Comparison of Fentanyl and Midazolam for the Sedation of Infants Under Mechanical Ventilation ; A Randomized Clinical Trial

Copyright © 2017 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http:// creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 1. Background Neonatal respiratory distress syndrome (NRDS), also known as hyaline membrane disease (HMD), is a lifethreatening pulmonary disorder and a medical emergency. It involves approximately 1% of all deliveries worldwide.1 Based on United States statistics, 60 000 to 80 000 infants are born with NRDS each year, of which 6000 to 12 000 usually die. About 20% of these infants are affected by a chronic pulmonary disease called bronchopulmonary dysplasia (BPD). The main cause of this disease is a shortage or lack of surfactant, which results in decreased functional residual volume and an increased tendency of the lungs for atelectasis and collapse.1 The building block of respiratory distress syndrome (RDS) treatment is the prescription of surfactant therapy and respiratory support.2-4 There are a variety of methods for helping the respiration of infants with RDS, including mechanical ventilation.5,6 Shallow breathing results in restlessness and stress in infants, which affect pulmonary function; thus, sedative medications are used to preserve better pulmonary function.7 Fentanyl, an opioid drug, is used in injection form (0.5 mcg/kg) during mechanical ventilation to induce sedation.8 Benzodiazepines such as midazolam (0.1 mg/kg) are also Abstract

used to induce sedation and sleep by effecting GABA receptors. 9There are different opinions about the benefits and superiority of these drugs.

Objective
Because of the controversies in opinion, the present study aimed to assess and compare the effects of fentanyl and midazolam on the required time of mechanical ventilation in infants with RDS.

Methods
This randomized clinical trial was conducted between July 2016 and March 2017 at the neonatal intensive care unit (NICU) of Najmiyeh University Hospital, Tehran, Iran. Figure 1 shows a flowchart of the trial.Infants with a confirmed diagnosis of RDS based on chest radiography, respiratory rate, arterial blood gas (ABG), first and fifth minute Apgar scores, grunting, cyanosis, and physical examination by a single neonatologist were enrolled in the trial.Infants between 2.5 and 4 kg of weight who needed intubation and mechanical ventilation were included in the study.Patients with weights lower than 2.5 kg or greater than 4 kg as well as those with congenital heart disease, brain anomalies, or metabolic or chromosomal syndromes were excluded from the trial.Demographic as well as peri-natal information such as birthweight, gestational age, mother's disease during pregnancy, Apgar scores, and method of delivery were recorded in a pre-designed checklist.
After the study process was explained and informed consent forms were obtained from the parents, the patients were randomly allocated to two groups; the first group underwent sedation with midazolam (0.1 mg/kg), and the second group received 0.5 mcg/kg of fentanyl during ventilation.Duration of hospitalization, required time of ventilation, drug complications, feeding intolerance, pneumothorax incidence, and need for re-intubation were recorded and compared between the 2 groups.
Data analyses were performed using the Statistical Package for Social Sciences (SPSS) version 21 for Windows software (IBM Corp, Armonk, NY).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 two groups.Mean and standard deviation (SD) were used to describe categorical variables.
In total, patients were hospitalized for 11.16 ± 3.56 days in both groups.Infants in the midazolam group had a mean length of stay of 11.96±3.41days, while infants in the fentanyl group had a mean length of stay of 10.36 ± 3.57 days (P value = 0.039).Mean duration of mechanical ventilation was 4.6±2.14days in the midazolam-group and 4.06 ± 2.04 days in fentanyl group (P value = 0.252).
Table 3 summarizes the information on respiratory rate, heart rate, need for mechanical ventilation, oxygen dependency, mean arterial oxygen pressure, and mean arterial CO2 pressure in the study groups.Mean respiratory rate was 73.33 ± 10.52 per/minute before and 56.66 ± 11.84 per/minute after intervention in all infants (P value = 0.00).Mean respiratory rate was significantly decreased in each group after intervention; however, these means were not significantly different between the two groups after intervention (P value = 0.313).Mean heart rate was 140.16±10.33per/minute before and 133.3 ± 22.45 per/minute after intervention in the study individuals (P value = 0.011).Infants in the midazolam group had a significantly lower heart rate after intervention (P value = 0.001).Before intervention 38 (63.3%) infants and after intervention 38 (63.3%) infants needed mechanical ventilation (P value = 0.001).Of all 60 patients, 45 (75%) infants before and 44 (73.3%) infants after intervention were oxygen-dependent (P value = 0.768).There was no significant difference between the two groups in oxygen dependency after intervention.Mean arterial oxygen pressure was 55.43 ± 8.79 mm Hg before and 65.5 ± 5.91 mm Hg after intervention in the study individuals (P value = 0.321).There was no significant difference between the 2 groups in mean arterial oxygen pressure after intervention (P value = 0.139).Mean arterial CO2 pressure was 38.33 ± 5.71 mm Hg before and 38.53 ± 3.97 mm Hg after intervention (P value = 0.702).This value was significantly lower in the fentanyl group infants after intervention (P value = 0.001).Pneumothorax was present only in 2 infants and pneumonia in 17 infants (Table 4).The most prevalent drug complication was drowsiness with 19 cases followed by apnea (13 infants), seizure (10 infants), respiratory depression (5 infants), irritability (5 cases), and hypotension (2 cases).

