MANUSCRIPT CITATION

Dekker J, Lopriore E, van Zanten HA, Tan RNGB, Hooper SB, te Pas AB. Sedation during minimal invasive surfactant therapy: a randomized controlled trial. Arch Dis Child Fetal Neonatal Ed 2019; 104:F378-F383. PMID: 30068669

REVIEWED BY

Dr Stephanie L Kuek
Neonatal Registrar
The Royal Women’s Hospital

A/Prof Susan E Jacobs
Deputy Clinical Director, Neonatal Paediatrician
Neonatal Services
The Royal Women’s Hospital

Dr Brett J. Manley
Consultant Neonatologist
Newborn Research Centre
The Royal Women’s Hospital

TYPE OF INVESTIGATION

Treatment

QUESTION

In preterm infants 26-36 weeks’ completed gestational age (GA) receiving “minimal invasive surfactant treatment” (MIST) (P), does low dose propofol sedation (I) compared with routine comfort measures (C) decrease the percentage of infants with a COMFORTneo score <14 (O) during the procedure (T)?

METHODS

• Design: Prospective, single-centre, randomized controlled trial
• Allocation: Allocation concealed with opaque, sealed envelopes
• Blinding: Allocation blinded to outcome assessors
• Follow-up period: Infants were observed for 24 hours following MIST procedure
• Setting: Single-centre tertiary neonatal intensive care unit (NICU): Leiden University Medical Centre (LUMC), The Netherlands
• Patients: Infants admitted to NICU January 2015 – July 2017 receiving MIST, involving direct laryngoscopy with passage of a semi-rigid catheter through the vocal cords with administration of surfactant
  • Criteria for MIST: fraction of inspired oxygen >0.3 and continuous positive airway pressure ≥ 8 cm H₂O
  • Included:
    • 110 infants were assessed for eligibility with 88 randomised: 46 to sedation group, 42 to no-sedation group
  • Exclusion criteria:
    • Imminent need for intubation due to respiratory insufficiency
    • Pneumothorax or pulmonary haemorrhage
  • Other reasons for exclusion:
    • Inclusion in the study inappropriate
    • Haemodynamic instability
    • Consent not given or deferred consent not possible
    • Logistical reasons
• Intervention: Infants randomised to the sedation group received intravenous propofol 1 mg/kg immediately prior to MIST. Both intervention and control groups were given standard comfort care with sucrose and containment with swaddling or gently placing the hands of a caregiver on the infant’s body. All infants born <30 weeks’ GA received caffeine, and infants born ≥30 weeks’ GA received caffeine for recurrent apnoea.
• Outcomes:
  • Primary outcome: Percentage of infants with a COMFORTneo score <14 during procedure.
    • COMFORTneo score is a validated score for objective management of (dis)comfort in preterm infants, used routinely by trained nursing staff once per shift at LUMC NICU. It measures alertness, calmness/ agitation, respiratory response or crying, body movement, facial tension and body muscle tone. The lower the score, the more comfortable the infant is assessed to be, with scores <14 indicating adequate comfort.
    • COMFORTneo score was assessed using videos, coded and edited for blinding, with the face and at least one extremity of the infant visible. These were assessed independently by two NICU nurses, with an additional nurse rating the videos until inter-rater reliability was achieved (Cohen’s κ>0.4).
  • Secondary outcomes:
    • Complications:
      • Occurrence of nasal intermittent positive pressure ventilation (nIMV) during or immediately after the procedure
      • Intubation during or within 24 hours of the procedure
      • Desaturation <85%, hypotension with mean blood pressure below GA, bradycardia <80 beats per minute, nasal haemorrhage during MIST
      • Pneumothorax, pulmonary haemorrhage, resuscitation, intraventricular haemorrhage grade III or IV, death
      • Number of attempts at insertion of semi-rigid catheter
      • Duration (in seconds) of MIST
      • Heart rate and blood pressure during and after MIST
• Analysis and Sample Size:
  • Based on a previous trial, to reduce the proportion of infants with a COMFORTneo score >14 when using propofol from 56% to 25%, with 80% power and alpha error 5% (two-tailed test), the investigators calculated a sample of 39 infants per arm was required.
  • Demographics were compared with χ2 test (binary), Student’s t-test (means) and Mann-Whitney U test (medians).
  • Linear outcomes were analysed with two-way factorial analysis of variance or linear mixed-effect regression model. Categorical outcomes were analysed with Fisher’s exact test. Two sided p values <0.05 were considered statistically significant.
• Patient follow-up: Of the 88 randomised infants , 78 (89%) were included in the analysis. Four infants from the sedation group and six infants from the no-sedation group were excluded after randomisation due to no retrospective consent or no video recording.

MAIN RESULTS

Demographics: There were no significant differences in demographic data between the two groups, including the age MIST at which was performed, the number of intubation attempts, or the duration of the procedure.

Primary outcome: The percentage of infants with a COMFORTneo score <14 (assessed as comfortable) during MIST was significantly higher in the sedated group: 32/42 (76%) vs. 8/36 (22%), p <0.001. The mean +/- standard deviation (SD) of the COMFORTneo score was also significantly lower in the sedated group (12±3 vs 17±4; p <0.001).

