January 2015 Phoenix Pulmonary Journal Club: Noninvasive Ventilation In Acute Respiratory Failure

Noninvasive positive pressure ventilation has expanded its role in the treatment of both chronic and acute respiratory failure. Its initial use in conditions such as obstructive sleep apnea, neuromuscular disease and tracheobronchomalacia, have been shown to improve quality of life and reduce mortality. Over the past 20 years studies have looked at using noninvasive ventilation in the management of acute respiratory failure from pulmonary edema, asthma and COPD exacerbations. During this month's journal club we reviewed 3 articles evaluating the efficacy of noninvasive ventilation in acute respiratory failure.

Gupta D, Nath A, Agarwal R, Behera D. A prospective randomized controlled trial on the efficacy of noninvasive ventilation in severe acute asthma. Respir Care. 2010;55(5):536-43. [PubMed]

This was a small unblinded randomized controlled trial (RCT) looking at the efficacy using noninvasive ventilation (NIV) in acute asthma. A total of 53 patients were included and divided into 2 groups of 28 patients (NIV) and 25 patients (standard). Both groups were treated with oxygen, intravenous corticosteroids and nebulizer treatments. Patients randomized to the NIV arm were then placed on Bilevel positive airway pressure (BiPAP) 8/4 cm H₂O and pressure was titrated to maximum of 20/10 based on serial spirometry and arterial blood gases (ABG) taken at 1, 2, and 4 hrs. The primary outcome was an improvement in forced expiratory volume in 1 second (FEV1) by 50% and length of hospital stay. The results showed that there was no statistical difference in within the 2 groups with regards to improvement in FEV1. There was a small decrease in length of ICU stay by 14 hours and a reduction in hospital stay by 16 hours. A secondary outcome did show that there were lower doses of salbutamol and ipratropium required within the NIV group. The study showed that the role of NIV in asthma has little benefit over usual therapy alone. A Cochran review of 5 studies evaluating the role of NIV in asthma was done in 2013 (1). The aggregate size was 203 patients. The review showed no reduction in mortality or need for intubation when NIV is used in the treatment of asthma. The role of NIV in asthma remains unproven and should be considered as non-standard therapy.

Gray A, Goodacre S, Newby DE, Masson M, Sampson F, Nicholl J; 3CPO Trialists. Noninvasive ventilation in acute cardiogenic pulmonary edema. N Engl J Med. 2008;359(2):142-51. [CrossRef] [PubMed]

This was a large prospective RCT looking at the effect of NIV in the acute treatment of cardiogenic pulmonary edema. The primary endpoint was mortality and need for intubation within 7 days. 1069 patients were enrolled and divided among three arms: 1. Standard therapy with oxygen (367 patients); 2. CPAP (346 patients); and 3. NIV (356 patients). Inclusion criteria included radiographic pulmonary edema on chest x-ray, pH < 7.35 and respiratory rate > 20. The average continuous positive airway pressure (CPAP) was 10 cm H20 and average BIPAP pressure was 14:7 cm.

The results showed that there was no difference in mortality rates or need for intubation among the 3 groups. There was an improvement in dyspnea, acidosis, and hypercapnia in the groups receiving CPAP or BIPAP. The study was well done and presented a large sample size. The results did not show any short term benefit in mortality, however, a Cochrane review in 2013 further analyzed a total of 32 studies with > 2000 patients and did show that use of either CPAP or BIPAP resulted in lower rates of intubation and mortality (2). In addition, it reduced ICU length of stay by 1 day. The role of CPAP or BIPAP in the treatment of cardiogenic pulmonary edema may be of benefit and offers little downside. CPAP has been advocated to be more beneficial in the management of systolic heart failure.

Brochard L, Mancebo J, Wysocki M, et al. Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med. 1995;333(13):817-22. [CrossRef] [PubMed]

