Comparison of a restricted transfusion schedule with erythropoietin therapy versus a restricted transfusion schedule alone in very low birth weight premature infants.

Objective: Erythropoietin (EPO) is commonly used in very low birth weight neonates to minimize blood transfusions during hospitalization. Data are limited comparing the use of EPO along with a restricted transfusion schedule versus a restricted transfusion schedule alone. We compared the effects of a restricted transfusion schedule with EPO versus a restricted transfusion schedule alone during two consecutive 6-month periods.

Methods: In period I, infants born at <30 weeks gestational age (GA) or < 1,500 g birth weight (BW) were treated prophylactically for six weeks with EPO 1,000 U/kg/wk in three divided doses and blood transfusions were given using a restricted transfusion schedule. This was the called the EPO Group. In period II, a restricted transfusion schedule was utilized, but EPO was not administered. This constituted the No EPO Group. No other changes in clinical practice were introduced in either period.

Results: There were 30 neonates in the EPO Group and 20 in the No EPO Group. There were no significant differences in sex, race, mean birth weight (1,074 [+ or -] 283 versus 965 [+ or -] 330 g), mean gestational age (28.9 [+ or -] 2.96 versus 27.8 [+ or -] 2.86 wks), 5 minute Apgar score (7.8 [+ or -] 1.2 versus 7.6 [+ or -] 1.1), or mean hematocrit (48.2% [+ or -] 6.05 versus 48.6% [+ or -] 6.31) at admission. There were no significant differences in the total number of transfusions between the two periods. In the EPO Group, 8/30 patients received 27 transfusions. Six transfusions violated guidelines based on hematocrit level. EPO was discontinued in three infants secondary to treatment-related neutropenia. There were two deaths unassociated with EPO treatment. Excluding deaths, 6 patients received 16 transfusions. In the No EPO Group, 8/20 patients received 13 transfusions. Two transfusions violated guidelines based on hematocrit. There were three deaths and one patient transfer. Excluding these four patients, 6 infants received 11 transfusions (P [less than or equal to] 1.) Among survivors, there were no significant differences in mean total length of stay (49.3 [+ or -] 22.7 versus 53.2 [+ or -] 26.4 d), mean discharge weight (2,144 [+ or -] 405 versus 2,358 [+ or -] 458 g), or average weight gain/d (20.7 [+ or -] 5.44 versus 22.6 [+ or -] 6.81 g), between the two groups respectively, nor were there significant differences when all babies were included in the analysis. There was a significant difference in mean hematocrit at discharge, respectively, (38.3% [+ or -] 6.84 versus 31.4% [+ or -] 6.26; P = 0.003) in survivors.

Conclusions: A restricted transfusion schedule without EPO use was associated with lower mean hematocrit at discharge, but not with an increased frequency of transfusions, nor significant differences in length of stay, discharge weight, or average daily weight gain. A restricted transfusion schedule alone avoided side effects and costs associated with EPO. Indications for transfusion and what constitutes appropriate levels of hemoglobin still require clinical investigation, including long-term clinical outcomes.

Key Words: erythropoietin, blood transfusion, prematurity, very low birth weight, anemia.

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Indications for transfusion of very low birth weight preterm infants remain controversial. Erythropoietin (EPO) is commonly used in the neonatal intensive care unit (NICU) in conjunction with vitamin E and iron supplementation to prevent the need for transfusion for anemia of prematurity. (1,2,3-7) Therapy may last as long as six weeks utilizing intravenous (IV) and/or subcutaneous (SC) administration. While some studies demonstrate that EPO increases hematocrit and hemoglobin, and reduces the number of transfusions and volume of transfused blood, (3,4) other studies suggest that the use of erythropoietin may not result in a reduction in the number of transfusions and advocate limiting blood draws as well as the use of a restricted transfusion schedule in very low birth weight infants. (2,5-7)

Our objective was to compare the effects of a restricted transfusion schedule with EPO therapy versus a restricted transfusion schedule alone, during two consecutive 6-month periods in infants < 1,500 g birth weight.

