Antioxidant supplementation for lung disease in cystic fibrosis

Oana Ciofu; Sherie Smith; Jens Lykkesfeldt

doi:10.1002/14651858.CD007020.pub4

Scolaris Content Display Scolaris Content Display

Contenido relacionado

Ir a:

Revisiones y protocolos relacionados
Guías
Temas

Revisiones y protocolos relacionados

Topics

Temas

Figure 1

Peroxide chain reaction characterized by initiation, propagation and termination. (RH: PUFA; R·: free radical; ROO·: peroxide; ROOH: hydroxyl peroxide; AH: vitamin E; A·: oxidized Vitamin E. Adapted from: Tappel AL. Vitamin E and free radical peroxidation of lipids. Annals of the New York Academy of Sciences. 1972; 203(1):12‐28.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Figure 2

Study flow diagram.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Figure 3

Risk of bias graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Figure 4

Risk of bias summary: review authors' judgements about each methodological domain for each included study.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1 Oral antioxidants versus control, Outcome 1 Lung function: FEV1 (% predicted) (mean change from baseline).

Analysis 1.1

Comparison 1 Oral antioxidants versus control, Outcome 1 Lung function: FEV₁ (% predicted) (mean change from baseline).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.2

Comparison 1 Oral antioxidants versus control, Outcome 2 Lung function: FVC (% predicted) mean change from baseline.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.3

Comparison 1 Oral antioxidants versus control, Outcome 3 QoL: Quality of Well Being Scale.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1 Oral antioxidants versus control, Outcome 4 Oxidative stress: lipid peroxidation (H2O2) (μmol/L).

Analysis 1.4

Comparison 1 Oral antioxidants versus control, Outcome 4 Oxidative stress: lipid peroxidation (H₂O₂) (μmol/L).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1 Oral antioxidants versus control, Outcome 5 Oxidative stress: lipid peroxidation (F2‐isoprostanes) (ng/L).

Analysis 1.5

Comparison 1 Oral antioxidants versus control, Outcome 5 Oxidative stress: lipid peroxidation (F₂‐isoprostanes) (ng/L).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.6

Comparison 1 Oral antioxidants versus control, Outcome 6 Oxidative stress: lipid peroxidation (malondialdehyde) (μmol/L) mea difference to baseline).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.7

Comparison 1 Oral antioxidants versus control, Outcome 7 Oxidative stress: urine 8‐iso‐PGF2α log 10 (pg/mL).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.8

Comparison 1 Oral antioxidants versus control, Outcome 8 Oxidative stress: sputum 8‐iso‐PGF2α log10 (pg/mL).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.9

Comparison 1 Oral antioxidants versus control, Outcome 9 Oxidative stress: sputum 8‐OHdG (log10) ng/ml.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.10

Comparison 1 Oral antioxidants versus control, Outcome 10 Oxidative stress: enzyme function ‐ GPX (U/g Hb).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.11

Comparison 1 Oral antioxidants versus control, Outcome 11 Oxidative stress: enzyme function ‐ SOD (U/mg Hb).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.12

Comparison 1 Oral antioxidants versus control, Outcome 12 Oxidative stress: potency (TEAC) (mmol/L).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.13

Comparison 1 Oral antioxidants versus control, Outcome 13 Plasma total antioxidant capacity (nmol) (change from baseline).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.14

Comparison 1 Oral antioxidants versus control, Outcome 14 Plasma total antioxidant capacity (log10) (CRE).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.15

Comparison 1 Oral antioxidants versus control, Outcome 15 Plasma antioxidant status: vitamin E (μmol/L).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.16

Comparison 1 Oral antioxidants versus control, Outcome 16 Plasma antioxidant status: β‐carotene (μmol/L).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.17

Comparison 1 Oral antioxidants versus control, Outcome 17 Plasma antioxidant status: selenium (μmol/L).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.18

Comparison 1 Oral antioxidants versus control, Outcome 18 Plasma antioxidant status: vitamin C (μmol/L).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.19

Comparison 1 Oral antioxidants versus control, Outcome 19 Plasma antioxidant status: whole blood GSH (μmol/L) (change from baseline).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.20

Comparison 1 Oral antioxidants versus control, Outcome 20 Plasma antioxidant status: plasma fatty acid status (mg/L).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.21

Comparison 1 Oral antioxidants versus control, Outcome 21 Plasma inflammation: IL‐6 (pg/mL) at 3 months (vitamin E).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.22

Comparison 1 Oral antioxidants versus control, Outcome 22 Plasma inflammation: TNF‐α (pg/mL) at 3 months (vitamin E).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.23

Comparison 1 Oral antioxidants versus control, Outcome 23 Plasma IL‐8 pg/mL (log 10) (change from baseline).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.24

Comparison 1 Oral antioxidants versus control, Outcome 24 Sputum IL‐8 pg/ml (log 10) (per volume).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.25

Comparison 1 Oral antioxidants versus control, Outcome 25 Sputum human neutrophil elastase (log 10) (mg/mg) per weight (change from baseline).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.26

Comparison 1 Oral antioxidants versus control, Outcome 26 Sputum neutrophil count (logarithm).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.27

Comparison 1 Oral antioxidants versus control, Outcome 27 Sputum myeloperoxidase (MPO) levels (log 10) (ng/mL).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.28

Comparison 1 Oral antioxidants versus control, Outcome 28 Nutritional status: BMI (change from baseline).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.29

Comparison 1 Oral antioxidants versus control, Outcome 29 Nutritional status: BMI percentile (change from baseline).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.30

Comparison 1 Oral antioxidants versus control, Outcome 30 Nutritional status: weight (kg) (change from baseline).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.31

Comparison 1 Oral antioxidants versus control, Outcome 31 Nutritional status: weight percentile (change from baseline).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.32

Comparison 1 Oral antioxidants versus control, Outcome 32 Antibiotic days per participant.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.33

Comparison 1 Oral antioxidants versus control, Outcome 33 Number of participants with at least one exacerbation.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.34

Comparison 1 Oral antioxidants versus control, Outcome 34 Number of hospitalizations.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.35

Comparison 1 Oral antioxidants versus control, Outcome 35 Adverse effects.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 1 Lung function: FEV1 (L) (change from baseline).

Analysis 2.1

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 1 Lung function: FEV₁ (L) (change from baseline).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 2 Lung function: FEV1 (% predicted) (change from baseline).

Analysis 2.2

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 2 Lung function: FEV₁ (% predicted) (change from baseline).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.3

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 3 Lung function FVC (L) (change from baseline).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.4

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 4 Lung function FVC (% predicted) (change from baseline).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.5

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 5 QoL total score (change from baseline).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.6

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 6 QoL respiratory score (change from baseline).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 7 Oxidative stress markers in exhaled breath condensate: H2O2 (μM).

