OBJECTIVE

The objective of this study was to evaluate and compare the effectiveness and safety of dexmedetomidine as monotherapy between neonates with mild hypoxic ischemic encephalopathy (HIE) and moderate to severe HIE treated with therapeutic hypothermia (TH).

METHODS

This retrospective study included neonates of gestational age ≥36 weeks with a diagnosis of HIE and undergoing TH between January 2014 and December 2021. Patients were included if they received at least 6 hours of continuous sedation with dexmedetomidine. Baseline characteristics, dose and duration of medication, adverse events, liver and kidney function tests, and hospital course were reviewed.

RESULTS

Of the 97 neonates included, 46 had mild, 42 had moderate, and 9 had severe HIE. Dexmedetomidine was initiated at a median 5 hours of life, and the median infusion duration was 77 (46–87) hours. Fifty-two (53.6%) required at least 1 breakthrough opioid or sedative during the first 24 hours of dexmedetomidine infusion. Overall, 40 patients (41.2%) had at least 1 bradycardia episode with heart rate <80 beats/min and 14 patients (14.4%) had heart rate <70 beats/min. Hypotension was experienced by 7 patients (7.2%). Fifty-two patients (53.6%) were intubated in the delivery room and 33/52 (63.5%) were extubated on day of life 1 during dexmedetomidine infusion.

CONCLUSIONS

Dexmedetomidine as monotherapy was effective and safe sedation for infants with HIE undergoing hypothermia. The most common side effect of dexmedetomidine was bradycardia. ­Dexmedetomidine may be considered as first and single agent for neonates with HIE undergoing TH.

Neonatal hypoxic ischemic encephalopathy (HIE) is one of the most common causes of neonatal morbidity and mortality with an incidence of 1 to 3 in 1000 live births in developed countries and approximately 10 times higher in resource-limited countries.14  Therapeutic hypothermia (TH) is currently the only effective treatment but produces physiologic stress, elevating circulating cortisol and norepinephrine concentrations after asphyxia when compared with normothermia.5,6  Preclinical models have suggested that inadequate sedation may reduce the benefits of cooling.7,8  In adults, sedation/analgesia medications during TH are associated with earlier attainment and better maintenance of target temperatures.9  Opioid administration is a common practice during TH in neonates with HIE. Opioid use for sedation and analgesia during HIE has increased in the United States from 38% in 2007 to 68% in 2015.10  Opioids have been associated with significant side effects, including tolerance, physical dependency, paradoxical agitation, withdrawal, inconsistent sedation, respiratory depression, and gastrointestinal dysmotility.1013  Moreover, opioids, especially morphine, accumulate substantially after hypoxia-ischemia and during hypothermia, and require dosing adjustments during TH.14  Dexmedetomidine is a centrally acting alpha-2 adrenergic receptor agonist that may offer an alternative to opioids. Dexmedetomidine provides sedation, anxiolysis, and analgesia, but does not suppress ventilation or cause gastric dysmotility.1518  Following the latent phase of hypoxic-ischemic insult, blockade of noradrenaline-mediated alpha-2 adrenergic receptors results in loss of suppression and exacerbates neuronal loss.19,20  Alpha-2 adrenergic receptor stimulation increases expression of enzymes responsible for neuronal survival and synaptic plasticity and suppresses inflammatory cytokines.21,22  Animal neonatal models of HIE suggest that the alpha agonist dexmedetomidine protects against brain matter loss and improves neurologic functional deficit induced by hypoxic-ischemic insult.21,23,24 

In our institution, we have been using dexmedetomidine since 2014 as single, continuous sedation during TH in neonates with HIE undergoing TH. The aim of this study was to evaluate and compare the effectiveness and safety of dexmedetomidine in infants with mild and moderate to severe HIE treated with TH.

This was a retrospective cohort study with a review of charts of neonates admitted with a diagnosis of HIE and treated with TH, between January 2014 and December 2021, at Cleveland Clinic Children’s Main Hospital.

