Azithromycin reduces inflammation-amplified hypoxic-ischemic brain injury in neonatal rats.

BACKGROUND: Systemic inflammation amplifies neonatal hypoxic-ischemic (HI) brain injury. Azithromycin (AZ), an antibiotic with anti-inflammatory properties, improves sensorimotor function and reduces tissue damage after neonatal rat HI brain injury. The objective of this study was to determine if AZ is neuroprotective in two neonatal rat models of inflammation-amplified HI brain injury. DESIGN/METHODS: Seven-day-old (P7) rats received injections of toll-like receptor agonists lipopolysaccharide (LPS) or Pam3Cys-Ser-(Lys)4 (PAM) prior to right carotid ligation followed by 50 min (LPS + HI) or 60 min (PAM + HI) in 8% oxygen. Outcomes included contralateral forelimb function (forepaw placing; grip strength), survival, %Intact right hemisphere (brain damage), and a composite score incorporating these measures. We compared postnatal day 35 outcomes in controls and groups treated with three or five AZ doses. Then, we compared P21 outcomes when the first (of five) AZ doses were administered 1, 2, or 4 h after HI. RESULTS: In both LPS + HI and PAM + HI models, AZ improved sensorimotor function, survival, brain tissue preservation, and composite scores. Benefits increased with five- vs. three-dose AZ and declined with longer initiation delay. CONCLUSIONS: Perinatal systemic infection is a common comorbidity of neonatal asphyxia brain injury and contributes to adverse outcomes. These data support further evaluation of AZ as a candidate treatment for neonatal neuroprotection. IMPACT: AZ treatment decreases sensorimotor impairment and severity of brain injury, and improves survival, after inflammation-amplified HI brain injury, and this can be achieved even with a 2 h delay in initiation. This neuroprotective benefit is seen in models of inflammation priming by both Gram-negative and Gram-positive infections. This extends our previous findings that AZ treatment is neuroprotective after HI brain injury in neonatal rats.

Lateralized neonatal EEG coherence during sleep predicts language outcome.

BACKGROUND: Enriched language exposure may benefit infants in the neonatal intensive care unit. We hypothesized that changes in neonatal electroencephalogram (EEG) coherence during sleep, in response to maternal voice exposure, predict language development. METHODS: Convalescent neonates underwent 12-h polysomnography. A recording of the mother's voice was randomized to continuous playback in the first or second 6 h. We calculated the imaginary coherence (ICOH-a measure of functional connectivity) between EEG leads. Spearman correlations were computed between ICOH and 18-month Bayley-III language scores. RESULTS: Thirty-five neonates were included (N = 18 33-to-<35 weeks gestation; N = 17 ≥ 35 weeks). Predictive value of ICOH during neonatal non-rapid eye movement (NREM) sleep was left lateralized, and varied with gestational age and voice playback. ICOH in the left-hemispheric (C3-Cz; T3-Cz) channels across multiple EEG frequency bands was associated with 18-month language scores (rho = -0.34 to -0.48). The association was driven by neonates born at 33-34 weeks gestation, and a trend suggested a possible effect of maternal voice at some EEG frequencies. Right hemisphere ICOH (C4-Cz; T4-Cz) was not associated with language outcome. CONCLUSIONS: Left-hemispheric EEG functional connectivity during neonatal NREM sleep shows early signs of physiologic asymmetry that may predict language development. We speculate that sleep analyses could have unique prognostic value. IMPACT: During neonatal NREM sleep, EEG functional connectivity predicts future language development. Left temporal and central EEG coherence-specifically the imaginary component of coherence-is predictive, whereas the same analysis from the right hemisphere is not. These results appear to vary according to the infant's gestational age, and a trend suggests they may be enhanced by measuring functional connectivity during exposure to the mother's voice. These findings identify early evidence of physiologic differentiation within the cerebral hemispheres and raise the possibility that neonatal NREM sleep has a role to play in language development.

Repurposing azithromycin for neonatal neuroprotection.

