Bedside and laboratory neuromonitoring in neonatal encephalopathy.

Several bedside and laboratory neuromonitoring tools are currently used in neonatal encephalopathy (NE) to assess 1) brain function [amplitude-integrated electroencephalogram (aEEG) and EEG], 2) cerebral oxygenation delivery and consumption [near-infrared spectroscopy (NIRS)] and 3) blood and cerebrospinal fluid biomarkers. The aim of the review is to provide the role of neuromonitoring in understanding the development of brain injury in these newborns and better predict their long-term outcome. Simultaneous use of these monitoring modalities may improve our ability to provide meaningful prognostic information regarding ongoing treatments. Evidence will be summarized in this review for each of these modalities, by describing (1) the methods, (2) the clinical evidence in context of NE both before and with hypothermia, and (3) the research and future directions.

Morphine affects brain activity and volumes in preterms: An observational multi-center study.

OBJECTIVE: We hypothesized that morphine has a depressing effect on early brain activity, assessed using quantitative aEEG/EEG parameter and depressed activity will be associated with brain volumes at term in extremely preterm infants. STUDY DESIGN: 174 preterm infants were enrolled in 3 European tertiary NICUs (mean GA:26 ± 1wks) and monitored during the first 72 h after birth with continuous 2 channel aEEG. Six epochs of aEEG recordings were selected and minimum amplitude of aEEG (min aEEG), percentage of time amplitude <5 µV (% of time < 5 µV), spontaneous activity transients (SATrate) and interSAT interval (ISI) were calculated. For infants receiving morphine, the cumulative morphine dosage was calculated. In a subgroup of 58 infants, good quality MRI at term equivalent age (TEA) and the cumulative morphine dose until TEA were available. The effects of morphine administration and cumulative dose on aEEG/EEG measures and on brain volumes were investigated. RESULTS: Morphine administration had a significant effect on all quantitative aEEG/EEG measures, causing depression of early brain activity [longer ISI (ß 2.900), reduced SAT rate (ß -1.386), decreased min aEEG (ß -0.782), and increased % of time < 5 µV (ß 14.802)] in all epochs. A significant effect of GA and postnatal age on aEEG/EEG measures was observed. Cumulative morphine dose until TEA had a significant negative effect on total brain volume (TBV) (ß -8.066) and cerebellar volume (ß -1.080). CONCLUSIONS: Administration of sedative drugs should be considered when interpreting aEEG/EEG together with the negative dose dependent morphine impact on brain development.

Efficacy and safety of lidocaine for treatment of neonatal seizures.

AIM: Treatment of neonatal seizures still relies primarily on phenobarbital, despite an estimated efficacy of less than 50% and concern over neurodegenerative side effects. The objective of this study was to evaluate the efficacy and safety of lidocaine as second-line treatment of neonatal seizures in infants following benzodiazepine treatment but without previous treatment with phenobarbital. METHODS: In a 10-year cohort, a retrospective chart review was conducted for all infants (gestational age ≥ 37 w, age ≤ 28 days) who had received lidocaine as second-line treatment of neonatal seizures prior to treatment with phenobarbital between January 2000 and June 2010. Infants were included if they had electroencephalographic seizures. RESULTS: Cessation of seizure activity was seen in 16 of 30 infants based on clinical and electroencephalographic features, and a probable response was seen in an additional 3 of 30 patients. Suspected adverse effects were seen in only one patient, who developed a transient bradycardia. CONCLUSION: Lidocaine has a moderate efficacy as second-line therapy following benzodiazepines for treating neonatal seizures and is not frequently associated with cardiovascular adverse effects. Lidocaine should therefore be considered in the treatment of seizures in the neonatal period to a higher extent than is the case today.

Early neurophysiology and MRI in predicting neurological outcome at 9-10 years after birth asphyxia.

OBJECTIVE: To assess whether early somatosensory evoked potentials (SEP) predict long-term neurodevelopmental outcome in normothermic, full-term infants with mild to moderate neonatal encephalopathy (NE), and to compare their predictive value to already available amplitude integrated EEG (aEEG) and magnetic resonance imaging (MRI). METHODS: Fifty-six infants with post-asphyxia NE were prospectively recruited, and their SEP, aEEG and MRI data were acquired during the first five days. Follow-up continued to 9-10 years for assessment of neuromotor and neurocognitive development. We analysed SEP latency (N1 component), normality of aEEG background pattern, as well as patterns of injury on the neonatal MRI. Neurological outcome measures at 9-10 years included conventional MRI, Movement-ABC and the WISC-III NL. RESULTS: A SEP latency <50 ms during the first five days was associated with a normal neuromotor outcome (p < 0.03), and a prolonged day 3 latency was associated with lower childhood IQ (p = 0.02). The presence of multiple seizures in aEEG, as well as a moderate or severe injury on the neonatal MRI was associated with a poor neuromotor score (p = 0.03 and p < 0.01, respectively). Combination of multiple techniques improved prediction of long-term outcome compared to single modality. CONCLUSION: Early SEPs provide information that is comparable to the already available aEEG and MRI paradigms in the prediction of long-term outcome of full-term infants with mild to moderate neonatal encephalopathy. SIGNIFICANCE: The present results call for further studies using early SEP to aid early assessment of infants treated with hypothermia.

