High-Dose N-Acetylcysteine in Chronic Obstructive Pulmonary Disease, Prone Positioning in Acute Respiratory Distress Syndrome, and Continuous Positive Airway Pressure and Exhaled Nitric Oxide in Obstructive Sleep Apnea

Tse HN, et al. High-Dose N-Acetylcysteine in Stable COPD: The 1-Year, Double-Blind, Randomized, Placebo-controlled HIACE Study. Chest (1)

Reviewed by Allison A. Lambert

Patients with chronic obstructive pulmonary disease (COPD) experiencing rapid decline in FEV₁ or frequent exacerbations suffer substantial morbidity and mortality. Oral N-acetylcysteine (NAC) has been proposed as adjunctive COPD therapy, given its antioxidant, antiinflammatory, and mucolytic effects. However, in a large, randomized, placebo-controlled trial (RCT) in 2005, NAC did not reduce the rates of decline in FEV₁ or VC, improve health status, or reduce exacerbation frequency (2). Insufficient NAC dose or the predominance of GOLD stage II disease and inhaled corticosteroid use was speculated to have attenuated potential benefits.

To determine the effects of higher-dose oral NAC (600 mg twice daily), Tse and colleagues conducted a 1-year double-blind RCT among 120 Chinese patients with stable COPD recruited from a single COPD clinic (1). The cohort was 93% male with a mean age of 71 years. Most participants were former smokers (74% NAC; 79% placebo), GOLD stage II (41% NAC; 39% placebo), or III (31% NAC; 37% placebo) and were using inhaled corticosteroids (74% NAC; 84% placebo). Forced expiratory flow at 25 to 75% of FVC (FEF_25–75%) was significantly improved at 16 weeks (+0.08 L NAC vs. +0.008 L placebo; P = 0.03) and 52 weeks (+0.08 L NAC vs. −0.002 L placebo; P = 0.047), although FEV₁, FVC, and inspiratory capacity were unchanged. At 1 year, measures of small airway flow were also improved with NAC therapy. The mean frequency of exacerbation was reduced (0.96/yr NAC vs. 1.71/yr placebo; P = 0.019), with a trend toward increasing proportion of exacerbation-free participants (53.8% NAC; 37.5% placebo; P = 0.088), reducing exacerbation admissions (0.5/yr NAC; 0.8/yr placebo; P = 0.196), and decreasing hospitalization days (1.8 d/yr NAC; 4.2 d/yr placebo; P = 0.08). St. George's Respiratory Questionnaire score, 6-minute walk distance, and Modified Medical Research Council dyspnea score were unchanged. No drug-related adverse events were reported.

RCT design, high-dose NAC therapy, and a well-characterized cohort strengthen the findings. Limitations include a small sample size, a limited number of COPD exacerbations, and a short duration of follow-up. The cohort of elderly Chinese male former smokers with GOLD stage II–III disease restricts generalizability.

This study reinvigorates the debated role of NAC for COPD therapy. Although the improvement in distal airflow measures and reduction in COPD exacerbation frequency are compelling, the lack of improvement in measures of morbidity highlights the need for cautious interpretation. Larger studies applying high-dose NAC to broader populations are needed.

Guérin C, et al.; PROSEVA Study Group. Prone Positioning in Severe Acute Respiratory Distress Syndrome. New Engl J Med (3)

Reviewed by Ann M. Parker

Prone positioning improves oxygenation in patients with acute respiratory failure, possibly by enhancing ventilation/perfusion matching, but several randomized controlled trials (RCTs) did not find a mortality benefit associated with this intervention (4). However, subgroup and metaanalyses suggested that patients with severe acute respiratory distress syndrome (ARDS) may indeed have lower mortality when managed in the prone versus the supine position (4, 5).