BACKGROUND: Inflammation contributes to neonatal hypoxic-ischemic brain injury pathogenesis. We evaluated the neuroprotective efficacy of azithromycin, a safe, widely available antibiotic with anti-inflammatory properties, in a neonatal rodent hypoxic-ischemic brain injury model. METHODS: Seven-day-old rats underwent right carotid artery ligation followed by 90-min 8% oxygen exposure; this procedure elicits quantifiable left forepaw functional impairment and right cerebral hemisphere damage. Sensorimotor function (vibrissae-stimulated forepaw placing, grip strength) and brain damage were compared in azithromycin- and saline-treated littermates 2-4 weeks later. Multiple treatment protocols were evaluated (variables included doses ranging from 15 to 45 mg/kg; treatment onset 15 min to 4 h post-hypoxia, and comparison of 1 vs. 3 injections). RESULTS: All azithromycin doses improved function and reduced brain damage; efficacy was dose dependent, and declined with increasing treatment delay. Three azithromycin injections, administered over 48 h, improved performance on both function measures and reduced brain damage more than a single dose. CONCLUSION: In this neonatal rodent model, azithromycin improved functional and neuropathology outcomes. If supported by confirmatory studies in complementary neonatal brain injury models, azithromycin could be an attractive candidate drug for repurposing and evaluation for neonatal neuroprotection in clinical trials.

Sleep-Disordered Breathing among Newborns with Myelomeningocele.

In a matched cohort study, we report that the apnea-hypopnea index is significantly higher in neonates with myelomeningocele (34 ± 22) compared with age-matched controls (19 ± 11; P = .021). Assessment of newborns with myelomeningocele for sleep-disordered breathing may facilitate early treatment; the impact on long-term neurodevelopment is unknown.

Therapeutic hypothermia translates from ancient history in to practice.

Acute postasphyxial encephalopathy around the time of birth remains a major cause of death and disability. The possibility that hypothermia may be able to prevent or lessen asphyxial brain injury is a "dream revisited". In this review, a historical perspective is provided from the first reported use of therapeutic hypothermia for brain injuries in antiquity, to the present day. The first uncontrolled trials of cooling for resuscitation were reported more than 50 y ago. The seminal insight that led to the modern revival of studies of neuroprotection was that after profound asphyxia, many brain cells show initial recovery from the insult during a short "latent" phase, typically lasting ~6 h, only to die hours to days later during a "secondary" deterioration phase characterized by seizures, cytotoxic edema, and progressive failure of cerebral oxidative metabolism. Studies designed around this conceptual framework showed that mild hypothermia initiated as early as possible before the onset of secondary deterioration, and continued for a sufficient duration to allow the secondary deterioration to resolve, is associated with potent, long-lasting neuroprotection. There is now compelling evidence from randomized controlled trials that mild induced hypothermia significantly improves intact survival and neurodevelopmental outcomes to midchildhood.

Phenobarbital and neonatal seizures affect cerebral oxygen metabolism: a near-infrared spectroscopy study.

BACKGROUND: Near-infrared spectroscopy (NIRS) measures oxygen metabolism and is increasingly used for monitoring critically ill neonates. The implications of NIRS-recorded data in this population are poorly understood. We evaluated NIRS monitoring for neonates with seizures. METHODS: In neonates monitored with video-electroencephalography, NIRS-measured cerebral regional oxygen saturation (rSO2) and systemic O2 saturation were recorded every 5 s. Mean rSO2 was extracted for 1-h blocks before, during, and after phenobarbital doses. For each electrographic seizure, mean rSO2 was extracted for a period of three times the duration of the seizure before and after the ictal pattern, as well as during the seizure. Linear mixed models were developed to assess the impact of phenobarbital administration and of seizures on rSO2 and fractional tissue oxygen extraction. RESULTS: For 20 neonates (estimated gestational age: 39.6 ± 1.5 wk), 61 phenobarbital doses and 40 seizures were analyzed. Cerebral rSO2 rose (P = 0.005), and fractional tissue oxygen extraction declined (P = 0.018) with increasing phenobarbital doses. rSO2 declined during seizures, compared with baseline and postictal phases (baseline 81.2 vs. ictal 77.7 vs. postictal 79.4; P = 0.004). Fractional tissue oxygen extraction was highest during seizures (P = 0.002). CONCLUSIONS: Cerebral oxygen metabolism decreases after phenobarbital administration and increases during seizures. These small, but clear, changes in cerebral oxygen metabolism merit assessment for potential clinical impact.

