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. Author manuscript; available in PMC: 2015 May 4.
Published in final edited form as: Pediatr Res. 2013 Nov 11;75(2):336–342. doi: 10.1038/pr.2013.213

PHARMACODYNAMICALLY OPTIMIZED ERYTHROPOIETIN TREATMENT COMBINED WITH PHLEBOTOMY REDUCTION PREDICTED TO ELIMINATE BLOOD TRANSFUSIONS IN SELECTED PRETERM INFANTS

Matthew R Rosebraugh 1, John A Widness 2, Demet Nalbant 2, Gretchen Cress 2, Peter Veng-Pedersen 3
PMCID: PMC4418561  NIHMSID: NIHMS683421  PMID: 24216541

Abstract

BACKGROUND

Preterm very low birth weight (VLBW) infants weighing <1.5 kg at birth develop anemia requiring red blood cell transfusions (RBCTx). Because laboratory blood loss is a primary cause of anemia leading to RBCTx in VLBW infants, our goal was to simulate the extent to which RBCTx can be reduced or eliminated by reducing laboratory blood loss in combination with pharmacodynamically optimized erythropoietin (Epo) treatment.

METHODS

26 VLBW infants receiving RBCTx were studied during the first month of life. Simulated RBCTx were based on previously published RBCTx criteria and data-driven Epo pharmacodynamic optimization using literature-derived RBC lifespan and blood volume data with correction for phlebotomy loss.

RESULTS

Simulated pharmacodynamic optimization of Epo administration and reduction in laboratory phlebotomies by ≥55% predicted a complete elimination of RBCTx in 1.0–1.5 kg infants. In infants <1.0 kg with 100% reduction in phlebotomy, RBCTx is predicted to be reduced by 45%. The mean volume of laboratory blood drawn from all infants was 63 mL/kg, of which 33% was required for analysis and 67% discarded.

CONCLUSION

When reducing laboratory blood loss and optimized Epo treatment are combined, marked reductions in RBCTx in VLBW infants were predicted, particularly among those with birth weights >1.0 kg.

INTRODUCTION

During the early weeks of life, anemia of prematurity develops in all surviving very low birth weight (VLBW) preterm infants (BW <1.5 kg). This anemia is the result of prematurity itself, laboratory blood sampling, shortened red blood cell (RBC) lifespan, inadequate erythropoiesis, hemorrhage, and unidentified factors (1). These contributors all tend to occur more commonly among the smallest, extremely low birth weight (ELBW) preterm infants (BW <1.0 kg) whose anemia and need for RBCTx is not pronounced. Clinically significant anemia is treated with RBC transfusions (RBCTx). Because the number of RBC transfusions that critically ill premature infants receive is associated with increased mortality (2) and because RBCTx themselves are associated expense and with complications including infection, fluid overload, electrolyte imbalance, and exposure to plasticizers, lead, and other toxins (3), a reduction in the number of RBC VLBW infants receive is desirable.

Because preterm infants are among the most highly transfused patient groups (4), the development of effective strategies to reduce RBCTx is important. Therapeutic strategies to counteract the most important contributors to neonatal anemia have been applied with the goal of reducing RBCTx. The three most important strategies include: 1) treatment with recombinant human erythropoietin (Epo); 2) institution of restrictive RBCTx criteria; and 3) reduction in laboratory phlebotomy blood loss. Although Epo treatment has been effective in reducing the number of RBCTx infants receive (5) and may have potentially beneficial neuroprotective properties (6), its administration in premature infants remains controversial because of its modest efficacy and its association with retinopathy of prematurity (5). Restrictive RBCTx criteria have been demonstrated to decrease RBCTx to VLBW preterm infants in the two largest clinical trials reported to date (7, 8). Unfortunately, results of these two trials suggest that restrictive RBCTx criteria may also be associated with parenchymal brain hemorrhage, periventricular leukomalacia, more frequent episodes of apnea, and poor neurodevelopmental outcomes (8, 9).

