[A comparison of the efficacy of aminophylline and doxapram in preventing idiopathic apnea in preterm newborn infants]. A blinded, randomized, placebo-controlled trial to compare theophylline and doxapram for the treatment of apnea of prematurity. Aminophylline versus doxapram in idiopathic apnea of prematurity: a double-blind controlled study. A randomized trial of inhaled versus intravenous steroids in ventilator-dependent preterm infants. Postoperative apnea in former preterm infants: prospective comparison of spinal and general anesthesia. Propofol compared with the morphine, atropine, and suxamethonium regimen as induction agents for neonatal endotracheal intubation: a randomized, controlled trial. Morphine increases synchronous ventilation in preterm infants. Prophylactic indomethacin for prevention of intraventricular hemorrhage in premature infants. Aminophylline versus doxapram in weaning premature infants from mechanical ventilation: preliminary report.
Doxapram is an analeptic of the respiratory system that has been used in the last few years for the treatment of idiopathic apnea spells in infants who show resistance to methylxantine. In this study we have compared the efficacy of aminophylline and doxapram for the prevention of idiopathic apnea spells in two groups of preterm infants comparable for gestational age, birthweight and postnatal age. The two drugs resulted to be effective in preventing the spells of apnea in 66% and 60% of the cases respectively. In the cases in which there was a partial or negative response, the association of the two substances resulted in a noticeable reduction of the apnea spells. The positive effect of the association of aminophylline and doxapram is probably due to the different action mechanism on the stimulation of the respiratory system. A blinded, randomized, placebo-controlled trial was conducted to evaluate the effectiveness of theophylline and doxapram therapy in 31 infants with significant apnea of prematurity. Of 10 infants, two had a short-term response to placebo, 8 of 10 infants to theophylline, and 7 of 11 infants to doxapram (placebo vs treatment with theophylline or doxapram: p = 0.01). The two infants who initially responded to placebo remained responsive for the duration of the study. Of the eight infants in whom treatment with placebo failed, five were randomly assigned to receive theophylline, for a total of 15 infants treated with theophylline, and two of the eight were randomly assigned to receive doxapram, for a total of 13 infants treated with doxapram; the remaining infant required tracheal intubation. Of the 15 infants randomly assigned to receive theophylline, seven responded for the duration of the study; of the eight infants who did not respond to treatment with theophylline, five responded to doxapram, one responded to a combination of theophylline and doxapram, and two remained resistant to treatment. Of the 13 infants randomly assigned to receive doxapram four responded for the duration of the study; of the nine who did not respond to doxapram, seven responded to theophylline, one responded to a combination of theophylline and doxapram, and one remained resistant to treatment. This study demonstrates that although therapy with theophylline or doxapram is associated with a significant short-term reduction in the incidence of apnea compared with that in placebo-treated infants, the long-term response to treatment is frequently incomplete and is not sustained more than 1 week. A double-blind controlled study, in two parts, was undertaken to compare the effectiveness of aminophylline and doxapram therapy in idiopathic apnea of prematurity. In the first part of this study, eight of 15 infants responded to doxapram therapy with complete cessation of apneic spells and six of 11 infants responded similarly to administration of aminophylline. These differences were statistically insignificant. In the second part of the study, assessment was made of whether the addition of doxapram to aminophylline therapy was effective in treatment of apnea of prematurity that had been unresponsive to aminophylline alone. Of ten infants who continued to have apneic spells during treatment with aminophylline, eight responded to the addition of doxapram with complete cessation of apnea. Nine infants received placebo in addition to aminophylline, and none had a reduction in frequency of apnea. Intravenous steroids improve the respiratory course in ventilator-dependent preterm infants but have adverse effects. We hypothesized that inhaled steroids would be as effective, but with less systemic effects.
                We conducted a randomized, prospective trial comparing inhaled beclomethasone, either 400 or 800 microg/d, to intravenous dexamethasone in preterm infants dependent on conventional mechanical ventilation and supplemental oxygen at 2 weeks of age.
