Fetal brain response to worsening acidosis: an experimental study in a fetal sheep model of umbilical cord occlusions.

Perinatal anoxia remains an important public health problem as it can lead to hypoxic-ischaemic encephalopathy (HIE) and cause significant neonatal mortality and morbidity. The mechanisms of the fetal brain's response to hypoxia are still unclear and current methods of in utero HIE prediction are not reliable. In this study, we directly analysed the brain response to hypoxia in fetal sheep using in utero EEG. Near-term fetal sheep were subjected to progressive hypoxia induced by repeated umbilical cord occlusions (UCO) at increasing frequency. EEG changes during and between UCO were analysed visually and quantitatively, and related with gasometric and haemodynamic data. EEG signal was suppressed during occlusions and progressively slowed between occlusions with the increasing severity of the occlusions. Per-occlusion EEG suppression correlated with per-occlusion bradycardia and increased blood pressure, whereas EEG slowing and amplitude decreases correlated with arterial hypotension and respiratory acidosis. The suppression of the EEG signal during cord occlusion, in parallel with cardiovascular adaptation could correspond to a rapid cerebral adaptation mechanism that may have a neuroprotective role. The progressive alteration of the signal with the severity of the occlusions would rather reflect the cerebral hypoperfusion due to the failure of the cardiovascular adaptation mechanisms.

Use of EEG in neonatal hypoxic-ischemic encephalopathy: A French survey of current practice and perspective for improving health care.

OBJECTIVES: Controlled therapeutic hypothermia (CTH) is a standard of care in the management of neonatal hypoxic-ischemic encephalopathy HIE in newborns after 36 weeks of gestational age (WGA) in France. The electroencephalogram (EEG) plays a major role in HIE diagnosis and follow-up. We conducted a French national survey on the current use of EEG in newborn undergoing CTH. METHODS: Between July and October 2021, an email survey was sent to the heads of the Neonatal intensive care units (NICUs) in metropolitan and overseas French departments and territories. RESULTS: Out of 67, 56 (83%) of NICUs responded. All of them performed CTH in children born after 36 WGA with clinical and biological criteria of moderate to severe HIE. 82% of the NICUs used conventional EEG (cEEG) before 6 h of life (H6), prior to CTH being performed, to inform decisions about its use. However, half of the 56 NICUs had limited access after regular working hours. 51 of the 56 centers (91%) used cEEG, either short-lasting or continuous monitoring during cooling, while 5 centers conducted only amplitude EEG (aEEG). Only 4 of 56 centers (7%) used cEEG systematically both prior to CTH and for continuous monitoring under CTH. DISCUSSION: The use of cEEG in the management of neonatal HIE was widespread in NICUs, but with significant disparities when considering 24-hour access. The introduction of a centralized neurophysiological on-call system grouping several NICUs would be of major interest for most centers which do not have the facility of EEG outside working hours.

Associations between fetal heart rate variability and umbilical cord occlusions-induced neural injury: An experimental study in a fetal sheep model.

INTRODUCTION: This study evaluated the association between fetal heart rate variability (HRV) and the occurrence of hypoxic-ischemic encephalopathy in a fetal sheep model. MATERIAL AND METHODS: The experimental protocol created a hypoxic condition with repeated cord occlusions in three phases (A, B, C) to achieve acidosis to pH <7.00. Hemodynamic, gasometric and HRV parameters were analyzed during the protocol, and the fetal brain, brainstem and spinal cord were assessed histopathologically 48 h later. Associations between the various parameters and neural injury were compared between phases A, B and C using Spearman's rho test. RESULTS: Acute anoxic-ischemic brain lesions in all regions was present in 7/9 fetuses, and specific neural injury was observed in 3/9 fetuses. The number of brainstem lesions correlated significantly and inversely with the HRV fetal stress index (r = -0.784; p = 0.021) in phase C and with HRV long-term variability (r = -0.677; p = 0.045) and short-term variability (r = -0.837; p = 0.005) in phase B. The number of neurological lesions did not correlate significantly with other markers of HRV. CONCLUSIONS: Neural injury caused by severe hypoxia was associated with HRV changes; in particular, brainstem damage was associated with changes in fetal-specific HRV markers.

Neurophysiological recordings improve the accuracy of the evaluation of the outcome in perinatal hypoxic ischemic encephalopathy.

