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Not yet recruitingNCT06985290COOL-SEDUpdated May 22, 2025

Dexmedetomidine Versus Morphine During Cooling Therapy in Neonates

A Phase 2 interventional study of Dexmedetomidine Infusion and Morphine Infusion in Hypoxic Ischemic Brain Injury, Neonatal Encephalopathy and Perinatal Anoxic-ischemic Brain Injury, sponsored by Ipsita Goswami. Not yet recruiting at 1 site in Canada. Open to participants aged Up to 20 Hours. Per ClinicalTrials.gov, last updated 2025-05-22.

Sponsored by Ipsita Goswami · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
50
Allocation
Randomized
Ages
Up to 20 Hours
Sex
All
01

Study summary

About \~3/ 1000 live-born newborns may suffer from brain injury due to a transient drop in oxygen supply to the brain during the birth process. The degree of brain injury that ensues in the first 72 hours after the injury is directly proportional to the severity of long-term childhood disabilities (e.g., cerebral palsy and developmental delays). Whole-body cooling during the first 3 days of life is proven effective in reducing the severity of brain injury. However, cooling therapy leads to pain, shivering, stress, and discomfort. The best way to alleviate the pain and agitation of cooled newborns is unknown. Standard practice is to provide morphine infusion to reduce pain. Recently, a new drug called "dexmedetomidine" has been tested in small studies and has been found to be safe during cooling in newborns. Dexmedetomidine has added beneficial effects such as anti-inflammation, faster recovery, and shorter hospital stays. This study is going to test the feasibility of conducting a future clinical trial to compare the effects of using Dexmedetomidine versus morphine in the management of cooling-related pain/agitation on the severity of brain injury in the first week of life. The study will also examine the effect of dexmedetomidine compared to morphine on short-term clinical outcomes, parental experiences and developmental outcomes at 1 year.

02

Conditions studied

  • Hypoxic Ischemic Brain Injury
  • Neonatal Encephalopathy
  • Perinatal Anoxic-ischemic Brain Injury

Keywords

  • sedation
  • analgesia
  • dexmedetomidine
  • morphine
03

Who can participate

Ages eligible
Up to 20 Hours
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  1. Gestational age >= 35 weeks
  2. Birth weight >= 2500g
  3. Sign of perinatal hypoxic event (any of the following): (a) Arterial Cord blood gas or postnatal gas within 1 hour of life pH \<= 7.00 OR Base Deficit >= 16 (b) Arterial Cord blood gas postnatal gas within 1 hour of life pH 7.00 -7.15 AND Acute sentinel intrapartum event
  4. Sign of Neonatal Encephalopathy
  5. Initiation of Therapeutic Hypothermia within 8 hours of life

Exclusion criteria

Exclusion criteria:

  1. Informed consent not obtained within 20 hours of life
  2. Congenital Brain Malformations (antenatally known)
  3. Major Chromosomal Anomaly (antenatally diagnosed)
  4. Congenital neuromuscular disorder
04

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
50 participants (estimated)

Study arms

  • Experimental
    Dexmedetomidine Group

    Dexmedetomidine infusion as sedation during therapeutic hypothermia and rewarming

    Drug: Dexmedetomidine Infusion

  • Active comparator
    Morphine Group

    Morphine infusion as sedative during therapeutic hypothermia and rewarming

    Drug: Morphine Infusion

Interventions

  • DrugDexmedetomidine Infusion

    Dexmedetomidine infusion given for sedation during therapeutic hypothermia. Dexmedetomidine infusion at a starting dose of 0.2 μg/kg/h, with titration in 0.1 μg/kg/h increments with a maximum of 0.5 μg/kg/h based on objective assessment of sedation.

  • DrugMorphine Infusion

    Morphine infusion given for sedation during therapeutic hypothermia. Morphine infusion at a starting dose of 4 μg/kg/h, with titration in 2 μg/kg/h increments with a maximum of 10 μg/kg/h based on objective assessment of sedation.