Analysis 2.7

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 7 Oxidative stress markers in exhaled breath condensate: H₂O₂ (μM).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.8

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 8 Sputum oxidative stress: lipid peroxidation (8‐isoprostan).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.9

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 9 Sputum antioxidant status: free glutathione in sputum (pM).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.10

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 10 Sputum antioxidant status: total glutathione in sputum (pM).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.11

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 11 Sputum antioxidant status: glutathione in sputum neutrophils (MFI).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.12

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 12 Plasma antioxidant status: free glutathione (pM).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.13

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 13 Plasma antioxidant status: total glutathione (pM).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.14

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 14 Plasma antioxidant status: glutathione in blood neutrophils (MFI).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.15

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 15 Sputum oxidative stress: protein carbonyls (U).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.16

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 16 Local inflammation: cytokines in sputum IL‐8 (pg/mL).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.17

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 17 Local inflammation: cytokines in sputum IL‐10 (pg/mL).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.18

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 18 Local inflammation: cytokines in sputum TNF‐α (pg/mL).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.19

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 19 Nutritional status: BMI (change from baseline).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.20

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 20 Nutritional status: weight (kg).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.21

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 21 Number of pulmonary exacerbations during the study.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.22

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 22 Time to first pulmonary exacerbation (days).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.23

Comparison 2 Inhaled antioxidant (glutathione) versus control, Outcome 23 Adverse events.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Summary of findings for the main comparison. Summary of findings: oral antioxidants (NAC/GSH) compared to placebo

Oral antioxidants (NAC/GSH) compared to placebo for cystic fibrosis
Patient or population: adults and children with cystic fibrosis Settings: outpatients Intervention: oral antioxidants NAC/GSH Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	NAC/GSH
Lung function: FEV₁ % predicted mean change from baseline Follow‐up: 3 months	The mean change in FEV₁ % predicted ranged across control groups from ‐8.6% to ‐1.64%.	The mean change in FEV₁ % predicted in the intervention groups was 2.83% higher (2.16% lower to 7.83% higher).	NA	125 (4)	⊕⊝⊝⊝ very low^1,2,3	The studies included in this analysis looked at different dosages of NAC. In 2 studies (n = 67), 600 mg/daily was divided in 3 doses (Ratjen 1985; Stafanger 1989), while in the remaining studies the doses were 2700 mg daily (n = 70) (Conrad 2015) and 2800 mg daily (n = 21) (Dauletbaev 2009) divided in 3 and 4 doses, respectively.
Lung function: FEV₁ % predicted mean change from baseline Follow‐up: 6 months	Change in FEV₁ was significantly higher in the intervention group compared to the control group, MD 4.38 (95% CI 0.89 to 7.87).		NA	62 (1)	⊕⊕⊕⊝ moderate³	Results from the only included study favour NAC (2700 mg daily). A further study (n = 47) reported FEV₁ % predicted at 6 months of GSH (administered as L‐glutathione), MD 17.40% (95% CI 13.97 to 20.83) (Visca 2015), but the studies were not combined due to the different action of the intervention. Both studies reported in favour of the antioxidant treatment.
Quality of life: change in mean CFQ‐R score from baseline Follow‐up: 6 months	There was no significant difference in the change from from baseline in either group for CFQ‐R score at 6 months, MD ‐0.03 (95% CI ‐0.53 to 0.47).		NA	61 (1)	⊕⊕⊕⊝ moderate³	Both groups showed a non‐significant decrease in CFQ‐R score (quality of life worsened) (P = 0.91).
Nutritional status: change from baseline in BMI Follow‐up: 6 months	There was no significant difference from baseline in either group for BMI score at 6 months, MD 0.20 (95% CI ‐0.23 to 0.63).		NA	62 (1)	⊕⊕⊕⊝ moderate³	There was no difference in the change in BMI between the intervention and control group. A further study (n = 47) reported on the change in BMI percentile after 6 months of oral supplementation with GSH (Visca 2015); BMI percentile increased significantly more with GSH supplementation than control, MD 17.20% (95% CI 14.35 to 20.05).
Pulmonary exacerbations: mean time to next exacerbation Follow‐up: 6 months	Outcome not reported.					Although time to exacerbation was not reported, the Conrad study (n = 70) reported no difference in the number of participants with pulmonary exacerbations requiring antibiotics between NAC and control at 6 months, RR 0.83 (95% CI 0.50 to 1.390) and also reported no difference in the number of participants hospitalised, RR 0.94 (95% CI 0.49 to 1.81) (Conrad 2015).
Adverse events Follow‐up: 6 months	Reported adverse effects were more common in the intervention group for: sinusitis, OR 2.92 (95% CI 0.11 to 74.05); diarrhoea, OR 1.29 (95% CI 0.27 to 6.25); and elevated liver enzymes, OR 2.92 (95% CI 0.11 to 74.05); but were more common in the control group for distal intestinal obstruction syndrome, OR 0.31 (95% CI 0.01 to 7.77).			70 (1)	⊕⊕⊕⊝ moderate³	Two further studies (n = 41) reported no adverse events in either control or intervention group (Götz 1980; Mitchell 1982). One study (n = 21) reported an adverse effect (gastrointestinal bleeding) which was considered to have a "possible" relationship to the medication (Dauletbaev 2009).
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BMI: body mass index; CI: confidence interval; FEV₁ : forced expiratory volume in 1 second; GSH: glutathione; MD: mean difference; NAC: N‐acetylcysteine; OR: odds ratio; RR: risk ratio.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
1. Downgraded once due to risk of bias across the included studies for this outcome; 1 study had a low risk of bias overall, but the remaining 3 had an unclear or high risk of bias across some of the domains particularly around allocation concealment and blinding. 2. Downgraded once due to inconsistency of results. There was heterogeneity with an I² value of 49% across the studies; this may be due to the different doses of NAC given and the quality of the underlying studies. 3. Downgraded once due to imprecision from small participant numbers.

Summary of findings for the main comparison. Summary of findings: oral antioxidants (NAC/GSH) compared to placebo

Ir a la tabla de la revisión

Summary of findings 2. Summary of findings: oral vitamin E supplementation versus placebo or no treatment

Oral antioxidant vitamin E supplement compared with placebo or no treatment for cystic fibrosis
Patient or population: children and adults with cystic fibrosis Settings: outpatients Intervention: oral antioxidant vitamin E supplement Comparison: placebo or no treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo/no treatment	Vitamin E supplement
Lung function: FEV₁ % predicted mean change from baseline Follow‐up: 3 months	Outcome not reported.
Lung function: FEV₁ % predicted mean change from baseline Follow‐up: 6 months	Outcome not reported.
Quality of life Follow‐up: 6 months	Outcome not reported.
Nutritional status: change from baseline in BMI Follow‐up: 6 months	Outcome not reported.
Pulmonary exacerbations: mean time to next exacerbation Follow‐up: 6 months	Outcome not reported.
Adverse events Follow‐up: 3 months	No difference was found in the number of adverse events due to: sinusitis, OR 1.00 (95% CI 0.13 to 7.94); or exacerbations OR 1.00 (95% CI 0.06 to 17.25). Reported adverse effects were more common in the intervention group for: distal intestinal obstruction syndrome, OR 3.16 ( 95% CI 0.12 to 82.64); diarrhoea, OR 3.16 (95% CI 0.12 to 82.64); and elevated liver enzymes, OR 3.16 (95% CI 0.12 to 82.64).			38 (1)	⊕⊕⊝⊝ low^1,2
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BMI: body mass index; CI: confidence interval; FEV₁ : forced expiratory volume in 1 second; OR: odds ratio.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
1. Downgraded once due to risk of bias within the included study across the domains of randomisation, allocation concealment, incomplete outcome reporting and selective reporting. 2. Downgraded due to low numbers of participants and small number of participants.

