Short apneas and periodic breathing in preterm infants in the neonatal intensive care unit-Effects of sleep position, sleep state, and age.

This observational study investigated the effects of sleep position and sleep state on short apneas and periodic breathing in hospitalized preterm infants longitudinally, in relation to postmenstrual age. Preterm infants (25-31 weeks gestation, n = 29) were studied fortnightly after birth until discharge, in prone and supine positions, and in quiet sleep and active sleep. The percentage of time spent in each sleep state (percentage of time in quiet sleep and percentage of time in active sleep), percentage of total sleep time spent in short apneas and periodic breathing, respectively, the percentage of falls from baseline in heart rate, arterial oxygen saturation and cerebral tissue oxygenation index during short apneas and periodic breathing, and the associated percentage of total sleep time with systemic (arterial oxygen saturation < 90%) and cerebral hypoxia (cerebral tissue oxygenation index < 55%) were analysed using a linear mixed model. Results showed that the prone position decreased (improved) the percentage of falls from baseline in arterial oxygen saturation during both short apneas and periodic breathing, decreased the proportion of infants with periodic breathing and the periodic breathing-associated percentage of total sleep time with cerebral hypoxia. The percentage of time in quiet sleep was higher in the prone position. Quiet sleep decreased the percentage of total sleep time spent in short apneas, the short apneas-associated percentage of falls from baseline in heart rate, arterial oxygen saturation, and proportion of infants with systemic hypoxia. Quiet sleep also decreased the proportion of infants with periodic breathing and percentage of total sleep time with cerebral hypoxia. The effects of sleep position and sleep state were not related to postmenstrual age. In summary, when sleep state is controlled for, the prone sleeping position has some benefits during both short apneas and periodic breathing. Quiet sleep improves cardiorespiratory stability and is increased in the prone position at the expense of active sleep, which is critical for brain maturation. This evidence should be considered in positioning preterm infants.

Intrauterine inflammation and postnatal intravenous dopamine alter the neurovascular unit in preterm newborn lambs.

BACKGROUND: Intrauterine inflammation is considered a major cause of brain injury in preterm infants, leading to long-term neurodevelopmental deficits. A potential contributor to this brain injury is dysregulation of neurovascular coupling. We have shown that intrauterine inflammation induced by intra-amniotic lipopolysaccharide (LPS) in preterm lambs, and postnatal dopamine administration, disrupts neurovascular coupling and the functional cerebral haemodynamic responses, potentially leading to impaired brain development. In this study, we aimed to characterise the structural changes of the neurovascular unit following intrauterine LPS exposure and postnatal dopamine administration in the brain of preterm lambs using cellular and molecular analyses. METHODS: At 119-120 days of gestation (term = 147 days), LPS was administered into the amniotic sac in pregnant ewes. At 126-7 days of gestation, the LPS-exposed lambs were delivered, ventilated and given either a continuous intravenous infusion of dopamine at 10 µg/kg/min or isovolumetric vehicle solution for 90 min (LPS, n = 6; LPSDA, n = 6). Control preterm lambs not exposed to LPS were also administered vehicle or dopamine (CTL, n = 9; CTLDA, n = 7). Post-mortem brain tissue was collected 3-4 h after birth for immunohistochemistry and RT-qPCR analysis of components of the neurovascular unit. RESULTS: LPS exposure increased vascular leakage in the presence of increased vascular density and remodelling with increased astrocyte "end feet" vessel coverage, together with downregulated mRNA levels of the tight junction proteins Claudin-1 and Occludin. Dopamine administration decreased vessel density and size, decreased endothelial glucose transporter, reduced neuronal dendritic coverage, increased cell proliferation within vessel walls, and increased pericyte vascular coverage particularly within the cortical and deep grey matter. Dopamine also downregulated VEGFA and Occludin tight junction mRNA, and upregulated dopamine receptor DRD1 and oxidative protein (NOX1, SOD3) mRNA levels. Dopamine administration following LPS exposure did not exacerbate any effects induced by LPS. CONCLUSION: LPS exposure and dopamine administration independently alters the neurovascular unit in the preterm brain. Alterations to the neurovascular unit may predispose the developing brain to further injury.

Thyroid hormone analogues: Promising therapeutic avenues to improve the neurodevelopmental outcomes of intrauterine growth restriction.

