Reference intervals for common coagulation tests of preterm infants (CME).

BACKGROUND: Fresh-frozen plasma (FFP) is sometimes administered to nonbleeding preterm neonates who are judged to be at risk for bleeding because they have abnormal coagulation tests. The benefits/risks of this practice are not well defined. One limitation to progress is lack of reference intervals for the common coagulation tests, thus limiting precision about whether coagulation tests are indeed abnormal. STUDY DESIGN AND METHODS: In a sequential observational study, fetal blood was drawn at preterm birth (≤ 34 weeks) from the umbilical vein near the placenta. Fibrinogen, prothrombin time, activated partial thromboplastin time, D-dimer, platelet (PLT) count, and mean PLT volume were measured. Reference intervals were constructed using 5th and 95th percentile values. Associations were then sought between abnormal coagulation values at birth and bleeding problems identified during the first week. RESULTS: Coagulation tests were drawn at 175 preterm deliveries and the results were organized into reference intervals by gestational age. No abnormal coagulation value, either alone or in combination, predicted hemorrhage (intraventricular, gastrointestinal, or pulmonary) during the first week. However, fibrinogen exceeding the 95th percentile was associated with evidence of in utero infection/inflammation (correlations with elevated C-reactive protein, p<0.01, and elevated immature to total neutrophil ratio, p<0.001). CONCLUSIONS: Abnormal coagulation values at preterm birth do not predict bleeding during the first week. This suggests to us that bleeding in the days after preterm birth is not generally the result of in utero coagulopathy. These findings bring into question the value of coagulation screening of nonbleeding preterm infants and prophylactic FFP administration to those with abnormal values.

Association, among very-low-birthweight neonates, between red blood cell transfusions in the week after birth and severe intraventricular hemorrhage.

BACKGROUND: Previous reports describe a statistical association, among very-low-birthweight (VLBW, <1500 g) neonates, between red blood cell (RBC) transfusion in the first days after birth and development of severe intraventricular (brain) hemorrhage (IVH). STUDY DESIGN AND METHODS: We hypothesized that after we established a neonatal intensive care unit (NICU) transfusion management program in 2009, a decrease in early (first week after birth) RBC transfusion rate and a decrease in the incidence of severe IVH occurred concomitantly. RESULTS: During a 9-year period 2716 VLBW neonates were admitted to our NICUs. In 2004, 58% of VLBW neonates received one or more RBC transfusions during the first week. After a transfusion compliance program was established in 2009, this rate declined, reaching 25% by 2012. In parallel, the severe IVH rate also declined, from 17% in 2004 to 8% in 2012 (R(2) = 0.73). IVH occurred in 27% of those who received a RBC transfusion during the first week versus less than 2% of those with no early transfusion (p < 0.001). The decrease in IVH rate occurred exclusively among neonates born in an Intermountain Healthcare perinatal center and not among those initially cared for in an "outside" hospital and subsequently transported to an Intermountain NICU. CONCLUSIONS: It remains unclear whether transfusing VLBW neonates during the first days after birth is a proximate cause of IVH. However, the present report is consistent with previous studies showing that successful efforts to reduce early RBC transfusions is associated with a decrease in the incidence of severe IVH.

Unexplained extreme hyperbilirubinemia among neonates in a multihospital healthcare system.