This was a prospective RCT looking at the management of acute COPD exacerbations by standard treatment with antibiotics, steroids and oxygen verses standard therapy + NIV. A total of 85 patients were divided in 2 groups of 43 patients (standard treatment) and 42  patients (NIV). Inclusion criteria were shortness of breath, diagnosis of COPD by PFTS, pH< 7.35, respiratory rate > 30, and PaO2 < 45. Primary outcomes were need for intubation, mortality and length of hospital stay. Patients in the noninvasive NIV group received at least 6 hours per day of inspiratory pressure of 20 cm H₂O. The results showed that the use of noninvasive ventilation reduced the need for intubation from 74% (3 patients in standard arm) to 26% (11 patients in NIV arm). The use of NIV also resulted in reduced mortality, 29% (12 patients in Standard Arm) vs 9% (4 patients in NIV arm). Other clinical parameters such as respiratory rate, encephalopathy, and blood gas results were also improved at a greater level with the use of NIV. The length of stay was reduced in the NIV group regardless of whether the patient required intubation or not. Although this was a smaller study the results were compelling for the benefits of using NIV in acute COPD exacerbation. Subsequent studies looking at the role of NIV both in acute COPD exacerbation as well as chronic stable COPD have also been positive. Although there are no optimal pressures outlined for NIV settings, this study showed that a higher pressure of 20 cm H₂O of Inspiratory pressure was a good starting point. The use of NIV in acute COPD exacerbations has been shown to be beneficial and should be used with other standard pharmacological therapies.

Manoj Mathew, MD FCCP, MCCM

References

1. Landry A, Foran M, Koyfman A. Does noninvasive positive-pressure ventilation improve outcomes in severe asthma exacerbations? Ann Emerg Med. 2013;62(6):594-6. [CrossRef] [PubMed]
2. Vital FM, Ladeira MT, Atallah AN. Non-invasive positive pressure ventilation (CPAP or bilevel NPPV) for cardiogenic pulmonary oedema. Cochrane Database Syst Rev. 2013 May 31;5:CD005351. [CrossRef] [PubMed] 

Reference as: Mathew M. January 2015 Phoenix pulmonary journal club: noninvasive ventilation in acute respiratory failure. Southwest J Pulm Crit Care. 2015;10(1):52-3. doi: http://dx.doi.org/10.13175/swjpcc011-15 PDF

September 2014 Tucson Pulmonary Journal Club: PANTHEON Study

Zheng JP, Wen FQ, Bai CX, Wan HY, Kang J, Chen P et al. for the PANTHEON study group. Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomized, double-blind placebo-controlled trial. Lancet Respir Med. 2014; 2(3):187-94. [CrossRef] [PubMed]

Chronic obstructive pulmonary disease (COPD) is a common cause of morbidity, mortality, and healthcare utilization. Oxidative stress is thought to be important in COPD pathogenesis, and thus antioxidant therapy has been of great interest, including N-Acetylcysteine (NAC). However, prior studies of NAC in COPD patients have shown varied results. The PANTHEON study was designed to examine the effects of NAC on exacerbation rate in Chinese patients with COPD using a daily dose that is twice as high as that previously studied.

PANTHEON was a randomized double-blinded placebo-controlled trial that enrolled patients aged 40-80 years with GOLD class II, III and IV COPD from 34 academic pulmonary clinics in China. Patients with asthma, oxygen dependence, or poor compliance were excluded. The primary outcome was the COPD exacerbation rate following one year of observation. Exacerbations were defined using the Anthonisen instrument which relies on daily diary reporting. Important secondary outcomes included time to first exacerbation, time to subsequent exacerbations, number of patients requiring antibiotics or steroids, and number of patients requiring hospitalization. The enrollment goal was 1250 patients which would have provided have 95% power to detect a 20% reduction in the exacerbation; however, only 1006 patients were actually randomized. Nevertheless, the study was adequately powered for the primary outcome.

More than 80% of the patients were males; 46% had GOLD II severity, 53% had GOLD III severity, and 1% had GOLD IV severity. Mean FEV1 was 1.2 L. Twenty-five percent were non-smokers; 48% were using both ICS and a long-acting bronchodilator at enrollment; and 27% were taking theophylline.

As compared to placebo, twice daily treatment with 600mg of NAC led to a significant reduction in the annual COPD exacerbation rate (RR 0.78, 95% CI 0.67–0.90; p=0.001) and the rate of steroid or antibiotic-requiring exacerbations (RR 0.83 95% CI 0.69-0.99; p=0.04) but not the annual rate of hospitalizations. Interestingly, the time to first exacerbation did not differ between the groups but the time to second and third exacerbations was longer in the NAC group.

This study suggests that NAC, a relatively inexpensive compound that is available over-the-counter, may reduce exacerbation risk among patients with COPD. Given that NAC is safe and the costs would be borne entirely by the patient, it is reasonable to advise patients of this potential treatment option. Patients should be cautioned that the data supporting the benefits of NAC are not conclusive and the magnitude of benefit is likely to be modest. The major limitation includes reliance on a Chinese population of COPD patients in whom the benefits may not be generalizable to US patients. Of unknown importance is the fact that treatment benefits were limited to self-reported outcomes rather than objective observation of hospitalizations. To the extent that the self-reported data is free of bias, the failure to detect differences in hospitalizations may not matter to patients.

