ECG and heart rate variability changes in preterm and near-term fetal lamb following LPS exposure.

The aim of this study is to evaluate the myocardial response in the preterm and near-term fetal lamb with infection. Chronically instrumented fetal lambs were exposed to lipopolysaccharide (LPS), and the fetal electrocardiogram (FECG) ST waveform was examined using STAN. Fetal heart rate variability (FHRV) was automatically analyzed by adapting a polynomial function to the RR sequence in the FECG. Preterm fetuses exposed to >90 ng/kg LPS died within 8 hours of LPS administration, a response not seen in near-term fetuses. In both surviving and nonsurviving preterm fetuses, cardiovascular responses were characterized by decreased arterial pressure, negative T waves, and tachycardia accompanied by an increase in FHRV. Similar changes were not observed in the near-term fetuses after LPS. The study shows that preterm lambs are more sensitive to LPS in terms of myocardial/cardiovascular response than the more mature fetuses are. High FHRV and negative ST waveform seem to characterize the LPS-induced stress response in preterm fetuses.

STAN, a clinical audit: the outcome of 2 years of regular use in the city of Varberg, Sweden.

OBJECTIVE: To monitor and analyze (audit) the introduction of the STAN methodology in a district hospital. DESIGN: Retrospective study covering the total population of deliveries at term during 2004 and 2005. MATERIAL AND METHODS: 1,875 out of 3,193 term pregnancies (59%) were monitored using the STAN fetal heart monitor (Neoventa Medical, Moelndal, Sweden) and the associated clinical guidelines. Cord metabolic acidosis, neonatal outcome, and rates of operative deliveries for fetal distress were recorded. RESULTS: The overall cesarean section rate was significantly reduced in the STAN group. Emergency (crash) cesarean sections were significantly reduced from 1.51% to 0.27% in the cardiotocography- and STAN-monitored groups, respectively (OR 0.18, 95% CI 0.07-0.49). When cesarean section was performed only because of non-reassuring cardiotocography, cord acid base was significantly higher, 7.26 versus 7.19 (p<0.01), as compared to when STAN guidelines were followed. Total population rates for operative deliveries for fetal distress and cesarean section rates were 6.7% and 3.5% respectively. The corresponding metabolic acidosis rate was 0.5%. CONCLUSION: High STAN usage in a busy labor ward setting provided an outcome equaling that noted previously in a larger academic unit, demonstrating the safe implementation of the STAN methodology in a nonacademic unit.

White matter injury following prolonged free radical formation in the 0.65 gestation fetal sheep brain.

Free radicals seem to be involved in the development of cerebral white matter damage after asphyxia in the premature infant. The immature brain may be at increased risk of free radical mediated injury, as particularly the preterm infant has a relative deficiency in brain antioxidants systems, such as superoxide dismutase and glutathione peroxidase. In vitro studies show that immature oligodendrocytes express an intrinsic vulnerability to reactive oxygen species and free radical scavengers are able to protect immature oligodendrocytes from injury. The aim of this study was to examine the formation of ascorbyl radicals as a marker of oxidative stress in the preterm brain in association with cerebral white matter injury after intrauterine asphyxia. Fetal sheep at 0.65 gestation were chronically instrumented with vascular catheters and an occluder cuff around the umbilical cord. A microdialysis probe was placed in the periventricular white matter. Fetal asphyxia was induced by occlusion of the umbilical cord for 25 min (n = 10). Microdialysis samples were collected for 72 h and analyzed for ascorbyl radicals using electron spin resonance. Five instrumented fetuses served as controls. Three days after the insult, fetal brains were examined for morphologic injury. Umbilical cord occlusion resulted in prolonged and marked increase in ascorbyl radical production in the brain in connection with white matter injury, with activation of microglia cells in periventricular white matter and axonal injury. These data suggest that reperfusion injury following asphyxia in the immature brain is associated with marked free radical production.

Electrocardiographic changes following umbilical cord occlusion in the midgestation fetal sheep.

