0
Original Research: COPD |

High-Dose N-Acetylcysteine in Stable COPDEffect of High-dose N-Acetylcysteine in COPD: The 1-Year, Double-Blind, Randomized, Placebo-Controlled HIACE Study FREE TO VIEW

Hoi Nam Tse, MBChB, FCCP; Luca Raiteri, MD; King Ying Wong, MBBS; Kwok Sang Yee, MBBS; Lai Yun Ng, MBChB; Ka Yan Wai, MBBS; Ching Kong Loo, MBBS; Ming Houng Chan, MBBS
Author and Funding Information

From the Kwong Wah Hospital (Drs Tse, Ng, Wai, Loo, and Chan), Hong Kong, China; Wong Tai Sin Hospital (Drs Wong and Yee), Hong Kong, China; and Medical Department (Dr Raiteri), Innovation & Medical Sciences, Zambon Company SpA, Bresso, Italy.

Correspondence to: Hoi Nam Tse, MBChB, FCCP, Medical and Geriatric Department, Kwong Wah Hospital, Waterloo Road, Yau Ma Tei, Hong Kong, China; e-mail: drhoinam@gmail.com


Funding/Support: The study was sponsored by the Tung Wah Group of Hospitals Research Fund. Both the N-acetylcysteine and placebo used in this study were manufactured by Zambon Switzerland Ltd and provided by Zambon S.p.A, Bresso, Italy.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;144(1):106-118. doi:10.1378/chest.12-2357
Text Size: A A A
Published online

Background:  The mucolytic and antioxidant effects of N-acetylcysteine (NAC) may have great value in COPD treatment. However, beneficial effects have not been confirmed in clinical studies, possibly due to insufficient NAC doses and/or inadequate outcome parameters used. The objective of this study was to investigate high-dose NAC plus usual therapy in Chinese patients with stable COPD.

Methods:  The 1-year HIACE (The Effect of High Dose N-acetylcysteine on Air Trapping and Airway Resistance of Chronic Obstructive Pulmonary Disease—a Double-blinded, Randomized, Placebo-controlled Trial) double-blind trial conducted in Kwong Wah Hospital, Hong Kong, randomized eligible patients aged 50 to 80 years with stable COPD to NAC 600 mg bid or placebo after 4-week run-in. Lung function parameters, symptoms, modified Medical Research Council (mMRC) dyspnea and St. George’s Respiratory Questionnaire (SGRQ) scores, 6-min walking distance (6MWD), and exacerbation and admission rates were measured at baseline and every 16 weeks for 1 year.

Results:  Of 133 patients screened, 120 were eligible (93.2% men; mean age, 70.8 ± 0.74 years; %FEV1 53.9 ± 2.0%). Baseline characteristics were similar in the two groups. At 1 year, there was a significant improvement in forced expiratory flow 25% to 75% (P = .037) and forced oscillation technique, a significant reduction in exacerbation frequency (0.96 times/y vs 1.71 times/y, P = .019), and a tendency toward reduction in admission rate (0.5 times/y vs 0.8 times/y, P = .196) with NAC vs placebo. There were no significant between-group differences in mMRC dypsnea score, SGRQ score, and 6MWD. No major adverse effects were reported.

Conclusion:  In this study, 1-year treatment with high-dose NAC resulted in significantly improved small airways function and decreased exacerbation frequency in patients with stable COPD.

Trial registry:  ClinicalTrials.gov; No.: NCT01136239; URL: www.clinicaltrials.gov

Figures in this Article

The imbalance of oxidant/antioxidant agents (redox balance) plays an important role in COPD pathogenesis. Inhaled cigarette smoke, the main exogenous source of oxidative stress in COPD, stimulates elastase activity and induces apoptosis, resulting in lung damage and emphysema.1 In addition, oxidants also activate redox-sensitive transcription factors and signal transduction, and initiate expression of proinflammatory genes, resulting in significant pulmonary and systemic inflammation.2

Oral N-acetylcysteine (NAC) is a mucolytic agent with direct/indirect antioxidant and antiinflammatory properties that may be beneficial in COPD.3 NAC acts directly as a reactive oxygen species scavenger and acts as a precursor of reduced glutathione (GSH). NAC restores cellular redox status and modulates the inflammatory pathway in COPD by inhibiting redox-sensitive cell-signal transduction and proinflammatory gene expression.46

However, in previous studies, the clinical effects of regular NAC doses in patients with chronic bronchitis and COPD have been inconsistent. Systematic reviews7,8 showed that NAC could reduce COPD exacerbations vs placebo. Conversely, the BRONCUS9 (Bronchitis Randomized on NAC Cost-Utility Study) randomized, double-blind, placebo-controlled, 3-year study failed to demonstrate the beneficial effect of NAC on FEV1 and exacerbation frequency. The inconsistency of results obtained with NAC in COPD may be attributed to the NAC dose used (≤ 600 mg daily)3 and/or the use of inappropriate outcome parameters like FEV1, an insensitive marker for small airways disease and air trapping, having low correlation with patient-centered outcomes like dyspnea and exercise capacity.10

To study the potential, dose-related, antioxidant and antiinflammatory effects of NAC in COPD and on lung function, our study used higher NAC doses and more-sensitive outcome measurements for small airways function such as forced expiratory flow at 25% to 75% FVC (FEF25%-75%) and forced oscillation technique (FOT). Both are simple, noninvasive tools for assessing small airways function. FEF25%-75% is a low-cost technique11,12 measuring average flow at the midportion of lung volume; FOT is a convenient tool for measuring respiratory mechanics (resistance and reactance) by applying external oscillatory pressure during tidal breathing.13 In contrast to traditional spirometry (like FEV1), which predominantly identifies airflow limitations in large airways, FOT can differentiate airflow in small and large airways by varying oscillation frequency (multifrequency FOT).13,14 It addition, FOT has been demonstrated to be more sensitive to therapeutic intervention than spirometry.15 To our knowledge, this is the first study performed in Chinese patients with stable COPD to investigate the effect of 1-year, high-dose NAC treatment (600 mg bid) using FOT to assess small airways function.

Study Design and Methods

This 1-year, double-blind, randomized, placebo-controlled trial (the HIACE study [The Effect of High Dose N-acetylcysteine on Air Trapping and Airway Resistance of Chronic Obstructive Pulmonary disease—a Double-Blinded, Randomized, Placebo-Controlled Trial]) was conducted in Kwong Wah Hospital, Hong Kong.16 The study was approved by the Kowloon-West-Cluster Clinical Research Ethical Committee, Hospital Authority, Hong Kong (KWC-REC reference: KW/EX-09-140).

Patients were recruited from the COPD clinic from March 1, 2010, to February 28, 2011. Subjects aged 50 to 80 years, with stable COPD and postbronchodilator spirometry FEV1/FVC ratio < 0.7 were included in the study. Patients were excluded if they had coexisting pulmonary diseases, such as interstitial lung or active infectious diseases (eg, TB), if they refused to participate or failed to cooperate, or if dyspnea severity prevented lung function testing. Patients on long-term bilevel pressure ventilation or long-term oxygen therapy with chronic respiratory failure were also excluded.

Eligible patients experiencing an acute exacerbation were treated appropriately and they were recruited 4 weeks after remission of their exacerbation. All eligible patients with COPD gave their written informed consent and underwent a 4-week run-in period before randomization. Usual mucolytic treatments, if any, were stopped in the 4-week run-in period. Patients who were noncompliant or refused to participate were excluded. The design of the study is illustrated in Figure 1.