Intrauterine growth restriction (IUGR) is a pregnancy complication impairing fetal growth and development. The compromised development is often attributed to disruptions of oxygen and nutrient supply from the placenta, resulting in a number of unfavourable physiological outcomes with impaired brain and organ growth. IUGR is associated with compromised development of both grey and white matter, predisposing the infant to adverse neurodevelopmental outcomes, including long-lasting cognitive and motor difficulties. Cerebral thyroid hormone (TH) signalling, which plays a crucial role in regulating white and grey matter development, is dysregulated in IUGR, potentially contributing to the neurodevelopmental delays associated with this condition. Notably, one of the major TH transporters, monocarboxylate transporter-8 (MCT8), is deficient in the fetal IUGR brain. Currently, no effective treatment to prevent or reverse IUGR exists. Management strategies involve close antenatal monitoring, management of maternal risk factors if present and early delivery if IUGR is found to be severe or worsening in utero. The overall goal is to determine the most appropriate time for delivery, balancing the risks of preterm birth with further fetal compromise due to IUGR. Drug candidates have shown either adverse effects or little to no benefits in this vulnerable population, urging further preclinical and clinical investigation to establish effective therapies. In this review, we discuss the major neuropathology of IUGR driven by uteroplacental insufficiency and the concomitant long-term neurobehavioural impairments in individuals born IUGR. Importantly, we review the existing clinical and preclinical literature on cerebral TH signalling deficits, particularly the impaired expression of MCT8 and their correlation with IUGR. Lastly, we discuss the current evidence on MCT8-independent TH analogues which mimic the brain actions of THs by being metabolised in a similar manner as promising, albeit underappreciated approaches to promote grey and white matter development and improve the neurobehavioural outcomes following IUGR.

Longitudinal effects of early exposure to intermittent hypoxia on autonomic cardiovascular control in very preterm infants.

INTRODUCTION: Cardiorespiratory control is immature in infants born preterm compared to those born at term. Animal studies have shown that repetitive hypoxia associated with periodic breathing can alter autonomic control. We aimed to elucidate if the amount of time spent with apnoea and periodic breathing in the neonatal unit was associated with longitudinal changes in autonomic control assessed using heart rate variability. METHODS: Twenty-nine very preterm infants (10 M 19F) were studied during supine daytime sleep on 4 occasions. Study 1: 32-36 weeks post menstrual age (PMA) (n = 29), Study 2: 36-40 weeks PMA (n = 27), Study 3: 3-months corrected age (CA) (n = 20) and Study 4: 6-months CA (n = 26). The percentage total sleep time (%TST) spent having apnoeas in active (AS) and quiet sleep (QS) at each study was calculated. Total power, low frequency (LF, sympathetic + parasympathetic activity) high frequency (HF, parasympathetic activity), and LF/HF (sympathovagal balance) were calculated. Infants were divided into two groups based on the %TST spent with apnoeas above and below the median in AS and QS at Study 1. Data were normalised and compared with two-way ANOVA with Bonferroni post-hoc tests. RESULTS: When apnoeas were included in the analysis, in QS Total power and HF power were higher, and when apnoeas were excluded HF power was higher in QS but lower in AS in the above median group at Study 4. CONCLUSION: This study provides new evidence that short apnoeas, particularly periodic breathing, which is currently not detected or treated in the neonatal unit can affect autonomic cardiovascular control.

Blood pressure and cerebral oxygenation with physiologically-based cord clamping: sub-study of the BabyDUCC trial.

BACKGROUND: Cord-clamping strategies may modify blood pressure (BP) and cerebral tissue oxygen saturation (rStO2) immediately after birth. METHODS: We conducted a sub-study nested within the Baby-Directed Umbilical Cord-Clamping trial. Infants ≥32+0 weeks' gestation assessed as requiring resuscitation were randomly allocated to either physiologically-based cord clamping (PBCC), where resuscitation commenced prior to umbilical cord clamping, or standard care where cord clamping occurred early (ECC). In this single-site sub-study, we obtained additional measurements of pre-ductal BP and rStO2. In a separate observational arm, non-randomised vigorous infants received 2 min of deferred cord clamping (DCC) and contributed data for reference percentiles. RESULTS: Among 161 included infants, n = 55 were randomly allocated to PBCC (n = 30) or ECC (n = 25). The mean (SD) BP at 3-4 min after birth (primary outcome) in the PBCC group was 64 (10) mmHg compared to 62 (10) mmHg in the ECC group, mean difference 2 mmHg (95% confidence interval -3-8 mmHg, p = 0.42). BP and rStO2 were similar across both randomised arms and the observational arm (n = 106). CONCLUSION: We found no difference in BP or rStO2 with the different cord clamping strategies. We report reference ranges for BP and rStO2 for late-preterm and full-term infants receiving DCC. IMPACT: Among late-preterm and full-term infants receiving varying levels of resuscitation, blood pressure (BP, at 3-4 minutes and 6 min) and cerebral tissue oxygen saturation (rStO2) are not influenced by timing of cord clamping in relation to establishment of ventilation. Infants in this study did not require advanced resuscitation, where cord clamping strategies may yet influence BP and rStO2. The reference ranges for BP and rStO2 represent the first, to our knowledge, for vigorous late-preterm and full-term infants receiving deferred cord clamping. rStO2 > 90% (~90th percentile) may be used to define cerebral hyperoxia, for instance when studying oxygen supplementation after birth.

