Nebulized and oral thiol derivatives for pulmonary disease in cystic fibrosis

  • Review
  • Intervention

Authors


Abstract

Background

Cystic fibrosis is an inherited condition resulting in thickened, sticky respiratory secretions. Respiratory failure, due to recurrent pulmonary infection and inflammation, is the most common cause of mortality. Muco-active therapies (e.g. dornase alfa and nebulized hypertonic saline) may decrease sputum viscosity, increase airway clearance of sputum, reduce infection and inflammation and improve lung function. Thiol derivatives, either oral or nebulized, have shown benefit in other respiratory diseases. Their mode of action is likely to differ according to the route of administration. There are several thiol derivatives, and it is unclear which of these may be beneficial in cystic fibrosis.

Objectives

To evaluate the efficacy and safety of nebulized and oral thiol derivatives in people with cystic fibrosis.

Search methods

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches, hand searches of relevant journals, abstract books and conference proceedings.

Most recent search: 13 June 2013.

We also conducted a PubMed search on 26 February 2013 for relevant published articles.

Selection criteria

Randomized and quasi-randomized controlled trials comparing nebulized or oral thiol derivatives to placebo or another thiol derivative in people with cystic fibrosis.

Data collection and analysis

The authors independently assessed trials for inclusion, analysed risk of bias and extracted data.

Main results

Searches identified 23 trials; nine trials (255 participants) are included, of these seven trials are more than 10 years old. Three trials of nebulized thiol derivatives were identified (one compared 20% N-acetylcysteine to 2% N-acetylcysteine; another compared sodium-2-mercaptoethane sulphonate to 7% hypertonic saline; and another compared glutathione to 4% hypertonic saline). Although generally well-tolerated with no significant adverse effects, there was no evidence of significant clinical benefit in our primary outcomes in participants receiving these treatments.

Six trials of oral thiol derivatives were identified. Three trials compared N-acetylcysteine to placebo; one compared N-acetylcysteine, ambroxol and placebo; one compared carbocysteine to ambroxol; and one compared low and high-dose N-acetylcysteine. Oral thiol derivatives were generally well-tolerated with no significant adverse effects, however there was no evidence of significant clinical benefit in our primary outcomes in participants receiving these treatments.

Authors' conclusions

We found no evidence to recommend the use of either nebulized or oral thiol derivatives in people with cystic fibrosis. There are very few good quality trials investigating the effect of these medications in cystic fibrosis, and further research is required to investigate the potential role of these medications in improving the outcomes of people with cystic fibrosis.

Résumé scientifique

Dérivés de thiols, administrés par voie orale ou en pulvérisation, dans les maladies pulmonaires liées à la mucoviscidose

Contexte

La mucoviscidose est une affection héréditaire provoquant des sécrétions respiratoires épaisses et collantes. L'insuffisance respiratoire, causée par la récurrence d'infections et d'inflammations pulmonaires, est la cause de mortalité la plus fréquente. Les traitements muco-actifs (par ex. : la dornase alfa et une solution saline hypertonique administrée en pulvérisation) peuvent diminuer la viscosité des expectorations, faciliter l'expulsion des expectorations des voies respiratoires, réduire le nombre d'infections et d'inflammations et améliorer la fonction pulmonaire. Les dérivés de thiols, administrés par voie orale ou en pulvérisation, se sont révélés efficaces contre d'autres maladies respiratoires. Leur mode d'action est susceptible de varier selon la voie d'administration choisie. Il existe plusieurs dérivés de thiols et nous ignorons lesquels sont efficaces contre la mucoviscidose.

Objectifs

Évaluer l'efficacité et l'innocuité des dérivés de thiols administrés par voie orale et en pulvérisation chez les personnes atteintes de mucoviscidose.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre d'essais du groupe Cochrane sur la mucoviscidose et les autres maladies génétiques, composé de références identifiées lors de recherches exhaustives dans des bases de données électroniques, ainsi que des recherches manuelles de revues pertinentes, de recueils de résumés et d'actes de conférence.

Date des recherches les plus récentes :13 juin 2013.

Nous avons également fait une recherche dans PubMed le 26 février 2013.

Critères de sélection

Des essais contrôlés randomisés et des essais contrôlés quasi randomisés comparant des dérivés de thiols administrés par voie orale ou en pulvérisation à un placebo ou à un autre dérivé de thiols chez les personnes atteintes de mucoviscidose.

Recueil et analyse des données

Les auteurs ont indépendamment évalué les essais à inclure, analysé le risque de biais et extrait des données.

Résultats principaux

Les recherches ont identifié 23 essais ; neuf essais (255 participants) sont inclus (sept datant de plus de 10 ans). Trois essais concernant l'administration de dérivés de thiols en pulvérisation ont été identifiés (un comparait 20 % de N-acétylcystéine à 2 % de N-acétylcystéine ; un autre comparait du sodium-2-mercaptoéthane sulfonate à 7 % de solution saline hypertonique et un autre comparait du glutathion à 4 % de solution saline hypertonique). Malgré le fait qu'ils aient été généralement bien tolérés sans générer d'effets indésirables significatifs, il n'y avait aucune preuve d'effets bénéfiques cliniquement significatifs concernant nos critères de jugement principaux chez les participants bénéficiant de ces traitements.

Six essais portant sur des dérivés de thiols administrés par voie orale ont été identifiés. Trois essais comparaient la N-acétylcystéine à un placebo ; une comparait la N-acétylcystéine, l'ambroxol et un placebo, une comparait la carbocistéine à l'ambroxol, et une comparait la N-acétylcystéine à faible et haute dose . Les dérivés de thiols administrés par voie orale étaient généralement bien tolérés et ne présentaient aucun effet indésirable significatif. Toutefois, il n'y avait aucune preuve d'effets bénéfiques cliniquement significatifs concernant nos critères de jugement principaux chez les participants bénéficiant de ces traitements.

Conclusions des auteurs

Nous n'avons trouvé aucune preuve permettant de recommander l'administration de dérivés de thiols par voie orale ou en pulvérisation chez les personnes atteintes de mucoviscidose. Il existe très peu d'essais de bonne qualité examinant les effets de ces médicaments sur la mucoviscidose et d'autres recherches seront nécessaires pour identifier le rôle éventuel de ces médicaments dans l'amélioration des résultats chez les personnes atteintes de mucoviscidose.

Plain language summary

Compounds which can break down the structure of mucus for lung disease in cystic fibrosis

Cystic fibrosis is a genetic disorder which mainly affects the lungs. Chest infections recur in people with cystic fibrosis due to a build up of thick sputum (phlegm) in the air passages. Several treatments, including thiol derivatives, aim to loosen this sputum and so improve lung function and reduce the frequency of chest infections. Thiol derivatives may be either nebulized (breathed in) or oral (by mouth). They have been shown to help in other lung conditions, such as chronic obstructive pulmonary disease. This review aims to find out if there is enough evidence to recommend the use of nebulized or oral thiol derivatives for people with cystic fibrosis. We included nine trials; three assessed the effect of nebulized thiol derivatives. Of the nebulized trials, one compared 20% N-acetylcysteine to 2% N-acetylcysteine; another compared sodium-2-mercaptoethane sulphonate to 7% hypertonic saline; and the other compared glutathione to 4% hypertonic saline. Nebulized thiol derivatives were generally well-tolerated with no major adverse effects. However they showed no significant improvements in any of our outcome measures.

Six included trials assessed the effects of oral thiol derivatives.Three of these trials compared oral N-acetylcysteine to placebo; one compared oral N-acetylcysteine, oral ambroxol and placebo; and one compared oral carbocysteine and oral ambroxol (no placebo). None of the trials showed an overall significant benefit in any of the outcome measures of this review. Oral thiol derivatives were generally well-tolerated with no major adverse effects.

In summary, the trials included in the review did not provide any evidence that nebulized or oral thiol derivatives were either beneficial or harmful to people with cystic fibrosis. Further research investigating the effects of thiol derivatives in people with cystic fibrosis is required before their use can be recommended.

Résumé simplifié

Composés capables de décongestionner la structure du mucus dans les maladies pulmonaires liées à la mucoviscidose

La mucoviscidose est une maladie génétique qui touche principalement les poumons. Les infections pulmonaires réapparaissent chez les personnes atteintes de mucoviscidose en raison de l'accumulation d'expectorations épaisses (phlegme) dans les voies de passage de l'air. Plusieurs traitements, notamment les dérivés de thiols, ont pour objectif de fluidifier ces expectorations, donc d'améliorer la fonction pulmonaire et de réduire la fréquence de ces infections pulmonaires. Les dérivés de thiols peuvent être administrés en pulvérisation (inspirés) ou par voie orale (par la bouche). Ils se sont révélés efficaces contre d'autres affections pulmonaires, comme les maladies pulmonaires obstructives chroniques. L'objectif de la présente revue est de déterminer s'il existe suffisamment de preuves pour recommander l'administration de dérivés de thiols en pulvérisation ou par voie orale aux personnes atteintes de mucoviscidose. Nous avons inclus neuf essais, dont trois évaluaient les effets des dérivés de thiols administrés en pulvérisation. Sur les études concernant la pulvérisation de thiols, une comparait 20 % de N-acétylcystéine à 2 % de N-acétylcystéine ; une autre comparait du sodium-2-mercaptoéthane sulfonate à 7 % de solution saline hypertonique et une autre comparait du glutathion à 4 % de solution saline hypertonique. Les dérivés de thiols administrés en pulvérisation étaient généralement bien tolérés et ne présentaient aucun effet indésirable majeur. Toutefois, ils ne montraient aucune amélioration significative pour aucun de nos critères de jugement.

Six essais inclus évaluaient les effets des dérivés de thiols administrés par voie orale. Trois de ces essais comparaient la N-acétylcystéine orale à un placebo, une comparait la N-acétylcystéine orale, l'ambroxol oral et un placebo et une comparait la carbocistéine orale et l'ambroxol oral (aucun placebo). Aucun de ces essais ne montrait des effets bénéfiques significatifs globaux pour aucun des critères de jugement de cette revue. Les dérivés de thiols administrés par voie orale étaient généralement bien tolérés et ne présentaient aucun effet indésirable majeur.

En résumé, les essais inclus dans cette revue n'ont fourni aucune preuve selon laquelle les dérivés de thiols administrés en pulvérisation ou par voie orale étaient efficaces ou néfastes chez les personnes atteintes de mucoviscidose. D'autres recherches examinant les effets des dérivés de thiols chez les personnes atteintes de mucoviscidose seront nécessaires avant que leur administration ne puisse être recommandée.

Notes de traduction

Traduit par: French Cochrane Centre 22nd February, 2013
Traduction financée par: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux

Background

Description of the condition

Cystic fibrosis (CF) is a genetic multisystem disorder characterized by thick, tenacious secretions resulting in organ damage, primarily involving the lungs and gastrointestinal system. Over the past 30 years, survival in CF has increased dramatically due to the development of new therapies and aggressive nutritional supplementation (CFF 2007; Corey 1996). Despite these improvements, the most common cause of death is end-stage pulmonary disease and respiratory failure (Davis 2006). Lung damage occurs secondary to the excessive inflammatory response to bacteria that reside in the airways. The influx of neutrophils and stimulation of mucus secretion within the airways results in thick secretions which are difficult to clear. Furthermore, tenacious secretions adhere to the airways worsening mucociliary clearance and ciliary function. This creates an environment of increased bacterial burden, further inflammation, and thicker secretions.

Description of the intervention

Mucolytic therapy has been proposed as a method to decrease sputum viscosity, increase airway clearance of sputum, reduce bacterial load and inflammation, improve lung function, and ultimately increase survival (Henke 2007). It is typically initiated as part of the ongoing treatment regimen and the effects of such therapies are typically seen after regular use for a minimum of four weeks of treatment. Several mucolytic therapies are available for use in CF including dornase alfa (also known as rhDNase (Pulmozyme®)) (Fuchs 1994), hypertonic saline (Elkins 2006) and thiol derivatives such as N-acetylcysteine (NAC) (Duijvestijn 1999). Macrolides have been shown to affect mucus hypersecretion (Shimizu 2003) but are considered mucoregulatory rather than mucolytic agents. The Cochrane systematic reviews of both dornase alfa (Jones 2003) and hypertonic saline (Wark 2005) have demonstrated an improvement in lung function and a reduction in the need for antibiotic therapy for pulmonary exacerbations of CF. It is unclear whether thiol derivatives result in the same beneficial effects.

