Derivados del tiol nebulizados y por vía oral para la enfermedad pulmonar en la fibrosis quística
Resumen
Antecedentes
La fibrosis quística es una enfermedad hereditaria en la que las secreciones respiratorias son espesas y pegajosas. La insuficiencia respiratoria debida a la infección pulmonar recurrente y a la inflamación es la causa más frecuente de mortalidad. Los tratamientos con agentes mucoactivos (p.ej., alfa dornasa y solución salina hipertónica nebulizada) pueden disminuir la viscosidad y aumentar la eliminación del esputo de las vías respiratorias, reducir la infección y la inflamación y mejorar la función pulmonar. Los derivados del tiol, nebulizados o por vía oral, han mostrado beneficio en otras enfermedades respiratorias. Su modo de acción probablemente es diferente en dependencia de la vía de administración. Hay varios derivados del tiol y no está claro cuáles pueden ser beneficiosos en la fibrosis quística.
Objetivos
Evaluar la eficacia y seguridad de los derivados del tiol nebulizados y por vía oral en los pacientes con fibrosis quística.
Métodos de búsqueda
Se realizaron búsquedas en el registro de ensayos del Grupo Cochrane de Fibrosis Quística (Cochrane Cystic Fibrosis and Genetic Disorders Group) que incluye referencias identificadas en búsquedas exhaustivas en bases de datos electrónicas, búsquedas manuales en revistas pertinentes y en libros de resúmenes de actas de congresos.
Búsqueda más reciente: 13 junio 2013.
También se realizó una búsqueda en PubMed el 26 de febrero de 2013 de artículos publicados relevantes.
Criterios de selección
Los ensayos controlados aleatorizados y cuasialeatorizados que compararon los derivados del tiol nebulizados o por vía oral con placebo u otro derivado de tiol en pacientes con fibrosis quística.
Obtención y análisis de los datos
Los autores de la revisión evaluaron de forma independiente los ensayos para su inclusión, analizaron el riesgo de sesgo y extrajeron los datos.
Resultados principales
Las búsquedas identificaron 23 ensayos; se incluyen nueve ensayos (255 participantes), de los cuales siete tienen más de 10 años de antigüedad. Se identificaron tres ensayos de derivados del tiol nebulizados (uno comparó un 20% de N‐acetilcisteína con un 2% de N‐acetilcisteína; otro comparó el sulfonato de sodio‐2‐mercaptoetano con un 7% de solución salina hipertónica; y otro comparó el glutatión con un 4% de solución salina hipertónica). Aunque estos tratamientos generalmente fueron bien tolerados y no tuvieron efectos adversos significativos, no hubo evidencia de que produjeran algún beneficio clínico significativo en los resultados primarios de la revisión en los participantes que los recibieron.
Se identificaron seis ensayos de derivados del tiol oral. Tres ensayos compararon N‐acetilcisteína con placebo; uno comparó N‐acetilcisteína, ambroxol y placebo; uno comparó carbocisteína con ambroxol; y uno comparó N‐acetilcisteína en dosis bajas y altas. Los derivados del tiol por vía oral fueron en general bien tolerados, no tuvieron efectos adversos significativos, sin embargo, no hubo evidencia de que produjeran algún beneficio clínico significativo en los resultados primarios de esta revisión, en los participantes que recibieron estos tratamientos.
Conclusiones de los autores
No se encontró evidencia para recomendar el uso de los derivados del tiol por vía oral o nebulizados en los pacientes con fibrosis quística. Muy pocos ensayos de buena calidad han investigado el efecto de estos fármacos en la fibrosis quística, y se requiere investigación adicional sobre la función potencial de estos fármacos para mejorar los resultados de las personas con fibrosis quística.