                Seventy-eight infants were randomized. By day three of therapy, the intravenous steroid group had significantly decreased ventilator and oxygen requirements compared to either inhaled group. The inhaled 800-microg/d group trended toward more rapid decreases in ventilator and oxygen requirements than the 400-microg/d group. By day 14, all groups had similar reductions in ventilator and oxygen requirements. The incidence of adverse effects did not differ between groups.
                In this small, randomized study, inhaled steroids conferred no advantages to intravenous steroids in the management of ventilator-dependent preterm infants. Thirty-six former preterm infants undergoing inguinal hernia repair were studied. All were less than or equal to 51 weeks postconceptual age at the time of operation. Patients were randomly assigned to receive general or spinal anesthesia. Group 1 patients received general inhalational anesthesia with neuromuscular blockade. Group 2 patients received spinal anesthesia using 1% tetracaine 0.4-0.6 mg/kg in conjunction with an equal volume of 10% dextrose and 0.02 ml epinephrine 1:1000. In the first part of the study, infants randomized to receive spinal anesthesia also received sedation with im ketamine 1-2 mg/kg prior to placement of the spinal anesthetic (group 2 A). The remainder of group 2 patients did not receive sedation (group 2 B). Respiratory pattern and heart rate were monitored using an impedance pneumograph for at least 12 h postoperatively. Tracings were analyzed for evidence of apnea, periodic breathing and/or bradycardia by a pulmonologist unaware of the anesthetic technique utilized. None of the patients who received spinal anesthesia without ketamine sedation developed postoperative bradycardia, prolonged apnea, or periodic breathing. Eight of nine infants (89%) who received spinal anesthesia and adjunct intraoperative sedation with ketamine developed prolonged apnea with bradycardia. Two of the eight infants had no prior history of apnea. Five of the 16 patients (31%) who received general anesthesia developed prolonged apnea with bradycardia. Two of these five infants had no prior history of apnea. When infants with no prior history of apnea were analyzed separately, there was no statistically significant increased incidence of apnea in children receiving general versus spinal anesthesia with or without ketamine sedation. Because of the small numbers of patients studied, and the multiple factors that may influence the incidence of postoperative apnea (e.g., prior history of neonatal apnea), standard postoperative respiratory monitoring of these high-risk infants is still recommended following all anesthetic techniques. The purpose of this work was to compare the efficacy of propofol, a hypnotic agent, to the regimen of morphine, atropine, and suxamethonium as an induction agent for nonemergency neonatal endotracheal intubation. We hypothesized that propofol aids intubation by allowing the continuation of spontaneous breathing.
                We conducted a randomized, open-label, controlled trial of infants who required nonemergency endotracheal intubation. Primary outcome was successful intubation confirmed by chest auscultation and clinical examination of the infant.
                Infants randomly assigned to propofol (n = 33) and the morphine, atropine, and suxamethonium regimen (n = 30) were comparable in median gestational age (27 vs 28 weeks), birth weight (1020 vs 1095 g), weight at intubation (1068 vs 1275 g), and age at intubation (4 vs 3 days). Sleep or muscle relaxation were achieved within 60 seconds in both groups, but time to achieve successful intubation was more than twice as fast with propofol (120 vs 260 seconds). Blood pressure and heart rates were not different, but intraprocedural oxygen saturations were significantly lower in infants on the morphine, atropine, and suxamethonium regimen (trough arterial oxygen saturation: 60% vs 80%). Nasal/oral trauma was less common, and recovery time was shorter (780 vs 1425 seconds) in the propofol group. No significant adverse effects were seen in either group.
                Propofol is more effective than the morphine, atropine, and suxamethonium regimen as an induction agent to facilitate neonatal nasal endotracheal intubation. Importantly, hypoxemia was less severe, probably because of the maintenance of spontaneous breathing. A controlled environment may have promoted the ease of intubation, resulting in less trauma. The shorter duration of action would be advantageous in a compromised infant. To examine the short-term cardiorespiratory effects of intravenous morphine infusion in ventilated preterm infants.