Methods

To prevent anemia of prematurity and to limit the number of blood transfusions, the practice in our 30-bed tertiary level NICU was to begin EPO therapy in premature and very low birth weight infants. Infants < 30 weeks gestation and/or < 1,500 g at birth were treated with erythropoietin 1,000 U/kg/wk divided into 3 doses given in parenteral nutrition fluid or SC for six weeks or stopped at discharge if before six weeks. For infants receiving parenteral nutrition, iron supplementation in the form of iron dextran was provided in a dose of 1 mg/kg/d. Infants on full enteral feedings were supplemented with oral iron at 6 mg/kg/d. Vitamin E was provided at a dose of 25 U/d. In July 2003, we adopted a restricted transfusion schedule based on the transfusion protocol published by Ohls et al (2) We altered our clinical practice in January 2004, when we discontinued the use of EPO, vitamin E, and iron supplementation. Infants were supplemented with iron 2 mg/kg/d po beginning at 1 month of age. (8) This study retrospectively compares two cohorts, the EPO Group (July-December 2003) and the No EPO Group (January-June 2004) during a period of time when we employed a restricted transfusion schedule (Fig. 1). We calculated the total volume of blood drawn from surviving infants during their first two weeks of life. Because of the retrospective nature of this review, we wanted to assure that we captured all blood work performed, and thus did not solely rely on information from our flowsheets. This information was culled from our hematology, chemistry, and blood bank laboratories, but did not include blood samples for blood gases or Chemstrip determinations.

Results

There were 30 infants in the EPO Group and 20 infants in the No EPO Group during the study period. There were no significant differences between the two groups with respect to birth weight, gestational age, 5-minute Apgar score, or hematocrit at admission. There were no differences in racial or sexual characteristics between the two groups, nor was there a difference in mortality (Table 1).

There was no difference between the two groups in the volume of blood drawn per survivor during the first two weeks of life. The mean volume drawn per neonate in the EPO Group was 22.2 mL [+ or -] 7.69 mL. In the No EPO Group, the mean volume drawn per neonate was 26.9 mL [+ or -] 10.6 mL (P = 0.1) (Fig. 2). Eight out of 30 infants in the EPO Group received a total of 27 packed red blood cell transfusions. Six of the transfusions violated guidelines for transfusion on hematocrit. EPO was discontinued in three infants secondary to treatment-associated neutropenia. There were two deaths unassociated with EPO treatment. Excluding deaths, six patients received a total of 16 packed red blood cell transfusions. Eight out of 20 infants in the No EPO Group received a total of 13 transfusions. Two of these violated guidelines for transfusion based on hematocrit. There were three deaths and one patient transfer in this group. Excluding these four patients, six infants received a total of 11 transfusions (P [less than or equal to] 1.) The timing of transfusions in the smallest infants, < 1,000 g at birth, can be seen in Table 2.

[FIGURE 2 OMITTED]

Among survivors, there were no significant differences in mean total length of stay (49.3 [+ or -] 22.7 versus 53.2 [+ or -] 26.4 d), mean discharge weight (2,144 [+ or -] 405 versus 2,358 [+ or -] 458 g), or average weight gain/d (20.7 [+ or -] 5.44 versus 22.6 [+ or -] 6.81 g), between the EPO and No EPO groups respectively, nor were there significant differences when all babies were included in the analysis. There was a significant difference in mean hematocrit at discharge (38.3% [+ or -] 6.84 versus 31.4% [+ or -] 6.26; P = 0.003) in survivors (Table 3).

