Dennis E. Mayock

A Phase I/II Trial of High-Dose Erythropoietin in Extremely Low Birth Weight Infants: Pharmacokinetics and Safety

OBJECTIVES. High-dose recombinant erythropoietin is neuroprotective in animal models of neonatal brain injury. Extremely low birth weight infants are at high risk for brain injury and neurodevelopmental problems and might benefit from recombinant erythropoietin. We designed a phase I/II trial to test the safety and determine the pharmacokinetics of high-dose recombinant erythropoietin in extremely low birth weight infants. METHODS. In a prospective, dose-escalation, open-label trial, we compared 30 infants who were treated with high-dose recombinant erythropoietin with 30 concurrent control subjects. Eligible infants were <24 hours old, ≤1000 g birth weight, and ≤28 weeks of gestation and had an umbilical artery catheter in place. Each infant received 3 intravenous doses of 500, 1000, or 2500 U/kg at 24-hour intervals beginning on day 1 of age. Blood samples were collected at scheduled intervals to determine recombinant erythropoietin pharmacokinetics. Safety parameters were also evaluated. In the concurrent control group, only clinical data were collected. RESULTS. Mean erythropoietin concentrations 30 minutes after recombinant erythropoietin infusion were 5973 ± 266, 12291 ± 403, and 34197 ± 1641 mU/mL after 500, 1000, or 2500 U/kg, respectively. High-dose recombinant erythropoietin followed nonlinear pharmacokinetics as a result of decreasing clearance from the lowest dosage (17.3 mL/hour per kg for 500 U/kg) to the highest dosage (8.2 mL/hour per kg for 2500 U/kg). Steady state was achieved within 24 to 48 hours. Both 1000 and 2500 U/kg recombinant erythropoietin produced peak serum erythropoietin concentrations that were comparable to neuroprotective concentrations that previously were seen in experimental animals. No excess adverse events occurred in the recombinant erythropoietin–treated infants compared with control infants. CONCLUSIONS. Early high-dose recombinant erythropoietin is well tolerated by extremely low birth weight infants, causing no excess morbidity or mortality. Recombinant erythropoietin dosages of 1000 and 2500 U/kg achieved neuroprotective serum levels.

Erythropoietin for Neuroprotection in Neonatal Encephalopathy: Safety and Pharmacokinetics

OBJECTIVE: To determine the safety and pharmacokinetics of erythropoietin (Epo) given in conjunction with hypothermia for hypoxic-ischemic encephalopathy (HIE). We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies (ie, maximum concentration = 6000–10 000 U/L; area under the curve = 117 000–140 000 U*h/L). METHODS: In this multicenter, open-label, dose-escalation, phase I study, we enrolled 24 newborns undergoing hypothermia for HIE. All patients had decreased consciousness and acidosis (pH < 7.00 or base deficit ≥ 12), 10-minute Apgar score ≤ 5, or ongoing resuscitation at 10 minutes. Patients received 1 of 4 Epo doses intravenously: 250 (N = 3), 500 (N = 6), 1000 (N = 7), or 2500 U/kg per dose (N = 8). We gave up to 6 doses every 48 hours starting at <24 hours of age and performed pharmacokinetic and safety analyses. RESULTS: Patients received mean 4.8 ± 1.2 Epo doses. Although Epo followed nonlinear pharmacokinetics, excessive accumulation did not occur during multiple dosing. At 500, 1000, and 2500 U/kg Epo, half-life was 7.2, 15.0, and 18.7 hours; maximum concentration was 7046, 13 780, and 33 316 U/L, and total Epo exposure (area under the curve) was 50 306, 131 054, and 328 002 U*h/L, respectively. Drug clearance at a given dose was slower than reported in uncooled preterm infants. No deaths or serious adverse effects were seen. CONCLUSIONS: Epo 1000 U/kg per dose intravenously given in conjunction with hypothermia is well tolerated and produces plasma concentrations that are neuroprotective in animals. A large efficacy trial is needed to determine whether Epo add-on therapy further improves outcome in infants undergoing hypothermia for HIE.