Thiol derivatives are compounds which contain a functional group of a sulfur atom and a hydrogen atom. This sulfhydryl group enables thiol derivatives to break down the gel structure of mucus, by substituting sulfhydryl groups for the disulfide bonds connecting mucin proteins (Dasgupta 1996). NAC is the classic thiol derivative, but several other compounds are included under this heading, including glutathione (GSH), cysteine, nacystelyn (NAL), sodium-2-mercaptoethane sulphonate, carbocysteine, erdosteine and mecysteine. In vitro, NAC has been demonstrated to reduce the viscosity and elasticity of mucus when directly in contact with airway secretions (Sheffner 1964). This may make sputum easier to clear; however, thinner secretions could potentially be harder to expectorate due to this reduced viscosity. NAC is a very acidic compound (pH 2.2), and when inhaled results in airway irritation, induction of cough and bronchospasm. Manufacturers therefore suggest that individuals receive pre-treatment with a bronchodilator prior to inhalation. It has been suggested that induction of cough by inhaled NAC, rather than mucolysis, may explain any beneficial effect of NAC on expectoration. This mechanism may reduce airway inflammation by improving clearance of the pro-inflammatory neutrophil breakdown products of which CF sputum largely consists. NAL, a lysine salt of NAC, has an approximately neutral pH and is well-tolerated when inhaled (App 2002). When studied in vitro, NAL has been demonstrated to have a more potent mucolytic activity than NAC, and, also in vitro, has an additional inhibitory effect on human neutrophil elastase (Marriott 1993).

How the intervention might work

Nebulized thiol derivatives

NAC is a very acidic compound (pH 2.2), and when inhaled results in airway irritation, induction of cough and bronchospasm. Manufacturers therefore suggest that individuals receive pre-treatment with a bronchodilator prior to inhalation. It has been suggested that induction of cough by inhaled NAC, rather than mucolysis, may explain any beneficial effect of NAC on expectoration. This mechanism may reduce airway inflammation by improving clearance of the pro-inflammatory neutrophil breakdown products of which CF sputum largely consists. NAL, a lysine salt of NAC, has an approximately neutral pH and is well-tolerated when inhaled (App 2002). When studied in vitro, NAL has been demonstrated to have a more potent mucolytic activity than NAC, and, also in vitro, has an additional inhibitory effect on human neutrophil elastase (Marriott 1993).

Oral thiol derivatives

Orally-administered thiol derivatives are proposed to work by a different mechanism to inhaled thiol derivatives. Inhalation of thiol derivatives aims to deliver the compound to the lower airway in an attempt to act directly on airway secretions as a mucolytic. However, when administered orally there is no detectable NAC in bronchoalveolar lavage (Cotgreave 1987). Therefore orally-administered thiol derivatives are unlikely to have a direct effect as a mucolytic. Oral NAC is broken down (deacetylated) to cysteine, whose thiol group has reducing and antioxidant properties (Bonanomi 1980). Neutrophils in the CF airway cause damage by releasing oxidants, and are deficient in GSH, an important endogenous cellular antioxidant. High-dose oral NAC increases neutrophil GSH levels, decreases airway neutrophil recruitment and reduces neutrophilic release of airway elastase (Tirouvanziam 2006a). The sulfhydryl group also allows NAC to interact directly with oxidants, functioning as an oxidant scavenger (Ventresca 1989). Therefore, orally-administered thiol derivatives most likely act by reducing pulmonary oxidative stress and inflammation, and subsequently attenuating airway and parenchymal destruction. NAC also prevents inactivation of alpha-1-antitrypsin by neutrophil elastase in vitro, and could also prevent lung damage in CF by this mechanism (Borregaard 1987). In addition, oral thiol derivatives may have a mechanism of action in reducing airway inflammation by regulating redox signalling (Rahman 2006).

It must be stressed that the characteristics of CF sputum are different to that of sputum seen in other pulmonary diseases, such as chronic obstructive pulmonary disease (COPD). CF sputum contains low levels of mucin, and consists predominantly of pus derived from neutrophil degradation (Henke 2004). This observation may impact on the ability of inhaled thiol derivatives to reduce sputum viscosity in CF, since mucin is their primary target.

In summary, inhaled thiol derivatives are proposed to act primarily by their mucolytic effects, whereas when orally administered these compounds are more likely to act predominantly as antioxidants, with also a possible anti-inflammatory effect. These potential differing mechanisms of action are supported by in vitro evidence. Different pharmacokinetics, mechanisms of action and adverse effects can be expected depending on the thiol derivative utilized, the dose used, and the mode of administration.

Why it is important to do this review

The aim of this review is to collate and analyse the results of randomized controlled trials (RCTs) examining the clinical (in vivo) effects of both inhaled and oral thiol derivatives in the therapy of lung disease in people with CF. We thereby aim to provide clear evidence-based guidance regarding their effectiveness and safety in this group of individuals.

Objectives

The aims of this review are to:

  1. evaluate efficacy of both inhaled and oral thiol derivatives in people with CF.

  2. evaluate safety of both inhaled and oral thiol derivatives in people with CF.

Methods

Criteria for considering studies for this review

Types of studies

All published and unpublished randomized and quasi-randomized controlled trials. There was no language restriction for this review.

Types of participants

All individuals diagnosed with CF based on standard diagnostic criteria (sweat testing or genetics and clinical features or family history) were included. There were no restrictions on pulmonary disease severity, gender, or pancreatic status.

Types of interventions

Trials investigating thiol derivatives given at any dose or frequency, via nebulized or oral administration, for a minimum of four weeks duration were eligible for inclusion. We felt four weeks to be the minimum amount of time needed to see an effect from the treatment. Outcomes for participants who received thiol derivatives were compared to participants receiving no treatment or to control groups including placebo or any other medication. Nebulized and oral interventions were considered separately in this review. Thiol derivatives considered for inclusion were acetylcysteine (or N-acetylcysteine), sodium-2-mercaptoethane sulphonate, carbocysteine, erdosteine, nacystelyn, glutathione, cysteine and mecysteine.

Types of outcome measures

The following outcomes were recorded separately for both nebulized and oral thiol derivatives.

Primary outcomes
  1. Pulmonary function testing (PFT)

    1. forced expiratory volume in one second (FEV1) per cent predicted (change from baseline and absolute data)

    2. forced vital capacity (FVC) per cent predicted (change from baseline and absolute data)

Secondary outcomes
  1. Other PFT measurements which reflect airflow obstruction or gas trapping or both, e.g. peak expiratory flow (PEF), vital capacity (VC), FEV1/VC, mid-expiratory flow 25-75 (MEF25-75), residual volume/total lung capacity (RV/TLC) (change from baseline and absolute data)

  2. Inflammatory markers (change from baseline)

    1. serum (white blood cell (WBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR))

    2. sputum (IL-8)

  3. Quality of life (QOL) (change from baseline as measured by a validated QOL scale)

  4. Need for oral antibiotics for pulmonary exacerbation

    1. number of weeks of treatment

    2. number of courses

  5. Need for intravenous antibiotics for pulmonary exacerbation

    1. number of weeks of treatment

    2. number of courses

  6. Adverse events

  7. Number of days in hospital for respiratory exacerbation

  8. Adherence

  9. Acquisition of new respiratory pathogens (%)

  10. Six-minute walk distance

  11. Sputum characteristics (including measures of viscosity and elasticity)

Search methods for identification of studies

Electronic searches

We identified relevant trials using the Cystic Fibrosis Trials Register using the terms: acetylcysteine OR N-acetylcysteine OR carbocysteine OR erdosteine OR mecysteine OR nacystelyn OR glutathione OR cysteine OR sodium-2-mercaptoethane sulphonate.

The Cystic Fibrosis Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library), quarterly searches of MEDLINE, a search of EMBASE to 1995 and the prospective handsearching of two journals - Pediatric Pulmonology and the Journal of Cystic Fibrosis. Unpublished work was identified by searching the abstract books of three major cystic fibrosis conferences: the International Cystic Fibrosis Conference; the European Cystic Fibrosis Conference and the North American Cystic Fibrosis Conference. For full details of all searching activities for the register, please see the relevant sections of the Cystic Fibrosis and Genetic Disorders Group Module.

Date of last search: 13 June 2013.

To ensure completeness of our literature search, we conducted a separate PubMed search on 26 February 2013 (Appendix 1). We manually reviewed abstracts and identified randomized controlled trials published since 2008.

Data collection and analysis

We used RevMan software to conduct the statistical analysis (RevMan 2011).

Selection of studies

Two authors (EN, AS during the initial review; JT, AS during the update) assessed the articles identified against the inclusion criteria for this review in an independent fashion. Where possible, authors contacted primary investigators if any details were unclear. They resolved any disagreements by discussion and advice from the other co-authors.

Data extraction and management

Two authors (EN, AS during the initial review; JT, AS during the update) extracted data from the articles in an independent fashion. Where possible, authors contacted primary investigators if their methodology was unclear. They resolved any disagreements by discussion and advice from the other co-authors.

Where possible we grouped outcome data into those measured at one month, up to three months, up to six months, up to twelve months and then annually thereafter. If outcome data were recorded at other time periods we examined these as well.

One of the included trials is a three-arm trial, and we are including it in two comparisons (oral thiols versus placebo and oral thiols versus other oral agents) (Ratjen 1985). By so doing, we realize that some participants will be counted twice in this review.

One trial’s published results are presented in graph form, or median values and interquartile ranges (Dauletbaev 2009). The authors attempted to contact the investigators to obtain raw data, but did not receive a response in time for this article. The trial’s results are described in this review, but are not included in the statistical analysis.

The authors of the three published abstracts listed as 'Awaiting assessment' were not contacted for this update, but will be contacted and we hope to have data to assess these for inclusion in a future update of the review.

Assessment of risk of bias in included studies

The authors assessed the articles to establish the risk of bias in each trial using a component approach and selected judgements in line with guidance in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Where possible, authors contacted primary investigators if their methodology was unclear.

Measures of treatment effect

When assessing differences between groups, we recorded the mean difference (MD) from baseline for each group as our treatment effect measure for continuous variables. Where applicable, we calculated a pooled estimate of treatment effect by calculating the MD and the 95% confidence intervals (CIs).

With binary outcomes, we planned to use the risk ratio (RR) and the 95% CIs as a measure of treatment effect; however, we were only able to present results using continuous data.

Unit of analysis issues

We included both parallel group trials as well as trials with a cross-over design. Ideally we would have liked to analyse cross-over trials using techniques outlined by Elbourne (Elbourne 2002); however, due to limitations on the data available we were only able to treat these trials as parallel trials and present data for the end of treatment. We realise that this approach is conservative as it ignores within-patient correlation and so does not make use of the advantages of the cross-over design. Also, this approach ignores the fact that patients appear in both arms of the trial and are not independent of each other (Elbourne 2002). We did not combine the data from cross-over trials with parallel trials as we were unable to employ the methods recommended by Curtin (Curtin 2002).

For longitudinal data, we reported the time-points that measurements were taken by the primary investigators and which measures were reported in the papers. In the review we present data from end of treatment. We preferred to report data for the change from baseline at end of treatment, but if the original paper reported only absolute data (means, standard deviations (SD) of groups or raw data), we planned to calculate the mean difference and the variance of the difference imputed using the Follmann method (Follmann 1992). This method allows the use of separate sources of incomplete information to help choose a better variance estimate. This method can be summarised by the formula: Var(change) = Var(pre-test) + Var(post-test) - 2 x SD(pre-test) x SD(post-test) x pre-test-post-test correlation coefficient. We also planned to report these absolute values post-treatment. Where the correlation coefficient was unknown we estimated it to be 0.4 (a moderate correlation) in order to perform the calculation.

Dealing with missing data

When possible, the authors (JT, EN, AS) contacted primary investigators if missing data were required.

Assessment of heterogeneity

We planned to assess the heterogeneity of the trials using the Q test, with heterogeneity being considered to be present if the Q test was statistically significant at the P < 0.10 level. When assessing the magnitude of any heterogeneity present, we planned to use the I2 statistic (Higgins 2003), the value of which depends on the magnitude and direction of effects, and evidence for heterogeneity (Higgins 2011). We interpret values of I2 below 33% as representing a low amount of heterogeneity, greater or equal to 33% and below 66% representing a moderate amount of heterogeneity, and greater or equal to 66% representing a high amount of heterogeneity.

Assessment of reporting biases

We intended on assessing publication bias using a funnel plot; however, there were insufficient trials (minimum of 10 required) to conduct this analysis.

With regards to selective reporting of outcomes, we were unable to compare the original trial protocols with the final published papers; however, there did not appear to be any obvious omissions to the outcomes reported on by the trial investigators.