Discussion

Indications for red blood cell transfusions in very low birth weight infants remain controversial. (9) Although there are numerous guidelines available for reference, studies to guide transfusion practices in the neonatal intensive care unit are lacking, and it is uncertain what hemoglobin levels are therapeutic for a specific individual. Recent reviews of the topic conclude that hemoglobin levels are a poor predictor of tissue oxygen delivery. (1,10-12) Clinical findings of apnea, poor weight gain, tachypnea, and tachycardia, are often utilized as indicators for packed red blood cell transfusion, but studies supporting transfusion are contradictory. (1,6,10,11) In addition, there is a desire to limit transfusions because of the well-known potential adverse consequences. These include infectious complications such as HIV, hepatitis B, and cytomegalovirus and noninfectious complications such as volume overload, hyperkalemia, and graft-versus-host disease. (1,13,14)

Because of these potential complications, there has been interest in limiting transfusions in neonates. Several studies have shown reductions in the number of blood transfusions given to very low birth weight infants during the past decade. (4,6,10,11) This is true despite an increasing survival rate in very low birth weight infants and a concomitant increase in hospital length of stay. Explanations for the decrease in the number of transfusions include limiting the volume of blood tests, the utilization of a smaller volume of blood to perform these tests, the use of noninvasive means of assessing oxygenation and ventilation (pulse oximetry and transcutaneous monitoring), the use of erythropoietin therapy, and the adoption of various restricted transfusion criteria.

Erythropoietin therapy has been utilized for the treatment and prevention of anemia of prematurity. Erythropoietin use results in an increase in hemoglobin, hematocrit, and reticulocyte count. (4,5) In several studies its use has been associated with a decrease in the number of blood transfusions and the volume of blood transfused. (4,5) However it is possible that liberal guidelines for transfusion in some of these studies overestimated the efficiency of erythropoietin therapy. (5) There is also a strong correlation between the need for blood transfusion and phlebotomy losses (5,10) and it has been suggested that employing restricted transfusion guidelines as well as minimizing blood sampling might obviate the need for erythropoietin exposure. (2,6-8,12,15)

The issue of long-term safety also needs to be considered. The optimal level of hemoglobin or hematocrit in small, sick, and recovering premature infants has yet to be determined. A recent study examined growth and neurodevelopmental outcome in neonates treated with erythropoietin compared with controls. (15) Infants treated with erythropoietin were statistically more likely to have head circumferences below the 10th percentile and were more likely to have a score of <70 on the Psychomotor Development Index (PDI) of the Bayley-II Scales of Infant Development, Revised, in comparison to infants in the control group. While the authors point out that the means between the groups were not statistically significant and that infants with smaller head circumferences did not represent a higher percentage of infants with a PDI <70, practitioners should be cautious about adopting this therapy as routine care in the absence of data regarding long-term safety. Of note, in this study, there was no difference in the number of infants who received blood transfusion following discharge or in the need for rehospitalization.

Our study sought to compare the effect of a restricted transfusion schedule in conjunction with the use of EPO therapy in comparison to the use of a restricted transfusion schedule alone. Although our study was a retrospective trial, there were no differences between the two groups studied, and the volume of blood drawn per patient in the two groups during the first two weeks of life were similar, consistent with the findings of Ohls et al. (2)

Conclusions

Our results are consistent with prior studies demonstrating that adopting a restricted transfusion schedule is as effective as the use of erythropoietin therapy in limiting the total number of blood transfusions in very low birth weight infants. The use of a restricted transfusion schedule also avoids potential complications and reduces the costs associated with routine erythropoietin administration. The optimal level of hemoglobin based on severity of illness, symptoms, and age, and the long-term safety of erythropoietin used in neonates remains to be determined through additional clinical trials that include long-term follow-up.

Acknowledgments

Many thanks to the following individuals for their help and insights: Cynthia Arnold, MS, CRNP; Jane Cirelli, MS, CRNP; Jeanne Abby Dentry, CRNP; Norma V. Gungon, MD; Diana L. Hnat; Stephen A. Liverman, MD; Angela M. Tamayo, MD; Virma V. Torres, MD, and Linda D. Updegraff, CRNP.

We also thank the nurses, respiratory therapists, and all administrative and professional staff who provided care to our babies during the study period.