                A randomized double-blind placebo-controlled trial in a neonatal intensive care unit. Twenty-six preterm infants (29-36 weeks gestation) with hyaline membrane disease requiring ventilatory assistance on the first day after birth were included in the study. A loading dose of morphine 100 micrograms/kg over 30 min followed by a continuous intravenous infusion at 10 micrograms/kg per hour was given. Primary measures were heart rate, blood pressure, respiratory rate and interaction of spontaneous respiration with mechanical ventilation. Secondary measures were durations of oxygen therapy, ventilator therapy and hospitalization as well as incidence of bronchopulmonary dysplasia, periventricular haemorrhage and pneumothorax.
                Morphine-treated infants spent a significantly greater percentage of total ventilated time breathing in synchrony with their ventilators (median [IQ] = 72[58-87] vs 31[17-51]%; P = 0.0008). Heart rate and respiratory rate, but not blood pressure, were reduced in morphine-treated infants. Duration of oxygen therapy was reduced (median [IQ] = 4.5[3-7] vs 8[4.75-12.5] days; P = 0.046).
                Intravenous morphine infusion increases synchronicity of spontaneous and ventilator-delivered breaths in preterm infants. Morphine reduces heart rate and respiratory rate without reducing blood pressure, and may help to reduce duration of oxygen therapy in preterm infants with hyaline membrane disease. The impact of early prophylactic use of intravenous indomethacin on the incidence and severity of periventricular-intraventricular hemorrhage and patent ductus arteriosus in 199 oxygen-requiring premature infants (less than or equal to 1300 g birth weight) was prospectively investigated. The trial was controlled, the infants were randomized, and the investigators were unaware of the group assignments. Patients with minimal (grade I) or no periventricular-intraventricular hemorrhage determined by prestudy echoencephalography were randomized within two birth weight subgroups (500 to 899 and 900 to 1300 g) to receive either prophylactic indomethacin (n = 99) or an equal volume of saline-vehicle placebo (n = 100). The first dose (0.2 mg/kg) was given within 12 hours of delivery and two subsequent doses (0.1 mg/kg) were administered at 12 hourly intervals. Prophylactic indomethacin significantly reduced the incidence of grades II to IV periventricular-intraventricular hemorrhage. Intraventricular hemorrhage was half as common in infants given prophylactic indomethacin as in control infants (23% v 46%, P less than .002). The reduction was manifested in both birth weight subgroups. Results of this study also confirmed a lower incidence of clinically significant patent ductus arteriosus in infants who received prophylactic indomethacin in contrast to those who received placebo (11% v 42%, P less than .001). No significant differences were found between treatment and control groups in the duration of oxygen therapy, mechanical ventilation, or hospitalization or in the incidence of pneumothorax, chronic lung disease, sepsis, necrotizing enterocolitis, retinopathy of prematurity, or death. Early prophylactic indomethacin initiated within 12 hours of delivery is effective in reducing the incidence of intraventricular hemorrhage as well as clinically significant patent ductus arteriosus in very low birth weight premature infants. A small, double-blind crossover study compared the efficacy of aminophylline and doxapram in ventilator weaning of eight premature infants recovering from respiratory distress syndrome (RDS). Although neither drug was significantly better than the other, four infants were weaned from mechanical ventilation after drug administration. It is suggested that drugs stimulating the respiratory center may aid in shortening the duration of mechanical ventilation in premature infants recovering from RDS.
Intravenous doxapram and intravenous methylxanthine appear to be similar in their short term effects for treating apnea in preterm infants, although these trials are too small to exclude an important difference between the two treatments or to exclude the possibility of less common adverse effects. Long term outcome of infants treated in these trials has not been reported. Further studies would require a large number of infants to clarify whether there might be differences in responses or adverse effects with these two drugs at different ages.