Summary of findings 2. Summary of findings: oral vitamin E supplementation versus placebo or no treatment

Ir a la tabla de la revisión

Summary of findings 3. Summary of findings: oral β‐carotene compared to placebo

Oral antioxidant β‐carotene compared to placebo for cystic fibrosis
Patient or population: children and adults with cystic fibrosis Settings: outpatients Intervention: oral antioxidant β‐carotene Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	β‐carotene
Lung function: FEV₁ % predicted mean change from baseline Follow‐up: 3 months	Outcome not reported.
Lung function: FEV₁ % predicted mean change from baseline Follow‐up: 6 months	There was no significant difference from baseline in either group for FEV₁ % predicted at 6 months, MD 0.90 (‐20.09 to 21.89).		NA	24 (1)	⊕⊝⊝⊝ very low^1,2,3	P = 0.93
Quality of life Follow‐up: 6 months	Outcome not reported.
Nutritional status: change from baseline in BMI Follow‐up: 6 months	Outcome not reported.
Pulmonary exacerbations: mean time to next exacerbation Follow‐up: 6 months	Outcome not reported.
Adverse events Follow‐up: 6 months	The study reported no adverse events in either group.		NA	24 (1)	⊕⊝⊝⊝ very low^1,2,3
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BMI: body mass index; CI: confidence interval; FEV₁ : forced expiratory volume in 1 second; MD: mean difference.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
1. Downgraded once due to unclear or high risk of bias across most domains, particularly randomisation, allocation concealment and publication bias. 2. Downgraded once due to imprecision from a small sample size. 3. Downgraded once because of a high risk of publication bias with the study being published multiple times without reference to other publications.

Summary of findings 3. Summary of findings: oral β‐carotene compared to placebo

Ir a la tabla de la revisión

Summary of findings 4. Summary of findings: oral antioxidant combination compared to control

Oral antioxidant combination compared with control for cystic fibrosis
Patient or population: children with cystic fibrosis Settings: outpatients Intervention: oral antioxidant combination (vitamins E, C, A, β‐carotene and selenium) Comparison: control (continuation of a low‐dose supplement)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control (continuation of low dose supplement)	Combination of oral antioxidants
Lung function: FEV₁ % predicted mean change from baseline Follow‐up: 3 months	Outcome not reported at this time point.					After 2 months of a combined supplement, a single study reported a significant difference in favour of control, MD ‐4.30% (95% CI ‐5.64 to ‐2.96).
Lung function: FEV₁ % predicted mean change from baseline Follow‐up: 6 months	Outcome not reported.
Quality of life: Quality of Well Being score change from baseline Follow‐up: six months	Outcome not reported at this time point.					Results significantly favoured control over antioxidant supplementation at 2 months, SMD ‐0.66 points (95% CI ‐1.26 to ‐0.07). A higher score indicates better quality of life.
Nutritional status: change from baseline in BMI Follow‐up: 6 months	Outcome not reported.
Pulmonary exacerbations: mean time to next exacerbation Follow‐up: 6 months	Outcome not reported.
Adverse events Follow‐up: 6 months	Outcome not reported.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BMI: body mass index; CI: confidence interval; FEV₁ : forced expiratory volume in 1 second; MD: mean difference; SMD: standardised mean difference.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.

Summary of findings 4. Summary of findings: oral antioxidant combination compared to control

Ir a la tabla de la revisión

Summary of findings 5. Summary of findings: oral antioxidant mixed supplement compared with control

Oral antioxidant mixed supplement compared with control for cystic fibrosis
Patient or population: adults and children with cystic fibrosis Settings: outpatients Intervention: AquADEKs‐2 containing standard amounts of fat‐soluble vitamins (A, D, E, K) as in typical CF multivitamin supplements plus several antioxidants including β‐carotene, mixed tocopherols (different forms of vitamin E), CoQ10, mixed carotenoids (lutein, lycopene and zeaxanthin), and the minerals zinc and selenium Comparison: control multivitamin softgel capsules
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control capsules	Mixed supplement
Lung function: FEV₁ % predicted mean change from baseline Follow‐up: 3 months	Outcome not reported at this time point.					At 4 months the MD between the groups was 1.44 higher (95% CI ‐2.23 to 5.11) favouring the mixed supplement. The effect was not significant P = 0.44.
Lung function: FEV₁ % predicted mean change from baseline Follow‐up: 6 months	Outcome not reported.
Quality of life: Quality of Well Being score change from baseline Follow‐up: 6 months	Outcome not reported.
Nutritional status: change from baseline in BMI Follow up: 6 months	Outcome not reported at this time point.					The study did however report that at 4 months there was no difference in weight z scores between the intervention and control group (Sagel 2018).
Pulmonary exacerbations: mean time to next exacerbation Follow‐up: 6 months	There was a significantly lower risk of first pulmonary exacerbation in the antioxidant group than the control group at 4 months, HR 0.5 (95% CI 0.25 to 0.98) (P = 0.04).		NA	69 (1)	⊕⊕⊝⊝ low^1,2	This result was reported directly from the paper.
Adverse events Follow‐up: 6 months	No significant differences were found in the number of adverse events due to: sinusitis, OR 2.12 (95% CI 0.18 to 24.44); DIOS, OR 0.24 (95% CI 0.03 to 2.22); diarrhoea, OR 2.19 (95% CI 0.37 to 12.76); or pulmonary exacerbations, OR 0.54 (95% CI 0.21 to 1.39).		NA	69 (1)	⊕⊕⊝⊝ low^1,2	Although not statistically significant, adverse events were more common in the intervention group for sinusitis and diarrhoea whilst they were more common in the control group for DIOS and pulmonary exacerbations.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BMI: body mass index; CI: confidence interval; DIOS: distal intestinal obstruction syndrome; FEV₁ : forced expiratory volume in 1 second; HR: hazard ratio; MD: mean difference; OR odds ratio.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
1. Downgraded once due to risk of bias within the single study. There were concerns about allocation concealment and also because the enrolment number was not reached. 2. Downgraded once due to imprecision from low event rates.