Data synthesis

We did not identify any heterogeneity between trials, and used a fixed-effect model in our analysis; however, if in future we establish moderate or high degrees of heterogeneity, we will utilize a random-effects model.

Subgroup analysis and investigation of heterogeneity

Several thiol derivatives are available, and therefore we planned to perform subgroup analysis for each compound. The dose of the thiol derivative used may alter outcomes, and therefore we planned to perform subgroup analysis according to dose. There were insufficient trials to perform either of these subgroup analyses on this occasion, but we plan to perform these analyses in a future update of the review when we are able to combine a sufficient number of trials to allow this. Clinically important outcomes vary depending on gender, age and severity of lung disease (FEV1 70% to 80% will be considered mild; 60% to 70% moderate; 50% to 60% moderately severe; 34% to 50% severe; and less than 34% very severe (ATS 1991)), and therefore we also planned to perform an analysis using these subgroups. We planned to analyze age and lung function as continuous variables as well as categorical variables in an attempt to identify any high-risk groups. The degree of airway inflammation may also impact on the response to therapy with thiol derivatives, and therefore we also planned to perform subgroup analysis according to whether the trial was performed during an acute pulmonary exacerbation or during a period of disease stability. Again, there were insufficient trials to perform these subgroup analyses in this review, but we plan to perform these analyses in a future update where possible. Lung function will be categorized according to ATS guidelines for disease severity as described above (ATS 1991), and age will be categorized in 10-year blocks where possible.

Sensitivity analysis

We intended to conduct a sensitivity analyses based on the degree of risk of bias of the trials in the review; however, there were insufficient trials to proceed with this analysis.

Results

Description of studies

Results of the search

The search process identified 27 published research papers from a variety of international journals. These papers referred to 23 separate trials, of which we were able to include nine trials. We excluded 11 trials and deferred classification of three trials (published as abstracts only) for this update.

Included studies

We identified nine trials eligible for inclusion; three trials examined the effects of nebulized thiol derivatives (Bishop 2005; Howatt 1966; Weller 1980) and six trials evaluated oral thiol derivatives in people with CF (Caramia 1995; Dauletbaev 2009; Mitchell 1982; Ratjen 1985; Stafanger 1988; Stafanger 1989). Clinical details regarding the participants, interventions and outcomes are given in the table Characteristics of included studies.

Nebulized thiol derivatives

Three trials compared nebulized thiol derivatives to other nebulized medications (Bishop 2005; Howatt 1966; Weller 1980). There was considerable heterogeneity between trials and therefore data from only two of these trials could be pooled for analysis (Bishop 2005; Weller 1980); also, the number of outcomes for which data could be pooled was very limited.

Participants

All trials had small numbers of participants (between eight and 29 participants in each trial). Two trials included both adults and children (Bishop 2005; Howatt 1966) and one trial included children only (Weller 1980).

Trial Design

One trial was of parallel design (Bishop 2005) and two of the trials were of cross-over design (Howatt 1966; Weller 1980). The two cross-over trials both compared two treatment arms (Howatt 1966; Weller 1980 ). Only one of the cross-over trials contained a washout period between treatment blocks (Weller 1980).

Duration of treatment blocks ranged from one month to two months; duration of the trials ranged from two to four months.

Interventions

One of the included trials assessed the effects of nebulized NAC (Howatt 1966), another assessed the effects of nebulized sodium-2-mercaptoethane sulphonate (Weller 1980) and the final trial assessed the effects of nebulized glutathione (Bishop 2005). Since different thiol derivatives can be expected to have different clinical effects, it is not appropriate to combine the results of trials assessing different compounds.

None of the trials compared the effects of nebulized thiol derivatives against a true placebo. The Howatt trial compared the effects of nebulized 20% NAC and nebulized 2% NAC (it is unknown whether nebulized 2% NAC has a clinical effect) (Howatt 1966). The Weller trial compared the effects of nebulized sodium-2-mercaptoethane sulphonate and nebulized hypertonic (7%) saline (Weller 1980) and the Bishop trial compared nebulized glutathione versus nebulized hypertonic saline (4%) (Bishop 2005). Nebulized hypertonic saline, both at concentrations of 4% and 7%, has been demonstrated to have beneficial effects on the clinical course of CF lung disease, so is not a true placebo (Wark 2005).

The number of daily treatments was different in all three trials; in the Bishop trial there were four inhalations daily (Bishop 2005); in the Howatt trial there were three inhalations daily (Howatt 1966); and in the Weller trial there were twice daily inhalations (Weller 1980).

In the Howatt trial, participants either received the drug during positive pressure breathing treatments or while using a Devilbiss nebulizer (Howatt 1966).

Outcome measures

All three trials assessed pulmonary function at the end of treatment, but used a variety of different measures (Bishop 2005; Howatt 1966; Weller 1980). The Howatt paper only provides a table outlining the number of pulmonary function tests which improved or got worse compared to the previous month; however there is insufficient detail in the table to ascertain which specific pulmonary function tests improved (Howatt 1966). All of the trials also reported baseline values (Bishop 2005; Howatt 1966; Weller 1980).

Two trials asked participants to record cough frequency and sputum volume and color (Bishop 2005; Weller 1980). In addition Bishop asked participants to record general wellness and sputum viscosity (Bishop 2005); and Weller asked participants to record any adverse effects (Weller 1980).

One trial additionally measured BMI and six-minute walk distance (Bishop 2005). Howatt evaluated participants clinically based on the method of Shwachman and Kulczycki (Howatt 1966). Weller additionally undertook blood tests (complete blood count, liver function tests, renal function and electrolytes) and chest x-rays (Weller 1980).

Oral thiol derivatives

Six trials reported on the effects of oral thiol derivatives; three of the included trials reported on the effects of oral NAC compared to placebo (Mitchell 1982; Stafanger 1988; Stafanger 1989); one trial compared the effects of oral NAC, oral ambroxol and placebo (Ratjen 1985); one trial compared the effects of oral ambroxol and oral carbocysteine (Caramia 1995); and the remaining trial compared low- and high-dose NAC (Dauletbaev 2009). Since the Ratjen paper reports on a three-arm trial, and we are including it in two comparisons (oral thiols versus placebo and oral thiols versus other oral agents), we realize that some participants will be counted twice in this review.

Participants

The number of participants in the trials ranged from 20 to 52. One trial experienced a high drop out rate (40%) (Stafanger 1989); because of the unusually high dropout rate (which we will discuss further under 'Risk of bias in included studies') and the fact that the results for only 10 participants out of 52 were presented in the paper, we felt that this was unreliable data and therefore it was not included in the analysis for this review.

One trial studied children only (Mitchell 1982), the others recruited a mixture of children and adults. All trials stated how many males and females were recruited and the proportions were approximately equal in most trials. All trials reported on clinical status at randomization. Two trials recorded ‘mild to moderate pulmonary disease’ (Mitchell 1982; Ratjen 1985); one trial recorded good clinical status (Caramia 1995); one trial recorded ‘stable disease’ (Dauletbaev 2009); two trials reported on colonization with Pseudomonas aeruginosa (Stafanger 1988; Stafanger 1989). The earlier trial recruited participants who weren't chronically infected and the later trial recruited participants who were chronically infected with Pseudomonas aeruginosa.

Trial Design

Three trials were of parallel design (Caramia 1995; Dauletbaev 2009; Ratjen 1985). The other three trials were of cross-over design (Mitchell 1982; Stafanger 1988; Stafanger 1989). Two trials described the use of a washout period prior to the start of the intervention and between interventions for cross-over trials (Mitchell 1982; Stafanger 1989). A third cross-over trial does not state any washout period between treatment arms (Stafanger 1988). The duration of each treatment period was three months in four of the trials (Mitchell 1982; Ratjen 1985; Stafanger 1988; Stafanger 1989), 80 days in the fifth trial (Caramia 1995), and 81 days in the remaining trial (Dauletbaev 2009).

Interventions

Four trials compared oral NAC to placebo (Mitchell 1982; Ratjen 1985; Stafanger 1988; Stafanger 1989); one of these trials also compared oral ambroxol to placebo (Ratjen 1985). Of the trials comparing oral NAC to placebo, two trials stated that both active and placebo drugs were given in granular form and could not be distinguished from each other (Mitchell 1982; Ratjen 1985).Two trials compared one oral thiol derivative to another oral thiol derivative (Caramia 1995; Ratjen 1985) The first trial compared oral carbocysteine syrup to oral ambroxol syrup (Caramia 1995) and the second trial compared oral NAC granules to oral ambroxol granules (Ratjen 1985). One trial compared low- and high-dose NAC (Dauletbaev 2009).

Drugs were administered three times daily in all trials with the following exceptions: in the trial of oral carbocysteine syrup versus oral ambroxol syrup, the oral ambroxol syrup was given four times daily to children under 14 years of age (Caramia 1995); in the two trials by Stafanger, oral NAC was given twice daily if the participant's weight was over 30 kg (Stafanger 1988; Stafanger 1989); in the trial by Dauletbaev, low- and high-dose NAC was administered once daily (Dauletbaev 2009).

Daily dosage of oral NAC was 200 mg three times daily in two trials (Mitchell 1982; Ratjen 1985). The dose of NAC in both Stafanger papers was 200 mg three times daily in participants weighing less than 30 kg and 400 mg twice daily in participants weighing more than 30 kg (Stafanger 1988; Stafanger 1989). The dose of oral ambroxol was 30 mg three times daily in one trial (Ratjen 1985), and in the other trial participants under 14 years of age received 10 mg four times daily and adults received 33 mg three times daily (Caramia 1995). The dosage of carbocysteine used in the Caramia paper was 270 mg three times daily in participants under 14 years of age and 900 mg three times daily in adults (Caramia 1995). Dauletbaev’s trial compared the effects of NAC administered 700 mg once daily and 2800 mg once daily (Dauletbaev 2009)

Outcome measures

All trials measured outcomes at baseline and end of treatment (Caramia 1995; Dauletbaev 2009; Mitchell 1982; Ratjen 1985; Stafanger 1988; Stafanger 1989). Four trials also measured outcomes in the interim period: Caramia measured outcomes at 20, 40 and 60 days (Caramia 1995); Dauletbaev measured outcomes at 22, 46, 64, and 127 days (Dauletbaev 2009); Ratjen measured outcomes at six weeks (but the trial only reports end of treatment data) (Ratjen 1985); both Stafanger trials measured outcomes on a monthly basis (Stafanger 1988; Stafanger 1989).

All trials measured pulmonary function with a variety of outcome measures, although the two Stafanger papers only reported results for pulmonary function for 23 out of 41 participants (Stafanger 1988) and for 10 participants (whose baseline PEF was less than 70% predicted) out of 52 participants (Stafanger 1989). Four trials assessed sputum characteristics (Caramia 1995; Mitchell 1982; Stafanger 1988; Stafanger 1989). Four trials took blood samples: Caramia performed an arterial blood gas analysis (Caramia 1995); Dauletbaev measured extracellular glutathione (Dauletbaev 2009); two trials measured white blood cell count, sedimentation rate and antibody titres for Staphylococcus aureus, Pseudomonas aeruginosa, and Hemophilus influenza (Stafanger 1988; Stafanger 1989). Four trials reported on adverse events (Caramia 1995; Dauletbaev 2009; Mitchell 1982; Ratjen 1985). Two trials reported on cough frequency (Caramia 1995; Mitchell 1982). Caramia additionally reported participants' subjective measurement of dyspnea (Caramia 1995) and Mitchell additionally reported on antibiotic usage (Mitchell 1982).

Excluded studies

Eleven trials were excluded because they did not meet the inclusion criteria. Seven trials were excluded as the duration of the intervention was less than four weeks (App 2002; Casale 2012; Gotz 1980; Griese 2004; Maayan 1989; Tecklin 1976; Snyder 2002); three trials were excluded as they were not randomized (Dasgupta 1996; Tirouvanziam 2006b, Dietzsch 1975); one trial was excluded as the intervention was not relevant (Cezeaux 1967).

Studies awaiting assessment

The classification of three abstracts was deferred due to insufficient available information (Griese 2013; Tirouvanziam 2011; van Daele 2011).

Risk of bias in included studies

The details of the risk of bias of the reviewed trials are given in the table Characteristics of included studies. The information was extracted from the published papers.

Nebulized thiol derivatives

Three trials looked at nebulized thiol derivatives (Bishop 2005; Howatt 1966; Weller 1980).

