Aminophylline in COPD Exacerbations: Just Say No

Abstract & Commentary

By David J. Pierson, MD, Editor, Professor, Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, Seattle, is Editor for Critical Care Alert.

Synopsis: In a well-designed double-blind placebo-controlled clinical trial in COPD patients admitted with an exacerbation, aminophylline produced no clinically relevant benefit but increased the incidence of nausea.

Source: Duffy N, et al. Thorax. 2005;60:713-717.

In this study from the University of Liverpool, Duffy and associates sought to determine whether the addition of intravenous aminophylline produced clinically important improvements in the rates of symptomatic recovery or increases in pulmonary function, and whether it shortened hospital stay, in comparison with standard therapy without aminophylline, among patients with COPD who were admitted with an exacerbation. The latter was strictly defined according to accepted criteria, and patients with asthma, pneumonia, pneumothorax, malignancy, or serious cardiac disease were excluded. Because the use of noninvasive ventilation has become standard therapy for such patients if they are acidemic, and could have confounded the results, only patients with arterial pH > 7.32 were included.

All patients received nebulized albuterol and ipratropium every 6 hours, 30 mg of oral prednisolone every day, controlled oxygen therapy, and antibiotics as selected by their primary physicians. They were also randomized to receive either aminophylline (5 mg/kg loading dose followed by 0.5 mg/kg/hr maintenance infusion) or saline, intravenously, according to a carefully designed double-blind, double-dummy design involving adjustment and monitoring directed by individuals not involved in the patients’ care. The patients and their primary physicians, who made all management and disposition decisions, did not know whether aminophylline or saline placebo was being given. In addition to arterial blood gases and spirometry, patients were assessed by 2 different standardized daily symptom scores and followed prospectively for nausea and other possible side effects of aminophylline.

During the study period, 320 patients were screened, of whom 132 were deemed eligible, and 80 agreed to be randomized into the study. The 39 aminophylline patients and 41 placebo patients were well-matched by all criteria. Eleven patients died and 10 refused eventual follow-up, with equivalent distribution in treatment and control groups, leaving 29 aminophylline and 30 placebo patients for complete evaluation at 6 weeks following hospital discharge.

Arterial blood gases measured after 2 hours of treatment showed a small but statistically significant fall in PCO2 (mean difference of 1.25 mm Hg) and increase in pH (mean difference, 0.01 units) with aminophylline as compared to placebo. However, 46% of the aminophylline-treated patients complained of nausea, compared to 22% of the placebo-treated patients (P < 0.05). There were no statistically significant differences in the rates of change in dyspnea, post-bronchodilator spirometry, or length of hospital stay in the 2 groups. The authors conclude that, despite small but statistically significant alterations in acid-base balance, aminophylline produced no improvement in symptoms or clinical course and caused more nausea than placebo.

Commentary

Aminophylline is included among the second-line therapies recommended by current clinical practice guidelines for COPD management.1-3 However, this agent is a weak bronchodilator and its ratio of therapeutic-to-toxic effects is the worst of all currently available agents. Theophylline preparations are more likely to cause distressing symptoms and potentially life-threatening cardiovascular effects than any of the other current main-line therapies for asthma and COPD. Yet the use of aminophylline and its relatives remains widespread in the care of many patients, both for long-term maintenance and during exacerbations. This study is the largest, most rigorous examination of the effects of aminophylline on the course of exacerbations of COPD yet undertaken. Although aminophylline’s initial effects on PCO2 and pH were statistically significant, they were certainly not of a magnitude that could be important to either clinicians or patients. This statement is borne out by the lack of any demonstrable effect on symptoms of outcomes.

Ian Town, in an editorial accompanying the Duffy study,4 concluded the following: ". . . in considering the generalisability of the study, aminophylline might still be considered in the management of life threatening episodes of COPD by an experienced doctor in selected cases, together with other measures such as non-invasive ventilation. In such circumstances the benefits of respiratory stimulation and any effect on respiratory muscles may be more important than bronchodilation per se. However, for most clinical situations involving mild-to-moderate COPD exacerbations, we now have a clear answer to the question whether aminophylline should be used—and it is no.’"

Professor Town is more diplomatic than I can be on this issue. Aminophylline is a poor bronchodilator with potentially life-threatening side effects that require expensive and inconvenient monitoring. This study is the most carefully done to date, and, like the best-designed clinical studies preceding it and at least one meta-analysis, demonstrates no clinical benefit. Duffy et al excluded patients with initial arterial pH < 7.32, but there is no reason to believe that the therapeutic effect of aminophylline would be greater in more acidemic patients, and the likelihood of serious arrhythmias in such patients would be expected to be greater. We now have available much more effective, far safer bronchodilators. As far as I am concerned, the books should be closed on this antiquated and hazardous agent, at least in the acute setting. Just say no to aminophylline in exacerbations of COPD!

References

  1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). www.goldcopd.com.
  2. American Thoracic Society/European Respiratory Society Task Force. Standards for the Diagnosis and Management of Patients with COPD [Internet]. Version 1.2. New York: American Thoracic Society; 2004 [updated 2005 September 8]. www.thoracic.org/copd
  3. National Collaborating Centre for Chronic Conditions. Chronic obstructive pulmonary disease. Thorax. 2004;59(Suppl 1):1-232. thorax.bmjjournals.com/content/vol59/suppl_1
  4. Town GI. Thorax. 2005;60:709.