Summary of findings 5. Summary of findings: oral antioxidant mixed supplement compared with control

Ir a la tabla de la revisión

Summary of findings 6. Summary of findings: inhaled antioxidants compared with placebo

Inhaled antioxidants compared with placebo for cystic fibrosis
Patient or population: children and adults with cystic fibrosis Settings: outpatients Intervention: nebulised GSH Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Nebulised GSH
Lung function: FEV₁ % predicted mean change from baseline Follow‐up: 3 months	The mean change in FEV₁ % predicted ranged across control groups from ‐3.54% to 0.32%.	The mean change in FEV₁ % predicted in the intervention groups was 3.5% higher (1.38% higher to 5.62% higher).	NA	258 (3)	⊕⊕⊕⊝ moderate¹	Data significantly favoured the antioxidant group (P = 0.001). This effect remained when the pediatric data were removed from the analysis.
Lung function: FEV₁ % predicted mean change from baseline Follow‐up: 6 months	The mean change in FEV₁ % predicted ranged across control groups from ‐4.18% to 1.53%.	The mean FEV₁ % predicted in the intervention groups was 2.3% higher (0.12% lower to 4.71% higher).	NA	258 (3)	⊕⊕⊕⊝ moderate¹	These results include adult and pediatric data. The adult‐only data were also analysed, but there was no significant difference between groups, MD 2.17% (95% CI ‐1.07 to 5.41).
Quality of life: change in CFQoL score from baseline Follow‐up: 6 months	There was no difference between groups MD 0.80 (95% CI ‐1.63 to 3.23) (P = 0.52).		NA	153 (1)	⊕⊕⊕⊝ moderate²	2 further studies found no significant difference between groups at 12 months (data taken from the papers) (Calabrese 2015a; Calabrese 2015b).
Nutritional status: change from baseline in BMI Follow‐up: 6 months	Outcome not reported at this time point. See comment.					No statistically significant difference was found between groups with regard to BMI either at 2 months, MD 0.10 (95% CI ‐0.74 to 0.94) or at 12 months, MD 0.04 (95% CI ‐8.20 to 8.27).
Pulmonary exacerbations: mean time to next exacerbation Follow‐up: 6 months	Outcome not reported at this time point. See comment.					The time to first exacerbation was 163 days in the GSH treated group and 141 days in the control group. This difference was reported as not statistically significant by the authors using Wilcoxon rank sum test; not directly analysed in this review due to skewed data.
Adverse events Follow‐up: 6 months	No significant differences were seen between groups for any adverse events.		NA	223 (3)	⊕⊕⊝⊝ low^1,3	1 study reported no serious adverse events (Bishop 2005). 2 studies reported that none of the reported adverse events led to discontinuation of the drug and that no death occurred (Calabrese 2015a; Calabrese 2015b). A further study reported that the number of serious adverse events were similar between the group treated with GSH inhalations and the placebo group (11% and 10%, respectively) (Griese 2013).
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BMI: body mass index; CFQoL: cystic fibrosis quality of life; CI: confidence interval; FEV₁ : forced expiratory volume in 1 second; GSH: glutathione; MD: mean difference.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
1. Downgraded once due to risk of bias in the included studies, particularly through lack of blinding caused by the intervention having a distinctive taste and smell. 2. Downgraded once due to risk of bias within the single included study for this outcome. The study was at high risk of bias in the blinding domain as the intervention has a distinctive taste and smell. The participants were also allowed to continue oral N‐acetylcysteine (NAC) (a precursor of GSH). 3. Downgraded once due to imprecision caused by low event rates for many of the reported adverse events.

Summary of findings 6. Summary of findings: inhaled antioxidants compared with placebo

Ir a la tabla de la revisión

Table 1. Time points for reporting data in studies of oral supplementation

Study	Time point reported
Study	1 month	2 months	3 months	4 months	5 months	6 months	9 months	12 months
Conrad 2015			✓			✓
Dauletbaev 2009			✓
Götz 1980	✓
Harries 1971	✓
Homnick 1995b								✓
Keljo 2000			✓
Levin 1961		✓				✓
Mitchell 1982			✓
Portal 1995a					✓
Ratjen 1985			✓
Renner 2001			✓			✓
Sagel 2018	✓			✓
Stafanger 1988			✓
Stafanger 1989			✓
Visca 2015			✓			✓
Wood 2003		✓

Table 1. Time points for reporting data in studies of oral supplementation

Ir a la tabla de la revisión

Table 2. Time points for reporting data in studies of inhaled supplementation

Study	Time point reported
Study	1 month	2 months	3 months	4 months	5 months	6 months	9 months	12 months
Bishop 2005		✓
Calabrese 2015a; Calabrese 2015b	✓		✓			✓	✓	✓
Griese 2013	✓		✓			✓
Howatt 1966				✓

Table 2. Time points for reporting data in studies of inhaled supplementation

Ir a la tabla de la revisión

Table 3. Improvement in plasma vitamin E levels (μmol/L) after supplementation with antioxidants in people with CF

Supplement	Time point	Result
Fat‐soluble vitamin E	1 month (Harries 1971)	MD 13.47 μmol/L (95% CI 9.05 to 17.89)
Water‐miscible vitamin E	1 month (Harries 1971)	MD 26.7μmol/L (95% CI 15.90 to 37.50)
	2 months (Levin 1961)	MD 11.61 μmol/L (95% CI 4.31 to 18.91)
	6 months (Levin 1961)	MD 19.73 μmol/L (95% CI 12.48 to 26.98)
Combined supplement	2 months (Wood 2003)	MD 10.20 μmol/L (95% CI 5.21 to 15.19)
Oral GSH	6 months (Visca 2015)	MD 4.26 μmol/L (95% CI 2.03 to 6.49)
Antioxidant‐enriched multivitamin	1 month (Sagel 2018)	MD ‐3.48 μmol/L (95% CI ‐8.01 to 1.05)
Antioxidant‐enriched multivitamin	4 months (Sagel 2018)	MD ‐1.86 μmol/L (95% CI ‐6.36 to 2.64)
CF: cystic fibrosis CI: confidence interval GSH: glutathione MD: mean difference

Table 3. Improvement in plasma vitamin E levels (μmol/L) after supplementation with antioxidants in people with CF

Ir a la tabla de la revisión

Table 4. Changes in plasma levels of cytokines IL‐6 (pg/mL) and TNF‐α (pg/mL) after 3 months of supplementation with vitamin E (Keljo 2000)

Subgroup	IL‐6 (pg/mL)	TNF‐α (pg/mL)
FEV₁ > 85% and no DNase	MD ‐2.02 (95% CI ‐4.63 to 0.59)	MD ‐1.37 (95% CI ‐3.61 to 0.87)
FEV₁ > 85% and no DNase	MD ‐0.31 (95% CI ‐4.03 to 3.41)	MD 0.33 (95% CI ‐0.49 to 1.15)
FEV₁ range 70% ‐ 85% and DNase	MD ‐0.24 (95% CI ‐3.80to 3.32)	MD ‐0.94 (95% CI ‐1.61 to ‐0.26)
CI: confidence interval FEV₁: forced expiratory volume in 1 second MD: mean difference

