Quantitative EEG and prediction of outcome in neonatal encephalopathy: a review.

Electroencephalogram (EEG) is an important biomarker for neonatal encephalopathy (NE) and has significant predictive value for brain injury and neurodevelopmental outcomes. Quantitative analysis of EEG involves the representation of complex EEG data in an objective, reproducible and scalable manner. Quantitative EEG (qEEG) can be derived from both a limited channel EEG (as available during amplitude integrated EEG) and multi-channel conventional EEG. It has the potential to enable bedside clinicians to monitor and evaluate details of cortical function without the necessity of continuous expert input. This is particularly useful in NE, a dynamic and evolving condition. In these infants, continuous, detailed evaluation of cortical function at the bedside is a valuable aide to management especially in the current era of therapeutic hypothermia and possible upcoming neuroprotective therapies. This review discusses the role of qEEG in newborns with NE and its use in informing monitoring and therapy, along with its ability to predict imaging changes and short and long-term neurodevelopmental outcomes. IMPACT: Quantitative representation of EEG data brings the evaluation of continuous brain function, from the neurophysiology lab to the NICU bedside and has a potential role as a biomarker for neonatal encephalopathy. Clinical and research applications of quantitative EEG in the newborn are rapidly evolving and a wider understanding of its utility is valuable. This overview summarizes the role of quantitative EEG at different timepoints, its relevance to management and its predictive value for short- and long-term outcomes in neonatal encephalopathy.

Acute Diffusion-Weighted Imaging Signaling Severe Periventricular Leukomalacia in Preterm Infants: Case Report and Review of Literature.

Introduction: Periventricular leukomalacia occurs in up to 25% of very preterm infants resulting in adverse neurodevelopmental outcomes. In its acute phase, periventricular leukomalacia is clinically silent. Although ultrasonography is widely available, its sensitivity in the early detection of periventricular leukomalacia is low. Case Report and Published Literature: We identified a preterm infant with early diffusion-weighted imaging changes that later evolved to periventricular leukomalacia. Thirty-two cases of abnormal diffusion-weighted imaging reliably heralding severe periventricular leukomalacia in the preterm infant have been published in the literature. Notable features include the following: (1) infants were more mature preterm infants (29-36 weeks' gestation); (2) findings were often serendipitous with benign clinical courses; (3) diffusion-weighted imaging changes only were evident in the first weeks of life with later evolution to more classical abnormalities on conventional magnetic resonance imaging (MRI) or ultrasonography. Conclusion: Diffusion-weighted imaging in the first week of life may be a reliable early marker of severe periventricular leukomalacia injury in more mature preterm infants.

Differences between early and late MRI in infants with neonatal encephalopathy following therapeutic hypothermia.

BACKGROUND: MRI is the gold standard test to define brain injury in infants with neonatal encephalopathy(NE). As imaging findings evolve considerably over the first week, early imaging may not fully reflect the final nature of the injury. This study aimed to compare day 4 versus second week MRI in infants with NE. METHODS: Retrospective cohort study including infants who received therapeutic hypothermia(TH) for NE and had two MRIs: early (≤7days) and late (>7days). MRIs were clinically reported and also reviewed by study investigators. RESULTS: 94infants with NE were included (40mild,49moderate,5severe). Twenty-four infants(26%) had a normal early scan of which 3/24(13%) had injury noted on repeat MRI. Seventy infants(74%) had abnormal findings noted on early MRI, of which 4/70(6%) had further evolution of injury while 11/70(16%) had complete resolution of findings. Applying a grading system resulted in a change of grade in 7 infants. CONCLUSION: In infants who received TH for NE, 19% had changes noted between their early and late MRIs. While the impact on predicting neurodevelopmental outcome was not studied, relying solely on early MRI may overestimate injury in a proportion of infants and miss injury in others. Combining early and late MRI allows for better characterization of injury. IMPACT: MRI is the gold standard tool to define brain injury in infants with NE, however, imaging findings evolve considerably over the first week of life. Most centers perform a single MRI on day 4 after rewarming. In our cohort, 19% of infants had a notable change in their MRI findings between early (within the first week) and late (beyond the first week) scans. Relying solely on early MRI may overestimate injury in a proportion of infants and miss injury in others. Combining early and late MRI following hypothermia allows for better characterization of brain injury.

Novel metrics to characterize temporal lobe of very preterm infants on term-equivalent brain MRI.

