Comparing the Efficacy of Aminophylline and Caffeine in Treatment of Apnea of Prematurity; A Randomized Clinical Trial

Introduction:

Apnea of prematurity (AOP) is a common problem in preterm infants which also involves term infants less commonly. AOP occurs in infants with gestational ages of lower than 37 weeks without precise reason and is one of the most common causes of medication therapy in infants (1-3).AOP may be hereditary or associated with other conditions such as sepsis, anemia, pneumonia, metabolic disorders, GERD or neurologic disorders. Prevention of preterm labor is the most effective method for anticipating prematurity complications such as respiratory distress syndrome, intraventricular hemorrhage, bronchopulmonary dysplasia, retinopathy of prematurity as well as apnea (1, 4-8).

Caffeine, Theophylline, and Aminophylline have been used for treatment of AOP as respiratory stimulators. Previously, Theophylline was the most common standard treatment for AOP and needed serial serum level monitoring. Since FDA approval of Caffeine for infants, it has been widely replaced for Theophylline as the first medication for management of AOP (4). Methylxantines improve duration of ventilation, CO2 sensitivity, hypoxia, respiratory depression, diaphragmatic activity and fatigue and decrease apnea incidence in 2-7 days after prescription (4, 9, 10).

In the present study we aimed to compare effectiveness and adverse effects of Aminophylline versus Caffeine in apnea of prematurity as a randomized clinical trial.

Patients and methods:

This randomized clinical trial study was conducted between March and September 2017 at NICU ward of Najmiyeh University Hospital, Tehran, Iran. Study protocol was registered at ethics committee of Baqiyatallah University of Medical Sciences. Figure 1 shows the flowchart of the trial. Premature infants who were hospitalized in NICU ward of Najmiyeh Hospital due to apnea were assessed for eligibility. Diagnosis was confirmed by a neonatologist and through symptoms such as heart rate, cyanosis, bradychardia and apnea. Patients were selected using simple random selection. Infants with gestational age of less than 35 weeks and birthweight of less than 1800 gr were included in the trial. Patients with craniomaxillofacial or chromosomal anomalies as well as those who did not develop apnea in first 5 days of birth were excluded from the study. Demographic information as well as blood pressure, respiratory rate, oxygen saturation before and after ventilation, duration of hospitalization, need for re-intubation, blood sugar and feeding tolerance were recorded in a pre-designed checklist. Also, complications such as necrotizing enterocolitis (NEC), pneumothorax, intraventricular hemorrhage (IVH), need for NCPAP, pneumonia and bronchopulmonary dysplasia (BPD) as well as adverse effects of medications were recorded.

After explanation of study protocol for parents and signing an informed consent form infants were randomly allocated to two groups using random number table; infants in group A received 5mg/kg of Aminophylline as bullous dose and 1.5 mg/kg TDS; while, Group B infants underwent treatment with 20mg/kg of Caffeine as bullous dose and 5mg/kg daily. We had no lost to follow-ups and all the patients completed the trial.

Data were analyzed using SPSS software version 21 (SPSS Inc., Chicago, IL) for Microsoft Windows. Normal distributed variables (approved by 1-sample Kolmogorov-Smirnov test) were compared using independent sample t test between the groups. The chi square test was used to compare categorical variables in the 2 groups. Mean and standard deviation (SD) were used for describing categorical variables. A p value of less than 0.05 was considered as statistically significant.

 Figure 1. Study flowchart

Results:

Eventually 64 (21 female and 43 male) premature infants were investigated (p=0.185).Mean of gestational age in infants who received caffeine (group A) was 31.27 weeks and in infants who received aminophylline (group B) was 31.07 weeks (p=0.806) .Also mean birthweight in group A was 1481.25 gr and 1476 gr in group B (p=0.949). Mean Apgar score was 7.23 in group A and 7.73in group B (p=0.061).

We investigated some variables that have effects on the condition of the newborns under study. One of the mothers in group A had gestational diabetes and two mothers had this problem in group B (p=0.595).Gestational blood pressure was observed in 7 mothers of group A and 5 mothers of group B(p=0.756).Prevalence of placental abruption was 8% in group B mothers while there were no cases of placental abruption in group A(p=0.210). Received doses of each drug (except studied drugs) by two groups have been summarized in table 1.

