Implications of an Elevated Nucleated Red Blood Cell Count in Neonates with Moderate to Severe Hypoxic-Ischemic Encephalopathy.

OBJECTIVES: To investigate associations between nucleated red blood cell (NRBC) count in neonates with hypoxic-ischemic encephalopathy (HIE), acute perinatal sentinel events, and neurodevelopmental outcomes and to examine the mechanism(s) causing elevated counts. STUDY DESIGN: We included newborn infants with HIE treated with therapeutic hypothermia with ≥3 NRBC counts during their neonatal intensive care unit hospitalization and neurodevelopmental evaluations at a mean of 24 ± 6 months. RESULTS: Ninety-five of 152 infants who met our study criteria (63%) had a normal NRBC count after birth, defined as ≤95th percentile of the upper reference interval, and the other 57 (37%) had an elevated count. Documented sentinel events during labor resulting in emergency delivery (eg, acute abruption) (n = 79) were associated with a normal NRBC count (OR, 257; 95% CI, 33-1988). Of the 152 infants evaluated, 134 (88%) survived to discharge. The odds of surviving were 3-fold greater (OR, 3.0; 95% CI, 1.1-8.3) when the first NRBC count was normal than when it was elevated. Normal counts were moderately predictive of infants without neurodevelopmental impairment at a 2-year evaluation (P < .001). NRBC half-life was longer in infants with an elevated NRBC count compared with those with a normal count (60 hours vs 39 hours; P < .01). CONCLUSIONS: In infants with HIE, a normal NRBC count after birth was associated with acute intrapartum events necessitating emergent delivery. Normal counts were modestly predictive of a better prognosis. We speculate that the elevated NRBC counts at birth resulted from hypoxia that occurred earlier or chronically. Impaired clearance of NRBCs from the blood might be one mechanistic explanation for the high counts.

Darbepoetin administration to neonates undergoing cooling for encephalopathy: a safety and pharmacokinetic trial.

BACKGROUND: Despite therapeutic hypothermia, neonates with encephalopathy (NE) have high rates of death or disability. Darbepoetin alfa (Darbe) has comparable biological activity to erythropoietin, but has extended circulating half-life (t(1/2)). Our aim was to determine Darbe safety and pharmacokinetics as adjunctive therapy to hypothermia. STUDY DESIGN: Thirty infants (n = 10/arm) ≥36 wk gestation undergoing therapeutic hypothermia for NE were randomized to receive placebo, Darbe low dose (2 µg/kg), or high dose (10 µg/kg) given intravenously within 12 h of birth (first dose/hypothermia condition) and at 7 d (second dose/normothermia condition). Adverse events were documented for 1 mo. Serum samples were obtained to characterize Darbe pharmacokinetics. RESULTS: Adverse events (hypotension, altered liver and renal function, seizures, and death) were similar to placebo and historical controls. Following the first Darbe dose at 2 and 10 µg/kg, t(1/2) was 24 and 32 h, and the area under the curve (AUC(inf)) was 26,555 and 180,886 h*mU/ml*, respectively. In addition, clearance was not significantly different between the doses (0.05 and 0.04 l/h). At 7 d, t(1/2) was 26 and 35 h, and AUC(inf) was 10,790 and 56,233 h*mU/ml*, respectively (*P < 0.01). CONCLUSION: Darbe combined with hypothermia has similar safety profile to placebo with pharmacokinetics sufficient for weekly administration.

Serum ferritin values in neonates <29 weeks' gestation are highly variable and do not correlate with reticulocyte hemoglobin content.

