Abstract

Introduction: Neonatal intensive care units are a highly stressful environment exposing immature infants to pain and non-pain related stress. Our aim was to assess intranasal dexmedetomidine as sedation during stressful and painful episodes in VLBW infants.

Methods: Data were retrospectively collected from medical charts of infants before and after routine use of dexmedetomidine for sedation in a single centre. Primary outcomes were N-PASS scores after sedation and respiratory support parameters. Secondary outcomes included hemodynamic and respiratory adverse effects, length of hospital stay, days to full feeding, and neonatal morbidities. A multivariate logistic regression model was used to assess the effect of several variables on a dependent variable, and the association with intranasal dexmedetomidine administration.

Results: Sixty-three preterm very low birth weight infants were included. Birth weight and gestational were comparable between the groups. (28.3 vs 29.2, and 1076 vs 1218gr respectively). Infants were treated by intravenous fentanyl or midazolam, and intranasal dexmedetomidine. N-Pass scores were comparable before and after sedation between the groups. (2.72 and 2.54 before and 2.24 and 2.45 after). Rates of adverse effects and major neonatal morbidities were comparable between groups. There was statistically significant, although mild reduced use of adjunctive midazolam in infants treated with intranasal dexmedetomidine.

Conclusions: Our data indicate that in our cohort, intranasal dexmedetomidine served as a worthy option for sedation of preterm VLBW infants.

Keywords: NICU; Preterm Infants; Dexmedetomidine; Sedation

Abbreviations: BW: Birth Weight; BPD: Bronchopulmonary Dysplasia, GA: Gestational Age; IV: Intravenous, IVH: Intraventricular Haemorrhage; NEC: Necrotizing Enterocolitis; NICU: Neonatal Intensive Care Unit; PVL: Periventricular Leukomalacia; ROP: Retinopathy Of Prematurity; VLBW: Very Low Birth Weight

Introduction

Neonatal Intensive Care Units (NICU’s) are a highly stressful environment for immature infants. Preterm infants are exposed to pain and non-pain related distress, including interchanging caregivers, and multiple disturbing visual and auditory stimuli [1]. Pathways mediating nociception develop between 20 and 24 weeks of gestation, while descending inhibitory pathways mature much later, beyond term [2]. Preterm infants therefore, have poor localization and discrimination of sensory input, leading to increased responses to painful stimuli [3,4]. These negatively interfere with individual self-regulation and co-regulation processes, which are fundamental for adaptive behaviour throughout development [5,6]. Painful, and non-painful stress in ventilated infants and neonates, are treated nowadays with a variety of mostly intravenously administered sedatives, mainly opioids and benzodiazepines. In addition, non-pharmacological strategies such as swaddling are practiced to reduce pain and stress [7]. Traditionally, management of pain and stress consists of opioids, often morphine or fentanyl [8]. Morphine improves ventilator synchrony in ventilated neonates [9], and is associated with lower pain scores [10]. Side effects including hypotension, respiratory depression, and delay of enteral feeding were reported following sedation with morphine [11]. Furthermore, experimental data from animal studies show chronic morphine exposure in early life may result in reduced brain volume, decreased neuronal packing density and less dendritic growth and branching, which may be associated with learning and motor disabilities later in life [12]. Moreover, Postnatal studies in preterm infants exposed to opioids, demonstrate an association with decreased cerebellar volume and poorer 18-month motor and cognitive scores [13,14]. Benzodiazepines, most commonly midazolam, inhibit Gamma Aminobutyric Acid A receptors [15], and have a sedative but not an analgesic effect. Midazolam may induce respiratory depression and hypotension. A systematic review found insufficient evidence to recommend midazolam for sedation in preterm infants, and raised safety concerns, particularly regarding neurotoxicity [16]. Dexmedetomidine is a highly selective α2- adrenergic receptor agonist that provides analgesia, anxiolysis, and sedation via reduction in sympathetic outflow from the locus coeruleus and release of substance-P from the dorsal horn of the spinal cord, without compromising respiratory function [17]. Although safety and efficacy of dexmedetomidine have been established in the adult population [18], its use in infants and newborns, particularly in preterm infants, is still off-label. Chrysostomou et al. reported a phase II/III trial designed to investigate the safety, efficacy, and pharmacokinetic profile of IV dexmedetomidine in preterm and full-term neonates ≥28 to ≤44 weeks gestational age. They found that IV dexmedetomidine was effective for sedating preterm and full-term neonates and was well tolerated without significant adverse effects [19]. Several studies showed that intranasal dexmedetomidine may be a satisfied alternative for short sedation in the pediatric and neonatal population [19-23]. The aim of this study is to examine the possibility that intranasal dexmedetomidine is an alternative for sedation of preterm infants in the NICU during pain and non-pain related stress. We aimed at assessing adverse effects, and short and long- term outcomes, in comparison to fentanyl and adjunctive midazolam, which are used routinely in our unit for infants requiring sedation.

Methods

This is a retrospective single centre before/after study.