Figure Jump LinkFigure 1. Flowchart of the study design. CVA = cerebrovascular accident; FU = follow-up; NAC = N-acetylcysteine.Grahic Jump Location
Randomization and Blinding

After the 4-week run-in period, eligible patients with COPD were randomly allocated to NAC 600 mg bid or placebo. For blinding, NAC and placebo were identical in appearance (a 600-mg effervescent tablet). Patients and investigators were blinded to treatment allocation during the study. Randomization and allocation details were known only to a third party. Recruited subjects were managed by their physicians in the usual manner, with NAC or placebo prescribed in addition to usual drug treatment according to GOLD (Global Initiative for Obstructive Lung Disease) guidelines.17

Outcome Measures

The investigators monitored patient progress, examining them every 16 weeks at an outpatient clinic. Primary outcome measurements were small airways function parameters: FEF25%-75% and FOT parameters. Other spirometric parameters, including inspiratory capacity (IC), FEV1, and FVC were also measured.

Secondary outcome measurements included COPD exacerbation rate (as defined by two of the following three symptoms: increase in shortness of breath, volume, or purulence of sputum), hospitalization rate due to COPD exacerbations, dyspnea (modified Medical Research Council [mMRC] dyspnea scale), and quality of life (St. George’s Respiratory Questionnaire [SGRQ]). Permission was obtained for the use of SGRQ in the study.

At baseline, information such as demographic characteristics (age, sex), current medications, and medical comorbidities was collected by questionnaire. mMRC dypsnea score, lung function tests, SGRQ score, and 6-min walking distance (6MWD) results were also recorded.

Symptoms were recorded at each follow-up visit (every 16 weeks). The physician checked compliance to treatment by counting the number of returned tablets. Good compliance to treatment was defined as the consumption of > 70% of dispensed medication. Adverse drug effects, exacerbation episodes, and recent changes in current medications were recorded at follow-up visits. Lung function tests, such as spirometry, FOT, SGRQ score, and 6MWD, were measured at 0, 16, and 52 weeks.

Lung Function Tests

Spirometry and FOT were used to monitor lung function during the study. Both spirometry and FOT tests were performed by trained specialist nurses.

Spirometry:

Spirometry was performed using a Spirobank-G (Medical International Research USA Inc). Spirometric data (FEV1, FVC, FEV1/FVC ratio, %FEV1, FEF25%-75%, and IC) were measured according to American Thoracic Society standards for lung function tests.18 Chinese spirometric reference values were used.19

Both spirometry and plethysmography (MedGraphics Elite Series Plethsmograph; Medical Graphics Corp) were used to measure baseline lung function. Comparisons of lung function measured using spirometry and plethysmography (FEV1, FVC, FEF25%-75%, and IC) were performed using a correlation test and a Bland and Altman plot to validate Spirobank-G use for lung function assessment in the whole study.

Forced Oscillation Technique:

FOT was performed using the i2m (Chess mt NV) with a nose clip and mouthpiece to stabilize patients’ tongue position. Respiratory mechanics were measured using multifrequency (4-48 Hz), pseudorandomized noise impulses with the patient in sitting position and cheeks supported by both hands to reduce airway shunting. The machine was calibrated before each test, which was performed by a trained respiratory nurse according to European Respiratory Society Task Force recommendations.20 Only values with a minimal coherence function of 95% were considered valid. The mean of three valid measurements was calculated. FOT parameters used were frequency resonance (FRes), the frequency at which reactance equals zero, frequency dependence (FDep), the slope of resistance vs oscillation-frequency, resistance at 6 Hz, and reactance at 6 Hz.

Statistical Methods

Sample size was calculated on the assumption that 20% improvement in FOT parameters (reactance and resistance) would be detected with NAC vs placebo, with an α error of 0.05, and study power of 0.8. Reactance and resistance SDs from a previous trial21 were used as a reference. A minimal sample size of 86 patients was adopted in our study.

Statistical analysis was performed using SPSS, version 20.0 (IBM). Data were expressed as mean ± SEM unless otherwise stated; all hypothesis tests were two-sided; P < .05 was considered significant. Comparison of variables between study groups at baseline was made using the Student t test or χ2 test, as appropriate. Changes in lung function variables and other continuous parameters were analyzed by a paired t test and repeated measurement analysis of variance was used to detect any significant differences between the two groups in the change in lung function parameters at different time points.

Study Population

Of 133 eligible patients with COPD who were recruited, 13 were excluded in the run-in period (Fig 1): Eight subjects withdrew consent, four were lost to follow-up, and one refused lung function testing. Of the remaining 120 subjects, 58 were allocated to high-dose NAC and 62 to placebo. During the 1-year follow-up, 12 subjects were lost to follow-up and 108 patients completed the study (NAC, n = 52; placebo, n = 56).

Baseline Characteristics of the Study Subjects

Demographic characteristics of study subjects are summarized in Table 1; there were no significant differences between treatment and placebo groups at baseline. The frequencies of COPD exacerbation and admissions in the previous year were also similar in the two groups. The majority of the subjects were elderly, male exsmokers with moderate to severe COPD (Table 1, 2). Similar proportions of subjects were receiving inhaled corticosteroids, long-acting muscarinic agonists, and combined inhaled corticosteroids and long-acting β agonists in both groups.

Table Graphic Jump Location
Table 1 —Baseline Demographic Characteristics of Subjects With COPD in NAC and Placebo Groups

Data given as % (actual proportion) unless otherwise indicated. GOLD = Global Initiative for Obstructive Lung Disease; ICS = inhaled corticosteroid; LABA = long-acting β agonist; LAMA = long-acting muscarinic agonist; mMRC = modified Medical Research Council; NAC = N-acetylcysteine; NS = not statistically significant; SABA = short-acting β2 agonist; SAMA = short-acting muscarinic agonist.

a 

Lung function parameters were measured by plethysmography.

Table Graphic Jump Location
Table 2 —Baseline Lung Function Parameters of Subjects With COPD in NAC and Placebo Groups

Data given as mean±SEM unless otherwise indicated. BD = bronchodilator; FEF25%-75% = forced expiratory flow 25-75%; IC = inspiratory capacity; RV = residual volume; TLC = total lung capacity. See Table 1 legend for expansion of other abbreviations.

Follow-up Visit
Lung Function Tests:

Spirometry (Spirobank-G)—Results from the Bland and Altman plot were satisfactory for FEV1, FVC, FEF25%-75%, and IC. There was also an excellent linear correlation between spirometry and plethysmography measurements for FEV1, FVC, and FEF25%-75% (R2 > 0.9); the linear correlation relationship between spirometry and plethysmography for IC was fair (R2 0.55).

There were no significant differences in FEF25%-75% between study groups at baseline. During 1-year follow-up, there was a significant improvement in FEF25%-75% with NAC (from 0.72 ± 0.07 L/s to 0.80 ± 0.07 L/s) while FEF25%-75% remained static with placebo (from 0.679 ± 0.07 L/s to 0.677 ± 0.07 L/s) (repeated measurement analysis of variance test, P = .037) (Fig 2A). As shown in Figure 2B, there was a significantly greater increase in FEF25%-75% from baseline in the NAC group at both 16 weeks (+0.08 L [11.6%] vs +0.008 L [1.2%]) and 52 weeks (+0.08 L [11.6%] vs −0.002 L [−2.9%]), compared with placebo. There were no significant differences for changes in other spirometric parameters (FEV1, FVC, and IC) between NAC and placebo during the study period (Table 3).

