Caffeine for Apnea of Prematurity trial: benefits may vary in subgroups. Theophylline treatment in the extubation of infants weighing less than 1,250 grams: a controlled trial. A randomized, controlled trial of aminophylline in ventilatory weaning of premature infants. Efficacy of theophylline for prevention of post-extubation respiratory failure in very low birth weight infants. The therapeutic actions of theophylline in preterm ventilated infants.
To determine whether the benefits of caffeine vary in three subgroups of 2006 participants in the Caffeine for Apnea of Prematurity (CAP) trial.
                Post-hoc subgroup analyses were performed on the basis of: (1) indication for commencement of study drug: treat apnea, prevent apnea, or facilitate extubation; (2) positive pressure ventilation (PPV) at randomization: endotracheal tube (ETT), noninvasive ventilation, or none; and (3) timing of commencement of study drug: early or late (< or =3 versus >3 days). Outcomes assessed were those showing treatment effects in the original analyses. We investigated the consistency of caffeine effects by using regression models that incorporated treatment/subgroup factor interactions.
                There was little evidence of a differential treatment effect of caffeine in subgroups defined by the clinical indication for starting study drug. The size and direction of the caffeine effect on death or disability differed depending on PPV at randomization (P = .03). Odds ratios (95% CI) were: no support, 1.32 (0.81-2.14); noninvasive support, 0.73 (0.52-1.03); and ETT, 0.73 (0.57-0.94). Adjustment for baseline factors strengthened this effect (P = .02). Starting caffeine early resulted in larger reductions in days of respiratory support. Postmenstrual age at time of discontinuing PPV was shorter with earlier treatment (P = .01). Mean differences (95% CI) were: early, 1.35 weeks (0.90-1.81); and late 0.55 weeks (-0.11-0.99). Adjustment for baseline factors weakened this effect (P = .03).
                There is evidence of variable beneficial effects of caffeine. Infants receiving respiratory support appeared to derive more neurodevelopmental benefits from caffeine than infants not receiving support. Earlier initiation of caffeine may be associated with a greater reduction in time on ventilation.
                Copyright 2010 Mosby, Inc. All rights reserved. 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 determine whether maximal inspiratory force predicts successful neonatal extubation, and whether aminophylline affects maximal inspiratory force or the success rate of extubation.
                Double-blind, prospective, randomized, placebo-controlled trial.
                Tertiary level neonatal intensive care unit.
                A total of 20 ventilated, preterm, newborn infants: birth weight < 2.5 kg; gestation < 35 wks.
                Intravenous aminophylline 4 mg/kg bolus followed by 2.5 mg/kg every 6 hrs x three doses, then 1.5 mg/kg every 6 hrs; or placebo. Drug administration began when infants were receiving an FIO2 of < 0.4 and were progressively weaning from assisted mechanical ventilation. A standardized weaning protocol was instituted, and patients were extubated when they were able to tolerate a mechanical ventilatory rate of < 5 cycles/min.
                Occlusion pressures, including maximal inspiratory force, were measured before aminophylline and daily until endotracheal extubation. Arterial blood gases were measured every 3 hrs, and 24-hr cardiac and respiratory recordings were performed postextubation. Three of ten aminophylline-treated patients failed extubation compared with two of ten placebo infants (p = nonsignificant). Mean apnea frequency postextubation was 0.02/hr in the aminophylline group compared with 0.3/hr in the placebo group (p < .05). Aminophylline had no effect on successful extubation or on maximal inspiratory force. Maximal inspiratory force was not correlated with the success of extubation. Apnea frequency postextubation was significantly reduced by aminophylline.
                Aminophylline is an effective prophylaxis for postextubation apnea in the preterm infant but does not affect maximal inspiratory force or increase the success rate of extubation in this patient population. nan 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).
Methylxanthines increase the chances of successful extubation of preterm infants within one week of age. Important neurodevelopmental outcomes are improved by methylxanthine therapy. In any future trials, there is a need to stratify infants by gestational age (a better indicator of immaturity than birth weight). Caffeine, with its wider therapeutic margin, would be the better treatment to evaluate against placebo.