Cerebral regional tissue Oxygen Saturation to Guide Oxygen Delivery in preterm neonates during immediate transition after birth (COSGOD III): an investigator-initiated, randomized, multi-center, multi-national, clinical trial on additional cerebral tissue oxygen saturation monitoring combined with defined treatment guidelines versus standard monitoring and treatment as usual in premature infants during immediate transition: study protocol for a randomized controlled trial.

BACKGROUND: Transition immediately after birth is a complex physiological process. The neonate has to establish sufficient ventilation to ensure significant changes from intra-uterine to extra-uterine circulation. If hypoxia or bradycardia or both occur, as commonly happens during immediate transition in preterm neonates, cerebral hypoxia-ischemia may cause perinatal brain injury. The primary objective of the COSGOD phase III trial is to investigate whether it is possible to increase survival without cerebral injury in preterm neonates of less than 32 weeks of gestation by targeting cerebral tissue oxygen saturation (crSO2) using specified clinical treatment guidelines during the immediate transition period after birth (the first 15 min) in addition to the routine monitoring of arterial oxygen saturation (SpO2) and heart rate (HR). METHODS/DESIGN: COSGOD III is an investigator-initiated, randomized, multi-center, multi-national, phase III clinical trial. Inclusion criteria are neonates of less than 32 weeks of gestation, decision to provide full life support, and parental informed consent. Exclusion criteria are severe congenital malformations of brain, heart, lung, or prenatal cerebral injury or a combination of these. The premature infants will be randomly assigned to study or control groups. Both groups will have a near-infrared spectroscopy (NIRS) device (left frontal), pulse oximeter (right palm/wrist), and electrocardiogram placed immediately after birth. In the study group, the crSO2, SpO2, and HR readings are visible, and the infant will receive treatment in accordance with defined treatment guidelines. In the control group, only SpO2 and HR will be visible, and the infant will receive routine treatment. The intervention period will last for the first 15 min after birth during the immediate transition period and resuscitation. Thereafter, each neonate will be followed up for primary outcome to term date or discharge. The primary outcome is mortality or cerebral injury (or both) defined as any intra-ventricular bleeding or cystic periventricular leukomalacia (or both). Secondary outcomes are neonatal morbidities. DISCUSSION: crSO2 monitoring during immediate transition has been proven to be feasible and improve cerebral oxygenation during immediate transition. The additional monitoring of crSO2 with dedicated interventions may improve outcome of preterm neonates as evidenced by increased survival without cerebral injury. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03166722 . Registered March 5, 2017.

Amplitude-integrated electroencephalography shows alterations in children born preterm displaying poor literacy precursor skills.

AIM: To assess whether amplitude-integrated electroencephalography (aEEG) alterations in the newborn period are associated with poor precursor skills of literacy at five years of age in children born preterm. METHODS: Between October 2007 and September 2011 248 preterm infants were eligible for the study at Innsbruck Medical University Hospital. aEEG was analysed for dominating background activity, calculation of the percentage of continuous activity, the Burdjalov scoring system, the minimum, mean and maximum amplitude. At the age of five years, we evaluated preterm born children by the Bielefelder screening (BISC) to assess for early diagnosis of reading problems and weak spelling and classified them as normal performers (n = 64) or poor performers (n = 20). Completion of testing was not possible for one infant. RESULTS: The minimum amplitude was significantly lower in the poor BISC performance group as compared to the normal BISC performance group at postnatal week two. The percentage of continuous background activity was significantly higher in infants with normal BISC performance than in infants with poor BISC performance at postnatal week three. CONCLUSION: Children with poor developed precursor skills of literacy showed alterations in aEEG signals. The aEEG could be useful in further diagnosing preterm infants at risk for developmental complications.

Outcome of infants born at < 32 weeks' gestation in a single-centre level III neonatology unit - relation to feeding strategy.

OBJECTIVE: This study aimed to determine survival, neonatal morbidity, and outcomes at 1 and 2 years in children who were born very preterm, and to analyse any relation to enteral feeding. METHODS: We performed a prospective, observational study on very preterm infants (range: 23-31 weeks' gestation) born at Innsbruck Medical University Hospital, Austria, between 2007 and 2014 (n = 557). RESULTS: The overall survival rate was 94.6%. Survival rates were 77.8%, 78.6%, 90.9%, and 90.9% among those born at 24, 25, 26, and 27 weeks, and 97.3%, 95.3%, 98.3%, and 100% among those born at 28, 29, 30, and 31 weeks of gestation, respectively. The overall prevalence of chronic lung disease among survivors was 7.3%. The prevalence of necrotizing enterocolitis requiring surgery, intraventricular haemorrhage grades 3 and 4, and severe retinopathy of prematurity was 3.1%, 2.1%, and 6.2%, respectively. There was no difference in short-term morbidity or neurodevelopmental outcome at 1 or 2 years of corrected age between infants who were fed with human milk at discharge and those who were formula-fed. CONCLUSION: In the current study, mortality and short-term morbidity rates were low. No differences regarding feeding strategy were detected.