The influence of age on the distribution of morphine and morphine-3-glucuronide across the blood-brain barrier in sheep.

BACKGROUND AND PURPOSE: The effect of age on the distribution of morphine and morphine-3-glucuronide (M3G) across the blood-brain barrier (BBB) was studied in a sheep model utilizing intracerebral microdialysis. The effect of neonatal asphyxia on brain drug distribution was also studied. EXPERIMENTAL APPROACH: Microdialysis probes were inserted into the cortex, striatum and blood of 11 lambs (127 gestation days) and six ewes. Morphine, 1 mg x kg(-1), was intravenously administered as a 10 min constant infusion. Microdialysis and blood samples were collected for up to 360 min and analysed using liquid chromatography-tandem mass spectrometry. The half-life, clearance, volume of distribution, unbound drug brain : blood distribution ratio (K(p,uu)) and unbound drug volume of distribution in brain (V(u,brain)) were estimated. KEY RESULTS: Morphine K(p,uu) was 1.19 and 1.89 for the sheep and premature lambs, respectively, indicating that active influx into the brain decreases with age. Induced asphyxia did not affect transport of morphine or M3G across the BBB. Morphine V(u,brain) measurements were higher in sheep than in premature lambs. The M3G K(p,uu) values were 0.27 and 0.17 in sheep and premature lambs, indicating a net efflux from the brain in both groups. CONCLUSIONS AND IMPLICATIONS: The morphine K(p,uu) was above unity, indicating active transport into the brain; influx was significantly higher in premature lambs than in adult sheep. These results in sheep differ from those in humans, rats, mice and pigs where a net efflux of morphine from the brain is observed.

Inflammation at birth and the insulin-like growth factor system in very preterm infants.

BACKGROUND: Foetal inflammation is associated with an increased risk of brain damage in preterm infants whereas IGF-I is essential for cerebral development and exhibits anti-apoptotic properties. AIM: To assess levels of IGF-I and IGF binding proteins at very preterm birth and to evaluate their relationship with foetal pro-inflammation and cerebral damage. METHODS: Levels of IGF-I, IGF binding protein 3 (IGFBP-3), high- (hp) and low-phosphorylated (lp) IGFBP-1 in cord blood and neonatal blood at 72 h after delivery were analysed in relation to levels of cytokines and cerebral damage as detected by ultrasound in 74 inborn infants [mean gestational age (GA) 27.1 weeks]. Evaluation was performed separately according to birth weight for GA. RESULTS: In cord blood of infants appropriate for gestational age (AGA) higher levels of IL-6 and IL-8 were associated with lower IGF-I (r =-0.38, p = 0.008 and r =-0.36, p = 0.014). Higher levels of IL-6, IL-8 and TNF-alpha were associated with both higher levels of lpIGFBP-1 (r = 0.54, p < 0.001, r = 0.50, p < 0.001 and r = 0.13, p = 0.012, respectively) and hpIGFBP-1 (r = 0.55, p < 0.001, r = 0.45, p = 0.002 and r = 0.32, p = 0.026, respectively). Infants with intraventricular haemorrhage grade III (n = 5) had higher levels of lp/hpIGFBP-1 in cord blood (p = 0.001 and 0.002, respectively). CONCLUSION: Pro-inflammation at birth is associated with changes in the IGF-system. This may be of importance for development of brain damage in preterm infants.

Role of cerebral function monitoring in the newborn.

For many years, newborn infants admitted to neonatal intensive care units have had routine electrocardiography and been monitored for respiratory rate, heart rate, oxygen saturation, and blood pressure. Only recently has it also been considered important to monitor brain function using continuous electroencephalography. The role of cerebral function monitoring in sick full term and preterm infants is reviewed.

Midazolam and amplitude-integrated EEG.

