Caffeine or theophylline for neonatal apnoea? Caffeine citrate for the treatment of apnea of prematurity: a double-blind, placebo-controlled study. High-dose caffeine suppresses postoperative apnea in former preterm infants. Treatment of acute asthma. Is combination therapy with sympathomimetics and methylxanthines indicated? Caffeine for Apnea of Prematurity trial: benefits may vary in subgroups. The efficacy of caffeine in the treatment of recurrent idiopathic apnea in premature infants. Emergency room of treatment of asthma. Relationships among therapeutic combinations, severity of obstruction and time course of response. A comparison of cyclophosphamide, adriamycin, 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisone (CMFVP) in patients with metastatic breast cancer: a Southeastern Cancer Study Group project. Double-blind evaluation of methylprednisolone versus placebo for acute asthma episodes.
Caffeine, in the dose usually recommended (12.5 mg/kg loading dose and 3 mg/kg daily maintenance), and a higher dose regimen (25 mg/kg loading and 6 mg/kg daily maintenance), was compared with theophylline (7.5 mg/kg loading and 3 mg/kg thrice daily maintenance). The study was a randomised controlled trial in the treatment of a group of 44 infants of less than 31 weeks' gestation (mean gestational age 28.3 weeks) who were suffering from frequent apnoeic attacks. All three regimens produced a significant reduction in apnoeic attacks within 24 hours, but only the higher dose caffeine and theophylline groups showed a significant improvement in apnoea within eight hours. The use of caffeine for the treatment of neonatal apnoea is recommended, because a once daily dose is more easily administered, and because it was found that plasma concentrations were more predictable than those of theophylline. If used in very preterm infants, however, its is suggested that a higher dose regimen than that previously recommended be used to achieve a faster response. To evaluate the efficacy and safety of caffeine citrate for treatment of apnea of prematurity.
                Multicenter, parallel, randomized, double-blind, placebo-controlled trial with open-label rescue.
                Nine neonatal intensive care units.
                Eighty-five infants, 28-32 weeks postconception and 24 hours or more after birth who had six or more apnea episodes within 24 hours.
                Caffeine citrate 10 mg/kg (as caffeine base) administered intravenously, followed by 2.5 mg/kg/day orally or intravenously, or placebo, for up to 10 days. Infants failing double-blind therapy could receive open-label rescue.
                Success was defined as 50% or greater reduction in apnea episodes and elimination of apnea. Caffeine citrate was significantly more effective than placebo in reducing apnea episodes by at least 50% in 6 days (p<0.05), and approached statistical significance (p<0.10) in 3 days. It was significantly better than placebo in eliminating apnea in 5 days (p<0.05), and approached significance (p<0.10) in 2 days. The number of infants with an aggregate of 7-10 days of at least a 50% reduction in apnea events or elimination of apnea was significantly higher in the caffeine citrate than in the placebo group. Adverse events did not differ significantly between groups. No correlations were found between success and mean daily plasma concentrations or baseline characteristics. Volume of distribution and clearance increased with weight, supporting weight-adjusted dosing of caffeine citrate.
                Caffeine citrate 10 mg/kg caffeine base (equivalent to 20 mg/kg caffeine citrate) intravenously followed by 2.5 mg/kg/day caffeine base (equivalent to 5 mg/kg/day caffeine citrate) either intravenously or orally for 10 days is safe and effective for treating apnea of prematurity in infants 28-32 weeks postconception. Thirty-two former preterm infants (less than or equal to 44 weeks postconceptual age) undergoing inguinal hernia repair were prospectively studied. General inhalational anesthesia with neuromuscular blockade was used. No barbiturates or opioids were given. Infants were randomly divided into two groups. Group 1 received iv caffeine 10 mg/kg immediately after induction of anesthesia. Group 2 received iv saline. Respiratory pattern, heart rate, and SpO2 were monitored using an impedance pneumograph and a pulse oximeter, respectively, for at least 12 h postoperatively. Tracings were analyzed for evidence of apnea, periodic breathing, and/or bradycardia by a pulmonologist unaware of the drug given. None of the patients who received caffeine developed postoperative bradycardia, prolonged apnea, or periodic breathing, and none had postoperative SpO2 less than 90%. In the control group 13 (81%) developed prolonged apnea 4-6 h postoperatively. Fifty percent of the patients had SpO2 less than 90% at the time. This study shows that iv caffeine 10 mg/kg is effective in the control of apnea in otherwise healthy expremature infants between 37 and 44 weeks of postconceptual age. It is still recommended, however, that all infants at risk be monitored for at least 12 h for apnea and bradycardia following general anesthesia. The role of bronchodilator regimens combining a sympathomimetic and a methylxanthine in the treatment of acute exacerbations of asthma remains controversial. This report describes the outcome of 157 emergency room visits for asthma in which patients were randomly assigned to single-drug therapy with intravenous aminophylline, subcutaneous epinephrine, or inhaled isoproterenol or to one of three regimens combining a sympathomimetic and a methylxanthine. The increase in one-second forced expiratory volume after one hour of treatment with the two-drug combinations (0.79 +/- 0.07 