Bhupinder Natt MD¹, Christine Berry MD¹, Joe K. Gerald MD, PhD²

¹Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Arizona Medical Center; Tucson, AZ

²College of Public Health, University of Arizona Medical Center; Tucson, AZ

Reference as: Natt B, Berry C, Gerald JK. September 2014 Tucson pulmonary journal club: PANTHEON study. Southwest J Pulm Crit Care. 2014;9(4):249-50. doi: http://dx.doi.org/10.13175/swjpcc144-14 PDF

August 2014 Phoenix Pulmonary Journal Club: The Use of Macrolide Antibiotics in Chronic Respiratory Disease

This month's journal club reviewed  the role of macrolide antibiotics in chronic respiratory disease. Macrolide usage was suggested from observational studies in Japan in diffuse panbroncholitis, a disorder associated with chronic respiratory infection, usually Pseudomonas aeruginosa (1). Clinical improvement was noted despite doses of antibiotics well below the minimal inhibitory concentration (MIC) of the antibiotic. This  suggested the antibiotic was likely working by an anti-inflammatory effect. These observations were extended to cystic fibrosis (CF) where prophylactic macrolide therapy in CF patients infected with Pseudomonas has become standard therapy (2). More recently, low dose macrolide therapy has been applied to non-CF lung diseases such as chronic obstructive pulmonary disease (COPD), bronchiectasis and asthma.

Time did not permit a review of all studies so a representative sample was discussed. In patients with COPD, the four randomized, placebo-controlled trials reviewed all suggested that chronic therapy with macrolide antibiotics reduced COPD exacerbations (3-5). This beneficial effect was confirmed by 2 recent meta-analysis (6,7). Similarly,  three recent randomized trials in bronchiectasis demonstrated a reduction in exacerbations (8-10). In asthma the data is not as clear. A recent trial did not demonstrate an overall reduction in asthma exacerbations or lower respiratory tract infections (11). However, in the patients with non-eosinophilic, predominantly neutrophilic, asthma there was a reduction.  An excellent review of the use of macrolides in acute and chronic asthma was recently published. (12). The article includes a review of the anti-inflammatory and immunomodulatory properties of the macrolides.

The respiratory disorders where macrolides have been shown to have clinic benefit such as diffuse panbroncholitis, cystic fibrosis, COPD, bronchiectasis and non-eosinophilic asthma are all diseases associated an influx of neutrophils into the airways. The beneficial clinic effects of macrolides are consistent with their effect in reducing neutrophil chemotactic factors such as interleukin (IL)-8 (13). However, macrolides have also been reported to have adverse clinical effects such as QT prolongation in patients with heart disease, impaired hearing and development of bacterial resistance (4,6,14). Whether all COPD patients should be treated with macrolides is controversial but most in the audience used these in patients with frequent exacerbations. It was also pointed out that other antibiotics such as the tetracyclines also have anti-inflammatory effects and have been shown to be efficacious in some respiratory diseases (15). Whether the tetracyclines are equally or more effective than the macrolides with fewer serious side effects is unknown.

Richard A. Robbins, MD¹

Allen R. Thomas, MD²

Manoj Mathew, MD³

¹Phoenix Pulmonary and Critical Care Research Foundation, ²Phoenix VA Medical Center, ³Banner Good Samaritan Medical Center.