Table 4. Changes in plasma levels of cytokines IL‐6 (pg/mL) and TNF‐α (pg/mL) after 3 months of supplementation with vitamin E (Keljo 2000)

Ir a la tabla de la revisión

Table 5. CF Quality of life scores stratified according to age

Study ID	Age	GSH		Placebo
Study ID	Age	Baseline mean (SD)	At 12 months mean (SD)	Baseline mean (SD)	At 12 months mean (SD)
Calabrese 2015a	Over 18 years	882.75 (147.63)	891.69 (165.09)	871.18 (124.56)	879.47 (139.9)
Calabrese 2015b	14 to 18 years	949.23 (82.94)	955.34 (94.95)	1044.5 (65.53)	1049.12 (76.87)
	12 ‐ 13 years	506.12 (34.15)	527.39 (132.25)	679.24 (55.79)	705.55 (40.93)
	12 ‐ 13 years (parents)	634.93 (122.59)	643.06 (75.86)	975.34 (57.05)	959.79 (130.95)
	6 to 11 years	544.21 (127.59)	925.16 (104.95)	573.64 (103.19)	574.95 (107.73)
	6 to 11 years (parents)	771.79 (231.05)	779.59 (222.27)	745.23 (164.84)	767.59 (154.02)
GSH: glutathione SD: standard deviation

Table 5. CF Quality of life scores stratified according to age

Ir a la tabla de la revisión

Comparison 1. Oral antioxidants versus control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Lung function: FEV₁ (% predicted) (mean change from baseline) Show forest plot	8		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.1 At 2 months (combined supplement)	1	46	Mean Difference (IV, Random, 95% CI)	‐4.3 [‐5.64, ‐2.96]
1.2 At 3 months (NAC)	4	125	Mean Difference (IV, Random, 95% CI)	2.83 [‐2.16, 7.83]
1.3 at 4 months (multivitamins with antioxidants versus multivitamin alone	1	69	Mean Difference (IV, Random, 95% CI)	1.44 [‐2.23, 5.11]
1.4 At 6 months (NAC)	1	62	Mean Difference (IV, Random, 95% CI)	4.38 [0.89, 7.87]
1.5 At 6 months (GSH)	1	47	Mean Difference (IV, Random, 95% CI)	17.4 [13.97, 20.83]
1.6 At 6 months (β‐carotene)	1	24	Mean Difference (IV, Random, 95% CI)	0.9 [‐20.09, 21.89]
2 Lung function: FVC (% predicted) mean change from baseline Show forest plot	5		Mean Difference (IV, Random, 95% CI)	Subtotals only

2.1 At 2 months (combined supplement)	1	46	Mean Difference (IV, Random, 95% CI)	‐4.2 [‐11.28, 2.88]
2.2 At 3 months (NAC)	3	115	Mean Difference (IV, Random, 95% CI)	3.34 [‐4.30, 10.97]
2.3 At 6 months (NAC)	1	62	Mean Difference (IV, Random, 95% CI)	3.75 [‐0.13, 7.63]
2.4 At 6 months (GSH)	1	47	Mean Difference (IV, Random, 95% CI)	14.80 [10.07, 19.53]
3 QoL: Quality of Well Being Scale Show forest plot	2		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only

3.1 At 2 months (combined supplement)	1	46	Std. Mean Difference (IV, Random, 95% CI)	‐0.66 [‐1.26, ‐0.07]
3.2 at 3 months (NAC) CF‐Q respiratory domain scale	1	62	Std. Mean Difference (IV, Random, 95% CI)	0.33 [‐0.17, 0.83]
3.3 at 6 months (NAC) CF‐Q respiratory domain scale	1	61	Std. Mean Difference (IV, Random, 95% CI)	‐0.03 [‐0.53, 0.47]
4 Oxidative stress: lipid peroxidation (H₂O₂) (μmol/L) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

4.1 At 5 months (selenium)	1	27	Mean Difference (IV, Random, 95% CI)	15.90 [‐13.16, 44.96]
5 Oxidative stress: lipid peroxidation (F₂‐isoprostanes) (ng/L) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

5.1 At 2 months (combined supplement)	1	46	Mean Difference (IV, Random, 95% CI)	1.0 [‐23.94, 25.94]
6 Oxidative stress: lipid peroxidation (malondialdehyde) (μmol/L) mea difference to baseline) Show forest plot	2	51	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.45, 0.25]

6.1 At 5 months (selenium)	1	27	Mean Difference (IV, Random, 95% CI)	‐0.26 [‐0.67, 0.15]
6.2 At 6 months (β‐carotene)	1	24	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.38, 0.58]
7 Oxidative stress: urine 8‐iso‐PGF2α log 10 (pg/mL) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

7.1 At 4 months	1	69	Mean Difference (IV, Random, 95% CI)	0.09 [‐0.10, 0.28]
8 Oxidative stress: sputum 8‐iso‐PGF2α log10 (pg/mL) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

8.1 at 4 months	1	65	Mean Difference (IV, Random, 95% CI)	0.02 [‐0.12, 0.16]
9 Oxidative stress: sputum 8‐OHdG (log10) ng/ml Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

9.1 At 4 months	1	65	Mean Difference (IV, Random, 95% CI)	‐0.07 [‐0.24, 0.10]
10 Oxidative stress: enzyme function ‐ GPX (U/g Hb) Show forest plot	2	73	Mean Difference (IV, Random, 95% CI)	4.96 [‐3.26, 13.19]

10.1 At 2 months (combined supplement)	1	46	Mean Difference (IV, Random, 95% CI)	1.6 [0.30, 2.90]
10.2 At 5 months (selenium)	1	27	Mean Difference (IV, Random, 95% CI)	10.20 [2.22, 18.18]
11 Oxidative stress: enzyme function ‐ SOD (U/mg Hb) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

11.1 At 2 months (combined supplement)	1	46	Mean Difference (IV, Random, 95% CI)	0.27 [‐1.24, 1.78]
12 Oxidative stress: potency (TEAC) (mmol/L) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

12.1 At 6 months (β‐carotene)	1	24	Mean Difference (IV, Random, 95% CI)	0.04 [‐0.17, 0.25]
13 Plasma total antioxidant capacity (nmol) (change from baseline) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

13.1 At 3 months (β‐carotene)	1	24	Mean Difference (IV, Random, 95% CI)	0.1 [‐0.18, 0.38]
13.2 At 6 months (β‐carotene)	1	24	Mean Difference (IV, Random, 95% CI)	0.04 [‐0.30, 0.38]
14 Plasma total antioxidant capacity (log10) (CRE) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

14.1 At 1 month	1	66	Mean Difference (IV, Random, 95% CI)	0.0 [‐0.02, 0.02]
14.2 At 4 months	1	72	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.04, 0.02]
15 Plasma antioxidant status: vitamin E (μmol/L) Show forest plot	5		Mean Difference (IV, Random, 95% CI)	Subtotals only