Patient Selection and Unit Protocol. The need to initiate TH was determined by the clinician and based on an adaptation of standard criteria previously described by Shankaran and colleagues.25  Entry criteria for TH include a gestational age of 36 weeks or more, birth weight of 1.8 kg or greater, and age of 6 hours or less. All neonates included had evidence of HIE defined by a pH of 7.0 or less and/or a base deficit greater than 16 mmol/L, or a pH between 7.01 and 7.15 and/or a base deficit between 10 and 15.9 mmol/L in umbilical cord blood or any blood during the first hour after birth, Apgar score of 5 or less at 10 minutes of life, or prolonged resuscitation at birth defined as chest compressions and/or intubation or mask ventilation at 10 minutes of life. All patients were classified by a neonatal intensive care unit physician, using modified Sarnat staging (level of consciousness, spontaneous activity, posture, muscle tone, primitive reflexes, and autonomic function), as having mild, moderate, or severe encephalopathy. An infant’s condition was scored as mild if they had at least 1 domain consistent with mild, but did not meet criteria for moderate or severe HIE; as moderate if they had 3 or more domains consistent with moderate or severe HIE, but more domains were moderate than severe; and as severe if they had 3 or more domains consistent with moderate or severe HIE, but more domains were severe than moderate.26,27  Babies born with lethal congenital malformations, chromosomal anomalies, or receiving another continuous sedation were excluded. Infants with severe coagulopathy or birth/head trauma were assessed individually by the clinician for TH. Whole body cooling to 33.5°C was performed for 72 hours, followed by slow warming over at least 6 hours at a rate of 0.5°C per hour until esophageal temperature reached the desired temperature of 36.5°C.25 

Patients were included in the study if they required at least 6 hours of continuous sedation with dexmedetomidine within 12 hours after birth. They received dexmedetomidine, which was initiated at 0.2 mcg/kg/hr and increased by 0.1 mcg/kg/hr, based on N-PASS (neonatal pain, agitation, and sedation scale) scores and breakthrough opioid or sedation dose requirements. N-PASS is the first neonatal-specific sedation assessment tool studied and validated as an assessment tool both for pain and sedation. Based on N-PASS tool, sedation is scored from −2 → +2 for each criterion, including crying/irritability, behavior state, facial expressions, extremities tone, and vital signs (heart rate, respiration rate, blood pressure, oxygen saturation). The score ranges from −10 to +10 and, the goal score is −2 to +2.28,29 

In our institution, N-PASS scoring is performed by a registered nurse with hands on care at every 2 to 3 hours and as needed. An N-PASS score of ≥+3 was the prompt to give a bolus of opioid or sedative. If patients required breakthrough opioid or sedative for ≥3 consecutive doses or for >4 to 5 doses/24 hr, this prompted an increase in dexmedetomidine dose. Dexmedetomidine was decreased by 0.1 mcg/kg/hr for bradycardia, or appearance of oversedation, and reevaluated every 1 to 2 hours before another dose adjustment. Oversedation is defined as no response to any stimuli. Dexmedetomidine was paused if bradycardia was not responsive to decreased dosage until bradycardia was resolved. After rewarming and once normothermia was reestablished, dexmedetomidine was discontinued without weaning the dose unless clinical status warranted continued sedation or pain medication. Bradycardia was defined as a sustained heart rate of <80 beats per minute (bpm) for at least 3 consecutive readings in a 1- to 2-hour period.

Dexmedetomidine dose was not influenced by blood pressure changes. Systemic hypotension was identified by the need for volume expansion or inotropic support after starting dexmedetomidine infusion. Systemic hypertension was identified as systolic pressure or mean arterial pressure at ≥95th percentile for gestational age for at least 3 consecutive readings in a 1- to 2-hour period.

Outcomes. The primary outcome was to determine if dexmedetomidine was an effective monotherapy for sedation and analgesia with reduction of N-PASS scores and need for additional bolus medications in infants with HIE undergoing TH. The secondary outcome was to categorize and compare incidence of side effects of dexmedetomidine, including bradycardia, hypotension, and hypertension, between patients with mild and moderate to severe HIE. The third outcome was to determine and compare clinical outcomes between patients with mild and moderate to severe HIE who received dexmedetomidine during TH.

Data Collection. Data were collected from patients with HIE, including patient demographics, modified Sarnat score, medication information (time of initiation, duration, cumulative dose), adverse events (bradycardia, hypotension and hypertension episodes), laboratory assessments (liver and kidney function tests), and hospital course (length of hospital stay, duration in reaching full enteral and oral feeds, tube feeding at discharge, noninvasive and mechanical ventilation need and duration).

Statistical Analysis. Continuous variables were described by using medians and IQRs; categorical variables were described by using counts and percentages. Demographic and clinical characteristics were compared between patients with mild and moderate/severe HIE by using Wilcoxon rank sum test for continuous/ordinal characteristics and Pearson chi-square test or Fisher exact test for categorical characteristics, as appropriate. All analyses were performed on a complete-case basis; subjects with missing data for certain variables were excluded only for analyses in which those variables were used. SAS 9.4 software (SAS Institute, Cary, NC) was used for all analyses. Statistical significance was defined as a p value of less than 0.05.

