Apnoea of immaturity. 1. A controlled trial of theophylline and face mask continuous positive airways pressure. Limitations of theophylline in the treatment of apnea of prematurity. The therapeutic actions of theophylline in preterm ventilated infants. Comparative efficacy of theophylline and caffeine in the treatment of idiopathic apnea in premature infants. A randomized, controlled trial of theophylline in patients with severe chronic obstructive pulmonary disease. Theophylline treatment in the extubation of infants weighing less than 1,250 grams: a controlled trial. Is oral theophylline effective in combination with both inhaled anticholinergic agent and inhaled beta 2-agonist in the treatment of stable COPD? Sustained-release theophylline reduces dyspnea in nonreversible obstructive airway disease. Theophylline in obstructive sleep apnea. A double-blind evaluation.
A randomised controlled trial of theophylline versus face-mask continuous positive airways pressure (CPAP) treatment for recurrent apnoea of immaturity was carried out in 32 infants of 25 to 32 weeks' gestation. Continuous recording of electrocardiogram and impedence pneumogram added objective assessment to the nurses' observations for 11 courses of treatment. The CPAP group had more adverse perinatal factors but the frequency of apnoeic attacks before treatment was comparable. Infants given theophylline had a greater reduction in the incidence of prolonged apnoeic attacks, and this difference persisted after allowing for the effect of perinatal complications. Continuous recordings showed a greater reduction in episodes of bradycardia of less than or equal to 80/minute with theophylline. Five of 18 infants given theophylline needed intermittent positive pressure ventilation for apnoea compared with 12 of 14 given CPAP. The poor response in 17 of 32 infants suggests a need for a more effective method of preventing or treating apnoea in very immature babies, in whom adverse perinatal factors often coexist. Theophylline is commonly used to treat apnea of prematurity. To determine the effectiveness of theophylline with respect to gestational and postnatal age, we conducted a controlled study in 43 premature infants with idiopathic apnea. Three of the 21 treated and eight of the 22 control infants developed respiratory failure. Eight of the 11 infants with respiratory failure had gestational ages of less than 31 weeks and had more than four apneic episodes during the first day of life. In the treated infants without respiratory failure, the number of apneic episodes by 24-hour intervals declined six days earlier than in the control infants. Apnea disappeared, however, at a similar time in both groups. Three treated infants and three control infants had apneic episodes persisting beyond the neonatal period. Patients treated with theophylline did not develop respiratory failure as often as control infants did. However, despite a reduction of apneic episodes, theophylline did not shorten the course of apnea of prematurity. 40 preterm, ventilated infants (gestational ages 24-33 weeks) were entered into a double-blind randomised trial to assess the effect of oral theophylline on lung function and ventilator dependence. Theophylline administration was associated with a significant improvement in compliance (P less than 0.05) and hastened weaning from ventilation (P less than 0.01). The purpose of our prospective randomized study was to compare the efficacy of theophylline ethylenediamine and caffeine sodium citrate in the treatment of idiopathic apnea in premature infants. Sixteen infants with three or more severe apneic attacks were studied. Twenty-four-hour cardiorespiratory recordings immediately before and after randomization and four days later showed similar significant decreases of the apnea frequency in both theophylline- (group 1, n = 8) and caffeine-treated infants (group 2, n = 8). No undesirable side effects were observed, except for tachycardia in one infant in group 1. We suggest reasons for preferring caffeine to theophylline in the control of idiopathic apnea in premature infants: caffeine is as efficient and easier to administer. To assess the effects of theophylline in chronic obstructive pulmonary disease, we conducted a randomized, placebo-controlled, double-blind, crossover trial in 60 patients with severe but stable disease. The patients (mean age, 61 years) were studied before and after two months of placebo and two months of treatment with a sustained-release preparation of theophylline (10 mg per kilogram of body weight per day), administered orally. The two treatments were administered in a random order and separated by an eight-day washout period. After taking theophylline for two months (mean plasma concentration, 14.8 mg per liter), as compared with the two months of placebo, the patients had significant improvements in dyspnea, pulmonary gas exchange (partial pressure of arterial oxygen, 66 vs. 61 mm Hg [P less than 0.0001]; partial pressure of arterial carbon dioxide, 44 vs. 49 mm Hg [P less than 0.0001]), vital capacity (63 percent vs. 58 percent of the predicted value [P less than 0.0001]), and forced expiratory volume in one second (36 percent vs. 32 percent of the predicted value [P less than 0.0001]), with no significant change in airway resistance or functional residual capacity. Minute ventilation increased by a mean of 18 percent (P less than 0.0001) in the patients taking theophylline because of increased tidal volume, with no change in respiratory frequency. The respiratory-muscle performance of the patients taking theophylline improved by approximately 29 percent (P less than 0.0001), as indicated by a decline in the ratio of inspiratory pleural pressure during quiet breathing to maximal pleural pressure. We conclude that theophylline improves respiratory function and dyspnea in patients with severe chronic obstructive pulmonary disease and that these improvements are probably due to better respiratory-muscle performance. The role of theophylline in weaning infants weighing less than 1,250 g at birth from mechanical ventilation was evaluated. Infants were randomized into control or theophylline treatment groups when they