Amplitude-integrated EEG (aEEG) is currently used in an increasing number of neonatal intensive care units. The method has been practised in newborn infants for more than 20 y. However, it was not until recently, when the method proved to be accurate for very early prediction of outcome in asphyxiated newborn infants, that it gained more widespread neonatal use. The use of aEEG in units for neonatal intensive care has increased the awareness that sick infants develop subclinical seizure activity, and that several medications affect the aEEG background.

Preterm male infants need more initial respiratory and circulatory support than female infants.

AIM: The aim of this study was to investigate possible gender-related differences in clinical parameters during the first week of life that could explain the higher morbidity and mortality of preterm male infants. METHODS: In total, 130 clinical variables were collected from 236 inborn infants (130 male and 106 female infants) with gestational age (GA) < 29 wk. A subgroup of 175 extremely low birthweight infants (ELBW) < 1000 g (n = 86 males; n = 89 females) was analysed separately. RESULTS: At 6 postnatal h, 60.8% of the male infants needed mechanical ventilation versus 46.2% of the females (p = 0.026). Chronic lung disease (CLD) developed in 36.2% of males versus 9.8% of female infants (p = 0.004). Inotrope support with dopamine was used in more than 50% of the infants; additional inotrope support to dopamine was needed by 19.4% of male and 9.7% of female infants (p = 0.041). The gender-related difference in need for inotrope support was more evident among the ELBW infants; 67.1% of male infants needed inotrope support versus 50.6% of females (p = 0.028). At 12-24 h, male ELBW infants had lower minimum mean arterial blood pressure (mean (SD) 25(4) mmHg vs 28(6) mmHg, p = 0.004)) and lower minimum PaCO2 than females infants (4.3 (1.1) kPa vs 4.7 (0.9) kPa, p = 0.043). CONCLUSIONS: There are early gender-related differences in need for ventilatory and circulatory support that may contribute to the worse long-term outcome in prematurely born male infants.

Tolerance to early human milk feeding is not compromised by indomethacin in preterm infants with persistent ductus arteriosus.

AIM: Early human milk feeding is beneficial for gut and brain development. Persistent ductus arteriosus (PDA) and indomethacin may compromise enteral function in preterm infants. For many years enteral milk feedings have continued in preterm infants receiving indomethacin for PDA. The aim of this study was to investigate whether this strategy is efficient in terms of risks and tolerance to early enteral feeding. METHODS: This retrospective study included 64 inborn infants of <29 wk gestational age (GA), 32 infants who received indomethacin for symptomatic PDA (case infants) and 32 matched controls. Case infants had a mean (SD) GA of 26.3 wk (1.3) and body weight 839 g (203) versus controls GA 26.4 wk (1.2) and body weight 896 g (213) (p = 0.82 and 0.27, respectively). Case infants had higher respiratory morbidity; 90.6% versus 50% of controls needed mechanical ventilation (p = 0.000). RESULTS: Case infants received human milk from a median (range) age of 4.0 h (1.5-27.5), and controls from 5.3 h (2.0-38.0) (p = 0.092). The first dose of indomethacin was given at a mean age of 1.7 d (1.0). There were no differences between the two groups in feeding volumes or gastric residuals on days 1 to 7. Mean (SD) feeding volume on day 7 was 64 ml/kg (31) in case infants and 76 ml/kg (30) in controls (p = 0.23). Four infants developed necrotizing enterocolitis: two case infants and two controls (p = 1.00). CONCLUSION: Early enteral feeding with human milk, starting within the first hours of life, seems to be as well tolerated in preterm infants treated with indomethacin for PDA as in their matched controls.

Evaluation of screening procedures for congenital cataracts.

AIM: To evaluate the efficacy of two different Swedish screening procedures for early detection of congenital cataracts in comparison with no screening. METHODS: Children born between January 1992 and December 1998 in Swedish regions with an established eye-screening routine procedure, diagnosed with congenital cataract, and operated on before 1 y of age, were included in a retrospective study. Age at referral and age at time of the operation were compared between regions using different screening procedures: screening in the maternity wards (Region 1), at the well-baby clinics (Region 2) and one region without any screening (Region 3). RESULTS: Seventy-two children were included in the study. Concerning early diagnosis and surgery, Region 1 differed significantly from Regions 2 and 3, which were more similar and were combined for further analysis. The difference in detected cases was greatest at 21 d of age (55% vs 18%; p < 0.001), but persisted even at 100 d of age (78% vs 64%; p < 0.02). Region 1 screening resulted in more and earlier cases detected than the other two regions (22 vs 15 per 100,000 births). In 72% of all cases, surgery was performed in response to referrals from either the maternity wards (36%), or the well-baby clinics (36%). However, half of the cases from the well-baby clinics were detected too late, i.e. at > 100 d. CONCLUSION: Eye screening in the maternity ward is preferable to well-baby clinic screening and to no screening at all, since it leads to early detection. Screening should also be performed routinely at well-baby clinics within the period when successful treatment is possible.