PICO
Resumen en términos sencillos
Compuestos que pueden romper la estructura del moco que se produce en la enfermedad pulmonar de la fibrosis quística
La fibrosis quística es un trastorno genético que afecta principalmente a los pulmones. Las infecciones del tórax reaparecen en los pacientes con fibrosis quística debido a la acumulación de esputo espeso (flema) en las vías aéreas. Varios tratamientos, incluidos los derivados del tiol, procuran licuar este esputo para mejorar la función pulmonar y reducir la frecuencia de infecciones respiratorias. Los derivados del tiol pueden administrarse nebulizados (respirados) o por vía oral (por la boca). Se ha mostrado que son útiles en otros trastornos pulmonares, como la enfermedad pulmonar obstructiva crónica. Esta revisión tiene como objetivo determinar si existe evidencia suficiente para recomendar el uso de derivados de tiol nebulizados u orales para los pacientes con fibrosis quística. Se incluyeron nueve ensayos; tres evaluaron el efecto de los derivados del tiol nebulizado. De los ensayos nebulizados, uno comparó un 20% de N‐acetilcisteína con un 2% de N‐acetilcisteína; otro comparó el sulfonato de sodio‐2‐mercaptoetano con un 7% de solución salina hipertónica; y el otro comparó el glutatión con un 4% de solución salina hipertónica. Los derivados del tiol nebulizados generalmente se toleraron bien, y no tienen efectos adversos importantes. Sin embargo, no mostraron mejorías significativas en ninguna de las medidas de resultado.
Seis ensayos incluidos evaluaron los efectos de los derivados del tiol oral. Tres de estos ensayos compararon N‐acetilcisteína oral con placebo; uno comparó N‐acetilcisteína oral, ambroxol oral y placebo; y uno comparó carbocisteína oral y ambroxol oral (sin placebo). Ninguno de los ensayos mostró un beneficio significativo general en ninguna de las medidas de resultado de esta revisión. Los derivados del tiol por vía oral en general se toleraron bien, sin efectos adversos importantes.
En resumen, los ensayos incluidos en la revisión no aportaron evidencia de que los derivados del tiol nebulizados o por vía oral fueron beneficiosos o nocivos para los pacientes con fibrosis quística. Es necesario realizar investigaciones adicionales sobre los efectos de los derivados del tiol en los pacientes con fibrosis quística antes de que pueda recomendarse su uso.
Authors' conclusions
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:
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evaluate efficacy of both inhaled and oral thiol derivatives in people with CF.
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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
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Pulmonary function testing (PFT)
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forced expiratory volume in one second (FEV1) per cent predicted (change from baseline and absolute data)
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forced vital capacity (FVC) per cent predicted (change from baseline and absolute data)
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Secondary outcomes
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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)
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Inflammatory markers (change from baseline)
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serum (white blood cell (WBC), C‐reactive protein (CRP), erythrocyte sedimentation rate (ESR))
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sputum (IL‐8)
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Quality of life (QOL) (change from baseline as measured by a validated QOL scale)
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Need for oral antibiotics for pulmonary exacerbation
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number of weeks of treatment
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number of courses
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Need for intravenous antibiotics for pulmonary exacerbation
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number of weeks of treatment
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number of courses
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Adverse events
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Number of days in hospital for respiratory exacerbation
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Adherence
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Acquisition of new respiratory pathogens (%)
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Six‐minute walk distance
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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).
Comparison 1 Nebulized thiols versus other nebulized medications, Outcome 1 Change in forced expiratory volume in 1 second.
Comparison 1 Nebulized thiols versus other nebulized medications, Outcome 2 Change in forced vital capacity.
Comparison 1 Nebulized thiols versus other nebulized medications, Outcome 3 Peak expiratory flow.
Comparison 1 Nebulized thiols versus other nebulized medications, Outcome 4 Vmax50% Vital capacity.
Comparison 1 Nebulized thiols versus other nebulized medications, Outcome 5 Forced expiratory flow 25‐75.
Comparison 1 Nebulized thiols versus other nebulized medications, Outcome 6 RV/TLC.
