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Caffeine pharmacokinetics following umbilical vein injection during delayed cord clamping in preterm lambs

Pediatric Research (2024)Cite this article

Abstract

Background

Spontaneous breathing during and after delayed cord clamping (DCC) stabilizes cardiopulmonary transition at birth. Caffeine stimulates breathing and decreases apnea in premature newborns. We evaluated the pharmacokinetics and physiological effects of early caffeine administration-direct injection into the umbilical vein (UV) during DCC or administered through a UV catheter (UVC) after delivery.

Methods

Eighteen extremely premature lambs (125–127d, term gestation 145d) were exteriorized and instrumented. Lambs received caffeine-citrate at high (40 mg/kg) or standard-dose (20 mg/kg) via direct UV (DUV) injection during DCC, or via the UVC.

Results

Mean peak plasma caffeine concentrations were lower with high-dose DUV compared to UVC (18 ± 4.3 vs. 46 ± 12 mg/L, p < 0.05). With standard-dose caffeine, mean peak plasma levels were 7.48 ± 2.6 with DUV and 28.73 ± 9.4 mg/L with UVC. The volume of distribution was higher in the DUV group compared to UVC (2.5 ± 1.0 vs. 0.69 ± 0.15 L/kg) with an estimated 39 ± 18% entering the maternal circulation. Maternal peak concentrations were 0.79 ± 0.71 and 1.43 ± 0.74 mg/L with standard and high-dose DUV, respectively.

Conclusions

Caffeine injected directly into the UV during DCC is feasible but achieves lower concentrations due to high volume of distribution including maternal circulation. Further trials evaluating DUV caffeine injection should use higher caffeine doses.

Impact

  • Respiratory stimulation with early caffeine may reduce the need for intubation in preterm infants.

  • In the preterm lambs, caffeine injection directly into the umbilical vein during delayed cord clamping is feasible.

  • Plasma caffeine concentrations are less than half when administered directly into the umbilical vein during delayed cord clamping compared to administration via an umbilical venous catheter following birth likely attributed to a larger volume of distribution or injection site leak.

  • There were no significant hemodynamic alterations following caffeine injection.

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Fig. 1: Plasma caffeine concentrations.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. UNICEF, W., World Bank, UN-DESA Population Division. Levels and Trends in Child Mortality Report 2019, http://www.unicef.org/reports/levels-and-trends-child-mortality-report-2019 (2019).

  2. Parker, J. C., Hernandez, L. A. & Peevy, K. J. Mechanisms of ventilator-induced lung injury. Crit. Care Med. 21, 131–143 (1993).

    Article  CAS  PubMed  Google Scholar 

  3. Keszler, M. & Sant’Anna, G. Mechanical ventilation and bronchopulmonary dysplasia. Clin. Perinatol. 42, 781–796 (2015).

    Article  PubMed  Google Scholar 

  4. Clark, R. H., Bloom, B. T., Spitzer, A. R. & Gerstmann, D. R. Reported medication use in the neonatal intensive care unit: data from a large national data set. Pediatrics 117, 1979–1987 (2006).

    Article  PubMed  Google Scholar 

  5. Schmidt, B. et al. Caffeine therapy for apnea of prematurity. N. Engl. J. Med. 354, 2112–2121 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Kraaijenga, J. V., Hutten, G. J., de Jongh, F. H. & van Kaam, A. H. The effect of caffeine on diaphragmatic activity and tidal volume in preterm infants. J. Pediatr. 167, 70–75 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Andersson, O. et al. Effect of delayed cord clamping on neurodevelopment at 4 years of age: a randomized clinical trial. JAMA Pediatr. 169, 631–638 (2015).

    Article  PubMed  Google Scholar 

  8. Katheria, A. C., Brown, M. K., Rich, W. & Arnell, K. Providing a placental transfusion in newborns who need resuscitation. Front. Pediatr. 5, 1 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Katheria, A. et al. A randomized clinical trial of umbilical cord milking vs delayed cord clamping in preterm infants: neurodevelopmental outcomes at 22-26 months of corrected age. J. Pediatr. 194, 76–80 (2018).

    Article  PubMed  Google Scholar 

  10. Blank, D. A. et al. Baby-directed umbilical cord clamping: a feasibility study. Resuscitation 131, 1–7 (2018).

    Article  PubMed  Google Scholar 

  11. Fulton, C., Stoll, K. & Thordarson, D. Bedside resuscitation of newborns with an intact umbilical cord: experiences of midwives from British Columbia. Midwifery 34, 42–46 (2016).

