Safety and Effectiveness of Dexmeditomidine for sedation in neonates

Date First Published:
October 4, 2018
Last Updated:
October 4, 2018
Report by:
Ullas Angadi , Haley Hutton, Simon Hannam, Specialist Registrar / Consultant (Great Ormond Street Hospital )
Search checked by:
Haley Hutton, Great Ormond Street Hospital
Three-Part Question:
Is [Dexmeditomidine] safe and more effective than standard sedatives for [sedation] in [neonates] on mechanical ventilator?
Clinical Scenario:
A two day old term neonate with meconium aspiration syndrome is on mechanical ventilation in a level III neonatal unit. He is diagnosed to have PPHN with a possibility to remain on the ventilator at least for another 24 hours. We know that dexmedetomidine is used in the paediatric intensive care units for sedation. But, can it be used in neonates? Is it more effective and safe compared to standard sedatives?
Search Strategy:
Medline 1966-05/18 using the Ovid interface
Pubmed 1966-05/18:
Search Details:
Medline
(dexmedetomidine.mp. or exp.DEXMEDETOMIDINE/) AND ( neonat*mp. Or newborn.mp.) AND ( sedation.mp.)
Pubmed ((((dexmedetomidine) OR precedex)) AND (((neonat*) OR preterm) OR prematur*)) AND sedation AND "humans"[MeSH Terms]
Outcome:
Altogether 58 papers were found in Medline and 56 in Pubmed, of which 9 papers were found relevant to the problem. Only studies which included neonatal population with age less than 28days including preterm neonates were considered
Relevant Paper(s):
Study Title Patient Group Study type (level of evidence) Outcomes Key results Study Weaknesses
A phase II/III, multicenter, safety, efficacy, and pharmacokinetic study of dexmedetomidine in preterm and term neonates Chrysostomou C, Schulman SR, Herrera Castellanos M, Cofer BE, Mitra S, da Rocha MG, et al 2014 United States 42 mechanically ventilated neonates (28 -44 weeks)

Group I (28 to <36 weeks) n = 18


Group II (36 to 44 weeks) n = 24
Prospective cohort The primary efficacy endpoint : number of patients requiring midazolam for sedation during dexmedetomidine administration Secondary endpoints : the use of medications (fentanyl or morphine) for analgesia; changes from baseline in vital signs (HR, blood pressure [BP], respiratory rate), and oxygen saturation; time spent with a total N-PASS score >3; and time to extubation from dexmedetomidine initiation Additional sedation was administered in only 4 (10%) patients group I required no extra sedation group II 4 patients (17%) were given midazolam Additional analgesia was administered to 17 patients (40%) Fentanyl was given in 3 patients in group I (17%). In group II, 9 patients received only fentanyl (37%), 2 received fentanyl and morphine (8%), and 3 received only morphine (12%). 3 (5%) out of 56 adverse events(AEs) (62%) were related to dexmedetomidine. No serious AEs and no AEs or hemodynamic changes requiring dexmedetomidine discontinuation
Characterization of dexmedetomidine dosing and safety in neonates and infants. Estkowski LM, Morris JL, Sinclair EA 2015 United States Patients younger than 12 months with corrected gestational ages of at least 37 weeks
Neonates=28
(only data in neonates discussed here )
 Retrospective cohort primary objective of this study was to describe the off-label use of dexmedetomidine in infants and neonates . Secondary objectives included describing the occurrence of at least 1 episode of bradycardia or hypotension and comparing dosing and adverse effects between infants and neonates. The median minimum dexmedetomidine dose was 0.29 mcg/kg/hr (IQR, 0.2–0.31) The median maximum dose was 0.4 mcg/kg/hr [IQR, 0.26–0.6] Additional sedative use 15/28 [54%]. Bradycardia. 2/28 [7%] 4/28 (14%) had CV adverse events requiring discontinuation retrospective study limits the control of confounding factors

No standard clinical criteria for dexmedetomidine use.