We report a series of neonates who developed a total serum bilirubin (TSB) >20mg/dL during a recent ten-year period in a multihospital healthcare system. The incidence of a TSB >20mg/dL fell after instituting a pre-hospital discharge bilirubin screening program in 2003/2004 (91.3 cases/10,000 births before vs. 72.4/10,000 after), but the incidence has subsequently remained unchanged. No specific cause for the hyperbilirubinemia was identified in 66% of (n=32) cases with a TSB >30 mg/dL or in 76% of (n=112) cases with a TSB 25.0-29.9 mg/dL. We hypothesized that hemolysis was a common contributing mechanism, but our review of hospital records indicated that in most instances these infants were not evaluated sufficiently to test this hypothesis. Records review showed maternal and neonatal blood types and direct antiglobulin testing were performed in >95% cases, but rarely were other tests for hemolysis obtained. In the ten-year period reviewed there were zero instances where erythrocyte morphology from a blood film examination or Heinz body evaluation by a pediatric hematologist or pathologist were performed. In 3% of cases pyruvate kinase was tested, 3% were evaluated by hemoglobin electrophoresis, 3% had a haptoglobin measurement, and 16% were tested for G6PD deficiency. Thus, determining the cause for hyperbilirubinemia in neonates remains a problem at Intermountain Healthcare and, we submit, elsewhere. As a result, the majority of infants with a TSB >25mg/dL have no specific causation identified. We speculate that most of these cases involve hemolysis and that the etiology could be identified if searched for more systematically. With this in mind, we propose a "consistent approach" to evaluating the cause(s) of hyperbilirubinemia among neonates with a TSB >25mg/dL.

Red blood cell transfusion of preterm neonates with a Grade 1 intraventricular hemorrhage is associated with extension to a Grade 3 or 4 hemorrhage.

BACKGROUND: Some preterm infants with a Grade 1 intraventricular hemorrhage (IVH) are subsequently found to have a Grade 3 or 4 IVH, while in others the Grade 1 resolves without extending. STUDY DESIGN AND METHODS: We identified all neonates in our health system in the past 6 years with a Grade 1 IVH and compared those where the hemorrhage extended versus resolved. RESULTS: Grade 1 IVH was identified in 417 neonates; 24 subsequently became a Grade 3, and 22 a Grade 4. These 46 were born earlier, 25 ± 2 weeks versus 30 ± 3 weeks (p = 0.000), with lower birth weight, 811 ± 284 g versus 1432 ± 603 g (p = 0.000); lower 5-minute Apgar scores, 5 ± 2 versus 8 ± 2 (p = 0.000); and slightly lower cord pH, 7.24 ± 0.16 versus 7.28 ± 0.10 (p = 0.009). Older gestational age was the most significant contributor lowering the odds of IVH extension (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.92-0.98). Administering a red blood cell (RBC) transfusion up to and on the day the Grade 1 was detected was the most significant contributor increasing the odds (OR, 2.92; 95% CI, 2.19-3.90) of extension. In both groups (resolving vs. extending) criteria for ordering transfusions were similar as was the proportion of transfusions given out of compliance with guidelines. CONCLUSIONS: An association exists between RBC transfusion and extension of a Grade 1 IVH into a Grade 3 or 4. However, the explanation is unclear and could involve either the reasons transfusion are ordered or the transfusions themselves. Additional studies are needed to discover why neonates are more likely to have IVH extension if transfused.

Implementing a program to improve compliance with neonatal intensive care unit transfusion guidelines was accompanied by a reduction in transfusion rate: a pre-post analysis within a multihospital health care system.

BACKGROUND: We previously reported that in the year 2006, approximately 35% of the transfusions administered in the Intermountain Healthcare neonatal intensive care units (NICU) were noncompliant with our transfusion guidelines. In January 2009 we instituted an electronic NICU transfusion ordering and monitoring system as part of a new program to improve compliance with transfusion guidelines. STUDY DESIGN AND METHODS: In the four largest NICUs of Intermountain Healthcare, we performed a pre-post analysis of compliance with transfusion guidelines and transfusion usage. RESULTS: After beginning the new transfusion compliance program all four NICUs had an increase in compliance from 65% to 90%. Accompanying the improved compliance, all four NICUs had a reduction in transfusions administered. Specifically, compared with 2007 and 2008, there were 984 fewer NICU transfusions given in 2009. This included 554 fewer red blood cell (RBC) transfusions, 174 fewer platelet transfusions, and 256 fewer frozen plasma infusions. We calculate that in 2009, a total of 200 NICU patients who in previous years would have received one or more transfusions instead received none. Applying specific Intermountain Healthcare billing data to the observed transfusion reductions, this new program resulted in an annual decrease of $780,074 in blood bank charges (blood administration charges were not included). During the 3-year period, January 2007 through December 2009, we detected no change in NICU demographics, major morbidities, length of hospital stay, or mortality rate. CONCLUSION: Implementing a systemwide NICU program to improve compliance with already-established transfusion guidelines increased compliance from 65% to 90%. Improved compliance with transfusion guidelines was accompanied by a significant reduction in transfusions given, with no increase in NICU length of stay or mortality rate.