Neuroinflammation in the Rat Brain After Exposure to Diagnostic Ultrasound.

OBJECTIVE: To date there have been no studies exploring the potential for neuroinflammation as an intracranial bio-effect associated with diagnostic ultrasound during neonatal cranial scans in a mammalian in vivo model. The study described here was aimed at investigating the effects of B-mode and Doppler mode ultrasound on inflammation in the rat brain. METHODS: Twelve Wistar rats (7-9 wk old) were divided into a control group and an ultrasound-exposed group (n = 6/group). A craniotomy was performed, followed by 10 min of B-mode and spectral Doppler interrogation of the middle cerebral artery. The control group was subjected to sham treatment, with the transducer held stationary over the craniotomy site, but the ultrasound machine switched off. Animals were euthanized 48 h after exposure, and the brains formalin fixed for immunohistochemical analysis using allograft inflammatory factor 1 (IBA-1) and glial fibrillary acidic protein (GFAP) as markers of microglia and astrocytes, respectively. The numbers of IBA-1- and GFAP-immunoreactive cells were manually counted and expressed as areal density (cells/mm2). Results were analyzed using Student's unpaired t-test and one-way repeated-measures analysis of variance. RESULTS: The ultrasound-exposed brain exhibited significant increases in IBA-1 and GFAP immunoreactive cell density in all regions of B-mode and Doppler mode exposure compared with the control group (p < 0.001). CONCLUSION: Ten minutes of B-mode and Doppler mode ultrasound may induce neuroinflammatory changes in the rat brain. This suggests that exposure of brain tissue to current diagnostic ultrasound intensities may not be completely without risk.

Consensus guidelines for the diagnosis and management of isolated sulfite oxidase deficiency and molybdenum cofactor deficiencies.

Sulfite intoxication is the hallmark of four ultrarare disorders that are caused by impaired sulfite oxidase activity due to genetic defects in the synthesis of the molybdenum cofactor or of the apoenzyme sulfite oxidase. Delays on the diagnosis of these disorders are common and have been caused by their unspecific presentation of acute neonatal encephalopathy with high early mortality, followed by the evolution of dystonic cerebral palsy and also by the lack of easily available and reliable diagnostic tests. There is significant variation in survival and in the quality of symptomatic management of affected children. One of the four disorders, molybdenum cofactor deficiency type A (MoCD-A) has recently become amenable to causal treatment with synthetic cPMP (fosdenopterin). The evidence base for the rational use of cPMP is very limited. This prompted the formulation of these clinical guidelines to facilitate diagnosis and support the management of patients. The guidelines were developed by experts in diagnosis and treatment of sulfite intoxication disorders. It reflects expert consensus opinion and evidence from a systematic literature search.

Temporal Trends in Severe Brain Injury and Associated Outcomes in Very Preterm Infants.

INTRODUCTION: Severe brain injury (SBI), including severe intraventricular haemorrhage (sIVH) and cystic periventricular leukomalacia, poses significant challenges for preterm infants, yet recent data and trends are limited. METHODS: Analyses were conducted using the Australian and New Zealand Neonatal Network data on preterm infants born <32 weeks' gestation admitted at Monash Children's Hospital, Australia, from January 2014 to April 2021. The occurrence and trends of SBI and sIVH among preterm infants, along with the rates and trends of death and neurodevelopmental impairment (NDI) in SBI infants were assessed. RESULTS: Of 1,609 preterm infants, 6.7% had SBI, and 5.6% exhibited sIVH. A total of 37.6% of infants with SBI did not survive to discharge, with 92% of these deaths occurring following redirection of clinical care. Cerebral palsy was diagnosed in 65.2% of SBI survivors, while 86.4% of SBI survivors experienced NDI. No statistically significant differences were observed in the temporal trends of SBI (adjusted OR [95% CI] 1.08 [0.97-1.20]; p = 0.13) or sIVH (adjusted OR [95% CI] 1.09 [0.97-1.21]; p = 0.11). Similarly, there was no statistically significant difference noted in the temporal trend of the composite outcome, which included death or NDI among infants with SBI (adjusted OR [95% CI] 0.90 [0.53-1.53]; p = 0.71). CONCLUSION: Neither the rates of SBI nor its associated composite outcome of death or NDI improved over time. A notable proportion of preterm infants with SBI faced redirection of care and subsequent mortality, while most survivors exhibited adverse neurodevelopmental challenges. The development of better therapeutic interventions is imperative to improve outcomes for these vulnerable infants.

