Search

Power spectral analysis of fetal heart rate variability has been proposed to provide a non-invasive estimate of autonomic balance. However, there are few systematic data before birth. We therefore examined developmental changes in the frequency power spectrum at very low (0-0.04 Hz), low (0.04-0.15 Hz) and high frequencies (0.15-0.4 Hz), as well as the ratio of low- to high-frequency power (LF/HF), in chronically catheterized, healthy fetal sheep at 0.6 (n = 8), 0.7 (n = 7) and 0.8 gestational age (ga; n = 11). In a second study, 0.8 ga fetuses received either atropine (4.8 mg bolus, then 4.8 mg h(-1) for 30 min, n = 6) or 6-hydroxydopamine (20 mg ml(-1) at 2.5 ml h(-1) for 3 h; n = 9). Data were analysed by sleep state, defined by low-voltage-high-frequency (LV) or high-voltage-low-frequency (HV) EEG. Total spectral power increased with gestational age (P < 0.05), while LF/HF decreased from 0.6 to 0.7 ga. At 0.8 ga, heart rate and LF/HF were significantly higher during HV than LV sleep (P < 0.05). Consistent with this, although total spectral power was not significantly greater during HV sleep, there was a significant interaction between sleep state and frequency band (P = 0.02). Both atropine (P = 0.05) and 6-hydroxydopamine (P < 0.05) were associated with an overall reduction in spectral power but no significant effect on the LF/HF ratio. This study does not support substantial, consistent differences between the frequencies of sympathetic and parasympathetic activity in late-gestation fetal sheep.

Dopamine is commonly used for blood pressure support in the neonate, but has limited empirical evidence to support its use. We tested the hypothesis that after near-terminal asphyxia in utero, dopamine infusions would prevent secondary hypotension. Fetal sheep (122-129 days of gestation; term is 147 days) received umbilical cord occlusion for 15 min or sham occlusion (n = 5). If the mean arterial blood pressure fell below 90% of baseline within 6 h after occlusion, fetuses were randomized to either dopamine infusion starting at 4 μg kg(-1) min(-1) and titrated according to mean arterial blood pressure up to a maximum of 40 μg kg(-1) min(-1) (n = 5) or to the same volume of normal saline (n = 5). Dopamine infusion, initiated at a median of 180 min after occlusion (range 96-280 min), was associated with a marked but transient increase in mean arterial blood pressure and fall in femoral blood flow compared with saline. Terminal hypotension developed later in four of the five fetuses that received maximal dopamine infusions than in five of five receiving saline infusion [517 (range 240-715) versus 106 min (range 23-497) after the start of infusions, P < 0.05]. In conclusion, dopamine infusion delayed but did not prevent terminal hypotension after severe asphyxia.

Late preterm infants, born between 34 and 36 weeks gestation, have significantly higher morbidity than neonates born at full term, which may be partly related to reduced sensitivity of the arterial baroreflex. The present study assessed baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) in near-term fetal sheep at 123 ± 1 days gestation. At this age, although fetuses are not fully mature in some respects (term is 147 days), sleep-state cycling is established [between high-voltage, low-frequency (HV) and low-voltage, high-frequency (LV) sleep], and neural myelination is similar to the term human infant. Fetal sheep were instrumented to record blood pressure (BP), HR (n = 15) and RSNA (n = 5). Blood pressure was manipulated using vasoactive drugs, phenylephrine and sodium nitroprusside. In both HV and LV sleep, phenylephrine was associated with increased arterial BP and decreased HR. In HV sleep, phenylephrine was associated with a fall in RSNA, from 124 ± 14 to 58 ± 11% (P < 0.05), but no significant change in RSNA in LV sleep. In contrast, the fall in BP after sodium nitroprusside was associated with a significant increase in HR during LV but not HV sleep, and there was no significant effect of hypotension on RSNA. These data demonstrate that in near-term fetal sheep baroreflex activity is only partly active and is highly modulated by sleep state. Critically, there was no RSNA response to marked hypotension; this finding has implications for the ability of the late preterm fetus to adapt to low BP.

