Multimodal Assessment of Newborns at Risk of Neonatal Hypoxic Ischaemic Encephalopathy –The MONItOr Study
Hypoxic Ischemic Encephalopathy (HIE) is a well-recognised cause of brain injury in newborns, with an incidence of 1.5 per 1000 live births 1. In Ireland and the UK, HIE is the third commonest cause of neonatal mortality, accounting for 9% of all deaths, and 21% of term deaths 2. HIE is defined as a condition that occurs when the brain is deprived of an adequate oxygen supply, due to either reduced cerebral oxygen concentration (hypoxia) or blood supply (ischemia). It is clinically graded as mild, moderate, or severe, based on the neurological features of the infant.
The pathophysiology of brain injury in HIE is complex, but it can be summarised as a two phase process, a primary insult caused by hypoxia or/and ischemia, and a secondary insult that occurs following circulatory restoration, which is termed reperfusion injury 3. The primary insult is marked by a primary energy failure, caused by a decline in high energy phosphate levels and an increase in cerebral lactate. After a latent period, a secondary energy failure occurs 6 to 48 hours following the initial insult, leading to further brain damage due to mitochondrial dysfunction. During this phase, the brain pH shifts to alkalosis despite a high lactate level 4. This evolving process can affect all organs and lead to multiorgan dysfunction. Signs of injury to the cardiovascular system may include reduced myocardial contractility, severe hypotension, passive cardiac dilatation, and tricuspid regurgitation 5, which during our study will be evaluated using non-invasive cardiac output monitoring and echocardiogram.
Regarding the HIE treatment, publications of several international trials, and their subsequent meta-analysis have shown that early induced hypothermia is beneficial in HIE, improving survival and reducing neurological disability 6-7. Induced hypothermia has now become a standard of care in moderate/severe HIE. However, to be effective it must be commenced within 6 hours of delivery, before the secondary energy failure occurs. In this narrow window of time the population who would benefit from treatment must be identified, resuscitated, stabilised and started on therapeutic hypothermia.
Unfortunately, the infant’s condition at birth doesn’t correlate well with the degree of the injury, nor with the neurodevelopmental outcome. Relying on the perinatal events and the clinical picture in the first 6 hours of life to make an accurate decision regarding therapeutic hypothermia can prove to be unreliable in some cases. With this current study we are hoping to identify more rapidly and accurately those infants at highest risk of HIE injury and reliably predict the neurodevelopmental outcome. In order to achieve this, we will be collecting and analysing a series of blood biomarkers. Additional information will be gathered for the prediction of neurodevelopmental outcome in our infants with HIE including continuous electroencephalography (EEG), transcutaneous carbon dioxide (CO2) monitoring, near infrared spectroscopy (NIRS) and magnetic resonance (MR).
Cardiovascular function will be assessed in all infants using non-invasive cardiac output (NICOM) and echocardiography.
Another focus of our study will be on seizure activity post hypoxic-ischaemic injury. HIE is one of the main causes of seizures in the neonatal period, which have been shown to add to the initial brain injury and relate to a worse neurodevelopmental outcome 8. To detect seizure activity and measure seizure burden in our cohort we are using the gold standard, continuous video-EEG monitoring. To better understand the pathophysiological process of seizure in HIE, we will look for correlation between CO2 levels (using transcutaneous CO2 monitoring), cerebral oxygenation (using NIRS) and brain energy metabolism (using magnetic resonance spectroscopy).
We are hoping this study will also aid in the development of future therapeutic strategies that will improve the outcome of infants with hypoxic-ischaemic injury.
- To document the early neurophysiological changes which occur in the first 6-12 hours following birth in infants with neonatal hypoxic ischaemic encephalopathy using continuous multi-channel EEG, NIRS and cardiac output monitoring.
- To establish whether the evolution of these physiological changes in combination with blood biomarkers can predict outcome as defined by the development of seizures, MRI abnormalities, neurological assessment at discharge and outcome at 18-24 months.
The INFANT centre continues to store and analyse data from participants to the study as a consent declaration was obtained from the Health Research Consent Declaration Committee (HRCDC) in 2020 which permits the continued storage and processing specifically for the study and related research. The Health Research Regulation (HRR) is also adhered to.
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The following are list of publications that have been produced from this study:
- Garvey AA, O’Neill R, Livingstone V, Pavel AM, Finn D, Boylan GB, Murray DM, Dempsey EM. Non-invasive Continuous Cardiac Output Monitoring in Infants with Hypoxic Ishaemic Encephalopathy. In review.
- Garvey AA, O’Toole JM, Livingstone V, Pavel AM, Panaite L, Ryan MA, Boylan GB, Murray DM, Dempsey EM. Evolution of Early Cerebral NIRS in Hypoxic Ischaemic Encephalopathy. In review
- Beamer E, O’Dea MI, Garvey AA, Smith J, Menéndez-Méndez A, Kelly L, Pavel A, Quinlan S, Alves M, Jimenez-Mateos EM, Tian F, Dempsey E, Dale N, Murray DM, Boylan GB, Molloy EJ, Engel T. Novel Point-of-Care Diagnostic Method for Neonatal Encephalopathy Using Purine Nucleosides. Front Mol Neurosci. 2021 Sep 9;14:732199. doi: 10.3389/fnmol.2021.732199. eCollection 2021.
- Garvey AA, Pavel AM, Murray DM, Boylan GB, Dempsey EM. Does early Cerebral Near-infrared Spectroscopy (NIRS) monitoring predict outcome in Neonates with Hypoxic-Ischaemic Encephalopathy (HIE)? A Systematic Review. Neonatology. In press.
- Garvey AA, Pavel AM, O’Toole JM, Walsh BH, Korotchikova I, Livingstone V, Dempsey EM, Murray DM, Boylan GB. Multichannel EEG Abnormalities during the first 6 hours in Infants with Mild Hypoxic Ischemic Encephalopathy. Pediatr Res (2021). https://doi.org/10.1038/s41390-021-01412-x
- O’Neill R, Dempsey EM, Garvey AA, Schwarz CE. Non-Invasive Cardiac Output Monitoring in Neonates. Front Pediatr. 2021 Jan 28;8:614585. doi: 10.3389/fped.2020.614585. eCollection 2020.
- Garvey AA, Kooi EMW, Smith A, Depmsey EM. Interpretation of Cerebral Oxygenation Changes in the Preterm Infant. Children (Basel). 2018 Jul 9;5(7). pii: E94. doi: 10.3390/children5070094
- Garvey AA, Dempsey EM. Applications of near infrared spectroscopy in the neonate. Curr Opin Pediatr. 2018;30(2):209-15
- Fetal and Neonatal Neurology Congress, Paris March 2021; Early Cerebral NIRS in Hypoxic Ischaemic Encephalopathy
- Neonatal NIRS Consortium Webinar June 2020; Early Cerebral NIRS in Hypoxic Ischaemic Encephalopathy
- Neonatal Research Symposium November 2019; Neurophysiological alterations during the first 6 hours in Infants with mild Hypoxic Ischaemic Encephalopathy
- Congress of Joint Neonatal European Societies September 2019; Neurophysiological alterations during the first 6 hours in Infants with mild Hypoxic Ischaemic Encephalopathy