BACKGROUND: Preterm birth adversely impacts brain development and contributes to neurodevelopmental impairment; the temporal lobe may be particularly vulnerable to the impact of very preterm (VP) birth. Yet, no prior magnetic resonance imaging (MRI) scoring system incorporated a method to quantify temporal lobe size in VP infants. METHODS: We developed and applied three metrics (temporal lobe length, extra-axial space, and temporal horn width) to quantify temporal lobe structure on term-equivalent brain MRIs obtained from 74 VP and 16 term infants. We compared metrics between VP and term infants and explored associations of each metric with perinatal risk factors. RESULTS: All metrics had excellent reliability (intra-class correlation coefficient 0.62-0.98). VP infants had lower mean temporal lobe length (76.8 mm versus 79.2 mm, p = 0.02); however, the difference attenuated after correction for postmenstrual age. VP infants had larger temporal horn widths compared with term infants (2.6 mm versus 1.8 mm, p < 0.001). Temporal lobe length was positively associated with gestational age, birth weight, and male sex, and negatively associated with the duration of parenteral nutrition. CONCLUSIONS: The proposed metrics are reliable and sensitive in distinguishing differences in temporal lobe development between VP and full-term infants. IMPACT: We developed a novel method for quantifying temporal lobe size among very preterm infants at term equivalent using simple metrics performed on brain MRI. Temporal lobe metrics were reliable, correlated with brain volume from volumetric analysis, and were sensitive in identifying differences in temporal lobe development among preterm compared with term infants, specifically larger temporal horn size in preterm infants. This temporal lobe metric system will enable future work to delineate the perinatal and postnatal factors that impact temporal lobe growth, and better understand the relationship between temporal lobe disturbance and neurodevelopment in very preterm infants.

Brain Injury in Infants Evaluated for, But Not Treated with, Therapeutic Hypothermia.

Defining neonatal encephalopathy clinically to qualify for therapeutic hypothermia is challenging. This study examines magnetic resonance imaging outcomes of 39 infants who were evaluated and not cooled using criteria inclusive of mild encephalopathy. Infants evaluated for therapeutic hypothermia are at risk for brain injury and may benefit from neuroimaging and follow-up.

Non-invasive continuous cardiac output monitoring in infants with hypoxic ischaemic encephalopathy.

OBJECTIVE: To describe early, continuous, non-invasive measures of cardiac output (CO) and evolution over time in infants with hypoxic-ischaemic encephalopathy (HIE). STUDY DESIGN: Prospective observational study of 44 infants with HIE (23 mild, 17 moderate, 4 severe) and 17 term controls. Infants with HIE had non-invasive CO monitoring (NICOM) continuously in the neonatal unit. Term controls had NICOM recorded at 6 and 24 h. A mixed-modelling approach was used to assess change in CO over time by group. RESULTS: Infants with moderate HIE have significantly lower CO than the mild group at all timepoints (10.7 mls/kg/min lower, 95% CI:1.0,20.4, p = 0.03) which increases over time, driven by a gradual increase in stroke volume (SV). CO increased further during rewarming predominantly due to an increase in HR. CONCLUSION: TH has a significant impact on HR but SV appears largely unaffected. NICOM may provide a non-invasive, continuous, low-cost alternative to monitoring CO in infants with HIE however further research is warranted.

Evolution of early cerebral NIRS in hypoxic ischaemic encephalopathy.

AIM: To describe early cerebral oxygenation (cSO2 ) and fractional tissue oxygen extraction (FTOE) values and their evolution over the first days of life in infants with all grades of hypoxic-ischaemic encephalopathy (HIE) and to determine whether cSO2 and FTOE measured early (6 and 12 h) can predict short-term outcome. METHODS: Prospective, observational study of cerebral near-infrared spectroscopy (NIRS) in infants >36 weeks' gestation with HIE. Ten one-hour epochs of cSO2 and FTOE were extracted for each infant over the first 84 h. Infants with moderate and severe HIE received therapeutic hypothermia (TH). Abnormal outcome was defined as abnormal magnetic resonance imaging (MRI) and/or death. RESULTS: Fifty-eight infants were included (28 mild, 24 moderate, 6 severe). Median gestational age was 39.9 weeks (IQR 38.1-40.7) and birthweight was 3.35 kgs (IQR 2.97-3.71). cSO2 increased and FTOE decreased over the first 24 h in all grades of HIE. Compared to the moderate group, infants with mild HIE had significantly higher cSO2 at 6 h (p = 0.003), 9 h (p = 0.009) and 12 h (p = 0.032) and lower FTOE at 6 h (p = 0.016) and 9 h (0.029). cSO2 and FTOE at 6 and 12 h did not predict abnormal outcome. CONCLUSION: Infants with mild HIE have higher cSO2 and lower FTOE than those with moderate or severe HIE in the first 12 h of life. cSO2 increased in all grades of HIE over the first 24 h regardless of TH status.