Study population

Study population included VLBW (birth weight < 1,500 gr) preterm infants born prior to 32 weeks’ gestation in a single centre. Data were extracted from medical records of infants born prior to the use of dexmedetomidine in our unit between 20142016, and from medical records of infants born during 2017-2019 when intranasal dexmedetomidine was used routinely in our unit for sedation. Data were extracted from records of VLBW born consecutively during the analysed period. Infants with major congenital anomalies, and those who did not survive 72 hours were excluded from this study.

Sedation protocol

Sedation drugs were administered according to the unit’s protocol, which includes the administration of sedation PRN (pro re nata) to infants assessed as experiencing pain related, or non-pain related stress. This practice was not changed between the two study periods. IV fentanyl was administered at a dose of 1-2 mcg/kg, and IV midazolam at a dose of 0.05-0.1 mg/kg. Dexmedetomidine was diluted (100mcg with 10ml 0.9% NaCl) and administered intranasal via a 1 ml syringe at 1-2 mcg/kg, administered to both nares. Intravenous fentanyl was administered PRN to infants during the pre and post dexmedetomidine period, as per the nurses’ discretion. During the post dexmedetomidine period, when dexmedetomidine became our first line of sedation, fentanyl was administered as second line in ventilated infants. Respiratory and nutritional management has remained unchanged in the two study periods.

Assessing of pain and/or agitation

Pain/ agitation were assessed using the Neonatal Pain, Agitation and Sedation Scale (N-PASS). Five indicators were included, crying/irritability, behaviour/state, facial expression, extremities/tone and vital signs. Scores range from -10 in heavily sedated infants to +11, with scores of over 3 suggesting need for intervention [24]. In our unit VLBW infants are rarely heavily sedated, therefore the actual NPASS score range is most commonly 0-13. Pain/stress evaluation was performed 30 minutes and 1 hour after administration of any sedative agent (dexmedetomidine, fentanyl or midazolam). In infants who did not require sedation pain/stress evaluation was performed every 3 hours.

Outcomes

Primary outcomes were defined as N-PASS scores after sedation and respiratory support parameters. Secondary outcomes included hemodynamic and respiratory adverse effects (hypotension, apneas), length of hospital stay, days to full feeding, and neonatal morbidities including necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD) defined by the need for oxygen or any respiratory support at 36 weeks corrected age, late onset sepsis occurring beyond the seventh day of life, high grade (grades 3-4) intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), and retinopathy of prematurity (ROP).

Statistical analysis

To test the association between two categorical variables, either the Chi-square test or the Fisher’s exact test was applied. The comparison of a quantitative variable between two independent groups was carried out using the two-sample t-test. The paired t-test was used for testing change within group, for a quantitative variable, including NPASS score, which included multiple observations of the same infant. A multivariate logistic regression and ANCOVA models were used to assess the effect of several variables on a dependent variable, and the with intranasal dexmedetomidine administration. All statistical tests applied were two-tailed, and a p-value of 0.05 or less was considered statistically significant.

Results

The study population included a total of 63 preterm very low birth weight (VLBW) infants: 33 in the conventional sedation group (cohort 1), of infants who were not treated with intranasal dexmedetomidine, and 30 in the dexmedetomidine group (cohort 2). Infants receiving PRN dexmedetomidine were administered a mean of 5 doses per day during the first 2 weeks of life. The two cohorts were comparable in demographic characteristics including birth weight, gestational age, and sex. There were more infants with a 1-minute Apgar score under 7 in cohort 1, but the 5-minute Apgar score was comparable between the cohorts (Table 1). NPASS score after sedation, respiratory support parameters including oxygen days, and length of invasive ventilation were found comparable between infants treated with intranasal dexmedetomidine and those who were not, as well as the frequency of hypotension and apnea episodes. Multivariate regression analysis showed GA and BW were statistically significantly associated with neonatal morbidities and outcomes including BPD, days to extubation, oxygen days, days to full enteral diet, days to full oral diet, and hospital stay. There was no difference between the dexmedetomidine and no dexmedetomidine groups for these outcomes. We also found that BW and GA were not different between the dexmedetomidine and no dexmedetomidine groups. We found a statistically significant reduced use of adjunctive midazolam in infants treated with intranasal dexmedetomidine when compared to infants who were not. This difference was not affected by BW, GA or gender (Table 2). Multivariate analysis demonstrated neonatal morbidities were associated as expected with gestational age and birth weight, but not with the use dexmedetomidine (Table 3). ANCOVA analysis demonstrated the use of adjunctive midazolam was decreased in infants treated with intranasal dexmedetomidine when compared to infants who were not, but not associated with gender, birth weight or gestational age (Table 4).

Table 1: Patient characteristics.

Table 2: Univariate analysis of outcome of preterm infants treated with and without intranasal Dexmedetomidine.

Table 3: Logistic regression of outcome variables in preterm infants and treatment with intranasal dexmedetomidine.

Table 4: Association between preterm infants’ short-term outcomes and treatment with intranasal dexmedetomidine, gestational age, and birth weight.