Aminophylline

Background: Aminophylline therapy in elderly patients with COPD is rarely studied. This study attempted to explore the symptoms, pulmonary function improvement, and adverse events related to aminophylline therapy in COPD patients of different age groups.

Methods and results: We designed a 10-week prospective study. Two groups of COPD patients were classified based on age (30 patients in group 1, 55 to 74 years old; 30 patients in group 2, 75 to 90 years old), with matched disease severity. After stopping all methylxanthines for 2 weeks in the washout period, therapy began with long-acting 225-mg aminophylline compounds bid po for 8 weeks. Pulmonary functions, respiratory symptoms, and laboratory examinations were checked at the initial visit and at every 4-week visit. After aminophylline therapy, the drug serum level showed no significant difference in either group (9.73 [+ or -] 6.35 mg/dL [+ or -] SD] in group 1 and 7.82 [+ or -] 6.68 mg/dL in group 2, p = 0.359). Improvements of [FEV.sub.1] and FVC were noted in both groups; however, there was no significant difference. Peak expiratory flow rate (PEFR) was significantly improved in group 1 but not in group 2 (group 1, from 3.51 to 3.97 L/s, p < 0.05; group 2, from 2.78 to 3.08 L/s, p > 0.05). The degree of improvement in symptom scores was not different between the groups, except there was significantly less chest tightness in group 2 (from 0.79 [+ or -] 0.74 to 0.40 [+ or -] 0.50, p < 0.05). Electrolyte imbalance and arrhythmia did not appear in either group.

Conclusions: Our study demonstrated that the safety and drug concentration of aminophylline at a standard dose are not different in the sixth to ninth decades of COPD patients. Younger patients have more improvement in PEFR than older patients; however, older COPD patients have more symptoms relief in chest tightness after aminophylline therapy.

Key words: age; aminophylline; COPD; pulmonary function; side effect

Abbreviations: DLCO = diffusing capacity of the lung for carbon monoxide; PEFR = peak expiratory flow rate

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Theophylline is a methylxanthine similar in structure to the common dietary xanthines caffeine and theobromine. Aminophylline is the ethylenediamine salt of theophylline with higher solubility at a neutral pH. Aminophylline has been indicated for the treatment of asthma and COPD for > 50 years, and remains one of the most widely prescribed drugs for the treatment of obstructive airway diseases, as it is inexpensive. Accumulating evidence indicates that IV aminophylline has many side effects, and is of less benefit in acute exacerbations of COPD. (1) In many industrialized countries, however, theophylline has become a second-line treatment that is used only for some poorly controlled patients. This has been reinforced by various guidelines for COPD therapy. The frequency of side effects and the relatively low efficacy of theophylline have recently led to reduced usage, because inhaled [[beta].sub.2]-agonists are far more effective as fast-onset bronchodilators, and inhaled corticosteroids have a greater anti-inflammatory effect. (2,3) However, adding theophylline can decrease the dosage of inhaled corticosteroid in the control of moderate COPD. (4)

Aminophylline is absorbed rapidly after oral administration. Peak serum levels occur in 1.5 to 2 h. The half-life is 4 to 8 h in young adults, and is shorter in children and smokers. Theophylline is eliminated by the hepatic cytochrome P-450 system (85 to 90%) and urinary excretion (10 to 15%). Diet, cardiac or liver disease, tobacco use, and several medications affecting the cytochrome P-450 system can affect the half-life of theophylline. Therapeutic serum levels range from 10 to 20 [micro]g/mL. Toxic levels are considered to be those > 20 [micro]g/mL; however, medication, diet, and underlying diseases can alter the narrow therapeutic window of theophylline, and adverse effects may also occur within the normal therapeutic range. (5) Theophylline affects the cardiovascular, neurologic, GI, and metabolic systems. Hypokalemia, hyperglycemia, hypercalcemia, hypophosphatemia, and acidosis commonly occur after an acute overdose. (5) In the United States, the 2002 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System documented 585 theophylline overdose exposures treated in health-care facilities; 39 exposures were reported to have major adverse outcomes, and eight fatalities were noted. (6) The age population of COPD patients is always > 50 years old, and the reduced-dose usage of theophylline is often recommended in these elderly people. Therefore, in this study, we explored the efficacy and safety of aminophylline in elderly COPD patients, and compared the differences between the < 75-year-old group and the senior group.