Figure Jump LinkFigure 2. A, The trend of FEF25-75% (L/s) in both NAC and placebo groups over a 1-year period. B, Mean changes in FEF25-75% (L/s) compared with baseline in both NAC and placebo groups at 16 weeks and 52 weeks. FEF25-75% = forced expiratory flow 25% to 75%. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location
Table Graphic Jump Location
Table 3 —Changes From Baseline in Lung Function Parameters (by Spirometry) at 16 and 52 Wk in NAC and Placebo Groups

See Table 1 and 2 legends for expansion of abbreviations.

a 

Statistically significant value (P ≤ .05).

FOT—

Over 1 year, reactance improved significantly with NAC vs placebo: Reactance at 6 Hz improved with NAC, whereas it deteriorated with placebo (+0.48 [+22.3%] vs −0.22 [−10.7%]; P = .04), and FRes was significantly reduced with NAC vs placebo (−5.86 [−21.7%] vs −1.03 [−3.7%]; P = .02) (Fig 3).

Figure Jump LinkFigure 3. A-D, The trend and change in forced oscillation technique (FOT) parameters over 1 y in both the NAC and placebo groups. Figures show changes in (A) Fres (P = .02), (B) FDep (P = .01), (C) reactance at 6 Hz (P = .04), and (D) resistance at 6 Hz (P = .09). *P < .05. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location

NAC also provided significant improvement in resistance: FDep improved (decrease in negativity) with NAC and deteriorated (increase in negativity) with placebo (+0.02 [+25.3%] vs −0.04 [−58.3%]; P = .01). There was also a tendency toward reduction in resistance at 6 Hz with NAC vs placebo, although this did not reach statistical significance (−0.29 [−7.4%] vs +0.204 [+5%]; P = .09) (Fig 3).

Frequency of COPD Exacerbations:

Of 146 COPD exacerbations recorded during the study, 50 occurred with NAC and 96 occurred with placebo. The mean frequency of COPD exacerbations with NAC was significantly lower than placebo (reduction rate, 0.75) during the year (NAC 0.96/y vs placebo 1.71/y; P = .019) (Fig 4). Moreover, there was a higher proportion of exacerbation-free patients with NAC at the end of the study vs placebo (53.8% vs 37.5%), although this did not reach statistical significance (P = .088) (Fig 5).

Figure Jump LinkFigure 4. Frequency of COPD exacerbations in NAC and placebo groups in the 1-year follow-up period. *P < .05. See Figure 1 legend for expansion of abbreviation.Grahic Jump Location
Figure Jump LinkFigure 5. Percentage of patients who were exacerbation-free at the end of study.Grahic Jump Location
Frequency of Admissions Due to COPD Exacerbation:

Similar results were observed for admissions due to COPD exacerbation during the study period, although this did not reach statistical significance: 71 admissions (26 episodes with NAC and 45 with placebo). NAC had a lower mean COPD admission frequency (NAC 0.5/y vs placebo 0.80/y; P = .196) and lower hospitalization days due to COPD exacerbation (NAC 1.8 d/y vs placebo 4.2 d/y; P = .08) (Fig 6). Besides, there were no differences between NAC and placebo in terms of respiratory symptoms (mMRC dypsnea score), quality of life (SGRQ), and exercise capacity (6MWD) (P = not significant) (Table 4).

Figure Jump LinkFigure 6. A, B, Comparison of (A) frequency of COPD-related admissions and (B) total days of hospitalization due to COPD exacerbation between the high-dose NAC and placebo groups in the 1-y study period. NS = not significant. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location
Table Graphic Jump Location
Table 4 —Changes in SGRQ Score, 6MWD, and mMRC Dypsnea Score With High-Dose NAC or Placebo

Data given as mean±SEM unless otherwise indicated. 6MWD = 6-min walking distance test; SGRQ score = St. George’s Respiratory Questionnaire. See Table 1 legend for expansion of other abbreviations.

Adverse Effects

No major adverse effects occurred in either group. There was no increase in incidence of minor adverse effects with NAC (three of 58 [5.2%]) vs placebo (five of 62 [8%]) (Table 5). Three patients died during the year: one receiving placebo (acute renal failure) and two receiving NAC (acute ischemic stroke and pneumonia); all three were unrelated to treatment.

Table Graphic Jump Location
Table 5 —Adverse Effects in the NAC and Placebo Groups

Data given as No., unless otherwise indicated. GERD = gastroesophageal reflux disorder. See Table 1 legend for expansion of other abbreviation.

a 

One person complained of both dry eye and muscle pain.

Dose-Dependent Effect of NAC: Use of High-Dose NAC

Compared with placebo, our study showed that high-dose NAC treatment provided significant improvements in FEF25%-75% and in reactance (reactance at 6 Hz and FRes) and resistance (resistance at 6 Hz and FDep). Small conducting airways, usually defined as airways < 2 mm in internal diameter without cartilage, are major sites of airflow limitation in both asthma and COPD.22 Resistance to airflow varies with the fourth power of the airway radius; for this reason, increased thickness of the airway walls, as well as luminal obstruction by mucoinflammatory exudates, reducing airway radius, are independent determinants of airflow limitation.23 Obstruction of small conducting airways by mucoinflammatory exudates was identified in the past using autopsy tissues, but only recently, mucoinflammatory exudate obstruction was shown to be independently associated with airflow limitation in subjects with COPD undergoing lung resection,24 and mucus exudates have been demonstrated in the small conducting airways of living subjects with COPD.25

The definition of airflow obstruction or limitation usually requires a postbronchodilator FEV1/FVC < 70%.26 However, FEV1/FVC provides little information on distal airways,27 and other markers of distal airways impairment using spirometry and/or body plethysmography are under evaluation. FEF25%-75% is the spirometric variable most commonly considered as an indicator of small airways obstruction23; it correlates highly with the FEV1/FVC ratio, but the decrease with increasing obstruction is steeper than with FEV1/FVC in patients with mild disease.23 Other issues with FEF25%-75% are related to effort dependence, marked measurement variability, and changes in FVC occurring with bronchodilation and air trapping, thereby altering the lung volume range at which FEF25%-75% is calculated.23

FOT was used specifically to assess expiratory flow limitation, a key element in COPD pathophysiology because it induces dynamic hyperinflation,28 and consists of applying periodic pressure variations during normal tidal breathing, thus, eliciting respiratory flow variations.23 Correlation between pressure variations applied and flow variations achieved are used to calculate resistance and reactance.23 Reactance is determined jointly by the elastic properties dominant at low frequencies and inertive forces that increase with frequency.20

It has been suggested that resistance at low oscillation frequency and FDep are sensitive indicators for small airways13,14 and show satisfactory correlation with multiple-breath nitrogen washout parameters.29 Current evidence suggests that FDep is strongly linked to clinical outcome parameters such as activity-related dyspnea in patients with COPD30 and is sensitive enough to detect early airways disease in susceptible individuals such as smokers, even when routine pulmonary function parameters remain within normal limits.31,32

To date, there are no published COPD data on oscillometric changes induced by antiinflammatory drugs (eg, inhaled corticosteroids), yet the impact of inflammation on reactance is demonstrated by data obtained in COPD exacerbations.23 This is the first study, to our knowledge, that has evaluated and demonstrated the efficacy of high-dose NAC treatment on small airways function in patients with COPD. Despite most previous studies failing to show a beneficial effect with NAC 600 mg daily in COPD,9,33,34 our study demonstrated that 1-year, high-dose, NAC (600 mg bid) improved small airways function in patients with COPD.