Pathogenesis and prevention of intraventricular hemorrhage.

Despite improvements in the mortality rates of preterm infants, rates of germinal matrix intraventricular hemorrhage (IVH) have remained static with an overall incidence of 25% in infants less than 32 weeks. The importance of the lesion relates primarily to the underlying injury to the developing brain and the associated long-term neurodevelopmental consequences. This clinical-orientated review focuses on the pathogenesis of IVH and discusses the evidence behind proposed prevention strategies.

Does Early Cerebral Near-Infrared Spectroscopy Monitoring Predict Outcome in Neonates with Hypoxic Ischaemic Encephalopathy? A Systematic Review of Diagnostic Test Accuracy.

INTRODUCTION: Hypoxic ischaemic encephalopathy (HIE) remains one of the top 10 contributors to the global burden of disease. Early objective biomarkers are required. Near-infrared spectroscopy (NIRS) may provide a valuable insight into cerebral perfusion and metabolism. We aimed to determine whether early NIRS monitoring (<6 h of age) can predict outcome as defined by grade of encephalopathy, brain MRI findings, and/or neurodevelopmental outcome at 1-2 years in infants with HIE. METHODS: We searched PubMed, Scopus, Web of Science, Embase, and The Cochrane Library databases (July 2019). Studies of infants born ≥36+0 weeks gestation with HIE who had NIRS recording commenced before 6 h of life were included. We planned to provide a narrative of all the studies included, and if similar clinically and methodologically, the results would be pooled in a meta-analysis to determine test accuracy. RESULTS: Seven studies were included with a combined total of 161 infants. Only 1 study included infants with mild HIE. A range of different oximeters and probes were utilized with varying outcome measures making comparison difficult. Although some studies showed a trend towards higher cSO2 values before 6 h in infants with adverse neurodevelopmental outcomes, in the majority, this was not significant until beyond 24 h of life. CONCLUSION: Very little data currently exists to assess the use of early NIRS to predict outcome in infants with HIE. Further studies using a standardized approach are required before NIRS can be evaluated as a potential objective assessment tool for early identification of at-risk infants.

Novel Point-of-Care Diagnostic Method for Neonatal Encephalopathy Using Purine Nucleosides.

Background: Evidence suggests that earlier diagnosis and initiation of treatment immediately after birth is critical for improved neurodevelopmental outcomes following neonatal encephalopathy (NE). Current diagnostic tests are, however, mainly restricted to clinical diagnosis with no molecular tests available. Purines including adenosine are released during brain injury such as hypoxia and are also present in biofluids. Whether blood purine changes can be used to diagnose NE has not been investigated to date. Methods: Blood purines were measured in a mouse model of neonatal hypoxia and infants with NE using a novel point-of-care diagnostic technology (SMARTChip) based on the summated electrochemical detection of adenosine and adenosine metabolites in the blood. Results: Blood purine concentrations were ∼2-3-fold elevated following hypoxia in mice [2.77 ± 0.48 µM (Control) vs. 7.57 ± 1.41 µM (post-hypoxia), p = 0.029]. Data in infants with NE had a 2-3-fold elevation when compared to healthy controls [1.63 ± 0.47 µM (Control, N = 5) vs. 4.87 ± 0.92 µM (NE, N = 21), p = 0.0155]. ROC curve analysis demonstrates a high sensitivity (81%) and specificity (80%) for our approach to identify infants with NE. Moreover, blood purine concentrations were higher in infants with NE and seizures [8.13 ± 3.23 µM (with seizures, N = 5) vs. 3.86 ± 0.56 µM (without seizures, N = 16), p = 0.044]. Conclusion: Our data provides the proof-of-concept that measurement of blood purine concentrations via SMARTChip technology may offer a low-volume bedside test to support a rapid diagnosis of NE.

Multichannel EEG abnormalities during the first 6 hours in infants with mild hypoxic-ischaemic encephalopathy.

