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Rescue designs in analgesic trials from 0 to 2 years of age: scoping review

Pediatric Research volume 95, pages 1237–1245 (2024)Cite this article

Abstract

Pediatric analgesic trials are challenging, especially in newborns and infants. Following an FDA-academic consensus meeting, we analyzed pragmatic rescue designs in postoperative trials of local anesthetics, acetaminophen, opioids, and NSAIDs involving children ages 0–2 years and assessed surgical volumes to provide trial design recommendations. Searches of PubMed, Embase, CINAHL, The Cochrane Library, and Web of Science were conducted. A scoping approach identified trends in analgesic trials with an emphasis on randomized controlled trials (RCTs) utilizing immediate rescue designs. Age-specific surgical volumes were estimated from French national databases. Of 3563 studies identified, 23 RCTs used study medication(s) of interest and immediate rescue paradigms in children ages 0–2 years. A total of 270 studies met at least one of these criteria. Add-on and head-to-head designs were common and often used sparing of non-opioid or opioid rescue medication as a primary outcome measure. According to French national data, inguinal and penile surgeries were most frequent in ages 1 month to 2 years; abdominal and thoracic surgeries comprise approximately 75% of newborn surgeries. Analgesic trials with rescue sparing paradigm are currently sparse among children ages 0–2 years. Future trials could consider age-specific surgical procedures and use of add-on or head-to-head designs.

Impact

  • Clinical trials of analgesic medications have been challenging in pediatrics, especially in the group from newborns to 2 years of age. Following an FDA-academic workshop, we analyzed features of completed analgesic trials in this age group. Studies using immediate rescue in placebo control, add-on, and head-to-head trial designs are pragmatic approaches that can provide important information regarding clinical effectiveness, side effects, and safety. Using a French national dataset with a granular profile of inpatient, outpatient, and short-stay surgeries, we provide information to future investigators on relative frequencies of different operations in neonates and through the first 2 years of life.

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Fig. 1: Study selection process.
Fig. 2: Distribution of general characteristics in local anesthetic trials.
Fig. 3: Distribution of general characteristics in acetaminophen trials.
Fig. 4: Distribution of general characteristics in opioid trials.
Fig. 5: Categories of the most common surgical procedures in France, by age group.

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Acknowledgements

We are thankful for Claire McEwen, Jillian Rhodes, and Jacob Zhang for their significant contributions to study screening and data extraction. We would also like to acknowledge Dr Sophie Tezenas du Montcel and Dr Aurélia Retbi from the Department of Medical Information at Saint Antoine Hospital in Paris for their retrieval and organization of the surgical data from the PMSI. Supported in part by the Sara Page Mayo Endowment for Pediatric Pain Research.

Author information

Author notes

  1. These authors contributed equally: Kyra Haskes, Carolina Donado.

  2. These authors jointly supervised this work: Charles Berde, Joe Kossowsky.

Authors and Affiliations

  1. Department of Anesthesiology, Critical Care & Pain Medicine, Boston Children’s Hospital, Boston, MA, USA

    Kyra Haskes, Carolina Donado, Charles B Berde & Joe Kossowsky

  2. Department of Anaesthesia, Harvard Medical School, Boston, MA, USA

    Carolina Donado, Charles B Berde & Joe Kossowsky

  3. Pediatric Emergency Department, Assistance Publique-Hôpitaux de Paris, Hôpital Armand Trousseau-Sorbonne Université, Paris, France

    Ricardo Carbajal

  4. Institut National de La Santé et de La Recherche Médicale, UMR1153, Paris, France

    Ricardo Carbajal

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  1. Kyra Haskes
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Contributions

Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data: K.H., C.D., R.C., J.K., C.B. Drafting the article or revising it critically for important intellectual content: K.H., C.D., R.C., J.K., C.B. Final approval of the version to be published: K.H., C.D., R.C., J.K., C.B.

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Correspondence to Charles B Berde.

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Haskes, K., Donado, C., Carbajal, R. et al. Rescue designs in analgesic trials from 0 to 2 years of age: scoping review. Pediatr Res 95, 1237–1245 (2024). https://doi.org/10.1038/s41390-023-02897-4

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