The Cerebellar-Cerebral Microstructure Is Disrupted at Multiple Sites in Very Preterm Infants with Cerebellar Haemorrhage.

BACKGROUND: Recent advances in magnetic resonance imaging (MRI) techniques have prompted reconsideration of the anatomical correlates of adverse outcomes in preterm infants. The importance of the contribution made by the cerebellum is now increasingly appreciated. The effect of cerebellar haemorrhage (CBH) on the microstructure of the cerebellar-cerebral circuit is largely unexplored. OBJECTIVES: To investigate the effect of CBH on the microstructure of cerebellar-cerebral connections in preterm infants aged <32 gestational weeks. METHODS: Infants underwent diffusion tensor MRI at term-equivalent age. MRI was evaluated for CBH and additional supratentorial brain injury using a validated scoring system. Region of interest-based measures of brain microstructure (fractional anisotropy [FA] and apparent diffusion coefficient) were quantified in 5 vulnerable regions (the centrum semiovale, posterior limb of the internal capsule, corpus callosum, and superior and middle cerebellar peduncles). Group differences between infants with CBH and infants without CBH were assessed. RESULTS: There were 267 infants included in the study. Infants with CBH (isolated and combined) had significantly lower FA values in all regions investigated. Infants with isolated CBH showed lower FA in the middle and superior cerebellar peduncles and in the posterior limb of the internal capsule. CONCLUSIONS: This study provides evidence that CBH causes alterations in localised and remote WM pathways in the developing brain. The disruption of the cerebellar-cerebral microstructure at multiple sites adds further support for the concept of developmental diaschisis, which is propagated as an explanation for the consequences of early cerebellar injury on cognitive and affective domains.

Routine Magnetic Resonance Imaging at Term-Equivalent Age Detects Brain Injury in 25% of a Contemporary Cohort of Very Preterm Infants.

INTRODUCTION: In recent years, significant investigation has been undertaken by means of magnetic resonance imaging (MRI) in an attempt to identify preterm infants at risk for adverse outcome. The primary objective is to provide a comprehensive characterization of cerebral injury detected by conventional MRI at term-equivalent age in an unselected, consecutive, contemporary cohort of preterm infants born <32 gestational weeks. Secondly, this study aims to identify risk factors for the different injury types in this population. METHODS: Data for all preterm infants born <32 gestational weeks and admitted to Innsbruck Medical University Hospital were prospectively collected (October 2010 to December 2015). Cerebral MRI was evaluated retrospectively using a validated scoring system that incorporates intraventricular haemorrhage (IVH), white matter disease (WMD) and cerebellar haemorrhage (CBH). RESULTS: 300 infants were included in the study. MRI showed 24.7% of all infants to have some form of brain injury. The most common injury type was IVH (16.0%). WMD and CBH were seen in 10.0% and 8.0%. The prevalence of common neonatal risk factors was greater within the group of infants with CBH. In particular indicators for respiratory disease were observed more often: longer ventilation duration, more frequent need for supplemental oxygen at day 28, higher rates of hydrocortisone treatment. Catecholamine treatment was the only neonatal risk factor that was overrepresented in infants with WMD. DISCUSSION: Cerebral MRI at term-equivalent age, as addition to cranial ultrasound, detected brain injury in 25% of preterm survivors. The diagnosis of IVH was already made by neonatal ultrasound in most cases. In contrast, only a minority of the CBH and none of the non-cystic WMD have been detected prior to MRI. Decreasing gestational age and neonatal complications involved with immaturity have been identified as risk factors for CBH, whereas WMD was found in relatively mature infants with circulatory disturbances.

Case report of a central venous access device-associated thrombosis with aortic embolism in a preterm infant.