The difference between our study and previous research may be attributed to the higher dosage of NAC used, as it has been suggested that NAC’s antioxidant effect is dose dependent.3 In vitro studies3538 revealed that NAC exerts its mucolytic effect at low doses, whereas the antioxidant effect appears only at higher doses (1,200-1,800 mg daily). In fact, NAC bioavailability ranges from only 6% to 10% in humans,39 implying that higher NAC doses are necessary when antioxidant effects are desired. Moreover, there is evidence showing that increasing NAC dose can also increase its bioavailability and reduce the time to maximal plasma concentration.39

The insufficiency of “low-dose” NAC was demonstrated in Cotgreave’s study5: Low-dose NAC (600 mg daily) did not change cysteine and GSH levels in BAL in normal subjects. Similarly, Bridgeman et al40 confirmed that GSH plasma levels increased in patients with COPD after 5 days of high-dose NAC (600 mg tid), but no effect was seen at a low dosage (600 mg daily). Furthermore, while high-dose NAC (1,200 mg daily) effectively reduced exhaled hydrogen peroxide (a source of oxidative stress) in patients with stable COPD,41 whereas there was no effect on exhaled hydrogen peroxide with 6 months’ low-dose NAC (600 mg daily).42 This evidence strongly supports our finding that high-dose NAC (≥ 1,200 mg daily) is needed for antioxidant effect. Kasielski et al42 suggested that low-dose NAC (600 mg daily) may reduce hydrogen peroxide levels over 9 to 12 months, but not at 6 months, implying that a longer treatment period is needed for low-dose NAC to take effect. Furthermore, an indication that higher-dose NAC might be more effective was also provided by the IFIGENIA (Study of the Effects of High-Dose N-Acetylcysteine in Idiopathic Pulmonary Fibrosis) study,43 in which 1-year, high-dose NAC (1,800 mg daily) plus standard therapy in patients with idiopathic pulmonary fibrosis had a significant and clinically relevant effect on vital capacity and diffusion capacity.

Effect of High-Dose NAC on Lung Function
Mechanism of High-Dose NAC on Small Airways:

NAC acts directly as a free-radical scavenger as well as a precursor of GSH, a major, cellular thiol antioxidant and redox recycler. NAC can, therefore, restore cellular redox status and, in turn, modulate the COPD inflammatory pathway by inhibiting the redox-sensitive, cell-signal transduction and expression of proinflammatory genes.46 In fact, in vitro studies have shown that NAC reduces hydrogen peroxide-induced epithelial cell damage.44 High-dose NAC also attenuates airway wall epithelial thickening and reduces secretory cell hyperplasia induced by cigarette smoke in rats.45,46 Furthermore, in humans, NAC increases GSH in BAL47 and decreases exhaled hydrogen peroxide.41,42 These antiinflammatory effects may explain NAC-induced improvements in small airway function.

Effect of High-Dose NAC on Air Trapping:

Beneficial effects of NAC on air trapping are supported by previous studies. Analysis of data from the large, 3-year, BRONCUS study9 demonstrated that NAC reduced hyperinflation even at low dosage. Another randomized, controlled trial (RCT)48 suggested that NAC 1,200 mg daily reduced air trapping over 12 weeks, as shown by increased postexercise IC and FRC, and reduction in residual volume/total lung capacity (RV/TLC) ratio with NAC 1,200 mg daily vs placebo. This study48 only included patients with stable, moderate to severe COPD (FEV1 < 70% predicted normal) with significant hyperinflation (mean RV/TLC ratio = 137% predicted).

There are a number of proposed mechanisms for the beneficial effect of antioxidants (high-dose NAC) on air trapping in COPD. First, antioxidants may exert direct protective effects on emphysema development; in preclinical studies, oral NAC administration attenuated lesions induced by elastase in rats.49,50 Second, the beneficial effects on air trapping might be due to antioxidant and antiinflammatory effects on small airways in COPD. This theory is supported by our present study, showing that high-dose NAC (600 mg bid) reduced small airways resistance in COPD, as indicated by significant FEF25%-75% and FOT improvement in stable COPD. This improvement in resistance resulted in significant reduction in air trapping in the emphysematous subgroup of patients with COPD. However, our present study failed to demonstrate any significant improvement in IC or FVC with NAC. Unlike the previously discussed RCT,48 which showed a beneficial effect with NAC in patients with predominant emphysema (mean RV/TLC ratio = 137% predicted), ours was a heterogeneous cohort with various degrees of air trapping. This heterogeneity may explain the difficultly in detecting IC improvement.

Effect of High-Dose NAC on COPD Exacerbation

A significant reduction in COPD exacerbation frequency was observed with high-dose NAC (reduction rate, 0.75/y), in accordance with findings from a systemic review7 on the use of mucolytics in COPD/bronchitis, which concluded that oral mucolytics could halve exacerbation rates compared with placebo. Furthermore, the large-scale PEACE (Effect of Carbocisteine on Acute Exacerbation of COPD) RCT51 that investigated long-term mucolytic use (carbocysteine) in COPD, suggested that carbocysteine (1,500 mg) significantly reduced the exacerbation rate in Chinese patients with COPD.

We propose that this COPD exacerbation rate reduction might be related to antioxidant and antiinflammatory effects of high-dose NAC, resulting in improved small airways function in COPD, as illustrated by FEF25%-75% and FOT improvements in our study. This improvement in small airways function may reduce air trapping48 and reduce COPD exacerbation frequency.

Furthermore, since mucus and inflamed epithelia are the preferred site for bacterial attachment, resulting in exacerbation,52 NAC might reduce exacerbation by inhibiting bacterial adherence to ciliated epithelial cells. Moreover, the NAC mucolytic effect could decrease sputum and mucus viscosity in the airways and NAC might also disrupt epithelial bacterial receptor sites, inhibiting the attachment of bacteria. In vitro studies have provided evidence for this theory, suggesting that oral mucolytics reduce the attachment of bacteria to the pharyngeal epithelial cells in healthy subjects.52,53

Effects of High-Dose NAC Admission Rate, Dyspnea, Quality of Life, and Exercise Capacity

In addition to exacerbation frequency effects, a trend toward reduction in COPD admission frequency (0.5 times/y vs 0.80 times/y; P = .196) and average number of hospitalization days (1.8 d/y vs 4.2 d/y, P = .08) was seen with NAC vs placebo, though this did not reach statistical significance. This was consistent with data from the systemic review7 suggesting that oral mucolytics could reduce the number of disability days (−0.56, 95% CI, −0.77 to −0.35) and hospitalization risk. A retrospective study showed that NAC intake was related to a 30% decreased risk of hospital readmission for COPD and that this reduction was dose dependent.54

Because of the illustrated exacerbation-frequency reduction and NAC’s mechanisms of action in COPD, we believe that lack of statistical significance for reduced hospital admissions in our study was probably due to the small sample size. Further studies with larger sample sizes are needed to evaluate cost-effectiveness of high-dose NAC in reducing admissions, hospitalization, and hospital-related costs.

Conversely, our study failed to show a significant effect of high-dose NAC on COPD symptoms, exercise capacity, or quality of life parameters. There are a number of possible reasons for this. First, the small sample size might have had inadequate power to achieve statistical significance for these clinical parameters. Second, unlike bronchodilators, NAC acts on COPD through its antioxidant, antiinflammatory, and mucolytic properties. Therefore, NAC might not relieve dyspnea directly in patients with COPD, although a beneficial effect in small airways function was demonstrated in our study.

Safety in Chronic NAC Therapy

Our study suggested that chronic use of NAC 600 mg bid was safe and well tolerated. No significant differences in adverse effects were observed vs placebo (5.2% vs 8%). The most common side effects reported in our study were GI discomfort including diarrhea and gastroesophageal reflux disease symptoms. No major side effects were reported. In fact, chronic use of an even higher dose of NAC (1,800 mg daily) has been reported in the treatment of interstitial pulmonary fibrosis.43 In that study, high-dose NAC was well tolerated with minimal adverse effects.