Sympathetic nerve activity (SNA) has two main properties, the presence of co-ordinated bursts of activity, indicative of many nerve fibres firing at a similar time, and entrainment of the bursts to the cardiac cycle, due to inhibitory input from baroreceptors to a network of cell groups within the CNS. Although this patterning is used as a 'gold standard' for the identification of successful nerve recordings, the maturation of these basic features of SNA from fetal life to adulthood has not been investigated. Using a telemetry-based nerve amplifier, renal SNA (RSNA) was recorded in preterm (99 ± 1 days gestation; term 147 days) and near-term fetal sheep (119 ± 0 days gestation), without anaesthesia or paralysis, and contrasted with RSNA recorded in adult sheep. All three age groups showed a classic bursting pattern of RSNA and co-ordination of bursts with the cardiac cycle. However, the delay between diastole and the next peak in RSNA was longest in preterm fetuses (319 ± 1 ms), compared with near-term fetuses (250 ± 13 ms), and shortest in the adult sheep (174 ± 38 ms). This was independent of the maturational decrease in heart rate. The near-term fetuses showed a marked but sleep-state-dependent increase in resting RSNA compared with preterm fetuses. Although entrainment with the pressure pulse suggests that the intricate circuitry within the CNS is developed in the preterm fetus, the decrease in the length of the delay suggests continuing maturation of this key feature of RSNA in the last third of gestation and after birth.

Exposure to severe hypoxia leads to delayed cerebral and peripheral hypoperfusion. There is evidence in the very immature brain that transient abnormal glutaminergic receptor activity can occur during this phase of recovery. We therefore examined the role of N-methyl-D-aspartate (NMDA) receptor activity in mediating secondary hypoperfusion in preterm fetal sheep at 70% of gestation. Fetuses received either sham asphyxia or asphyxia and were studied for 12 h recovery. The specific, non-competitive NMDA receptor antagonist dizocilpine maleate (2 mg kg-1 bolus plus 0.07 mg kg h-1i.v.) or saline (vehicle) was infused from 15 min after asphyxia until 4 h. In the asphyxia-vehicle group abnormal epileptiform EEG transients were observed during the first 4 h of reperfusion, the peak of which corresponded approximately to the nadir in peripheral and cerebral hypoperfusion. Dizocilpine significantly suppressed this activity (2.7+/-1.3 versus 11.2+/-2.7 counts min-1 at peak frequency, P<0.05) and markedly delayed and attenuated the rise in vascular resistance in both peripheral and cerebral vascular beds observed after asphyxia, effectively preventing the initial deep period of hypoperfusion in carotid blood flow and femoral blood flow (P<0.01). However, while continued infusion did attenuate subsequent transient tachycardia, it did not prevent the development of a secondary phase of persistent but less profound hypoperfusion. In conclusion, the present studies suggest that in the immature brain the initial phase of delayed cerebral and peripheral hypoperfusion following exposure to severe hypoxia is mediated by NMDA receptor activity. The timing of this effect in the cerebral circulation corresponds closely to abnormal EEG activity, suggesting a pathological glutaminergic activation that we speculate is related to evolving brain injury.

It has been hypothesized that the hypothalamic-pituitary-adrenal (HPA) axis is immature in the preterm fetus and that this compromises their ability to adapt to hypoxic stress; however, there are few direct data. We therefore examined the effects of asphyxia on HPA responses in chronically instrumented preterm fetal sheep (104 days of gestation; term is 147 days), allocated to a sham control group (n = 7) or 25 min of complete umbilical cord occlusion (n = 8), followed by recovery for 72 h. During umbilical cord occlusion there was a rapid rise in ACTH levels (230.4 +/- 63.5 versus 14.1 +/- 1.8 ng ml(-1) in sham controls, 16-fold) and cortisol levels (7.4 +/- 4.9 versus 0.2 +/- 0.1 ng ml(-1), 31-fold), with further increases after release of cord occlusion. ACTH levels were normalized by 24 h, while plasma cortisol levels returned to sham control values 72 h after asphyxia. Fetal arterial blood pressure was elevated in the first 36 h, with a marked increase in femoral vascular resistance, and correlated positively with cortisol levels after asphyxia (P = 0.05). In conclusion, the preterm fetus shows a brisk, substantial HPA response to severe hypoxia.