Discussion
In this study, it was found that the mean length of stay was significantly higher in the midazolam group infants compared with the fentanyl group infants.No significant difference was observed between the 2 groups in mean duration of mechanical ventilation.Mean respiratory rate was significantly decreased after intervention in both groups, but the difference between the groups was not significant.In addition, mean heart rate was significantly decreased after intervention in the midazolam group; however, it was slightly increased in the fentanyl group infants.The number of infants who needed mechanical ventilation was not significantly changed after intervention; only one infant in the fentanyl group was off the ventilator.Mean arterial oxygen pressure was increased in study individuals after intervention, but this rate was not statistically significant.Mean arterial CO2 pressure was not significantly different after intervention; however, it was significantly lower in the fentanyl group infants.
Other similar studies have been conducted to assess the effects and complications of midazolam and fentanyl.The present study, however, was conducted with more detail by evaluating the abovementioned parameters in premature infants who were under mechanical ventilation.
Another similar study by Ancora et al evaluated the analgesic effect of fentanyl on infants under mechanical ventilation in comparison with a placebo group.The mean pain score was significantly lower for infants in the fentanyl group than those in the placebo group.Also, the authors reported that mean duration of ventilation was higher for infants in the fentanyl group.In their study, the mean length of stay was 10 days for the fentanyl group and 7 days for the placebo group. 10hu et al conducted a systematic review and metaanalysis in which they evaluated the effect of remifentanil on the duration of mechanical ventilation in comparison with other opioids such as fentanyl and morphine.They concluded that remifentanil reduces the duration of ventilation as well as the ICU length of stay (LOS).However, no significant differences were reported regarding hospital LOS, mortality, agitation, or costs. 11n their study, Welzing et al compared the need for mechanical ventilation of infants under 60 days of age in 2 groups, midazolam/fentanyl-and midazolam/ remifentanil-treated infants.They found that infants in the midazolam/remifentanil group had a lower duration of mechanical ventilation than those in the midazolam/ fentanyl group. 12omantsik et al systematically reviewed studies in which clonidine was used for sedation and as an analgesia in neonates under mechanical ventilation.They reported that there is lack of efficient evidence; only one trial with 122 individuals was included which did not show any superiority in the clonidine prescription. 13

Conclusion
In conclusion, the findings of the current study suggest that midazolam is a more suitable medication for the sedation of infants under mechanical ventilation in comparison with fentanyl; however, its side effects, such as apnea, pneumonia, and seizure, should be considered.
Future studies with a larger sample volume are recommended.Furthermore, measurement of midazolam and fentanyl serum levels is suggested in further studies.

Table 1 .
Pregnancy-Related Complications in Study Individuals

Table 2 .
Additional Medications Administered During Trial

Table 3 .
Information on Respiratory Rate, Heart Rate, Need for Mechanical Ventilation, Oxygen Dependency, Mean Arterial Oxygen Pressure, and Mean Arterial CO2 Pressure in Study Groups

Table 4 .
Distribution of Treatment Complications Among Study Individuals