Population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants with vasopressor-resistant hypotension.

OBJECTIVES: To determine the population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants receiving IV hydrocortisone for treatment of vasopressor-resistant hypotension and to identify patient-specific sources of pharmacokinetic variability. DESIGN: Prospective observational cohort study. SETTING: Level 3 neonatal ICU. PATIENTS: Sixty-two critically ill neonates and infants receiving IV hydrocortisone as part of standard of care for the treatment of vasopressor-resistant hypotension: median gestational age 28 weeks (range, 23-41), median weight 1.2 kg (range, 0.5-4.4), and 29 females. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Unbound baseline cortisol and postdose hydrocortisone concentrations measured from blood samples being drawn for routine laboratory tests. A one-compartment model best described the data. Allometric weight and postmenstrual age were significant covariates on unbound hydrocortisone clearance and volume of distribution. Final population estimates for clearance, volume of distribution, and baseline cortisol concentration were 20.2 L/hr, 244 L, and 1.37 ng/mL, respectively. Using the median weight and postmenstrual age of our subjects (i.e., 1.2 kg and 28 wk) in the final model, the typical unbound hydrocortisone clearance and volume of distribution were 1.0 L/hr and 4.2 L, respectively. The typical half-life for unbound hydrocortisone was 2.9 hours. A sharp and continuous increase in unbound hydrocortisone clearance was observed at 35 weeks postmenstrual age. CONCLUSIONS: We report the first pharmacokinetic data for unbound hydrocortisone, the pharmacologically active moiety, in critically ill neonates and infants with vasopressor-resistant hypotension. Unbound hydrocortisone clearance increased with body weight and was faster in children with an older postmenstrual age. Unbound hydrocortisone clearance increased sharply at 35 weeks postmenstrual age and continued to mature thereafter. This study lays the groundwork for evaluating unbound hydrocortisone exposure-response relationships and drawing definitive conclusions about the dosing of IV hydrocortisone in critically ill neonates and infants with vasopressor-resistant hypotension.

Esophageal and rectal temperatures as estimates of core temperature during therapeutic whole-body hypothermia.

We monitored whole-body cooling concurrently by both esophageal and rectal probes. Esophageal temperature was significantly higher compared with simultaneous rectal temperature during cooling, with a temperature gradient ranging from 0.46 to 1.03°C (median, 0.8°C; IQR, 0.6-0.8°C). During rewarming, this temperature difference disappeared.

Population pharmacokinetics of phenobarbital in infants with neonatal encephalopathy treated with therapeutic hypothermia.

OBJECTIVE: Phenobarbital is the first-line treatment for neonatal seizures. Many neonates with hypoxic ischemic encephalopathy are treated with therapeutic hypothermia, and about 40% have clinical seizures. Little is known about the pharmacokinetics of phenobarbital in infants with hypoxic ischemic encephalopathy who undergo therapeutic hypothermia. The objective of this study was to determine the effect of therapeutic hypothermia on phenobarbital pharmacokinetics, taking into account maturational changes. SETTING: Level 3 neonatal ICU. PATIENTS: Infants with hypoxic ischemic encephalopathy and suspected seizures, all treated with phenobarbital. Some of these infants also received treatment with therapeutic hypothermia. INTERVENTIONS: None. DESIGN: A retrospective cohort study of 39 infants with hypoxic ischemic encephalopathy treated with phenobarbital (20 were treated with therapeutic hypothermia and 19 were not). MEASUREMENTS AND MAIN RESULTS: Data on phenobarbital plasma concentrations were collected in 39 subjects with hypoxic ischemic encephalopathy with or without therapeutic hypothermia. Using nonlinear mixed-effects modeling, population pharmacokinetics of phenobarbital were developed with a total of 164 plasma concentrations. A one-compartment model best described the pharmacokinetics. The clearance of phenobarbital was linearly related to body weight and matured with increasing age with a maturation half-life of 22.1 days. Therapeutic hypothermia did not influence the pharmacokinetic parameters of phenobarbital. CONCLUSIONS: Therapeutic hypothermia does not influence the clearance of phenobarbital after accounting for weight and age. Standard phenobarbital dosing is appropriate for the initial treatment of seizures in neonates with hypoxic ischemic encephalopathy treated with therapeutic hypothermia.