Allocation

All three trials were described as randomized; however, two of these did not describe the randomization process and were therefore deemed to have an unclear risk of bias (Bishop 2005; Weller 1980). The Howatt trial randomized the order of drugs for the four-month period by making up two slips of paper for each of the six possible combinations; the participants then drew a schedule from an envelope (Howatt 1966). The trial was deemed to have a low risk of bias.

One trial does not clearly discuss allocation concealment and therefore it was judged to have an unclear risk of bias (Weller 1980). The other two trials do give details of adequate allocation concealment and were judged to have a low risk of bias (Bishop 2005; Howatt 1966). Bishop reports that no member of the clinical team was involved in the generation of allocation to treatments (Bishop 2005). In the Howatt trial, the drugs were supplied in 10 ml vials labelled with a letter code and the key to the code was supplied in a sealed envelope, which was not opened until the trial was completed (Howatt 1966).

Blinding

All three trials were described as "double-blind" (Bishop 2005; Howatt 1966; Weller 1980). Two of these trials described attempts to mask the characteristics of the different treatments (e.g. taste and odour) (Bishop 2005; Howatt 1966). These trials therefore were deemed to have low risk of bias. The Weller trial made no attempt to mask the characteristics of the different treatments and was therefore judged to have a risk of bias (Weller 1980).

Incomplete outcome data

One trial reported data from all the randomized participants and were therefore judged to have a low risk of bias (Howatt 1966).

Both the other two trials reported withdrawals (Bishop 2005; Weller 1980). The numbers of drop outs in the are low and equal across treatment groups, therefore these trials have a low risk of bias.

One trial did not present data for all the participants randomized, but did not discuss the reasons for this (Howatt 1966). This trial is therefore judged to have a high risk of bias.

Weller did not report any data for FEV1 (Weller 1980). In recently published trials it would be expected that this standard lung function test would be measured at clinic visits and information recorded. The lack of these data in a published paper could signal a potential source of bias; it may have not been reported due to negative results. However, the trial in question is nearly 30 years old and this measure of lung function may not have been employed by the trialists.

Other potential sources of bias

The Howatt trial has a number of potential sources of bias (Howatt 1966). Firstly, there is no washout period between treatments. Secondly, the drug delivery system was not consistent amongst all participants. Two participants received the drug during positive pressure breathing treatments while four participants used a Devilbiss nebulizer. Thirdly, the paper provides a table outlining the number of pulmonary function tests which improved or worsened compared to the previous month; however, there is insufficient detail in the table to ascertain which specific pulmonary function tests improved. This is an important factor since certain pulmonary function tests are clinically relevant and important outcomes to measure, while other aspects of the testing can be highly variable and difficult to interpret. And finally, the paper only provided lung function data for two of the eight people in the trial (Howatt 1966).

Oral thiol derivatives

Six trials looked at oral thiol derivatives (Caramia 1995; Dauletbaev 2009; Mitchell 1982; Ratjen 1985; Stafanger 1988; Stafanger 1989).

Allocation

All six trials were described as randomized; however, five of the trials did not describe the randomization process and were therefore deemed to have an unclear risk of bias (Caramia 1995; Dauletbaev 2009; Mitchell 1982; Stafanger 1988; Stafanger 1989). In the Ratjen trial randomization was done by computer and the trial was judged to have a low risk of bias (Ratjen 1985).

None of the six trials clearly discussed allocation concealment and therefore were judged to have an unclear risk of bias (Caramia 1995; Dauletbaev 2009; Mitchell 1982; Ratjen 1985; Stafanger 1988; Stafanger 1989).

Blinding

The Caramia trial was single-blinded, with investigators being aware of the treatment allocation (Caramia 1995). This trial design introduces a significant potential bias into the interpretation of the results of this trial.

The other five trials were described as "double-blind" (Dauletbaev 2009; Mitchell 1982; Ratjen 1985; Stafanger 1988; Stafanger 1989). Two of these described attempts to mask the characteristics of the different treatments (e.g. taste and odour); these trials therefore were deemed to have low risk of bias (Mitchell 1982; Ratjen 1985). None of the other three trials which were described as double-blind discussed any attempts to mask the characteristics of the different treatments (e.g. taste, odour, and size); these trials therefore have been judged to have a potential risk of bias (Dauletbaev 2009; Stafanger 1988; Stafanger 1989).

Incomplete outcome data

Two trials reported data from all the randomized participants and were therefore judged to have a low risk of bias (Caramia 1995; Dauletbaev 2009). We have attempted to contact Dr Caramia to obtain further data relevant to his trial, but as yet we have not had any reply. If we obtain further data on this paper we plan to include this in a future update of the review.

Two trials reported withdrawals (Mitchell 1982; Ratjen 1985), but one of these does not give any reasons for the drop outs (Mitchell 1982). Mitchell does not give details of why the participants did not complete the trial, nor does he state from which treatment group they withdrew, so this trial has an unclear risk of bias (Mitchell 1982). Also, the four withdrawals were not included in the final analysis (Mitchell 1982). The numbers of drop outs in the Ratjen trial were low and equal across treatment groups, therefore this trial has a low risk of bias (Ratjen 1985).

Two trials do not present data for all the participants randomized, but do not discuss the reasons for this (Stafanger 1988; Stafanger 1989). There was an unusually high dropout rate in the later trial where data for only 10 participants out of 52 were presented in the paper (Stafanger 1989). These two trials are therefore judged to have a high risk of bias.

Other potential sources of bias

Due to the limited amount of data reported in the Caramia paper there is a risk of bias with regards to selective reporting (Caramia 1995). Furthermore, a second trial presented data for certain outcomes in graph form only, making it difficult to obtain precise results; additionally, data were presented as median values and interquartile ranges (Dauletbaev 2009). In the same trial, although data on quality of life was collected, it was not published (Dauletbaev 2009).

One trial has a very serious potential risk of bias as some of the data presented in the tables is incorrect (the data for total and mean values in columns 5 and 6 in Table 2 of the final published paper are not calculated correctly) (Stafanger 1989).

Two cross-over trials have a risk of bias due to either no washout period between treatments (Stafanger 1988) or an unclear duration of the washout period (Stafanger 1989).

Effects of interventions

Nebulized thiol derivatives versus other nebulized medications

There are three trials included in this comparison (Bishop 2005; Howatt 1966; Weller 1980).

Primary outcomes
1. Pulmonary function testing (PFT)
a. forced expiratory volume in one second (FEV1) per cent predicted

Two trials reported on this outcome (Bishop 2005; Howatt 1966), but we were only able to enter data into the analysis for one trial (Bishop 2005). We have reported the results from the second trial narratively.

The data from the Bishop trial showed no significant difference in the change in FEV1 comparing participants receiving nebulized glutathione and nebulized 4% saline, mean difference (MD) 0.90% (95% CI -6.45% to 8.25%) (Bishop 2005).

The Howatt trial reported no statistically significant difference in FEV1 following periods when participants had received nebulized 20% NAC or nebulized 2% NAC (Howatt 1966).

b. forced vital capacity (FVC) per cent predicted

Two trials reported on this outcome (Bishop 2005; Weller 1980) and we were able to enter data from both trials in the analysis but did not combine the results since one trial was parallel and one was cross-over. We found no significant difference between treatment and control groups, in either the parallel trial MD 0.60 (95% CI -6.49 to 7.69) (Bishop 2005) or the cross-over trial MD 4.00 (95% CI -6.18 to 14.18) (Weller 1980).

Secondary outcomes
1. Other pulmonary function test (PFT) measurements

All three trials reported other PFT measurements (Bishop 2005; Howatt 1966; Weller 1980), but only the Bishop and Weller trial presented data that we were able to enter into the analysis, again not combined due to differences in trial design (Bishop 2005; Weller 1980). The results for change in PEF were significant in favour of nebulized thiol derivatives, MD 40.20 (95% CI 4.96 to 75.44) for the parallel trial (Bishop 2005), but not for the cross-over trial, MD 9.00 (95% CI -3.66 to 21.66) (Weller 1980). We were not able to combine data from any other PFTs (MEF25-75, MEF50, Vmax50%VC, RV/TLC, vital capacity, peak inspiratory flow) and none of the trials reported any significant differences (Bishop 2005; Howatt 1966; Weller 1980). We have presented data for: Vmax50%VC, MD 10.00 (95% CI -5.52 to 25.52) (Weller 1980); forced expiratory flow, MD 6.20 (95% CI -6.79 to 19.19) (Bishop 2005); and RV/TLC, MD -4.00 (95% CI -16.11 to 8.11) (Weller 1980).

2. Inflammatory markers
a. serum (WBC, CRP, ESR)

None of the included trials reported on this outcome measure.

b. sputum (IL-8)

None of the included trials reported on this outcome measure.

3. Quality of life (QOL)

None of the included trials reported on this outcome measure.

4. Need for oral antibiotics for pulmonary exacerbation
a. number of weeks of treatment

The Weller trial reported that "courses of antibiotics were prescribed as frequently during baseline periods as during either treatment period". There was no indication as to whether antibiotics were oral or intravenous, and no details were supplied as to the number of weeks or number of courses of antibiotics (Weller 1980).

None of the other included trials reported on antibiotic treatment, either oral or intravenous.

b. number of courses

See comments above (in 4a) with regards to antibiotic therapy.

5. Need for intravenous antibiotics for pulmonary exacerbation
a. number of weeks of treatment

See comments above (in 4a) with regards to antibiotic therapy.

b. number of courses

See comments above (in 4a) with regards to antibiotic therapy.

6. Adverse events

The nebulized thiol derivatives investigated in the included trials were generally well-tolerated (Bishop 2005; Howatt 1966; Weller 1980).

The Bishop trial reported no increased incidence of adverse effects in participants receiving nebulized glutathione compared to nebulized 4% hypertonic saline (Bishop 2005). The Howatt trial reported that participants complained that nebulized NAC "smelled and tasted bad"; and one participant in the same trial "complained of severe coughing attacks" while receiving nebulized 20% NAC "which would cause her to discontinue her treatment" (Howatt 1966). Several participants in the Weller trial "noted that the inhalations initially made them cough, this occurring equally at the start of both therapies, but usually settling within days", but that "no major adverse effects were noted during either therapy" (Weller 1980). It should be noted that nebulized thiol derivatives are used for their potential mucolytic properties, and therefore increased cough is not necessarily an adverse effect.

7. Number of days in hospital for respiratory exacerbation

Only two trials reported on this outcome, but we were unable to enter any data in the graphs (Bishop 2005; Weller 1980). Bishop reported that "three patients were hospitalized ... due to non-improvement of conditions present at baseline". Two of these participants were receiving nebulized 4% saline and the other was receiving nebulized glutathione. Weller reported that "three patients were admitted to hospital during the course of the trial ... one of these was an inpatient for most of the trial. The other two were admitted electively because of poor growth and persisting respiratory symptoms, one during the initial baseline period and one during the second month of saline treatment" (Weller 1980).

8. Adherence

Only one trial reported on this outcome and stated that one participant receiving nebulized glutathione "was grossly noncompliant, ie, stopped the treatment after the first 5 days of the trial". No reason was given for this non-adherence, but the participant was included in the modified ITT analysis (Bishop 2005).

9. Acquisition of new respiratory pathogens (%)

Only one trial reported on this outcome (Weller 1980). It was reported that there "was no change in sputum microbiology - for example, appearance of Pseudomonas aeruginosa" between the intervention groups (Weller 1980).

10. Six-minute walk distance

Only the Bishop trial reported on this outcome (Bishop 2005). There was no significant difference in 6-minute walk distance between participants receiving nebulized glutathione and nebulized 4% saline, MD 26.90m (95% CI -115.40m to 169.20m) (Bishop 2005).

11. Sputum characteristics

All three trials reported on this outcome (Bishop 2005; Howatt 1966; Weller 1980); but we were only able to enter data from one trial for sputum viscosity in the analysis (Bishop 2005).

Bishop reported no significant differences in sputum amount, viscosity or color between the participants receiving nebulized glutathione or nebulized 4% saline; we present data for sputum viscosity, MD -0.40 (95% CI -1.53 to 0.73) (Bishop 2005).

The Howatt trial reported that several participants noticed their "sputum was thinner and it seemed easier to bring up" in both groups (Howatt 1966).

The Weller reported "no significant differences in cough frequency, sputum volume, or sputum colour on analysis" in either group (Weller 1980).

Oral thiol derivatives versus placebo

There are four trials included in this comparison (Mitchell 1982; Ratjen 1985; Stafanger 1988; Stafanger 1989)

Primary outcomes
1. Pulmonary function testing (PFT)
a. forced expiratory volume in one second (FEV1) per cent predicted

Three trials reported on this outcome (Ratjen 1985; Stafanger 1988; Stafanger 1989); however, we were only able to enter data in the analysis from one of these trials (Ratjen 1985).