BACKGROUND: Thrombosis in neonates is commonly a central venous access device (CVAD) associated complication. Furthermore, a patent foramen ovale (PFO) is frequently seen in preterm infants. Even though a coincidence of both is not unusual, detaching of the thrombus and organisation of an aortic embolism has not been described until now. Treatment recommendations of CVAD-associated thrombosis in neonates do not consider frequently seen complications of preterm infants e.g. intraventricular haemorrhage. This is the first case of a very preterm infant with pre-existing intraventricular haemorrhage, who developed a CVAD-associated thrombosis and thromboembolic complications. CASE PRESENTATION: The authors report on a very preterm girl with a pre-existing intraventricular haemorrhage and a CVAD-associated thrombus that, after removal of the CVAD, led to assumed pulmonary embolism and to an extended aortic embolism with consequent cerebral stroke. The girl was treated with unfractionated heparin (UFH) for about 50 days. During the further in-hospital stay the girl developed a mild bronchopulmonary dysplasia. Follow-up revealed clinical signs of cerebral palsy. CONCLUSION: Even though preterm infants are often diagnosed with a PFO which constitutes the risk for paradoxical embolism, such complications do not occur frequently due to the physiological heart pressure proportion. Nevertheless, it is important to monitor vital parameters and cerebral perfusion after removing a CVAD with confirmed associated thrombosis, because thromboembolic complications are possible. If practicable, patients with a confirmed CVAD-associated thrombosis should be anticoagulated before removing the CVAD. However, in our patient it was rational to remove the CVAD without prior anticoagulation due to the pre-existing intraventricular haemorrhage. There are various treatment recommendations for thrombosis or embolism in infants. However, there are no clear recommendations in very preterm infants with a high risk of cerebral bleeding respectively a pre-existing intraventricular haemorrhage. We decided to treat our patient with unfractionated heparin until the affected vessels were recanalised. Finally, it remains a case-by-case decision how to treat CVAD-associated thrombosis and consequent embolism depending on the patient's medical history.

Sleep and Respiration in 100 Healthy Caucasian Sleepers--A Polysomnographic Study According to American Academy of Sleep Medicine Standards.

STUDY OBJECTIVES: Despite differences between American Academy of Sleep Medicine (AASM) and Rechtschaffen and Kales scoring criteria, normative values following the current AASM criteria are lacking. We investigated sleep and respiratory variables in healthy adults over the lifespan, and established polysomnographic normative values according to current standards. DESIGN: Prospective polysomnographic investigation. SETTING: Academic referral hospital sleep laboratory. PARTICIPANTS: One hundred healthy sleepers aged 19-77 y were selected from a representative population sample by a two-step screening. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: All subjects underwent one full-night polysomnography. Sleep and arousals were scored according to AASM standards. Respiration was scored according to AASM 2007 and 2012 criteria in order to compare both methods. Percentile curves showed age-related differences in sleep architecture: a decrease was found for sleep efficiency [≤ 30 y: 87.0 (71.9-94.1)% versus > 60 y: 79.7 (44.5-90.9)%], total sleep time [≤ 30 y: 413.5 (345.6-451.9) min versus > 60 y: 378.3 (216.0-440.0) min], the percentages of N3 [≤ 30 y 20.7 (15.2-37.5)% versus > 60 y: 14.9 (2.4-35.6)%] and rapid eye movement sleep [≤ 30 y 15.5 (7.5-23.6)% versus. > 60 y: 10.3 (1.9-21.9)%], whereas the percentage of wake time after sleep onset increased with age [≤ 30 y 6.0 (1.9-22.8)% versus > 60 y: 15.2 (6.3-48.7)%]. The apnea-hypopnea index (AHI) was higher when applying the AASM 2012 criteria [AHI AASM 2007 0.7 (0.0-21.5)/h versus 2012: 1.7 (0.0-25)/h; P < 0.001]. Eight percent of subjects had an AHI > 15/h. CONCLUSIONS: This study provides normative data on sleep macrostructure, microstructure, and respiration in adults following AASM standards. Furthermore, we demonstrated that respiration scoring according to AASM 2012 results in higher AHIs, and challenge the use of age-independent respiratory cutoff values.

Validation of an integrated software for the detection of rapid eye movement sleep behavior disorder.

