David J. Durand

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.

Response of premature infants with severe respiratory failure to inhaled nitric oxide

Elevated pulmonary vascular resistance is seen in premature infants with severe respiratory distress syndrome (RDS). Inhaled nitric oxide (NO) has been shown to decrease pulmonary vascular resistance and to improve oxygenation in some patients with respiratory failure. The purpose of this study was to determine whether premature infants with severe RDS would respond to inhaled NO with an improvement in oxygenation. Eleven premature infants (mean gestational age 29.8 weeks) with severe respiratory failure caused by RDS were treated with NO in four concentrations [1, 5, 10, 20 parts per million (ppm) NO] and with placebo (0 ppm NO). Arterial blood gas measurements were drawn immediately before and at the end of each of the 15‐minute treatments and were used to determine the arterial/alveolar oxygen ratio (Pao2/PAo2).

Effects of a protein-free, synthetic surfactant on survival and pulmonary function in preterm lambs

We have created a totally synthetic, protein-free surfactant (Exosurf) composed of dipalmitoylphosphatidylcholine, hexadecanol, and tyloxapol. We studied the effects of endotracheal instillation of Exosurf on survival and pulmonary function of preterm lambs delivered at 131 to 133 days gestation (term 148 days). Exosurf treatment was compared with instillation of surface-active material prepared from lung lavages of adult sheep and with no instillation. Lambs were delivered by cesarean section, paralyzed, and mechanically ventilated. The Exosurf group survived longer (80% alive at 11 hours) than did the no instillation group (30% alive at 11 hours) (P less than 0.05). There were no statistically significant differences between the Exosurf and sheep surfactant groups. We conclude that Exosurf, a synthetic surfactant, produces significant improvement in survival and pulmonary function in preterm lambs.

Association between prenatal cocaine exposure and sudden infant death syndrome

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Prospective evaluation of postnatal steroid administration: a 1-year experience from the California Perinatal Quality Care Collaborative.

OBJECTIVE. Postnatal steroids (PNSs) are used frequently to prevent or treat chronic lung disease (CLD) in the very low birth weight (VLBW) infant, and their use continues despite concerns regarding an increased incidence of longer-term neurodevelopmental abnormalities in such infants. More recently, there has been a suggestion that corticosteroids may be a useful alternative therapy for hypotension in VLBW infants, but there have been no prospective reports of such use for a current cohort of VLBW infants. METHODS. The California Perinatal Quality Care Collaborative (CPQCC) requested members to supplement their routine Vermont Oxford Network data collection with additional information on any VLBW infant treated during their hospital course with PNS, for any indication. The indication, actual agent used, total initial daily dose, age at treatment, type of respiratory support, mean airway pressure, fraction of inspired oxygen, and duration of first dosing were recorded. RESULTS. From April 2002 to March 2003 in California, 22 of the 62 CPQCC hospitals reported supplemental data, if applicable, from a cohort of 1401 VLBW infants (expanded data group [EDG]), representing 33.2% of the VLBW infants registered with the CPQCC during the 12-month period. PNSs for CLD were administered to 8.2% of all VLBW infants in 2003, 8.6% of infants in the 42 hospitals that did not submit supplemental data (routine data-set group, compared with 7.6% in EDG hospitals). Of the 1401 VLBW infants in the EDG, 19.3% received PNSs; 3.6% received PNSs for only CLD, 11.8% for only non-CLD indications, and 4.0% for both indications. At all birth weight categories, non-CLD use was significantly greater than CLD use. The most common non-CLD indication was hypotension, followed by extubation stridor, for which 36 (16.3%) infants were treated. For hypotension, medications used were hydrocortisone followed by dexamethasone. Infants treated with PNSs exclusively for hypotension had a significantly higher incidence of intraventricular hemorrhage, periventricular leukomalacia, and death when compared with infants treated only for CLD or those who did not receive PNSs. CONCLUSIONS. The common early use of hydrocortisone for hypotension and the high morbidity and mortality in children receiving such treatment has not been recognized previously and prospective trials evaluating the short- and long-term risk/benefit of such treatment are urgently required.

Oral theophylline and diuretics improve pulmonary mechanics in infants with bronchopulmonary dysplasia