type 2 error given the size of this study
not able to assess long-term outcomes
Dexmedetomidine versus standard therapy with fentanyl for sedation in mechanically ventilated premature neonates O’Mara K, Gal P, Wimmer J et al., 2012 United States 48 premature neonates requiring mechanical ventilation Retrospective case-control To compare the efficacy and safety of dexmedetomidine and fentanyl for sedation primary efficacy outcome was the need for adjunctive analgesia or sedation Days on mechanical ventilation, stooling patterns, feeding tolerance, and neurologic outcomes were also evaluated Patients in the dexmedetomidine group required less adjunctive sedation (any bolus dose(s) of fentanyl or lorazepam given in addition to the continuous infusion or scheduled boluses of the treatment drug) and had more days free of additional sedation in comparison to fentanyl (54.1% vs. 16.5%, p<0.0001). There were no differences in hemodynamic parameters between the 2 groups. Duration of mechanical ventilation was shorter in the dexmedetomidine group (14.4 vs. 28.4 days, p<0.001). time from initiation to achievement of full enteral feeds (26.8 vs. 50.8 days, p<0.0001) were shorter in the dexmedetomidine group. Incidence of culture-positive sepsis was lower in the dexmedetomidine group (48% vs. 88%). The incidence of either severe intraventricular hemorrhage or periventricular leukomalacia was not statistically significantly reduced (2% vs. 7%). small sample size
retrospective case-control design.
differences in maturity
no long-term neurologic outcomes
Preliminary Experience with Dexmedetomidine in Neonatal Anesthesian Dilek O , Yasemin G, Atci M 2011 Turkey 16 neonates age 2-28 days
 Prospective cohort study Assess hemodynamic responses to nociceptive stimuli Blood pressure, heart rate, SPO2, DETCO2, inhaled & end tidal sevoflurane concentration and body temperature were monitored No significant difference was observed in the measured values of hemodynamic parameter at different intervals and the base line values. No patient had hypotension bradycardia hypertension hypoxia or respiratory depression. Patients had mild hypothermia during post-operative period Small sample size
Only for the duration of surgery
Adjunctive sevoflurane and ketamine used
Successful use of dexmedetomidine for sedation in a 24-week gestational age neonate O'Mara K , Gal P, Ransommd JL, et al. 2009 United States 9day old , 24-week gestational age neonate case report The dexmedetomidine infusion allowed weaning of mechanical ventilation settings and eventual extubation of the infant, Rapid tapering of other sedative medications. No significant adverse effects were directly attributed to dexmedetomidine use during this time Single case report
Extreme preterm physiology
Dexmedetomidine pharmacology in neonates and infants after open heart surgery Su F, Gastonguay MR, Nicolson SC, DiLiberto M, Ocampo-Pelland A, Zuppa AF. 2016 United States 23 neonates(2.3–4.2kg) and 36 infants with open heart surgery evaluated
( results tabulated only for neonates)
 Prospective cohort study Pharmacokinetics ,safety and efficacy continuous infusions up to 0.3 ?g/kg/h in neonates were well tolerated after open heart surgery Neonates require an approximately 30% to 40% reduction in weight-based dose (microgram per kilogram) to achieve similar plasma concentrations at steady state when compared with infants Neonates achieve higher plasma concentrations (>600 pg/mL) with longer times to steady-state concentration (>10 hours) when administered equivalent microgram per kilogram doses 1 neonate receiving 0.25 ?g/kg/h had Accelerated junctional rhythm requiring no intervention 1 neonate receiving 0.35 ?g/kg/h had Junctional rhythm, with Decreased heart rate resolved Resolved after discontinuation of dexmedetomidine 2 neonates on 0.5 ?g/kg/h had Atrial ectopy and Hypotension with one requiring CPR Small sample size
Only cardiac patients on bypass. Total bypass time might have affected the metabolism confounded by gestational maturity.
Results cannot be extrapolated to whole neonatal disease population.
