Document Type

Dissertation

Date of Degree

Fall 2012

Degree Name

PhD (Doctor of Philosophy)

Degree In

Pharmacy

First Advisor

Peter Veng-Pedersen

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 <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.

Pages

xx, 283 pages

Bibliography

Includes bibliographical references (pages 267-283).

Copyright

Copyright 2012 Matthew Robert Rosebraugh

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