Karen Luyt

Time Is Brain: Starting Therapeutic Hypothermia within Three Hours after Birth Improves Motor Outcome in Asphyxiated Newborns

Objective: Therapeutic hypothermia (HT) is the standard treatment for newborns after perinatal asphyxia. Preclinical studies report that HT is more effective when started early. Methods: Eighty cooled newborns were analyzed and grouped according to when cooling was started after birth: early (≤180 min) or late (>181 min). For survivors we analyzed whether starting cooling early was associated with a better psychomotor or mental developmental index (PDI or MDI, Bayley Scales of Infant Development II) than late cooling. Results: Forty-three newborns started cooling early and 37 started late. There was no significant difference in the severity markers of perinatal asphyxia between the groups; however, nonsurvivors (n = 15) suffered more severe asphyxia and had significantly lower centiles for weight (BWC; p = 0.009). Of the 65 infants that survived, 35 were cooled early and 30 were cooled late. There was no difference in time to start cooling between those who survived and those who did not. For survivors, median PDI (IQR) was significantly higher when cooled early [90 (77-99)] compared to being cooled later [78 (70-90); p = 0.033]. There was no increase in cardiovascular adverse effects in those cooled early. There was no significant difference in MDI between early and late cooling [93 (77-103) vs. 89 (76-106), p = 0.594]. Conclusion: Starting cooling before 3 h of age in surviving asphyxiated newborns is safe and significantly improves motor outcome. Cooling should be initiated as soon as possible after birth in eligible infants.

Functional metabotropic glutamate receptors are expressed in oligodendrocyte progenitor cells

We investigated the expression of metabotropic glutamate receptor (mGluR) isoforms in CG‐4 rodent oligodendroglial progenitor cells (OPC) and rat brain oligodendrocytes. Our RT‐PCR analysis detected mRNAs for mGluR3 and mGluR5 isoforms in OPCs. Although neurons express both mGluR5a and mGluR5b splice variants, only mGluR5a was identified in OPCs. Antibodies to mGluR2/3 and mGluR5 detected the corresponding receptor proteins in immunoblots of OPC membrane fractions. Furthermore, immunocytochemical analysis identified mGluR5 in oligodendrocyte marker O4‐positive OPCs. The expression of mGluR5 was also demonstrated in oligodendrocyte marker (O4 and O1) positive cells in white matter of postnatal 4‐ and 7‐day‐old rat brain sections using immunofluorescent double labelling and confocal microscopy. The mGluR5 receptor function was assessed in CG‐4 OPCs with fura‐2 microfluorometry. Application of the mGluR1/5 specific agonist (S)‐3,5‐dihydroxyphenylglycine (DHPG) induced calcium oscillations, which were inhibited by the selective mGluR5 antagonist 2‐methyl‐6‐(phenylethynyl) pyridine hydrochloride (MPEP). The DHPG induced calcium oscillations required Ca2+ release from intracellular stores. In OPCs the group II mGluR agonist (2S,2′R,3′R)‐2‐(2′,3′‐dicarboxycyclopropyl)glycine (DCG‐IV) decreased forskolin‐stimulated cAMP synthesis, indicating the presence of functional mGluR3. The newly identified mGluR3 and mGluR5a may be involved in the differentiation of oligodendrocytes, myelination and the development of white matter damage.

Oligodendroglial metabotropic glutamate receptors are developmentally regulated and involved in the prevention of apoptosis

Oligodendrocytes (OLs) are responsible for axon myelination and are the principal cells targeted in preterm white matter injury. The cellular and molecular mechanisms involved in white matter development and immature OL injury are incompletely understood. Metabotropic glutamate receptors (mGluRs) modulate neuronal development and survival, and have recently been identified in oligodendrocyte progenitor cells (OPCs). Using the highly homogeneous CG‐4 OPC line and O4 marker‐immunoselected primary OLs, we established the differentiation stage‐specific expression profile of mGluR3 and mGluR5 mRNAs and proteins in the oligodendroglial lineage and type‐2‐astrocytes (ASTs). Our quantitative analysis indicated no changes in mGluR3, but a significant down‐regulation of mGluR5a mRNA and protein expression during differentiation of OPCs into OLs or ASTs. The down‐regulation of mGluR5a had functional consequences, with significantly fewer OLs and ASTs than OPCs responding to the group I mGluR agonist (RS)‐3,5‐dihydroxyphenylglycine with intracellular Ca2+ concentration oscillations. Neither stimulation nor inhibition of mGluR3 or mGluR5 altered OPC migration, suggesting that these receptors do not play prominent roles in the regulation of OPC motility. The activation of mGluR5 completely protected OPCs and substantially reduced staurosporine‐induced apoptosis in OLs. This suggests that the down‐regulation of mGluR5 in premyelinating OLs is likely to contribute to their increased vulnerability, and that the targeting of mGluR5 may be a potential therapeutic strategy for future development.