MATERIALS AND METHODS

We designed a 10-week prospective study, and patients were enrolled from March 2002 to September 2002. Patients who fulfilled the 2001 Global Initiative for Chronic Obstructive Lung Disease guidelines for moderate COPD (7) and who had 30 to 80% [FEV.sub.1] predicted values on the first visit were enrolled into the study. The exclusion criteria were an exacerbation of the disease status within the recent 2 months, a > 12% [FEV.sub.1] increase after a bronchodilator test, and the presence of chronic renal and heart disease. We used an adherence-to-protocol analysis, and the study population comprised 60 patients classified into two groups based on age (30 patients in group 1, 55 to 74 years old; 30 patients in group 2, 75 to 90 years old). After stopping all methylxanthines for a 2-week washout period, the patients underwent lung function testing including diffusing capacity of the lung for carbon monoxide (DLCO). Long-acting aminophylline compounds were then administered, 225 mg bid po for 8 weeks, and other medications for COPD currently in use were continued. The severity of daily respiratory symptoms, including sleep disturbance and daytime symptoms (breathlessness, cough and chest tightness), were each given a score of 0 to 4, where 0 denoted no symptoms and 4 indicated the greatest severity (Table 1). This scoring system has also been adapted by a clinical trial (8) of formoterol in patients with COPD.

Pulmonary function and laboratory examinations were checked at every 4-week visit. The protocol was approved by the research and ethical committees of our hospital, and all informed consents were obtained from the patients.

For the statistical analysis, the study was designed with a sample size of 60 completed, per protocol, to achieve at least 80% power, in order to detect a 0.35-L difference of FVC and 1.0 difference of total symptom score. Baseline characteristics were compared using unpaired t tests for continuous variables and [chi square] tests for categorical variables. The mixed-factorial, two-way analysis of variance was used to evaluate the effect of aminophylline treatment, the difference in the two age groups, and the interaction of these two factors in the 60 COPD patients. The post hoc tests for differences between before and after treatment in each group were determined by Dunn (Bonferroni) correction. A p value < 0.05 was considered statistically significant. All analyses were carried out using statistical software (GB-STAT, Version 6.0; Dynamic Microsystems; Silver Spring, MD).

RESULTS

The demographic characteristics of the patients in the two age groups are shown in Table 2. The mean age of the patients in group 1 was 64.2 years (SD, 6.3; range, 55 to 74 years), and in group 2 was 80.1 years (SD, 4.6; range, 75 to 90 years). There were no statistical differences in the body mass index, heart rate, and respiratory rate in the two groups. Although the baseline actual values of [FEV.sub.1], FVC, and peak expiratory flow rate (PEFR) were higher in group 1 (1.31, 2.27, and 3.51 L/s, respectively) than in group 2 (1.09, 1.85, and 2.78 L/s, respectively), the percentage of predicted values was not different. Other pulmonary function parameters, including [FEV.sub.1]/ FVC, functional residual capacity, residual volume, total lung capacity, and DLCO, did not differ between the two groups.

After 2 months of therapy with aminophylline, the serum theophylline levels showed no significant difference in both groups (9.73 [+ or -] 6.35 mg/dL in group 1 and 7.82 [+ or -] 6.68 mg/dL in group 2, p = 0.359). Pulmonary function before and after treatment in the two groups is summarized in Table 3. [FEV.sub.1] was increased after aminophylline therapy in the patients of group 1 (1.31 to 1.44 L) and the group 2 patients (1.09 to 1.16 L), but neither of them had statistic significance. PEFR was significant increased in group 1 (3.51 to 3.97 L/s, p < 0.05) but not in group 2 (2.78 to 3.08 L/s). The symptom scores and electrolytes before and after treatment were summarized in Table 4. Group 2 showed more severe symptom scores with borderline statistic significance (p = 0.062). There was no significant improvement in sleep disturbance, breathlessness, and cough in both groups. However, the patients of group 2 showed significantly abated chest tightness after treatment (from 0.79 [+ or -] 0.74 to 0.40 [+ or -] 0.50, p < 0.05). Slight decreasing serum levels of sodium and potassium were related to treatment, but not significantly, and were not affected by age. Neither electrolyte imbalance nor arrhythmia was found on either group in the study period.