OBJECTIVES: To compare serum ferritin and RET-He values among extremely low gestational age neonates ELGANs with other markers of iron-deficient erythropoiesis. STUDY DESIGN: This is a secondary analysis of the NICHD Darbepoetin Trial. Study data from placebo recipients who had a serum ferritin, a RET-He, and a mean corpuscular volume (MCV) measurement within a 24-hour period were analyzed for correlation. RESULTS: Mixed linear regression models showed no association between ferritin and RET-He at both early (ß = 0.0016, p = 0.40) and late (ß = -0.0001, p = 0.96) time points. Positive associations were observed between RET-He and MCV at baseline, early, and late time points (p < 0.01, =0.01, <0.001, respectively), while ferritin was not associated with MCV at any time point. CONCLUSIONS: Our study shows that RET-He is better correlated with MCV as a marker of iron-limited erythropoiesis than ferritin. The results suggest that ferritin is limited as a marker of iron sufficiency in premature infants. STUDY IDENTIFICATION: FDA IND Number 100138; ClinicalTrials.gov number NCT03169881; NRN ID number NICHD-NRN-0058 (Darbe).

Blanket temperature during therapeutic hypothermia and outcomes in hypoxic ischemic encephalopathy.

OBJECTIVE: Determine whether blanket temperatures during therapeutic hypothermia (TH) are associated with 18-22 month outcomes for infants with hypoxic ischemic encephalopathy (HIE). STUDY DESIGN: Retrospective cohort study of 181 infants with HIE who received TH in two randomized trials within the Neonatal Research Network. We defined summative blanket temperature constructs and evaluated for association with a primary composite outcome of death or moderate/ severe disability at 18-22 months. RESULTS: Each 0.5 °C above 33.5 °C in the mean of the highest quartile blanket temperature was associated with a 52% increase in the adjusted odds of death/ disability (aOR 1.52, 95% CI 1.09-2.11). Having >8 consecutive blanket temperatures above 33.5 °C rendered an aOR of death/disability of 5.04 in the first 24 h (95% CI 1.54-16.6) and 6.92 in the first 48 h (95% CI 2.20-21.8) of TH. CONCLUSIONS: Higher blanket temperature during TH may be an early, clinically useful biomarker of HIE outcome.

Population Pharmacokinetics of Darbepoetin Alfa in Conjunction with Hypothermia for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy.

AIM: The aim of this study was to determine the population pharmacokinetics of darbepoetin alfa in hypothermic neonates with hypoxic-ischemic encephalopathy treated with hypothermia. METHODS: Neonates ≥36 weeks gestation and <12 h postpartum with moderate to severe hypoxic-ischemic encephalopathy who were undergoing hypothermia treatment were recruited in this randomized, multicenter, investigational, new drug pharmacokinetic study. Two intravenous darbepoetin alfa treatment groups were evaluated: 2 and 10 µg/kg. Serum erythropoietin concentrations were measured using an enzyme-linked immunosorbent assay. Monolix 4.3.1 was used to estimate darbepoetin alfa clearance and volume of distribution. Covariates tested included: birthweight, gestational age, postnatal age, postmenstrual age, sex, Sarnat score, and study site. RESULTS: Darbepoetin alfa pharmacokinetics were well described by a one-compartment model with exponential error. Clearance and the volume of distribution were scaled by birthweight (centered on the mean) a priori. Additionally, gestational age (also centered on the mean) significantly affected darbepoetin alfa clearance. Clearance and volume of distribution were estimated as 0.0465 L/h (95% confidence interval 0.0392-0.0537) and 1.58 L (95% confidence interval 1.29-1.87), respectively. CONCLUSIONS: A one-compartment model successfully described the pharmacokinetics of darbepoetin alfa among hypothermic neonates treated for hypoxic-ischemic encephalopathy. Clearance decreased with increasing gestational age.

Intrauterine growth restriction impacts tolerance to total parenteral nutrition in extremely low birth weight infants.

