Manuscript Citation:

Cosnahan A, Angert R, Jano E, Wachtel E. Dexmedetomidine versus intermittent morphine for sedation of neonates with encephalopathy undergoing therapeutic hypothermia. Journal of Perinatology 2021; 41(9):2284-2291. PMID 33649447

 REVIEWED BY:

Kelli Jo Welter, PharmD

Children’s Hospital Colorado, Aurora, Colorado

kelli.welter@childrenscolorado.org

319-480-6087

 

Emma Ross, PharmD, BCPPS

Children’s Hospital Colorado, Aurora, Colorado

emma.ross@childrenscolorado.org

 

Robert Dietz, MD, PhD

University of Colorado School of Medicine, Aurora, Colorado

robert.dietz@cuanschutz.edu

TYPE OF INVESTIGATION:

Treatment

QUESTION

In neonates with hypoxic ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH), is dexmedetomidine safe and effective for analgesia and sedation? 

METHODS

• Design: Retrospective observational cohort study
• Allocation: Not applicable
• Blinding: Not applicable
• Follow-up period: 14 days of life
• Setting: This is a study which analyzed neonates admitted for TH at Bellevue Hospital Center and NYU Langone Health from January 2018 to April 2020.
• Patients: 70 neonates ≥36 weeks with HIE undergoing TH
  • Inclusion criteria:
    • Gestational age of 36 weeks or greater
    • Birth weight of 1.8 kg or greater
    • Less than or equal to 6 h of age
    • Evidence of hypoxic-ischemic injury defined as severe acidosis on cord of patient blood gas (pH 7.0 or less and/or base deficit of greater than 16), 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
    • Evidence of moderate to severe encephalopathy, based on a modified Sarnat exam (level of consciousness, spontaneous activity, neuromuscular control including tone, posture and stretch reflexes, primitive reflexes including suck, Moro and tonic neck, autonomic function including pupil dilation and reactivity and heart rate, and any evidence of seizures)
  • Exclusion criteria:
    • Major congenital abnormalities
    • Neurologically significant large intracranial hemorrhage
  • Intervention: This study compared sedation practices during two different time periods:
    • January 2018 – March 2019: Morphine 0.1 mg/kg/dose IV every 4 hours (n=36) during TH (72 h) and rewarming
    • March 2019 – April 2020: Dexmedetomidine initiated at 0.3 mcg/kg/h, increased by 0.1 mcg/kg/h (maximum dose 2 mcg/kg/h) based on pain scores and breakthrough morphine dose requirements (n=34) during TH (72 h) and rewarming
    • In both groups, neonates received morphine 0.05-0.1 mg/kg/dose every 4 hours as needed for breakthrough shivering and pain (NPASS>3)
  • Outcomes:
    • Primary outcome: efficacy of dexmedetomidine for sedation and analgesia for neonates undergoing TH for HIE
      • Defined as reduction in pain score during TH and overall requirement for cumulative dosage of morphine in mg/kg
    • Secondary outcomes: impact on hemodynamic measures (heart rate, mean arterial pressure, oxygen saturation), respiratory support requirements, tolerance of enteral feeds after rewarming, and short-term neurological outcomes
  • Analysis and Sample Size: 70 neonates who underwent TH that received either dexmedetomidine or morphine
  • Patient follow-up (% included in analysis): 100% 

MAIN RESULTS

• Summary of main results (Table 1):
  • Patients in the dexmedetomidine group received more breakthrough morphine but less cumulative morphine
  • Patients in the morphine group on mechanical ventilation required increased support throughout TH
  • No differences in bradycardia, mean arterial pressures, oxygen saturations, or vasopressor requirement
• No significant differences in timing of enteral feeding initiation between groups)
• No detectable differences in vEEG patterns post-TH between groups
• No significant differences between antiepileptic medication requirements between groups

 

Table 1: Summary of main results

Outcome Measure	Morphine Group (n=36)	Dexmedetomidine Group (n=34)	p value
Breakthrough morphine received (mg/kg)	0.04 ± 0.09	0.13 ± 0.13	0.001
Cumulative morphine received (mg/kg)	1.79 ± 0.23	0.13 ± 0.13	<0.0001
Invasive respiratory support required during TH; n(%) Increased FiO2 required (invasive support only); n (%) Increased support or respiratory rate (invasive support only); n (%)	19 (52.8)     2 (10.5)     6 (31.6)	17 (50)     0 (0)     0 (0)	0.82     0.49     0.02
Time to initiation of feeds (days)	5.62 ± 2.50	5.14 ± 1.88	0.38
Heart rate (HR) Time point in hours: result	36, 42, 48, 72: HR trended higher but WNL across both groups	36, 42, 48, 72: HR trended lower but WNL across both groups	<0.05
Mean Arterial Pressure (MAP) Time point in hours: result	36: MAP slightly higher but WNL across both groups	36: MAP slightly lower but WNL across both groups	<0.05

TH: Therapeutic Hypothermia; WNL: within normal limits

CONCLUSION

This small retrospective observational cohort study of neonates receiving dexmedetomidine during TH demonstrated less opioid use without an increased incidence of bradycardia.