We studied the effects of orally administered theophylline and diuretics (chlorothiazide and spironolactone) on pulmonary mechanics in 16 infants with bronchopulmonary dysplasia. Their gestational age (mean +/- SD) was 28.5 +/- 3.4 weeks, and postnatal age at the time of study 19.5 +/- 10.7 weeks. The infants were randomized to two groups. Group 1 received successively placebo, theophylline, and theophylline plus diuretics; Group 2 received theophylline, placebo, and placebo plus diuretics on successive 4-day periods. Pulmonary function was measured before beginning the study (baseline) and at the end of each 4-day period. No significant changes in pulmonary function were noted after treatment with placebo. After treatment with theophylline, dynamic compliance (Cdyn) increased from baseline (mean +/- SD) 0.075 +/- 0.017 to 0.091 +/- 0.028 mL/cm H2O/cm (P less than 0.01), airway resistance (Raw) decreased from 67.19 +/- 36.71 to 41.44 +/- 22.50 cm H2O/L/sec (P less than 0.001), maximal expiratory flow at functional residual capacity (VmaxFRC) increased from 0.261 +/- 0.240 to 0.357 +/- 0.299 thoracic gas volume (TGV)/sec (P less than 0.01), and time constant decreased from 0.312 +/- 0.224 to 0.275 +/- 0.247 sec (P less than 0.02). After treatment with combined placebo and diuretics, Cdyn increased to 0.103 +/- 0.023 mL/cm H2O/cm (P less than 0.05), Raw decreased to 31.76 +/- 24.90 cm H2O/L/sec (P less than 0.001), VmaxFRC increased to 0.638 +/- 0.595 TGV/sec (P less than 0.02), and time constant decreased to 0.180 +/- 0.141 sec (P less than 0.05). After treatment with combined theophylline and diuretics, Cdyn increased to 0.118 +/- 0.017 mL/cm H2O/cm (P less than 0.001), Raw decreased to 35.98 +/- 25.85 cm H2O/L/sec (P less than 0.02), VmaxFRC increased to 0.479 +/- 0.377 TGV/sec (P less than 0.02), and time constant decreased to 0.180 +/- 0.137 sec (P less than 0.01). We conclude that theophylline and diuretics have additive effects on the improvement of pulmonary function in infants with bronchopulmonary dysplasia.

Improving pulmonary function does not decrease oxygen consumption in infants with bronchopulmonary dysplasia

To determine whether the high oxygen consumption VO2 in infants with bronchopulmonary dysplasia (BPD) is caused by increased mechanical power of breathing, and if improvement of pulmonary mechanics would reduce mechanical power of breathing and VO2 we gave 16 infants with oxygen-dependent BPD at 19.5 +/- 10.7 (mean +/- SD) weeks of age placebo, theophylline, and orally administered diuretics or theophylline plus diuretics. Pulmonary mechanics, mechanical power of breathing, and VO2 were measured at the beginning and end of each study period. In the placebo group, all infants had elevated VO2 (7.4 +/- 1.4 mL/kg/min) and carbon dioxide production (6.6 +/- 1.2 mL/kg/min), increased airway resistance (59 +/- 30 cm H2O/L/sec), decreased dynamic compliance (0.073 +/- 0.024 mL/cm H2O/cm), increase respiratory rate (52 +/- 11), and increased mechanical power of breathing (2.22 +/- 1.05 kg.cm/kg/min). Treatment with theophylline, diuretics, and theophylline plus diuretics resulted in a significant improvement in pulmonary mechanics and mechanical power of breathing, but not in VO2. These results suggest that the increased VO2 in infants with BPD is not secondary to increased mechanical power of breathing.

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.

Clinical prediction models for bronchopulmonary dysplasia: a systematic review and external validation study

BackgroundBronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Very different models using clinical parameters at an early postnatal age to predict BPD have been developed with little extensive quantitative validation. The objective of this study is to review and validate clinical prediction models for BPD.MethodsWe searched the main electronic databases and abstracts from annual meetings. The STROBE instrument was used to assess the methodological quality. External validation of the retrieved models was performed using an individual patient dataset of 3229 patients at risk for BPD. Receiver operating characteristic curves were used to assess discrimination for each model by calculating the area under the curve (AUC). Calibration was assessed for the best discriminating models by visually comparing predicted and observed BPD probabilities.ResultsWe identified 26 clinical prediction models for BPD. Although the STROBE instrument judged the quality from moderate to excellent, only four models utilised external validation and none presented calibration of the predictive value. For 19 prediction models with variables matched to our dataset, the AUCs ranged from 0.50 to 0.76 for the outcome BPD. Only two of the five best discriminating models showed good calibration.ConclusionsExternal validation demonstrates that, except for two promising models, most existing clinical prediction models are poor to moderate predictors for BPD. To improve the predictive accuracy and identify preterm infants for future intervention studies aiming to reduce the risk of BPD, additional variables are required. Subsequently, that model should be externally validated using a proper impact analysis before its clinical implementation.

High surgical burden for infants with severe chronic lung disease (sCLD)

BACKGROUND/PURPOSE Infants with severe chronic lung disease (sCLD) may require surgical procedures to manage their medical problems; however, the scope of these interventions is undefined. The purpose of this study was to characterize the frequency, type, and timing of operative interventions performed in hospitalized infants with sCLD. METHODS The Childrens Hospital Neonatal Database was used to identify infants with sCLD from 24 childrens hospitals NICUs hospitalized over a recent 16-month period. RESULTS 556 infants were diagnosed with sCLD; less than 3% of infants had operations prior to referral and 30% were referred for surgical evaluation. In contrast, 71% of all sCLD infants received ≥1 surgical procedure during the CHND NICU hospitalization, with a mean of 3 operations performed per infant. Gastrostomy insertion (24%), fundoplication (11%), herniorrhaphy (13%), and tracheostomy placement (12%) were the most commonly performed operations. The timing of gastrostomy (PMA 48±10 wk) and tracheostomy (PMA 47±7 wk) insertions varied, and for infants who received both devices, only 33% were inserted concurrently (13/40 infants). CONCLUSIONS A striking majority of infants with sCLD received multiple surgical procedures during hospitalizations at participating NICUs. Further work regarding the timing, coordination, perioperative complications, and clinical outcomes for these infants is warranted.