Respiratory benefit in preterm lambs is progressively lost when the concentration of fetal plasma betamethasone is titrated below two nanograms per milliliter.

Autor:	Fee EL; Division of Obstetrics and Gynaecology, Medical School, The University of Western Australia, Perth, Western Australia, Australia.; School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia., Takahashi T; Division of Obstetrics and Gynaecology, Medical School, The University of Western Australia, Perth, Western Australia, Australia.; Centre for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan., Takahashi Y; Division of Obstetrics and Gynaecology, Medical School, The University of Western Australia, Perth, Western Australia, Australia.; Centre for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan., Carter SWD; Division of Obstetrics and Gynaecology, Medical School, The University of Western Australia, Perth, Western Australia, Australia., Clarke MW; Metabolomics Australia, Centre for Microscopy, Characterization and Analysis, The University of Western Australia, Perth, Western Australia, Australia.; School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia., Milad MA; Milad Pharmaceutical Consulting LLC, Plymouth, Michigan, United States., Usuda H; Division of Obstetrics and Gynaecology, Medical School, The University of Western Australia, Perth, Western Australia, Australia.; Centre for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan., Ikeda H; Division of Obstetrics and Gynaecology, Medical School, The University of Western Australia, Perth, Western Australia, Australia.; Centre for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan., Kumagai Y; Centre for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan., Saito Y; Centre for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan., Ireland DJ; Division of Obstetrics and Gynaecology, Medical School, The University of Western Australia, Perth, Western Australia, Australia.; School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia., Newnham JP; Division of Obstetrics and Gynaecology, Medical School, The University of Western Australia, Perth, Western Australia, Australia., Saito M; Division of Obstetrics and Gynaecology, Medical School, The University of Western Australia, Perth, Western Australia, Australia.; Centre for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan., Jobe AH; Division of Obstetrics and Gynaecology, Medical School, The University of Western Australia, Perth, Western Australia, Australia.; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, Ohio, United States., Kemp MW; Division of Obstetrics and Gynaecology, Medical School, The University of Western Australia, Perth, Western Australia, Australia.; Centre for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan.; School of Veterinary Medicine, Murdoch University, Perth, Western Australia, Australia.; Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Jazyk:	angličtina
Zdroj:	American journal of physiology. Lung cellular and molecular physiology [Am J Physiol Lung Cell Mol Physiol] 2023 Nov 01; Vol. 325 (5), pp. L628-L637. Date of Electronic Publication: 2023 Sep 12.
DOI:	10.1152/ajplung.00139.2023
Abstrakt:	Antenatal steroid therapy is the standard of care for women at imminent risk of preterm delivery. Current dosing regimens use suprapharmacological doses to achieve extended fetal steroid exposures. We aimed to determine the lowest fetal plasma betamethasone concentration sufficient to achieve functional preterm lung maturation. Ewes with single fetuses underwent surgery to install a fetal jugular catheter. Adopting a stepwise design, ewes were randomized to either a saline-only group (negative control group; n = 9) or one of four betamethasone treatment groups. Each betamethasone group fetus received a fetal intravenous infusion to target a constant plasma betamethasone level of either 1 ) 2 ng/mL (2 ng/mL positive control group, n = 9); 2 ) 1 ng/mL, (1 ng/mL group, n = 10); 3 ) 0.5 ng/mL (0.5 ng/mL group, n = 10); or 4 ) 0.25 ng/mL (0.25 ng/mL group, n = 10). Fetuses were infused for 48 h, delivered, and ventilated. The positive control group, negative control group, and mid-point 0.5 ng/mL group animals were tested first. An interim analysis informed the final betamethasone group tested. Positive control group animals had large, statistically significant improvements in respiratory function. Based on an interim analysis, the 1.0 ng/mL group was studied in favor of the 0.25 ng/mL group. Treatment efficacy was progressively lost at plasma betamethasone concentrations lower than 2 ng/mL. We demonstrated that the acute respiratory benefit conveyed by antenatal steroid exposure in the fetal sheep is progressively lost when constant fetal plasma betamethasone concentrations are reduced below a targeted value of 2 ng/mL. NEW & NOTEWORTHY Lung maturation benefits in preterm lambs were progressively lost when fetal plasma betamethasone concentrations fell below 2 ng/mL. The effective floor threshold for a robust, lung-maturing exposure likely lies between 1 and 2 ng betamethasone per milliliter of plasma. Hypothalamic pituitary adrenal axis signaling and immunocyte populations remained materially disrupted at subtherapeutic steroid concentrations. These data demonstrate the potential to improve antenatal steroid therapy using reduced dose regimens informed by glucocorticoid pharmacokinetics and pharmacodynamics.
Databáze:	MEDLINE
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