Feeding and developmental outcomes after neonatal seizures-A prospective observational study.

Objective: Among neonates with acute symptomatic seizures, we evaluated whether inability to take full feeds at time of hospital discharge from neonatal seizure admission is associated with worse neurodevelopmental outcomes, after adjusting for relevant clinical variables. Methods: This prospective, 9-center study of the Neonatal Seizure Registry (NSR) assessed characteristics of infants with seizures including: evidence of brainstem injury on MRI, mode of feeding upon discharge, and developmental outcomes at 12, 18, and 24 months. Inability to take oral feeds was identified through review of medical records. Brainstem injury was identified through central review of neonatal MRIs. Developmental outcomes were assessed with the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) at 12, 18, and 24 months corrected age. Results: Among 276 infants, inability to achieve full oral feeds was associated with lower total WIDEA-FS scores (160.2±25.5 for full oral feeds vs. 121.8±42.9 for some/no oral feeds at 24 months, p<0.001). At 12 months, a G-tube was required for 23 of the 49 (47%) infants who did not achieve full oral feeds, compared with 2 of the 221 (1%) who took full feeds at discharge (p<0.001). Conclusions: Inability to take full oral feeds upon hospital discharge is an objective clinical sign that can identify infants with acute symptomatic neonatal seizures who are at high risk for impaired development at 24 months.

Bumetanide augments the neuroprotective efficacy of phenobarbital plus hypothermia in a neonatal hypoxia-ischemia model.

INTRODUCTION: The NaKCl cotransporter NKCC1 facilitates intraneuronal chloride accumulation in the developing brain. Bumetanide (BUM), a clinically available diuretic, inhibits this chloride transporter and augments the antiepileptic effects of phenobarbital (PB) in neonatal rodents. In a neonatal cerebral hypoxia-ischemia (HI) model, elicited by right carotid ligation, followed by 90 min 8% O(2) exposure in 7-d-old (P7) rats, PB increases the neuroprotective efficacy of hypothermia (HT). We evaluated whether BUM influenced the neuroprotective efficacy of combination treatment with PB and HT. METHODS: P7 rats underwent HI lesioning; 15 min later, all received PB (30 mg/kg), and 10 min later, half received BUM (10 mg/kg, PB-HT+BUM) and half received saline (PB-HT+SAL). One hour after HI, all were cooled (30 °C, 3 h). Contralateral forepaw sensorimotor function and brain damage were evaluated 1-4 wk later. RESULTS: Forepaw functional measures were close to normal in the PB-HT+BUM group, whereas deficits persisted in PB-HT+SAL controls; there were corresponding reductions in right cerebral hemisphere damage (at P35, % damage: PB-HT+BUM, 21 ± 16 vs. 38 ± 20 in controls). DISCUSSION: These results provide evidence that NKCC1 inhibition amplifies PB bioactivity in the immature brain and suggest that coadministration of PB and BUM may represent a clinically feasible therapy to augment the neuroprotective efficacy of therapeutic HT in asphyxiated neonates.

Beyond the Clinical Trials: Off-Protocol Therapeutic Hypothermia.

Mild therapeutic hypothermia has been extensively studied and validated as an effective and safe treatment for term and near-term infants with moderate and severe hypoxic encephalopathy meeting narrow inclusion criteria. Unanswered questions remain about whether cooling treatment can be optimized to improve outcomes even further, and whether it is reasonable to offer treatment to infants excluded from the foundational studies. Consideration of "off-protocol" cooling practices requires methodical review of available evidence and analysis using both a clinical and a research ethical framework.