Strengths and Limitations

To our knowledge, this is the first study demonstrating, with sensitive FOT assessment, beneficial effects of high-dose NAC on small airways function in patients with stable COPD. Our study suggested beneficial effects, especially in terms of small airways function and exacerbation frequency reduction, and demonstrated safety in chronic, high-dose NAC in stable COPD.

The sample size in our study was too small to detect improvement in lung function parameters (ie, FOT) with NAC and the study may be underpowered to detect changes in other clinical parameters. Therefore, studies with larger sample sizes are warranted to assess the effects of maintenance treatment with high-dose NAC in COPD.

High-dose NAC (600 mg bid) was a well tolerated treatment. It significantly decreased small airways resistance, as shown by improvements in FEF25%-75% and FOT, and reduced exacerbation frequency in patients with stable COPD.

Author contributions: Drs Tse, Yee, and Wong had full access of all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Tse: contributed to the conception and design of the study; data acquisition, analysis, and interpretation; and drafting the submitted manuscript; and served as principal author.

Dr Raiteri: contributed to revision of the manuscript.

Dr Wong: contributed to conception and design of the study, data acquisition and interpretation, and revision of the manuscript.

Dr Yee: contributed to supervision of the study and revision of the manuscript.

Dr Ng: contributed to data acquisition and revision of the manuscript.

Dr Wai: contributed to data acquisition and revision of the manuscript.

Dr Loo: contributed to supervision of the study and revision of the manuscript.

Dr Chan: contributed to supervision of the study and revision of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Raiteri was an employee at Zambon SpA during the period of this study. The other authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: Zambon S.p.A. donated the study drugs and did not place any restrictions on statements made in the final version of the manuscript. The Tung Wah Group of Hospitals Research Fund had no active role in the study.

Other contributions: We would like to thank pharmacists Michael Ling, MS, BPharm; Joyce Ng, MSc clinical pharmacy; and Elaine Lo, MSc clinical pharmacy, for their contribution and participation in randomization, group allocation, and drug dispensing. We would like to thank C. C. Cheng, BSc Nursing; H. M. Lau, BSc Nursing; K. H. Lo, BSc Nursing; W. K. Yeung, BSc Nursing; C. K. Hung, BSc Nursing; M. C. Siu, BSc Nursing; K. T. Cheung, BSc Nursing; S. Y. Wong, BSc Nursing; and F. Y. Chow, BSc Nursing for performing lung function tests. We would also like to thank Lawrence Fung, MSc health care; and Raymond Tang, professional diploma in physiotherapy, for performing SGRQ and 6MWD assessments.

6MWD

6-min walking distance

FDep

frequency dependence

FEF25%-75%

forced expiratory flow 25% to 75%

FOT

forced oscillation technique

FRes

frequency resonance

GSH

reduced glutathione

IC

inspiratory capacity

mMRC

modified Medical Research Council

NAC

N-acetylcysteine

RCT

randomized controlled trial

RV/TLC

residual volume/total lung capacity ratio

SGRQ

St. George’s Respiratory Questionnaire score

Evans MD, Pryor WA. Cigarette smoking, emphysema, and damage to alpha 1-proteinase inhibitor. Am J Physiol. 1994;266(6 pt 1):L593-L611. [PubMed]
 
Rahman I, MacNee W. Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J. 2000;16(3):534-554. [CrossRef] [PubMed]
 
Sadowska AM, Manuel-Y-Keenoy B, De Backer WA. Antioxidant and anti-inflammatory efficacy of NAC in the treatment of COPD: discordant in vitro and in vivo dose-effects: a review. Pulm Pharmacol Ther. 2007;20(1):9-22. [CrossRef] [PubMed]
 
Aruoma OI, Halliwell B, Hoey BM, Butler J. The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med. 1989;6(6):593-597. [CrossRef] [PubMed]
 
Cotgreave IA. N-acetylcysteine: pharmacological considerations and experimental and clinical applications. Adv Pharmacol. 1997;38:205-227. [PubMed]
 
Moldéus P, Cotgreave IA, Berggren M. Lung protection by a thiol-containing antioxidant: N-acetylcysteine. Respiration. 1986;50(Suppl 1):31-42.
 
Poole P, Black PN. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2010;; (2):CD001287
 
Grandjean EM, Berthet P, Ruffmann R, Leuenberger P. Efficacy of oral long-term N-acetylcysteine in chronic bronchopulmonary disease: a meta-analysis of published double-blind, placebo-controlled clinical trials. Clin Ther. 2000;22(2):209-221. [CrossRef] [PubMed]
 
Decramer M, Rutten-van Mölken M, Dekhuijzen PN, et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet. 2005;365(9470):1552-1560. [CrossRef] [PubMed]
 
Antonelli-Incalzi R, Imperiale C, Bellia V, et al; SaRA Investigators. Do GOLD stages of COPD severity really correspond to differences in health status? Eur Respir J. 2003;22(3):444-449. [CrossRef] [PubMed]
 
McFadden ER Jr, Linden DA. A reduction in maximum mid-expiratory flow rate. A spirographic manifestation of small airway disease. Am J Med. 1972;52(6):725-737. [CrossRef] [PubMed]
 
Gelb AF, Zamel N. Simplified diagnosis of small-airway obstruction. N Engl J Med. 1973;288(8):395-398. [CrossRef] [PubMed]
 
Goldman MD, Saadeh C, Ross D. Clinical applications of forced oscillation to assess peripheral airway function. Respir Physiol Neurobiol. 2005;148(1-2):179-194. [CrossRef] [PubMed]
 
Grimby G, Takishima T, Graham W, Macklem P, Mead J. Frequency dependence of flow resistance in patients with obstructive lung disease. J Clin Invest. 1968;47(6):1455-1465. [CrossRef] [PubMed]
 
Evans TM, Rundell KW, Beck KC, Levine AM, Baumann JM. Airway narrowing measured by spirometry and impulse oscillometry following room temperature and cold temperature exercise. Chest. 2005;128(4):2412-2419. [CrossRef] [PubMed]
 
US National Institutes of Health. The effect of high dose n-acetylcysteine on airtrapping and airway resistance of chronic obstructive pulmonary disease—a double-blinded, randomized, placebo-controlled trial. NCT01136239.ClinicalTrials.gov. Bethesda, MD: National Institutes of Health; 2010.http://www.clinicaltrials.gov/ct2/show/NCT01136239. Updated June 2, 2010.
 
Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Global Initiative for Chronic Obstructive Lung Disease website.http://www.goldcopd.org/uploads/users/files/GOLD_Report_2011_Feb21.pdf. Accessed December 7, 2012.
 