Among very-low-birth-weight neonates is red blood cell transfusion an independent risk factor for subsequently developing a severe intraventricular hemorrhage?

BACKGROUND: A severe intraventricular hemorrhage (IVH) in a preterm neonate can result in life-long disabilities or death. Pathogenic mechanisms responsible for IVH are incompletely understood. We postulated that if the timing of a severe IVH could be approximated by serial ultrasound, potentially relevant antecedents could be identified. STUDY DESIGN AND METHODS: We retrospectively identified all very-low-birth-weight (VLBW) neonates in our health system, over a 5-year period, with an initial head ultrasound showing no hemorrhage but a subsequent ultrasound showing a Grade 3 or 4. Controls that did not develop an IVH were matched with cases using demographic features and degree of illness measures. RESULTS: Fifty-four cases were matched (1:2) with controls. No differences were found between cases and controls in initial pH, sepsis, ventilation, coagulation studies, or proportion with severe thrombocytopenia. However, during the period when the head ultrasound was normal, cases were more likely to have had a red blood cell (RBC) transfusion (p < 0.001). In 94% of the cases the sequence was 1) no IVH, 2) RBC transfusion, and 3) severe IVH. With the use of logistic regression, each subsequent RBC transfusion during the first week was determined to double the risk of a severe IVH (each transfusion increases relative risk, 2.02; 95% confidence interval, 1.54-3.33). Sensitivity analysis indicated a high likelihood that RBC transfusion, independent of hemoglobin level or other factors, increases the risk of developing a severe IVH. CONCLUSION: These findings suggest a new hypothesis. Namely, RBC transfusions given before the development of an IVH are an independent risk factor for developing a severe IVH.

Postponing or eliminating red blood cell transfusions of very low birth weight neonates by obtaining all baseline laboratory blood tests from otherwise discarded fetal blood in the placenta.

BACKGROUND: Safely reducing the proportion of very low birth weight neonates (<1500 g) that receive a red blood cell (RBC) transfusion would be an advance in transfusion practice. STUDY DESIGN AND METHODS: We performed a prospective, single-centered, case-control, feasibility analysis, preparatory to designing a definitive trial. Specifically, we sought to determine whether we could obtain all baseline neonatal intensive care unit blood tests from the placenta, after placental delivery, thereby initially drawing no blood from the neonate. RESULTS: Ten cases where all baseline blood tests were drawn from the placenta, and 10 controls where all tests were drawn from the neonate, were closely matched for birth weight, gestational age, sex, and race. Early cord clamping was used for all 20. Over the first 18 hours the hemoglobin increased in nine cases versus two controls (p = 0.005). During the first 72 hours one case versus five controls qualified for and received an RBC transfusion. In the first week the cases received four transfusions and the controls received 16 (p = 0.02). None of the cases had an intraventricular hemorrhage (IVH) but four of the controls had a Grade 1 and two had a Grade 3 (p = 0.01). CONCLUSION: We speculate that this method is feasible and generally postpones the first RBC transfusion until beyond the period of peak vulnerability to IVH.

Is "transfusion-associated necrotizing enterocolitis" an authentic pathogenic entity?

