Tania R. Gunn

Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs.

Hypothermia has been proposed as a neuroprotective strategy. However, short-term cooling after hypoxia-ischemia is effective only if started immediately during resuscitation. The aim of this study was to determine whether prolonged head cooling, delayed into the late postinsult period, improves outcome from severe ischemia. Unanesthetized near term fetal sheep were subject to 30 min of cerebral ischemia. 90 min later they were randomized to either cooling (n = 9) or sham cooling (n = 7) for 72 h. Intrauterine cooling was induced by a coil around the fetal head, leading initially to a fall in extradural temperature of 5-10 degrees C, and a fall in esophageal temperature of 1.5-3 degrees C. Cooling was associated with mild transient systemic metabolic effects, but not with hypotension or altered fetal heart rate. Cerebral cooling reduced secondary cortical cytotoxic edema (P < 0.001). After 5 d of recovery there was greater residual electroencephalogram activity (-5.2+/-1.6 vs. -15.5+/-1.5 dB, P < 0.001) and a dramatic reduction in the extent of cortical infarction and neuronal loss in all regions assessed (e.g., 40 vs. 99% in the parasagittal cortex, P < 0.001). Selective head cooling, maintained throughout the secondary phase of injury, is noninvasive and safe and shows potential for improving neonatal outcome after perinatal asphyxia.

Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep

Objective. Cerebral hypothermia has been shown to reduce damage from experimental hy-poxia-ischemia if started shortly after reperfusion. However, in the newborn infant it may not be feasible to determine prognosis so soon after exposure to asphyxia. The aim of this study was to determine whether head cooling, delayed until shortly before the onset of postasphyxial seizure activity, is neuroprotective. Methods. Unanesthetized near-term fetal sheep in utero were subjected to 30 minutes of cerebral ischemia. Later, at 5.5 hours, they were randomized to either cooling (n = 7) or sham cooling (n = 10) for 72 hours. Intrauterine cooling was induced by circulating cold water through a coil around the fetal head. The water temperature was titrated to reduce fetal extradural temperature from 39.1 ± 0.1°C to between 30°C and 33°C, while maintaining esophageal temperature >37°C. Results. Cerebral cooling suppressed the secondary rise in cortical impedance (a measure of cytotoxic edema), but did not prevent delayed seizures, 8 to 30 hours after ischemia. Transient metabolic changes including increased plasma lactate and glucose levels were seen with a moderate sustained rise in blood pressure. This severe cerebral insult resulted in depressed residual parietal electroencephalographic activity after 5 days recovery (−14.2 ± 1.5 decibels), associated with a watershed distribution of neuronal loss (eg, 94 ± 4% in parasagittal cortex and 77 ± 4% in the lateral cortex). Hypothermia was associated with better recovery of electroencephalographic activity (−8.9% ± 1.8 decibels) and substantially reduced neuronal loss in the parasagittal cortex (46 ± 13%), the lateral cortex (9 ± 4%), and other regions except the cornu ammonis sectors 1 and 2 of the hippocampus. Conclusions. Delayed selective head cooling begun before the onset of postischemic seizures and continued for 3 days may have potential to significantly improve the outcome of moderate to severe hypoxic-ischemic encephalopathy.

Antecedents of neonatal encephalopathy with fetal acidaemia at term

Objective To identify the relative contribution of antenatal hypoxia, obstetric catastrophe during labour and fetal monitoring practice to the occurrence of neonatal encephalopathy associated with acidaemia at term.

Therapeutic hypothermia: from lab to NICU.

Abstract The possibility of a therapeutic role for cerebral hypothermia during or after resuscitation from perinatal asphyxia has been a long-standing focus of research. However, early studies had limited and contradictory results. It is now known that severe hypoxia-ischemia may not cause immediate cell death, but may precipitate a complex biochemical cascade leading to the delayed development of neuronal loss. These phases include a latent phase after reperfusion, with initial recovery of cerebral energy metabolism but EEG suppression, followed by a secondary phase characterized by accumulation of cytotoxins, seizures, cytotoxic edema, and failure of cerebral oxidative metabolism from 6 to 15 h post insult. Although many of the secondary processes can be injurious, they appear to be primarily epiphenomena of the ‘execution’ phase of cell death. This conceptual framework allows a better understanding of the experimental parameters that determine effective hypothermic neuroprotection, including the timing of initiation of cooling, its duration and the depth of cooling attained. Moderate cerebral hypothermia initiated in the latent phase, between one and as late as 6 h after reperfusion, and continued for a sufficient duration in relation to the severity of the cerebral injury, has been consistently associated with potent, long-lasting neuroprotection in both adult and perinatal species. The results of the first large multicentre randomized trial of head cooling for neonatal encephalopathy and previous phase I and II studies now strongly suggest that prolonged cerebral hypothermia is both generally safe – at least in an intensive care setting – and can improve intact survival up to 18 months of age. Both long-term followup studies and further large studies of whole body cooling are in progress.