DISCUSSION

For years, aminophylline has been recommended for use as a bronchodilator in many COPD treatment guidelines (7,9-14); more recently, the 2003 Global Initiative for Chronic Obstructive Lung Disease9 suggested methylxanthines as a long-acting bronchodilator for moderate-to-severe COPD management. IV aminophylline dosage adjustments based on age and underlining medical conditions have been documented, (15) but there is no real recommendation for an oral aminophylline dosage in the current literature. Au et al (16) reported elderly (> 60 years old) COPD patients receiving IV aminophylline had a 36% lower theophylline clearance and a 40% longer serum theophylline elimination half-life than did patients < 60 years old. However, Armijo et al (17) reported the differential pharmacokinetics of oral aminophylline in elderly COPD patients aged 60 to 87 years, and there was no significant correlation between the patient age and drug clearance within this elderly population. Although elderly patients have several risk factors that may increase the serum theophylline level, such as reduced drug clearance, cardiovascular diseases, and multiple concomitant medication,16 we demonstrated no significant difference of the theophylline serum levels after 2 months of aminophylline treatment in different old-age groups.

Since COPD more commonly occurs in men, and most patients at Taipei Veterans General Hospital are elderly Chinese men, all of the patients in this study were Chinese men > 55 years old. Until now, no scientific data have demonstrated that aminophylline toxicity is specific to race or gender. There was no significant interaction of age and oral long-acting aminophylline treatment in COPD patients; however, further post hoc tests revealed a significant improvement of PEFR in group 1 and relief of symptom of chest tightness in group 2 (Tables 3 and 4). The improvement of PEFR indicated that the caliber of the airways was significantly dilated in relatively younger COPD patients. The treatment responses of PEFR and [FEV.sub.1] were not equivalent, and [FEV.sub.1] showed a smaller degree of improvement in all patients. The degree of improvement of FVC and [FEV.sub.1] were similar; hence, [FEV.sub.1]/FVC ratios were almost constant during treatment. The symptoms of COPD are related to lung hyperinflation, airflow limitation, and airway hyperreactivity. All of the symptoms were improved in most patients after treatment, but only relief of chest tightness in group 2 reached statistic significant level. A study (18) of asthma concluded that the symptom of chest tightness in obstructive lung disease was caused by airway receptors stimulation, while others (19) suggested that the chest tightness was related to lung hyperinflation and airflow limitation. No significant adverse event, such as arrhythmia, anxiety, nausea, or vomiting, was noted during the study period. Electrolytes were essentially normal, although the potassium concentration slightly decreased approximately 5%, even within the normal range, in patients in group 1. However, a recent large-scale prospective study (20) in Japan suggested that sustained-release theophylline can be used safely in elderly patients ([greater than or equal to] 65 years old) with asthma or COPD.

Our study has some limitation. The lack of a placebo-control group may complicate the interpretation of this open study, but it is also an ethical issue. Another problem is the relative short duration of the study, which may not provide strong evidences on the long-term safety of oral aminophylline. Others (10,12) assume that longer treatment may lead to further electrolyte imbalance. Thus, more large-scale randomized control studies may be necessary to answer these issues.

In conclusion, when oral, long-acting aminophylline is used in elderly COPD patients, dosage adjustment may not be a requisite. Our study demonstrated that the safety and drug concentration of aminophylline at a standard dose did not differ from the sixth to ninth decades of life. Younger COPD patients have more improvement in PEFR than older patients; however, older COPD patients have more symptoms relief in chest tightness after aminophylline therapy.

ACKNOWLEDGMENT: The authors thank Professor Yu-Ru Kou for his help with statistic analysis.

Manuscript received November 10, 2004; revision accepted March 1, 2005.

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Cheng-Yu Chen, MD; Kuang-Yao Yang, MD; Yu-Chin Lee, MD; and Peury-Perng Perng, MD, PhD

* From the Institute of Emergency and Critical Medicine (Dr. Chen), Institute of Clinical Medicine (Dr. Yang), and School of Medicine (Dr. Lee), National Yang-Ming University; and Chest Department (Dr. Perng), Taipei Veterans General Hospital, Taipei, Taiwan, ROC.

Correspondence to: Kuang-Yao Yang, MD, Chest Department, Taipei Veterans General Hospital, No. 201, Sec. 2 Shih-Pai Rd, Taipei, Taiwan, ROC; e-mail: kyyang@vghtpe.gov.tw

correction.

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