Between January 2014 and December 2021, a total of 124 patients were admitted to the neonatal intensive care unit (NICU) of Cleveland Clinic Children’s Main Hospital for TH. Twenty-seven patients were excluded for the following reasons: 8 received dexmedetomidine infusion for less than 6 hours, 8 received both morphine and dexmedetomidine infusions, 5 received only morphine infusion, 3 received only intermittent sedation, and 3 had lethal congenital or chromosomal anomalies. Of the 97 neonates included, 46 met criteria for mild HIE, 42 infants were categorized as having moderate HIE, and the remaining 9 infants experienced severe HIE. Owing to low patient numbers for the severe group, moderate to severe groups were combined for statistical analysis. Patients with moderate to severe HIE had lower 10-minute Apgar scores; had a higher base deficit in cord arterial blood gases; had lower pH, bicarbonate, a higher base deficit, and lactate in 1-hour of life blood gases; and were more likely to have seizures than those with mild HIE (p < 0.05) (Table 1).

Table 1.

Baseline Characteristics of Patients*

Baseline Characteristics of Patients*
Baseline Characteristics of Patients*

Dexmedetomidine was initiated at a median 5 hours of life, with median initial dose of 0.2 (IQR, 0.2–0.2) mcg/kg/hr and median maximum dose of 0.3 (IQR, 0.2–0.4) mcg/kg/hr for all patients with HIE. The median infusion duration was 77 hours, with a median cumulative dose of 16.6 mcg/kg. Fifty-five patients (56.7%) required at least 1 bolus of opioids during TH with 47 of the 55 (85.5%) occurring in the first 24 hours of dexmedetomidine initiation. Seven patients (7.2%) required at least 1 bolus of sedatives (midazolam or lorazepam) during TH with 5 (71.4%) occurring in the first 24 hours. There was no significant difference for dosing and adverse events of dexmedetomidine between mild and moderate to severe HIE cases. (Table 2). There were no clinically significant differences in pain scores any time points, and median pain score was zero.

Table 2.

Medication and Adverse Events*

Medication and Adverse Events*
Medication and Adverse Events*

Forty patients (41.2%) had at least 1 episode of bradycardia (heart rate (HR) <80 bpm). There was no difference in bradycardia rates between mild and moderate to severe HIE. More than half of the patients with bradycardia had the drug dose decreased (52.5%) or discontinued (57.5%). Among those with HR <80 bpm and dose decreased, 8 patients (6/10 with mild, 2/11 with moderate to severe HIE) were able to continue dexmedetomidine therapy. Only 14 patients (14.4%) had low HR (<70 bpm), and approximately three-quarters had medication dose decreased (71.4%) or discontinued (78.6%). Among patients with HR <70 bpm and dose decreased, 3 (2/5 with mild, 1/9 with moderate to severe HIE) were able to continue dexmedetomidine therapy. Patients with hypotension in need of treatment were rare (n = 7): 4.3% in the mild and 9.8% in the moderate to severe group. None of our patients had hypertension (Table 2).

In mild HIE, median alanine transaminase (ALT) concentrations were within normal range (10–54 U/L) at 4 time points (at dexmedetomidine initiation, TH, rewarming, and post TH); aspartate aminotransferase (AST) concentrations (normal: 14–40 U/L) were elevated at initiation of dexmedetomidine but were almost normalized post TH (see Table 3). In moderate to severe HIE, median ALT concentrations were within normal range at 4 time points, but AST concentrations were significantly elevated (p < 0.001) at initiation of dexmedetomidine, gradually decreasing but remaining elevated post TH. ALT concentrations were higher at all time points, except at rewarming, and AST concentrations were consistently higher at 4 time points in moderate to severe HIE, compared with those in mild HIE (p < 0.05). Median conjugated bilirubin concentrations were elevated (normal: <0.2 mg/dL) at dexmedetomidine initiation in both mild and moderate to severe HIE (see Table 3). Conjugated bilirubin concentrations started trending down in mild HIE and trending up in moderate to severe HIE post TH. Conjugated bilirubin concentrations were higher in moderate to severe HIE than in mild HIE post TH (p < 0.05).

Table 3.