05

What researchers measure

Primary outcomes

  1. Recruitment Rate

    Proportion of eligible neonates enrolled. Calculation = (Number of neonates enrolled) X 100/(Total eligible neonates)

    Time frame: Day 1

  2. Follow Up Rate

    Percentage of neonates completing the study. Calculation = (Neonates who completed the study) x 100/ (Total neonates consented)

    Time frame: From enrollment to 1 year of age

  3. Adverse Event Rate

    Incidence of adverse events Measurement of Adverse Event Rate = (Number of neonates experiencing) x100/ (Total neonates exposed to the intervention)

    Time frame: From enrollment to 7 days of life

  4. Discontinuation Rate

    Need for intervention discontinuation due to adverse effects. Measurement of Discontinuation Rate = (Number of neonates for whom the intervention discontinued) x 100/ (Total neonates consented)

    Time frame: From enrollment to 7 days of life

  5. Protocol Adherence Rate

    Percentage of correct drug adjustment based on changes in COMFORTneo scale as per protocol. Calculation of Drug Administration Compliance = (Number of correctly administered medication per month) x 100/ (Total number of participant enrolled per month)

    Time frame: through study completion, average 1 year

Secondary outcomes

  1. Severity of Brain Injury on Magnetic Resonance Imaging (MRI)

    The T1 and T2 weighted images, diffusion-weighted images, and magnetic resonance spectroscopy (MRS) are additionally evaluated to determine the level of brain damage. MRI scoring system reported by Weeke et al. will be used to classify brain injury based on 4 subscores, including grey matter (basal ganglia, thalamus, PLIC, brainstem, perirolandic cortex, and hippocampus), white matter/cortex (including optic radiation and corpus callosum), and cerebellum.

    Time frame: From enrollment to 10 days of life

  2. Seizure Burden during Therapeutic Hypothermia

    Total duration of seizures noted during the first 72 hours of life

    Time frame: From enrollment to 72 hours of life

  3. Stress levels measured by Salivary cortisol assay at 24 and 48 hours

    Salivary cortisol levels will be used as an objective marker of neonatal stress measured in µg/dL.

    Time frame: From enrollment to 48 hours of life

  4. Neonatal Sedation and Discomfort Levels

    COMFORT neo scores during the period of therapeutic hypothermia. It consists of 7 behavioural items (alertness, calmness/agitation, respiratory response, crying, body movement, facial tension and muscle tone), of which six items should be scored (respiratory response or crying depends on the presence of invasive ventilation). The neonate will be observed for 2 minutes to score. Total scores range from 7 to 35. A score \>14 is considered a sign of distress and undersedation. A score \< 9 suggests oversedation.

    Time frame: From enrollment to 4 days of life

  5. Time to Reach Full Oral Feeds

    Days of life when participant is receiving all oral feeds either breast or bottle

    Time frame: up to 4 weeks of life

  6. Cumulative dose of PRN opioid boluses given during therapeutic hypothermia

    Total dose of morphine and fentanyl given during therapeutic hypothermia measured in mg/kg of morphine equivalent

    Time frame: up to 4 days of life

  7. Length of Hospital Stay

    Day of life when discharged home

    Time frame: up to 4 weeks of life

  8. Days on invasive and non-invasive respiratory support

    Day of life when comes off all respiratory support to room air

    Time frame: Up to 4 weeks of life

Other outcomes

  1. Parental Stress Index

    Parental Stress Index - Short Form (PSI-SF) will be administered to parents of study subjects at discharge from NICU to compare stress levels between neonates of the two groups. The short form is derived from the original Parental Stress Index (PSI). It consists of 36 items across three subscales namely (i) Parental Distress (PD): stress related to personal factors (e.g., depression, lack of support), (ii) Parent-Child Dysfunctional Interaction (P-CDI): stress about the child not meeting expectations and (iii) Difficult Child (DC): stress due to child's behavioral difficulties. Each item is rated 1 (Strongly Disagree) to 5 (Strongly Agree). Percentiles based on normative data are used to interpret scores. \>85th percentile indicates clinically significant stress, 90th-99th percentile indicates highly elevated stress.

    Time frame: Up to 4 weeks of life

  2. Parental Experiences

    Parental experiences captured through semi-structured interviews will be audio-recorded and transcribed.