Amplitude-integrated encephalography in pyridoxine-dependent seizures and pyridoxine-responsive seizures.

UNLABELLED: Pyridoxine-dependent seizures are rare in newborn infants, although recent data suggest that the prevalence probably is underestimated. In all newborn infants with recurrent epileptic seizures the general recommendation is to administer pyridoxine and simultaneously record an electroencephalogram (EEG). CONCLUSION: One infant with pyridoxine-responsive seizures and another with pyridoxine-dependent seizures had different electroclinical responses on amplitude-integrated EEG monitoring (aEEG) when pyridoxine was administered.

No indications of increased quiet sleep in infants receiving care based on the newborn individualized developmental care and assessment program (NIDCAP).

UNLABELLED: It has been proposed that the developmentally supportive care of very-low-birthweight (VLBW) infants provided by the Newborn Individualized Developmental Care and Assessment Program (NIDCAP) can improve the infants' opportunities for rest and sleep. The aim of the present study was to determine whether quiet sleep (QS) in VLBW infants is affected by NIDCAP care. Twenty-two infants with a gestational age of <32 wk at birth randomly received either NIDCAP (n = 11) or conventional care (n = 11). These two groups were comparable (mean (SD)) with respect to birthweight (1021 (240) vs 913 (362)g, respectively) and gestational age (27.1 (1.7) vs 26.4 (1.8) wk). The infants in the NIDCAP group were cared for in a separate room by a group of specially trained nurses and subjected to weekly NIDCAP observations until they reached a postconceptional age (PCA) of 36 wk. Quiet sleep (QS) was assessed from 24-h amplitude-integrated EEGs recorded at 32 and 36 wk of PCA. The percentage of time [mean (SD)] spent in QS at 32 wk of PCA was 33.5 (2.6) % for the NIDCAP group and 33.3 (6.9) % for the control infants (ns). At 36 wk, the corresponding values were 24.5 (3.2) % and 25.7 (4.7) %, respectively (ns). The number of QS periods/24 h decreased equally in both groups in association with maturation: from 24.6 (3.3) to 16.8 (1.8) and from 25.0 (5.8) to 17.5 (3.3), at 32 wk, and 36 wk of PCA, respectively (NS). CONCLUSIONS: There were no indications of increased QS at 32 or 36 wk of postconceptional age among VLBW infants who received care based on NIDCAP.

Reduced postnatal cerebral glucose metabolism measured by PET after asphyxia in near term fetal lambs.

The effects of fetal asphyxia on cerebral function and development, involve the transition from fetal to neonatal life. Changes in cerebral glucose metabolism may be an early postnatal indicator of fetal asphyxia. The objective is to develop an experimental lamb model involving the transition from fetal to neonatal life and to examine the effect of fetal asphyxia with cerebral hypoxic ischemia on early postnatal cerebral glucose metabolism. Fetal asphyxia was induced by total umbilical cord occlusion in eight near-term fetal lambs (134-138 days) with the ewe under isoflurane-opiate anesthesia. The mean occlusion time until cardiac arrest was 14.5 (4.2) min (SD). Lambs were immediately delivered and standardized resuscitation was instituted after 2 min asystole. At 4 hr postnatal age, [18-F]Fluoro-2-deoxy-glucose (18-FDG) was injected intravenously in eight asphyxiated lambs and in eight controls. Cerebral glucose metabolism was examined by positron emission tomography (PET). As a result the mean arterial blood pressure, acid-base values, blood glucose and serum lactate at 4 hr postnatal age did not differ significantly between lambs subjected to umbilical cord occlusion and controls. EEG was abnormal in all lambs subjected to cord occlusion and normal in the controls at 4 hr postnatal age. Global cerebral metabolic rate (CMRgl) as determined by PET was significantly lower in lambs subjected to cord occlusion mean/median (SD) 22.2/19.6 (8.4) micromol/min/100 g) than in controls mean/median (SD) 37.8/35.9 (6.1); P < 0.01). Global CMRgl is significantly reduced in newborn lambs 4 hr after fetal asphyxia induced by umbilical cord occlusion. A reduction in CMRgl is an early indicator of global hypoxic cerebral ischemia.