Serum Laboratory Assessment*

Serum Laboratory Assessment*
Serum Laboratory Assessment*

Blood urea nitrogen median concentrations were within normal range (4–19 mg/dL) at 4 time points in both mild and moderate to severe HIE. Creatine concentrations were within normal range (0.31–0.88 mg/dL) at 4 time points in mild HIE. In moderate to severe HIE, creatine concentrations were elevated at initiation of dexmedetomidine, and normalized at rewarming. Creatinine concentrations were higher at all time points, except at dexmedetomidine initiation in moderate to severe HIE, compared with those in mild HIE (p < 0.05) (Table 3).

Patients with moderate to severe HIE had a longer NICU length of stay (11 vs 9 days, p < 0.05), were more likely to be intubated on admission (64.7% vs 41.3%), had longer duration of intubation (median [IQR], 1 [1–3] vs 1 [1–1] day; p < 0.05), although 19/33 (57%) were extubated after day of life 1. Patients with moderate to severe HIE were more likely to be discharged with tube feeding at home (nasogastric [n = 4] or gastric tube [n = 3]: 13.7% vs 0%; p < 0.05). Only 21.6% of all patients required noninvasive ventilation: time transitioned to room air was longer in moderate to severe HIE than in mild HIE (4.0 vs 1.5 days, p < 0.05). None of the neonates spontaneously breathing or undergoing noninvasive ventilation at dexmedetomidine initiation required intubation. The median time for reaching full enteral feeds and oral feeds was 6 days for both, which was not significantly different between HIE severity groups (Table 4).

Table 4.

Hospital Course*

Hospital Course*
Hospital Course*

One patient in the moderate to severe HIE group died during hospitalization.

Use of opioids for sedation in neonates with HIE during TH is a common practice, but these drugs have been associated with significant side effects. Dexmedetomidine provides sedation but does not suppress ventilation, does not cause gastric dysmotility, and has neuroprotective effects.18,21,23,24,30,31  In our retrospective study we described our experience with dexmedetomidine as a single, continuous sedative used in infants with HIE undergoing TH. To the best of our knowledge, this study is the largest study in infants with HIE who received dexmedetomidine during TH.

Efficacy of Dexmedetomidine. We used N-PASS scores to assess efficacy of dexmedetomidine and need for additional opioid/sedative doses. Average N-PASS score was zero at all time points. About half of the patients required at least 1 breakthrough opioid/sedative during TH, which most received in the first 24 hours of initiation of dexmedetomidine. Other studies in similar patient populations also reported decreased breakthrough opioid requirement or decreased cumulative dose of opioids in the dexmedetomidine group compared with the morphine or fentanyl group.32-35 McAdams and colleagues36  suggested a loading dose of dexmedetomidine may be needed to achieve effective plasma concentrations owing to a longer elimination half-life in newborns with HIE. Loading doses may decrease breakthrough opioid/sedative doses in the first 24 hours.

Adverse Events. Dexmedetomidine has potential adverse effects including bradycardia, hypotension, and hypertension.3235,37  Dexmedetomidine is a centrally acting α-2 adrenergic receptor agonist; adverse effects of bradycardia and hypotension might be caused by a reduction in norepinephrine, leading to sympatholytic effect from activation of central presynaptic α-2A receptors in the medullary vasomotor center.38  The limited published data on dexmedetomidine use for sedation in neonates report bradycardia is the most common side effect.33,3840  We have been using dexmedetomidine as a single, continuous medication sedation since 2014. Our initial dose is 0.2 mcg/kg/hr, and titration is based on level of sedation and heart rate. In our unit, bradycardia is defined as ≤80 bpm for interventions during TH. In our study, 41% of the patients had at least 1 episode of bradycardia (HR <80 bpm), and more than half had the drug dose decreased or discontinued. Elliott and colleagues40  compared heart rate trends in 3 groups of neonates with HIE undergoing TH: dexmedetomidine (n = 14), fentanyl (n = 120), and both (n = 32). Their dosing practices were like those of our practice; however, heart rate alarm limit was set at 90 bpm. Nearly half of the neonates required dosage decrease or discontinuation owing to low heart rate. However, only 14 of 166 neonates received dexmedetomidine monotherapy.40  In our population, 14.4% of patients had a HR <70 bpm; of those, approximately three-quarters had a medication dose decrease or discontinuation. Therapeutic hypothermia itself decreases basal metabolism and causes lower heart rates.6  It is currently unknown at what heart rate we should adjust dexmedetomidine dose without compromising cardiac output in infants with HIE undergoing TH. After this study we changed our heart rate limit, set at 70 bpm for interventions during TH.