15.1 At 1 month (water‐miscible vitamin E)	1	18	Mean Difference (IV, Random, 95% CI)	26.7 [15.90, 37.50]
15.2 At 1 month (fat‐soluble vitamin E)	1	19	Mean Difference (IV, Random, 95% CI)	13.47 [9.05, 17.89]
15.3 At 1 month (antioxidant‐enriched multivitamin)	1	66	Mean Difference (IV, Random, 95% CI)	‐3.48 [‐8.01, 1.05]
15.4 At 2 months (water‐miscible vitamin E and combined supplement	2	83	Mean Difference (IV, Random, 95% CI)	10.65 [6.53, 14.77]
15.5 at 4 month (antioxidant ‐enriched multivitamin)	1	72	Mean Difference (IV, Random, 95% CI)	‐1.86 [‐6.36, 2.64]
15.6 At 6 months (water‐miscible vitamin E)	1	33	Mean Difference (IV, Random, 95% CI)	19.73 [12.48, 26.98]
15.7 At 6 months (oral GSH)	1	44	Mean Difference (IV, Random, 95% CI)	4.26 [2.03, 6.49]
16 Plasma antioxidant status: β‐carotene (μmol/L) Show forest plot	2	70	Mean Difference (IV, Random, 95% CI)	0.13 [0.02, 0.25]

16.1 At 2 months (combined supplement)	1	46	Mean Difference (IV, Random, 95% CI)	0.1 [0.02, 0.18]
16.2 At 6 months (β‐carotene)	1	24	Mean Difference (IV, Random, 95% CI)	0.24 [0.02, 0.46]
17 Plasma antioxidant status: selenium (μmol/L) Show forest plot	2	73	Mean Difference (IV, Random, 95% CI)	0.48 [0.27, 0.68]

17.1 At 2 months (combined supplement)	1	46	Mean Difference (IV, Random, 95% CI)	0.6 [0.39, 0.81]
17.2 At 5 months (selenium)	1	27	Mean Difference (IV, Random, 95% CI)	0.39 [0.27, 0.51]
18 Plasma antioxidant status: vitamin C (μmol/L) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

18.1 At 2 months (combined supplement)	1	46	Mean Difference (IV, Random, 95% CI)	8.0 [‐15.05, 31.05]
19 Plasma antioxidant status: whole blood GSH (μmol/L) (change from baseline) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

19.1 at 3 months	1	61	Mean Difference (IV, Random, 95% CI)	19.00 [‐183.58, 221.58]
19.2 at 6 months	1	60	Mean Difference (IV, Random, 95% CI)	64.10 [‐170.05, 298.25]
20 Plasma antioxidant status: plasma fatty acid status (mg/L) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

20.1 At 2 months (combined supplement)	1	46	Mean Difference (IV, Random, 95% CI)	166.0 [‐61.38, 393.38]
21 Plasma inflammation: IL‐6 (pg/mL) at 3 months (vitamin E) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

21.1 FEV1 > 85% and no DNase	1	12	Mean Difference (IV, Random, 95% CI)	‐2.02 [‐4.63, 0.59]
21.2 FEV1 > 85% and DNase	1	9	Mean Difference (IV, Random, 95% CI)	‐0.31 [‐4.03, 3.41]
21.3 FEV1 range 70% ‐ 85% and DNase	1	11	Mean Difference (IV, Random, 95% CI)	‐0.24 [‐3.80, 3.32]
22 Plasma inflammation: TNF‐α (pg/mL) at 3 months (vitamin E) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

22.1 FEV1 > 85% and no DNase	1	12	Mean Difference (IV, Random, 95% CI)	‐1.37 [‐3.61, 0.87]
22.2 FEV1 > 85% and DNase	1	14	Mean Difference (IV, Random, 95% CI)	0.33 [‐0.49, 1.15]
22.3 FEV1 range 70% ‐ 85% and DNase	1	11	Mean Difference (IV, Random, 95% CI)	‐0.94 [‐1.61, ‐0.26]
23 Plasma IL‐8 pg/mL (log 10) (change from baseline) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

23.1 At 3 months	1	61	Mean Difference (IV, Random, 95% CI)	0.01 [‐0.19, 0.21]
23.2 At 6 months	1	56	Mean Difference (IV, Random, 95% CI)	‐0.09 [‐0.32, 0.14]
24 Sputum IL‐8 pg/ml (log 10) (per volume) Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

24.1 At 3 months (NAC)	2	92	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.15, 0.14]
24.2 At 4 months ( antioxidant enriched vitamins)	1	65	Mean Difference (IV, Random, 95% CI)	‐0.06 [‐0.24, 0.12]
24.3 At 6 months (NAC)	1	56	Mean Difference (IV, Random, 95% CI)	0.19 [‐0.03, 0.41]
25 Sputum human neutrophil elastase (log 10) (mg/mg) per weight (change from baseline) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

25.1 At 3 months	1	61	Mean Difference (IV, Random, 95% CI)	‐0.04 [‐0.24, 0.16]
25.2 At 6 months	1	56	Mean Difference (IV, Random, 95% CI)	0.11 [‐0.11, 0.33]
26 Sputum neutrophil count (logarithm) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

26.1 at 3 months	1	63	Mean Difference (IV, Random, 95% CI)	1.90 [‐8.08, 11.88]
26.2 at 6 months	1	61	Mean Difference (IV, Random, 95% CI)	2.60 [‐11.85, 17.05]
27 Sputum myeloperoxidase (MPO) levels (log 10) (ng/mL) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

27.1 At 4 months (multivitamins with antioxidants versus multivitamin alone	1	65	Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.48, 0.22]
28 Nutritional status: BMI (change from baseline) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

28.1 At 3 months (NAC)	1	64	Mean Difference (IV, Random, 95% CI)	0.30 [‐0.02, 0.62]
28.2 At 6 months (NAC)	1	62	Mean Difference (IV, Random, 95% CI)	0.2 [‐0.23, 0.63]
29 Nutritional status: BMI percentile (change from baseline) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

29.1 At 3 months (GSH)	1	40	Mean Difference (IV, Random, 95% CI)	9.2 [6.22, 12.18]
29.2 At 6 months (GSH)	1	40	Mean Difference (IV, Random, 95% CI)	17.20 [14.35, 20.05]
30 Nutritional status: weight (kg) (change from baseline) Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

30.1 At 3 months (NAC)	2	84	Mean Difference (IV, Random, 95% CI)	0.24 [‐0.73, 1.22]
30.2 At 6 months (NAC)	1	62	Mean Difference (IV, Random, 95% CI)	0.60 [‐0.51, 1.71]
30.3 At 6 months (water‐miscible vitamin E)	1	36	Mean Difference (IV, Random, 95% CI)	‐0.30 [‐7.19, 6.59]
31 Nutritional status: weight percentile (change from baseline) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