When entered into the analysis, data from the Ratjen trial showed no significant difference in  FEV1, MD 5.00 per cent predicted (95% CI -15.22 to 25.22) between those participants who received oral NAC compared to placebo.

In the earlier trial, Stafanger reported no overall significant difference in FEV1 comparing participants receiving oral NAC and those receiving placebo (Stafanger 1988).

In the later trial, Stafanger reported no overall significant difference in FEV1 comparing periods when participants received oral NAC and those when they received placebo (Stafanger 1989).

b. forced vital capacity (FVC) per cent predicted

Two trials reported on this outcome, but we were unable to enter data into the analysis for either trial (Stafanger 1988; Stafanger 1989).

In the 1988 trial, Stafanger reported no overall significant difference in FVC comparing participants receiving oral NAC and those receiving placebo (Stafanger 1988).

In the 1989 trial, Stafanger also reported no overall significant difference in FVC comparing periods when participants received oral NAC and periods when they received placebo (Stafanger 1989).

Secondary outcomes
1. Other PFT measurements

All four trials reported a range of other PFT measurements (Mitchell 1982; Ratjen 1985; Stafanger 1988; Stafanger 1989). Two trials presented data that we were able to enter into the analysis, but we were not able to combine these as they were used different outcome measures (Mitchell 1982; Ratjen 1985).

Data from the Mitchell trial show no significant difference in PEF between the periods when participants received oral NAC compared to when they received placebo, MD -3.00 (95% CI -60.52 to 54.52) (Mitchell 1982).

Ratjen showed no significant difference in any measurements of pulmonary function testing when participants received oral NAC and placebo: PEF, MD 5.90 (95% CI -17.75 to 29.55); TLC, MD -1.70 (95% CI -14.60 to 11.20); FVC75%, MD 15.90 (95% CI -10.55 to 42.35); FVC50%, MD -7.90 (95% CI -36.87 to 21.07); FVC25%, MD -4.00 (95% CI -34.92 to 26.92); FEV1/VC, MD 7.20 (95% CI -10.47 to 24.87); TGV, MD 4.20 (95% CI -29.08 to 37.48); VC, MD -1.00 (95% CI -12.53 to 10.53); and RV/TLC, MD -17.20 (95% CI -67.98 to 33.58)) (Ratjen 1985). Ratjen also reported no significant difference in airway resistance, but we were not able to enter data into the analysis for this outcome (Ratjen 1985).

In the 1988 trial, Stafanger reported no significant difference in PEF between periods when participants received oral NAC compared to periods when they received placebo (Stafanger 1988).

In the 1989 trial, Stafanger reported no overall significant difference in PEF comparing periods when participants received oral NAC and when they received placebo (Stafanger 1989).

2. Inflammatory markers
a. serum (WBC, CRP, ESR)

Only two trials reported on this outcome (Stafanger 1988; Stafanger 1989). Both trials reported no difference in white blood cell count or erythrocyte sedimentation rate between those who received NAC and those who received placebo.

b. sputum (IL-8)

None of the included trials reported on this outcome measure.

3. Quality of life (QOL)

None of the included trials reported on this outcome measure.

4. Need for oral antibiotics for pulmonary exacerbation
a. number of weeks of treatment

Four trials reported on this outcome (Mitchell 1982; Ratjen 1985; Stafanger 1988; Stafanger 1989); but only one trial presented data which we could enter into our analysis (Mitchell 1982). There is a high possibility that these data may be skewed since people with CF who require antibiotics usually receive them for at least two weeks, but a small group of people who are more severely infected will receive them for much longer.

Mitchell does not differentiate between the use of oral or intravenous antibiotic therapy, but states there was no significant difference between antibiotic treatment between participants in the NAC group versus those in the placebo group, MD -0.40 weeks (95% CI -2.98 to 2.18) (Mitchell 1982).

In the paper, Ratjen reported that "no patients needed intermittent antibiotic therapy during the course of the trial" (Ratjen 1985). Neither of the trials by Stafanger reported any difference in antibiotic treatment between periods when the participants received oral NAC or placebo (Stafanger 1988; Stafanger 1989). There was no indication as to whether antibiotics were oral or intravenous, and no details were supplied as to the number of weeks or number of courses of antibiotics. It should be noted that all participants in later trial by Stafanger entered the trial having recently completed a course of intravenous antibiotics (Stafanger 1989).

b. number of courses

See comments above (in 4a) with regards to antibiotic therapy.

5. Need for intravenous antibiotics for pulmonary exacerbation
a. number of weeks of treatment

See comments above (in 4a) with regards to antibiotic therapy.

b. number of course

See comments above (in 4a) with regards to antibiotic therapy.

6. Adverse events

Three trials reported on this outcome (Mitchell 1982; Ratjen 1985; Stafanger 1989). Two of these trials did not report any adverse effects in either treatment or control groups (Mitchell 1982; Ratjen 1985). In the 1989 trial, Stafanger reported that one individual developed Quincke's oedema and one developed a rash while receiving oral NAC (Stafanger 1989). In both participants these adverse effects settled once oral NAC was stopped. Two participants also developed abdominal pain, one while receiving oral NAC and one receiving placebo (Stafanger 1989). A further participant in this same trial felt that "she coughed more frequently and less productively with NAC and stopped the treatment". All of these participants were excluded from the trial due to these adverse effects (Stafanger 1989).

7. Number of days in hospital for respiratory exacerbation

Only one trial reported on this outcome (Stafanger 1988). This trial reported that none of the participants receiving either oral NAC or placebo were hospitalized during the trial (Stafanger 1988).

8. Adherence

Three trials reported on this outcome (Ratjen 1985; Stafanger 1988; Stafanger 1989).

Ratjen reported that two participants dropped out of the trial due to "irregular drug intake" (Ratjen 1985). In the earlier trial, Stafanger reported that two participants were excluded due to "poor co-operation", but did not specify whether this reflected poor adherence (Stafanger 1988). Similarly, in the 1989 trial, Stafanger reported that 10 participants were excluded due to "poor co-operation", but did not elaborate (Stafanger 1989).

9. Acquisition of new respiratory pathogens (%)

None of the included trials reported on this outcome measure.

10. Six-minute walk distance

None of the included trials reported on this outcome measure.

11. Sputum characteristics

All four trials required participants to complete subjective scores of sputum characteristics whilst receiving the different interventions (Mitchell 1982; Ratjen 1985; Stafanger 1988; Stafanger 1989). One of the included trials presented data for this outcome measure (Stafanger 1988) and the other three trials reported these results narratively (Mitchell 1982; Ratjen 1985; Stafanger 1989). None of the four trials reported significant differences in these subjective scores of sputum characteristics between participants receiving oral NAC and placebo (Mitchell 1982; Ratjen 1985; Stafanger 1988; Stafanger 1989). Ratjen also reported narratively that there were no significant differences in a subjective score of sputum characteristics between participants receiving oral ambroxol and placebo (Ratjen 1985).

Oral thiols derivatives versus other oral thiol derivatives

There are two trials included in this comparison (Caramia 1995; Ratjen 1985).

Primary outcomes
1. Pulmonary function testing (PFT)
a. forced expiratory volume in one second (FEV1) per cent predicted

Both trials reported on this outcome (Caramia 1995; Ratjen 1985), but only data from one trial were included in the analysis (Ratjen 1985). Ratjen showed no significant difference in FEV1 between groups receiving oral NAC and oral ambroxol -4.20% (95% CI -26.19% to 17.79%) (Ratjen 1985). Caramia presents data showing the change from baseline, but not from both the treatment and control groups, so we are unable to enter the data into the analysis (Caramia 1995). Caramia also reported that there was no significant difference in FEV1 between groups receiving oral carbocysteine and oral ambroxol (Caramia 1995).

b. forced vital capacity (FVC) per cent predicted

Neither of the included trials reported on this outcome measure.

Secondary outcomes
1. Other PFT measurements

Two trials reported on a range of other PFT measurements, but only data from one trial could be included in the analysis (Ratjen 1985).

The Ratjen paper showed no significant differences in other PFT measurements between participants receiving oral NAC and oral ambroxol: PEF, MD -0.60 (95% CI -22.21 to 21.01); TLC, MD 1.30 (95% CI -11.18 to 13.78); FVC75%, MD 6.00 (95% CI -18.83 to 30.83); FVC50%, MD 0.00 (95% CI -30.02 to 30.02); FVC25%, MD -4.10 (95% CI -37.74 to 29.54); FEV1/VC, MD -0.90 (95% CI -15.70 to 13.90); TGV, MD 13.50 (95% CI -13.92 to 40.92); VC, MD 2.80 (95% CI -12.75 to 18.35); and RV/TLC, MD -11.50 (95% CI -82.21 to 59.21) (Ratjen 1985). Data from the Caramia trial found no significant differences in TV, PEF, MEF25 or MEF75 between participants receiving oral carbocysteine and oral ambroxol (Caramia 1995).

2. Inflammatory markers
a. serum (WBC, CRP, ESR)

Neither of the included trials reported on this outcome measure.

b. sputum (IL-8)

Neither of the included trials reported on this outcome measure.

3. Quality of life (QOL)

Neither of the included trials reported on this outcome measure.

4. Need for oral antibiotics for pulmonary exacerbation
a. number of weeks of treatment

Neither of the included trials reported on this outcome measure.

b. number of courses

Neither of the included trials reported on this outcome measure.

5. Need for intravenous antibiotics for pulmonary exacerbation
a. number of weeks of treatment

Neither of the included trials reported on this outcome measure.

b. number of course

Neither of the included trials reported on this outcome measure.

6. Adverse events

Neither Caramia nor Ratjen reported any adverse effects in participants receiving oral thiol derivatives (Caramia 1995; Ratjen 1985).

7. Number of days in hospital for respiratory exacerbation

Neither of the included trials reported on this outcome measure.

8. Adherence

Neither of the included trials reported on this outcome measure.

9. Acquisition of new respiratory pathogens (%)

Neither of the included trials reported on this outcome measure.

10. Six-minute walk distance

Neither of the included trials reported on this outcome measure.

11. Sputum characteristics

Ratjen reported no significant differences in a subjective score of sputum characteristics between participants receiving oral NAC and oral ambroxol (Ratjen 1985).

Caramia included a subjective score of sputum characteristics, but also assessed sputum viscosity and elasticity objectively using an oscillometric visco-elastometer (Caramia 1995). There was no difference in the subjective score between participants receiving oral carbocysteine or oral ambroxol (Caramia 1995), and there were also no differences in viscosity or elasticity between participants receiving the two treatments (Caramia 1995).

Oral low-dose versus oral high-dose N-acetylcysteine

One trial is included in this comparison (Dauletbaev 2009).

Primary outcomes
1. Pulmonary function testing (PFT)
a. forced expiratory volume in one second (FEV1) per cent predicted

Dauletbaev found that there was no significant change in FEV1 during the trial. However, we were not able to extract data from the graphs presented (Dauletbaev 2009). We have contacted the investigators for the data and will include them in a future update of the review if we receive them.

b. forced vital capacity (FVC) per cent predicted

Dauletbaev did not report on this outcome measure.

Secondary outcomes
1. Other PFT measurements

Dauletbaev did not report on this outcome measure.

2. Inflammatory markers
a. serum (WBC, CRP, ESR)

Dauletbaev did not report on this outcome measure.

b. sputum (IL-8)

Dauletbaev reported that neither the low-dose nor the high-dose NAC groups had a significant change in sputum IL-8. Precise values could not be extracted from graphs. On inspection of the graphs, sputum IL-8 had a stable trend in both groups (Dauletbaev 2009).

3. Quality of life (QoL)

Dauletbaev collected data on QoL; however, these data were not published (Dauletbaev 2009).

4. Need for oral antibiotics for pulmonary exacerbation
a. number of weeks of treatment

Dauletbaev did not report on this outcome measure.

b. number of courses

Dauletbaev did not report on this outcome measure.

5. Need for intravenous antibiotics for pulmonary exacerbation
a. number of weeks of treatment

Dauletbaev did not report on this outcome measure.

b. number of course

Dauletbaev did not report on this outcome measure.

6. Adverse events

In Dauletbaev’s trial, 24 "mild-to-moderate" adverse effects occurred in each of the low-dose and high-dose NAC groups during the duration of the trial. Most adverse events were noted to be CF pulmonary exacerbations. Two serious adverse effects (polypectomia) occurred in the low-dose group, and one (hemoptysis) in the high-dose arm. Since the paper reports the number of adverse events, but not participants experiencing an adverse event, we were unable to enter data into a graph for this trial (Dauletbaev 2009).

