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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]
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.
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.
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.
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
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.
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.
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.
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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Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CHARACTERISTICS OF STUDIES
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
Outcomes Clinical: duration of febrile state, dyspnoea, thoracic semeiologic alterations, cough
Notes Italian
Jadad score: 2
Risk of bias
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
Notes Italian
Possibly not comparable treatment because various antibiotics were used
Jadad score: 3
Risk of bias
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)
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
Notes Italian
side effects: 2 patients vomiting in the acetylcysteine group, with 1 dropout;
Jadad score: 5
Risk of bias
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
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
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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
Notes French
Jadad score: 5
Results tables were not available
Risk of bias
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
Notes Italian
Jadad score: 2
Risk of bias
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pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Characteristics of excluded studies [ordered by study ID]
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pulmonary disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
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)
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
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]
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]
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]
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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]
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
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]
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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)
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)
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
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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
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)
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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
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
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Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Characteristics of studies included to evaluate safety (Continued)
X-ray
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.
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
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Table 1. Characteristics of studies included to evaluate safety (Continued)
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
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
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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
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-
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Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Characteristics of studies included to evaluate safety (Continued)
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
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
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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
WHAT’S NEW
Last assessed as up-to-date: 5 July 2008.
HISTORY
Protocol first published: Issue 3, 2001
Review first published: Issue 1, 2009
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]
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.