BACKGROUND: Necrotizing enterocolitis (NEC) sometimes occurs after a transfusion, but it is unclear whether this is a chance association or cause and effect. STUDY DESIGN AND METHODS: We compared features of neonates that developed surgical NEC within 48 hours after transfusion with others that developed NEC not preceded by transfusion. We assessed the blood used for transfusion and feeding practices among NEC cases and controls. RESULTS: Forty neonates developed surgical NEC after a transfusion and 72 developed NEC unrelated to a transfusion. Those with NEC after transfusion were born at earlier gestation (mean 27 weeks, 90% confidence interval [CI] 26-28 years vs. mean 30, 90% CI 29-31; p < 0.001) and were of lower birth weight (mean 981 g, 90% CI 835-1128 g vs. mean 1371 g, 90% CI 1245-1496; p < 0.001) and developed NEC later during their neonatal intensive care unit course (day of life: mean 23, 90% CI 20-27 vs. mean 16, 90% CI 13-19; p < 0.001). Transfusions were more prevalent among those that developed NEC (p < 0.001). The blood transfused to those that developed NEC was not older, but those who developed NEC had been fed larger volumes of milk in the 24 hours before and during transfusion (p = 0.04) and were more likely to have been fed a bovine product during that period (p = 0.004). CONCLUSION: Approximately one-third of surgical NEC cases in our system occurred after a transfusion. We speculate that a target area for reducing the prevalence of posttransfusion NEC involves feeding practices immediately before and during RBC transfusion.

Very high users of platelet transfusions in the neonatal intensive care unit.

BACKGROUND: In neonatal intensive care unit (NICU) practice, a small percentage of the patients receive a large proportion of the platelet (PLT) transfusions administered. This study sought to better define this very-high-user group. To accomplish this, records of all NICU patients in a multihospital health care system who, during a recent 5(1/2)-year period, received 20 or more PLT transfusions were examined. STUDY DESIGN AND METHODS: Electronic medical record repositories of Intermountain Healthcare neonates with dates of birth from January 1, 2002, through June 30, 2007, who received 20 or more PLT transfusions were identified. The causes of the thrombocytopenia were sought, whether each transfusion given was a treatment for bleeding versus prophylaxis was determined, whether each transfusion was compliant with our transfusion guidelines was judged, and the outcomes were tabulated. RESULTS: During this period, 45 patients received 20 or more PLT transfusions (median, 29; range, 20-79). Medical conditions could be categorized into six diagnoses: 1) extracorporeal membrane oxygenation (ECMO) for congenital diaphragmatic hernia (CDH; n = 13), 2) fungal sepsis (n = 8), 3) ECMO for reasons other than CDH (n = 8), 4) necrotizing enterocolitis (n = 7), 5) bacterial sepsis (n = 7), and 6) congenital hyporegenerative thrombocytopenia (n = 2). Nineteen percent of the transfusions were ordered for oozing, bruising, or bleeding and 81 percent for prophylaxis. Thirty-six percent of transfusions were given in violation of our transfusion guidelines. Forty-nine percent of the high users died, but no deaths were due to hemorrhage. All survivors developed chronic lung disease, and all survivors weighing less than 1250 g at birth developed retinopathy of prematurity. CONCLUSIONS: Almost all patients that received 20 or more PLT transfusions had an acquired, consumptive thrombocytopenia. All could have received fewer transfusions had the guidelines already in place been observed. Eighty-one percent fewer PLT transfusions would have been administered had the paradigm been transfusing only if oozing, bruising, or bleeding was present.

Testing platelet mass versus platelet count to guide platelet transfusions in the neonatal intensive care unit.

BACKGROUND: Platelet (PLT) transfusions can bestow significant benefits but they also carry risks. This study sought a safe means of reducing PLT transfusions to neonatal intensive care unit (NICU) patients with thrombocytopenia by comparing two transfusion guidelines, one based on PLT count and the other on PLT mass (PLT count times mean PLT volume). STUDY DESIGN AND METHODS: Using a prospective, two-centered, before versus after design, PLT transfusion usage and hemorrhagic events were contrasted during a period when PLT count-based transfusion guidelines were in use (Period 1) versus a period when PLT mass-based guidelines were in use (Period 2). RESULTS: No differences were observed between Periods 1 and 2 in NICU admissions, sex, race/ethnicity, percentage of inborn patients, or percentage of patients with a PLT count less than 50 x 10(9) or 51 x 10(9) to 99 x 10(9)/L. In the first period 3.6% of NICU admissions received one or more PLT transfusions. This fell to 1.9% during the second period (p < 0.002). The number of PLT transfusions administered per transfused patient was the same in both periods: 2.0 (1-23) (median [range]) in Period 1 and 2.0 (1-17) in Period 2 (p > 0.40). Significantly fewer PLT transfusions were given in Period 2 for prophylaxis (patient not bleeding; p < 0.001 vs. Period 1). The number given for bleeding did not change between the two periods. In Period 2 no increases were seen in rate of intraventricular hemorrhage (IVH); Grade 3 or 4 IVH; or pulmonary, gastrointestinal, or cutaneous bleeding. CONCLUSIONS: The use of PLT mass-based NICU transfusion guidelines was associated with fewer PLT transfusions and no recognized increase in hemorrhagic problems.