American Thoracic Society. Standardization of spirometry, 1994 update. Am J Respir Crit Care Med. 1995;152(3):1107-1136. [CrossRef] [PubMed]
 
Ip MS, Ko FW, Lau AC, et al; Hong Kong Thoracic Society; American College of Chest Physicians (Hong Kong and Macau Chapter). Updated spirometric reference values for adult Chinese in Hong Kong and implications on clinical utilization. Chest. 2006;129(2):384-392. [CrossRef] [PubMed]
 
Oostveen E, MacLeod D, Lorino H, et al; ERS Task Force on Respiratory Impedance Measurements. The forced oscillation technique in clinical practice: methodology, recommendations and future developments. Eur Respir J. 2003;22(6):1026-1041. [CrossRef] [PubMed]
 
Crim C, Celli B, Edwards LD, et al; ECLIPSE investigators. Respiratory system impedance with impulse oscillometry in healthy and COPD subjects: ECLIPSE baseline results. Respir Med. 2011;105(7):1069-1078. [CrossRef] [PubMed]
 
Macklem PT, Mead J. Resistance of central and peripheral airways measured by a retrograde catheter. J Appl Physiol. 1967;22(3):395-401. [PubMed]
 
Burgel PR, Bourdin A, Chanez P, et al. Update on the roles of distal airways in COPD. Eur Respir Rev. 2011;20(119):7-22. [CrossRef] [PubMed]
 
Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(26):2645-2653. [CrossRef] [PubMed]
 
Caramori G, Di Gregorio C, Carlstedt I, et al. Mucin expression in peripheral airways of patients with chronic obstructive pulmonary disease. Histopathology. 2004;45(5):477-484. [CrossRef] [PubMed]
 
Rabe KF, Hurd S, Anzueto A, et al; Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007;176(6):532-555. [CrossRef] [PubMed]
 
Bourdin A, Burgel PR, Chanez P, Garcia G, Perez T, Roche N. Recent advances in COPD: pathophysiology, respiratory physiology and clinical aspects, including comorbidities. Eur Respir Rev. 2009;18(114):198-212. [CrossRef] [PubMed]
 
Calverley PM, Koulouris NG. Flow limitation and dynamic hyperinflation: key concepts in modern respiratory physiology. Eur Respir J. 2005;25(1):186-199. [CrossRef] [PubMed]
 
King GG, Downie SR, Verbanck S, et al. Effects of methacholine on small airway function measured by forced oscillation technique and multiple breath nitrogen washout in normal subjects. Respir Physiol Neurobiol. 2005;148(1-2):165-177. [CrossRef] [PubMed]
 
Mahut B, Caumont-Prim A, Plantier L, et al. Relationships between respiratory and airway resistances and activity-related dyspnea in patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2012;7:165-171. [PubMed]
 
Brochard L, Pelle G, de Palmas J, et al. Density and frequency dependence of resistance in early airway obstruction. Am Rev Respir Dis. 1987;135(3):579-584. [PubMed]
 
Faria AC, Costa AA, Lopes AJ, Jansen JM, Melo PL. Forced oscillation technique in the detection of smoking-induced respiratory alterations: diagnostic accuracy and comparison with spirometry. Clinics (Sao Paulo). 2010;65(12):1295-1304. [CrossRef] [PubMed]
 
Black PN, Morgan-Day A, McMillan TE, Poole PJ, Young RP. Randomised, controlled trial of N-acetylcysteine for treatment of acute exacerbations of chronic obstructive pulmonary disease [ISRCTN21676344]. [ISRCTN21676344]. BMC Pulm Med. 2004;4:13. [CrossRef] [PubMed]
 
Poole PJ, Black PN. Oral mucolytic drugs for exacerbations of chronic obstructive pulmonary disease: systematic review. BMJ. 2001;322(7297):1271-1274. [CrossRef] [PubMed]
 
Benrahmoune M, Thérond P, Abedinzadeh Z. The reaction of superoxide radical with N-acetylcysteine. Free Radic Biol Med. 2000;29(8):775-782. [CrossRef] [PubMed]
 
Gressier B, Cabanis A, Lebegue S, et al. Decrease of hypochlorous acid and hydroxyl radical generated by stimulated human neutrophils: comparison in vitro of some thiol-containing drugs. Methods Find Exp Clin Pharmacol. 1994;16(1):9-13. [PubMed]
 
Kharazmi A, Nielsen H, Schiøtz PO. N-acetylcysteine inhibits human neutrophil and monocyte chemotaxis and oxidative metabolism. Int J Immunopharmacol. 1988;10(1):39-46. [CrossRef] [PubMed]
 
Stolarek R, Białasiewicz P, Nowak D. N-acetylcysteine effect on the luminol-dependent chemiluminescence pattern of reactive oxygen species generation by human polymorphonuclear leukocytes. Pulm Pharmacol Ther. 2002;15(4):385-392. [CrossRef] [PubMed]
 
Borgström L, Kågedal B. Dose dependent pharmacokinetics of N-acetylcysteine after oral dosing to man. Biopharm Drug Dispos. 1990;11(2):131-136. [CrossRef] [PubMed]
 
Bridgeman MM, Marsden M, Selby C, Morrison D, MacNee W. Effect of N-acetyl cysteine on the concentrations of thiols in plasma, bronchoalveolar lavage fluid, and lung tissue. Thorax. 1994;49(7):670-675. [CrossRef] [PubMed]
 
De Benedetto F, Aceto A, Dragani B, et al. Long-term oral n-acetylcysteine reduces exhaled hydrogen peroxide in stable COPD. Pulm Pharmacol Ther. 2005;18(1):41-47. [CrossRef] [PubMed]
 
Kasielski M, Nowak D. Long-term administration of N-acetylcysteine decreases hydrogen peroxide exhalation in subjects with chronic obstructive pulmonary disease. Respir Med. 2001;95(6):448-456. [CrossRef] [PubMed]
 
Demedts M, Behr J, Buhl R, et al; IFIGENIA Study Group. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2005;353(21):2229-2242. [CrossRef] [PubMed]
 
Cotgreave IA, Moldéus P. Lung protection by thiol-containing antioxidants. Bull Eur Physiopathol Respir. 1987;23(4):275-277. [PubMed]
 
Jeffery PK, Rogers DF, Ayers MM. Effect of oral acetylcysteine on tobacco smoke-induced secretory cell hyperplasia. Eur J Respir Dis Suppl. 1985;139:117-122. [PubMed]
 
Rubio ML, Sanchez-Cifuentes MV, Ortega M, et al. N-acetylcysteine prevents cigarette smoke induced small airways alterations in rats. Eur Respir J. 2000;15(3):505-511. [CrossRef] [PubMed]
 
Bridgeman MM, Marsden M, MacNee W, Flenley DC, Ryle AP. Cysteine and glutathione concentrations in plasma and bronchoalveolar lavage fluid after treatment with N-acetylcysteine. Thorax. 1991;46(1):39-42. [CrossRef] [PubMed]
 
Stav D, Raz M. Effect of N-acetylcysteine on air trapping in COPD: a randomized placebo-controlled study. Chest. 2009;136(2):381-386. [CrossRef] [PubMed]
 
Hanaoka M, Droma Y, Chen Y, et al. Carbocisteine protects against emphysema induced by cigarette smoke extract in rats. Chest. 2011;139(5):1101-1108. [CrossRef] [PubMed]
 
Rubio ML, Martin-Mosquero MC, Ortega M, Peces-Barba G, González-Mangado N. Oral N-acetylcysteine attenuates elastase-induced pulmonary emphysema in rats. Chest. 2004;125(4):1500-1506. [CrossRef] [PubMed]
 
Zheng JP, Kang J, Huang SG, et al. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study. Lancet. 2008;371(9629):2013-2018. [CrossRef] [PubMed]
 
Niederman MS, Rafferty TD, Sasaki CT, Merrill WW, Matthay RA, Reynolds HY. Comparison of bacterial adherence to ciliated and squamous epithelial cells obtained from the human respiratory tract. Am Rev Respir Dis. 1983;127(1):85-90. [PubMed]
 
Suer E, Sayrac S, Sarinay E, et al. Variation in the attachment of Streptococcus pneumoniae to human pharyngeal epithelial cells after treatment with S-carboxymethylcysteine. J Infect Chemother. 2008;14(4):333-336. [CrossRef] [PubMed]
 