31.1 At 3 months (GSH)	1	44	Mean Difference (IV, Random, 95% CI)	8.1 [5.64, 10.56]
31.2 At 6 months (GSH)	1	44	Mean Difference (IV, Random, 95% CI)	17.0 [14.64, 19.36]
32 Antibiotic days per participant Show forest plot	2	70	Mean Difference (IV, Random, 95% CI)	‐4.28 [‐15.16, 6.60]

32.1 At 2 months (combined supplement)	1	46	Mean Difference (IV, Random, 95% CI)	4.0 [‐14.06, 22.06]
32.2 At 6 months (β‐carotene)	1	24	Mean Difference (IV, Random, 95% CI)	‐8.0 [‐18.78, 2.78]
33 Number of participants with at least one exacerbation Show forest plot	2	143	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.59, 1.09]

33.1 At 4 months (multivitamins with antioxidants versus multivitamin alone	1	73	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.53, 1.14]
33.2 At 6 months (NAC)	1	70	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.50, 1.39]
34 Number of hospitalizations Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

34.1 At 6 months (NAC)	1	70	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.49, 1.81]
35 Adverse effects Show forest plot	3		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only

35.1 Sinusitis	3	181	Odds Ratio (M‐H, Random, 95% CI)	1.58 [0.38, 6.55]
35.2 Distal intestinal obstruction syndrome	3	181	Odds Ratio (M‐H, Random, 95% CI)	0.47 [0.09, 2.34]
35.3 Diahorrea	3	181	Odds Ratio (M‐H, Random, 95% CI)	1.76 [0.58, 5.32]
35.4 Pulmonary exacerbations	2	111	Odds Ratio (M‐H, Random, 95% CI)	0.57 [0.23, 1.41]
35.5 Elevated liver enzymes (ALT)	2	108	Odds Ratio (M‐H, Random, 95% CI)	3.04 [0.31, 30.19]

Comparison 1. Oral antioxidants versus control

Ir a la tabla de la revisión

Comparison 2. Inhaled antioxidant (glutathione) versus control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Lung function: FEV₁ (L) (change from baseline) Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.1 At 1 month	3	258	Mean Difference (IV, Random, 95% CI)	0.05 [‐0.01, 0.11]
1.2 At 3 months	3	258	Mean Difference (IV, Random, 95% CI)	0.09 [0.03, 0.15]
1.3 At 6 months	3	258	Mean Difference (IV, Random, 95% CI)	0.07 [0.00, 0.14]
1.4 At 9 months	2	105	Mean Difference (IV, Random, 95% CI)	0.03 [‐0.14, 0.20]
1.5 At 12 months	2	105	Mean Difference (IV, Random, 95% CI)	‐0.00 [‐0.13, 0.12]
2 Lung function: FEV₁ (% predicted) (change from baseline) Show forest plot	4		Mean Difference (IV, Random, 95% CI)	Subtotals only

2.1 At 1 month	3	258	Mean Difference (IV, Random, 95% CI)	1.91 [‐0.07, 3.88]
2.2 At 2 months	1	16	Mean Difference (IV, Random, 95% CI)	0.90 [‐6.45, 8.25]
2.3 At 3 months	3	258	Mean Difference (IV, Random, 95% CI)	3.50 [1.38, 5.62]
2.4 At 6 months	3	258	Mean Difference (IV, Random, 95% CI)	2.30 [‐0.12, 4.71]
2.5 At 9 months	2	105	Mean Difference (IV, Random, 95% CI)	2.52 [‐4.61, 9.65]
2.6 At 12 months	2	105	Mean Difference (IV, Random, 95% CI)	2.96 [‐2.54, 8.46]
3 Lung function FVC (L) (change from baseline) Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

3.1 At 1 month	3	258	Mean Difference (IV, Random, 95% CI)	0.05 [‐0.01, 0.12]
3.2 At 3 months	3	258	Mean Difference (IV, Random, 95% CI)	0.08 [0.01, 0.16]
3.3 At 6 months	3	258	Mean Difference (IV, Random, 95% CI)	0.05 [‐0.03, 0.13]
3.4 At 9 months	2	105	Mean Difference (IV, Random, 95% CI)	0.01 [‐0.17, 0.19]
3.5 At 12 months	2	105	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.10, 0.09]
4 Lung function FVC (% predicted) (change from baseline) Show forest plot	4		Mean Difference (IV, Random, 95% CI)	Subtotals only

4.1 At 1 month	3	258	Mean Difference (IV, Random, 95% CI)	2.12 [‐0.23, 4.47]
4.2 At 2 months	1	16	Mean Difference (IV, Random, 95% CI)	0.60 [‐6.53, 7.73]
4.3 At 3 months	3	258	Mean Difference (IV, Random, 95% CI)	3.60 [1.33, 5.88]
4.4 At 6 months	3	258	Mean Difference (IV, Random, 95% CI)	3.33 [‐0.62, 7.27]
4.5 At 9 months	2	105	Mean Difference (IV, Random, 95% CI)	5.48 [‐1.76, 12.73]
4.6 At 12 months	2	105	Mean Difference (IV, Random, 95% CI)	4.27 [‐0.00, 8.54]
5 QoL total score (change from baseline) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

5.1 at 1 month	1	153	Mean Difference (IV, Random, 95% CI)	2.2 [‐0.23, 4.63]
5.2 at 3 months	1	153	Mean Difference (IV, Random, 95% CI)	1.20 [‐1.46, 3.86]
5.3 at 6 months	1	153	Mean Difference (IV, Random, 95% CI)	0.8 [‐1.63, 3.23]
6 QoL respiratory score (change from baseline) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

6.1 at 1 month	1	153	Mean Difference (IV, Random, 95% CI)	2.7 [‐2.15, 7.55]
6.2 at 3 months	1	153	Mean Difference (IV, Random, 95% CI)	‐0.5 [‐4.80, 3.80]
6.3 at 6 months	1	153	Mean Difference (IV, Random, 95% CI)	‐3.3 [‐8.05, 1.45]
7 Oxidative stress markers in exhaled breath condensate: H₂O₂ (μM) Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

7.1 At 12 months	2	105	Mean Difference (IV, Random, 95% CI)	‐0.16 [‐0.40, 0.09]
8 Sputum oxidative stress: lipid peroxidation (8‐isoprostan) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

8.1 At 3 months	1	42	Mean Difference (IV, Random, 95% CI)	‐51.3 [‐128.22, 25.62]
8.2 At 6 months	1	42	Mean Difference (IV, Random, 95% CI)	‐5.6 [‐95.70, 84.50]
9 Sputum antioxidant status: free glutathione in sputum (pM) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

9.1 At 1 month	1	55	Mean Difference (IV, Random, 95% CI)	131.3 [‐36.81, 299.41]
9.2 At 3 months	1	47	Mean Difference (IV, Random, 95% CI)	81.4 [‐8.01, 170.81]
9.3 At 6 months	1	50	Mean Difference (IV, Random, 95% CI)	59.1 [3.68, 114.52]
10 Sputum antioxidant status: total glutathione in sputum (pM) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