Preterm infants experience a nadir in cerebral oxygenation during sleep three months after hospital discharge.

AIM: Preterm infants are at increased risk of Sudden Infant Death Syndrome (SIDS) and frequently experience short central apnoeas which can occur in isolation or a repetitive pattern (periodic breathing). We investigated the relationship between central apnoeas experienced before and over the 6 months after hospital discharge and cerebral oxygenation. METHODS: Preterm infants born between 28 and 32 weeks gestational age (GA) were studied during supine daytime sleep at 32-36 weeks post menstrual age (PMA) (n = 40), 36-40 weeks PMA (n = 27), 3-months corrected age (CA) (n = 20) and 6-months CA (n = 26). Cerebral tissue oxygenation (TOI), peripheral oxygenation (SpO2) and heart rate were recorded continuously. The percentage total sleep time (%TST) spent having central apnoeas at each study and cerebral fractional oxygen extraction (SpO2-TOI/SpO2) were calculated. RESULTS: %TST spent with central apnoeas decreased with increasing age in both active sleep (AS) and quiet sleep (QS). TOI tended to be lower and cerebral fractional oxygen extraction higher at 3 months compared to the other studies and this reached statistical significance compared to 32-36 weeks in QS. CONCLUSION: The nadir in cerebral tissue oxygenation at 3 months of age coincides with the peak risk period for SIDS and this may contribute to increased risk in these infants.

The clinicopathological characteristics and survival outcomes of primary expansile vs. infiltrative mucinous ovarian adenocarcinoma: a retrospective study sharing the experience of a tertiary centre.

Background: Mucinous ovarian carcinomas (MOCs) are rare ovarian tumours accounting for 3% of all epithelial ovarian carcinomas (EOCs). They are either expansile or infiltrative, based on the tumour's histological pattern of invasion. MOCs have a distinct molecular profile, natural history, chemo-sensitivity, and prognosis compared to other EOCs. The aim of this study was to describe patient and tumour characteristics, as well as survival outcomes of expansile and infiltrative primary MOCs. Methods: This was a retrospective cohort study conducted at a tertiary cancer centre. Patients had surgery for primary MOC between Jul 1, 2010 and Oct 28, 2022. All patients discussed at the Oxford multidisciplinary team (MDT) meeting with a diagnosis of MOC were included. We excluded patients with mucinous metastatic carcinoma (MMC), dual histological diagnoses, those who died before treatment was initiated, and patients with incomplete records. Results: A total of 47 patients were identified and 14 were excluded. Out of the remaining 33 MOCs, 23 (70.6%) were expansile and 10 (30.4%) were infiltrative. The median follow-up was 37 months (95% CI: 14.1-69.8). Patients with infiltrative tumours were older than those with expansile tumours (median age 62 vs. 55 years, P=0.049). Infiltrative tumours were diagnosed at a more advanced International Federation of Gynaecology and Obstetrics (FIGO) stage compared to expansile tumours: FIGO stage II/III 50% vs. 8.2% (P=0.002). We found paired-box gene 8 (PAX8) more frequently expressed in expansile tumours (75% vs. 37.5%, P=0.099). Adjuvant treatment was administered in 50% of patients with infiltrative disease, compared to only 13% of those with expansile disease (P=0.036). 80% of patients who have relapsed had received adjuvant chemotherapy, compared to 17.2% of patients without relapse (P=0.012). At 3 years, there was a statistically significant difference in progression-free survival (PFS) (94.7% vs. 65.6%, P=0.02) between the expansile and infiltrative groups, but no difference in overall survival (OS) (88.8% vs. 90%, P=0.875). Conclusions: Patients with infiltrative tumours were older, more likely to have bilateral tumours and more likely to have an advanced FIGO stage at diagnosis. Adjuvant treatment was more likely to be administered to patients with infiltrative tumours, however, this did not prevent relapse. PFS at 3 years was significantly higher in patients with expansile tumours. PAX8 was more frequently expressed by expansile tumours.