Short-term effects of incubator covers on quiet sleep in stable premature infants.

UNLABELLED: Incubator covers are increasingly being used in neonatal care as part of minimal disturbance strategies. The aim of this study was to examine possible effects of incubator covers on sleep patterns in stable premature infants. Quiet sleep (QS) can be investigated by amplitude-integrated electroencephalography (aEEG) at 32-34 wk gestational age. In nine premature infants (gestational ages 26-32 wk, median 29) QS periods were measured at a postconceptional age of 32-34 wk (median 34) during two consecutive 24 h periods, one period with a padded dark cover over the incubator and one period without the cover, in a randomized order. There were no significant differences between the two 24 h periods (with incubator cover and without cover, respectively) regarding the duration of the QS periods, the percentage of QS of the total recording time (%QS) or the duration of QS intervals. However, there was a positive correlation between postnatal age in days and the mean duration of QS periods when incubator covers were used (r = 0.90, p = 0.001). When the covers were used there was a difference between the girls and the boys in the duration of QS intervals (p = 0.032); the QS intervals increased in the five girls from median (range) 63.2 (49.4-94.6) min to 77.2 (59.3-100.9) min (p = 0.043). There was no difference in the duration of QS periods between girls and boys. CONCLUSION: Incubator covers seem to have some short-term effects on sleep quality in premature infants but the clinical significance and possible long-term effects are not known.

Long-distance transports of newborn infants with congenital heart disease.

Little has been published about specific problems that may occur during long-distance transports of newborn cardiac patients. During a 4-year period after centralization of pediatric heart surgery in Sweden, 286 transports were prospectively investigated. A majority (77.3%) of the transports were carried out by nonspecialized teams. Ten severe adverse events, including the death of 1 infant, occurred during the 286 transports (3.5%). Another infant died later of cerebral complications from hypoxia, rendering a transport-related mortality of 0.7%. Twenty-two infants (7.7%) were severely hypoxic (oxygen saturation < or =65%) at arrival, and 12 of these infants suffered from transposition of the great arteries. During the second 2-year period increased use of intravenous prostaglandin E1 and transportation from tertiary-level units was associated with better transport outcome. During the same time period, overall 30-day postoperative mortality for pediatric cardiac surgery decreased from 4.0% to 1.2% in our hospital. When highly specialized treatment is centralized for quality reasons it is also important that risks associated with transport are considered and that the quality of transport is high. For some cardiac malformations antenatal diagnosis and referral of the mother for delivery to a center with pediatric cardiac surgery would probably further increase the chance of healthy survival in some infants.

Early prediction of outcome with aEEG in preterm infants with large intraventricular hemorrhages.

BACKGROUND: The electrocortical background contains prognostic information in full-term asphyxiated newborn infants already during the first postnatal hours. In preterm infants with intra-ventricular hemorrhages (IVH) the background activity in EEG and amplitude-integrated EEG (aEEG) is depressed during the first days of life, and the extent of the depression correlates with the degree of IVH. However, it has not been previously evaluated whether very early aEEG can predict later outcome also in pre-term infants. OBJECTIVE: To investigate if early prediction of outcome is possible from aEEG in preterm infants with large IVH. METHODS: aEEG recordings from the first postnatal week were investigated in 64 preterm infants with IVH grade III - IV. For every 24-hour period the aEEG background pattern was classified, and the maximum and minimum numbers of bursts/h, respectively,were counted. Outcome was divided into three categories: died (n = 36), survived (n = 28) with "poor" outcome, i.e., severe cerebral palsy and not able to walk and/or mental retardation (n = 8), and survived with "fair" outcome, i.e., healthy or mild cerebral palsy (n = 19). One surviving child was lost in the follow-up. RESULTS: There were significant differences in maximum bursts/h (MaxB) at 0-24 hours (p = 0.033), 24-48 hours (p = 0.011), 48-72 hours (p=0.049) and 72-96 hours (p=0.032), respectively, between the infants who died and the surviving infants. At 24-48 hours the median (range) MaxB in the surviving infants with "fair" outcome was 156 (103-179) versus 102 (73-156) in the surviving infants with "poor" outcome (p = 0.002). With the assumption that MaxB < 130 was predictive of death or survival with "poor" outcome, 68 % and 78% of infants were correctly predicted at 0-24 hours and 24-48 hours, respectively. CONCLUSIONS: This study shows that outcome may be predicted with aEEG already during the first days of life in preterm infants with large IVH. The findings should be confirmed in prospective studies since they may have clinical implications if specific medical interventions become available.