Clinical: cough, English Unclear


trial; dren (4 months - acetylcysteine temperature, Jadad score: 0
Cefuroxime for 13 years) 20 - 30 mg/kg/ sputum viscosity,
all patients day intrinsic sputum
characteristics;
Bacteriological:
respiratory secre-
tion cultures;

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 29
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Characteristics of studies included to evaluate safety (Continued)

X-ray

Careddu 1989 RCT 40 children (5 - Oral Clinical: cough, Italian Unclear


Active treatment 12 years) carbocysteine; dyspnoea, expec- Jadad score: 2
(nesosteine) 900 mg/day toration;
Biological: blood
exam

Castello 1979 Controlled trial; 13 children (1 of Oral Clinical: moni- Italian Unclear
Antibiotics if 15 months + 12: carbocysteine; toring; Jadad score: 0
necessary 2 - 12 years) 3 spoons / day viscosimetry
(2% under
4 years; 5%
above
4 years)

Chalumeau Targeted phar- 6 children (< 2 19.5 - 34.6 mg/ Clinical: cough, French Not used
2002 macovigilance years) kg/day; sputum viscosity
study 3 received oral
carbocysteine;
3 received oral
acetylcysteine.

Dano 1971 Uncontrolled 37 children (5 - Inhaled Clinical: moni- English Unclear


trial 17 years) acetylcysteine toring; Jadad score: 0
2 ml 10% PFT
+ 2 ml 20%

Fiocchi 1989 RCT 100 children (all Oral Clinical: cough, Italian Unclear
All patients re- > 2 years) acetylcysteine cough produc- Side effects: 2
ceived antibi- 20 mg/kg/day 3 tivity and tho- patients vomit-
otics if necessary times a day for racic semeilogic ing in acetylcys-
28 days alteration teine group, with
PFT 1 dropout
Jadad score: 5

Gaudier 1968 Uncontrolled 50 children (< 15 Oral Clinical: moni- French Unclear
trial years) acetylcysteine; toring (evolution Jadad score: 0
2 spoons 2% / of asthma)
day

Ginocchi 1978 Uncontrolled 44 chil- Oral Clinical: cough, Italian Unclear


trial; dren (2 months - carbocysteine dyspnoea, expec- Jadad score: 0
Antibiotics in 33 13 years) 2 spoons / day toration, sputum
children under 5 years; viscosity;
3 spoons / day Biological: blood
above exam

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 30
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Characteristics of studies included to evaluate safety (Continued)

Gusberti 1985 RCT; 40 chil- Oral Clinical: cough, Italian Unclear


Active treatment dren (4 months - acetylcysteine dyspnoea, expec- Jadad score: 1
(AS/CIS 4%, 5 13 years) 200 mg three toration
ml x 3) times a day (difficulty, quan-
tity and quality),
temperature;
Biological: blood
exam

Henocq 1985 RCT 50 children (1 Oral IgA level French Unclear


Control patients month - 4 years) carbocysteine Jadad score: 2
received no treat- 5 ml 2% per 5
ment kg/day

Jean 1982 Uncontrolled 29 children (< 10 Inhaled Clinical: cough, French Unclear
trial years) acetylcysteine dyspnoea, expec- Jadad score: 0
Thiamphenicol 200 mg/day un- toration, sputum
for all patients der 3 months; viscosity,
400 mg/day temperature;
above Bacteriological;
X-ray;
PFT
Bronchoscopy

Leupold 1970 Uncontrolled 36 children (7 - Inhaled Clinical: moni- German Unclear


trial 16 years) acetylcysteine toring Jadad score: 0
15 min: 18 pa- PFT
tients at 20%
and 18 patients
at 10%

Loscialpo Uncontrolled 84 children (2 - Inhaled Clinical: cough, Italian Unclear


Ramundo 1968 trial 12 years) acetylcysteine dyspnoea, fever; Jadad score: 0
Thiamphenicol 1.5 ml 10% Biological: blood
for all patients above 5 years; exam
3 ml 10 % under X-ray
(the first 5 days
twice a day then
once a day)

Malka 1990 RCT 106 children (all Oral Clinical: cough, French Unclear
All patients re- > 2 years); carbocysteine; expecto- 9 patients with
ceived antibi- all patients re- 200 mg/day un- ration, bronchial side effects (in
otics if necessary ceived antibi- der 5 years; congestion, dys- the carbo-
otics if necessary 300 mg/day pnoea cysteine group: 2
above for 7 days PFT nausea, 3 diar-
rhoea, 1 stom-
ach pain; in the

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 31
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Characteristics of studies included to evaluate safety (Continued)

placebo group: 1
nausea, 2 stom-
ach pain)
Jadad score: 3

Mayaud 1980 Uncontrolled 112 children (< Oral and intra- Clinical: French Unclear
trial 8 years; 33: < 1 muscular acetyl- fever, expectora- Jadad score: 0
Thiamphenicol year) cysteine tion (quality);
for all patients 50 mg/kg/day Biological: blood
exam
Bacterio-
logical: quality of
sputum
X-ray

Michael 1986 Uncontrolled 374 children Oral Clinical: cough, German Unclear
trial (mean: 5 years +/ carbocysteine; sputum viscosity, Jadad score: 1
- 3) 500 mg/day un- expectoration,
der 4 years; breathing
750 mg/day
above