Previous pediatric studies have shown clinically significant hypotension associated with the use of dexmedetomidine.37,41  In our patient population approximately 5% of patients in the mild and 10% in the moderate to severe group had systemic hypotension and needed treatment. Most of these infants (5/7 [71%]) had systemic hypotension before the initiation of dexmedetomidine. Dexmedetomidine may cause systemic hypertension,32,37  but none of our patients had systemic hypertension.

Laboratory Findings and Hospital Course. Dexmedetomidine is metabolized primarily by the liver and eliminated primarily through the urine after biotransformation via glucuronidation, hydroxylation, and N-methylation, and pharmacokinetics are altered by hypoxia-ischemia and TH. Dexmedetomidine exhibits 94% protein binding to serum albumin and to α-1 glycoprotein and may require dose reduction with hepatic dysfunction, although dexmedetomidine dose adjustment usually is not necessary in renal failure.31,38,42  Our study reported liver and kidney function before, during, and after TH. The moderate to severe HIE group had higher ALT, AST, direct bilirubin, and creatinine concentrations than infants in the mild HIE group, as expected owing to severity of insult (see Table 3). Infants with mild HIE had mild elevation of hepatic and renal function markers, which normalized after TH. In patients with moderate to severe HIE, liver and kidney functions also gradually decreased during dexmedetomidine infusion, suggesting elevated liver and kidney function markers were the result of hypoxic injury.

One of the other advantages of dexmedetomidine compared with morphine is its not affecting respiratory drive negatively.15,35  In a National Institute of Child Health and Human Development (NICHD) therapeutic hypothermia trial, the opioid group had longer duration of mechanical ventilation and supplemental oxygen than the control neonates (9 days vs 3 days, p < 0.0001).43  Cosnahan and colleagues33  reported increased fraction of inspired oxygen and ventilator support in the morphine group compared with the dexmedetomidine group in infants with HIE undergoing hypothermia. Similar findings were reported by Naveed and colleagues34  with 19 patients in the fentanyl group and 26 patients in the dexmedetomidine group in neonates with HIE undergoing TH; the dexmedetomidine group had shorter time to extubation after birth at a median of 3 vs 11 days. In our study 53.6% of patients were intubated on admission and 63.5% were extubated on day of life 1. None of the neonates spontaneously breathing or undergoing noninvasive ventilation at dexmedetomidine initiation required intubation. Dexmedetomidine was not associated with any extubation failures and was continued after extubation in all patients.

Opioids also negatively affect gastrointestinal motility, whereas dexmedetomidine does not decrease gastrointestinal motility. In the NICHD therapeutic hypothermia trial, time to attain full oral feedings was longer for infants treated with opioids than for control neonates (13 days vs 8 days, p = 0.04).43  In a recent study comparing dexmedetomidine with fentanyl in neonates with HIE undergoing TH, the dexmedetomidine group had earlier time to transition to full enteral feeds than the fentanyl group (8.5 vs 13 days).34  The practice of keeping infants on nothing-by-mouth protocols during cooling is still common.44  A recent study demonstrated that minimal enteral feeding during TH is safe and leads to a shorter time to full enteral feeding and higher rates of breast milk feeding at discharge.45  We have recently started minimal enteral feeding (10–20 mL/kg/day) during TH. During the study period we were not feeding the patients with HIE, so could not assess their feeding tolerance during TH. Median time to reach full oral feeds was 6 days in mild and 7 days in moderate to severe HIE groups.

Opioids prolong the time to hospital discharge for neonates; in a retrospective analysis of sedation/analgesic exposure (including opioids, benzodiazepines, and barbiturates) in late preterm and term infants with HIE enrolled in a TH trial, a longer length of stay (14 vs 24 days, p = 0.08) was noted for treated neonates than for control neonates.43  In our group, median length of hospital stay was 9 days in the mild and 11 days in the moderate to severe HIE group (Table 4).

Strengths and Limitations. Our study is the largest report of dexmedetomidine use for neonates with HIE during TH. This is also the only study to report liver and kidney function before, during, and after TH in infants with HIE undergoing TH who received dexmedetomidine.

There are several limitations to this study: it was a retrospective, monotherapy study, with no comparison with morphine or fentanyl. We were not able to account for all the potential confounding variables affecting the need for sedation dose arrangements. We also did not include all medications and interventions during TH that can affect heart rate and blood pressure.

