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Three Part Question

In [patients with acute exacerbation of COPD] is [intravenous aminophylline effective] in [reducing the duration of hospital stay?]

Clinical Scenario

A 60 year old man with known COPD presents to the emergency admissions unit with a history of breathlessness, worsening cough with expectoration. He is hypoxic, blood gases show ph 7.36, PaCO2 6.7, PaO2 7.0 on 24% oxygen. You start him on regular salbutamol and ipratropium nebulisers, steroids and antibiotics. He appears still breathless after 2 hrs with respiratory rate of 36/ min. You wonder whether addition of intravenous aminophylline would hasten his recovery and discharge.

Search Strategy

1. Pubmed: 10 articles highly relevant. Search Criteria: intravenous[All Fields] AND ("aminophylline"[MeSH Terms] OR aminophylline[Text Word]) AND ("chronic obstructive pulmonary disease"[Text Word] OR "pulmonary disease, chronic obstructive"[MeSH Terms] OR COPD[Text Word])
2.NHS Dialog using CINAHL 1982 to May 2006, EMBASE 1974 to May 2006, MEDLINE 1996 to May 2006: 14 articles. Search Criteria: intravenous aminophylline and COPD or Methylxanthines and COPD, limit to Humans and English language, remove duplicates.

Search Outcome

One Cochrane database directly addressing our question and another randomised controlled trial published after the Cochrane review answering our question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
N Duffy et al June 2005 United Kingdom	80 patients with non-acidotic exacerbations of COPD	Randomised double-blind placebo controlled study.	1.Change in post-bronchodilator FEV1 over first 5 days of admission	1. No difference in the post-bronchodilator FEV1 between aminophylline and the placebo groups.	No reversibility studies on patients to exclude asthmatics.Only includes non-acidotic patients
			2. Difference in arterial PH	2. Significant difference in arterial PH over first two hours of treatment. (Aminophylline group had shown a larger increase in PH, p= 0.001)
			3.Changes in respiratory rate	3. No Difference between the two groups
			4. Mean length of hospital stay	4. No Difference between the two groups
			5. Follow-up at 6 weeks	5. No difference in spirometric parameters or health status between the two groups
Barr RG 2003 USA	RCTs of patients presenting with acute COPD exacerbations treated with methylxanthines or placebo	Systematic review	Changes in FEV1 at 2 hours	1 study2: small non-significant benefit with methylxanthines. Relative change in FEV1: 27% [ 95% CI: 3 to 51%] for methylxanthines Vs 22% [95% CI: 13 to 31%] for placebo	Only four trials were included in the metaanalysis. Individual trials were relatively small.
			Changes in FEV1 at 3 days of hospitalization ( 2 studies)3,4	Pooled results of the trials for FEV1 were homogenous ( p=0.36) and a fixed effects model showed a combined WMD of 101 ml (95% CI: 26 to 177ml) in favour of methylxanthines
			Clinical endpoints
			1. Reduction in hospital admission	1 Study1: statistically non-significant reduction in hospital admissions with methylxanthines use OR: 0.3; (95% CI: 0.1 to 0.8)
			2. Length of hospital stay	1 Study4: non-significant reduction in length of stay in the methylxanthine group (absolute difference - 1.4 (95% confidence interval - 2.9 to 0.1) days).
			3. Relapses within 7 days requiring medication	2 trials1,2: statistically non- significant increase in relapses in methyxanthine group. OR: 1.5;( 95% CI 0.4 to 5.2)
			4. Adverse effects	3 trials 1,3,4:Nausea, vomiting significantly higher for the patients receiving methylxanthines (OR: 4.6; 95% CI 1.7 to 12.6) than for receiving a placebo More frequent tremor with methylxanthines ( OR: 1.8; 95% CI 0.7 to 4.6) Increased incidence of arrhythmias and palpitations ( OR: 4.1; 95% CI: 0.9 to 19.6)

Comment(s)