References

1. Nagai H, Shishido H, Yoneda R, Yamaguchi E, Tamura A, Kurashima A. Long-term low-dose administration of erythromycin to patients with diffuse panbronchiolitis. Respiration. 1991;58(3-4):145-9. [CrossRef] [PubMed] 
2. Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, Coquillette S, Fieberg AY, Accurso FJ, Campbell PW 3rd; Macrolide Study Group. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA. 2003;290(13):1749-56. [CrossRef] [PubMed]
3. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. 2008;178(11):1139-47. [CrossRef] [PubMed]
4. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA Jr, Criner GJ, Curtis JL, Dransfield MT, Han MK, Lazarus SC, Make B, Marchetti N, Martinez FJ, Madinger NE, McEvoy C, Niewoehner DE, Porsasz J, Price CS, Reilly J, Scanlon PD, Sciurba FC, Scharf SM, Washko GR, Woodruff PG, Anthonisen NR; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-98. [CrossRef] [PubMed]
5. Uzun S, Djamin RS, Kluytmans JA, Mulder PG, van't Veer NE, Ermens AA, Pelle AJ, Hoogsteden HC, Aerts JG, van der Eerden MM. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2014;2(5):361-8. [CrossRef] [PubMed]
6. Li H, Liu DH, Chen LL, Zhao Q, Yu YZ, Ding JJ, Miao LY, Xiao YL, Cai HR, Zhang DP, Guo YB, Xie CM. Meta-analysis of the adverse effects of long-term azithromycin use in patients with chronic lung diseases. Antimicrob Agents Chemother. 2014;58(1):511-7. [CrossRef] [PubMed]
7. Herath SC, Poole P. Prophylactic antibiotic therapy in chronic obstructive pulmonary disease. JAMA. 2014;311(21):2225-6. [CrossRef] [PubMed]
8. Wong C, Jayaram L, Karalus N, Eaton T, Tong C, Hockey H, Milne D, Fergusson W, Tuffery C, Sexton P, Storey L, Ashton T. Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet. 2012;380(9842):660-7. [CrossRef]  [PubMed]
9. Altenburg J, de Graaff CS, Stienstra Y, Sloos JH, van Haren EH, Koppers RJ, van der Werf TS, Boersma WG. Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial. JAMA. 2013;309(12):1251-9. [CrossRef] [PubMed] 
10. Serisier DJ, Martin ML, McGuckin MA, Lourie R, Chen AC, Brain B, Biga S, Schlebusch S, Dash P, Bowler SD. Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: the BLESS randomized controlled trial. JAMA. 2013;309(12):1260-7. [CrossRef] [PubMed]
11. Brusselle GG, Vanderstichele C, Jordens P, Deman R, Slabbynck H, Ringoet V, Verleden G, Demedts IK, Verhamme K, Delporte A, Demeyere B, Claeys G, Boelens J, Padalko E, Verschakelen J, Van Maele G, Deschepper E, Joos GF. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013 Apr;68(4):322-9. [CrossRef] [PubMed] 
12. Wong EH, Porter JD, Edwards MR, Johnston SL. The role of macrolides in asthma: current evidence and future directions.  Lancet Respir Med. 2014 2:657-70. [CrossRef] [PubMed]
13. Abe S, Nakamura H, Inoue S, Takeda H, Saito H, Kato S, Mukaida N, Matsushima K, Tomoike H. Interleukin-8 gene repression by clarithromycin is mediated by the activator protein-1 binding site in human bronchial epithelial cells. Am J Respir Cell Mol Biol. 2000;22(1):51-60. [CrossRef] [PubMed] 
14. Albert RK, Schuller JL; COPD Clinical Research Network. Macrolide antibiotics and the risk of cardiac arrhythmias. Am J Respir Crit Care Med. 2014;189(10):1173-80. [CrossRef] [PubMed] 
15. Rempe S, Hayden JM, Robbins RA, Hoyt JC. Tetracyclines and pulmonary inflammation. Endocr Metab Immune Disord Drug Targets. 2007;7(4):232-6. [CrossRef] [PubMed] 

Reference as: Robbins RA, Thomas AR, Mathew M. August 2014 Phoenix pulmonary journal club: the use of macrolide antibiotics in chronic respiratory disease. Southwest J Pulm Crit Care. 2014;9(2):130-2. doi: http://dx.doi.org/10.13175/swjpcc109-14 PDF

July 2012 Pulmonary Journal Club

Castro M, Rubin AS, Laviolette M, Fiterman J, De Andrade Lima M, Shah PL, Fiss E, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med 2010;181:116-24. (Click here for full text version of the reviewed manuscript)

Bronchial Thermoplasty is a procedure that inserts a radiofrequency catheter to deliver thermal energy to the bronchial smooth muscle. The procedure is done via bronchoscopy. The application of thermal energy reduces smooth muscle mass and contraction, thereby reducing bronchoconstriction and airflow obstruction. Preliminary investigations were performed in 2004 with larger nonrandomized trials to follow in 2006. This study was the first large randomized, double-blinded, sham-controlled trial looking at the effects of bronchial thermoplasty on asthma related quality of life.