BACKGROUND: Infants with mild HIE are at risk of significant disability at follow-up. In the pre-therapeutic hypothermia (TH) era, electroencephalography (EEG) within 6 hours of birth was most predictive of outcome. This study aims to identify and describe features of early EEG and heart rate variability (HRV) (<6 hours of age) in infants with mild HIE compared to healthy term infants. METHODS: Infants >36 weeks with mild HIE, not undergoing TH, with EEG before 6 hours of age were identified from 4 prospective cohort studies conducted in the Cork University Maternity Services, Ireland (2003-2019). Control infants were taken from a contemporaneous study examining brain activity in healthy term infants. EEGs were qualitatively analysed by two neonatal neurophysiologists and quantitatively assessed using multiple features of amplitude, spectral shape and inter-hemispheric connectivity. Quantitative features of HRV were assessed in both the groups. RESULTS: Fifty-eight infants with mild HIE and sixteen healthy term infants were included. Seventy-two percent of infants with mild HIE had at least one abnormal EEG feature on qualitative analysis and quantitative EEG analysis revealed significant differences in spectral features between the two groups. HRV analysis did not differentiate between the groups. CONCLUSIONS: Qualitative and quantitative analysis of the EEG before 6 hours of age identified abnormal EEG features in mild HIE, which could aid in the objective identification of cases for future TH trials in mild HIE. IMPACT: Infants with mild HIE currently do not meet selection criteria for TH yet may be at risk of significant disability at follow-up. In the pre-TH era, EEG within 6 hours of birth was most predictive of outcome; however, TH has delayed this predictive value. 72% of infants with mild HIE had at least one abnormal EEG feature in the first 6 hours on qualitative assessment. Quantitative EEG analysis revealed significant differences in spectral features between infants with mild HIE and healthy term infants. Quantitative EEG features may aid in the objective identification of cases for future TH trials in mild HIE.

Feasibility of non-invasive cardiac output monitoring at birth using electrical bioreactance in term infants.

BACKGROUND: Non-invasive cardiac output monitoring (NICOM) provides continuous estimation of cardiac output. This has potential for use in the delivery suite in the management of acutely depressed term infants. This study aims to measure cardiac output in term infants at delivery and in the first hours of life. METHODS: Parents of term infants due to be born by elective caesarean section or vaginal delivery at Cork University Maternity Hospital, Ireland were approached in the antenatal period to participate. Cardiac output was measured using a CHEETAH NICOM device, which uses electrical bioreactance technology, at birth and at 2 hours of life. RESULTS: Forty-nine newborns were included. The median gestational age was 39 (IQR: 39-40) weeks and the median birth weight was 3.50 (IQR: 3.14-3.91) kg. Cardiac output measurements were obtained at a median of 8 (IQR: 5-12) min of life. The mean (SD) cardiac output was 101 (24) mL/kg/min in the delivery room and 89 (22) mL/kg/min at 2 hours of life. There was a statistically significant decrease in cardiac output from birth to 2 hours of life (difference in mean (95% CI): 13.5 (9.2 to 17.9) mL/kg/min, p<0.001, n=47). There were no adverse effects associated with NICOM. DISCUSSION: This technique is feasible and safe in the delivery room. Mean cardiac output measures using NICOM are lower than those found in studies which used echocardiography to determine cardiac output at birth.

Simulation in Neonatal Resuscitation.

Approximately 1 in 10 newborns will require basic resuscitation interventions at birth. Some infants progress to require more advanced measures including the provision of positive pressure ventilation, chest compressions, intubation and administration of volume/cardiac medications. Although advanced resuscitation is infrequent, it is crucial that personnel adequately trained in these techniques are available to provide such resuscitative measures. In 2000, Louis Halmalek et al. called for a "New Paradigm in Pediatric Medical Education: Teaching Neonatal Resuscitation in a Simulated Delivery Room Environment." This was one of the first articles to highlight simulation as a method of teaching newborn resuscitation. The last decades have seen an exponential growth in the area of simulation in newborn care, in particular in newborn resuscitation and stabilization. Simulation is best defined as an instructional strategy "used to replace or amplify real experiences with guided experiences that evoke or replicate substantial aspects of the real world in a fully interactive manner." Simulation training has now become an important point of how we structure training and deliver improved healthcare to patients. Some of the key aspects of simulation training include feedback, deliberate practice, outcome measurement, retention of skills and curriculum integration. The term "Train to win" is often used in sporting parlance to define how great teams succeed. The major difference between sports teams is that generally their game day comes once a week, whereas in newborn resuscitation every day is potentially "game day." In this review we aim to summarize the current evidence on the use of simulation based education and training in neonatal resuscitation, with particular emphasis on the evidence supporting its effectiveness. We will also highlight recent advances in the development of simulation based medical education in the context of newborn resuscitation to ensure we "train to win."