Effects of instituting the "BEST Program" (Breast Milk Early Saves Trouble) in a level III NICU.

A program is developed to increase the use of breast milk during the first week, for patients<2 kg birth weight. This is termed the "BEST program," using the acronym "Breast milk Early Saves Trouble." An analysis of feeding practices and outcomes during the 12 months before versus the 12 months after implementing this program was conducted. Demographic features of the patients in the 2 periods were similar. In the "Before Intervention" period, 33% received human milk exclusively in the first 7 feeding days; 50% in the "Intervention" period (P=.009). In the Before Intervention period, 74% received some breast milk; 82% in the Intervention group (P=.046). Banked human milk increased from 2% to 33% of patients (P>or=.001), and a trend was seen in more mothers who initially wanted to bottle-feed but subsequently changed to breastfeeding (P=.08). A trend was also seen in more infants discharged home breastfeeding (P=.09).

Fatal bowel necrosis in two polycytemic term neonates.

We observed 2 term neonates with polycythemia (hematocrit > 70%) who developed necrotizing entercolitis (NEC) in the first week after birth. Both required laparotomy, after which the surgeons stated that the entire bowel appeared nonviable. Both had been fed formula exclusively and both received full feedings (> or = 160 mL/kg/day) by 72 hr after birth.

Implementing feeding guidelines for NICU patients<2000 g results in less variability in nutrition outcomes.

BACKGROUND: We devised a consistent approach to instituting and advancing enteral nutrition among neonatal intensive care unit (NICU) patients<2000 g birth weight. We then assessed variability in feeding-related outcomes during a period before (period 1) vs after (period 2) implementing these guidelines. METHODS: Using data from period 1 vs period 2, we statistically compared the equivalence of variance, focusing on certain feeding-related outcomes. Specific outcomes we chose to examine were (1) day of life when the first enteral feedings were given, (2) number of days during the entire hospitalization when no feedings were given, (3) number of days parenteral nutrition (PN) was administered, and (4) day of life when feedings of 80 mL/k/d and 100 kcal/k/d enteral were achieved. RESULTS: Fifty-eight patients<2000 g were admitted to the NICU in period 1, of which 56 survived to discharge home. In period 2, 68 patients<2000 g were admitted and 66 survived to discharge. Demographic features of the patients in periods 1 and 2 did not differ. In both periods, feedings were begun on a median of day 1. However, in period 1 the range was from day 0 to day 24, and in period 2, the range was from day 0 to day 6 (equivalence of variance p<.001). After feedings were initiated, they were withheld for a median of 2 days (range, 0-23) during the remainder of the hospitalization in period 1 vs a median of 1 day (range, 0-12) in period 2 (p<.001). During period 1, PN was used for a median of 10 days (range, 0-72) vs 7 (range, 0-47) in period 2 (p=.001). During period 1, more variability occurred in the day of life when 80 mL/k/d and 100 kcal/k/d were achieved (both p<.001). No differences were seen in necrotizing enterocolitis, intestinal perforation, mortality, or length of hospital stay. CONCLUSIONS: Implementing feeding guidelines was associated with significantly less variability in feeding-related outcomes. We speculate that this is a reflection of better feeding tolerance, which resulted from a more consistent approach to initiating and advancing enteral feedings.