References

1. Cohen A, Manno C. Transfusion practices in infants receiving assisted ventilation. Clin Perinatol 1998;25:97-111.

2. Ohls RK, Ehrenkranz RA, Wright LL, et al. Effects of early erythropoietin therapy on the transfusion requirements of preterm infants below 1250 grams birth weight: a multicenter, randomized, controlled trial. Pediatrics 2001;108:934-942.

3. Maier RF, Obladen M, Seigalla P, et al. The effect of epoietin beta on the need for transfusion in very low birth weight infants. N Engl J Med 1994;330:1173-1178.

4. Shannon KM, Keith JF III, Mentzer WC, et al. Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants. Pediatrics 1995;95:1-8.

5. Donato H, Vain N, Rendo P, et al. Effect of early versus late administration of recombinant erythropoietin on transfusion requirements in premature infants: results of a randomized, placebo-controlled, multi-center trial. Pediatrics 2000;105:1066-1072.

6. Franz AR, Pohlandt F. Red blood cell transfusions in very and extremely low birth weight infants under restrictive transfusion guidelines: is exogenous erythropoietin necessary? Arch Dis Child Fetal Neonatal Ed 2001;84:96F-100F.

7. Ohls RK. Erythropoietin treatment in extremely low birth weight infants: blood in versus blood out. J Pediatr 2002;141:3-6.

8. Nutritional needs of the preterm infant. In: Pediatric Nutrition Handbook. 5th edition. Elk Grove Village, American Academy of Pediatrics, 2004.

9. Ringer SA, Richardson DK, Sacher RA, et al. Variations in transfusion practice in neonatal intensive care. Pediatrics 1998;101:194-200.

10. Keyes WG, Donohue MS, Spivak J et al. Assessing the need for transfusion of premature infants and role of hematocrit, clinical signs, and erythropoietin level. Pediatrics 1989;84:412-417.

11. Lachance C, Chessex P, Fouron JC, et al. Myocardial, erythropoietic, and metabolic adaptation to anemia of prematurity. J Pediatr 1994;125:278-282.

12. Bifano EM, Curran TR. Minimizing donor blood exposure in the neonatal intensive care unit: current trends and future prospects. Clin Perinatol 1995;22:657-669.

13. Schreiber GB, Busch MP, Kleinman SH, et al. The risk of transfusion transmitted viral infections. N Engl J Med 1996;334:1685-1690.

14. Maier RF, Sonntag J, Walka MM, et al. Changing practices of red blood cell transfusion in infants with birth weights less than 1000 g. J Pediatr 2000;136:220-224.

15. Ohls RK, Ehrenkranz RA, Das A, et al. Neurodevelopmental outcome and growth at 18 to 22 months' corrected age in extremely low birth weight infants treated with early erythropoietin and iron. Pediatrics 2004;114:1287-1291.

Howard J. Birenbaum, MD, Maria A. Pane, MD, Sabah M. Helou, MD, and Karen P. Starr, MS, CRNP

From the Division of Neonatology, Department of Pediatrics, Greater Baltimore Medical Center, Baltimore, MD.

Reprint requests to Howard J. Birenbaum, MD, Division of Neonatology, Department of Pediatrics, Greater Baltimore Medical Center, 6701 North Charles Street, Baltimore, MD 21204. Email: [e-mail]

Accepted June 14, 2006.

RELATED ARTICLE: Key Points

* Erythropoietin is commonly used in very low birth weight infants to prevent anemia, as is a restricted transfusion schedule without erythropoietin.

* Although hematocrit levels were higher in the erythropoietin-treated group, there was no difference between the groups regarding frequency of transfusions, length of stay, discharge weight, or average daily weight gain.

* A restricted transfusion schedule alone avoided side effects and costs associated with erythropoietin.