7. Number of days in hospital for respiratory exacerbation

Dauletbaev did not report on this outcome measure.

8. Adherence

Dauletbaev described greater than 80% adherence in both the low-dose and the high-dose NAC groups (Dauletbaev 2009).

9. Acquisition of new respiratory pathogens (%)

Dauletbaev did not report on this outcome measure.

10. Six-minute walk distance

Dauletbaev did not report on this outcome measure.

11. Sputum characteristics

Dauletbaev did not report on this outcome measure.

Discussion

Summary of main results

There have been very few good quality trials investigating the effects of nebulized or oral thiol derivatives in CF. The nine included trials assessed different thiol derivatives and used very different trial designs.

For nebulized thiol derivatives, the included trials report no evidence that any of the nebulized thiol derivatives have a significant beneficial effect on the primary outcome measures of this review (FEV1 per cent predicted and FVC per cent predicted). There were conflicting results with regards to the effect of nebulized thiol derivatives on other pulmonary function tests, but overall no convincing evidence that they are of clinical benefit. There was also no evidence of a beneficial effect of nebulized thiol derivatives on any of the other secondary outcome measures in this review. In summary, we have found no evidence to recommend that nebulized thiol derivatives should be used in routine clinical practice in patients with CF.

For oral thiol derivatives, the six included trials assessed three different drugs, using different preparations (tablets, granules and syrup) and doses (some using a fixed dose and some dosing according to body weight). None of the included trials demonstrated a significant benefit of oral thiol derivatives on any of the primary or secondary outcome measures of this review.

Several methodological challenges were apparent during this review. The vast majority of the trials included very small sample sizes and may have been underpowered. Although pulmonary function testing was typically reported, the type of pulmonary function testing was highly variable with some trials reporting on percent predicted FEV1 while others reported the peak expiratory flow measurements. This may represent selective reporting whereby only certain measurements were recorded in the final papers and may be a source of potential bias. No trials were powered to look at other clinically important outcomes such as need for hospitalization, new acquisition of bacteria, or changes in quality of life. Two of the larger trials had unacceptably high dropout rates which raised significant questions as to the reliability of the trial results (Stafanger 1988; Stafanger 1989). Because some groups of individuals with CF may respond more than others, we had planned to do subgroup analyses for factors such as severity of lung disease and age. None of the trials provided adequate information on these subgroups, making it impossible to carry out any subgroup analyses.

Overall completeness and applicability of evidence

The included trials were generally complete, although the exclusion criteria of the trials and the age range of the included participants limits their applicability to the general CF population.

Quality of the evidence

The evidence on which this review is based is limited in terms of the quantity and quality of included trials. In all nine trials the generation of allocation sequences was stated as randomized, but in only two of these (Howatt 1966; Ratjen 1985) was the method of randomization considered to be adequate. The concealment of treatment allocation was unclear in seven of the included trials, with only two (Howatt 1966; Ratjen 1985) having an adequate method of allocation concealment. Eight of the nine included trials stated that they were double blinded, with one stating that it was single blinded (Caramia 1995). Four trials backed up this statement with an explanation of how they had masked the characteristics of the different interventions (Bishop 2005; Howatt 1966; Mitchell 1982; Ratjen 1985); but four trials made no apparent attempt to disguise the interventions (Dauletbaev 2009; Stafanger 1988; Stafanger 1989; Weller 1980). Additionally, in the 'placebo-controlled' trials assessing nebulized thiol derivatives, the placebo intervention was either a weaker solution of the active intervention, or was an active intervention in its own right (such as nebulized hypertonic saline). In the case of nebulized hypertonic saline the beneficial effect of this intervention has only been confirmed in recent years and was not known to the investigators in the relevant included trials.

Potential biases in the review process

One of the co-authors of this review, Professor Felix Ratjen, is lead investigator on one of the included trials.

Agreements and disagreements with other studies or reviews

The results of this review are broadly in agreement with the systematic review of NAC in CF prepared by Duijvestijn and Brand (Duijvestijn 1999).

Authors' conclusions

Implications for practice

From this review of eligible trials, we have not been able to identify any evidence to recommend the use of nebulized thiol derivatives in people with CF. We have also not been able to find any evidence to recommend the use of oral thiol derivatives in the management of CF lung disease.

Implications for research

Despite the paucity of literature on the effectiveness of thiol derivatives in CF, these are still potentially useful drugs for further trial because thickened mucous, leading to chronic infection and inflammation and respiratory failure is still the most common cause of early death in CF. Therapies aimed at improving sputum clearance and therefore reducing pulmonary infection and inflammation are sorely needed. The other effective mucolytic therapies that are available for pulmonary disease in CF are unable to be tolerated by some people due to side effects (mainly bronchospasm) and can also be prohibitively expensive (in the case of dornase alfa). Thiol derivatives are relatively inexpensive, and, especially when administered orally, are well-tolerated. Further trials are required to investigate the potential beneficial effects of both nebulized and oral thiol derivatives in CF lung disease.

Well-designed randomized placebo-controlled double-blind trials of people with CF over six years of age are required to adequately assess the potential benefit of these medications. Pulmonary function testing cannot be reliably done in individuals under the age of six years. A wide range of disease severities and age groups should be included in these trials and in sufficient numbers so that data on these subgroups can be analyzed separately. It is not clear from the literature if mucolytic therapy is helpful in early disease to prevent decline in lung function or whether it is more advantageous later in the disease course when mucous production is increased. Enrolling participants with a wide range of disease severity may help to elucidate this. As mucolytic therapy takes time to exert its effect, the duration of the trials should be no less than four months, with six months of follow-up to evaluate the long-term effects of therapy with thiol derivatives. Pulmonary function (specifically FEV1 and FVC), would be reasonable primary endpoints, while other secondary endpoints such as markers of inflammation, the need for both IV and oral antibiotics therapy, the number of days in hospital, QoL, the acquisition of new respiratory pathogens, and radiologic improvement would be key in assessing the efficacy of these medications. Additionally, lung clearance index (LCI) should be considered as an endpoint, since this technique is a sensitive method of assessing the small airway disease that could theoretically be altered by thiol derivatives in CF individuals (Davies 2008). Mortality, although an important hard endpoint, would not be recommended as an outcome measure as it is unlikely changes in mortality would be detected in a 4- to 12-month trial given the median survival in CF at present.

Acknowledgements

We would like to acknowledge the helpful advice and constructive criticism offered by Professor Bruce K Rubin in the preparation of this review. We would also like to thank Jan Tecklin for helping us in obtaining data.

Data and analyses

Download statistical data

Comparison 1. Nebulized thiols versus other nebulized medications
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Change in forced expiratory volume in 1 second1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Change in forced vital capacity2 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2.1 Up to 3 months (parallel)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2.2 Up to 3 months (cross-over)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Peak expiratory flow2 Mean Difference (IV, Fixed, 95% CI)Totals not selected
3.1 Up to 3 months (parallel)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3.2 Up to 3 months (cross-over)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Vmax50% Vital capacity1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
4.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Forced expiratory flow 25-751 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 RV/TLC1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
6.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Six-minute walk test [metres]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
7.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Sputum viscosity1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
8.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 1.1.

Comparison 1 Nebulized thiols versus other nebulized medications, Outcome 1 Change in forced expiratory volume in 1 second.

Analysis 1.2.

Comparison 1 Nebulized thiols versus other nebulized medications, Outcome 2 Change in forced vital capacity.

Analysis 1.3.

Comparison 1 Nebulized thiols versus other nebulized medications, Outcome 3 Peak expiratory flow.

Analysis 1.4.

Comparison 1 Nebulized thiols versus other nebulized medications, Outcome 4 Vmax50% Vital capacity.

Analysis 1.5.

Comparison 1 Nebulized thiols versus other nebulized medications, Outcome 5 Forced expiratory flow 25-75.

Analysis 1.6.

Comparison 1 Nebulized thiols versus other nebulized medications, Outcome 6 RV/TLC.

Analysis 1.7.

Comparison 1 Nebulized thiols versus other nebulized medications, Outcome 7 Six-minute walk test [metres].

Analysis 1.8.

Comparison 1 Nebulized thiols versus other nebulized medications, Outcome 8 Sputum viscosity.

Comparison 2. Oral thiols versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Change in forced expiratory volume in 1 second [% predicted]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Peak expiratory flow [L/min]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Change in peak expiratory flow [% predicted]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
3.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Change in total lung capacity [% predicted]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
4.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Change in flow 75% FVC [% predicted]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Change in flow 50% FVC [% predicted]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
6.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Change in flow 25% FVC [% predicted]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
7.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Change in forced expiratory volume in 1 sec/vital capacity [% predicted]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
8.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Change in total gas volume [% predicted]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
9.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
10 Change in vital capacity [% predicted]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
10.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
11 Change in residual volume/total lung capacity [% predicted]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
11.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
12 Antibiotic treatment [weeks]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
12.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 2.1.

Comparison 2 Oral thiols versus placebo, Outcome 1 Change in forced expiratory volume in 1 second [% predicted].

Analysis 2.2.

Comparison 2 Oral thiols versus placebo, Outcome 2 Peak expiratory flow [L/min].

Analysis 2.3.

Comparison 2 Oral thiols versus placebo, Outcome 3 Change in peak expiratory flow [% predicted].

Analysis 2.4.

Comparison 2 Oral thiols versus placebo, Outcome 4 Change in total lung capacity [% predicted].

Analysis 2.5.

Comparison 2 Oral thiols versus placebo, Outcome 5 Change in flow 75% FVC [% predicted].

Analysis 2.6.

Comparison 2 Oral thiols versus placebo, Outcome 6 Change in flow 50% FVC [% predicted].

Analysis 2.7.

Comparison 2 Oral thiols versus placebo, Outcome 7 Change in flow 25% FVC [% predicted].

Analysis 2.8.

Comparison 2 Oral thiols versus placebo, Outcome 8 Change in forced expiratory volume in 1 sec/vital capacity [% predicted].

Analysis 2.9.

Comparison 2 Oral thiols versus placebo, Outcome 9 Change in total gas volume [% predicted].

Analysis 2.10.

Comparison 2 Oral thiols versus placebo, Outcome 10 Change in vital capacity [% predicted].

Analysis 2.11.

Comparison 2 Oral thiols versus placebo, Outcome 11 Change in residual volume/total lung capacity [% predicted].

Analysis 2.12.

Comparison 2 Oral thiols versus placebo, Outcome 12 Antibiotic treatment [weeks].

Comparison 3. Oral thiols versus other oral agents
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Change in forced expiratory volume in 1 second [% predicted]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Change in peak expiratory flow [% predicted]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Change in total lung capacity [% predicted]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
3.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Change in flow 75% FVC [% predicted]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
4.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Change in flow 50% FVC [% predicted]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Change in flow 25% FVC [% predicted]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
6.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Change in forced expiratory volume in 1 sec/vital capacity [% predicted]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
7.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Change in thoracic gas volume [% predicted]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
8.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Change in vital capacity [% predicted]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
9.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
10 Change in residual volume/total lung capacity [% predicted]1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
10.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 3.1.

Comparison 3 Oral thiols versus other oral agents, Outcome 1 Change in forced expiratory volume in 1 second [% predicted].

Analysis 3.2.

Comparison 3 Oral thiols versus other oral agents, Outcome 2 Change in peak expiratory flow [% predicted].

Analysis 3.3.

Comparison 3 Oral thiols versus other oral agents, Outcome 3 Change in total lung capacity [% predicted].

Analysis 3.4.

Comparison 3 Oral thiols versus other oral agents, Outcome 4 Change in flow 75% FVC [% predicted].

Analysis 3.5.

Comparison 3 Oral thiols versus other oral agents, Outcome 5 Change in flow 50% FVC [% predicted].

Analysis 3.6.

Comparison 3 Oral thiols versus other oral agents, Outcome 6 Change in flow 25% FVC [% predicted].

Analysis 3.7.

Comparison 3 Oral thiols versus other oral agents, Outcome 7 Change in forced expiratory volume in 1 sec/vital capacity [% predicted].

Analysis 3.8.

Comparison 3 Oral thiols versus other oral agents, Outcome 8 Change in thoracic gas volume [% predicted].

Analysis 3.9.

Comparison 3 Oral thiols versus other oral agents, Outcome 9 Change in vital capacity [% predicted].

Analysis 3.10.

Comparison 3 Oral thiols versus other oral agents, Outcome 10 Change in residual volume/total lung capacity [% predicted].