BACKGROUND: Clinical studies show that analysis of the fetal electrocardiographic (FECG) ST waveform at term gives important information on the myocardial response to intrapartum asphyxia. However, it is not known whether the preterm fetus responds in a similar fashion. The objective of the present study was to evaluate the FECGST response to umbilical cord occlusion in the preterm fetal sheep. METHODS: Fetal sheep at midgestation were subjected to 25 min umbilical cord occlusion (n = 7) and compared to controls (n = 5). Changes in the FECGST waveform were recorded together with arterial blood pressure, heart rate, and acid base status during the occlusion and for 3 days afterward. RESULTS: Umbilical cord occlusion resulted in immediate bradycardia (control: 187 +/- 7 bpm versus occlusion: 102 +/- 7 bpm), hypertension (control: 43.2 +/- 1.1 mmHg versus occlusion: 59.8 +/- 2.2 mmHg), and an initial increase in the T/QRS ratio (control: 0.10 +/- 0.02 versus occlusion: 0.60 +/- 0.10, P < 0.001), followed by hypotension (21.7 +/- 1.2 mmHg), normalization of the T/QRS ratio, and in some cases the development of negative T waves toward the end of the occlusion. CONCLUSIONS: These studies show that the midgestation fetal sheep has the capacity to react to umbilical cord occlusion with a significant increase in the amplitude of the ST waveform together with an augmentation of blood pressure, which then subsides as the occlusion continues. The appearance of negative ST segment appears to signify significant cardiac dysfunction. The characteristic progression of ST-waveform changes in response to umbilical cord occlusion in midgestation fetal sheep, suggests that monitoring the ST waveform may contribute clinically important information also in the preterm individual.

Maturational effects of lipopolysaccharide on white-matter injury in fetal sheep.

White-matter damage has been associated with the development of cerebral palsy in children born both prematurely and at term, and it has been suggested that intrauterine infection can contribute to the brain injury. However, the relative importance of age on white-matter injury following infectious exposure in utero remains unclear. In this study, fetal sheep were exposed to systemic endotoxemia by administration of Escherichia coli lipopolysaccharide (88.7 +/- 7.7 ng/kg) at 65% or 85% of gestation. These gestational ages approximately correspond to human brain development in preterm and near-term infants respectively. White-matter injury was evaluated 3 days after lipopolysaccharide exposure with regard to microglia activation and loss of neurofilament and myelin basic protein. The expression of oligodendrocytes at different maturational stages was demonstrated in preterm and near-term fetuses with the oligodendroglial markers O4 and 2 ,3 -cyclic nucleotide 3 -phospodiesterase. Forty percent of the fetuses in the preterm group and 22% in the near-term group died within 8 hours of the endotoxin exposure. Three of six preterm and two of seven near-term surviving fetuses demonstrated pathologic changes in the brain with regard to increased microglia activation and loss of neurofilament staining. The number of activated microglia was enhanced in the subcortical white matter in both the preterm lipopolysaccharide-exposed fetuses (lipopolysaccharide: 235 +/- 64 cells/mm2; control: 72 +/- 28 cells/mm2; P = .0374) and the near-term fetuses (lipopolysaccharide: 180 +/- 40 cells/mm2; control 23 +/- 16 cells/mm2; P = .0152). There was a loss of neurofilament staining in both preterm fetuses (lipopolysaccharide: 2.20 +/- 0.77 pixel units; control: 0.20 +/- 0.10 pixel units; P = .0306) and near-term fetuses (lipopolysaccharide: 1.15 +/- 0.48 pixel units; control: 0.06 +/- 0.06 pixel units; P = .0285). O4-positive cells were detected at both gestational ages, whereas 2,3-cyclic nucleotide 3-phospodiesterase-positive cells and myelin basic protein staining were mainly detected in the near-term fetuses. In summary, we found white-matter injury in a proportion of both preterm and near-term fetuses after administration of lipopolysaccharide. These results are in agreement with clinical evidence suggesting that both preterm and term infants are at risk of periventricular leukomalacia in association with intrauterine infection.

White matter injury following systemic endotoxemia or asphyxia in the fetal sheep.

White matter injury is the most frequently observed brain lesion in preterm infants. The etiology remains unclear, however, both cerebral hypoperfusion and intrauterine infections have been suggested as risk factors. We compared the neuropathological outcome, including the effect on oligodendrocytes, astrocytes, and microglia, following either systemic asphyxia or endotoxemia in fetal sheep at midgestation. Fetal sheep were subjected to either 25 minutes of umbilical cord occlusion or systemic endotoxemia by administration of Escherichia coli lipopolysaccharide (LPS O111:B4, 100 ng/kg, IV). Periventricular white matter lesions were observed in 2 of 6 asphyxiated fetuses, whereas the remaining animals showed diffuse injury throughout the subcortical white matter and neuronal necrosis in subcortical regions, including the striatum and hippocampus. LPS-treatment resulted in focal inflammatory infiltrates and cystic lesions in periventricular white matter in 2 of 5 animals, but with no neuron specific injury. Both experimental paradigms resulted in microglia activation in the white matter, damaged astrocytes, and loss of oligodendrocytes. These results show that the white matter at midgestation is sensitive to injury following both systemic asphyxia and endotoxemia. Asphyxia induced lesions in both white and subcortical grey matter in association with microglia activation, and endotoxemia resulted in selective white matter damage and inflammation.