COMMENTARY

Use of sedation during TH is important to provide compassionate care and prevent stress and shivering. While non-pharmacologic approaches should be utilized first-line, some neonates require sedation to limit stress and provide comfort. A neonatal piglet study of HIE suggested that TH is not neuroprotective in the absence of sedation (1).  However, animal studies have demonstrated that sedatives, analgesics, and/or anesthetics may have long-term deleterious effects on the developing brain through inhibition of NMDA glutamate receptors or enhancement of GABA-mediated depolarization triggering widespread apoptotic neurodegeneration (2, 3).Healthcare providers must balance managing stress and pain with the risks that accompany sedation in neonates.

 

Morphine and fentanyl, both opioid agonists, have historically been used during TH to provide sedation. However, these agents have significant side effects including respiratory depression, delayed gastrointestinal motility, and hypotension. Additionally, the global hypoxic-ischemic insult that occurs during HIE leads to a high incidence of acute kidney injury and acute liver injury (4), which may slow metabolism and clearance of medications such as morphine and fentanyl. These pharmacokinetic alterations, along with PK alterations related to TH itself, can lead to accumulation of the medication, further increasing the risk of adverse effects (4,5). In a secondary analysis of 169 neonates enrolled in one study, neonates receiving morphine were more likely to be hypotensive (49% vs. 25%, p=0.02) and had a longer hospital stay (12 days vs. 9 days, p=0.009) compared to those who did not receive morphine (6).

 

Dexmedetomidine is an α2-adrenergic agonist that provides analgesia, anxiolysis, and sedation. The activation of central α2-receptors prevents shivering during TH, inhibits inflammatory cytokines and may result in endogenous neuroprotection (5). Dexmedetomidine does not appear to have significant impact on the respiratory drive or gastrointestinal motility. The most common use-limiting adverse effect is bradycardia. Pharmacokinetic alterations have been demonstrated in animals but there is limited data in neonates, with a single study reporting comparable or lower clearance, larger volume of distribution, and longer elimination half-life in patients with HIEundergoing TH compared to those without HIE (7). In a single-center retrospective cohort study of 19 neonates with HIE undergoing TH, dexmedetomidine was administered at an average rate of 0.3 mcg/kg/h (range 0.2-0.5 mcg/kg/h). Two patients received dexmedetomidine monotherapy, and 17 received fentanyl initially. Thirteen of those 17 patients had fentanyl discontinued within 4 hours of starting dexmedetomidine. The authors concluded that dexmedetomidine was effective for sedation in neonates with HIE undergoing TH (8).

 

The study presented here adds to the growing body of literature that dexmedetomidine may be effective and safe for sedation and analgesia during TH. It is important to note the small sample size and lack of a significant differences between groups for many of the respiratory and gastrointestinal outcomes assessed. Despite the limitations of this study, the potential benefits of dexmedetomidine should be considered when selecting a sedative in neonates undergoing TH.  Future research should focus on gathering additional pharmacokinetic data for dexmedetomidine in HIE/TH and the evaluation of longer-term neurologic outcomes in neonates undergoing TH.

 

FUNDING

 

This review did not have a funding source.

 

 

CONFLICT OF INTEREST

 

The authors have no conflicts of interest to report.

 

 

REFERENCES

1. Thorason M, Status S, Lobert EM, Whitelaw A, Acolet D, Lindgren C, et al. Twenty-Four Hours of Mild Hypothermia in Unsedated Newborn Pigs Starting after a Severe Global Hypoxic-Ischemic Insult Is Not Neuroprotective. Pediatric Research 2001; 50:405-411.

2. Vutskits L, Xie Z. Lasting impact of general anaesthesia on the brain: mechanisms and relevance. Nat Rev Neurosci 2016; 17:705–17.

3. Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003; 23:876–82.

4. O’Dea M, Sweetman D, Bonifacio SL, El-Dib M, Austin T, Molloy EJ. Management of multi organ dysfunction in neonatal encephalopathy. Front Pediatr 2020; 8:239.

5. McPherson C, Frymoyer A, Ortinau C, Miller S, Groenendaal F, et al. Management of comfort and sedation in neonates with neonatal encephalopathy treated with therapeutic hypothermia. Seminars in Fetal and Neonatal Medicine 2021; 26(4):101264.

6. Liow et al. Preemptive Morphine During Therapeutic Hypothermia After Neonatal Encephalopathy: A Secondary Analysis. Therapeutic Hypothermia and Temperature Management 2020; 10(1):45-52.

7. McAdams R, Pak D, Lalovic B, Phillips B, Shen D. Dexmedetomidine pharmacokinetics in neonates with hypoxic-ischemic encephalopathy receiving hypothermia. Anesthesiol Res Pract 2020; 2582965.

8. O’Mara K, Weiss M. Dexmedetomidine for Sedation of Neonates with HIE Undergoing Therapeutic Hypothermia: A Single-Center Experience. Am J Perinatol Rep 2018; 8:e168-e173.