The utility of sildenafil in pulmonary hypertension: a focus on bronchopulmonary dysplasia

The treatment of pulmonary hypertension (PH) secondary to bronchopulmonary dysplasia (BPD) in infants has evolved in recent years, improving both quality of life and survival for patients. One of the potential agents for this condition is sildenafil, a phosphodiesterase-V inhibitor with proven efficacy within the idiopathic PH population. However, only limited evidence exists for its use as either monotherapy or part of a combination approach towards the management of PH in BPD. This review summarises the evidence base for sildenafil alone and in combination with other recognised therapeutic agents for ameliorating paediatric PH in the presence of BPD. It also examines the suitability for current practice with the aim of clarifying regimens that produce improved patient outcomes. We conclude that sildenafil is both safe and effective in this utility. Doses should be started at 0.5 mg/kg every 8 h before titrating up towards 2 mg/kg every 6 h to effect reductions in pulmonary vascular resistance and arterial pressure. Evidence suggests that if continued until PH resolution, this improves survival from 61% to 81% at 12 months. Furthermore, there are also data suggesting that in treatment refractory PH cases, the addition of endothelin antagonists and prostacyclin analogues to sildenafil therapy can also be considered.

Compared with specialist registrars, experienced staff nurses shorten the duration of weaning neonates from mechanical ventilation

Objective To compare the overall performance of specially trained neonatal nurses acting autonomously, unsupervised, and without a protocol with specialist registrars when weaning neonates from mechanical ventilation. Design Prospective, randomized, controlled trial. Setting A single neonatal intensive care unit. Patients Neonates requiring conventional mechanical ventilation (n = 50). Interventions Infants on conventional ventilation were randomly assigned to receive either nurse-led (n = 25) or registrar-led (n = 23) weaning. A total of 48 infants completed the study (two infants in the registrar group were excluded when their parents withdrew consent). Measurements and Main Results The main outcome measure, median weaning time, was 1200 mins (95% confidence interval [CI], 621–1779 mins) in the nurse group and 3015 mins (95% CI, 2650–3380 mins) in the registrar group (p = .0458). The median time from treatment assignment to the first ventilator change was 60 mins (95% CI, 52–68 mins) in the nurse group and 120 mins (95% CI, 103–137 mins) in the registrar group (p = .35). On average, the nurses made ventilator changes every 4.5 hrs (95% CI, 2.9–6 hrs) and the registrars every 7.2 hrs (95% CI, 5.4–9 hrs;p = .003). The median number (range) of backward steps taken per infant was 0 (0–5 steps) in the nurse group and 1 (0–5 steps) in the registrar group (p = .019). Conclusions The findings of this study suggest that additional domains of neonatal critical care could be reviewed for their potential transfer to appropriately prepared nurses.

High frequency functional brain networks in neonates revealed by rapid acquisition resting state fMRI

Understanding how spatially remote brain regions interact to form functional brain networks, and how these develop during the neonatal period, provides fundamental insights into normal brain development, and how mechanisms of brain disorder and recovery may function in the immature brain. A key imaging tool in characterising functional brain networks is examination of T2*‐weighted fMRI signal during rest (resting state fMRI, rs‐fMRI). The majority of rs‐fMRI studies have concentrated on slow signal fluctuations occurring at <0.1 Hz, even though neuronal rhythms, and haemodynamic responses to these fluctuate more rapidly, and there is emerging evidence for crucial information about functional brain connectivity occurring more rapidly than these limits. The characterisation of higher frequency components has been limited by the sampling frequency achievable with standard T2* echoplanar imaging (EPI) sequences. We describe patterns of neonatal functional brain network connectivity derived using accelerated T2*‐weighted EPI MRI. We acquired whole brain rs‐fMRI data, at subsecond sampling frequency, from preterm infants at term equivalent age and compared this to rs‐fMRI data acquired with standard EPI acquisition protocol. We provide the first evidence that rapid rs‐fMRI acquisition in neonates, and adoption of an extended frequency range for analysis, allows identification of a substantial proportion of signal power residing above 0.2 Hz. We thereby describe changes in brain connectivity associated with increasing maturity which are not evident using standard rs‐fMRI protocols. Development of optimised neonatal fMRI protocols, including use of high speed acquisition sequences, is crucial for understanding the physiology and pathophysiology of the developing brain. Hum Brain Mapp 36:2483–2494, 2015.