This multicenter prospective RCT of prone versus supine positioning capitalized on the findings of earlier trials. Guerin and colleagues (3) included only severely hypoxemic patients with ARDS (Pa_O2/Fi_O2 < 150 mm Hg on Fi_O2 > 0.6; PEEP > 5 cm H₂O) mechanically ventilated for <36 hours. All 27 study sites had ≥5 years of experience with the use of prone positioning. Of the 576 eligible patients, 474 were randomized after 12 to 24 hours of stability. Patients in the prone group were positioned prone within 1 hour of randomization and maintained the prone position for ≥16 hours daily until recovery or Day 28. The mean Vt in both groups was 6 ± 0.6 ml per kilogram of ideal body weight. Patients in the prone group were prone for 73% of ICU patient-hours. Unadjusted mortality at 28 and 90 days was significantly lower in the prone versus the supine group (mean, 16%; 95% confidence interval [CI], 11–21 vs. mean, 33%; 95% CI, 26–39 [P < 0.001] and mean, 24%; 95% CI, 18–29 vs. mean, 41%, 95% CI, 35–47 [P < 0.001], respectively). Importantly, mortality in the supine group was comparable to that of control groups in previous trials of prone positioning (4, 5). Moreover, at Day 90, patients in the prone group had more ventilator-free days than patients in the supine group. Cardiac arrests occurred more often in the supine group, but overall complication rates did not differ between groups.

Compared with other trials of this intervention, this RCT may have had more encouraging results for several reasons. Previous RCTs were smaller, used shorter durations of prone positioning, enrolled less severely hypoxemic patients, delayed the intervention to later in the course, and/or used higher Vt levels (4, 5). This trial did have salient limitations: blinding was not feasible, and inclusion of only patients with severe ARDS in centers with substantial experience with prone positioning may limit the generalizability of the results. Nonetheless, Guerin and colleagues’ (3) findings and striking effect size support systematic efforts to incorporate prone positioning into the early management of severe ARDS.

Chua AP, et al. Long-Term Continuous Positive Airway Pressure Therapy Normalizes High Exhaled Nitric Oxide Levels in Obstructive Sleep Apnea. J Clin Sleep Med (6)

Reviewed by Karoline K. Moon

Obstructive sleep apnea (OSA) is an independent risk factor for cardiovascular disease and impaired glucose metabolism. Upper airway inflammation has been implicated as an indicator of upper airway collapse. Fraction of exhaled nitric oxide (Fe_NO) has been used as a marker for airway inflammation, but studies looking at Fe_NO levels in OSA have shown conflicting results (7, 8).

Chua and colleagues conducted a prospective study of Fe_NO levels in patients with and without OSA before and after treatment with continuous positive airway pressure (CPAP) in patients with OSA (6). A total of 104 patients had Fe_NO measured before and after an overnight polysomnogram (PSG). Seventy-five patients had PSG-confirmed OSA, and they also had Fe_NO measured before and after CPAP titration and 1 to 3 months after CPAP initiation. Fe_NO pre-PSG was higher in patients with OSA than in non-OSA patients (13.4 ± 6.5 vs. 6.5 ± 3.5 ppb; P < 0.001). In patients with OSA, Fe_NO increased to 19.0 ± 7.7 ppb after PSG (P < 0.001). Fe_NO levels correlated (P < 0.001) with OSA severity. In the 37 patients who had CPAP titration, Fe_NO levels rose after titration (14.7 ± 6.6 to 22.7 ± 7.7 ppb; P < 0.001) and decreased after 1 to 3 months of treatment compared with pre-PSG and pre-CPAP levels (to 11.7 ± 4.4 ppb; P < 0.001). All patients met Medicare criteria for CPAP compliance.

Strengths of this study are the prospective design, measuring Fe_NO before and after PSG, and the longer duration of CPAP treatment before measuring Fe_NO at follow-up, which were not done in prior studies. Limitations include its small size, with 38 dropouts in the OSA group. The correlation found between Fe_NO and apnea/hypopnea index severity implicates increased airway inflammation in the etiology of OSA and its associated cardiovascular and metabolic effects. Fe_NO levels rose after PSG and CPAP titration in the OSA group, presumably because Fe_NO levels fell during the day while the patients were awake and then rose overnight because of renewed airway inflammation. Fe_NO can be measured in clinic and can support an OSA diagnosis. Additionally, there is potential utility for monitoring treatment with CPAP and possibly other interventions, such as oral appliances or surgery. However, some of the limitations for this use are the unknown normal values in this population, the seasonal variation in Fe_NO, and the association of higher levels of Fe_NO with obesity and metabolic syndrome.