• 
• 

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:

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]

Search 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)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Chrysostomou C 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
Estkowski LM. et al 2015 United States 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
O'Mara K et al. 2012 United States 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
Dilek O et al 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
O'Mara K 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
Su F et al. 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.
Kubota T et al. 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
Chernyshuk S et al. 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
Shiota M etal 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

Comment(s)

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.

Clinical 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 Journal of Pediatrics 2014;164(2):276-82
2. Estkowski LM, Morris JL, Sinclair EA Characterization of dexmedetomidine dosing and safety in neonates and infants. The Journal of Pediatric Pharmacology and Therapeutics Mar-Apr;20(2):112-8
3. O’Mara K, Gal P, Wimmer J et al., Dexmedetomidine versus standard therapy with fentanyl for sedation in mechanically ventilated premature neonates The Journal of Pediatric Pharmacology and Therapeutics vol. 17, no. 3, pp. 252–262
4. Dilek O , Yasemin G, Atci M Preliminary Experience with Dexmedetomidine in Neonatal Anesthesian J Anaesthesiol Clin Pharmacol 2011 Jan-Mar; 27(1): 17–22
5. O'Mara K , Gal P, Ransommd JL, et al. Successful use of dexmedetomidine for sedation in a 24-week gestational age neonate Ann Pharmacother. 2009;43(10):1707-1713
6. Su F, Gastonguay MR, Nicolson SC, DiLiberto M, Ocampo-Pelland A, Zuppa AF. Dexmedetomidine pharmacology in neonates and infants after open heart surgery Anesth Analg 2016;122:1556–66
7. Kubota T, Fukasawa T, Kitamura E, Magota M, Kato Y, Natsume J, Okumura A Epileptic seizures induced by dexmedetomidine in a neonate. Brain Dev. 2013 Apr;35(4):360-2.. Epub 2012 Jun 21
8. Chernyshuk S, Yemets H, Zhovnir V . , Comparison of postoperative sedation and analgesia of neonates in cardiac surgery: dexmedetomidine vs standard regimen Intensive Care Medicine Experimental 2016, 4(Suppl 1):A800
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 Pediatric Anesthesia Jun 2012 22(6):603-5