Gerrits CM, Herings RM, Leufkens HG, Lammers JW. N-acetylcysteine reduces the risk of re-hospitalisation among patients with chronic obstructive pulmonary disease. Eur Respir J. 2003;21(5):795-798. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Flowchart of the study design. CVA = cerebrovascular accident; FU = follow-up; NAC = N-acetylcysteine.Grahic Jump Location
Figure Jump LinkFigure 2. A, The trend of FEF25-75% (L/s) in both NAC and placebo groups over a 1-year period. B, Mean changes in FEF25-75% (L/s) compared with baseline in both NAC and placebo groups at 16 weeks and 52 weeks. FEF25-75% = forced expiratory flow 25% to 75%. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location
Figure Jump LinkFigure 3. A-D, The trend and change in forced oscillation technique (FOT) parameters over 1 y in both the NAC and placebo groups. Figures show changes in (A) Fres (P = .02), (B) FDep (P = .01), (C) reactance at 6 Hz (P = .04), and (D) resistance at 6 Hz (P = .09). *P < .05. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4. Frequency of COPD exacerbations in NAC and placebo groups in the 1-year follow-up period. *P < .05. See Figure 1 legend for expansion of abbreviation.Grahic Jump Location
Figure Jump LinkFigure 5. Percentage of patients who were exacerbation-free at the end of study.Grahic Jump Location
Figure Jump LinkFigure 6. A, B, Comparison of (A) frequency of COPD-related admissions and (B) total days of hospitalization due to COPD exacerbation between the high-dose NAC and placebo groups in the 1-y study period. NS = not significant. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Baseline Demographic Characteristics of Subjects With COPD in NAC and Placebo Groups

Data given as % (actual proportion) unless otherwise indicated. GOLD = Global Initiative for Obstructive Lung Disease; ICS = inhaled corticosteroid; LABA = long-acting β agonist; LAMA = long-acting muscarinic agonist; mMRC = modified Medical Research Council; NAC = N-acetylcysteine; NS = not statistically significant; SABA = short-acting β2 agonist; SAMA = short-acting muscarinic agonist.

a 

Lung function parameters were measured by plethysmography.

Table Graphic Jump Location
Table 2 —Baseline Lung Function Parameters of Subjects With COPD in NAC and Placebo Groups

Data given as mean±SEM unless otherwise indicated. BD = bronchodilator; FEF25%-75% = forced expiratory flow 25-75%; IC = inspiratory capacity; RV = residual volume; TLC = total lung capacity. See Table 1 legend for expansion of other abbreviations.

Table Graphic Jump Location
Table 3 —Changes From Baseline in Lung Function Parameters (by Spirometry) at 16 and 52 Wk in NAC and Placebo Groups

See Table 1 and 2 legends for expansion of abbreviations.

a 

Statistically significant value (P ≤ .05).

Table Graphic Jump Location
Table 4 —Changes in SGRQ Score, 6MWD, and mMRC Dypsnea Score With High-Dose NAC or Placebo

Data given as mean±SEM unless otherwise indicated. 6MWD = 6-min walking distance test; SGRQ score = St. George’s Respiratory Questionnaire. See Table 1 legend for expansion of other abbreviations.

Table Graphic Jump Location
Table 5 —Adverse Effects in the NAC and Placebo Groups

Data given as No., unless otherwise indicated. GERD = gastroesophageal reflux disorder. See Table 1 legend for expansion of other abbreviation.

a 

One person complained of both dry eye and muscle pain.

References

Evans MD, Pryor WA. Cigarette smoking, emphysema, and damage to alpha 1-proteinase inhibitor. Am J Physiol. 1994;266(6 pt 1):L593-L611. [PubMed]
 
Rahman I, MacNee W. Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J. 2000;16(3):534-554. [CrossRef] [PubMed]
 
Sadowska AM, Manuel-Y-Keenoy B, De Backer WA. Antioxidant and anti-inflammatory efficacy of NAC in the treatment of COPD: discordant in vitro and in vivo dose-effects: a review. Pulm Pharmacol Ther. 2007;20(1):9-22. [CrossRef] [PubMed]
 
Aruoma OI, Halliwell B, Hoey BM, Butler J. The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med. 1989;6(6):593-597. [CrossRef] [PubMed]
 
Cotgreave IA. N-acetylcysteine: pharmacological considerations and experimental and clinical applications. Adv Pharmacol. 1997;38:205-227. [PubMed]
 
Moldéus P, Cotgreave IA, Berggren M. Lung protection by a thiol-containing antioxidant: N-acetylcysteine. Respiration. 1986;50(Suppl 1):31-42.
 
Poole P, Black PN. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2010;; (2):CD001287
 
Grandjean EM, Berthet P, Ruffmann R, Leuenberger P. Efficacy of oral long-term N-acetylcysteine in chronic bronchopulmonary disease: a meta-analysis of published double-blind, placebo-controlled clinical trials. Clin Ther. 2000;22(2):209-221. [CrossRef] [PubMed]
 
Decramer M, Rutten-van Mölken M, Dekhuijzen PN, et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet. 2005;365(9470):1552-1560. [CrossRef] [PubMed]
 
Antonelli-Incalzi R, Imperiale C, Bellia V, et al; SaRA Investigators. Do GOLD stages of COPD severity really correspond to differences in health status? Eur Respir J. 2003;22(3):444-449. [CrossRef] [PubMed]
 
McFadden ER Jr, Linden DA. A reduction in maximum mid-expiratory flow rate. A spirographic manifestation of small airway disease. Am J Med. 1972;52(6):725-737. [CrossRef] [PubMed]
 
Gelb AF, Zamel N. Simplified diagnosis of small-airway obstruction. N Engl J Med. 1973;288(8):395-398. [CrossRef] [PubMed]
 
Goldman MD, Saadeh C, Ross D. Clinical applications of forced oscillation to assess peripheral airway function. Respir Physiol Neurobiol. 2005;148(1-2):179-194. [CrossRef] [PubMed]
 
Grimby G, Takishima T, Graham W, Macklem P, Mead J. Frequency dependence of flow resistance in patients with obstructive lung disease. J Clin Invest. 1968;47(6):1455-1465. [CrossRef] [PubMed]
 
Evans TM, Rundell KW, Beck KC, Levine AM, Baumann JM. Airway narrowing measured by spirometry and impulse oscillometry following room temperature and cold temperature exercise. Chest. 2005;128(4):2412-2419. [CrossRef] [PubMed]
 
US National Institutes of Health. The effect of high dose n-acetylcysteine on airtrapping and airway resistance of chronic obstructive pulmonary disease—a double-blinded, randomized, placebo-controlled trial. NCT01136239.ClinicalTrials.gov. Bethesda, MD: National Institutes of Health; 2010.http://www.clinicaltrials.gov/ct2/show/NCT01136239. Updated June 2, 2010.
 
Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Global Initiative for Chronic Obstructive Lung Disease website.http://www.goldcopd.org/uploads/users/files/GOLD_Report_2011_Feb21.pdf. Accessed December 7, 2012.
 