Reducing laboratory phlebotomy loss is the third, and perhaps most promising strategy for decreasing RBCTx. Because the total blood volume removed from preterm infants for laboratory testing frequently exceeds their total blood volume at birth (1, 10) and because laboratory phlebotomy loss has been directly correlated with the volume of RBCs transfused (1), reducing laboratory phlebotomy loss has potential for being a highly effective strategy for reducing RBCTx. Furthermore, data showing that the majority of blood drawn from preterm infants is discarded indicates that future non-pharmacological approaches to reduce laboratory blood loss, e.g., use of point-of-care analyzers and monitors, delayed clamping or milking of the umbilical cord at delivery, and remaining placenta blood for initial blood testing, are feasible (11).

Although these three strategies for reducing RBCTxs in preterm infants have all shown promise by our group (8, 10) and others (7, 12), application of a combination of these strategies has greater potential for reducing RBCTxs than any of these alone. We thus hypothesized that RBCTx can be eliminated in a significant proportion of preterm infants by optimizing Epo dosing in combination with reductions in laboratory phlebotomy loss.

METHODS

Subjects

The study was approved by the University of Iowa Committee on Research on Human Subjects. Informed written parental consent was obtained. Study subjects included have been reported in previous publications with different primary objectives (10, 13, 14).

Subjects eligible for enrollment included the offspring of women presenting in labor at <29 weeks gestation whose infants delivered at <29 weeks gestation and were intubated in the first day of life. Infants excluded were those presenting with hematological disease (except for anemia of prematurity), those receiving RBCTx prior to enrollment, or those receiving erythropoiesis stimulating agents. A total of 162 mothers or infants met study eligibility criteria. Of those eligible for enrollment, 119 were not approached because: 1) they had been approached for another study (n=39); 2) of the significant additional workload imposed on clinical laboratory personnel allowing them to include only two research subjects for study at a time (n=62); 3) prior blood transfusion before consent (n=13); and 4) lack of staff availability (n=5).

A total of 43 families were approached: 11 before delivery and 32 after delivery. Consent was obtained from 33 families while 10 families refused. Women who consented antenatally but who delivered at >29 weeks became ineligible (n=6). Twenty-seven infants were enrolled and studied for approximately the first month of life (31.6 ± 2.2 days). One enrolled infant was omitted because the infant did not receive any RBCTx during the first month of life.

VLBW study subjects were divided into two subgroups: those with BW from 1.0 to 1.5 kg, and those with BW <1.0 kg. This was done because it is well established that infants <1.5 kg receive increasing numbers of RBCTx with decreasing BW as the severity of cardiorespiratory illness increases (1).

Study Procedures

Demographic, laboratory, and RBCTx data were obtained from the electronic medical record. Data included the type of individual laboratory testing performed, whether sampling was done using a syringe through a central arterial or venous catheter or by peripheral capillary heelstick, the volume of blood required by test instruments, and the volume of blood requested by laboratory personnel. Weights of 97% of all 2,656 individual laboratory blood samples drawn (138±21 tests per infant) were determined to the nearest 0.1 mg prior to analysis (13). Following clinical analyses, leftover blood was centrifuged and the plasma or serum frozen at −70°C for later analysis. Leftover anticoagulated blood samples less than 3 days old were analyzed for hematological parameters using the Sysmex XE-2100 hematology analyzer (Sysmex Corporation, Kobe, Japan). Plasma Epo levels required for the Epo optimization were analyzed using a double antibody radioimmunoassay (15).