Effects of Transfusions in Extremely Low Birth Weight Infants: A Retrospective Study

OBJECTIVES To determine the risks and benefits associated with the transfusion of packed red blood cells (PRBCs) in extremely low birth weight (ELBW) infants. We hypothesized that when ELBW infants underwent transfusion with the University of Washington Neonatal Intensive Care Unit (NICU) 2006 guidelines, no clinical benefit would be discernible. STUDY DESIGN We conducted a retrospective chart review of all ELBW infants admitted to the NICU in 2006. Information on weight gain, apnea, heart rate, and respiratory support was collected for 2 days preceding, the day of, and 3 days after PRBC transfusion. The incidence, timing, and severity of complications of prematurity were documented. RESULTS Of the 60 ELBW infants admitted to the NICU in 2006, 78% received PRBC transfusions. Transfusions were not associated with improved weight gain, apnea, or ventilatory/oxygen needs. However, they were associated with increased risk of bronchopulmonary dysplasia, necrotizing enterocolitis, and diuretic use (P < .05). Transfusions correlated with phlebotomy losses, gestational age, and birth weight. No association was found between transfusions and sepsis, retinopathy of prematurity, or erythropoietin use. CONCLUSIONS When our 2006 PRBC transfusion guidelines were used, no identifiable clinical benefits were identified, but increased complications of prematurity were noted. New, more restrictive guidelines were developed as a result of this study.

Cocaine and the use of alcohol and other drugs during pregnancy

Recent reports of adverse pregnancy outcomes associated with prenatal cocaine exposure have raised questions about the actual numbers of infants who are exposed to cocaine in utero. Whereas toxicologic urine screens obtained at delivery can detect cocaine use in the preceding few days, they fail to yield a comprehensive picture of use during and immediately before pregnancy. According to postpartum self-report, 15% of a teaching hospital sample and 3% of a private hospital sample of mothers had used cocaine during pregnancy or in the previous month (total = 876). Rates at the teaching hospital reflect a fifteenfold increase over the past 12-year period, when compared with previously obtained data. Cocaine users were significantly more likely to report that they drank alcohol, smoked cigarettes, and took other illicit drugs during pregnancy than women who denied using cocaine. Mothers at highest risk for cocaine use were those who were black (20%), were single-separated-divorced (24% to 33%), and had less than a high school education (21%).

High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial

OBJECTIVE: To determine if multiple doses of erythropoietin (Epo) administered with hypothermia improve neuroradiographic and short-term outcomes of newborns with hypoxic-ischemic encephalopathy. METHODS: In a phase II double-blinded, placebo-controlled trial, we randomized newborns to receive Epo (1000 U/kg intravenously; n = 24) or placebo (n = 26) at 1, 2, 3, 5, and 7 days of age. All infants had moderate/severe encephalopathy; perinatal depression (10 minute Apgar <5, pH <7.00 or base deficit ≥15, or resuscitation at 10 minutes); and received hypothermia. Primary outcome was neurodevelopment at 12 months assessed by the Alberta Infant Motor Scale and Warner Initial Developmental Evaluation. Two independent observers rated MRI brain injury severity by using an established scoring system. RESULTS: The mean age at first study drug was 16.5 hours (SD, 5.9). Neonatal deaths did not significantly differ between Epo and placebo groups (8% vs 19%, P = .42). Brain MRI at mean 5.1 days (SD, 2.3) showed a lower global brain injury score in Epo-treated infants (median, 2 vs 11, P = .01). Moderate/severe brain injury (4% vs 44%, P = .002), subcortical (30% vs 68%, P = .02), and cerebellar injury (0% vs 20%, P = .05) were less frequent in the Epo than placebo group. At mean age 12.7 months (SD, 0.9), motor performance in Epo-treated (n = 21) versus placebo-treated (n = 20) infants were as follows: Alberta Infant Motor Scale (53.2 vs 42.8, P = .03); Warner Initial Developmental Evaluation (28.6 vs 23.8, P = .05). CONCLUSIONS: High doses of Epo given with hypothermia for hypoxic-ischemic encephalopathy may result in less MRI brain injury and improved 1-year motor function.

Outcomes of extremely low birth weight infants given early high-dose erythropoietin

Objective:To evaluate long-term outcomes of 60 extremely low birth weight (ELBW) infants treated with or without three injections of high-dose erythropoietin (Epo).Study Design:A retrospective analysis of anthropometric and neurodevelopmental outcome data comparing 30 ELBW infants enrolled in a phase I/II study examining the pharmacokinetics of high-dose Epo (500, 1000 and 2500 U/kg × 3 doses) administered to 30 concurrent controls.Result:Birth characteristics and growth from 4 to 36 months were similar for untreated and Epo-treated patients. Multiple linear regression analysis of neurodevelopmental follow-up scores from 17/25 Epo-treated and 18/26 control infants identified that Epo correlated with improvement of cognitive (R=0.22, P=0.044) and motor (R=0.15, P=0.026) scores. No negative long-term effects of Epo treatment were evident.Conclusion:Retrospective analysis of the only available long-term follow-up data from ELBW infants given high-dose Epo treatment suggests that Epo treatment is safe and correlates with modest improvement of neurodevelopmental outcomes.