required minimal ventilatory support (peak inspiratory pressure 12 cm H2O, positive end-expiratory pressure 2 cm H2O, rate 12 breaths per minute, and FiO2 less than 0.3), and they were extubated 24 hours later. Infants required reintubation if they had (1) PaCO2 greater than 55 mm Hg and pH less than 7.20, (2) FiO2 greater than 0.5, or (3) apnea associated with a heart rate less than 100 beats per minute that required frequent stimulation (more than 20 episodes during a 16-hour period). Among 32 infants (birth weight less than 1,000 g) who reached minimal ventilatory support before seven days after delivery, 13 of 18 (72%) control infants required reintubation, whereas only four of 14 (28%) theophylline-treated infants required reintubation. On the other hand, among infants (birth weight less than 1,000 g) who reached minimal ventilatory support after seven days following delivery, only one of six (17%) of the control group required reintubation and no improvement could be seen with theophylline treatment. Similarly, among control infants (birth weight 1,001 to 1,250 g), only ten of 45 (23%) required reintubation after reaching low intermittent manditory ventilation settings. In summary, most infants recovering from respiratory distress syndrome who had birth weights (1) greater than 1,000 g or (2) less than 1,000 g and who were older than seven days could be successfully extubated from minimal ventilatory support without theophylline treatment.(ABSTRACT TRUNCATED AT 250 WORDS) To investigate the additive effect of oral theophylline on combined inhaled anticholinergic agent and beta 2-agonist therapy, 12 patients with stable COPD (64.6 +/- 5.9 years) completed a randomized, double-blind placebo-controlled crossover trial of oral theophylline for a 4-week period (400 mg for 2 weeks, followed by 600 mg for 2 weeks). All of the patients continued to inhale both salbutamol, 200 micrograms, and ipratropium bromide, 40 micrograms, using a metered-dose inhaler four times a day. Spirometry was assessed before, and 15 and 60 min after the inhalation of bronchodilators at 2-week intervals. Even after the inhalation of salbutamol and ipratropium, theophylline significantly improved FEV1 and daily peak expiratory flow rate compared with the placebo. No significant improvement in the daily symptom scores for cough, sputum, wheezing, or shortness of breath was observed throughout the different phases of treatment. This study shows that the additive bronchodilating effect of theophylline, when used in combination with salbutamol, 200 micrograms, and ipratropium, 40 micrograms, is significant but small in stable COPD. The addition of theophylline did not significantly improve the patient's symptoms. Oral theophylline, when used in combination with an inhaled anticholinergic agent and an inhaled beta 2-agonist, may be of limited value in the treatment of stable COPD. Although orally administered theophylline has been prescribed widely in patients with nonreversible airway obstruction, symptomatic benefit has not been established. To assess the effects of orally administered theophylline on dyspnea, we performed a randomized, double-bind, crossover, placebo-theophylline clinical trial in 12 ambulatory male patients with moderate to severe nonreversible airway obstruction. Dyspnea was rated using 2 clinical indexes based on 3 components affecting breathlessness: functional impairment, magnitude of task that evokes dyspnea, and the associated magnitude of effort. Dyspnea and physiologic parameters were measured on 4 occasions: at baseline, 4 wk after initial treatment, a second baseline after a 2-wk washout period, and 4 wk after the second medication. For the 12 patients, mean age (+/- SD) was 60 +/- 7 yr, forced expiratory volume in one second was 1.36 +/- 0.67 L (mean, 40% of predicted), and arterial oxygen tension was 71 +/- 10 mmHg. During the treatment phase, all patients had a therapeutic theophylline blood level (range, 12 to 19 micrograms/ml). Theophylline significantly decreased the components of functional impairment (p = 0.02) and magnitude of task (p = 0.02) relating to dyspnea, as well as the overall dyspnea rating (p = 0.01). There were no significant differences between placebo and theophylline therapy for spirometry, arterial blood gas tensions, and the 12-min walking distance. Thus, sustained-release theophylline significantly reduced dyspnea in these ambulatory patients with moderate to severe nonreversible airway obstruction without altering lung function, gas exchange, or exercise performance. Twelve patients with documented obstructive sleep apnea were enrolled in a double-blind placebo controlled crossover trial of oral theophylline, (Uniphyllin) 800 mg, taken at night for four weeks. Overnight polysomnography, using standard techniques, was performed at the end of each treatment period. The total number of apneas (A) and hypopneas (H) decreased significantly while receiving theophylline compared to placebo, from 398 (69), mean (SEM), to 283 (72), p less than 0.01. Sleep quality was, however, significantly worse while receiving theophylline. Obstructive A and H were very much decreased with theophylline (p less than .001), and even when the data were adjusted for the more disturbed sleep with theophylline, this decrease remained significant; the obstructive A and H index fell from 49 (8.7) on placebo to 40 (9) while receiving theophylline, p = 0.02. There was no difference in the numbers of central or mixed A and H, and mean A and H duration was unchanged on the two study nights. Oxygen desaturations greater than 4 percent were less with theophylline treatment (p = 0.02), but mean overnight SaO2 was unchanged. We conclude that theophylline may be beneficial in patients with OSA, but part of the improvement is due to a deterioration in sleep quality.
Theophylline is more effective than mask CPAP for preterm infants with apnea. Since CPAP is no longer administered by mask, the results of this review have limited importance for current clinical practice. Further evaluation of the benefits and harms of CPAP vs theophylline for preterm infants with apnea requires further trials in which CPAP is administered by current methods.