Measuring End-Tidal Carbon Monoxide of Jaundiced Neonates in the Birth Hospital to Identify Those with Hemolysis.

BACKGROUND: End-tidal breath carbon monoxide (ETCOc) levels correlate with catabolism of heme, but until recently, this measurement was not readily available for application to neonatology practice. OBJECTIVES: We performed a prospective, multihospital, test-of-concept study where ETCOc was measured during the birth hospitalization of neonates with a total bilirubin (TB) value >75th percentile on the Bhutani bilirubin nomogram. This was done to test the feasibility and ease of use of this new device. METHODS: Neonates with an elevated ETCOc (with a >95th percentile reference interval previously established) were labeled as having 'hemolytic jaundice'. We recommended a follow-up TB check <24 h after hospital discharge to these families. RESULTS: One hundred and fifteen neonates were eligible for the study, the parents of 103 provided consent, and measurements were obtained for 100. Sixty-three had normal and 37 had elevated ETCOc values. By means of a direct antiglobulin test (DAT; Coombs), 11 of these 37 were found positive for ABO hemolytic disease; the remaining 26 had other etiologies. Thirty-six of the 37 with an elevated ETCOc had repeat TB monitoring <24 h after discharge home. None of the 100 were rehospitalized for jaundice treatment compared with a rate of 2.99 rehospitalizations per 100 control neonates who had a TB value >75th percentile (p = 0.079). CONCLUSION: ETCOc measurement is a feasible means of assessing hemolysis in jaundiced neonates during the birth hospitalization. When hemolysis is identified, parents are likely to comply with instructions to bring the infant for a TB checkup <24 h after discharge home.

Single-dose darbepoetin administration to anemic preterm neonates.

OBJECTIVE: Darbepoetin is longer acting and more potent than recombinant erythropoietin (rEpo). In certain situations, preterm neonates might benefit from rEpo, and for such patients darbepoetin would require fewer doses at a lower cost. However, the proper dose and dosing interval have not been established. STUDY DESIGN: We performed a prospective trial in two level III Neonatal Intensive Care Units. Patients <32 weeks gestation at birth, with a birth weight (BW) <1500 g, were eligible for participation if they were >21-days-old and had a hemoglobin (Hgb) concentration

Cognitive outcomes of preterm infants randomized to darbepoetin, erythropoietin, or placebo.

BACKGROUND: We previously reported decreased transfusions and donor exposures in preterm infants randomized to Darbepoetin (Darbe) or erythropoietin (Epo) compared with placebo. As these erythropoiesis-stimulating agents (ESAs) have shown promise as neuroprotective agents, we hypothesized improved neurodevelopmental outcomes at 18 to 22 months among infants randomized to receive ESAs. METHODS: We performed a randomized, masked, multicenter study comparing Darbe (10 µg/kg, 1×/week subcutaneously), Epo (400 U/kg, 3×/week subcutaneously), and placebo (sham dosing 3×/week) given through 35 weeks' postconceptual age, with transfusions administered according to a standardized protocol. Surviving infants were evaluated at 18 to 22 months' corrected age using the Bayley Scales of Infant Development III. The primary outcome was composite cognitive score. Assessments of object permanence, anthropometrics, cerebral palsy, vision, and hearing were performed. RESULTS: Of the original 102 infants (946 ± 196 g, 27.7 ± 1.8 weeks' gestation), 80 (29 Epo, 27 Darbe, 24 placebo) returned for follow-up. The 3 groups were comparable for age at testing, birth weight, and gestational age. After adjustment for gender, analysis of covariance revealed significantly higher cognitive scores among Darbe (96.2 ± 7.3; mean ± SD) and Epo recipients (97.9 ± 14.3) compared with placebo recipients (88.7 ± 13.5; P = .01 vs ESA recipients) as was object permanence (P = .05). No ESA recipients had cerebral palsy, compared with 5 in the placebo group (P < .001). No differences among groups were found in visual or hearing impairment. CONCLUSIONS: Infants randomized to receive ESAs had better cognitive outcomes, compared with placebo recipients, at 18 to 22 months. Darbe and Epo may prove beneficial in improving long-term cognitive outcomes of preterm infants.