Autonomic cardiovascular control is altered by intermittent hypoxia in preterm infants.

AIM: Preterm infants frequently experience short apnoeas and periodic breathing. Animal studies have shown that repetitive hypoxia associated with periodic breathing can alter autonomic control. We aimed to elucidate if apnoea and periodic breathing were associated with changes in autonomic control assessed using heart rate variability, thus exacerbating the consequences of respiratory disturbance. METHODS: Forty very preterm infants (15 M/25 F) were studied at 34.3 weeks post-menstrual age with daytime polysomnography. Total power, low frequency (LF, sympathetic+parasympathetic activity) high frequency (HF, parasympathetic activity) and LF/HF (sympathovagal balance) were calculated. RESULTS: Infants were divided into those with above and below the median total sleep time spent with respiratory events: Active sleep (AS) 13%, Quiet sleep (QS) 10%. In AS, including respiratory events, Total power (p < 0.05) and HF power (p < 0.05) were higher in the above median group. During AS excluding respiratory events, Total power (p < 0.05) and HF power (p = 0.061) were higher and LF power (p < 0.01) and LF/HF (p < 0.05) were lower in the above median group. There were no differences in HRV parameters in QS. CONCLUSION: This study provides new evidence that short apnoeas, particularly periodic breathing, which is currently not detected or treated in the neonatal unit can affect autonomic cardiovascular control.

Developmental consequences of short apneas and periodic breathing in preterm infants.

OBJECTIVE: We investigated the relationship between respiratory events experienced before and after hospital discharge and developmental outcomes at 6 months corrected age (CA). STUDY DESIGN: Preterm infants born between 28-32 weeks gestational age (GA) were studied at 32-36 weeks postmenstrual age (PMA), 36-40 weeks PMA, 3- and 6-months CA. Percentage total sleep time (%TST) with respiratory events (isolated apneas, sequential apneas and periodic breathing (PB)) at each study was calculated. Stepwise multiple linear regressions determined significant predictors of developmental outcomes at 6 months. RESULT: %TST with respiratory events at term were significant predictors of language (R2 = 0.165, ß = -0.416) and motor (R2 = 0.180, ß = -0.485) composite scores of the Bayley Scales of Infant Development at 6 months, independent of GA, birth weight and sex. CONCLUSIONS: In clinically stable very preterm infants at term equivalent age, time spent having respiratory events, was related to a reduction in language and motor outcomes at 6 months.

Near-infrared spectroscopy monitoring of neonatal cerebrovascular reactivity: where are we now?

Cerebrovascular reactivity defines the ability of the cerebral vasculature to regulate its resistance in response to both local and systemic factors to ensure an adequate cerebral blood flow to meet the metabolic demands of the brain. The increasing adoption of near-infrared spectroscopy (NIRS) for non-invasive monitoring of cerebral oxygenation and perfusion allowed investigation of the mechanisms underlying cerebrovascular reactivity in the neonatal population, confirming important associations with pathological conditions including the development of brain injury and adverse neurodevelopmental outcomes. However, the current literature on neonatal cerebrovascular reactivity is mainly still based on small, observational studies and is characterised by methodological heterogeneity; this has hindered the routine application of NIRS-based monitoring of cerebrovascular reactivity to identify infants most at risk of brain injury. This review aims (1) to provide an updated review on neonatal cerebrovascular reactivity, assessed using NIRS; (2) to identify critical points that need to be addressed with targeted research; and (3) to propose feasibility trials in order to fill the current knowledge gaps and to possibly develop a preventive or curative approach for preterm brain injury. IMPACT: NIRS monitoring has been largely applied in neonatal research to assess cerebrovascular reactivity in response to blood pressure, PaCO2 and other biochemical or metabolic factors, providing novel insights into the pathophysiological mechanisms underlying cerebral blood flow regulation. Despite these insights, the current literature shows important pitfalls that would benefit to be addressed in a series of targeted trials, proposed in the present review, in order to translate the assessment of cerebrovascular reactivity into routine monitoring in neonatal clinical practice.

Cerebral haemodynamic response to somatosensory stimulation in preterm lambs is enhanced following sildenafil and inhaled nitric oxide administration.

