DEXMEDETOMIDINE FOR THE MANAGEMENT OF POSTOPERATIVE PAIN AND SEDATION IN NEWBORNS

MANUSCRIPT CITATION

Sellas MN, Kyllonen KC, Lepak MR, Rodriguez RJ. Dexmedetomidine for the Management of Postoperative Pain and Sedation in Newborns. J Pediatr Pharmacol Ther. 2019 May-Jun;24(3):227-233. doi: 10.5863/1551-6776-24.3.227. PMID: 31093022

REVIEWED BY

Hassanein Moustafa, MBBCh, MSc (Paed), MRCPCH

Senior Clinical fellow in neonates

Department of Neonatology
New Cross Hospital
Wolverhampton, United Kingdom

h.moustafa@nhs.net 

TYPE OF INVESTIGATION

Treatment – Safety and efficacy

QUESTION

(P) In postsurgical neonates (I) does concomitant use of dexmedetomidine (DEX) with opioid infusions (C) compared to the standard care with opioids only (O) reduce the patient exposure to opioids without significantly increasing side effects and providing adequate sedation and pain control (T) during the postoperative period. 

METHODS

• Design: A retrospective observational cohort study
• Allocation: Neonates were allocated into 2 cohorts based on whether they did or did not receive DEX as a postoperative medication. Patients were matched based on gestational age at birth and surgical intervention
• Blinding: Not applicable
• Follow-up period: Follow up data were collected for a minimum 6 hour following surgical procedures
• Setting: This study analysed neonates admitted between January 2010 and August 2015 to the level IV NICU at the Cleveland Clinic Children’s Hospital
• Patients:
  • Inclusion criteria:

• • Neonates who had an invasive surgical procedure and required at least 6 hours of continuous sedation and/or analgesia with morphine, fentanyl, and/or DEX postoperatively

• Exclusion criteria:

• • Patients who had been diagnosed with neonatal abstinence syndrome
  • Patients who only had a placement of a central catheter as a surgical procedure

• Data collected included:

• • Gestational age at birth
  • Birth weight
  • Sex
  • Postconceptional age at the time of surgery
  • Type of surgical intervention
  • Length of NICU stay
  • Use of mechanical ventilation

• Intervention:

Patient comfort was assessed by nursing staff by means of the Neonatal Pain, Agitation, and Sedation Scale (N-PASS) tool for degree of pain relief and sedation. The patient is assigned a score ranging from −2 (well sedated) to +2 (experiencing pain/agitation) for each variable, to determine the level of sedation and analgesia. For each patient, the N-PASS was evaluated throughout the time patients were receiving DEX. Higher scores received intervention, first with nonpharmacologic methods and then, if unresolved, pharmacologic measures.

• • Outcomes:
    • Primary outcome: 

• • • • Number of bradycardic episodes. Bradycardia was defined as a sustained heart rate <80 beats per minute for at least 3 consecutive readings in a 1- to 2-hour period.
      • Hypotensive events. Systemic hypotension was identified by the need for volume expansion or inotropic support associated with the initiation or escalation of an infusion or the administration of a bolus dose.
      • Respiratory depression events between groups during the continuous sedation/analgesia infusion. Respiratory depression was defined as the patient having a respiratory rate < 20 breaths per minute in non-intubated patients.

• • • Secondary outcomes:
      • Comparison of the cumulative opioid dose in morphine equivalents. Morphine equivalents were calculated using the conversion factor of 10 mg intravenous morphine is equivalent to 0.1 mg fentanyl.
      • Comparison of the number of supplemental opioid doses administered. Supplemental dosing is defined as doses given in addition to the infusion of DEX or opioids and intermittent opioid doses, given for patient comfort, after the continuous infusion was no longer necessary.
      • The dosage amount associated with the adverse effects between the 2 cohorts.
  • Analysis and Sample Size:
    • Thirty-nine patients in the DEX group were matched by gestational age and surgical procedure to 39 patients who did not received DEX
  • Patient follow-up: (% included in analysis): 100%  

MAIN RESULTS

Summary of main results (Table 1 &2)

• There was no difference in gestational age or weight at birth between the DEX and no-DEX groups. However, the DEX group’s median postconceptional date was older at the time of surgery (p = 0.003).
• Patients in the DEX group experienced more episodes of bradycardia (p = 0.01).
• There was no difference between groups in episodes of hypotension or respiratory depression.
• The cumulative dose of opioids was significantly lower in the DEX group compared with the no-DEX group (p = 0.01).
• There was no difference in the number of supplemental doses of opioids given between the groups. 

1 pdf

CONCLUSIONS

The authors conclude that addition of DEX to opioid infusions resulted in a significant decrease in the cumulative dose of opioids. However, this was associated with more episodes of bradycardia than opioids alone.