This study was performed in 30 centers over 6 countries. The primary endpoint was the effect of this procedure on asthma quality of life questionnaire (AQLQ). Secondary endpoints looked at symptom free days, morning peak expiratory flow values, FEV1, asthma exacerbations, emergency room visits and doctor visits and missed day from work. Inclusion criteria were age 18-65, asthma diagnoses with need for inhaled corticosteroid and long acting beta agonist, nonsmoker x 1 year, FEV1 > 60%, and an AQLQ of < 6.25. All patients were followed up to 1 year at intervals of 3, 6, 9, and 12 months. A total of 297 patients were included in the study with 198 pts in the treatment arm and 101 patients in the sham group. The treatment group received application of bronchial thermoplasty at intervals of 0, 3, and 6 weeks. The bronchoscopist was unblinded to the treatment arm but patients as well as all follow up personnel remained blinded throughout the study.

The results of the study showed that patients receiving bronchial thermoplasty did improve their AQLQ score by 1.35 vs. 1.16 in the SHAM group. A value of > 1.0 in the AQLQ is considered to me a moderate improvement. Secondary outcomes showed a 32% reduction in severe asthma exacerbations within the treatment arm when compared to SHAM. In addition there was also a decrease in days lost from work/school in the treatment arm. Interestingly enough the treatment arm did not show an improvement in FEV1 when compared to SHAM. Main side effects were post procedure bronchoconstriction and asthma exacerbations with a higher rate of side effects in the treatment group.

With our current institution now offering this procedure we find ourselves asking “who is now the ideal candidate for bronchial thermoplasty?” Phenotypes in asthma vary greatly and I believe we need to identify the correct phenotype before this procedure gains mass appeal and acceptance. Given the post procedure rates of acute exacerbations and need for hospital admissions, the procedure needs to be used with caution. The long term data and safety profile look promising, however we still need more information on the histologic response to bronchial thermoplasty. For now this new technology remains exciting but further longitudinal studies are needed to identify efficacy, safety and phenotype selection.

Manoj Mathew, MD

Associate Editor, Pulmonary Journal Club

Reference as: Mathew M. July 2012 pulmonary journal club. Southwest J Pulm Crit Care 2012;5:52-3. (Click here for a PDF version of the journal club)

April 2012 Pulmonary Journal Club

Johnston SL, Blasi F, Black PN, Martin RJ, Farrell DJ, Nieman RB; TELICAST Investigators. The effect of telithromycin in acute exacerbations of asthma. N Engl J Med 2006;354:1589-1600. (Click here for a PDF version of article)

Acute asthma exacerbations are typically treated with inhaled beta agonists, inhaled anticholinergics, and systemic glucocorticoids.  There has been minimal evidence for the use of antibiotics in treating acute asthma exacerbations including only 2 small placebo-controlled studies that demonstrated no benefit.

The Telithromycin, Chlamydophilia, and Asthma Trial (TELICAST) was a double-blinded, randomized, placebo-controlled study to determine the effect of telithromycin in patients with acute asthma exacerbations in addition to standard therapy.  Of the 278 patients who were enrolled, 270 underwent randomization to receive placebo (136 participants), or telithromycin (134 participants) for 10 days of therapy which was initiated within 24 hours after initial presentation.  The investigators found improvement of symptoms in the telithromycin group (40.4% reduction vs. 26.5%, p=0.005), however, there was no difference in peak expiratory flow rates (78.3 L per minute vs. 66.8 L per minute, p=0.28).  There was also a reduction in the asthma symptom score (51.1% vs. 28.5%, p=0.003) and an improvement in the FEV1 (0.63 L vs. 0.34 L, p=0.001) after 10 days of treatment.  Patients infected with C. penumoniae, M. pneumonia, or both in the telithromycin group had greater improvement in their FEV1 (0.67 vs. 0.38, p=0.002), while those without these infections had no statistically significant improvement in their FEV1 (0.58 L vs. 0.46 L, p=0.486).  Nausea was a common symptom in the telithromycin group as well as mild liver enzyme elevation in 2 patients.

This study demonstrates the possible benefits of treating acute asthma exacerbations with antibiotics, suggesting treating atypical bacteria may result in an improvement of symptoms and lung function.  Given conflicting data on this topic further study is needed to duplicate these results in addition to determining whether these results are due to the antimicrobial activity or immunomodulatory effects of macrolides.  This may be challenging due to the inherent difficulty in isolating atypical respiratory organisms.  When treating acute asthma exacerbations the use of macrolides in addition to standard therapy warrants consideration.

Jonathan Olsen, DO

Manoj Mathew, MD, FCCP, MCCM

Associate Editor, Southwest Journal of Pulmonary

   and Critical Care

Reference as: Olsen J, Mathew M. April 2012 pulmonary journal club. Southwest J Pulm Crit Care 2012;4:101. (Click here for a PDF version of the journal club)