Dexmedetomidine was an effective and safe treatment in infants with HIE during hypothermia. The most common side effect was bradycardia. A randomized controlled trial of dexmedetomidine as an adjunct to TH is needed to assess full effectiveness, safety, and short- and long-term outcomes for infants with HIE.

ALT

alanine aminotransferase;

AST

aspartate aminotransferase;

bpm

beats per minute;

HIE

hypoxic ischemic encephalopathy;

NICHD

National Institute of Child Health and Human Development;

NICU

neonatal intensive care unit;

N-PASS

neonatal pain, agitation, and sedation scale;

TH

therapeutic hypothermia

Neonatal intensive care unit physicians, pharmacists, medical teams, and nurses at Cleveland Clinic Children’s Hospital for their assistance. Preliminary results were presented at Newborn Brain Society Conference in Florida on February 2023.

1.
Liu
L
,
Johnson
HL
,
Cousens
S
,
et al.
Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000
.
Lancet
.
2012
;
379
(
9832
):
2151
2161
.
2.
Acun
C
,
Karnati
S
,
Padiyar
S
,
et al.
Trends of neonatal hypoxic ischemic encephalopathy prevalence and associated risk factors in the United States, 2010-2018
.
Am J Obstet Gynecol
.
2022
;
227
(
751
):
e1
e10
.
3.
Shipley
L
,
Gale
C
,
Sharkey
D
.
Trends in the incidence and management of hypoxic-ischemic encephalopathy in the therapeutic hypothermia era: a national population study
.
Arch Dis Child Fetal Neonatal Ed
.
2021
;
106
(
5
):
529
534
.
4.
Ezenwa
BN
,
Olorunfemi
G
,
Fajolu
I
,
et al.
Trends and predictors of in-hospital mortality among babies with hypoxic ischaemic encephalopathy at a tertiary ­hospital in Nigeria: a retrospective cohort study
.
PLoS One
.
2021
;
16
(
4
):
e0250633
.
5.
Davidson
JO
,
Fraser
M
,
Naylor
AS
,
et al.
Effect of cerebral hypothermia on cortisol and adrenocorticotropic hormone responses after umbilical cord occlusion in preterm fetal sheep
.
Pediatr Res
.
2008
;
63
(
1
):
51
55
.
6.
Frank
SM
,
Higgins
MS
,
Fleisher
LA
,
et al.
Adrenergic, respiratory, and cardiovascular effects of core cooling in humans
.
Am J Physiol
.
1997
;
272
(
2 pt 2
):
R557
R562
.
7.
Thoresen
M
,
Satas
S
,
Loberg
EM
,
et al.
Twenty-four hours of mild hypothermia in unsedated newborn pigs starting after a severe global hypoxic-ischemic insult is not neuroprotective
.
Pediatr Res
.
2001
;
50
(
3
):
405
411
.
8.
Angeles
DM
,
Wycliffe
N
,
Michelson
D
,
et al.
Use of opioids in asphyxiated term neonates: effects on neuroimaging and clinical outcome
.
Pediatr Res
.
2005
;
57
(
6
):
873
878
.
9.
DellAnna
AM
,
Taccone
FS
,
Halenarova
K
,
Citerio
G
.
Sedation after cardiac arrest and during hypothermia
.
Minerva Anestesiol
.
2014
;
80
(
8
):
954
962
.
10.
Berube
MW
,
Lemmon
ME
,
Pizoli
CE
,
et al.
Opioid and benzodiazepine use during hypothermia in encephalopathic neonates
.
J Perinatol
.
2020
;
40
(
1
):
79
88
.
11.
Pokela
ML
.
Effect of opioid-induced analgesia on beta-endorphin, cortisol and glucose responses in neonates with cardiorespiratory problems
.
Biol Neonate
.
1993
;
64
(
6
):
360
367
.
12.
Chay
PC
,
Duffy
BJ
,
Walker
JS
.
Pharmokinetic-pharmodynamic relationships of morphine in neonates
.
Clin Pharmacol Ther
.
1992
;
51
(
3
):
334
342
.
13.
Natarajan
G
,
Hamrich
SE
,
Zaniletti
I
,
et al.
Opioid exposure during therapeutic hypothermia and short-term outcomes in neonatal encephalopathy
.
J Perinatol
.
2022
;
42
(
8
):