Discussion Hospitalisation due to an acute exacerbation of chronic obstructive pulmonary disease (COPD) is one of the major causes of morbidity and mortality10. Methylxanthines produce several beneficial effects in patients with stable COPD5 including bronchodilatation, immunomodulation and bronchoprotection. They also reduce the diaphragmatic muscle fatigue, increase mucociliary clearance, block centrally mediated hypoventilation and decrease capillary leakage6. But their use in acute exacerbations along with routine measures is not supported by research evidence. Despite this the British Thoracic Society guidelines7, European Respiratory society and other guidelines either recommended or are non-committal about the use of methylxanthines in this setting. In reality, many patients with COPD have co morbidity, commonly cardiac and these patients were mostly excluded from the analyses. Thus the role of methylxanthines in this group as adjunctive therapy is not known. Similarly patients with acidotic respiratory failure were excluded in some studies and potentially these are the group who might benefit owing to the respiratory stimulant effects of methylxanthines. It is clearly evident from the Cochrane review8 and the more recent randomised control trial9 that there is no significant beneficial effect in adding intravenous aminophylline to the routine protocol. It is also clear that there is a significant increase in incidence of adverse effects and a risk of toxicity due to the narrow therapeutic index. Hence we conclude that routine addition of intravenous aminophylline in non-acidotic exacerbations of COPD confers no benefit and results in unwanted effects. References 1. Wrenn K, Slovis CM, Murphy F, Greenberg AS. Aminophylline therapy for acute bronchospastic disease in the emergency room. Ann Intern Med 1991; 115: 241-7. 2. Seidenfield JJ, JonesWN, Moss RE, Temper J. Intravenous aminophylline in the treatment of acute bronchospastic exacerbations of chronic obstructive pulmonary disease. Ann Emerg Med 1984; 13: 248-52. 3. Rice KL, Leatherman JW, Duane PG, Synder LS, Harmon KR, Abel J, et al. Aminophylline for acute exacerbations of chronic obstructive airway disease: A controlled trial.Ann Intern Med 1987: 107: 305-9. 4. Ram FSF, Poole PJ, Bagg W, Stewart, Black PN. Randomised, controlled trial of oral theophylline for the treatment of acute exacerbations of chronic obstructive pulmonary disease. Ann J Respir Crit Care Med 2000; 161 (suppl): A-489. 5. Ram FSF, Jones PW, Castro AA, DeBrito JA, Atallah AN, Lacasse Y et al. Oral theophylline for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2002; (4): CD003902. 6. Peleman RA, Kips JC, Pauwele RA. Therapeutic activities of theophylline in chronic obstructive pulmonary disease. Clin. Exp Allergy 1998; 28 ( suppl 3): 53-6. 7. British Thoracic Society Guidelines: www. Brit-thoracic.org.uk/bts-guidelines-copd-htm. 8. Barr RG, Rowe BH, Camarago CA Jr. Methylxanthines for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2003; (2): CD 002168. 9. N Duffy, P Walker, F Diamentea, PMA Calverley, L Davies. Intravenous aminophylline in patients admitted to hospital with non-acidotic exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial. Thorax 2005; 60: 713-717. 10. Calverley PM, Walker P. Chronic obstructive pulmonary disease.Lancet2003; 362: 1053-61.

Clinical Bottom Line

Addition of intravenous aminophylline in the management of non-acidotic acute exacerbations of COPD does not confer any additional clinical benefit nor does it reduce the duration of hospital stay. It is associated with an increased risk of unwanted effects.

References

1. N Duffy, P Walker, F Diamentea, PMA Calverley, L Davies. Intravenous aminophylline in patients admitted to hospital with non-acidotic exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial Thorax 2005 60: 713-717
2. Barr RG, Rowe BH, Camarago CA Jr Methylxanthines for exacerbations of chronic obstructive pulmonary disease Cochrane Database Syst Rev 2003; (2): CD 002168. Syst Rev 2003; (2): CD 002168.