Overview of the Simulation Modeling Applied

The computer simulations performed were designed to predict the number of RBCTx administered to preterm infants in combination with model optimized exogenous Epo dosing (14) in combination with concurrent reduction in laboratory phlebotomy loss (10). Predictions regarding the number of RBCTx administered were based on Hb cutoff levels for each of two different RBCTx criteria: 1) the actual Hb levels at which RBCTx has been administered; and 2) the modeled Hb levels when applying restrictive PINT study criteria for infants receiving respiratory support (7). The PINT study’s “restrictive” RBCTx criteria were selected because they were employed in the largest randomized RBCTx trial in preterm infants (n=451). Modeled Hb data was determined from simulations utilizing optimized Epo dosing and modeled laboratory phlebotomy reductions as described below. Also required for the modeling predictions of reductions in RBCTx were Epo pharmacokinetics and pharmacodynamics (PK/PD) data (see below), and essential hematological data from the literature, i.e., blood volume and RBC lifespan.

Epo Pharmacokinetic and Pharmacodynamic Optimization

Simulation of optimized Epo dosing requires both Epo PK and PD information. The elimination of Epo from the circulation occurs via a saturable, receptor-mediated pathway (16) in which the PK disposition model applied is given by:

dEPOdt=-P1·EPOP2+EPO (1)

where Epo is the exogenous simulated plasma Epo concentration at time t; P1 and P2 are disposition parameters, P1 is the maximum rate at which the exogenous Epo concentration declines following intravenous administration (U/ml•hr), P2 is the plasma Epo concentration at which Epo is eliminated at half its maximum rate (U/ml). The parameters in Equation 1 have been determined in the same group of preterm VLBW infants in a prior study (14). All Epo doses were simulated as an IV bolus with a bioavailability of 1.

The Epo optimization used the same Emax model we previously described (13, 14):

E(t)=Emax·Epo(t-tlag)EC50+Epo(t-tlag) (2)

where E(t) is the Hb production rate at time t; tlag is the lag time between the Epo stimulation of Epo receptors and the appearance of newly synthesized reticulocytes, i.e., new Hb appearing in the circulation; EC50 is the plasma concentration of Epo resulting in half of the maximum Hb production rate; Emax is the maximum achievable Hb production rate. The Emax parameter of individual study infants were determined previously (14).

Phlebotomy Reduction Applied in the Model

Phlebotomy for laboratory testing results in a decline in Hb levels as a result of the removal of both endogenously produced and transfused donor RBCs. The mathematical model applied to simulate infant Hb concentrations following different degrees of phlebotomy reduction has been previously reported by our group (10). To determine the Hb produced from simulated Epo doses while variably decreasing laboratory phlebotomy loss, we expanded our previous model as follows:

Hb(t)EPO,PHLE=Hb(t)EPO·∏j=1k(1-Fj)tk<t<tk+1 (3)

where Hb(t)EPO is the amount of Hb produced from Epo at time t (determined by Equation 2); Hb(t)EPO,PHLE is the amount of Hb produced from Epo in the presence of phlebotomies at time t; k is the number of phlebotomies which occurred before the current time; j is the given phlebotomy number; Fj is the fraction of the total blood volume removed in phlebotomy j.

Equation 3 contains no correction factor for RBC senescence because the assumed 66-day lifespan of the newly produced cells is longer than the study period, i.e., 30 days (13).

Epo Dosing Schedule and RBCTx Simulation

The same Epo dosing schedule used in our prior optimal Epo modeling simulation study of preterm infants was applied in the current study, i.e., 12 individual IV 600 U/kg Epo doses optimized for timing and dose administered. Optimized Epo dosing based on endogenous Epo PK/PD data showed significant potential for completely eliminating RBCTx in a subset of infants when using Epo doses within a previously reported range (17).

Following combined, concurrent simulation of both optimized Epo dosing and laboratory phlebotomy reduction, the resultant Hb profiles of individual infants were analyzed according to the two RBCTx criteria described above. When an individual infant’s simulated Hb concentration fell below one of these two specific RBCTx criteria, it was counted as a simulated RBCTx. All clinically simulated RBCTx were assumed to be the same volume of RBCTx administered in our NICU, i.e., 15 ml/kg of packed RBCs with an assumed Hct of 83.1% (10). Simulations were programmed in FORTRAN with graphical output performed using WINFUNFIT (18) or Microsoft Excel (Microsoft Redmond, WA).

