Supplementary Material for: Development of Best Evidence Dosing Recommendations for Term and Preterm Neonates (NeoDose Project)

<b><i>Abstract:</i></b> Many drugs are used off-label in neonates which leads to large variation in prescribed drugs and dosages in neonatal intensive care units (NICUs). The NeoDose project aimed to develop best evidence dosing recommendations (DRs) for term and preterm neonates using a three-step approach: 1) drug selection, 2) establishing consensus-based DRs, and 3) establishing best evidence DRs. <b><i>Methods:</i></b> The selection of drugs was based on frequency of prescribing, availability of a neonatal DR in the Dutch Pediatric Formulary, and the labeling status. Clinical need, pharmacological diversity, and Working Group Neonatal Pharmacology (WGNP) preferences were also taken into account, using a consensus-based approach. For the second step, we requested local dosing protocols from all ten Dutch NICUs and established consensus-based DRs within the WGNP, consisting of neonatologists, clinical pharmacologists, hospital pharmacists, and researchers. In the third step, the consensus-based DRs were compared with the available literature, using standardized PubMed searches. <b><i>Results:</i></b> Fourteen drugs were selected for which the local dosing protocols were collected. These protocols differed mostly in total daily dose, dosing frequency, and/or route of administration. Strikingly, almost none of the dosing protocols of these 14 drugs distinguished between preterm and term neonates. The working group established consensus-based DRs, which after literature review needed modification in 56%, mainly in terms of a dose increase. Finally, we established 37 best evidence DRs, 22 for preterm and 15 for term neonates, representing 19 indications. <b><i>Conclusion:</i></b> This project showed the successful three-step approach for the development of DRs for term and preterm neonates.

摘要：许多药物被超说明书用于新生儿群体，这导致新生儿重症监护病房（neonatal intensive care units, NICUs）内的处方药物及剂量存在较大差异。NeoDose项目旨在通过三步法为足月儿与早产儿制定最佳证据给药建议（dosing recommendations, DRs）：1）药物遴选；2）建立基于共识的给药建议；3）建立最佳证据给药建议。
方法：药物遴选依据处方频率、荷兰儿科处方集中是否存在新生儿给药建议，以及药品标签状态。同时结合临床需求、药理学多样性及新生儿药理学工作组（Working Group Neonatal Pharmacology, WGNP）的偏好，采用基于共识的方法进行遴选。第二步中，我们向荷兰全部10家新生儿重症监护病房征集了本地给药方案，并在由新生儿科医师、临床药理学家、医院药师及研究人员组成的WGNP内确立了基于共识的给药建议。第三步中，通过标准化的PubMed检索，将基于共识的给药建议与现有文献进行比对。
结果：最终遴选了14种药物，并收集了对应的本地给药方案。这些方案的差异主要体现在每日总剂量、给药频率及/或给药途径上。值得注意的是，这14种药物的给药方案中，几乎无一区分早产儿与足月儿。工作组确立了基于共识的给药建议，经文献审阅后，其中56%的建议需要调整，调整方向主要为剂量上调。最终，我们共确立了37项最佳证据给药建议，其中针对早产儿22项、足月儿15项，涵盖19种适应证。
结论：本项目证实了针对足月儿与早产儿制定给药建议的三步法切实可行且成效显著。