Appendices

Appendix 1. PubMed Search Strategy

A PubMed search was conducted on 26 February 2013 using the terms: cystic fibrosis AND (acetylcysteine OR n-acetylcysteine OR carbocysteine OR erdosteine OR mecysteine OR nacystelyn OR glutathione OR cysteine OR sodium-2-mercaptoethane sulphonate)

What's new

DateEventDescription
13 April 2015AmendedContact details updated.

History

Protocol first published: Issue 2, 2008
Review first published: Issue 1, 2009

DateEventDescription
13 June 2013New search has been performed

A new author, Dr Julian Tam, has joined the review team.

A search of the Cystic Fibrosis & Genetic Disorders Group's Cystic Fibrosis Register identified five new references to four studies for potential inclusion in this review; three of these studies (four references) are listed as 'Awaiting classification' until we are able to obtain the data needed to undertake our analysis (Griese 2013; Tirouvanziam 2011; van Daele 2011). One study was excluded (Casale 2012).

We identified a further study in a search of PubMed, which has been included in this update of the review (Dauletbaev 2009).

13 June 2013New citation required but conclusions have not changedAlthough we have included a single new study at this update, the conclusions of the review have not changed.
28 October 2010New search has been performedA search of the Group's Cystic Fibrosis Trials Register did not identify any new trials eligible for inclusion in this review.
12 November 2008AmendedConverted to new review format.

Contributions of authors

Dr Anne Stephenson conceived of the idea for the review. Dr Edward Nash and Dr Anne Stephenson jointly wrote the original review. Dr Julian Tam, Dr Edward Nash, and Dr Anne Stephenson wrote the updated review.

Dr Elizabeth Tullis and Prof Felix Ratjen supervised, gave comments and offered advice on the review.

Dr Nash acts as guarantor for the review.

Declarations of interest

One of the co-authors of this review, Professor Felix Ratjen, is lead investigator on one of the included trials.

Sources of support

Internal sources

  • Division of Respirology, St. Michael's Hospital, Canada.

External sources

  • No sources of support supplied

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Bishop 2005

Methods

Randomized, double-blind, placebo-controlled trial.

Single center in the USA.

8-week trial period, with participants receiving the same intervention for the whole 8 weeks.

A "modified" ITT analysis was carried out whereby all patient outcomes were included, regardless of compliance, except when patients were hospitalized or were missing data.

Participants

19 participants were recruited.

Mean age 13.1 years (range 6 - 19 years).

Stable clinical status with mild pulmonary disease.

Participants were paired by age and sex, and then each member of the pair was randomly assigned to the treatment or placebo groups.

1 participant in the placebo group dropped out 'just before the trial began', and was not included in the analysis.

InterventionsNebulized buffered reduced GSH versus nebulized placebo. GSH was buffered with sodium bicarbonate and dosed at 66mg/kg body weight. Placebo was composed of sodium chloride dosed at 15mg/kg body weight, and quinine at 25-30 μg/kg body weight. Participants were instructed to self-administer their intervention medication "across 4 inhalation sessions per day" and asked to "space these sessions 3- to 4-h apart". For the first week of the trial, participants "were instructed to use one fourth of the recommended total dosage, and in the second week to use one half of the recommended total dosage. After the second week, patients were instructed to use the full daily total dosage".
Outcomes

Primary outcome measures: FEV1(% predicted), FVC (% predicted), FEF25-75 (% predicted), PEF.

FEV1, FVC and FEF25-75 were measured once prior to starting the intervention period, and once after completing the intervention period. PEF was measured by the participant twice daily throughout the trial.

Secondary outcome measures:

Objective - BMI, 6-min walk distance (m).

These objective measures were recorded once prior to starting the intervention and once after completing the intervention.

Subjective:

  • Sputum color (scale ranging from 1 = clear to 6 = blood streaked)

  • Sputum amount (1=scant, 2 = <1 teaspoon), 3 = >1 teaspoon)

  • Sputum viscosity (1 = very thin, 2 = slightly sticky, 3 = very sticky)

  • Cough frequency (1 = no cough, 2 = infrequent, 3 = several times per day, 4 = every hour)

  • General wellness (1 = poor, 2 = fair, 3 = good, 4 = excellent)

  • Usual stamina (1 = poor, 2 = fair, 3 = good, 4 = excellent)

  • Improvement (1 = significantly worse, 2 = a bit worse, 3 = about the same, 4 = a bit better, 5 = significantly better).

The baseline measure for each of the subjective measures was taken as the 'average of the first 5 days of the trial', and the 'end of trial measure' was taken as the 'average of last 5 days of the trial'.

Adverse events.

NotesPaper states that in the analysis, 'differences between post-trial and baseline outcomes were analyzed using GLMM that allowed for correlation between outcomes with the age/sex pair used for randomization.'
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization process not described.
Allocation concealment (selection bias)Low riskNo member of the clinical team was involved in the generation of the sequence of allocation to treatments.
Blinding (performance bias and detection bias)
Participants
Low riskTrial described as "double-blind" and attempts were made to mask the characteristic odour of nebulized glutathione by adding quinine to the 4% hypertonic saline.
Blinding (performance bias and detection bias)
Clinicians/assessors
Low riskTrial described as "double-blind" and attempts were made to mask the characteristic odour of nebulized glutathione by adding quinine to the 4% hypertonic saline.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk3 individuals hospitalized during the trial were excluded from data analysis, and therefore data from 9 participants receiving nebulized glutathione, and 7 participants receiving nebulized 4% hypertonic saline were reported in the trial.
Other biasUnclear riskNo other sources of bias identified.

Caramia 1995

Methods

Randomized, single-blind, parallel-group design.

Single center in Italy.

80-day intervention period.

ITT analysis was carried out, with all participants completing the trial and all their data being analysed.

Participants

26 CF participants (12 males).

Age range 8 - 26 years (mean (SE) 15.9 (1.7) years in the SCMS-Lys group, 16.2 (1.5) years in the ABX group).

Good clinical status (Schwachmann index 76.2 (2.8) in the SCMS-Lys group, 77.3 (3.5) in the ABX group)

"Concomitant administration of antitussives, muco-actives, sedatives, H1-receptor antagonists and systemic corticosteroids was not allowed during the trial".

InterventionsOne group received SCMS-Lys at a dose of 900mg tid in adults and 270mg tid in children under 14 years of age. The other group received oral ABX at dose of 33mg tid in adults and 10 mg qid in children under 14 years of age.
Outcomes

At baseline, 20, 40, 60 and 80 days of the intervention period, participants had the following assessments performed:

  • Cough frequency, "intensity of dyspnoea/tachypnoea" and chest sound abnormalities as assessed and rated on a 5-point digital scale (1 = greatest degree of abnormality, 5 = absence of symptom or sign).

  • Viscosity and elasticity of expectorated sputum as assessed by an "oscillometric visco-elastometer".

  • Estimated sputum volume over the preceding 24-hour period was also rated (1 = >50 ml/day, 2 = 25-50 ml/day, 3 = <25 ml/day, 4 = 'little or no expectorate').

  • Arterial blood gas analysis.

  • Tidal volume, FEV1, PEF, MEF25, MEF50, MEF75 and 'Tiffeau index'.

  • Assessment of adverse effects.

In addition, the Shwachmann score was assessed at baseline and at 80 days.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization process not described.
Allocation concealment (selection bias)Unclear riskTrial does not clearly discuss allocation concealment.
Blinding (performance bias and detection bias)
Participants
Low riskSingle-blinded, with investigators being aware of the treatment allocation.
Blinding (performance bias and detection bias)
Clinicians/assessors
High riskSingle-blinded, with investigators being aware of the treatment allocation.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAll 26 participants completed the trial protocol and data from all participants were reported.
Other biasUnclear riskNo other sources of bias identified.

Dauletbaev 2009

Methods

Randomized, double-blind trial.

Trial described as "placebo-controlled", but only low-dose and high-dose NAC compared. No true placebo arm was included.

Single centre in Germany.

21-day wash-out period followed by 24-day placebo run-in period, then treatment over 81 days.

ITT analysis was carried out, with all participants completing the trial and all their data being analysed.

Participants

21 participants (16 males).

Mean age 27.7 (age range 21 - 35 years).
Stable disease within last 4 weeks before enrolment.
FEV1 > 40% predicted.

InterventionsLow-dose (400 mg/day) and high-dose (2800 mg/day) NAC.
OutcomesFEV1, extracellular glutathione in induced sputum, extracellular glutathione in blood plasma, number of leukocytes in induced sputum, TNF-alpha in induced sputum, IL-8 in induced sputum.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization process not described.
Allocation concealment (selection bias)Unclear riskTrial does not clearly discuss allocation concealment.
Blinding (performance bias and detection bias)
Participants
Unclear riskThe trial was described "double-blind". Attempts to mask different treatments (i.e. medication size) were not described.
Blinding (performance bias and detection bias)
Clinicians/assessors
Unclear riskThe trial was described "double-blind". Attempts to mask different treatments (i.e. medication size) were not described.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants randomized completed the trial, and were included in analysis.
Other biasHigh riskData on quality of life was collected, but not published. Results were published in graph form and/or median values and interquartile ranges.

Howatt 1966

Methods

Randomized, double-blind, controlled, cross-over design.
Single centre in USA.
4-month trial period, participants receiving interventions for 1 month at a time. No washout period.
No dropouts.

Data was analysed by ITT, however only limited data was presented in the paper.

Participants8 CF participants (3 male).
Age range 6 - 22 years (mean 12.6).
Clinical status ranged from "excellent" to "moderate" (based on the method of Shwachman and Kulczycki).
4 participants stopped using nebulized isoproterenol, antibiotics, 3% saline during the trial period, whereas the other 4 participants did not alter their pre-trial therapy.
None of the participants had ever received NAC before the trial.
InterventionsNebulized 20% NAC tid, versus nebulized 2% NAC tid.
OutcomesSubjective improvement in sputum thickness and ability to expectorate, PFTs (VC, PEF, PIF, E50, FEV1, SBO), adverse reactions.
Notes

Participants had a total of 4 months of treatment but could receive it monthly as follows:

1st combo: 20%NAC then 2%NAC then 20%NAC then 2%NAC

2nd combo: 2%NAC then 20%NAC then 2%NAC then 20%NAC

3rd combo: 20%NAC then 20%NAC then 2%NAC then 2%NAC

4th combo: 2%NAC then 2%NAC then 20%NAC then 20%NAC

5th combo: 2%NAC then 20%NAC then 20%NAC then 2%NAC

6th combo: 20%NAC then 2%NAC then 2%NAC then 20%NAC

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomized order of drugs by making up 2 slips of paper for each of the 6 possible combinations.
Allocation concealment (selection bias)Low riskDrugs were supplied in 10 ml vials labelled with a letter code and the key to the code was supplied in a sealed envelope, which was not opened until the trial was completed.
Blinding (performance bias and detection bias)
Participants
Low riskTrial described as "double-blind" and attempts were made to mask the characteristic odour of the treatments by using different concentrations of nebulized NAC.
Blinding (performance bias and detection bias)
Clinicians/assessors
Low riskTrial described as "double-blind" and attempts were made to mask the characteristic odour of the treatments by using different concentrations of nebulized NAC.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk8 participants were entered into the trial, but pulmonary function data is only reported for 2 out of these 8.
Other biasUnclear riskTrial has a risk of bias due to no washout period between treatments. The drug delivery system was not consistent amongst all participants. 2 participants received the drug during positive pressure breathing treatments while 4 participants used a Devilbiss nebulizer. A table is provided in the paper outlining the number of PFTs which improved or got worse compared to the previous month; however there is insufficient detail in the table to ascertain which specific PFTs improved.

Mitchell 1982

Methods

Randomized, double-blind, placebo-controlled, cross-over trial design.
Single centre in New Zealand.

Initial 2-week training period where all participants took placebo. Duration 6 months (3 months in each limb, with a 2-week training period and a 2-week wash out period when all participants took placebo).

Not ITT as 4 participants withdrew from the trial and were not included in final analysis.