    Time frame: From discharge to 4 weeks post-discharge

  3. Developmental Outcomes at 12 months

    Ages and Stages Questionnaire-3rd edition (ASQ-3) to assess five areas of childhood development: Communication, Gross motor, Fine motor, Problem-solving, and Personal-social through parent/caregiver reports. Each item is answered as Yes (10 points), Sometimes (5 points) and Not Yet (0 points). Each domain has 6 questions, hence a maximum 60 points per domain. After summing scores for each domain, total score is interpretated as: (i) Above Cutoff (Development is on schedule), (ii) Close to Cutoff (within 1 SD) (Monitor, Child may need re-screening soon) and (iii) Below Cutoff (Referral to specialist for further evaluation recommended).

    Time frame: Between 10-14 months of enrollment

06

Study locations

1 site
  • McMaster Children's Hospital
    Hamilton, Ontario L8N3Z5, Canada
07

References and documents

Publications

  • Alvik A, Groholt B. Examination of the cut-off scores determined by the Ages and Stages Questionnaire in a population-based sample of 6 month-old Norwegian infants. BMC Pediatr. 2011 Dec 19;11:117. doi: 10.1186/1471-2431-11-117. PubMed 22182217 ↗
  • Weeke LC, Groenendaal F, Mudigonda K, Blennow M, Lequin MH, Meiners LC, van Haastert IC, Benders MJ, Hallberg B, de Vries LS. A Novel Magnetic Resonance Imaging Score Predicts Neurodevelopmental Outcome After Perinatal Asphyxia and Therapeutic Hypothermia. J Pediatr. 2018 Jan;192:33-40.e2. doi: 10.1016/j.jpeds.2017.09.043. PubMed 29246356 ↗
  • Craig A, Deerwester K, Fox L, Jacobs J, Evans S. Maternal holding during therapeutic hypothermia for infants with neonatal encephalopathy is feasible. Acta Paediatr. 2019 Sep;108(9):1597-1602. doi: 10.1111/apa.14743. Epub 2019 Mar 5. PubMed 30721531 ↗
  • Meesters NJ, Dilles T, van Rosmalen J, van den Bosch GE, Simons SHP, van Dijk M. COMFORTneo scale: a reliable and valid instrument to measure prolonged pain in neonates? J Perinatol. 2023 May;43(5):595-600. doi: 10.1038/s41372-023-01628-1. Epub 2023 Feb 6. PubMed 36746985 ↗
  • van Dijk M, Roofthooft DW, Anand KJ, Guldemond F, de Graaf J, Simons S, de Jager Y, van Goudoever JB, Tibboel D. Taking up the challenge of measuring prolonged pain in (premature) neonates: the COMFORTneo scale seems promising. Clin J Pain. 2009 Sep;25(7):607-16. doi: 10.1097/AJP.0b013e3181a5b52a. PubMed 19692803 ↗
  • Elliott M, Fairchild K, Zanelli S, McPherson C, Vesoulis Z. Dexmedetomidine During Therapeutic Hypothermia: A Multicenter Quality Initiative. Hosp Pediatr. 2024 Jan 1;14(1):30-36. doi: 10.1542/hpeds.2023-007403. PubMed 38115800 ↗
  • McAdams RM, Pak D, Lalovic B, Phillips B, Shen DD. Dexmedetomidine Pharmacokinetics in Neonates with Hypoxic-Ischemic Encephalopathy Receiving Hypothermia. Anesthesiol Res Pract. 2020 Feb 25;2020:2582965. doi: 10.1155/2020/2582965. eCollection 2020. PubMed 32158472 ↗
  • Joshi M, Muneer J, Mbuagbaw L, Goswami I. Analgesia and sedation strategies in neonates undergoing whole-body therapeutic hypothermia: A scoping review. PLoS One. 2023 Dec 7;18(12):e0291170. doi: 10.1371/journal.pone.0291170. eCollection 2023. PubMed 38060481 ↗
  • Backe P, Bruschettini M, Blomqvist YT, Sibrecht G, Olsson E. Interventions for the Management of Pain and Sedation in Newborns Undergoing Therapeutic Hypothermia for Hypoxic-Ischemic Encephalopathy: A Systematic Review. Paediatr Drugs. 2023 Jan;25(1):27-41. doi: 10.1007/s40272-022-00546-7. Epub 2022 Dec 8. PubMed 36481984 ↗