Non-invasive Cardiac Output Monitoring in Neonates.

Circulatory monitoring is currently limited to heart rate and blood pressure assessment in the majority of neonatal units globally. Non-invasive cardiac output monitoring (NiCO) in term and preterm neonates is increasing, where it has the potential to enhance our understanding and management of overall circulatory status. In this narrative review, we summarized 33 studies including almost 2,000 term and preterm neonates. The majority of studies evaluated interchangeability with echocardiography. Studies were performed in various clinical settings including the delivery room, patent ductus arteriosus assessment, patient positioning, red blood cell transfusion, and therapeutic hypothermia for hypoxic ischemic encephalopathy. This review presents an overview of NiCO in neonatal care, focusing on technical and practical aspects as well as current available evidence. We discuss potential goals for future research.

Interpretation of Cerebral Oxygenation Changes in the Preterm Infant.

Near-infrared spectroscopy (NIRS) allows for continuous, non-invasive monitoring of end-organ tissue oxygenation. The use of NIRS, cerebral NIRS (cNIRS) in particular, in neonatal care has increased significantly over the last few years. This dynamic monitoring technique provides real-time information on the cerebral and haemodynamic status of the neonate and has the potential to serve as an important adjunct to patient care with some centres routinely utilising cNIRS to aid decision-making at the bedside. cNIRS values may be influenced by many variables, including cardiac, respiratory and metabolic parameters, and therefore it is essential to understand the pathophysiology behind alterations in cNIRS values. Correct interpretation is required to direct appropriate patient-specific interventions. This article aims to assist clinicians in deciphering cNIRS values by providing an overview of potential causes of fluctuations in cNIRS values, illustrated by common clinical scenarios, with particular emphasis on the preterm infant.

Inotropes for Preterm Infants: 50 Years on Are We Any Wiser?

For almost half a century, inotropes have been administered to preterm infants with the ultimate goal of increasing their blood pressure. A number of trials, the majority of which focused on dopamine administration, have demonstrated increased blood pressure following inotrope administration in preterm infants and have led to continued use of inotropes in our neonatal units. We have also seen an increase in the number of potential agents available to the clinician. However, we now know that hypotension is a much broader concept than blood pressure alone, and our aim should instead be focused on improving end organ perfusion, specifically cerebral perfusion. Only a limited number of studies have incorporated the organ-relevant hemodynamic changes and long-term outcomes when assessing inotropic effects in neonates, the majority of which are observational studies or have a small sample size. In addition, important considerations, including the developing/maturing adrenergic receptors, polymorphisms of these receptors, and other differences in the pharmacokinetics and pharmacodynamics of preterm infants, are only recently being recognized. Certainly, there remains huge variation in practice. The lack of well-conducted randomized controlled trials addressing these relevant outcomes, along with the difficulty executing such RCTs, leaves us with more questions than answers. This review provides an overview of the various inotropic agents currently being used in the care of preterm infants, with a particular focus on their organ/cerebral hemodynamic effects both during and after transition.

Applications of near infrared spectroscopy in the neonate.

PURPOSE OF REVIEW: There has been a significant increase in the utilization of NIRS in neonatal care over the last few years, with some centers now routinely utilizing this monitoring technique for direct intervention at the bedside. In this review, we provide a summary of the most up-to-date evidence on near infrared spectroscopy utilization, with particular emphasis on measurement of cerebral oxygenation in preterm infants. RECENT FINDINGS: There have been significant advances in the technology, leading to an increase in the number of available devices and in the use of this monitoring tool to reduce cerebral injury in preterm infants. The role of NIRS in assessing cerebral autoregulation in preterm and term infants, in evaluating somatic oxygenation, and in the management of newborns with hypoxic ischaemic encephalopathy is discussed. SUMMARY: Two recent pilot randomized controlled trials highlight the potential of cerebral oxygenation monitoring to direct management in the delivery room and the neonatal intensive care unit. However, we urge caution against routine use and await the results of further studies in this area before considering this type of monitoring as standard of care.