Background: Neurovascular coupling (NVC) leads to an increase in local cerebral blood flow and oxygenation in response to increased neural activity and metabolic demand. Impaired or immature NVC reported in the preterm brain, potentially reduces cerebral oxygenation following increased neural activity, predisposing to cerebral tissue hypoxia. Endogenous nitric oxide (NO) is a potent vasodilator and a major mediator of NVC and the cerebral haemodynamic response. NO modulators, such as inhaled nitric oxide (iNO) and sildenafil, induce vasodilation and are used clinically to treat pulmonary hypertension in preterm neonates. However, their impact on NVC in the preterm brain are unknown. We aimed to characterise the cerebral functional haemodynamic response in the preterm brain exposed to NO modulators. We hypothesized that iNO and sildenafil in clinical dosages would increase the baseline cerebral perfusion and the cerebral haemodynamic response to neural activation. Methods: Preterm lambs (126-7 days' gestation) were delivered and mechanically ventilated. The cerebral functional haemodynamic response was measured using near infrared spectroscopy as changes in cerebral oxy- and deoxyhaemoglobin (ΔoxyHb, ΔdeoxyHb), following left median nerve stimulations of 1.8, 4.8, and 7.8 s durations in control preterm lambs (n = 11), and following 4.8 and 7.8 s stimulations in preterm lambs receiving either sildenafil citrate (n = 6, 1.33 mcg/kg/hr) or iNO (n = 8, 20 ppm). Results: Following 1.8, 4.8, and 7.8 s stimulations, ∆oxyHb in the contralateral cortex increased (positive functional response) in 7/11 (64%), 7/11 (64%), and 4/11 (36%) control lambs respectively (p < 0.05). Remaining lambs showed decreased ΔoxyHb (negative functional response). Following 4.8 s stimulations, more lambs receiving sildenafil or iNO (83% and 100% respectively) showed positive functional response compared to the controls (p < 0.05). No significant difference between the three groups was observed at 7.8 s stimulations. Conclusion: In the preterm brain, prolonged somatosensory stimulations increased the incidence of negative functional responses with decreased cerebral oxygenation, suggesting that cerebral oxygen delivery may not match the oxygen demand. Sildenafil and iNO increased the incidence of positive functional responses, potentially enhancing NVC, and cerebral oxygenation.

Periodic breathing in clinically stable very preterm infants.

OBJECTIVE: We aimed to investigate the frequency and severity of periodic breathing (PB) in clinically stable very preterm infants and identify infant and maternal factors associated with increased time spent and severity of PB in these infants. METHOD: Thirty-eight infants (28-32 weeks gestational age) who were ≥3 days off noninvasive respiratory support, were studied for 2-3 h with a daytime sleep study at 31-36 weeks postmenstrual age. Percent total sleep time spent in PB (%TSTPB) and time spent with SpO2 <90%, <80%, and cerebral oxygenation <55% during PB were calculated. Infant and maternal characteristics were correlated with %TSTPB and hypoxia during PB. RESULTS: The majority of infants (92%) had at least one episode of PB and infants spent a median 9.1 [interquartile range: 1.2, 15.5] %TSTPB. 80%, 37%, and 37% of infants experienced SpO2 <90%, <80% and cerebral oxygenation <55%, respectively, during PB. Shorter duration of respiratory support, multigravida, multiparity, and maternal vitamin D deficiency were associated with higher %TSTPB. Multigravida, shorter duration on respiratory support, apnea of prematurity, and resuscitation at birth were associated with hypoxia during PB. CONCLUSIONS: The majority of very preterm infants exhibited PB when they were off respiratory support and considered clinically stable. The time spent in PB was very variable between infants and was associated with significant hypoxia in some infants. Fewer days spent on respiratory support was associated with both increased frequency and severity of PB. However, the potential contribution of PB to neurocognitive outcomes remains uncertain and warrants further investigations.

Duration and Consequences of Periodic Breathing in Infants Born Preterm Before and After Hospital Discharge.