BACKGROUND: Hepatobiliary dysfunction is well recognized as a complication of long-term total parenteral nutrition (TPN). Because intrauterine growth restriction (IUGR) alters a number of metabolic and physiologic variables in the fetus that probably affect the hepatocyte function and tolerance to feedings in the IUGR extremely low birth weight (ELBW), we hypothesized that this group of babies would have an increased incidence of TPN-associated cholestasis and chronic liver failure. METHODS: We performed a review of all ELBW infants (birth weight <1000 g) that received TPN for >7 days. RESULTS: Among 1768 infants admitted to the neonatal intensive care unit there were 103 ELBW who received TPN >7 days, 38 (37%) of them developed TPN cholestasis. Among 69 appropriate for gestational age (AGA)-ELBW infants, 19 (27%) developed cholestasis compared to 19/34 small for gestational age (SGA)-ELBW infants (56%) (p<0.0009). Maximum direct bilirubin values and days on TPN were similar in both groups. SGA-ELBW infants had an increased incidence and earlier onset of cholestasis when compared to AGA-ELBW patients. Liver biopsies and/or autopsies of infants that developed liver failure (four AGA/four SGA) showed extensive sinusoidal/portal fibrosis compatible with "TPN lesion". In the other 30 cases, liver function eventually returned to normal after TPN discontinuation. CONCLUSIONS: When compared, SGA-ELBW infants who received TPN >7 days, despite being more mature than AGA-ELBW infants, have an increased risk for TPN cholestasis and developed this complication earlier in life. However, the incidence of chronic liver failure was not different in these two groups.

The use of topical nitroglycerin ointment to treat peripheral tissue ischemia secondary to arterial line complications in neonates.

Catheterization of the aorta through the umbilical artery and/or of peripheral arteries in neonates may be accompanied by a number of complications, of which thrombotic phenomena and peripheral vasospasm are the most common. Two neonates with peripheral ischemia caused by vasospasm from indwelling umbilical artery catheterization and one infant with left hand ischemia due to a left radial artery line were successfully treated with 2% nitroglycerin ointment. No adverse effects were noted.

Different doses of dopamine have heterogeneous effects on cerebral hemodynamics and dopamine receptors in young rabbits as measured with near infrared spectroscopy.

BACKGROUND: Fluctuations in cerebral blood volume and cerebral oxygenation may be important in the pathogenesis of intraventricular hemorrhage and hypoxic-ischemic brain injury in the neonate. The cerebral hemodynamic response to dopamine infusion in premature infants is not well established. The newborn rabbit, a rather immature species at birth, is a suitable model for monitoring the physiological changes of the cerebral circulation. METHODS: The effect of dopamine upon cerebral hemodynamics and basal ganglia dopaminergic receptors were studied using four different dopamine doses. RESULTS: No significant changes in near infrared spectroscopy (NIRS) parameters were observed in the animals that received 0.5 (n = 5) and 1 microg/kg/min (n = 4) of dopamine intravenously. In contrast, in those animals that received dopamine at 5 microg/kg/min (n = 7) and 50 microg/kg/min (n = 7), there was a significant decrease in oxygenated hemoglobin. Moreover, this was accompanied by a significant increase in deoxygenated hemoglobin soon after drug infusion. Cerebral blood volume was increased in the group that received 5 microg/kg/min, but significantly decreased in the group that received 50 microg/kg/min. In both groups NIRS parameters returned to baseline values soon after stopping dopamine infusion. CONCLUSION: Despite evidence of a physiological response, we found no difference in the distribution of dopamine receptors between experimental and control animals. We therefore speculate that dopamine has an effect on the cerebrovasculature that could be mediated by factors other than changes in the basal ganglia dopamine receptors.

Cerebrovascular response in small preterm infants during routine nursery gavage feedings.

Although gavage feedings are considered a standard of care, they are often accompanied by hemodynamic changes that may have important effects on the cerebral circulation. In 23 premature infants receiving intermittent bolus gavage feeds, changes in cerebral hemodynamics and oxygenation were studied using near-infrared spectroscopy. Orogastric tube insertion resulted in an increased cerebral blood volume in 73% of the infants and in an increase in reduced hemoglobin and in cytochrome AA(3) oxygenase in approximately 66% of the patients. Within 10 min of initiating a gavage feed, cerebral blood volume, oxygenated hemoglobin, reduced hemoglobin, and cytochrome AA(3) oxygenase decreased from baseline in about 60% of the infants. Towards the end of the study, during the postfeeding period, cytochrome AA(3) oxygenase and oxygenated hemoglobin increased in 60%, while reduced hemoglobin decreased in 78% of the infants.