The relationship between clinically identifiable intrapartum sentinel events and short-term outcome after therapeutic hypothermia.

OBJECTIVE: To determine the impact of intrapartum sentinel events on short-term outcome post-hypothermia. STUDY DESIGN: Records of 77 infants of 36 weeks' gestation or more, who received therapeutic hypothermia, were reviewed. Some were delivered after a clinically identifiable intrapartum sentinel event (IISE). All survivors had brain magnetic resonance imaging (MRI) at 7 to 10 days of life. The primary outcome of neonatal death related to hypoxic-ischemic encephalopathy was compared in infants born with (n = 39) or without an IISE (n = 38). MRI abnormalities were also compared. Logistic regression analysis was used to determine the variables predicting the primary outcome. RESULTS: The two groups had similar Apgar scores, initial blood pHs, and early neurologic examinations. Base deficit was more severe in the IISE group. Neonatal death and hypoxic-ischemic injury was shown on brain MRI with basal nuclei, cortical, and subcortical white matter lesions extending beyond the watershed areas in infants surviving beyond the neonatal period were more common in the IISE group (P = .014; OR 11.1; 95% CI 1.3-92.6; and P = .034; OR 4.1; 95% CI 1.1-14.9, respectively). Multivariate analysis identified IISE (P = .023; OR 12.2; 95% CI 1.4-105.8) to be independently associated with neonatal death. CONCLUSIONS: IISEs are associated with neonatal death and severe injury as shown in brain MRI, even after hypothermia.

Phenobarbital augments hypothermic neuroprotection.

Seizures are associated with adverse outcome in infants with hypoxic-ischemic encephalopathy. We hypothesized that early administration of the anticonvulsant phenobarbital after cerebral hypoxia ischemia could enhance the neuroprotective efficacy of delayed-onset hypothermia. We tested this hypothesis in a neonatal rodent model. Seven-d-old rats (n = 104) underwent right carotid ligation, followed by 90 min 8% O2 exposure; 15 min later, they received injections of phenobarbital (40 mg/kg) or saline. One or 3 h later, all were treated with hypothermia (30 degrees C, 3 h). Function and neuropathology were evaluated after 7 d (early outcomes) or 1 mo (late outcomes). Early outcome assessment demonstrated better sensorimotor performance and less cortical damage in phenobarbital-treated groups; there were no differences between groups in which the hypothermia delay was shortened from 3 to 1 h. Late outcome assessment confirmed sustained benefits of phenobarbital + hypothermia treatment; sensorimotor performance was better (persistent attenuation of contralateral forepaw placing deficits and absence of contralateral forepaw neglect); neuropathology scores were lower (median, phenobarbital 2 and saline 8.5, p < 0.05); and less ipsilateral cerebral hemisphere %Damage (mean +/- SD, 11 +/- 17 versus 28 +/- 22, p < 0.05). These results suggest that early posthypoxia-ischemia administration of phenobarbital may augment the neuroprotective efficacy of therapeutic hypothermia.

Pulmonary dysfunction and therapeutic hypothermia in asphyxiated newborns: whole body versus selective head cooling.

