Acute centralization of blood flow in compromised human fetuses evoked by uterine contractions

BACKGROUND: During fetal hypoxia blood is redistributed to the brain ('brain-sparing'). Sequential changes of the cerebral and placental circulation in parallel in comparisons between basal conditions and acute hypoxic stress have not yet been thoroughly studied in human fetuses. AIM: To explore acute fetal middle cerebral artery (MCA) circulatory changes relative to umbilical artery (UA) blood flow in a clinical experimental model with hypoxic stress provoked by uterine contractions during an oxytocin challenge test (OCT). STUDY DESIGN: Prospective comparative between imminently compromised (OCT positive) and un-compromised (OCT negative) fetuses. SUBJECTS AND METHODS: 82 term pregnancies suspected of intrauterine growth restriction were exposed to simultaneous electronic fetal heart rate monitoring and Doppler recordings of pulsatility index (PI) in the UA and MCA during basal conditions and during uterine contractions and relaxations at an OCT. OUTCOME MEASURES: Sequential changes of UA and MCA PI, OCT positive vs. negative cases. Nonparametric statistics with a P < 0.05 considered significant. RESULTS: The UA PI was significantly higher in OCT positive cases (N = 10) compared with OCT negative cases (N = 72) during uterine contractions and relaxations, but not during basal measurements. During contractions and relaxations the MCA PI decreased significantly in both groups (brain-sparing), but significantly more in OCT positive cases. CONCLUSIONS: During acute hypoxic stress, changes towards a centralization of blood flow to the brain develop in imminently compromised (OCT positive) fetuses at an expense of the umbilicoplacental blood flow, and the brain-sparing flow is more pronounced than in un-compromised (OCT negative) fetuses.     

Restrained cerebral hyperperfusion in response to superimposed acute hypoxemia in growth-restricted human fetuses with established brain-sparing blood flow

OBJECTIVE: To investigate the cerebral circulatory response to superimposed acute hypoxemia in growth-restricted fetuses with established brain-sparing flow (BSF) during basal conditions. MATERIAL AND METHODS: 76 term fetuses suspected of growth restriction were exposed to Doppler velocimetry in the umbilical artery (UA) and middle cerebral artery (MCA), and in 38-39 cases also in Galen's vein (GV), straight sinus (SS), and transverse sinus (TS), before and during an oxytocin challenge test (OCT), and simultaneous to electronic fetal heart rate monitoring. Nonparametric statistical analyses compared presence/absence of established BSF (MCA-to-UA pulsatility index [PI] ratio <1.08) with a two-tailed P<0.05 considered significant. RESULTS: The OCT (positive/negative) was not different in the BSF group (BSFG, N=16) and the normal flow group (NFG, N=60) (P=0.2). During uterine contractions, the MCA PI decreased in the NFG, but not in the BSFG. De novo GV pulsations and increase of GV maximum flow velocity occurred during contractions in the NFG, but not in the BSFG. Significant SS flow velocity waveform changes were found in neither group and TS flow changes in the BSFG only. CONCLUSIONS: Fetuses without established brain-sparing flow during basal conditions responded with both arterial and venous brain-sparing flow during acute hypoxemia, whereas in fetuses with established brain-sparing flow the cerebral circulatory responses were absent or equivocal. Fetuses with established brain-sparing flow may have a limited capacity of further cerebral hyperperfusion during superimposed acute hypoxic stress.     

Nonlinear analyses of heart rate variability in normal and growth-restricted fetuses

BACKGROUND: Many studies on the physiology of the cardiovascular system reported that nonlinear chaotic dynamics may govern the generation of the heart rate signal. OBJECTIVE: To examine whether the heart rate dynamics of an intrauterine growth restricted (IUGR) fetus is different from a healthy normal fetus by nonlinear methods of time series analysis. DESIGN OF THE STUDY: One hundred nineteen fetal heart rate (FHR) recordings from healthy normal fetuses, and 69 recordings from IUGR fetuses were analyzed. Nonlinear analyses included attractor reconstruction, calculation of the largest Lyapunov exponents using the Wolf algorithm, and estimation of correlation dimension. The largest Lyapunov exponents from normal fetuses were checked by means of surrogate-data test. RESULTS: Abnormal FHR patterns of IUGR fetuses such as decreased variability and repetitive late decelerations presented a remarkably different structure in the reconstructed attractor. Surrogate data suggest that the FHR of healthy normal fetuses has unique nonlinear characteristics. The largest Lyapunov exponents were positive for all of 119 healthy normal fetuses, indicating that the FHR control system is sensitive to initial conditions. The values of IUGR fetuses were significantly lower than those of normal subjects. In normal fetuses, significant changes of correlation dimension according to gestational age were observed. In IUGR fetuses, however, such changes were not found. CONCLUSIONS: The heart rate dynamics of IUGR fetuses is less chaotic than that of normal fetuses. Decreased system complexity suggested by correlation dimension may limit the IUGR fetuses' ability to maintain cardiovascular integrity, and therefore, to adapt to the variety of internal and external cardiovascular stresses.     