OBJECTIVE: To investigate the amount of time spent in periodic breathing and its consequences in infants born preterm before and after hospital discharge. METHODS: Infants born preterm between 28-32 weeks of gestational age were studied during daytime sleep in the supine position at 32-36 weeks of postmenstrual age (PMA), 36-40 weeks of PMA, and 3 months and 6 months of corrected age. The percentage of total sleep time spent in periodic breathing (% total sleep time periodic breathing) was calculated and infants were grouped into below and above the median (8.5% total sleep time periodic breathing) at 32-36 weeks and compared with 36-40 weeks, 3 and 6 months. RESULTS: Percent total sleep time periodic breathing was not different between 32-36 weeks of PMA (8.5%; 1.5, 15.0) (median, IQR) and 36-40 weeks of PMA (6.6%; 0.9, 15.1) but decreased at 3 (0.4%; 0.0, 2.0) and 6 months of corrected age 0% (0.0, 1.1). Infants who spent above the median % total sleep time periodic breathing at 32-36 weeks of PMA spent more % total sleep time periodic breathing at 36-40 weeks of PMA (18.1%; 7.7, 23.9 vs 2.1%; 0.6, 6.4) and 6 months of corrected age 0.9% (0.0, 3.3) vs 0.0% (0.0, 0.0). CONCLUSIONS: Percentage sleep time spent in periodic breathing did not decrease as infants born preterm approached term corrected age, when they were to be discharged home. High amounts of periodic breathing at 32-36 weeks of PMA was associated with high amounts of periodic breathing at term corrected age (36-40 weeks of PMA), and persistence of periodic breathing at 6 months of corrected age.

Ganaxolone versus Phenobarbital for Neonatal Seizure Management.

OBJECTIVE: Seizures are more common in the neonatal period than at any other stage of life. Phenobarbital is the first-line treatment for neonatal seizures and is at best effective in approximately 50% of babies, but may contribute to neuronal injury. Here, we assessed the efficacy of phenobarbital versus the synthetic neurosteroid, ganaxolone, to moderate seizure activity and neuropathology in neonatal lambs exposed to perinatal asphyxia. METHODS: Asphyxia was induced via umbilical cord occlusion in term lambs at birth. Lambs were treated with ganaxolone (5mg/kg/bolus then 5mg/kg/day for 2 days) or phenobarbital (20mg/kg/bolus then 5mg/kg/day for 2 days) at 6 hours. Abnormal brain activity was classified as stereotypic evolving (SE) seizures, epileptiform discharges (EDs), and epileptiform transients (ETs) using continuous amplitude-integrated electroencephalographic recordings. At 48 hours, lambs were euthanized for brain pathology. RESULTS: Asphyxia caused abnormal brain activity, including SE seizures that peaked at 18 to 20 hours, EDs, and ETs, and induced neuronal degeneration and neuroinflammation. Ganaxolone treatment was associated with an 86.4% reduction in the number of seizures compared to the asphyxia group. The total seizure duration in the asphyxia+ganaxolone group was less than the untreated asphyxia group. There was no difference in the number of SE seizures between the asphyxia and asphyxia+phenobarbital groups or duration of SE seizures. Ganaxolone treatment, but not phenobarbital, reduced neuronal degeneration within hippocampal CA1 and CA3 regions, and cortical neurons, and ganaxolone reduced neuroinflammation within the thalamus. INTERPRETATION: Ganaxolone provided better seizure control than phenobarbital in this perinatal asphyxia model and was neuroprotective for the newborn brain, affording a new therapeutic opportunity for treatment of neonatal seizures. ANN NEUROL 2022;92:1066-1079.

The cerebral haemodynamic response to somatosensory stimulation in preterm newborn lambs is reduced following intrauterine inflammation and dopamine infusion.

BACKGROUND: Neurovascular coupling leads to an increase in local cerebral blood flow and oxygenation in response to increased neural activity. Reduced cerebral functional responses may predispose to tissue hypoxia when neural activity is increased. Intrauterine inflammation, identified clinically as chorioamnionitis, is a major contributor to the neuropathology arising after preterm birth. The impact of chorioamnionitis on the preterm cerebral functional haemodynamic response is unknown. Previously, we have reported that somatosensory stimulation produces predominantly positive cerebral haemodynamic responses (i.e., increased cerebral oxygenation) in preterm lambs, which are reduced with dopamine treatment. As preterm infants born after chorioamnionitis often suffer from hypotension and are treated with dopamine, we aimed to investigate how chorioamnionitis with and without dopamine treatment affect the cerebral haemodynamic response in preterm lambs. METHODS: At 119 days of gestation, intrauterine inflammation was induced by intra-amniotic injection of lipopolysaccharide (LPS) in pregnant ewes. At 126-7 days of gestation (term is ~147 days), these LPS-exposed lambs were delivered and mechanically ventilated. The cerebral functional response was assessed by near infrared spectroscopy as changes in cerebral oxy- and deoxyhaemoglobin (ΔoxyHb, ΔdeoxyHb), following left median nerve stimulation of 1.8, 4.8 and 7.8 s durations without dopamine; and 4.8 and 7.8 s stimulations with intravenous dopamine infusion. RESULTS: Stimulation for 1.8, 4.8 and 7.8 s durations led to negative functional responses (decreased ΔoxyHb) in 5 (62.5%), 5 (62.5%) and 4 (50%) of 8 preterm lambs respectively, while other lambs showed positive responses (increased ∆oxyHb). Dopamine infusion increased baseline tissue oxygenation index (TOI), oxyHb and total Hb. In lambs with a positive functional response, dopamine decreased the evoked ΔoxyHb response, increasing the overall incidence of negative cerebral haemodynamic responses. CONCLUSIONS: Somatosensory stimulation produced mostly negative responses with decreased cerebral oxygenation in preterm lambs exposed to intrauterine inflammation, contrasting with our previous findings of predominantly positive responses in non-inflamed, control, preterm lambs. Dopamine increased baseline cerebral oxygenation, but further increased the incidence of negative functional responses. Impaired neurovascular coupling leading to intermittent localised tissue hypoxia may therefore contribute to the neuropathy in infants with chorioamnionitis, with the risk of injury exacerbated with dopamine treatment.