Secondary outcomes: Desaturation episodes occurred more often in the sedated group, 38/42 (91%) vs. 25/36 (69%), p = 0.023, as did nIMV (39/42 (93%) vs 17/36 (47%) p <0.001. There were no significant differences between groups in intubation during the procedure, intubation in the 24 hours following the procedure, or in hypotension. The difference in heart rate measured before, during and after MIST was greater in the sedated group compared with the non-sedated group (Table 2).

CONCLUSION

The authors concluded that preterm infants were more often observed to be comfortable (COMFORTneo score <14) with propofol sedation during MIST compared with routine comfort measures only. However, they observed more desaturations and nIMV given in infants sedated with propofol.

COMMENTARY

Preterm infants feel pain (1), which may impact on their long-term emotional, psychological and neurological development (2). Clinicians try to minimise pain and be “less invasive” during NICU procedures, but must balance efficacy with safety and comfort. In the study by Dekker et al, preterm infants receiving propofol sedation during MIST were assessed to be more comfortable than infants managed with routine comfort measures. Infants receiving sedation were more likely to desaturate and receive nIMV, but this was transient, and without differences in other complications.

Traditionally surfactant has been administered to preterm infants via an indwelling endotracheal tube inserted under direct laryngoscopy. With MIST, also known as less-invasive surfactant administration (LISA) (3), surfactant is instilled into the trachea via a thin, flexible catheter to a spontaneously breathing infant, then the catheter is removed, avoiding ongoing mechanical ventilation (3). However, MIST still requires laryngoscopy, which is probably uncomfortable and painful. Whilst pre-medication for analgesia and sedation is routine during endotracheal intubation, its use during MIST remains controversial, and practice varies significantly between NICUs (4).

The core issue is the need for infants to spontaneously breathe during and after MIST.  The ideal premedication would provide rapid onset and offset analgesic and sedative effects without compromising spontaneous breathing, have minimal or no side effects, and be safe in the long-term. Multiple medications have been considered for sedation during MIST and other procedures in neonates (4). Propofol is a short-acting sedative with rapid onset and offset that may have analgesic properties (6). Its use in neonates remains ‘off label’ and long-term effects on neurodevelopment have not been evaluated (5). Fentanyl and remifentanil are potential analgesic agents, but both carry the risk of chest wall rigidity and over-sedation (5). Ketamine has both analgesic and sedative effects and lowers pain scores, but has been associated with a higher intubation rate (7). Other potential agents include dexmedetomidine, morphine, midazolam, nitrous oxide and paracetamol (4, 5). Alternative methods of surfactant administration that do not require laryngoscopy have been considered, including administration via a laryngeal mask (supraglottic) airway, pharyngeal deposition, and nebulisation (8). These methods may be even less invasive and completely avoid the need for analgesia and sedation (3).

This study by Dekker et al is the first to investigate sedation during MIST. It suggests that low dose propofol may provide comfort without significant adverse events in preterm infants undergoing MIST. It has some limitations, including insufficient power to make conclusions regarding differences in complications. It is not known if short-term apnoeic episodes are harmful, and long-term neurodevelopmental outcomes of propofol sedation need to be evaluated (5). Propofol is primarily a sedative, and whilst this study found that infants receiving propofol sedation were more comfortable, analgesic effects are unclear. Importantly, the neonatologists performing MIST were not blinded. Use of propofol remains investigational and should be restricted to the research setting.

The question of whether and how infants should be sedated for MIST remains uncertain, and future techniques for truly non-invasive surfactant administration may negate the need for sedation entirely. Further research is underway to help guide clinicians in balancing infant comfort and maximising outcomes for preterm infants requiring surfactant.

REFERENCES

1. Anand KJS and the International Evidence-Based Group for Neonatal Pain. Consensus Statement for the Prevention and Management of Pain in the Newborn. Arch Pediatr Adolesc Med 2001; 155(2):173-180.
2. Anand KJS, Hickey PR. Pain and its effects in the human neonate and fetus. New England Journal of Medicine 1987; 317:1321–9.
3. Herting E. Less invasive surfactant administration (LISA): chances and limitations. Arch Dis Child Fetal Neonatal Ed 2019; 104(6):F655-F659.
4. Fernandez C, Boix H, Camba F, Comunas JJ, Casillo F. Less Invasive Surfactant Administration in Spain: A Survey Regarding Its Practice, the Target Population, and Premedication Use. Am J Perinatol 2019 [Epub ahead of print].
5. Vento M, Bohlin K, Herting E, Roehr CC, Dargaville P. Surfactant Administration via Thin Catheter: A Practical Guide. Neonatology 2019; 116(3):211-226.
6. Chidambaran V, Costandi A, D’Mello A. Propofol: A Review of its Role in Paediatric Analgesia and Sedation. CNS Drugs 2015; 29 (7): 543-563.
7. Bourgoin L, Caeymaex L, Decorbert F, Jung C, Danan C, Durrmeyer X. Administering atropine and ketamine before less invasive surfactant administration