Are Melnick-Needles syndrome and oto-palato-digital syndrome type II allelic? Observations in a four-generation kindred

Melnick-Needles syndrome (MNS) is a female-limited skeletal dysplasia inherited in a X-linked dominant pattern. Males born to women with MNS may exhibit lethal multiple congenital anomalies, but recurrence of this phenotype within one family has not been reported. Males with oto-palato-digital syndrome type II (OPD II) also demonstrate a multiple congenital anomalies phenotype that includes skeletal dysplasia but the maternal phenotype includes only mild craniofacial anomalies. These two syndromes have been suggested as being allelic despite differences in the described maternal phenotypes. We present a four-generation kindred in which four males had a consistent multiple congenital anomalies phenotype. The females in this family have skeletal changes characteristic of MNS but have only mild craniofacial anomalies and also deafness attributable to ossicular deformity, traits more commonly found in OPD II. The expression of manifestations of MNS and OPD II in males and females in this kindred further suggest that these syndromes are allelic.

Does early hospital discharge with home support of families with preterm infants affect breastfeeding success? A randomized trial.

The aim of the present study was to determine if earlier discharge of preterm infants (<37 wk) from hospital is safe and if it affects breastfeeding rates. In a pilot observational study, premature infants received full oral (sucking) feeds for a mean (SD) 7.7 ± 7.9 d before discharge. In the main study, 308 preterm infants were randomly assigned to either Early Discharge (148 infants) when fully orally fed but not yet gaining weight or Routine Discharge (160 infants) when fully orally fed and also gaining weight before discharge. A further 122 mothers declined randomization. The Early Discharge group was followed by Visiting Nurse Specialists who were available 24 h a day, while the Routine group was followed by the Home Care Nurses available on week days. There were no significant differences between the groups in birthweight or gestational age. The Early Discharge group were discharged 2.5 ± 2 d after full oral feeding compared to 4.4 ± 2.7 d for the Routine group (p < 0.001) and 6.1 ± 5 d for those who declined. However, there was no significant difference between the Early and Routine groups for breastfeeding either at discharge (80 vs 83%), or 6 wk (55 vs 60%) or 6 mo after discharge (36 vs 36%), or for weight gain, or rates of re‐hospitalization (8.8% vs 11.9% at 6 wk, p = 0.37).

Pregnancy outcome in women with reflux nephropathy and the inheritance of vesico-ureteric reflux

In women with reflux nephropathy, we investigated whether pre‐existing hypertension and impaired renal function influence the rates of preeclampsia, renal function deterioration and preterm birth. The infants were investigated for vesico‐ureteric reflux (VUR). A prospective audit of 54 pregnancies in 46 women with reflux nephropathy was performed. Preeclampsia complicated 24% of pregnancies and was increased in women with pre‐existing hypertension (42%) compared with normotensive women (14%), (RR 3.0 (95% CI 1.1–7.8)). Nine (18%) women experienced deterioration in renal function during pregnancy. Women with mild or moderate renal impairment were at increased risk of renal function deterioration (RR 12.7 (95% CI 1.6–98.5); RR 19.8 (95% CI 2.6–155)), respectively. A third of infants were delivered preterm. The risk of preterm birth was increased if the mother had pre‐existing hypertension (p = 0.01) or moderate renal impairment (p = 0.002). Seventeen (43%) of the 40 infants who underwent micturating cystourethrography had VUR, consistent with autosomal dominant inheritance with reduced penetrance. In reflux nephropathy, pre‐existing hypertension was associated with an increased risk of preeclampsia and pre‐existing renal impairment with deterioration in renal function. Infants of women with reflux nephropathy should be screened for VUR.

Changes in risk factors for hypoxic-ischaemic seizures in term infants.