liter) was significantly greater than for epinephrine alone (0.57 +/- 0.08 liter; p less than 0.05) but did not differ significantly from that occurring with therapy with isoproterenol alone (0.72 +/- 0.09 liter; p = NS). This disparity reflects the greater bronchodilation effected by isoproterenol as a single agent than by epinephrine, in the dosing schedules and routes of administration chosen. Among patients presenting with severe airflow obstruction (one-second forced expiratory volume 35 percent or less of normal), the bronchodilator response to isoproterenol alone was 0.88 +/- 0.14 liter versus 0.51 +/- 0.11 for epinephrine alone (p less than 0.05). It is concluded that the observed benefit derived from use of combination therapy depends on the dosage and potency of the particular sympathomimetic to which a methylxanthine is added, and on the severity of the airflow obstruction at presentation. 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. This prospective controlled study was aimed at evaluating the efficacy of caffeine in treating recurrent idiopathic apnea in the premature infant. Eighteen preterm infants (29 to 35 weeks' gestation) were studied. Recordings during the first 24 hours and on the fifth day of caffeine treatment showed a significant decrease of severe apnea (P less than 0.01) and of mild apnea (P less than 0.001) in the treated group (group 1) as compared with the control group (group II). No treatment of apnea other than caffeine was required in group I, whereas six neonates in group II had such severe and frequent apneic episodes for more than 48 hours that withholding additional treatment was believed to be unethical. No undesirable side effects of caffeine treatment were observed. In an effort to determine the optimal emergency therapy for acute episodes of asthma, we randomly, assigned 102 acute ill patients to 60 minutes of treatment with inhaled isoproterenol alone, isoproterenol plus intravenous aminophylline or isoproterenol plus a single oral dose of an elixir of theophylline. Patients requiring treatment beyond this time were given an injectable sympathomimetic agent in addition. The combination of isoproterenol and a methylxanthine was not found to be better than isoproterenol alone, and the route of administration of methylxanthine was not an important determinant of either the serum theophylline level or the therapeutic response. A major variable that influenced the duration of therapy needed to produce a remission was the severity of the obstruction at presentation. Persons whose initial 1-second forced expiratory volumes were less than 30 percent of predicted and who did not improve 35 percent or more to at least 40 percent of predicted at the end of 60 minutes of intense treatment were those who ultimately required prolonged emergency room therapy and/or hospital admission for control of their symptoms. Thus, simple objective assessment of the degree of impairment at presentation coupled with the response to initial treatment will serve to identify early a high-risk group of asthmatic patients in whom the usual emergency room therapeutic modalities will often prove ineffective. In an ongoing prospective randomized study, 113 evaluable patients have received either a three-drug combination that included cyclophosphamide, Adriamycin and 5-fluorouracil (CAF) or a five-drug combination including cyclophosphamide, methotrexate, 5-fluorouracil, vincristine and prednisone (CMFVP) given intermittently 1 week out of 4. Responses (64%), median duration of response (32 weeks), and median duration of disease control (32 weeks) achieved with CAF were superior to those achieved with CMFVP (37%, 22 weeks, 17 weeks, respectively). Morbidity secondary to CAF was significant, with nausea and vomiting, malaise, total alopecia, and granulocytopenia being the main features. Twenty-eight children with persistent bronchospasm after outpatient therapy were treated for eight days with methylprednisolone or placebo in a prerandomized double-blind manner, in addition to treatment with optimal oral bronchodilators. At follow-up visits 1, 7, and 14 days after onset of therapy, a history was taken and physical examination and pulmonary function tests were performed. Initially and on the 14th day, patients underwent cosyntropin tests of adrenal function. Patients kept daily peak flow charts. Both groups improved with time. However, by 24 hours after starting methylprednisolone therapy, the placebo group continued to show reversibility after isoproterenol inhalation whereas the methylprednisolone group did not. By day 7 there were significantly more patients with normal 1-second forced expiratory volume (FEV1) and forced expiratory flow in the middle half of the forced vital capacity (FEF25-75%) in the methylprednisolone group and mean FEF25-75% was significantly higher for this group (P less than .02). By day 14, six days after finishing treatment with the study drugs, more patients in the placebo group had residual wheezing, but pulmonary function tests were now similar for the two groups. Although both groups showed a decline in cosyntropin responsiveness on day 14 compared with day 1, there was no difference between the steroid- and placebo-treated patients. This study proves that short-term corticosteroid therapy will accelerate resolution of moderately severe and severe-acute attacks of asthma without significant suppression of adrenal function.
Methylxanthine is effective in reducing the number of apnoeic attacks and the use of mechanical ventilation in the two to seven days after starting treatment. Caffeine is also associated with better longer term outcomes. In view of its lower toxicity, caffeine would be the preferred drug for the treatment of apnoea.