Compared with whole body cooling (WBC), selective head cooling (SHC) of asphyxiated newborns presumably allows effective brain cooling with less systemic hypothermia and potentially fewer systemic adverse effects. It is not known if pulmonary dysfunction, one of the potential adverse systemic effects of therapeutic hypothermic neuroprotection, differs with the method of cooling. We sought to investigate if pulmonary mechanics and gas exchange during therapeutic hypothermia differ between WBC and SHC. The severity of pulmonary dysfunction was determined in 59 asphyxiated newborns receiving therapeutic hypothermic neuroprotection by either SHC ( N = 31) or WBC ( N = 28). Ventilatory parameters and simultaneous alveolar-arterial oxygen gradient (A-a DO (2)) and partial pressure of carbon dioxide, arterial (PaCO (2)) were measured before the start of cooling (baseline), and at 4, 8, 12, 24, 48, and 72 hours of cooling. The diagnosis of persistent pulmonary hypertension of the newborn (PPHN) was established by echocardiography. Clinical monitoring and treatment during cooling, whether SHC or WBC, were similar. All (96%) but two infants (from the SHC group) required mechanical ventilation of varying duration during cooling, and nine infants (15%) developed PPHN. The baseline ventilator pressures requirement, and A-a DO (2) were similar among the 48 ventilated infants without PPHN (WBC 23, SHC 25) at the start of cooling. Ventilatory requirements remained modest and did not differ with the method of cooling. Similar numbers of infants without PPHN were able to be extubated after improvement in respiratory status while being cooled (WBC 42.8% versus SHC 37.9%, P = 0.79, odds ratio [OR] 1.2, 95% confidence interval [CI] 0.4 to 3.5). Nine infants (WBC 5, SHC 4) developed PPHN. Six of the nine (WBC 4, SHC 2) required inhaled nitric oxide therapy, and one infant from the WBC group subsequently required extracorporeal membrane oxygenation. The incidence of PPHN was similar in both the WBC and SHC groups (17.8% versus 12.9%, P = 0.72, OR 1.5, 95% CI 0.3 to 6.1). Pulmonary dysfunction is common but not severe in asphyxiated infants during therapeutic hypothermia. Pulmonary mechanics and gas exchange do not differ with the method of achieving hypothermia.

Maternal Voice and Infant Sleep in the Neonatal Intensive Care Unit.

BACKGROUND: Approximately 10% of US newborns require a NICU. We evaluated whether the NICU acoustic environment affects neonatal sleep and whether exposure to the mother's voice can modulate that impact. METHODS: In a level IV NICU with single-infant rooms, 47 neonates underwent 12-hour polysomnography. Their mothers were recorded reading children's books. Continuous maternal voice playback was randomized to either the first or second 6 hours of the polysomnogram. Regression models were used to examine sleep-wake stages, entropy, EEG power, and the probability of awakening in response to ambient noise during and without voice playback. RESULTS: After epochs with elevated noise, the probability was higher with (versus without) maternal voice exposure of neonates staying asleep (P = .009). However, the 20 neonates born at ≥35 weeks' gestation, in contrast to those born at 33 to 34 weeks, showed an age-related increase in percent time awake (R 2 = 0.52; P < .001), a decrease in overall sleep (R 2 = 0.52; P < .001), a reduction in rapid eye movement sleep bouts per hour (R 2 = 0.35; P = .003), and an increase in sleep-wake entropy (R 2 = 0.52; P < .001) all confined solely to the 6 hours of maternal voice exposure. These associations remained significant (P = .02 to P < .001) after adjustment for neurologic examination scores and ambient noise. CONCLUSIONS: Hospitalized newborns born at ≥35 weeks' gestation but not at 33 to 34 weeks' gestation show increasing wakefulness in response to their mother's voice. However, exposure to the mother's voice during sleep may also help protect newborns from awakening after bursts of loud hospital noise.

Sleep-disordered breathing is common among term and near term infants in the NICU.

OBJECTIVE: Among older infants and children, sleep-disordered breathing (SDB) has negative neurocognitive consequences. We evaluated the frequency and potential impact of SDB among newborns who require intensive care. STUDY DESIGN: Term and near-term newborns at risk for seizures underwent 12-h attended polysomnography in the neonatal intensive care unit (NICU). Bayley Scales of Infant Development, third edition (Bayley-III) were administered at 18-22 months. RESULT: The 48 newborns (EGA 39.3 ± 1.6) had a median pediatric apnea-hypopnea index (AHI) of 10.1 (3.3-18.5) and most events were central (vs obstructive). Maternal and prenatal factors were not associated with AHI. Moreover, neonatal PSG results were not associated with Bayley-III scores (P > 0.05). CONCLUSION: SDB is common among term and near-term newborns at risk for seizures. Follow-up at ages when more nuanced testing can be performed may be necessary to establish whether neonatal SDB is associated with long-term neurodevelopmental disability.

An Artificial Placenta Protects Against Lung Injury and Promotes Continued Lung Development in Extremely Premature Lambs.