STUDY OBJECTIVES AND DESIGN: Rapid eye movement sleep without atonia (RWA) is the polysomnographic hallmark of REM sleep behavior disorder (RBD). To partially overcome the disadvantages of manual RWA scoring, which is time consuming but essential for the accurate diagnosis of RBD, we aimed to validate software specifically developed and integrated with polysomnography for RWA detection against the gold standard of manual RWA quantification. SETTING: Academic referral center sleep laboratory. PARTICIPANTS: Polysomnographic recordings of 20 patients with RBD and 60 healthy volunteers were analyzed. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Motor activity during REM sleep was quantified manually and computer assisted (with and without artifact detection) according to Sleep Innsbruck Barcelona (SINBAR) criteria for the mentalis ("any," phasic, tonic electromyographic [EMG] activity) and the flexor digitorum superficialis (FDS) muscle (phasic EMG activity). Computer-derived indices (with and without artifact correction) for "any," phasic, tonic mentalis EMG activity, phasic FDS EMG activity, and the SINBAR index ("any" mentalis + phasic FDS) correlated well with the manually derived indices (all Spearman rhos 0.66-0.98). In contrast with computerized scoring alone, computerized scoring plus manual artifact correction (median duration 5.4 min) led to a significant reduction of false positives for "any" mentalis (40%), phasic mentalis (40.6%), and the SINBAR index (41.2%). Quantification of tonic mentalis and phasic FDS EMG activity was not influenced by artifact correction. CONCLUSION: The computer algorithm used here appears to be a promising tool for REM sleep behavior disorder detection in both research and clinical routine. A short check for plausibility of automatic detection should be a basic prerequisite for this and all other available computer algorithms.

A prospective questionnaire study in 100 healthy sleepers: non-bothersome forms of recognizable sleep disorders are still present.

STUDY OBJECTIVES: Despite several polysomnographic normative studies and multiple surveys of sleep disorders in the general population, few data have been collected on healthy sleepers. We aimed to survey the characteristics of healthy sleep. METHODS: We prospectively investigated the sleep history of 100 subjects of a representative population sample who reported undisturbed sleep and in whom relevant sleep disorders were ruled out by a two-step screening procedure. Approximately four subjects had to be contacted for identifying 1 eligible subject who participated. RESULTS: The median reported time in bed was from 23:00 (21:30-02:00) to 07:00 (05:30-11:00). The total sleep duration was 7.3 h (5-10 h), varying from 7.5 h in the age group ≤ 30 years to 7 h in subjects aged 40-60 years and to 8 h in subjects > 60 years (p = 0.002). The median sleep efficiency was high (93.3%, range: 55.6% to 100%). Fifty-one subjects reported occasional snoring. Forty-five subjects reported sporadic non-bothersome sleep-related movement disorders (25 sleep-related leg cramps, 22 lifetime bruxism, 5 restless legs syndrome), and 36 had a history of sporadic non-bothersome parasomnias (27 nightmares, 12 sleepwalking, 1 sleep paralysis). CONCLUSION: In this population of healthy sleepers, snoring is the most common finding. Moreover, non-bothersome forms of recognizable sleep-related movement disorders and parasomnias are surprisingly common. These findings may suggest that diagnostic criteria of sleep disorders should not only be based on the presence of symptoms but also account for a minimum frequency or discomfort.

Motor events during healthy sleep: a quantitative polysomnographic study.

STUDY OBJECTIVES: Many sleep disorders are characterized by increased motor activity during sleep. In contrast, studies on motor activity during physiological sleep are largely lacking. We quantitatively investigated a large range of motor phenomena during polysomnography in physiological sleep. DESIGN: Prospective polysomnographic investigation. SETTING: Academic referral sleep laboratory. PARTICIPANTS: One hundred healthy sleepers age 19-77 y were strictly selected from a representative population sample by a two-step screening procedure. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Polysomnography according to American Academy of Sleep Medicine (AASM) standards was performed, and quantitative normative values were established for periodic limb movements in sleep (PLMS), high frequency leg movements (HFLM), fragmentary myoclonus (FM), neck myoclonus (NM), and rapid eye movement (REM)-related electromyographic (EMG) activity. Thirty-six subjects had a PLMS index > 5/h, 18 had a PLMS index > 15/h (90th percentile: 24.8/h). Thirty-three subjects had HFLM (90th percentile: four sequences/night). All subjects had FM (90th percentile 143.7/h sleep). Nine subjects fulfilled AASM criteria for excessive FM. Thirty-five subjects had NM (90th percentile: 8.8/h REM sleep). For REM sleep, different EMG activity measures for the mentalis and flexor digitorum superficialis muscles were calculated: the 90th percentile for phasic mentalis EMG activity for 30-sec epochs according to AASM recommendation was 15.6%, and for tonic mentalis EMG activity 2.6%. Twenty-five subjects exceeded the recently proposed phasic mentalis cutoff of 11%. None of the subjects exceeded the tonic mentalis cutoff of 9.6%. CONCLUSION: Quantification of motor phenomena is a basic prerequisite to develop normative values, and is a first step toward a more precise description of the various motor phenomena present during sleep. Because rates of motor events were unexpectedly high even in physiological sleep, the future use of normative values for both research and clinical routine is essential.