RESULTS

Study Subjects

Of the 26 VLBW study subjects meeting study eligibility criteria, 18 were in the subgroup of ELBW infants and 8 were in the subgroup of infants with birth weight between 1.0 and 1.5 kg. During the 30-day study period, infants in the latter subgroup received 1.75±0.71 (mean±SD) RBCTx while the ELBW infants received 4.83±1.72 RBCTx. Of the 2,656 laboratory blood samples drawn from all subjects, 97% were weighed before analysis. When adjusted for BW, 63.0±32.5 ml/kg was removed from the entire study group. This corresponds to 30.5±9.5 ml/kg for VLBW infants weighing from 1.0 to 1.5 kg, and 74.1±25.3 ml/kg for ELBW infants (p<0.05).

Analysis of Usage of Phlebotomized Blood

Analysis of the blood removed for laboratory testing over the first month of life demonstrated that 33% percent of the volume of blood required by the testing instruments was required for analysis. Of the remaining 67% of blood removed, 8% was unrecoverable as blood remaining in syringes, on gauze pads, bedding, band aides, etc. The remaining 59% was not used in the analysis and was usually discarded. To characterize laboratory blood sampling, blood samples were categorized by the type of individual laboratory tests performed. Data for the entire study population was analyzed alone and was based on subgroupings of VLBW infants weighing from <1.0 kg and those weighing <1.0 kg (Figure 1). In the analysis, blood sampled was expressed both as ml/kg birth weight (Figure 1a) and as percentage of the total blood volume removed (Figure 1b). Each of the individually selected laboratory test categories provided information regarding the specific testing performed, e.g., hemoglobin (Hb), electrolytes, bilirubin, etc., and whether a syringe was used for sampling from a central arterial or venous catheter, or whether peripheral capillary sampling was performed. The three individually selected test categories on the left of Figure 1 comprised 67% of the total blood volume drawn. For the individual “Miscellaneous” category comprising ~20% of the total blood volume sampled, only 4.1% of the volume sampled was required by the instrument for analysis. This compares to the 33% required for all blood tests combined. When the two VLBW birth weight subgroups were compared, infants in the <1.0 kg BW subgroup had significantly greater blood volumes drawn relative to the 1.0–1.5 kg VLBW for all of the individual laboratory test categories (p<0.05).

Figure 1. Most laboratory blood sampled in VLBW preterm infants is lost or discarded.

Figure 1

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Mean (±SD) total blood sampled during the first month of life by individual selected laboratory test categories (indicated in the legend at the bottom of the figure) grouped by birth weight (<1.0 kg: n=18; 1.0–1.5 kg: n=8; and <1.5 kg: n=26) in mL per kg birth weight in Panel 1a. In Panel 1b the same data are expressed as cumulative percentages of the individual selected test categories in the same birth weight groupings. The hashed bars represent the blood volume required for analysis by specific test instruments and the shaded bars represent the remaining leftover blood. Also indicated is whether sampling was done using a syringe through a central arterial or venous catheter, or as peripheral capillary sampling.

Simulated Hb Profiles with Phlebotomy Reduction and Optimized Epo Dosing

Simulated Hb profiles for the individual 26 preterm infants during the first month of life were based on specified hypothetical percent reductions in laboratory phlebotomy loss and optimized Epo dosing. In Figure 2 the simulated mean Hb profiles with 0%, 50%, and 100% reduction in phlebotomy were compared to the subject’s mean actual Hb concentration. As a result of the numerous RBCTx and phlebotomies performed, the actual mean Hb concentration profile of all study subjects demonstrated an erratic, generally horizontal pattern. When optimized Epo dosing was combined with a 100% reduction in laboratory phlebotomy, i.e., 0% phlebotomy loss, modeled Hb concentration was maintained at a comparable level to that actually observed for mean Hb concentration for all but the last few days of the study period.