10.1 At 1 month	1	54	Mean Difference (IV, Random, 95% CI)	405.3 [105.27, 705.33]
10.2 At 3 months	1	48	Mean Difference (IV, Random, 95% CI)	329.2 [167.04, 491.36]
10.3 At 6 months	1	50	Mean Difference (IV, Random, 95% CI)	273.5 [‐19.52, 566.52]
11 Sputum antioxidant status: glutathione in sputum neutrophils (MFI) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

11.1 At 1 month	1	14	Mean Difference (IV, Random, 95% CI)	0.8 [‐0.06, 1.66]
11.2 At 3 months	1	15	Mean Difference (IV, Random, 95% CI)	3.70 [0.27, 7.13]
11.3 At 6 months	1	16	Mean Difference (IV, Random, 95% CI)	4.4 [1.52, 7.28]
12 Plasma antioxidant status: free glutathione (pM) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

12.1 At 6 months	1	57	Mean Difference (IV, Random, 95% CI)	2.20 [‐1.44, 5.84]
13 Plasma antioxidant status: total glutathione (pM) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

13.1 At 6 months	1	57	Mean Difference (IV, Random, 95% CI)	0.8 [‐2.07, 3.67]
14 Plasma antioxidant status: glutathione in blood neutrophils (MFI) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

14.1 At 6 months	1	13	Mean Difference (IV, Random, 95% CI)	‐2.9 [‐12.39, 6.59]
15 Sputum oxidative stress: protein carbonyls (U) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

15.1 At 1 month	1	49	Mean Difference (IV, Random, 95% CI)	4.20 [‐7.92, 16.32]
15.2 At 3 months	1	44	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐13.20, 13.00]
15.3 At 6 months	1	41	Mean Difference (IV, Random, 95% CI)	10.70 [‐2.63, 24.03]
16 Local inflammation: cytokines in sputum IL‐8 (pg/mL) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

16.1 At 6 months	1	53	Mean Difference (IV, Random, 95% CI)	‐478.3 [‐1536.75, 580.15]
17 Local inflammation: cytokines in sputum IL‐10 (pg/mL) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

17.1 At 6 months	1	53	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐10.12, 9.72]
18 Local inflammation: cytokines in sputum TNF‐α (pg/mL) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

18.1 At 6 months	1	53	Mean Difference (IV, Random, 95% CI)	19.8 [‐50.33, 89.93]
19 Nutritional status: BMI (change from baseline) Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

19.1 At 2 months	1	16	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.74, 0.94]
19.2 At 12 months	2	105	Mean Difference (IV, Random, 95% CI)	0.04 [‐8.20, 8.27]
20 Nutritional status: weight (kg) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

20.1 At 1 month	1	153	Mean Difference (IV, Random, 95% CI)	0.1 [‐0.23, 0.43]
20.2 At 3 months	1	153	Mean Difference (IV, Random, 95% CI)	1.0 [0.39, 1.61]
20.3 At 6 months	1	153	Mean Difference (IV, Random, 95% CI)	0.30 [‐0.37, 0.97]
21 Number of pulmonary exacerbations during the study Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

21.1 At 6 months	1	153	Mean Difference (IV, Random, 95% CI)	‐0.09 [‐0.30, 0.12]
21.2 At 12 months	2	105	Mean Difference (IV, Random, 95% CI)	‐0.18 [‐0.60, 0.23]
22 Time to first pulmonary exacerbation (days) Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

22.1 At 12 months	2	105	Mean Difference (IV, Random, 95% CI)	‐6.74 [‐48.76, 35.27]
23 Adverse events Show forest plot	4		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

23.1 Hospitalization for non‐acute pulmonary exacerbations	1	19	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.42 [0.04, 4.63]
23.2 Rhinitis/sinusitis or upper respiratory tract infection	3	223	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.04 [0.43, 2.55]
23.3 Cough	2	172	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.14 [0.63, 2.08]
23.4 Pharyngitis	2	172	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.12 [0.61, 2.06]
23.5 Stomach pain/cramps	2	70	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.71 [0.19, 2.56]
23.6 Headache	3	223	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.08 [0.55, 2.13]
23.7 Chest tightness/bronchospasm	2	70	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.41 [0.08, 2.28]
23.8 Nose bleed	2	70	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.31 [0.06, 1.59]
23.9 Shortness of breath	1	19	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.42 [0.04, 4.63]
23.10 Sputum increase	1	153	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.13 [0.55, 2.32]
23.11 Pyrexia	1	153	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.76 [0.69, 4.49]
23.12 Haemoptysis	3	258	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.94 [0.49, 1.79]
23.13 Lung disorder	1	153	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.98 [0.38, 2.57]
23.14 Sputum abnormal	1	153	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.59 [0.61, 4.14]
23.15 Infection	1	153	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.42 [0.53, 3.80]
23.16 Rales	1	153	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.11 [0.39, 3.11]
23.17 Oropharyngeal pain	1	153	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.48 [0.17, 1.35]
23.18 Condition aggravated	1	153	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.06 [0.52, 2.16]
23.19 Pancreatitis	1	51	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.12 [0.00, 6.06]
23.20 Constipation	1	51	Peto Odds Ratio (Peto, Fixed, 95% CI)	6.61 [0.13, 335.50]
23.21 Pityriasis	1	51	Peto Odds Ratio (Peto, Fixed, 95% CI)	6.61 [0.13, 335.50]
23.22 Impaired glucose tolerance	1	51	Peto Odds Ratio (Peto, Fixed, 95% CI)	6.61 [0.13, 335.50]
23.23 Distal intestinal obstruction	2	105	Peto Odds Ratio (Peto, Fixed, 95% CI)	6.14 [0.62, 60.94]

Comparison 2. Inhaled antioxidant (glutathione) versus control

Ir a la tabla de la revisión

The Cochrane Library

Scolaris Language Selector Scolaris Language Selector

Idioma de la Revisión Cochrane

Idioma de la web

Scolaris Content Language Banner Portlet Scolaris Content Language Banner Portlet

Scolaris Content Display Scolaris Content Display

Temas

Scolaris Language Selector Scolaris Language Selector

Scolaris Content Display Scolaris Content Display

Instituciones a las que se accedió previamente

Scolaris Content Display Scolaris Content Display

Usuarios institucionales

Instituciones a las que se accedió previamente

Otras opciones de acceso

	Idioma de la Revisión Cochrane Escoja su idioma de preferencia para las revisiones Cochrane y otros contenidos. Las secciones sin una traducción aparecerán en inglés.

	Idioma de la web Escoja su idioma de preferencia para la web de la Biblioteca Cochrane.

Idioma de la Revisión Cochrane

Idioma de la web

Contenido relacionado

Revisiones y protocolos relacionados

Temas

Copiar o descargar referencia

Idioma de la Revisión Cochrane

Idioma de la web

Instituciones a las que se accedió previamente

Usuarios institucionales

Instituciones a las que se accedió previamente

Otras opciones de acceso