The impact of a sepsis quality improvement project on neurodisability rates in very low birthweight infants

Objective Very low birthweight (VLBW; <1500 g) infants with late-onset sepsis (LOS) have an increased risk of neurodisability. Care bundles to reduce bloodstream infections in neonatal intensive care unit (NICU) are effective in reducing LOS. Our aim was to determine if a sepsis reduction bundle introduced through a quality improvement project would impact neurodevelopmental outcomes in VLBW infants. Design Cohort study. Setting Level 3 regional NICU in the South West of England. Patients VLBW infants born between 2002 and 2011. Interventions A sepsis reduction care bundle implemented between July 2006 and December 2007. Main outcome measures The primary outcome was risk of coagulase-negative Staphylococcus (CONS) infection diagnosed >3 days of age. Secondary outcomes were death and moderate cognitive impairment. A logistic regression model was derived using the birth era as the independent variable with adjustment for typical confounders. Results In total, 379 infants were born in the preintervention cohort and 378 in the postintervention cohort. The CONS infection rate was reduced after the intervention (26.7% vs 14.1% p<0.001). Death prior to discharge reduced without reaching statistical significance (14.1% vs10.9%, p=0.195). The rate of cognitive disability reduced in the postintervention cohort (18.8% vs 6.1%, p=0.042). The adjusted ORs (95% CI) for CONS infection, death and cognitive impairment were 0.46 (0.29 to 0.72), 0.73 (0.43 to 1.24) and 0.3 (0.07 to 1.33), respectively. Conclusions There appears to be an association between reduced cognitive disability and the implementation of a sepsis reduction bundle. Further study in larger series is required to confirm these findings.

Neonatal seizures: magnetic resonance imaging adds value in the diagnosis and prediction of neurodisability.

To determine the aetiological associations, neurological sequelae and role of magnetic resonance imaging (MRI) in term newborn infants with seizures.

Protecting the premature brain: Current evidence based strategies for minimising perinatal brain injury in preterm infants

Improving neurodevelopmental outcome for preterm infants is an important challenge for neonatal medicine. The disruption of normal brain growth and neurological development is a significant consequence of preterm birth and can result in physical and cognitive impairments. While advances in neonatal medicine have led to progressively better survival rates for preterm infants, there has only been a modest improvement in the proportion of surviving infants without neurological impairment, and no change in the proportion with severe disability. The overall number of children with neurodisability due to prematurity is increasing. Trials investigating novel therapies are underway and many have promising early results; however, in the interim, current treatments and management strategies that have proven benefit for neurodevelopment or reduction in neonatal brain injury are often underutilised. We collate the evidence for the efficacy of such interventions, recommended by guidelines or supported by large meta-analysis or randomised control trials. We address controversies that have hindered uptake and problems with translating research into practice. We then look to the future of preterm neuroprotective care.

Superior vena cava flow and intraventricular haemorrhage in extremely preterm infants.

Abstract Objective: To evaluate the relationship between superior vena cava flow (SVCF) measurements within the first 24 h of life, and development of intraventricular haemorrhage (IVH) in extremely preterm infants. Study design: Single centre retrospective cohort study of 108 preterm infants born less than 28 weeks’ gestation. Main outcome measure was degree of IVH at day 7 postnatal age. Results: The mean GA of the study group was 25.4 weeks. Mean SVCF was lower (75 ml/kg/min) in infants later diagnosed with IVH (n = 46) compared to infants, who did not develop IVH (87.7 ml/kg/min, p = 0.055). PDA diameter was inversely associated with SVCF (p = 0.024) and reversal of flow in the descending aorta (p = 0.001). Sensitivity analysis did not confirm an independent association of SVCF with development of IVH [OR 0.990 (0.978–1.002), p = 0.115]. Conclusion: Our study describes early SVCF in extremely preterm infants is associated with the extent of ductal shunting, but insensitive in predicting IVH.