1017
1025
.
14.
Frymoyer
A
,
Bonifacio
SL
,
Drover
DR
,
et al.
Decreased morphine clearance in neonates with hypoxic ischemic encephalopathy receiving hypothermia
.
J Clin Pharmacol
.
2017
;
57
(
1
):
64
76
.
15.
Rostas
SE
.
Dexmedetomidine: a solution to the dilemma of pain and agitation in the mechanically ventilated preterm neonate?
J Perinat Neonatal Nurs
.
2017
;
31
(
2
):
104
108
.
16.
Talke
P
,
Tayefeh
D
,
Sessler
R
,
et al.
Dexmedetomidine does not alter the sweating threshold, but comparably and linearly decreases the vasocontriction and shivering thresholds
.
Anesthesiology
.
1997
:
87
(
4
);
835
841
.
17.
Madden
CJ
,
Tupone
D
,
Cano
G
,
Morrison
SF
.
α2 adrenergic receptor-mediated inhibition of thermogenesis
.
J Neurosci
.
2013
:
33
(
5
);
2017
2028
.
18.
Lewis
SR
,
Nicholson
A
,
Smith
AF
,
Alderson
P
.
Alpha-2 adrenergic agonists for the prevention of shivering following general anesthesia
.
Cochrane Database of Sys Rev
.
2015
(
8
):
CD011107
.
19.
Dean
JM
,
Gunn
AJ
,
Wassink
G
,
et al.
Endogenous alpha-2-adrenergic receptor mediated neuroprotection after severe hypoxia in preterm fetal sheep
.
Neuroscience
.
2006
;
142
(
3
):
615
628
.
20.
Dean
JM
,
George
S
,
Naylor
AS
,
et al.
Partial protection with low dose infusion of the alpha-2-adrenergic receptor agonist clonidine after severe hypoxia in preterm fetal sheep
.
Neuropharmacology
.
2008
;
55
(
2
):
166
174
.
21.
Dahmani
S
,
Paris
A
,
Jannier
V
,
et al.
Dexmedetomidine increases hippocampal phosphorylated extracellular signal-regulated protein kinases 1 and 2 content by an alpha-2 adrenoreceptor-independent mechanism: evidence for the involvement of imidazoline I1 receptors
.
Anesthesiology
.
2008
;
108
(
3
):
457
466
.
22.
Taniguchi
T
,
Kidani
Y
,
Kanakura
H
,
et al.
Effects of dexmedetomidine on mortality rate and inflammatory response to endotoxin induced shock in rats
.
Crit Care Med
.
2004
;
32
(
6
):
1322
1326
.
23.
Paris
A
,
Mantz
J
,
Tonner
PH
,
et al.
The effects of dexmedetomidine on perinatal excitoxic brain injury are mediated by the alpha2A-adrenoreceptor subtype
.
Anesth Analg
.
2006
:
102
(
2
):
456
461
.
24.
Ma
D
,
Hossain
M
,
Rajakumaraswamy
N
,
et al.
Dexmedetomidine produces its neuroprotective effect via the alpha 2A-adrenoceptor subtype
.
Eur J Pharmacol
.
2004
;
502
(
1–2
):
87
97
.
25.
Shankaran
S
,
Laptook
AR
,
Ehrenkranz
RA
,
et al.
Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy
.
N Engl J Med
.
2005
;
353
(
15
):
1574
1584
.
26.
Sarnat
HB
,
Sarnat
MS
.
Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study
.
Arch Neurol
.
1976
;
33
(
10
):
696
705
.
27.
Walsh
BH
,
El-Shibiny
H
,
Munster
C
,
et al.
Differences in standardized neonatal encephalopathy exam criteria may impact therapeutic hypothermia eligibility
.
Pediatr Res
.
2022
;
92
(
3
):
791
798
.
28.
Hummel
P
,
Puchalski
M
,
Creech
SD
,
et al.
Clinical reliability, and validity of the NPASS: neonatal pain, agitation and sedation scale with prolonged pain
.
J Perinatol
.
2008
;
28
(
1
):
55
60
.
29.
Hillman
B
,
Tabrizi
M
,
Gauda
E
,
et al.
The Neonatal Pain, Agitation and Sedation Scale and the bedside nurse’s assessment of neonates
.
J Perinatol
.
2015
;
35
(
2
):
128
131
.
30.
McAdams
RM
,
Juul
SE
.
Neonatal encephalopathy: update on therapeutic hypothermia and other novel therapeutics
.
Clin Perinatol
.
2016
;
43
(
3
):
485
500
.
31.
McPherson
C
,
Frymoyer
A
,
Ortinau
CM