![Comparison 1 Nebulized thiols versus other nebulized medications, Outcome 7 Six‐minute walk test [metres].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-001-07.png)
Comparison 1 Nebulized thiols versus other nebulized medications, Outcome 7 Six‐minute walk test [metres].
Comparison 1 Nebulized thiols versus other nebulized medications, Outcome 8 Sputum viscosity.
![Comparison 2 Oral thiols versus placebo, Outcome 1 Change in forced expiratory volume in 1 second [% predicted].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-002-01.png)
Comparison 2 Oral thiols versus placebo, Outcome 1 Change in forced expiratory volume in 1 second [% predicted].
![Comparison 2 Oral thiols versus placebo, Outcome 2 Peak expiratory flow [L/min].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-002-02.png)
Comparison 2 Oral thiols versus placebo, Outcome 2 Peak expiratory flow [L/min].
![Comparison 2 Oral thiols versus placebo, Outcome 3 Change in peak expiratory flow [% predicted].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-002-03.png)
Comparison 2 Oral thiols versus placebo, Outcome 3 Change in peak expiratory flow [% predicted].
![Comparison 2 Oral thiols versus placebo, Outcome 4 Change in total lung capacity [% predicted].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-002-04.png)
Comparison 2 Oral thiols versus placebo, Outcome 4 Change in total lung capacity [% predicted].
![Comparison 2 Oral thiols versus placebo, Outcome 5 Change in flow 75% FVC [% predicted].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-002-05.png)
Comparison 2 Oral thiols versus placebo, Outcome 5 Change in flow 75% FVC [% predicted].
![Comparison 2 Oral thiols versus placebo, Outcome 6 Change in flow 50% FVC [% predicted].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-002-06.png)
Comparison 2 Oral thiols versus placebo, Outcome 6 Change in flow 50% FVC [% predicted].
![Comparison 2 Oral thiols versus placebo, Outcome 7 Change in flow 25% FVC [% predicted].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-002-07.png)
Comparison 2 Oral thiols versus placebo, Outcome 7 Change in flow 25% FVC [% predicted].
![Comparison 2 Oral thiols versus placebo, Outcome 8 Change in forced expiratory volume in 1 sec/vital capacity [% predicted].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-002-08.png)
Comparison 2 Oral thiols versus placebo, Outcome 8 Change in forced expiratory volume in 1 sec/vital capacity [% predicted].
![Comparison 2 Oral thiols versus placebo, Outcome 9 Change in total gas volume [% predicted].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-002-09.png)
Comparison 2 Oral thiols versus placebo, Outcome 9 Change in total gas volume [% predicted].
![Comparison 2 Oral thiols versus placebo, Outcome 10 Change in vital capacity [% predicted].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-002-10.png)
Comparison 2 Oral thiols versus placebo, Outcome 10 Change in vital capacity [% predicted].
![Comparison 2 Oral thiols versus placebo, Outcome 11 Change in residual volume/total lung capacity [% predicted].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-002-11.png)
Comparison 2 Oral thiols versus placebo, Outcome 11 Change in residual volume/total lung capacity [% predicted].
![Comparison 2 Oral thiols versus placebo, Outcome 12 Antibiotic treatment [weeks].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-002-12.png)
Comparison 2 Oral thiols versus placebo, Outcome 12 Antibiotic treatment [weeks].
![Comparison 3 Oral thiols versus other oral agents, Outcome 1 Change in forced expiratory volume in 1 second [% predicted].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-003-01.png)
Comparison 3 Oral thiols versus other oral agents, Outcome 1 Change in forced expiratory volume in 1 second [% predicted].
![Comparison 3 Oral thiols versus other oral agents, Outcome 2 Change in peak expiratory flow [% predicted].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-003-02.png)
Comparison 3 Oral thiols versus other oral agents, Outcome 2 Change in peak expiratory flow [% predicted].