Cerebral haemodynamic response to somatosensory stimulation in preterm lambs and 7-10-day old lambs born at term: Direct synchrotron microangiography assessment.

Neurovascular coupling has been well-defined in the adult brain, but variable and inconsistent responses have been observed in the neonatal brain. The mechanisms that underlie functional haemodynamic responses in the developing brain are unknown. Synchrotron radiation (SR) microangiography enables in vivo high-resolution imaging of the cerebral vasculature. We exploited SR microangiography to investigate the microvascular changes underlying the cerebral haemodynamic response in preterm (n = 7) and 7-10-day old term lambs (n = 4), following median nerve stimulation of 1.8, 4.8 and 7.8 sec durations.Increasing durations of somatosensory stimulation significantly increased the number of cortical microvessels of ≤200 µm diameter in 7-10-day old term lambs (p < 0.05) but not preterm lambs where, in contrast, stimulation increased the diameter of cerebral microvessels with a baseline diameter of ≤200 µm. Preterm lambs demonstrated positive functional responses with increased oxyhaemoglobin measured by near infrared spectroscopy, while 7-10-day old term lambs demonstrated both positive and negative responses. Our findings suggest the vascular mechanisms underlying the functional haemodynamic response differ between the preterm and 7-10-day old term brain. The preterm brain depends on vasodilatation of microvessels without recruitment of additional vessels, suggesting a limited capacity to mount higher cerebral haemodynamic responses when faced with prolonged or stronger neural stimulation.

Ventilatory control instability as a predictor of persistent periodic breathing in preterm infants.

BACKGROUND: Periodic breathing (PB) is common in preterm infants. We aimed to characterize the contribution of ventilatory control instability to the presence and persistence of PB longitudinally. METHODS: Infants born between 28 and 32 weeks of gestation were studied using daytime polysomnography at: 32-36 weeks postmenstrual age (PMA) (N = 32), 36-40 weeks PMA (N = 20), 3 months corrected age (CA) (N = 18) and 6 months CA (N = 19). Loop gain, a measure of sensitivity of the ventilatory control system, was estimated by fitting a mathematical model to ventilatory patterns associated with spontaneous sighs. RESULTS: The time spent in PB decreased from 32-36 weeks PMA to 6 months CA (P = 0.005). Across all studies, studies with PB (N = 62) were associated with higher loop gain compared to those without PB (N = 23) (estimated marginal mean ± SEM: 0.445 ± 0.01 vs 0.388 ± 0.02; P = 0.020). A threshold of loop gain >0.415 (measured at 32-36 weeks PMA) provided a sensitivity of 86% and a specificity of 75% to detect the presence of PB at 6 months CA. CONCLUSIONS: The course of PB in preterm infants is related to changes in loop gain. Higher loop gain at 32-36 weeks PMA was associated with a greater risk of persistent PB at 6 months CA. IMPACT: The developmental trajectory of periodic breathing and its relationship to ventilatory control instability is currently unclear. Unstable ventilatory control is a determinant of periodic breathing in preterm infants up to 6 months corrected age. Infants who display greater ventilatory control instability at 32-36 weeks postmenstrual age may be at increased risk of persistent periodic breathing at 6 months corrected age. Assessment of ventilatory control stability may assist in the early identification of infants at risk of persistent periodic breathing and its potential adverse effects.