    Article  PubMed  Google Scholar 

  12. Zhang, Y., Mehrotra, N., Budha, N. R., Christensen, M. L. & Meibohm, B. A tandem mass spectrometry assay for the simultaneous determination of acetaminophen, caffeine, phenytoin, ranitidine, and theophylline in small volume pediatric plasma specimens. Clin. Chim. Acta 398, 105–112 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Comer, A. M., Perry, C. M. & Figgitt, D. P. Caffeine citrate: a review of its use in apnoea of prematurity. Paediatr. Drugs 3, 61–79 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Aranda, J. V., Gorman, W., Bergsteinsson, H. & Gunn, T. Efficacy of caffeine in treatment of apnea in the low-birth-weight infant. J. Pediatr. 90, 467–472 (1977).

    Article  CAS  PubMed  Google Scholar 

  15. Turmen, T., Davis, J. & Aranda, J. V. Relationship of dose and plasma concentrations of caffeine and ventilation in neonatal apnea. Semin Perinatol. 5, 326–331 (1981).

    CAS  PubMed  Google Scholar 

  16. Natarajan, G., Botica, M. L., Thomas, R. & Aranda, J. V. Therapeutic drug monitoring for caffeine in preterm neonates: an unnecessary exercise? Pediatrics 119, 936–940 (2007).

    Article  PubMed  Google Scholar 

  17. Lee, T. C., Charles, B., Steer, P., Flenady, V. & Shearman, A. Population pharmacokinetics of intravenous caffeine in neonates with apnea of prematurity. Clin. Pharm. Ther. 61, 628–640 (1997).

    Article  CAS  Google Scholar 

  18. Ulanovsky, I., Haleluya, N. S., Blazer, S. & Weissman, A. The effects of caffeine on heart rate variability in newborns with apnea of prematurity. J. Perinatol. 34, 620–623 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Katheria, A. C. et al. A pilot randomized controlled trial of early versus routine caffeine in extremely premature infants. Am. J. Perinatol. 32, 879–886 (2015).

    Article  PubMed  Google Scholar 

  20. Dekker, J. et al. Caffeine to improve breathing effort of preterm infants at birth: a randomized controlled trial. Pediatr. Res. 82, 290–296 (2017).

    Article  CAS  PubMed  Google Scholar 

  21. Lodha, A. et al. Association of early caffeine administration and neonatal outcomes in very preterm neonates. JAMA Pediatr. 169, 33–38 (2015).

    Article  PubMed  Google Scholar 

  22. Patel, R. M., Leong, T., Carlton, D. P. & Vyas-Read, S. Early caffeine therapy and clinical outcomes in extremely preterm infants. J. Perinatol. 33, 134–140 (2013).

    Article  CAS  PubMed  Google Scholar 

  23. Lodha, A. et al. Early caffeine administration and neurodevelopmental outcomes in preterm infants. Pediatrics 143, e20181348 (2019).

    Article  PubMed  Google Scholar 

  24. Soloveychik, V., Bin-Nun, A., Ionchev, A., Sriram, S. & Meadow, W. Acute hemodynamic effects of caffeine administration in premature infants. J. Perinatol. 29, 205–208 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Binder-Heschl, C. et al. Haemodynamic effects of prenatal caffeine on the cardiovascular transition in ventilated preterm lambs. PLoS One 13, e0200572 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was made possible thanks to the UC Davis Department of Pediatrics Resident and Fellow Grant.

Funding

NIH/NICHD 5R01HD072929-10 (SL).

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Authors and Affiliations

  1. Department of Pediatrics, UC Davis School of Medicine, Sacramento, CA, USA

    Lida Zeinali, Evan Giusto, Houssam Joudi, Deepika Sankaran, Satyan Lakshminrusimha & Payam Vali

  2. UC Davis, School of Veterinary Medicine, Davis, CA, USA

    Heather Knych & Morgan Hardie

  3. Stem Cell Program, UC Davis School of Medicine, Davis, CA, USA

    Amy Lesneski

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  1. Lida Zeinali
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Contributions

L.Z., S.L., and P.V. designed the study. H.K., A.L., H.J., M.H.; E.G. and D.K. contributed to data acquisition. Data analysis and interpretation was performed by L.Z., H.K., S.L. and P.V.; L.Z. wrote the first draft of the manuscript. A.L., E.G., D.S., S.L. and P.V. critically revised the manuscript for important intellectual content. All the authors have approved the approved the final version of the manuscript submitted for publication and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

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Correspondence to Payam Vali.

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Zeinali, L., Giusto, E., Knych, H. et al. Caffeine pharmacokinetics following umbilical vein injection during delayed cord clamping in preterm lambs. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03117-3

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