Summary: Term infants with seizures and evidence of perinatal asphyxia were prospectively identified in 1 city and 2 time periods: 1978–1981 and 1991. Infants with multiple congenital abnormalities, hypocalcaemia or infection were excluded. Although there was little change in the overall incidence of neonatal seizures between 1978–1981 (1.9 per 1,000) and 1991 (1.78 per 1,000, N.S.) there was a marked reduction in small for dates infants with seizures: 8 of 19 infants in 1978–1981 compared to none of 16 in 1991 (p<0.005). In contrast, infants ≥41 weeks continued to show a markedly increased risk for asphyxia (relative risk 4.48,95% CI: 1.7–12.3). The mechanism of this improved outcome for small for gestational age infants is unknown, but speculatively may be due to improved obstetric monitoring techniques allowing early identification of compromised infants.

A Potential Role for Adenosine in the Inhibition of Nonshivering Thermogenesis in the Fetal Sheep

ABSTRACT: Adenosine is released by the placenta into the fetal circulation and has potent antilipolytic properties in vitro. Nonshivering thermogenesis cannot be demonstrated by cooling fetal sheep in utero but can be induced by supplemental oxygenation and umbilical cord occlusion; this suggests the presence of inhibitor(s) of placental origin. To test whether circulating adenosine could be such an inhibitor, a series of experiments was carried out in nine fetal sheep at 136–145 d gestation. Birth was simulated in utero by sequentially cooling the fetus 2.49 ± 0.23°C with no change in the low levels of plasma FFA or glycerol; ventilating with O2 via an exteriorized tracheostomy tube and umbilical cord occlusion. Thermogenic indices rose markedly, and plasma FFA and glycerol concentrations peaked at 725 ± 88 µEq/L (p < 0.01) and 771 ± 154 µmol/L, (p < 0.001), respectively, O2 consumption rose to 20 ± 2 mL/min/kg, and temperature increased 1.99 ± 0.35°C. The long-acting adenosine analog N6-(L-2-phenylisopropyl)-adenosine (PIA) was then infused (90 µg/kg bolus, then 300 µg/kg/h for 30 min); plasma FFA and glycerol decreased to 265 ± 56 µEq/L (p < 0.003) and 477 ± 102 µmol/L (p < 0.04), respectively; O2 consumption fell rapidly to 4.5 ± 0.3 mL/min/kg (p < 0.01); temperature decreased 1.89 ± 0.39°C (p < 0.001); and fetal arterial BP decreased to 38 ± 5 mm Hg (p < 0.004) in 30 min. A stepped dose-response study was performed in three fetal sheep. Birth was simulated in utero and then PIA was administered in escalating doses for five sequential 30-min periods with 60-min intervals in between, starting at 0.08 µg/kg bolus. The fetal arterial blood pressure was not affected by any of the relatively low doses of PIA used; however, all of the doses of PIA inhibited nonshivering thermogenesis in a dose-dependent manner. These results are consistent with adenosine suppression of brown adipose tissue thermogenesis in utero and suggest that adenosine may be an inhibitor of placental origin.

Reversible umbilical cord occlusion: effects on thermogenesis in utero.

ABSTRACT: The initiation of thermogenesis at birth is an important adaptation for survival. We examined the sequential effects of cooling, increased oxygenation, and repeated episodes of umbilical cord occlusion on nonshivering thermogenesis in six fetal sheep at 139 to 145 d of gestation. The fetal sheep were cooled by circulating cold water through a coil placed around the trunk for 4 h. The fetal core temperature fell 2.47 ± 0.24°C in the first 60 min of cooling with minimal changes in plasma FFA and glycerol levels. After fetal arterial O2 tension was increased above 6.65 kPa by ventilation, fetal temperature and thermogenic indices rose significantly in 60 min. After occlusion of the umbilical cord by a reversible occluder cuff, plasma FFA levels rapidly increased to 635 ± 69 μEq/L (p < 0.005) by 30 min, fetal temperature increased a further 0.96 ± 0.20°C (p < 0.001) and fetal O2 consumption peaked at 25.3 ± 4.9 mL·min-1·kg-1. Release of cord occlusion caused a rapid fall in FFA to 149 ± 23 μEq/L (p < 0.005) and a fall in fetal core temperature of 0.90 ± 0.13°C (p < 0.001) in 30 min. After irreversibly snaring the umbilical cord, the plasma FFA rose to 611 ± 83 μEq/L (p < 0.005) and the fetal temperature rose 0.78 ± 0.09°C (p < 0.02). The effects on thermogenesis of interrupting and reestablishing placental flow are rapid and reversible and suggest the presence of placental inhibitors of brown adipose tissue thermogenesis.