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. 2025 Aug 2.
doi: 10.1038/s41390-025-04310-8. Online ahead of print.

Can non-pharmacological comfort care replace fentanyl in LISA? The NONA-LISA feasibility study

Niklas Breindahl  1   2   3 , Tine Brink Henriksen  4   5 , Christian Heiring  6   7 , Emma Therese Bay  6   7 , Jannie Haaber  6 , Tenna Gladbo Salmonsen  4 , Peter Agergaard  4 , Emma Louise Malchau Carlsen  6   7 , Martin Grønnebæk Tolsgaard  7   8   9 , Lise Aunsholt  6   7
Affiliations

Can non-pharmacological comfort care replace fentanyl in LISA? The NONA-LISA feasibility study

Niklas Breindahl et al. Pediatr Res. .

Abstract

Background: Optimal comfort strategies in LISA remain unclear. This study aimed to evaluate the feasibility of a standardised approach to non-pharmacological comfort care guided by the COMFORTneo score in infants randomised to receive fentanyl or saline as premedication for LISA.

Methods: Infants born before 30 weeks' gestation were randomised to receive isotonic saline or fentanyl 0.5-1 mcg/kg intravenously as premedication for LISA. Both groups received standardised non-pharmacological comfort care. The outcomes were a modified COMFORTneo score ≥14 during the procedure, need for open-label fentanyl administration during the procedure, and inclusion rate using deferred consent. The NONA-LISA trial was registered on clinicaltrials.gov (NCT05609877).

Results: From September 2023 to May 2024, 17 infants were randomised (median gestational age, 28 weeks; 77% male); eight received fentanyl and nine received saline. Modified COMFORTneo score ≥14 occurred in 4/8 (fentanyl) and 3/9 (saline), and most cases were alleviated with improved non-pharmacological comfort care only. Two infants (saline) received open-label fentanyl.

Conclusions: Performing LISA with saline and standardised non-pharmacological comfort care guided by the modified COMFORTneo score was feasible. Pausing the procedure and improving non-pharmacological comfort care was sufficient in most cases with a modified COMFORTneo score ≥14 regardless of whether fentanyl or saline was used.

Impact: The Less Invasive Surfactant Administration (LISA) relies on regular spontaneous breathing to be effective. Analgesic or sedating premedication and a painful or uncomfortable stimulus can cause hypoventilation, which may prevent the LISA method from achieving its full potential. This feasibility study assesses if standardised non-pharmacological comfort care guided by the modified COMFORTneo score is feasible during LISA. Performing LISA with saline and standardised non-pharmacological comfort care guided by the modified COMFORTneo score is feasible and safe. It is possible to blind the use of premedication, and inclusion via deferred consent is feasible.

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Conflict of interest statement

Competing interests: The authors declare no competing interests. Informed consent: The Committee on Health Research Ethics in the Region of Southern Denmark approved the trial protocol for deferred consent (approval number H-21078489),20 and infants were enrolled in the NONA-LISA feasibility study using deferred consent with an opt-out approach. Written informed consent was obtained from the infant’s legal guardians as soon as possible after enrolment.20 The Danish Data Protection Agency approved the study protocol (approval number P-2022-594). An independent Data Management and Ethical Committee reviews the progression and safety of the NONA-LISA trial. The NONA-LISA trial was prospectively registered on clinicaltrials.gov (NCT05609877) on October 18, 2022.

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