Aminophylline for the Prevention of Apnea During Prostaglandin E₁ Infusion

METHODS

Consecutive neonates with either known or suspected ductal-dependent congenital heart disease were recruited, and informed written consent was obtained from their parents before study enrollment. Families of infants with prenatal diagnosis of suspected ductal-dependent congenital heart disease were approached for study recruitment at time of fetal echocardiogram. All infants enrolled were born at the study facility, and no infant was transported from outlying facilities before study enrollment. The study was approved by the University of Michigan Institutional Review Board. Infants were excluded if they had prior initiation of PGE₁, were already intubated, or were thought to have imminent cardiovascular compromise.

Infants were prospectively randomized in a double-blinded fashion to receive either aminophylline or placebo, and this study drug was administered either before or during initiation of PGE₁ therapy. Aminophylline was given as an initial 6 mg/kg intravenous bolus, followed by a 2 mg/kg intravenous dose every 8 hours for 72 hours, at which time the study drug was discontinued. The 72-hour study endpoint was chosen, as review of PGE₁ use in the preceding year at the University of Michigan found that apneic events occurred within the first 48 hours. Serum aminophylline levels were obtained at the 3rd and 6th dose, with goal levels between 6 and 12 μg/mL. Serum levels were drawn in both groups to complete the blinding. Aminophylline levels were reviewed by study investigators who were not involved in clinical assessment or management of the patient. PGE₁ was started at a dose of 0.01 μg/kg/min and increased on an hourly interval to a maximum of 0.03 μg/kg/min or higher if clinically indicated.

Infants were monitored by continuous cardiorespiratory telemetry in the cardiac intensive care unit or a monitored cardiac step-down unit. Infants were prospectively evaluated during the 72 hours of the study for the following factors: birth weight, gestational age, lowest hematocrit, maximum dose of prostaglandin infusion, use of sedation, need for fluid bolus or inotropic support to treat hypotension, arterial pH, need for prophylactic antibiotics, apnea, intubation, length of postoperative recovery, and survival to discharge. Apnea was defined as >15 seconds of no respiratory effort, or >10 seconds of no respiratory effort with associated bradycardia. Indications for intubation were apnea without resumption of spontaneous respiration, recurrent apnea, or hemodynamic instability. Infants were prospectively monitored for side effects of aminophylline therapy such as irritability, arrhythmias, or seizures.

For statistical comparison, unpaired Student t test and Fisher exact test were performed, with statistical significance defined as a P value <.05.

RESULTS

Consent for participating in the study was obtained for 44 of the 48 families approached; however, 2 infants were excluded as 1 required intubation at birth and the other inadvertently had PGE₁ started before the study drug. Forty-two infants completed the study, and their demographic data are depicted in Table 1. The infants were randomly assigned to either aminophylline or placebo groups, with 21 infants in each group. No infant in the aminophylline group had a toxic or subtherapeutic drug level (mean serum level, 7.6 ± 1.2 μg/mL). The 2 groups were similar in terms of their gestational age, birth weight, and hematocrit. The highest dose of PGE₁ used was also similar between the 2 groups, with 2 infants in the aminophylline group receiving 0.05 μg/kg/min of PGE₁ without apnea, and 1 infant in the placebo group receiving 0.1 μg/kg/min of PGE₁ with resultant apnea and need for intubation. The majority of infants had prenatal diagnoses of ductal-dependent congenital heart disease (Table 1). There was no significant difference between the 2 groups in terms of their cardiac diagnoses. The high percentage of patients with single ventricle anatomy (hypoplastic left heart syndrome, unbalanced atrioventricular septal defect, and double inlet left ventricle) reflects the referral bias at the University of Michigan. The 2 groups were similar in their need for preoperative inotropic support, lowest arterial pH, antibiotic therapy, irritability, length of hospitalization, and survival to discharge.

Table 2 demonstrates the use of sedation and the incidence of apnea in the 2 groups. The frequency of sedation and the medications used were similar between the 2 groups. Although no subject in the aminophylline group became apneic with sedation, 4 of the 6 infants receiving sedation in the placebo group became apneic immediately after sedation (P = .02 vs aminophylline group), and 3 required intubation. Overall, 2 infants in the aminophylline group became apneic, 1 subject 30 minutes after initiation of PGE₁, and the other 26 hours later. Neither infant required intubation for apnea. In the placebo group, 11 subjects became apneic (P = .006 vs aminophylline group). Apnea in this group occurred from as short as a few minutes after initiation of PGE₁ to as long as 40 hours later (Fig 1). Of these 11 infants with apnea, 6 required intubation for apnea (P = .02 vs aminophylline group). One infant in each group required intubation for hemodynamic instability without associated apnea. Analysis of the groups anatomic subtypes (Table 1) with respect to single ventricle anatomy as a risk factor for apnea found no significant relationship.

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Fig 1.

The time distribution of apneic events among infants in the 2 study groups is shown. The time to first apneic event is shown. Open circles represent apneic events without intubation in the aminophylline group. No infants in the aminophylline group required intubation for apnea. Open squares represent apneic events without intubation in the placebo group, and closed squares represent apneic events with subsequent intubation in the placebo group.

DISCUSSION

We are aware of no prior reports of the use of aminophylline for the prevention of apnea in infants with congenital heart disease on PGE₁ therapy. We found that aminophylline reduced the incidence of apnea, and the need for intubation, associated with PGE₁ therapy. Although apnea was strictly defined for the purposes of this study, its determination is still somewhat subjective, based on the individual clinician’s or nurse’s judgment. During this study, apnea was observed and recorded by either the attending cardiologist or the patient’s nurse, and was based on the subjective determination of respiratory cessation. Therefore, the more clearly defined study endpoint of intubation for apnea was also used. Importantly, both study endpoints were significantly different between the 2 groups.

At the standard dose,⁷ which was used in this study, aminophylline levels were within the desired range and no significant side effects were seen. Notably, 3 infants receiving aminophylline were noted by their nurses to be irritable, and this was not seen in any of the infants on placebo.

Apnea associated with PGE₁ is potentiated by concomitant use of sedatives.⁸ In neonates with complex congenital heart disease, procedures necessitating sedation such as echocardiography or cardiac catheterization are frequent. In this study group, aminophylline reduced the incidence of apnea for those neonates receiving concomitant sedation. There was a trend for similar protection by aminophylline against intubation for apnea related to sedation.

Prospective evaluation for side effects of aminophylline therapy used in these study subjects revealed no incidence of seizures or arrhythmias or other significant side effects. Three infants in the aminophylline group were noted to have a minor side effect of increased irritability. This was neither a statistically significant difference from the placebo group, nor associated with elevated serum aminophylline levels. In contrast, the benefits of avoidance of intubation are substantial. Infants not needing intubation can be maintained in a lower intensity nursing unit at a lower cost, and are more accessible to parental interaction. Additionally, the potential complications related to intubation and mechanical ventilation are avoided.

CONCLUSIONS

This study demonstrated a protective benefit of aminophylline to prevent apnea and intubation for apnea associated with PGE₁ administration in neonates with ductal-dependent congenital heart disease.