, et al
;
Newborn Brain Society Guidelines and Publications Committee. Management of comfort and sedation in neonates with neonatal encephalopathy treated with therapeutic hypothermia
.
Semin Fetal Neonatal Med
.
2021
;
26
(
4
):
101264
.
32.
O’Mara
K
,
Gal
P
,
Wimmer
J
,
et al.
Dexmedetomidine versus standard therapy with fentanyl for sedation in mechanically ventilated premature neonates
.
J Pediatr Pharmacol Ther
.
2012
;
17
(
3
):
252
262
.
33.
Cosnahan
AS
,
Angert
RM
,
Jano
E
,
Wachtel
EV
.
Dexmedetomidine versus intermittent morphine for sedation of neonates with encephalopathy undergoing therapeutic hypothermia
.
J Perinatol
.
2021
;
41
(
9
):
2284
2291
.
34.
Naveed
M
,
Bondi
DS
,
Shah
PA
.
Dexmedetomidine versus fentanyl for neonates with hypoxic ischemic encephalopathy undergoing therapeutic hypothermia
.
J Pediatr Pharmacol Ther
.
2022
;
27
(
4
):
352
357
.
35.
O’Mara
K
,
Weiss
MD
.
Dexmedetomidine for sedation of neonates with HIE undergoing therapeutic hypothermia: a single-center experience
.
AJP Rep
.
2018
;
8
(
3
):
e168
e173
.
36.
McAdams
RM
,
Pak
D
,
Lalovic
B
,
et al.
Dexmedetomidine pharmacokinetics in neonates with hypoxic-ischemic encephalopathy receiving hypothermia
.
Anesthesiol Res Pract
.
2020
;
2020
:
2582965
.
37.
Tobias
JD
.
Dexmedetomidine: applications in pediatric critical care and pediatric anesthesiology
.
Pediatr Crit Care Med
.
2007
;
8
(
2
):
115
131
.
38.
Chrysostomou
C
,
Schulman
SR
,
Castellanos
MH
,
et al.
A phase II/III, multicenter, safety, efficacy, and pharmacokinetic study of dexmedetomidine in preterm and term neonates
.
J Pediatr
.
2014
;
164
(
2
):
276
282
.
39.
Sellas
MN
,
Kyllonen
KC
,
Lepak
MR
,
Rodriguez
RJ
.
Dexmedetomidine for the management of postoperative pain and sedation in newborns
.
J Pediatr Pharmacol Ther
.
2019
;
24
(
3
):
227
233
.
40.
Elliott
M
,
Burnsed
J
,
Heinan
K
,
et al.
Effect of dexmedetomidine on heart rate in neonates with hypoxic ischemic encephalopathy undergoing therapeutic hypothermia
.
J Neonatal Perinatal Med
.
2022
;
15
(
1
):
47
54
.
41.
Reiter
PD
,
Pietras
M
,
Dobyns
E
.
Prolonged dexmedetomidine infusions in critically ill infants and children
.
Indian Pediatr
.
2009
:
46
(
9
):
767
773
.
42.
American Pharmacists Association
.
Pediatric & Neonatal Dosage Handbook: An Extensive Resource for Clinicians Treating Pediatric and Neonatal Patients
. 29th ed.
Hudson, Ohio
:
Lexicomp/Wolters Kluwer
;
2022
.
43.
Natarajan
G
,
Shankaran
S
,
Laptook
AR
,
et al.
Association between sedation-analgesia and neurodevelopment outcomes in neonatal hypoxic ischemic encephalopathy
.
J Perinatol
.
2018
;
38
(
8
):
1060
1067
.
44.
Chang
LL
,
Wyn
JL
,
Pacella
MJ
,
et al.
Enteral feeding as an adjunct to hypothermia in neonates with hypoxic-ischemic encephalopathy
.
Neonatology
.
2018
;
113
(
4
):
347
352
.
45.
Alburaki
W
,
Scringer-Wilkes
M
,
Dawoud
F
,
et al.
Feeding during therapeutic hypothermia is safe and may improve outcomes in newborns with perinatal asphyxia
.
J Matern Fetal Neonatal Med
.
2022
;
35
(
25
):
9440
9444
.

Disclosure. The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Ethical Approval and Informed Consent. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guidelines on human experimentation and have been approved by the appropriate committees at our institution. Given the nature of this retrospective study, informed consent was not required.