COMMENTARY

Neonates are exposed to various degrees of post-surgical pain.  This pain intensity and duration depend on the type of surgery, respiratory support required, and frequency of investigations carried out during the postoperative period. Surgical procedures during early neonatal period lead to release of stress hormones and have been found to be associated with increased neurodevelopmental disorders during the childhood period (1). Adequate sedation and analgesia in neonates following surgical interventions could help to reduce this stress response and decrease morbidity and mortality (2). There have been various available modalities of pharmacologic interventions to manage postoperative neonatal pain, which may be similar to those utilized in other surgical patients (3).

 

Morphine and fentanyl have been the most widely used opioids for managing postoperative neonatal pain for years. However, these agents are not free of risk.  Fentanyl use in neonates who underwent surgical procedures is associated with high incidence of postoperative hypothermia, which increases the risk of postoperative complications. Additionally, fentanyl may have adverse effects, which include delayed motility of gastrointestinal tract, prolonged hospital stay, respiratory depression and tolerance (4). Morphine exposure in extremely preterm babies has been found to be associated with long-term poor neurodevelopmental outcomes (5).

 

Dexmedetomidine is an upcoming agent that can provide analgesia, anxiolysis, and sedation via its selective α2-adrenergic central effect on the locus cerulus, which reduces the sympathetic outflow. Dexmedetomidine is found to facilitate early extubation in postoperative paediatric cardiac surgical patients while being as effective sedative as fentanyl with comparable haemodynamic parameters (6). A conducted multicentre study of dexmedetomidine safety, efficacy and pharmacokinetics in forty-two mechanically ventilated preterm and term neonates concluded that dexmedetomidine is an effective sedative and well-tolerated in this population without having any reported significant adverse effects (7). Another retrospective observational comparative study in a tertiary neonatal intensive care unit found that dexmedetomidine use in preterm neonates was associated with shorter duration of mechanical ventilation, less time to achieve full enteral feeds and lower incidence of culture-positive sepsis in comparison to fentanyl (8). In contrast to opioids, dexmedetomidine does not appear to be associated with respiratory depression or delayed gastrointestinal motility. However, the most commonly reported side effects of dexmedetomidine are bradycardia and hypotension, specifically when received concomitantly with opioids in postsurgical settings (9).

 

This study adds to the growing evidence of dexmedetomidine analgesic and sedative effect in neonates postoperatively, as its use is associated with less exposure to opioids. However, there may be higher incidence of bradycardia and hypotension when dexmedetomidine is administered in concomitant with opioids. Pain scores statistical difference between the two studied groups would have added more support to the study findings if included as one of the study outcomes. It might be worth conducting a large prospective randomized controlled study to assess efficacy of dexmedetomidine as a sole agent for postoperative neonatal sedation and analgesia in comparison to opioids, as well as including a long-term follow-up to evaluate its long-term safety in order to come to definitive recommendations regarding its use in this population.

REFERENCES

1. Hunt RW, Hickey LM, Burnett AC, Anderson PJ, Cheong JLY, Doyle LW, et al. Early surgery and neurodevelopmental outcomes of children born extremely preterm. Arch Dis Child Fetal Neonatal Ed 2018; 103(3): F227-F232.

2. Visoiu M. Evolving approaches in neonatal postoperative pain management. Semin Pediatr Surg 2022; 31(4):151203.

3. Brusseau R, McCann ME. Anaesthesia for urgent and emergency surgery. Early Hum Dev 2010; 86(11):703-14.

4. Berde CB, Jaksic T, Lynn AM, Maxwell LG, Soriano SG, Tibboel D. Anesthesia and analgesia during and after surgery in neonates. Clin Ther. 2005; 27(6):900-21.

5. Luzzati M, Coviello C, De Veye HS, Dudink J, Lammertink F, Dani C, et al. Morphine exposure and neurodevelopmental outcome in infants born extremely preterm. Dev Med Child Neurol 2023.

6. Prasad SR, Simha PP, Jagadeesh AM. Comparative study between dexmedetomidine and fentanyl for sedation during mechanical ventilation in post-operative paediatric cardiac surgical patients. Indian J Anaesth 2012; 56(6):547-52.

7. 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. J Pediatr 2014; 164(2):276-82.e1-3.

8. O’Mara K, Gal P, Wimmer J, Ransom JL, Carlos RQ, Dimaguila MA, et al. Dexmedetomidine versus standard therapy with fentanyl for sedation in mechanically ventilated premature neonates. J Pediatr Pharmacol Ther 2012; 17(3):252-62.

9. Dersch-Mills DA, Banasch HL, Yusuf K, Howlett A. Dexmedetomidine Use in a Tertiary Care NICU: A Descriptive Study. Ann Pharmacother 2019; 53(5):464-470.