Circadian patterns of heart rate variability in fetal sheep after hypoxia-ischaemia: A biomarker of evolving brain injury.

Hypoxia-ischaemia (HI) before birth is a key risk factor for stillbirth and severe neurodevelopmental disability in survivors, including cerebral palsy, although there are no reliable biomarkers to detect at risk fetuses that may have suffered a transient period of severe HI. We investigated time and frequency domain measures of fetal heart rate variability (FHRV) for 3 weeks after HI in preterm fetal sheep at 0.7 gestation (equivalent to preterm humans) until 0.8 gestation (equivalent to term humans). We have previously shown that this is associated with delayed development of severe white and grey matter injury, including cystic white matter injury (WMI) resembling that observed in human preterm infants. HI was associated with suppression of time and frequency domain measures of FHRV and reduced their circadian rhythmicity during the first 3 days of recovery. By contrast, circadian rhythms of multiple measures of FHRV were exaggerated over the final 2 weeks of recovery, mediated by a greater reduction in FHRV during the morning nadir, but no change in the evening peak. These data suggest that the time of day at which FHRV measurements are taken affects their diagnostic utility. We further propose that circadian changes in FHRV may be a low-cost, easily applied biomarker of antenatal HI and evolving brain injury. KEY POINTS: Hypoxia-ischaemia (HI) before birth is a key risk factor for stillbirth and probably for disability in survivors, although there are no reliable biomarkers for antenatal brain injury. In preterm fetal sheep, acute HI that is known to lead to delayed development of severe white and grey matter injury over 3 weeks, was associated with early suppression of multiple time and frequency domain measures of fetal heart rate variability (FHRV) and loss of their circadian rhythms during the first 3 days after HI. Over the final 2 weeks of recovery after HI, exaggerated circadian rhythms of frequency domain FHRV measures were observed. The morning nadirs were lower with no change in the evening peak of FHRV. Circadian changes in FHRV may be a low-cost, easily applied biomarker of antenatal HI and evolving brain injury.

Dissecting the contributions of the peripheral chemoreflex and myocardial hypoxia to fetal heart rate decelerations in near-term fetal sheep.

Brief repeated fetal hypoxaemia during labour can trigger intrapartum decelerations of the fetal heart rate (FHR) via the peripheral chemoreflex or the direct effects of myocardial hypoxia, but the relative contribution of these two mechanisms and how this balance changes with evolving fetal compromise remain unknown. In the present study, chronically instrumented near-term fetal sheep received surgical vagotomy (n = 8) or sham vagotomy (control, n = 11) to disable the peripheral chemoreflex and unmask myocardial hypoxia. One-minute complete umbilical cord occlusions (UCOs) were performed every 2.5 min for 4 h or until arterial pressure fell below 20 mmHg. Hypotension and severe acidaemia developed progressively after 65.7 ± 7.2 UCOs in control fetuses and 49.5 ± 7.8 UCOs after vagotomy. Vagotomy was associated with faster development of metabolic acidaemia and faster impairment of arterial pressure during UCOs without impairing centralization of blood flow or neurophysiological adaptation to UCOs. During the first half of the UCO series, before severe hypotension developed, vagotomy was associated with a marked increase in FHR during UCOs. After the onset of evolving severe hypotension, FHR fell faster in control fetuses during the first 20 s of UCOs, but FHR during the final 40 s of UCOs became progressively more similar between groups, with no difference in the nadir of decelerations. In conclusion, FHR decelerations were initiated and sustained by the peripheral chemoreflex at a time when fetuses were able to maintain arterial pressure. After the onset of evolving hypotension and acidaemia, the peripheral chemoreflex continued to initiate decelerations, but myocardial hypoxia became progressively more important in sustaining and deepening decelerations. KEY POINTS: Brief repeated hypoxaemia during labour can trigger fetal heart rate decelerations by either the peripheral chemoreflex or myocardial hypoxia, but how this balance changes with fetal compromise is unknown. Reflex control of fetal heart rate was disabled by vagotomy to unmask the effects of myocardial hypoxia in chronically instrumented fetal sheep. Fetuses were then subjected to repeated brief hypoxaemia consistent with the rates of uterine contractions during labour. We show that the peripheral chemoreflex controls brief decelerations in their entirety at a time when fetuses were able to maintain normal or increased arterial pressure. The peripheral chemoreflex still initiated decelerations even after the onset of evolving hypotension and acidaemia, but myocardial hypoxia made an increasing contribution to sustain and deepen decelerations.

Quantitative electroencephalographic patterns in normal preterm infants over the first week after birth.

BACKGROUND: Currently available tools to assist clinicians with prediction of neurodevelopmental outcome of preterm infants are inadequate. Modified cotside electroencephalography (EEG) has the ability to produce quantitative electrophysiologic measures. These measures may be useful in future prediction of outcome. AIM: To determine patterns of change in quantitative EEG measures in preterm infants during their first week after birth. DESIGN: Observational. SUBJECTS: Preterm infants born at less than 32 weeks completed gestation surviving to discharge with unremarkable serial ultrasound scans. OUTCOME MEASURES: Changes in continuity, amplitude and spectral edge frequency measures of EEGs obtained over the first week after birth. RESULTS: Results of EEGs performed using a novel EEG device on 63 infants are reported here. Their median (range) gestation was 29 (24-31) weeks and birthweight was 1,235 (540-1,980) g. Quantitative measures of EEG continuity increased over the first week after birth from 72 (25-99)% to 92 (54-100)% at the 25 microV threshold, and from 39 (10-87)% to 64 (34-75)% at the 50 microV threshold, both p<0.0001. There was a related 32% increase in median amplitude from 5.8 (2.6-10.6) microV on day 1 to 7.6 (4.3-9.4) microV on day 4, p=0.005. There was a trend for average spectral edge frequency to fall from 10.7 (9.3-12.9) Hz on day 1 to 9.9 (8.1-12.3) Hz on day 3, p=0.06. Each gestational tertile showed similar patterns. CONCLUSIONS: There are consistent changes in quantitative neurophysiologic measures over the first week after birth, and particularly measures of continuity over the first 4 days, in normal preterm infants.

Lowered electroencephalographic spectral edge frequency predicts the presence of cerebral white matter injury in premature infants.

OBJECTIVE: Current methods for early identification of cerebral white matter injury in the premature infant at the bedside are inadequate. This study investigated the utility of advanced spectral analysis of the neonatal electroencephalogram (EEG) in the early diagnosis of white matter injury in the premature infant. The critical measurement used, suggested largely by previous studies in animal models, was the spectral edge frequency (SEF), calculated here as the frequency below which 90% of the power in the EEG exists. METHODS: Fifty-nine very low birth weight infants (87% of eligible infants) had electrodes placed over the central and parietal regions (C3, P3, C4, and P4 sites according to the 10-20 international system) for the collection of EEG amplitude, intensity, and SEF. All averaged signals were analyzed off-line using software (Chart Analyzer; BrainZ Instruments, Auckland, NZ). All infants had a magnetic resonance imaging scan at term to identify the presence and severity of white matter injury. RESULTS: There was no significant difference between conventional EEG amplitude and intensity for infants with or without evidence of white matter injury. However, premature infants with increasingly severe white matter injury had progressively lower SEFs compared with infants who did not exhibit white matter injury. CONCLUSIONS: These data suggest that SEF-based measures are useful for defining the presence and severity of white matter injury at the bedside.