Nakayama 1977 RCT 152 children (0 - Oral Clinical: overall French Adequate
Patients received 18 years) carbocysteine; as- Jadad score: 5
brochodilata- 30 mg/kg/day ( sessment, cough,
tors, in 3 to 4 doses a stridor, expecto-
antibiotics, anti- day for 7 days) ration
histamine if pre- PFT
viously treated

Nikolic 1980 Uncontrolled 20 children (3 - Oral Clinical English Unclear


trial 14 years) acetylcysteine PFT Jadad score: 0
100 - 200 mg
three times a day

Ramenghi 1984 Uncontrolled 20 children (10 Intramuscular Clinical: cough, English Unclear
trial months - 2 years) acetylcysteine rale, vesicu- Jadad score: 0
Cefuroxim for 15 mg/kg/day lar murmur, irri-
all patients tability, hypo-al-
imentation;
Biological: blood
exam;
Bacteriological:
on pharyngotra-
cheal aspirate

Santangelo 1985 Uncontrolled 103 chil- Intramuscu- Clinical: moni- English Unclear
trial; dren (2 months - lar acetylcysteine toring; Jadad score: 0
Cefuroxim for 11 years) ; 20 - 30 mg/kg/ Bacterio-

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 32
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Characteristics of studies included to evaluate safety (Continued)

all patients day logical: secretion


cultures;
X-ray

Trastotenojo Controlled trial 60 chil- Oral Clinical: cough, English Unclear


1984 Antibiotics and dren (2 months - acetylcysteine dyspnoea, find- Jadad score: 2
bronchodilator if 13 years) 100 mg three ings on ausculta-
necessary times a day tion;
Biological: blood
exam
X-ray

Zanini 1974 RCT 30 children (18 Oral carbocys- Clinical: cough, Italian Unclear
In treat- < 1 year; 12 > 1 teine from 100 - dyspnoea, tem- Jadad score: 2
ment group 15 year) 400 mg/day de- perature level,
children received pending on age appetite, general
antibiotics + 4 for 5 - 9 days condition
inhaled AC; in
control group 8
children received
antibiotics

Table 2. Methodological quality of studies included to evaluate efficacy

Study ID Randomisation Blinding Losses to follow up Comments

Bellomo 1972 Random sampling num- Patients, providers and Not reported Comparison of antibiotics
bers outcome assessors blinded versus a
combination of antibiotic-
acetylcysteine preparation

Biscatti 1972 Random sampling num- Patients and providers Not reported Possibly not comparable
bers blinded, outcome assessor treatments because of di-
blinding not reported verse antibiotics used

Fiocchi 1989 Randomisation list Patients and 1 patient (in treatment Diverse antibiotics used
providers blinded, blind- group) without appropriate de-
ing of outcome assessors scription
not reported

Malka 1990 Drawing a number Patients and 3 patients (2 in treatment Possible in-
providers blinded, blind- group, 1 in placebo group) homogeneous groups be-
ing of outcome assessors cause of significantly more
not reported patients with dyspnoea in
treatment group at day 0

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 33
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 2. Methodological quality of studies included to evaluate efficacy (Continued)

Nakayama 1977 Random sampling num- Patients, providers and 12 patients (7 in treatment Possibly not comparable
bers outcome assessors blinded group, 5 in placebo group) treatment because of di-
verse drugs used

Zanini 1974 Randomisation manner Patients and Not reported


not reported providers blinded, blind-
ing of outcome assessors
not reported

WHAT’S NEW
Last assessed as up-to-date: 5 July 2008.

Date Event Description

5 August 2010 Amended Contact details updated.

HISTORY
Protocol first published: Issue 3, 2001
Review first published: Issue 1, 2009

Date Event Description

28 March 2008 New search has been performed Searches conducted.

19 February 2008 Amended Converted to new review format.

3 October 2006 New citation required but conclusions have not A subgroup analysis of infants under two years old is
changed added because of reports of paradoxical bronchial con-
gestion and obstruction in infants under two years old
receiving carbocystein and acetylcystein for acute cough

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 34
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CONTRIBUTIONS OF AUTHORS
Yvonne Duijvestijn (YD) participated in the writing of the protocol, then took the lead of the review, participated in the data collection
and analysis, wrote the first draft of the review.
Nadjette Mourdi (NM) participated in the data collection, performed the data analysis and participated in the writing of the review.
John Smucny (JS) participated in the writing of the protocol, in the data collection and analysis, and the writing of the review.
Martin Chalumeau (MC) had the original idea of the study, wrote the first draft of the protocol, participated in data collection and
analysis, and in the writing of the review.
Gerard Pons (GP) commented on several draft versions.

DECLARATIONS OF INTEREST
No financial conflict of interest.

INDEX TERMS
Medical Subject Headings (MeSH)
Acetylcysteine [adverse effects; ∗ therapeutic use]; Carbocysteine [adverse effects; ∗ therapeutic use]; Expectorants [adverse effects;
∗ therapeuticuse]; Randomized Controlled Trials as Topic; Respiratory Tract Infections [∗ drug therapy]

MeSH check words


Child; Child, Preschool; Humans; Infant

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho- 35
pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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