Table 1.Received doses of each medication by each group

None of the infants in two groups had necrotizing enterocolitis, sepsis or pneumonia. Among group A infants 17.60 % had patent ductus arteriosus (PDA) and it was 6.9% in group B infants(p=0.270). Three infants in group A and two infants in group B had intra ventricular hemorrhage (IVH)(p>0.999). One infant in group B had pneumothorax(p=0.46). Prevalence of oxygen dependence in infants with 35 gestational weeks age was 18.2% in group A and 0% in group B. There was a significant difference between two groups (p=0.045) .

The mean duration of mechanical ventilation was 57.2 days in group A infants , and this was 78.2 days in group B infants(p=0.582) .Mean duration of hospitalization was 18.4 days in group A and 14.5 days in group B(p=0.939) .

Table 2 summarizes the occurrence of apnea and Table 3 shows main outcome measures of study.  According to our study the mean respiratory rate was decreased in both groups after the test.  The mean heart rate in group A decreased, but in group B, the incidence of coronary heart disease was increased. The mean oxygen concentration raised in all newborns after receiving caffeine and aminophylline. After starting treatment and using caffeine and aminophylline, the number of infants who needed mechanical ventilation and oxygen dependence was decreased.

Table 2.Frequency of apnea occurrence during the first five days of study

We expected side effects such as seizure, restlessness, tachycardia, hyperglycemia, and feeding intolerance. One of the infants receiving caffeine (2.9%) and two infants from the aminophylline group (6.7%) had seizures (p=0.596). Restlessness and tachycardia were seen in only one of the infants (group A 2.9%, group B 3.4%) of each group (p>0.999). Six infants from the caffeine group (17.6%) and four neonates from the aminophylline group (13.8%) showed hyperglycemia (p=0.741). The percentage of newborns in the aminophylline group was affected by a lack of 27.6% of infants in the caffeine group and 5.9% were ultimately fed with the tolerance (p=0.035). Using both drugs in a small number of infants, side effects were observed. The incidence of nutritional intolerance was more pronounced in the newborns treated with aminophylline.

Table 3. Main outcome measures of study

Discussion:

In the present study we found that there is no statistically significant difference for mean duration of hospitalization and also mean duration of mechanical ventilation between two Aminophylline and Caffeine groups. Also results showed that patients in Aminophylline group had a significantly less oxygen dependency in 35^th week of gestational age in comparison with Caffeine group. We assessed patients’ response to Caffeine and Aminophylline by respiratory rate, heart rate, oxygen saturation, need for mechanical ventilation and oxygen dependency.

Both Aminophylline and Caffeine groups showed a significant improvement in respiratory rate, need for mechanical ventilation and oxygen dependency. On the other hand, oxygen saturation was not significantly improved in Aminophylline receiving patients. Hear rate was decreased in Caffeine group; this decrease was not significant though.

We also found that frequency of apnea occurrence was decreased in both groups during the first 5 days of intervention; however, caffeine was more effective in the first day in comparison with Aminophylline.

A similar study was conducted by Steer et al. comparing the effects of Aminophylline and Theophylline on treatment of apnea and mechanical ventilation dependency in premature infants. They reported no significant difference between two groups for rate of apnea after intervention; however, side effects such as tachycardia or feeding intolerance were lower in Caffeine group (11).

Korvadiya et al. compared the effect of Aminophylline and Theophylline on 40 Indian premature infants with apnea of prematurity. Infants were between 28 and 36 weeks of gestational age and had 2 or more episodes of apnea in the recent 24 hours. They reported no significant difference between these two groups in terms of response to treatment and adverse effects (12).  In 2016 Dobson et al. assessed the effect of Caffeine on non-invasive respiratory support and reported beneficial effects such as decrease in duration of positive pressure respiratory support as well as development risk of bronchopulmonary diseases (BPD) (13).

Conclusion:

In conclusion the finding of the present study suggest that there is no significant difference in decreasing apnea attacks, length of hospitalization and duration of mechanical ventilation between the two Aminophylline and Caffeine groups.Future studies are suggested to be conducted with a higher sample size and to compare the therapeutic effects of Aminophylline and Caffeine in different weight and gestational age groups.

Authors’ Contributions:

BN and MS designed the study and drafted the manuscript. BN and FA helped in manuscript drafting and analysis as well as acquisition of data. All authors have approved the final version of manuscript.

Conflict of Interest Disclosures:

There are no conflicts of interest in terms of the present manuscript.

Ethical approval/Consideration:

This study was registered at ethics committee of Baqiyatallah University of Medical Sciences, Tehran, Iran. A written informed consent was taken from patients’ guardians for participating in this study. All the personal information remained anonymous.