American Thoracic Society. Standardization of spirometry, 1994 update. Am J Respir Crit Care Med. 1995;152(3):1107-1136. [CrossRef] [PubMed]
 
Ip MS, Ko FW, Lau AC, et al; Hong Kong Thoracic Society; American College of Chest Physicians (Hong Kong and Macau Chapter). Updated spirometric reference values for adult Chinese in Hong Kong and implications on clinical utilization. Chest. 2006;129(2):384-392. [CrossRef] [PubMed]
 
Oostveen E, MacLeod D, Lorino H, et al; ERS Task Force on Respiratory Impedance Measurements. The forced oscillation technique in clinical practice: methodology, recommendations and future developments. Eur Respir J. 2003;22(6):1026-1041. [CrossRef] [PubMed]
 
Crim C, Celli B, Edwards LD, et al; ECLIPSE investigators. Respiratory system impedance with impulse oscillometry in healthy and COPD subjects: ECLIPSE baseline results. Respir Med. 2011;105(7):1069-1078. [CrossRef] [PubMed]
 
Macklem PT, Mead J. Resistance of central and peripheral airways measured by a retrograde catheter. J Appl Physiol. 1967;22(3):395-401. [PubMed]
 
Burgel PR, Bourdin A, Chanez P, et al. Update on the roles of distal airways in COPD. Eur Respir Rev. 2011;20(119):7-22. [CrossRef] [PubMed]
 
Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(26):2645-2653. [CrossRef] [PubMed]
 
Caramori G, Di Gregorio C, Carlstedt I, et al. Mucin expression in peripheral airways of patients with chronic obstructive pulmonary disease. Histopathology. 2004;45(5):477-484. [CrossRef] [PubMed]
 
Rabe KF, Hurd S, Anzueto A, et al; Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007;176(6):532-555. [CrossRef] [PubMed]
 
Bourdin A, Burgel PR, Chanez P, Garcia G, Perez T, Roche N. Recent advances in COPD: pathophysiology, respiratory physiology and clinical aspects, including comorbidities. Eur Respir Rev. 2009;18(114):198-212. [CrossRef] [PubMed]
 
Calverley PM, Koulouris NG. Flow limitation and dynamic hyperinflation: key concepts in modern respiratory physiology. Eur Respir J. 2005;25(1):186-199. [CrossRef] [PubMed]
 
King GG, Downie SR, Verbanck S, et al. Effects of methacholine on small airway function measured by forced oscillation technique and multiple breath nitrogen washout in normal subjects. Respir Physiol Neurobiol. 2005;148(1-2):165-177. [CrossRef] [PubMed]
 
Mahut B, Caumont-Prim A, Plantier L, et al. Relationships between respiratory and airway resistances and activity-related dyspnea in patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2012;7:165-171. [PubMed]
 
Brochard L, Pelle G, de Palmas J, et al. Density and frequency dependence of resistance in early airway obstruction. Am Rev Respir Dis. 1987;135(3):579-584. [PubMed]
 
Faria AC, Costa AA, Lopes AJ, Jansen JM, Melo PL. Forced oscillation technique in the detection of smoking-induced respiratory alterations: diagnostic accuracy and comparison with spirometry. Clinics (Sao Paulo). 2010;65(12):1295-1304. [CrossRef] [PubMed]
 
Black PN, Morgan-Day A, McMillan TE, Poole PJ, Young RP. Randomised, controlled trial of N-acetylcysteine for treatment of acute exacerbations of chronic obstructive pulmonary disease [ISRCTN21676344]. [ISRCTN21676344]. BMC Pulm Med. 2004;4:13. [CrossRef] [PubMed]
 
Poole PJ, Black PN. Oral mucolytic drugs for exacerbations of chronic obstructive pulmonary disease: systematic review. BMJ. 2001;322(7297):1271-1274. [CrossRef] [PubMed]
 
Benrahmoune M, Thérond P, Abedinzadeh Z. The reaction of superoxide radical with N-acetylcysteine. Free Radic Biol Med. 2000;29(8):775-782. [CrossRef] [PubMed]
 
Gressier B, Cabanis A, Lebegue S, et al. Decrease of hypochlorous acid and hydroxyl radical generated by stimulated human neutrophils: comparison in vitro of some thiol-containing drugs. Methods Find Exp Clin Pharmacol. 1994;16(1):9-13. [PubMed]
 
Kharazmi A, Nielsen H, Schiøtz PO. N-acetylcysteine inhibits human neutrophil and monocyte chemotaxis and oxidative metabolism. Int J Immunopharmacol. 1988;10(1):39-46. [CrossRef] [PubMed]
 
Stolarek R, Białasiewicz P, Nowak D. N-acetylcysteine effect on the luminol-dependent chemiluminescence pattern of reactive oxygen species generation by human polymorphonuclear leukocytes. Pulm Pharmacol Ther. 2002;15(4):385-392. [CrossRef] [PubMed]
 
Borgström L, Kågedal B. Dose dependent pharmacokinetics of N-acetylcysteine after oral dosing to man. Biopharm Drug Dispos. 1990;11(2):131-136. [CrossRef] [PubMed]
 
Bridgeman MM, Marsden M, Selby C, Morrison D, MacNee W. Effect of N-acetyl cysteine on the concentrations of thiols in plasma, bronchoalveolar lavage fluid, and lung tissue. Thorax. 1994;49(7):670-675. [CrossRef] [PubMed]
 
De Benedetto F, Aceto A, Dragani B, et al. Long-term oral n-acetylcysteine reduces exhaled hydrogen peroxide in stable COPD. Pulm Pharmacol Ther. 2005;18(1):41-47. [CrossRef] [PubMed]
 
Kasielski M, Nowak D. Long-term administration of N-acetylcysteine decreases hydrogen peroxide exhalation in subjects with chronic obstructive pulmonary disease. Respir Med. 2001;95(6):448-456. [CrossRef] [PubMed]
 
Demedts M, Behr J, Buhl R, et al; IFIGENIA Study Group. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2005;353(21):2229-2242. [CrossRef] [PubMed]
 
Cotgreave IA, Moldéus P. Lung protection by thiol-containing antioxidants. Bull Eur Physiopathol Respir. 1987;23(4):275-277. [PubMed]
 
Jeffery PK, Rogers DF, Ayers MM. Effect of oral acetylcysteine on tobacco smoke-induced secretory cell hyperplasia. Eur J Respir Dis Suppl. 1985;139:117-122. [PubMed]
 
Rubio ML, Sanchez-Cifuentes MV, Ortega M, et al. N-acetylcysteine prevents cigarette smoke induced small airways alterations in rats. Eur Respir J. 2000;15(3):505-511. [CrossRef] [PubMed]
 
Bridgeman MM, Marsden M, MacNee W, Flenley DC, Ryle AP. Cysteine and glutathione concentrations in plasma and bronchoalveolar lavage fluid after treatment with N-acetylcysteine. Thorax. 1991;46(1):39-42. [CrossRef] [PubMed]
 
Stav D, Raz M. Effect of N-acetylcysteine on air trapping in COPD: a randomized placebo-controlled study. Chest. 2009;136(2):381-386. [CrossRef] [PubMed]
 
Hanaoka M, Droma Y, Chen Y, et al. Carbocisteine protects against emphysema induced by cigarette smoke extract in rats. Chest. 2011;139(5):1101-1108. [CrossRef] [PubMed]
 
Rubio ML, Martin-Mosquero MC, Ortega M, Peces-Barba G, González-Mangado N. Oral N-acetylcysteine attenuates elastase-induced pulmonary emphysema in rats. Chest. 2004;125(4):1500-1506. [CrossRef] [PubMed]
 
Zheng JP, Kang J, Huang SG, et al. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study. Lancet. 2008;371(9629):2013-2018. [CrossRef] [PubMed]
 
Niederman MS, Rafferty TD, Sasaki CT, Merrill WW, Matthay RA, Reynolds HY. Comparison of bacterial adherence to ciliated and squamous epithelial cells obtained from the human respiratory tract. Am Rev Respir Dis. 1983;127(1):85-90. [PubMed]
 
Suer E, Sayrac S, Sarinay E, et al. Variation in the attachment of Streptococcus pneumoniae to human pharyngeal epithelial cells after treatment with S-carboxymethylcysteine. J Infect Chemother. 2008;14(4):333-336. [CrossRef] [PubMed]
 
Gerrits CM, Herings RM, Leufkens HG, Lammers JW. N-acetylcysteine reduces the risk of re-hospitalisation among patients with chronic obstructive pulmonary disease. Eur Respir J. 2003;21(5):795-798. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543