Figure 2. Simulated Epo dosing with phlebotomy reduction predicts Hb concentrations similar to actual Hb concentrations over the first month of life.

Figure 2

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The erratic, flat horizontal solid line represents the actual mean Hb levels measured for all study subjects. The bottom smoothed dashed line is the simulated Hb concentration with optimized Epo administration and no reduction in laboratory phlebotomy loss. The second solid more smooth line is the simulated Hb concentration with optimized Epo administration and a 50% reduction in laboratory phlebotomy loss. The top broken line is the simulated Hb concentration with both optimized Epo treatment and 100% reduction in laboratory phlebotomy loss.

Avoiding RBCTx with Optimal Epo Dosing and Phlebotomy Reduction

Using simulated Hb concentrations for individual study subjects, the model predicted the number of RBCTx administered for the two different RBCTx criteria applied. These two included the actually observed and the criteria applied in the premature infants in need of transfusion (PINT) study (Figures 3 and 4). As expected, a higher percentage of VLBW infants in the subgroup with birth weights from 1.0 to 1.5 kg were predicted to avoid RBCTx compared to ELBW infants. With 100% reduction in phlebotomies without simulated Epo dosing, none of the <1.0 kg infants were predicted to avoid RBCTx completely (data not shown). A consistent finding in the simulations of both VLBW subgroups was that the number of infants predicted to avoid RBCTx showed an abrupt increase in RBCTx reduction with a 50–80% reduction in laboratory blood loss.

Figure 3. Percent of infants with birth weight from 1.0–1.5 kg predicted to completely avoid RBCTx.

Figure 3

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Shown for this subgroup are data: (a) for simulated phlebotomy reduction alone; and, (b) for simulated phlebotomy reduction with simulated Epo administration (n=8). The dashed line represents the PINT RBCTx criteria and the solid line represents the actual RBCTx practice applied to individual study subjects.

Figure 4. Percent of infants with birth weight <1.0 kg predicted to completely avoid RBCTx with simulated phlebotomy reduction and Epo administration (n=18).

Figure 4

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The dashed line represents the PINT RBCTx criteria while the solid line represents the actual RBCTx practice.

DISCUSSION

Using state-of-the-art PK/PD simulation modeling in the present study we were able to predict the number of RBCTx received by infants following concurrent optimization of Epo dosing and simulated reduction in laboratory phlebotomy loss. With optimized Epo dosing and elimination of all laboratory phlebotomy loss, modeling predicted that RBCTx would be eliminated in all infants with BW 1.0–1.5 kg and in 45% of infants with BW <1.0 kg. Since the simulated therapeutic interventions in this study are hypothetical and therefore speculative, their feasibility and accuracy must be prospectively examined in practice. In this regard, although optimized Epo dosing applied in this study can be examined immediately for its ability to increase Hb production, future technological improvement in laboratory instrumentation combined with non-pharmacological interventions to reduce laboratory blood loss will be needed to significantly reduce laboratory blood loss (11).

Epo Administration

There have been numerous clinical trials in which Epo was administered to preterm infants with the goal of reducing or eliminating RBCTx (5). Although many of these clinical trials were successful in reducing neonatal RBCTx, the routine use of Epo remains controversial because of its modest efficacy in reducing RBCTx and because retrospective meta-analysis has identified an association of Epo treatment is begun in the first week of life with retinopathy of prematurity (5). Since only one Epo treatment trial has reported an association of Epo with retinopathy of prematurity (19), it is possible that the benefits of avoiding RBCTx may well outweigh its risks. Importantly, when Epo is administered at high doses, it may have neuroprotective properties, which could if confirmed in infants counterbalance the risks of retinopathy of prematurity (6). To resolve these important issues, additional prospective clinical trials of Epo in preterm infants will be necessary to better define the relationship of Epo therapy, retinopathy of prematurity, and neurodevelopmental outcome.