  • Walker SM. Long-term effects of neonatal pain. Semin Fetal Neonatal Med. 2019 Aug;24(4):101005. doi: 10.1016/j.siny.2019.04.005. Epub 2019 Apr 5. PubMed 30987942 ↗
  • Wu Y, Kapse K, Jacobs M, Niforatos-Andescavage N, Donofrio MT, Krishnan A, Vezina G, Wessel D, du Plessis A, Limperopoulos C. Association of Maternal Psychological Distress With In Utero Brain Development in Fetuses With Congenital Heart Disease. JAMA Pediatr. 2020 Mar 1;174(3):e195316. doi: 10.1001/jamapediatrics.2019.5316. Epub 2020 Mar 2. PubMed 31930365 ↗
  • Thoresen M, Satas S, Loberg EM, Whitelaw A, Acolet D, Lindgren C, Penrice J, Robertson N, Haug E, Steen PA. Twenty-four hours of mild hypothermia in unsedated newborn pigs starting after a severe global hypoxic-ischemic insult is not neuroprotective. Pediatr Res. 2001 Sep;50(3):405-11. doi: 10.1203/00006450-200109000-00017. PubMed 11518829 ↗
  • van Marken Lichtenbelt WD, Schrauwen P. Implications of nonshivering thermogenesis for energy balance regulation in humans. Am J Physiol Regul Integr Comp Physiol. 2011 Aug;301(2):R285-96. doi: 10.1152/ajpregu.00652.2010. Epub 2011 Apr 13. PubMed 21490370 ↗
  • Mohammad K, McIntosh S, Lee KS, Beltempo M, Afifi J, Tremblay S, Shah P, Wilson D, Bodani J, Khurshid F, Makary H, Ng E, Wintermark P; NeoBrainNetwork. Variations in care of neonates during therapeutic hypothermia: call for care practice bundle implementation. Pediatr Res. 2023 Jul;94(1):321-330. doi: 10.1038/s41390-022-02453-6. Epub 2023 Jan 9. PubMed 36624286 ↗
  • Goswami IR, Whyte H, Wintermark P, Mohammad K, Shivananda S, Louis D, Yoon EW, Shah PS; Canadian Neonatal Network Investigators. Characteristics and short-term outcomes of neonates with mild hypoxic-ischemic encephalopathy treated with hypothermia. J Perinatol. 2020 Feb;40(2):275-283. doi: 10.1038/s41372-019-0551-2. Epub 2019 Nov 13. PubMed 31723237 ↗
  • Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2013 Jan 31;2013(1):CD003311. doi: 10.1002/14651858.CD003311.pub3. PubMed 23440789 ↗
  • Shankaran S. Therapeutic hypothermia for neonatal encephalopathy. Curr Treat Options Neurol. 2012 Dec;14(6):608-19. doi: 10.1007/s11940-012-0200-y. PubMed 23007949 ↗
  • Kromm GH, Patankar H, Nagalotimath S, Wong H, Austin T. Socioemotional and Psychological Outcomes of Hypoxic-Ischemic Encephalopathy: A Systematic Review. Pediatrics. 2024 Apr 1;153(4):e2023063399. doi: 10.1542/peds.2023-063399. PubMed 38440801 ↗
  • Pisani F, Orsini M, Braibanti S, Copioli C, Sisti L, Turco EC. Development of epilepsy in newborns with moderate hypoxic-ischemic encephalopathy and neonatal seizures. Brain Dev. 2009 Jan;31(1):64-8. doi: 10.1016/j.braindev.2008.04.001. Epub 2008 May 19. PubMed 18490125 ↗

Individual participant data

Plan to share: Yes — De-identified individual participant data (IPD) will be shared with qualified researchers following publication of the primary study results. Data sharing will comply with applicable privacy regulations (e.g., PIPEDA/PHIPA).

Supporting information: Study protocol, Sap, Icf, Csr

08

Registry details

Key details

Study ID
NCT06985290
Lead sponsor
Ipsita Goswami
Responsible party
Ipsita Goswami (Associate Professor, McMaster University) — Sponsor-investigator
First posted
May 22, 2025
Start date
Jul 1, 2025 (estimated)
Primary completion
Sep 30, 2027 (estimated)
Completion
Jun 30, 2028 (estimated)
Last update
May 22, 2025

Study contacts

IPSITA GOSWAMI, MD
Contact
goswamii@mcmaster.ca
9055212100
Ipsita Goswami, MD
principal investigator · McMaster University

Oversight

Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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