The influence of behavioural states on cerebral blood flow velocity patterns in stable preterm infants

Previous Doppler ultrasound studies assessing cerebral blood flow velocities in the anterior cerebral artery (ACA) among healthy term and preterm infants, showed a widespread range for the calculated flow indices. However, only one of these studies accounted for the infant's behavioural state.

In the present study a stable pattern of the cerebral blood flow velocity tracings and of the Pulsatility Index (PI) was observed during state 1, whereas marked fluctuations in cerebral blood flow velocity and PI were found during state 4 or active wakefulness. During state 2, minor variations of cerebral blood flow velocity and PI occurred though tended to be less pronounced than during active wakefulness. Thus at the time of Doppler assessment the cerebral blood flow velocity pattern and its variability will be better understood by taking into account the behavioural state of the infant.     

Postnatal development of the cerebral blood flow velocity response to changes in CO2 and mean arterial blood pressure in the piglet

Cerebral blood flow velocity was studied during changes (haemorrhage) in mean arterial blood pressure or P _aCO₂ in 56 (aged 0–26 days) anaesthetized and ventilated piglets. The CO₂ reactivity increased with age from 6.5% kPa⁻'(< 1 day) to adult levels of 25% kPa⁻¹ for piglets over 4 days old. The mean arterial blood pressure reactivity was reduced from 1.3% mmHg⁻¹ (< 1 day old) to 0.0%/ mmHg (> 4 days old). The reactivities were similar with two different anesthetics: chloralose/urethane or pentobarbital. To validate the cerebral blood flow velocity data, both electromagnetic flow and precerebral Doppler ultrasound velocity were recorded from the same common carotid artery with extracranial branches tied off. There were no differences between the results with these two methods nor between these results and those obtained when the cerebral blood flow velocities were recorded from an intracerebral artery and the electromagnetic flowmeter recorded from the carotid artery. The vessel diameter appears stable during these interventions. In conclusion, the autoregulatory response and the reaction to P _aCO₂ appear poorly developed in the newborn piglet, but rapidly mature during the first 4 days of life.     

Pilot study of milrinone for low systemic blood flow in very preterm infants

OBJECTIVES: To examine the hemodynamic effects of milrinone given prophylactically to very preterm infants at high risk of low superior vena cava (SVC) flow and to investigate the preliminary efficacy and safety of an optimal dose. STUDY DESIGN: This was a prospective, open-label study in two stages. The first involved dose escalation in two cohorts. Milrinone infusions of 0.25 microg/kg per minute (n = 8) and then 0.5 microg/kg per minute (n = 11) were administered from 3 to 24 hours of age. Population pharmacokinetic modeling was used to develop an optimized dose regimen. Ten infants then were loaded with 0.75 microg/kg per minute for 3 hours, followed by 0.2 microg/kg per minute maintenance until 18 hours of age. Infants were monitored for blood pressure, serial echocardiograms, and blood milrinone levels. The primary outcome was maintenance of SVC flow greater than 45 mL/kg per minute through the first 24 hours. RESULTS: Low SVC flow developed in 36% of babies at both 0.25 microg/kg per minute and 0.5 microg/kg per minute of milrinone. Blood levels on these two regimens were slow to reach the target range and accumulated above this range by 24 hours. At 0.75 to 0.2 microg/kg per minute, no infant had SVC flow below 45 mL/kg per minute, compared with 61% in historic control subjects. Four infants needed an additional inotrope to support blood pressure. Blood levels were within the target range in 9 of 10 babies. CONCLUSIONS: We used population pharmacokinetic modeling to develop an optimal dosing regimen for milrinone. The efficacy and safety in this novel preventative approach to circulatory support is encouraging but inconclusive. We do not recommend the use of milrinone in preterm infants outside a research setting.