Phlebotomy Reduction

The current study demonstrated that 67% of the blood taken from infants for analysis was discarded or lost on to surfaces while only 33% was required by laboratory test instruments for analysis. Based on these data, requesting sample volumes closer to those needed for individual analyses could significantly reduce blood loss in study infants. Another alternative for reducing laboratory blood loss — at least for hematological analyses — is to utilize diluted blood samples (20). Clinical justification for the excess volumes of blood drawn from neonates is that the volume taken permits sample reanalysis when necessary, e.g., if the results are questionable because of instrument error, malfunction, or observing critical outlier values. Although such occurrences do exist, their frequency is uncertain and likely variable. Further discussion is needed regarding whether the magnitude of excess blood withdrawn in neonates is justified.

Post-delivery laboratory phlebotomy loss at the time VLBW infants and other critically ill infants are admitted to the NICU is the most intensive period of phlebotomy loss. A recently proposed effective approach mitigating this substantial blood loss is to perform initial laboratory testing on residual fetal blood in the placenta (21). Combining this approach with delayed cord clamping or cord stripping (22) to increase the initial circulating blood volume could help to further reduce RBCTx and their associated risks in the immediate postnatal period.

Clinical trials utilizing point-of-care bedside analyzers and in-line monitors to decrease phlebotomy loss have also demonstrated reductions in RBCTx administered to preterm infants (23, 24). Current blood monitors are capable of analyzing blood gases, electrolytes and Hb ex vivo and then returning the blood analyzed to the infant. Our group previously speculated that if the menu offered by blood monitors were expanded to include glucose, bilirubin, blood urea nitrogen and creatinine, phlebotomy reduction of 80% could be feasible (24). A significant reduction in laboratory blood loss in preterm infants can be accomplished without compromising clinical care (11).

Criteria Applied in Administering RBCTx

Discussion regarding the optimal RBCTx trigger criteria for VLBW infants is been a longstanding subject of controversy that is not addressed by the present data. Nonetheless, in practice when to transfuse is most commonly based on the infant’s Hb concentration, clinical status and/or postnatal age (7, 8, 24). In the current study, PK/PD simulation modeling was performed using the RBCTx criteria applied in the PINT study for infants with respiratory illness (7). In this analysis a significant 50% reduction in phlebotomized blood loss with Epo administration was predicted as being sufficient to maintain average Hb concentrations close to the actual observed mean Hb concentration. As better evidence-based RBCTx criteria are developed, simulations performed in this study can be readily modified to model predictions of RBCTx data for VLBW infants or other challenging patient populations in which Epo therapy and blood loss are important.

Combination Therapy for Avoiding RBCTx

The current study supports the work of Rabe et al. (12) in showing that a combination of therapeutic interventions can reduce RBCTx to a greater extent in preterm infants than individual interventions. As expected, a greater proportion of infants with BW 1.0–1.5 kg were predicted to avoid RBCTx compared to infants with BW <1.0 kg. When the simulations were performed using the restrictive RBCTx criteria applied in the PINT trial, a greater number of infants were predicted to avoid RBCTx than the number who actually received RBCTx. Thus, transfusion avoidance occurs due to increased erythropoiesis accompanying the simulated Epo dosing relative to the natural, non-stimulated erythropoiesis. When the percent phlebotomy reduction was increased from 50 to 80%, there was a substantial increase in the number of infants predicted to avoid RBCTx for both BW subgroups (Figures 3 and 4).

Benefits in Avoiding RBCTx in Preterm Infants

Since Epo administration (5) and the utilization of restrictive RBCTx criteria (25) remain controversial therapeutic interventions for reducing RBCTx among VLBW preterm infants, evidence is needed showing that the avoidance of RBCTx leads to better, more cost-effective clinical outcomes. RBCTx are expensive and cost between $522 and $1,183 per unit (26). In addition to the cost of administering RBCTx, complications associated with RBCTx include infection, fluid overload, electrolyte imbalance, and exposure to plasticizers, lead, and other toxins (5). Finally, it has recently been demonstrated that necrotizing enterocolitis, a potentially fatal condition among VLBW infants, is temporally associated with RBCTx (27).