![Comparison 3 Oral thiols versus other oral agents, Outcome 3 Change in total lung capacity [% predicted].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-003-03.png)
Comparison 3 Oral thiols versus other oral agents, Outcome 3 Change in total lung capacity [% predicted].
![Comparison 3 Oral thiols versus other oral agents, Outcome 4 Change in flow 75% FVC [% predicted].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-003-04.png)
Comparison 3 Oral thiols versus other oral agents, Outcome 4 Change in flow 75% FVC [% predicted].
![Comparison 3 Oral thiols versus other oral agents, Outcome 5 Change in flow 50% FVC [% predicted].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-003-05.png)
Comparison 3 Oral thiols versus other oral agents, Outcome 5 Change in flow 50% FVC [% predicted].
![Comparison 3 Oral thiols versus other oral agents, Outcome 6 Change in flow 25% FVC [% predicted].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-003-06.png)
Comparison 3 Oral thiols versus other oral agents, Outcome 6 Change in flow 25% FVC [% predicted].
![Comparison 3 Oral thiols versus other oral agents, Outcome 7 Change in forced expiratory volume in 1 sec/vital capacity [% predicted].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-003-07.png)
Comparison 3 Oral thiols versus other oral agents, Outcome 7 Change in forced expiratory volume in 1 sec/vital capacity [% predicted].
![Comparison 3 Oral thiols versus other oral agents, Outcome 8 Change in thoracic gas volume [% predicted].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-003-08.png)
Comparison 3 Oral thiols versus other oral agents, Outcome 8 Change in thoracic gas volume [% predicted].
![Comparison 3 Oral thiols versus other oral agents, Outcome 9 Change in vital capacity [% predicted].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-003-09.png)
Comparison 3 Oral thiols versus other oral agents, Outcome 9 Change in vital capacity [% predicted].
![Comparison 3 Oral thiols versus other oral agents, Outcome 10 Change in residual volume/total lung capacity [% predicted].](/es/cdsr/doi/10.1002/14651858.CD007168.pub3/media/CDSR/CD007168/image_n/nCD007168-CMP-003-10.png)
Comparison 3 Oral thiols versus other oral agents, Outcome 10 Change in residual volume/total lung capacity [% predicted].
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Change in forced expiratory volume in 1 second Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Change in forced vital capacity Show forest plot | 2 | 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 flow Show forest plot | 2 | 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 capacity Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 5 Forced expiratory flow 25‐75 Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 5.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 6 RV/TLC Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 6.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 7 Six‐minute walk test [metres] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 7.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 8 Sputum viscosity Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 8.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Change in forced expiratory volume in 1 second [% predicted] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Peak expiratory flow [L/min] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Change in peak expiratory flow [% predicted] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4 Change in total lung capacity [% predicted] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 5 Change in flow 75% FVC [% predicted] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 5.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 6 Change in flow 50% FVC [% predicted] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 6.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 7 Change in flow 25% FVC [% predicted] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 7.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 8 Change in forced expiratory volume in 1 sec/vital capacity [% predicted] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 8.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 9 Change in total gas volume [% predicted] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 9.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 10 Change in vital capacity [% predicted] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 10.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 11 Change in residual volume/total lung capacity [% predicted] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 11.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 12 Antibiotic treatment [weeks] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 12.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Change in forced expiratory volume in 1 second [% predicted] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Change in peak expiratory flow [% predicted] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Change in total lung capacity [% predicted] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4 Change in flow 75% FVC [% predicted] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 5 Change in flow 50% FVC [% predicted] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 5.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 6 Change in flow 25% FVC [% predicted] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 6.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 7 Change in forced expiratory volume in 1 sec/vital capacity [% predicted] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 7.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 8 Change in thoracic gas volume [% predicted] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 8.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 9 Change in vital capacity [% predicted] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 9.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 10 Change in residual volume/total lung capacity [% predicted] Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 10.1 Up to 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