An artificial placenta (AP) utilizing extracorporeal life support (ECLS) could protect premature lungs from injury and promote continued development. Preterm lambs at estimated gestational age (EGA) 114-128 days (term = 145) were delivered by Caesarian section and managed in one of three groups: AP, mechanical ventilation (MV), or tissue control (TC). Artificial placenta lambs (114 days EGA, n = 3; 121 days, n = 5) underwent venovenous (VV)-ECLS with jugular drainage and umbilical vein reinfusion for 7 days, with a fluid-filled, occluded airway. Mechanical ventilation lambs (121 days, n = 5; 128 days, n = 5) underwent conventional MV until failure or maximum 48 hours. Tissue control lambs (114 days, n = 3; 121 days, n = 5; 128 days, n = 5) were sacrificed at delivery. At the conclusion of each experiment, lungs were procured and sectioned. Hematoxylin and eosin (H&E) slides were scored 0-4 in seven injury categories, which were summed for a total injury score. Slides were also immunostained for platelet-derived growth factor receptor (PDGFR)-α and α-actin; lung development was quantified by the area fraction of double-positive tips of secondary alveolar septa. Support duration of AP lambs was 163 ± 9 (mean ± SD) hours, 4 ± 3 for early MV lambs, and 40 ± 6 for late MV lambs. Total injury scores at 121 days were 1.7 ± 2.1 for AP vs. 5.5 ± 1.6 for MV (p = 0.02). Using immunofluorescence, double-positive tip area fraction at 121 days was 0.017 ± 0.011 in AP lungs compared with 0.003 ± 0.003 in MV lungs (p < 0.001) and 0.009 ± 0.005 in TC lungs. At 128 days, double-positive tip area fraction was 0.012 ± 0.007 in AP lungs compared with 0.004 ± 0.004 in MV lungs (p < 0.001) and 0.016 ± 0.009 in TC lungs. The AP is protective against lung injury and promotes lung development compared with mechanical ventilation in premature lambs.

Impact of indolent inflammation on neonatal hypoxic-ischemic brain injury in mice.

This report describes a new experimental model to evaluate the effect of a recurrent systemic inflammatory challenge, after cerebral hypoxia-ischemia in immature mice, on the progression of brain injury. Treatment with a low dose of lipopolysaccharide (E. coli O55:B5, 0.2mg/kg for 3 days, then 0.1mg/kg for 2 days) daily for 5 days after unilateral cerebral hypoxia-ischemia (right carotid ligation followed by 35min in 10% O2) in 10-day-old mice resulted in increased right forebrain tissue damage (35.6% reduction in right hemisphere volume compared to 20.6% reduction in saline-injected controls), in bilateral reductions in corpus callosum area (by 12%) and myelin basic protein immunostaining (by 19%), and in suppression of injury-related right subventricular zone cellular proliferation. The post-hypoxic-ischemic lipopolysaccharide regimen that amplified brain injury was not associated with increased mortality, nor with changes in body temperature, weight gain or blood glucose concentrations. The results of the present study demonstrate that systemic inflammation influences the evolution of tissue injury after neonatal cerebral hypoxia-ischemia and may also impair potential recovery mechanisms.

Current controversies in hypothermic neuroprotection.

In 2005, three randomised controlled trials (RCTs) showed that treating infants with hypoxic-ischaemic encephalopathy (HIE) with hypothermia decreased the combined outcome of death or disability at 12-18 months, although treatment effects were modest. More recently, the US Food and Drug Administration (FDA) approved a device for selective head cooling. In addition, the protocol from another of the three trials, using equipment available in many hospitals, has been in the public domain for over a year. Why has this not led to a consensus that hypothermia is the standard of care for HIE? This is explored. Important questions for future research will focus on ways to improve on initial results with cooling, such as drug plus hypothermia combination therapy and refining duration and depth of cooling or duration of rewarming. Although the latter are important questions for future clinical trials, those who are convinced by the evidence to date should focus on safe implementation of cooling using protocols with established safety and efficacy and should consider ways to increase access to cooling for eligible babies.