Participants20 children (10 male) with CF.
Mean (SD) age 10.8 (5.9) years.
Stable mild to moderate pulmonary disease (mean (SD) Schwachman score 76 (10)).
Aerosolized mucolytic therapy was stopped during the trial period.
Interventions3 months on oral placebo and 3 months on 200 mg oral NAC tid.
OutcomesClinical assessment, body weight, CXR score, daily best-of-three PEF, antibiotic usage, cough frequency (scale of 0 - 3), and self-assessed sputum viscosity (scale of 0 - 3). Numerical results only provided for weight change, duration on antibiotics (not stated whether oral or intravenous) and PEF.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization process not described.
Allocation concealment (selection bias)Unclear riskTrial does not clearly discuss allocation concealment.
Blinding (performance bias and detection bias)
Participants
Unclear riskThe trial drugs were similar in appearance and the trial was described as being "double-blind" with no specific details on who was blinded. Both the active drug and the placebo were made of orange flavoured granules.
Blinding (performance bias and detection bias)
Clinicians/assessors
Unclear riskThe trial drugs were similar in appearance and the trial was described as being "double-blind" with no specific details on who was blinded. Both the active drug and the placebo were made of orange flavoured granules.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFour participants withdrew from the trial; therefore, 16 were included in the final analysis.
Other biasUnclear riskNo other sources of bias identified.

Ratjen 1985

MethodsRandomized, double-blind, placebo-controlled, parallel trial design.
Single centre in Germany.
2-week washout period prior to starting treatment.
Duration 12 weeks.
Not ITT (4 participants dropped out and were not included in final analysis).
Participants36 participants with CF (16 male).
Age 6 - 21 years (mean 13.9).
Mild to moderate lung disease.
Atopic individuals, and those on bronchodilators excluded.
Interventions3 treatment arms. Oral NAC 200 mg tid, oral ABX 30 mg tid or placebo, each for 12 weeks.
OutcomesPFTs (Raw, TGV, sRaw, REZ, VC, FEV1, FEV1/VC, V 75% FVC, V 50% FVC, V 25% FVC, PEF, TLC, RV/TLC) recorded after washout period, at 6 weeks and 12 weeks.
PFTs reported as mean values as percentage of normal, with no absolute values reported.
After the trial, parents and participants were asked whether they had improved, deteriorated or remained stable during the trial, and if they thought that they had received a drug or placebo during the trial.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomization.
Allocation concealment (selection bias)Unclear riskTrial does not clearly discuss allocation concealment.
Blinding (performance bias and detection bias)
Participants
Unclear riskThe trial drugs were similar in appearance and the trial was described as being "double-blind" with no specific details on who was blinded. Both the active drug and the placebo were of granular appearance and could not be distinguished with regard to taste, colour or odour.
Blinding (performance bias and detection bias)
Clinicians/assessors
Unclear riskThe trial drugs were similar in appearance and the trial was described as being "double-blind" with no specific details on who was blinded. Both the active drug and the placebo were of granular appearance and could not be distinguished with regard to taste, colour or odour.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk36 participants entered the trial with 4 withdrawals; therefore the final analysis was on 32 participants. 4 participants did not complete the trial due to irregular drug intake, missed clinic appointments, or clinical deterioration.
Other biasUnclear riskNo other sources of bias identified.

Stafanger 1988

MethodsRandomized, double-blind, placebo-controlled, cross-over design.
Single centre in Denmark.
6 months on each intervention, followed by 3 months follow-up.
Not ITT as 3 participants were excluded from the final analysis.
Participants41 participants with CF (23 males).
Age 2 - 31 years (mean 9.5).
None were infected by Pseudomonas aeruginosa. Stable disease, but disease severity not stated.
Exclusions: past history of peptic ulcer disease, liver or kidney disease and pregnancy.
Interventions3 periods, each 3 months duration. First period oral NAC (200mg tid if <30kg, 400mg bid if >30kg) or placebo, then cross over to the other intervention, then 3 months follow up.
OutcomesSubjective scores of symptoms, body weight, sputum bacteriology and PFTs (FEV1, FVC, PEF) recorded every month. 3-monthly serum WBC, ESR and Staphylococcal aureus, Haemophilus influenzae and Pseudomonas aeruginosa antibody titres. Time on antibiotics also recorded. Ciliary function was also studied (ciliary beat frequency and ciliary beating pattern) in 20 participants.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization process not described
Allocation concealment (selection bias)Unclear riskTrial does not clearly discuss allocation concealment.
Blinding (performance bias and detection bias)
Participants
Unclear riskTrial described as "double-blind" but no details were given on who was blinded.
Blinding (performance bias and detection bias)
Clinicians/assessors
Unclear riskTrial described as "double-blind" but no details were given on who was blinded.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudied 44 participants in this trial, and while 41 participants completed the trial, data on only 23 participants are presented in the paper.
Other biasUnclear riskTrial has a risk of bias due to no washout period between treatments.

Stafanger 1989

Methods

Randomized, double-blind, placebo-controlled, cross-over trial design.
Single centre in Denmark.
2 periods of 3 months receiving either active drug or placebo.
All participants received intravenous antibiotics routinely on a 3-monthly basis, once before starting the trial and again at the mid-point of the trial.

Not ITT as 21 participants were excluded from the final analysis.

Participants52 participants with CF, with 31 (17 males) completing it.
Mean age 15 years (range 7 - 33).
All were chronically infected with Pseudomonas aeruginosa.
Lung function ranged from severely impaired to normal.
All pre-trial treatments continued during the trial.
InterventionsOral NAC 200 mg tid (< 30kg), oral NAC 400 mg BD (> 30kg), or placebo (bicarbonate tablets).
OutcomesMonthly 'subjective score', body weight, sputum bacteriology and PFTs (FVC, FEV1, PEF). Blood test for WBC, ESR and antibodies to Staphylococcal aureus, Haemophilus influenzae and Pseudomonas aeruginosa at the start of the trial and at the end of each 3-month period. Ciliary function also assessed.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization process not described.
Allocation concealment (selection bias)Unclear riskTrial does not clearly discuss allocation concealment.
Blinding (performance bias and detection bias)
Participants
Unclear riskTrial described as "double-blind" but no details were given on who was blinded.
Blinding (performance bias and detection bias)
Clinicians/assessors
Unclear riskTrial described as "double-blind" but no details were given on who was blinded.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

52 individuals entered the trial, but only 31 completed the trial resulting in a 40% dropout rate.

The paper presents data only on a subgroup of participants (n = 10) who have baseline PEF < 70%. There is no data provided on the remaining 21 participants.

Other biasUnclear riskTrial has a very serious potential risk of bias as some of the data presented in the tables is incorrect (the data for total and mean values in columns 5 and 6 in Table 2 are not calculated correctly). There was also an unclear duration of the washout period. Participants were also excluded from the trial due to adverse effects.

Weller 1980

  1. a

    ABX: ambroxol hydrochloride
    BID: twice daily
    CF: cystic fibrosis
    CXR: chest X-ray
    ESR: erythrocyte sedimentation rate
    E50: forced flow rate when 50% of VC has been expired (synonymous with FEF50)
    FEF50: forced expiratory flow at 50% of VC
    FEV1: forced expiratory volume at one second
    FVC: forced vital capacity
    GSH: glutathione
    ITT: intention to treat
    MMEFR: maximum mid-expiratory flow rate
    MMV: maximum voluntary ventilation
    NAC: N-acetylcysteine
    PEF: peak expiratory flow
    PFT: pulmonary function test
    PIF: peak inspiratory flow
    QID: four times daily
    Raw: upper airway resistance
    REZ: oscillometric determination of airway resistance
    RV: residual volume
    SBO: small bowel obstruction
    SCMS-Lys: oral carbocysteine lysine salt monohydrate
    SD: standard deviation
    sRaw: specific airways resistance
    TGV: thoracic gas volume
    TID: three times daily
    TLC: total lung capacity
    TV: Tidal volume
    V 25% FVC: maximal expiratory flow in 25% vital capacity
    V 50% FVC: maximal expiratory flow in 50% vital capacity
    V 75% FVC: maximal expiratory flow in 75% vital capacity
    VC: vital capacity
    WBC: white blood cell

MethodsRandomized, double-blind, cross-over trial.
Single centre in UK.
2-month baseline periods preceded and followed 2 intervention periods each lasting 8 weeks.
Not ITT as 2 participants were not included in the final analysis.
Participants29 children with CF. 27 children completed the trial (13 male).
Age 6 - 15 years (mean 10.7).
Disease severity not reported.
InterventionsNebulized 3 ml sodium 2-mercaptoethane sulphonate (Mistabron) 20% solution bid or nebulized 3 ml 7% saline bid. Both nebulized from a Wright nebulizer operated by an air compressor (8 litres/minute).
OutcomesDiary card record of post-physiotherapy sputum volume, sputum color and cough frequency (recorded on a scale from 1 to 3). Sputum culture and PFTs (PEF, FVC, Vmax 50% VC and RV/TLC) taken every month. CXR (Crispin and Norman score), full blood count, liver function tests, electrolytes and creatinine taken at the beginning and end of the trial period.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization process not described.
Allocation concealment (selection bias)Unclear riskTrial does not clearly discuss allocation concealment.
Blinding (performance bias and detection bias)
Participants
Unclear riskTrial described as "double-blind" but no details were given on who was blinded. No attempts were made to disguise the taste or odour of the interventions.
Blinding (performance bias and detection bias)
Clinicians/assessors
Unclear riskTrial described as "double-blind" but no details were given on who was blinded. No attempts were made to disguise the taste or odour of the interventions.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk2 children were withdrawn from the trial (one due to an acute pulmonary exacerbation while receiving nebulized 7% hypertonic saline and one due to non-compliance), and therefore data for 27 children are reported in the trial.
Other biasUnclear riskNo other sources of bias identified.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    NAC: N-acetylcysteine
    NAL: nacystelyn
    rhDNase: recombinant dornase alfa

App 2002Intervention period less than 4 weeks.
Casale 2012Intervention period less than 4 weeks.
Cezeaux 1967Intervention not applicable (bronchial lavage under general anaesthetic).
Dasgupta 1996Non-randomized, in vitro trial of the effects of rhDNase and NAL on sputum spinnability and rheology.
Dietzsch 1975Trial not randomized.
Gotz 1980Intervention period less than 4 weeks.
Griese 2004Intervention period less than 4 weeks.
Maayan 1989Intervention period less than 4 weeks.
Snyder 2002Intervention period less than 4 weeks.
Tecklin 1976Intervention period less than 4 weeks.
Tirouvanziam 2006bNot a randomized controlled trial.

Characteristics of studies awaiting assessment [ordered by study ID]

Griese 2013

MethodsDouble-blind, placebo-controlled, randomized trial.
Participants153 participants (age ≥ 8 years, FEV1 ≥ 40% and ≤ 90%).
InterventionsGlutathione or placebo inhaled bid over 24 weeks.
Outcomes

No significant effect on absolute change in FEV1 during study period. Small effect on FEV1 at three months.

No statistically significant differences between groups in body weight, rate and time to pulmonary exacerbations, quality of life total and respiratory scores, adverse events, rate of premature withdrawals, and change in laboratory parameters.

Increased free and total glutathione in sputum after three and six months in glutathione group.

Notes 

Tirouvanziam 2011

MethodsRandomized, double-blind, placebo-controlled trial.
Participants

70 participants (35 male); F508 homozygous (49%), heterozygous (36%).

Age 7 - 18 years (27%), > 18 years (73%).

FEV1 40% - 60% (40%), 60% - 85% (60%).

InterventionsNAC 900 mg orally tid or placebo.
Outcomes

Results not published.

Change in logarithm of HNE activity measured in sputum, change in sputum neutrophil count, change in IL-8 concentration in sputum and plasma, change in glutathione in whole blood, incidence of pulmonary exacerbations, incidence and number of antibiotics for any reason, change in FEV1, CFQ-R, CFRD, level of NAC in whole blood, βFGF and VEGF in plasma and urine, S-nitrosylated NAC in whole blood, HIF-1α in blood cells, echocardiogram, DLCO.

Notes 

van Daele 2011

  1. a

    βFGF: basic fibroblast growth factor
    bid: twice daily
    BMI: body mass index
    CFQ-R: cystic fibrosis questionnaire - revised
    CFRD: cystic fibrosis related diabetes
    DLCO: diffusing capacity
    FEV1: forced expiratory volume at one second
    FVC: forced vital capacity
    HIF-1α: hypoxia-inducible factor 1
    HNE: human neutrophil elastase
    NAC: N-acetylcysteine
    tid: three times daily
    VEGF: vascular endothelial growth factor

MethodsOpen, placebo-controlled, cross-over trial.
Participants

15 participants (6 drop-outs), 55.5% female.

Mean age 23 years.

Mean BMI 20.4.

Mean FVC 93%.

Mean FEV1 76%.

InterventionsInhaled NAC or normal saline bid for 1 month.
OutcomesSputum elasticity and viscosity after one dose or after one month.
Notes 

Ancillary