Necrotizing enterocolitis in term infants.

This article is an overview of NEC in term neonates and also summarizes data from 52 cases within Intermountain Healthcare during the last 11 years. In all 52, NEC occurred among neonates already admitted to a neonatal intensive care unit for some other reason; thus, NEC invariably developed as a complication of treatment, not as a primary diagnosis. The authors speculate that the incidence of term NEC can be reduced by identifying neonatal intensive care unit patients at risk for NEC and applying appropriate-volume human milk feeding programs for these patients.

A randomized, masked, placebo-controlled study of darbepoetin alfa in preterm infants.

BACKGROUND: A novel erythropoiesis stimulating agent (ESA), darbepoetin alfa (Darbe), increases hematocrit in anemic adults when administered every 1 to 3 weeks. Weekly Darbe dosing has not been evaluated in preterm infants. We hypothesized that infants would respond to Darbe by decreasing transfusion needs compared with placebo, with less-frequent dosing than erythropoietin (Epo). METHODS: Preterm infants 500 to 1250 g birth weight and ≤48 hours of age were randomized to Darbe (10 µg/kg, 1 time per week subcutaneously), Epo (400 U/kg, 3 times per week subcutaneously) or placebo (sham dosing) through 35 weeks' gestation. All received supplemental iron, folate, and vitamin E, and were transfused according to protocol. Transfusions (primary outcome), complete blood counts, absolute reticulocyte counts (ARCs), phlebotomy losses, and adverse events were recorded. RESULTS: A total of 102 infants (946 ± 196 g, 27.7 ± 1.8 weeks' gestation, 51 ± 25 hours of age at first dose) were enrolled. Infants in the Darbe and Epo groups received significantly fewer transfusions (P = .015) and were exposed to fewer donors (P = .044) than the placebo group (Darbe: 1.2 ± 2.4 transfusions and 0.7 ± 1.2 donors per infant; Epo: 1.2 ± 1.6 transfusions and 0.8 ± 1.0 donors per infant; placebo: 2.4 ± 2.9 transfusions and 1.2 ± 1.3 donors per infant). Hematocrit and ARC were higher in the Darbe and Epo groups compared with placebo (P = .001, Darbe and Epo versus placebo for both hematocrit and ARCs). Morbidities were similar among groups, including the incidence of retinopathy of prematurity. CONCLUSIONS: Infants receiving Darbe or Epo received fewer transfusions and fewer donor exposures, and fewer injections were given to Darbe recipients. Darbepoetin and Epo successfully serve as adjuncts to transfusions in maintaining red cell mass in preterm infants.

Effect of therapeutic hypothermia in neonates with hypoxic-ischemic encephalopathy on platelet function.

OBJECTIVE: Platelet dysfunction has been described in adults during hypothermia. We sought to determine whether it also occurs in neonates. METHODS: We measured bleeding times and PFA-100 (platelet function analyzer) times in 10 neonates with hypoxic-ischemic encephalopathy during and after head cooling. RESULTS: The 10 neonates were born at 38.2 ± 1.6 weeks' gestation (mean ± SD), with birth weights of 3,222 ± 746 g, pH 6.79 ± 0.17, base excess -25 ± 8, and 10-min Apgar 4 ± 2. Cooling was instituted 111 min (range: 66-180) after birth and continued 72 h. Bleeding times before cooling averaged 170 s (95% CI: 100-240). These lengthened during hypothermia, averaging 410 s (p = 0.000) and shortened after rewarming (p = 0.000). PFA-100 times were similar: prolongation during cooling and normalization after rewarming. Six neonates had clinical bleeding problems in the first 24 h of cooling, but were managed successfully, and no intracranial hemorrhages were identified. CONCLUSION: Defective platelet plug formation occurs during therapeutic hypothermia of neonates in a manner similar to that described in adults. Platelet impairment can be severe, but rapidly improves after rewarming.