HYPOXIC VENTILATORY RESPONSE IN THE NEWBORN MONKEY

Summary: The hypoxic ventilatory response was determined in twelve unanesthetized newborn monkeys, Macaca nemestrina, Measurements of blood gases and ventilation were made during normoxia and hypoxia at the postnatal ages of 2, 7, and 21 days, Data were collected during quiet sleep. The infant monkey demonstrated a definite but transient hyperventilatory response following exposure to a Fi02 of 0.12 or 0.14 on the second day of life. Baseline ventilation increased 15% (Fi02 = 0.14) and 28% (Fi02 0.12) after 1 minute of hypoxia; p. 0.05 in both instanes. Return to baseline ventilation occurred between 3 and 5 minutes after hypoxic stimulus onset. This biphasic response to hypoxia converted to an adult-like, sustained hyperventilation during the ensuing three weeks of postnatal maturation. Episodes of periodic breathing and/or apnea were noted to occur during the induced hypoxemia. These data demonstrate that the infant subhuman primate has a ventilatory response to hypoxia that is similar to that of the human infant and is an excellent model for the study of the maturation of the respiratory control system.Speculation: The mechanisnis involved i n the unique neonatal response to hypoxia have not been elucidated. In light of current evidence, direct suppression of respiratory center output by an inhibitor seems the most likely possibility.However, adverse alterations in pulmonary mechanics brought on by the hypoxia itself or fatigue of the carotid body remain viable alternatives.

Erythropoietin and hypothermia for hypoxic-ischemic encephalopathy.

BACKGROUND Erythropoietin is neuroprotective in animal models of neonatal hypoxic-ischemic encephalopathy. We previously reported a phase I safety and pharmacokinetic study of erythropoietin in neonates. This article presents the neurodevelopmental follow-up of infants who were enrolled in the phase I clinical trial. METHODS We enrolled 24 newborns with hypoxic-ischemic encephalopathy in a dose-escalation study. Patients received up to six doses of erythropoietin in addition to hypothermia. All infants underwent neonatal brain magnetic resonance imaging (MRI) reviewed by a single neuroradiologist. Moderate-to-severe neurodevelopmental disability was defined as cerebral palsy with Gross Motor Function Classification System levels III-V or cognitive impairment based on Bayley Scales of Infant Development II mental developmental index or Bayley III cognitive composite score. RESULTS Outcomes were available for 22 of 24 infants, at mean age 22 months (range, 8-34 months). There were no deaths. Eight (36%) had moderate-to-severe brain injury on neonatal MRI. Moderate-to-severe disability occurred in one child (4.5%), in the setting of moderate-to-severe basal ganglia and/or thalamic injury. Seven infants with moderate-to-severe watershed injury exhibited the following outcomes: normal (three), mild language delay (two), mild hemiplegic cerebral palsy (one), and epilepsy (one). All 11 patients with a normal brain MRI had a normal outcome. CONCLUSIONS This study is the first to describe neurodevelopmental outcomes in infants who received high doses of erythropoietin and hypothermia during the neonatal period. The findings suggest that future studies are warranted to assess the efficacy of this new potential neuroprotective therapy.

Bronchopulmonary dysplasia: The need for epidemiologic studies

IT IS COMMONLY STATED that there is an increasing incidence of chronic pulmonary disease occurring in newborn infants within neonata l intensive care units. Substantive information on incidence, either past or present, is difficult to obtain since there has been no agreement on terminology, clinical definition, nor on an appropriate denominator for comparative studies. There is general agreement that bronehopulmonary dysplasia is a major contributor to prolot~ged hospitalization with high economic and emotional costs.

Postnatal Changes in Transdiaphragmatic Pressure in Piglets

ABSTRACT. We examined diaphragmatic force output in 25 anesthetized piglets ranging in postnatal age from 4 to 21 days (weight 1.3–4.0 kg) in order to determine whether the diaphragm produces greater force output with maturation for a given level of neural input. Transdiaphragmatic pressure (Pdi) served as our index of diaphragmatic force output and was measured during “supramaximal‘’ transvenous phrenic nerve stimulation at 100 Hz in order to control neural drive. Mean Pdi was 53 ± 17 cm H2O and ranged from a minimum of 29 cm H2O to a maximum of 83 cm H2O. A significant positive correlation between Pdi and postnatal age was observed (r = 0.79, p < 0.001). In addition, positive correlations were noted between Pdi and total body weight (r = 0.73, p < 0.001) and Pdi and diaphragmatic wet weight (r = 0.77, p < 0.001). The voltage needed to stimulate the phrenic nerves “supramaximally‘’ did not correlate with postnatal age (r = 0.02, p = 0.16). We conclude that a developmental pattern of increasing Pdi with increasing postnatal age, total body weight, and diaphragmatic wet weight exists in piglets and occurs within the context of a controlled level of neural drive.