OBJECTIVES: Our objective was to evaluate the potential additional value of electroencephalogram (EEG) and evoked potentials in neonates with hypoxic-ischemic encephalopathy to predict their disability at 1 and 2 years old. METHODS: 30 full-term infants after perinatal asphyxia who underwent therapeutic hypothermia were evaluated at 1 year and 2 years for disability using International Classification of Functioning, Disability and Health classification. Scores for EEG, sensory evoked potentials and brainstem auditory evoked potentials were evaluated after withdrawal of therapeutic hypothermia that lasted 72 h. A regression approach was investigated to build models allowing to distinguish neonates according to their disability at 1 and 2 years. Two models were built, the first by considering the clinical data and EEG before and after therapeutic hypothermia and the second by incorporating evoked potentials recording. RESULTS: Adding EEG and evoked potentials data after rewarming improved dramatically the accuracy of the model considering outcome at 1 and 2 years. INTERPRETATION: We propose to record systematically EEG and evoked potentials following rewarming to predict the outcome of neonates with hypoxic ischemic encephalopathy. Combination of altered evoked potentials with no improvement of EEG after rewarming appeared to be a robust criterion for a poor outcome.

Changes in S100B and troponin levels in a fetal sheep model of worsening acidosis.

BACKGROUND: S100B and cardiac troponin T (c-TnT) are relevant biomarkers at birth of hypoxic-ischemic encephalopathy (HIE) and myocardial ischemia secondary to metabolic acidosis during labor, respectively. The purpose was to assess in-utero changes in S100B and c-TnT levels in an experimental model of labor-like acidosis. METHODS: Repeated umbilical cord occlusions (UCOs) in ten experiments were performed in mild (phase A, 1 UCO/5 mn), moderate (phase B, 1 UCO/3 mn), and severe (phase C, 1 UCO/2 mn) period. The experiments were stopped if arterial pH reached 6.90. RESULTS: UCOs resulted in fetal acidosis with pH dropping to 6.99 ±0.13. When compared to the baseline period fetal S100B increased between phases A and B (7% ± 4 vs 17% ± 13, p = 0.030) and between phases A and C (7% ± 4 vs 24% ± 8, p < 0.001). Fetal c-TnT serum levels increased during occlusions: 102 ng/L (58-119) in phase A, vs 119 ng/L (103-198) in phase B vs 169 ng / L (128-268) in phase C (p < 0.05, for all). When compared to the baseline control period, fetal ΔcTnT was significantly modified throughout UCO series: 5.0% (-3; 45) in phase A, 51% (4; 263) in phase B, and 77% (56.5; 269) in phase C (p < 0.05 for all). CONCLUSIONS: S100B and c-TnT increased when fetal acidosis occurred, which reflects the potential neurological damage and fetal cardiovascular adaptation.

Quantitative approach to early neonatal EEG visual analysis in hypoxic-ischemic encephalopathy severity: Bridging the gap between eyes and machine.

OBJECTIVES: To identify relevant quantitative parameters for early classification of neonatal hypoxic-ischemic encephalopathy (HIE) severity from conventional EEGs. METHODS: Ninety EEGs, recorded in full-term infants within 6 h of life after perinatal hypoxia, were visually classified according to the French EEG classification into three groups of increasing HIE severity. Physiologically significant EEG features (signal amplitude, continuity and frequency content) were automatically quantified using different parameters. The EEG parameters selection was based on their ability to reproduce the visual EEG classification. Post hoc analysis based on clinical outcome was performed. RESULTS: Six EEG parameters were selected, with overall EEG classification performances between 61% and 70%. All parameters differed significantly between group 3 (severe) and groups 1 (normal-mildly abnormal) and 2 (moderate) EEGs (p < 0.001). Amplitude and discontinuity parameters were different between the 3 groups (p < 0.01) and were also the best predictors of clinical outcome. Conversely, pH and lactate did not differ between groups. DISCUSSION: This study provides quantitative EEG parameters that are complementary to visual analysis as early markers of neonatal HIE severity. These parameters could be combined in a multiparametric algorithm to improve their classification performance. The absence of relationship between pH lactate and HIE severity reinforces the central role of early neonatal EEG.

Fetal sheep cerebral electrical activity: A new technique to record EEG.

BACKGROUND: Sheep models are commonly used to study fetal cortical activity, including response to hypoxia. The standard technique consists of recording electrocorticogram (ECOG) in utero using electrodes placed on the dura mater. NEW METHOD: We propose a new method for recording the electroencephalogram (EEG) of fetal sheep, using electrodes placed above the skull bone and fixed to the cranial periosteum. RESULTS: Twelve animals were instrumented with this new technique. The EEG signal recorded in utero was of sufficient quality for visual and quantitative analysis of the fetal cortical activity. COMPARISON WITH EXISTING METHOD: This new method is less invasive than the standard method commonly used to record cerebral activity in fetal sheep, because it avoids drilling the skull by hand. The EEG signal recorded in utero had visual and quantitative characteristics comparable to ECOG. CONCLUSIONS: We present a new method of EEG recording that appears to be an acceptable alternative to the standard ECOG recording method. Fetal sheep EEG can be used to better understand the physiological mechanisms involved in the cerebral response to hypoxia.