Optimization of anemia management in preterm infants

308 Pages·2016·3.87 MB·English

by  Matthew Robert Rosebraugh

University of Iowa
Iowa Research Online
Theses and Dissertations
Fall 2012
Optimization of anemia management in preterm
infants
Matthew Robert Rosebraugh
University of Iowa
Copyright 2012 Matthew Robert Rosebraugh
This dissertation is available at Iowa Research Online: https://ir.uiowa.edu/etd/3524
Recommended Citation
Rosebraugh, Matthew Robert. "Optimization of anemia management in preterm infants." PhD (Doctor of Philosophy) thesis,
University of Iowa, 2012.
https://doi.org/10.17077/etd.hwpsy56k
Follow this and additional works at:https://ir.uiowa.edu/etd
Part of thePharmacy and Pharmaceutical Sciences Commons
OPTIMIZATION OF ANEMIA MANAGEMENT IN PRETERM INFANTS

by

Matthew Robert Rosebraugh

An Abstract

Of a thesis submitted in partial fulfillment
of the requirements for the Doctor of
Philosophy degree in Pharmacy
in the Graduate College of
The University of Iowa

December 2012

Thesis Supervisor: Professor Peter Veng-Pedersen
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ABSTRACT

Premature infants develop anemia in their first few weeks of life. This is the
result of heavy laboratory blood loss, shortened red blood cell lifespan, low plasma
erythropoietin levels and inadequate erythropoiesis. As treatment for clinically
significant anemia, approximately 80% of very low birth weight infants weighing less
than 1.5kg at birth and 95% of extremely low birth weight infants weighing less than
1.0kg at birth receive one or more red blood cell transfusions. To reduce or eliminate red
blood cell transfusions is important because they are expensive and associated with
complications including infection, fluid overload, electrolyte imbalance, transfusion
related acute lung injury and exposure to plasticizers, lead, and other toxins.
The primary objective of this thesis is to examine erythropoietin (Epo) dosing,
laboratory phlebotomy reduction and the use of restrictive red blood cell transfusion
criteria to determine the potential to reduce or eliminate the need for red blood cell
transfusions in preterm infants. In order to accomplish this objective, data were obtained
from 27 preterm infants including: erythropoietin concentrations, phlebotomy volumes,
transfusion information and multiple hematologic indices. The data were analyzed and
modeled according to pharmacokinetic and pharmacodynamic principles to determine,
through simulation studies, the potential for avoiding blood transfusions in preterm
infants. Results from this research suggests that Epo administration, phlebotomy
reductions and the use of restrictive blood transfusion criteria all have the potential to
reduce the need for blood transfusions in preterm infants. Specifically, a combination of
the three interventions was predicted to make blood transfusions unnecessary in all
infants with a birth weight between 1.0-1.5kg, and 45% of infants with a birth weight of
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<1.0kg. These findings are clinically important because avoiding transfusions may lead
to better clinical outcomes. The results propose strategies to utilize in future clinical
trials involving preterm infants.
The secondary objective of this thesis is to characterize the dynamic Epo receptor
behavior in newborn sheep and determine a pharmacodynamic model which utilizes
information from the Epo receptor dynamics. Results from this analysis show that the
Epo receptor pool is an important predictor of red blood cell production. An Epo
receptor based pharmacodynamic model is proposed that successfully predicted the red
blood cell production in newborn sheep. Additionally, the optimal time for Epo
administration was also determined in these newborn sheep based on the
pharmacodynamic model. This optimal Epo administration time corresponded to
approximately the time when the Epo receptor pool was the largest. Results from the Epo
receptor based studies in newborn sheep suggest Epo clinical trials in preterm infants
need to consider the dynamic Epo receptor behavior to produce the most optimal
outcome.

Abstract Approved: ____________________________________
Thesis Supervisor

____________________________________
Title and Department

____________________________________
Date
OPTIMIZATION OF ANEMIA MANAGEMENT IN PRETERM INFANTS
by
Matthew Robert Rosebraugh
A thesis submitted in partial fulfillment
of the requirements for the Doctor of
Philosophy degree in Pharmacy
in the Graduate College of
The University of Iowa
December 2012

Thesis Supervisor: Professor Peter Veng-Pedersen
Graduate College
The University of Iowa
Iowa City, Iowa
CERTIFICATE OF APPROVAL
_______________________
PH.D. THESIS
_______________
This is to certify that the Ph.D. thesis of
Matthew Robert Rosebraugh
has been approved by the Examining Committee
for the thesis requirement for the Doctor of Philosophy
degree in Pharmacy at the December 2012 graduation.
Thesis Committee: ___________________________________
Peter Veng-Pedersen, Thesis Supervisor
___________________________________
Lawrence Fleckenstein
___________________________________
Douglas Flanagan
___________________________________
Daryl J. Murry
___________________________________
Annette Schlueter
To my beloved wife, Michelle and my parents

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Tortured data will confess to anything.

Fredric M. Menger (1937), Candler Professor of Chemistry, Emory University

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ACKNOWLEDGEMENTS

I would like to thank my major advisor Dr. Peter Veng-Pedersen. Before I joined
his lab I had no computer programming experience and limited knowledge of
pharmacokinetics and pharmacodynamics. His guidance and support helped me to
become proficient at computers and analyzing pharmacokinetic data. Without Dr. Veng-
Pedersen’s help I would not have had such a successful career at the University of Iowa.
I also acknowledge Dr. Widness for his great help. His practical clinical insight into
infants treated in the Iowa neonatal intensive care unit was very helpful to my research. I
am also very grateful to our lab team who helped collect the data which was analyzed for
my research, Robert Schmidt, Earl Gingerich, Demet Nalbant and Jessica Goehring.
Finally, I must thank our research nurses Gretchen Cress and Nancy Krutzfield for
obtaining the infant data from the hospital and helping me answer many questions
pertaining to the data.
I would also like to thank my current and former lab mates whose informal
discussions were invaluable for my progress at the University of Iowa. I would like to
thank Dr. Keith Guillory for his financial support from 2006-2008. I thank the National
Institute of Health for their funding and support for my research. I am greatly
appreciative of all of the professors in the pharmaceutics department who worked with
me or taught my courses especially those faculty members who served on my
comprehensive committee and thesis committee.
Lastly, I would like to thank Dr. Pandit of Drake University who taught my
undergraduate pharmacokinetics course and encouraged me to continue on a research
path in graduate school. Most of all I would like to thank my wife, Michelle, and my
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parents, Bob and Melinda, for their constant support in my academic and personal
endeavors.
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