Hct/Hgb                          Respiratory Support and/or Symptoms

Hct [less than or equal to]35/   Infants requiring moderate or
  Hgb [less than or equal to]11    significant mechanical ventilation
                                   (MAP >8 cm [H.sub.2]O and Fi[O.sub.2]
                                   >0.4)
Hct [less than or equal to]30/   Infants requiring minimal respiratory
  Hgb [less than or equal to]10    support (any mechanical ventilation
                                   or endotracheal/nasal CPAP >6 cm
                                   [H.sub.2]O and Fi[O.sub.2]
                                   [less than or equal to]0.4)
Hct [less than or equal to]25/   Infants not requiring mechanical
  Hgb [less than or equal to]8     ventilation but who are on
                                   supplemental [O.sub.2] or CPAP with
                                   Fi[O.sub.2]
                                   [less than or equal to]0.4 and in
                                   whom 1 or more of the following is
                                   present:
                                   * [less than or equal to]24 h of
                                     tachycardia (HR >180) or tachypnea
                                     (RR >80)
                                   * an increased oxygen requirement
                                     from the previous 48 h, defined as
                                     [greater than or equal to]4-fold
                                     increase in nasal canula flow (ie,
                                     0.25 L/min to 1 L/min) or an
                                     increase in nasal CPAP
                                     [greater than or equal to]20% from
                                     the previous 48 h (ie, 5 cm to 6 cm
                                     [H.sub.2]O)
                                   * weight gain <10 g/kg/d over the
                                     previous 4 d while receiving
                                     [greater than or equal to]100
                                     kcal/kg/d
                                   * an increase in the episodes of
                                     apnea and bradycardia (>9 episodes
                                     in a 24-h period or
                                     [greater than or equal to]2
                                     episodes in 24 h requiring bag-mask
                                     ventilation) while receiving
                                     therapeutic doses of
                                     methylxanthines
                                   * undergoing surgery
Hct [less than or equal to]20/   Asymptomatic and an absolute
  Hgb [less than or equal to]7     reticulocyte count <100 000 cells/
                                   [micro]L

Hct/Hgb                          Transfusion Volume

Hct [less than or equal to]35/   15 mL/kg PRBC over 2-4 h
  Hgb [less than or equal to]11
Hct [less than or equal to]30/   15 mL/kg PRBC over 2-4 h
  Hgb [less than or equal to]10
Hct [less than or equal to]25/   20 mL/kg PRBCs over 2-4 h
  Hgb [less than or equal to]8     (divide into 2-10 mL/kg
                                   volumes if fluid-sensitive)
Hct [less than or equal to]20/   20 mL/kg PRBCs over 2-4 h
  Hgb [less than or equal to]7     (2-10 mL/kg volumes)

Fig. 1 Transfusion guidelines.

Table 1. Characteristics of the groups

                             EPO Group             No EPO Group
                             N = 30                N = 20

Birth weight (gms)           1074 [+ or -] 283     965 [+ or -] 330
Gestational age (weeks)        28.9 [+ or -] 2.96   27.8 [+ or -] 2.86
5' Apgar score                  7.8 [+ or -] 1.2     7.6 [+ or -] 1.1
Hematocrit on admission        48.2 [+ or -] 6.05   48.6 [+ or -] 6.31
Male                           11 (36.67%)          10 (50%)
Female                         19 (63.33%)          10 (50%)
[less than or equal to]1000    12 (40%)             10 (50%)
  grams
Black                          15 (50%)             10 (50%)
Deaths                          2                    3
Deaths                          1                    3
[less than or equal to]1000
  grams

Table 2. Timing of transfusions in infants [less than or equal to] 1000
grams

                            EPO Group   No EPO Group
                            (n = 7/12)  (n = 6/10)

Total transfusions          26          10
Transfusions in week 1      13           5
Transfusions in week 2       4           1
Transfusion beyond 2 weeks   9           4

Table 3. Characteristics of survivors

                           EPO Group             No EPO Group
                           N = 30                N = 20

Survived                     28                    17
Hematocrit at discharge      38.3 [+ or -] 6.84    31.4 [+ or -] 6.26*
Length of stay (days)        49.3 [+ or -] 22.7    53.2 [+ or -] 26.4
Daily weight gain (grams)    20.7 [+ or -] 5.44    22.6 [+ or -] 6.81
Discharge weight (grams)   2144 [+ or -] 405     2358 [+ or -] 458

*p = 0.003