Epileptic seizures induced by dexmedetomidine in a neonate. Kubota T, Fukasawa T, Kitamura E, Magota M, Kato Y, Natsume J, Okumura A 2012 Japan single term neonate case report Sedated by dexmedetomidine during artificial ventilation. EEG confirmed epileptic seizures and non-epileptic abnormal movements. Twelve hours after the discontinuation of dexmedetomidine achieved normal development, with no obvious neurological abnormalities Single case
Many confounding factors
Comparison of postoperative sedation and analgesia of neonates in cardiac surgery: dexmedetomidine vs standard regimen Chernyshuk S, Yemets H, Zhovnir V . , 2016 Ukraine 60 neonates
(30 patients on dexmeditmidine ) with congenital heart disease who underwent Arterial Switch Operation
PRCT Effectiveness, Side-effects, Outcome In study group time of ICU stay - 93.5 h - was significantly shorter than in control group -120 h (p-0.02). start of feeding in study group was earlier than in control group - 1- st vs 2-d day (p- 0.007) and 2-d vs 2.5-day (p-0.035), respectively. No decrease of mean blood pressure and heart rate in the study group as it could be expected. Small cohort
Only postoperative Atrial Switch operative population cohort
Dexmedetomidine infusion for sedation in the intensive care setting in an infant with airway compromise due to congenital mediastinal neuroblastoma Shiota M, Oda Y , Taniguchi M , Hamabata T ,Hata D 2012 Japan 7 day neonate on 56 days of dexmeditomidine case report Effectiveness, Side-effects, Outcome Allowed weaning of fentanyl and midazolam no developmental delay No side effects noted single case
Author Commentary:
The evidence available is of variable quality with most studies pointing to the conclusion that dexmedetomidine is potentially safe and useful as a sedative in neonates. However, a well-designed PRCT examining benefits of dexmedetomidine use over standard sedatives is warranted. Further cost effectiveness and long term neurological safety in neonates needs to be evaluated.
Bottom Line:
With careful patient selection and a conservative approach to dosing, dexmedetomidine may be safe for use in the neonatal population, but all aspects of a patient's medication regimen and clinical picture must be thoroughly evaluated when determining if the benefits of dexmedetomidine therapy outweigh the risks. Available evidence is still insufficient to recommend routine dexmedetomidine use in neonates. It is reasonable to await a prospective randomized controlled trial before dexmedetomidine is accepted as a standard of care in neonatal population
References:
  1. Chrysostomou C, Schulman SR, Herrera Castellanos M, Cofer BE, Mitra S, da Rocha MG, et al. A phase II/III, multicenter, safety, efficacy, and pharmacokinetic study of dexmedetomidine in preterm and term neonates
  2. Estkowski LM, Morris JL, Sinclair EA. Characterization of dexmedetomidine dosing and safety in neonates and infants.
  3. O’Mara K, Gal P, Wimmer J et al., . Dexmedetomidine versus standard therapy with fentanyl for sedation in mechanically ventilated premature neonates
  4. Dilek O , Yasemin G, Atci M. Preliminary Experience with Dexmedetomidine in Neonatal Anesthesian
  5. O'Mara K , Gal P, Ransommd JL, et al. . Successful use of dexmedetomidine for sedation in a 24-week gestational age neonate
  6. Su F, Gastonguay MR, Nicolson SC, DiLiberto M, Ocampo-Pelland A, Zuppa AF. . Dexmedetomidine pharmacology in neonates and infants after open heart surgery
  7. Kubota T, Fukasawa T, Kitamura E, Magota M, Kato Y, Natsume J, Okumura A . Epileptic seizures induced by dexmedetomidine in a neonate.
  8. Chernyshuk S, Yemets H, Zhovnir V . , . Comparison of postoperative sedation and analgesia of neonates in cardiac surgery: dexmedetomidine vs standard regimen
  9. Shiota M, Oda Y , Taniguchi M , Hamabata T ,Hata D . Dexmedetomidine infusion for sedation in the intensive care setting in an infant with airway compromise due to congenital mediastinal neuroblastoma