Limitations of Modeling Simulations

As with all simulation studies, limitations are encountered in predicting the number of RBCTx that infants are anticipated to receive. The predictions made in this study were based on estimates of blood volume, transfused RBC lifespan and pharmacodynamic parameters. Blood volumes were estimated from the pre- and post-transfusion Hb level based on the dilution principle (28) assuming 100% survival of transfused allogeneic donor red cells (29). The mean blood volume determined in this study, 93.2±24.9 ml/kg, is within the range reported for preterm infants (28, 30, 31). The lifespan of adult donor transfused RBCs is commonly referenced as 120 days based on healthy adults in steady-state erythropoiesis (32). It is possible that transfused RBCs have a shorter lifespan in VLBW infants as a result of environmental factors, e.g., hyperoxia or hypoxia (33).

The PK/PD model used in the present simulations has several limitations. These include the lack of feedback for the endogenous Epo level and the inability to consider the Epo receptor state. With regard to the first limitation, the administration of optimized Epo is likely to decrease the endogenous production of Epo (34). Nonetheless, since the Epo concentrations used in the simulations are far higher than the endogenous Epo concentrations, the effect is negligible. Regarding the second limitation, the pharmacodynamic model applied did not take into account dynamic changes in the Epo receptor state which has been shown to influence Epo pharmacodynamics in animals (15). Although reliable measures of Epo receptors are not currently available for preterm infants, the simulation model applied is easily modified to accommodate relevant new information.

Summary and Conclusions

The modeled simulations included in the current report demonstrate that specific reductions in RBCTx are possible in VLBW preterm infants using a combination of simulated, pharmacodynamically optimized Epo administration and reduction in laboratory phlebotomy loss. The current study predicts that with a 100% reduction in phlebotomies a total avoidance of RBCTx, is possible in the subset of all VLBW infants with BW between 1.0–1.5 kg, while an estimated 45% of infants with BW <1.0 kg were predicted to avoid RBCTx. Although the current study is simulation-based it provides a rationale for the design of future clinical trials in VLBW infants. Furthermore, it suggests that future clinical trials that simultaneously apply phlebotomy reduction measures, optimized Epo administration and restrictive RBCTx criteria can significantly reduce, and in some cases eliminate, the number of RBCTx administered to preterm VLBW infants. If confirmed in future clinical trials, the resultant clinical reduction in RBCTx can lower RBCTx-associated complications and associated costs.

Acknowledgments

The rabbit Epo antiserum used in the Epo RIA was a gift from Gisela K. Clemens, Ph.D. We appreciate the outstanding contributions of the clinical laboratory staff led by Mitchell J. Owen with oversight from Matthew D. Krasowski, M.D., Ph.D. We also appreciate the substantial contributions from our laboratory research team (Robert L. Schmidt, Earl L. Gingerich and Jessica A. Goehring) and our nursing research team (Gretchen A. Cress, Karen J. Johnson, Nancy E. Krutzfield, Sara K.B. Scott and Ruthann Schrock). Manuscript review and critique by Patrick Carroll, M.D., was helpful and insightful. Mark A. Hart provided expert editorial and secretarial help. Finally, we are grateful to Sysmex America, Inc. for the loan of the Sysmex XE-2100 hematology automated analyzer.

Statement of Financial Support: This study was supported by NIH P01 HL046925 and by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1RR024979.

ABBREVIATIONS

BW

birth weight

ELBW

extremely low birth weight (<1.0 kg)

Epo

erythropoietin

Hb

hemoglobin

PD

pharmacodynamics

PK

pharmacokinetics

PINT

premature infants in need of transfusion

RBC

red blood cell

RBCTx

RBC transfusion

VLBW

very low birth weight (<1.5 kg)

Footnotes

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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