Introduction: Inflammation and acidosis are two stress stimuli that correspond to pathophysiological processes occurring in placental-mediated vascular disorders. We aimed to investigate the effects of these stimuli on placental chorionic blood vessels reactivity using the ex-vivo placental perfusion model.Methods: Term placentas were obtained immediately after cesarean deliveries, and selected cotyledons were cannulated and dually perfused ex-vivo. Placentas were perfused with three different protocols: culture medium (M199-controls, n = 5), culture medium with lipopolysaccharide (inflammatory stimuli) (LPS,1 mu g/ml, n = 7), and acidotic culture medium (M - 199, pH: 6.9-7, n = 6). Each perfusion experiment was maintained for 180 min. Fetal perfusion pressure was continuously measured. Measurements in response to angiotensin II (AT II) at the end of the perfusion were compared between the treatment groups, including amplitude of the contraction response, relaxation factor, time to maximal constriction and the area under the pressure curve (AUC).Results: In response to ATII there was a significant difference in the amplitude of the contraction and the AUC between the treatment groups, (p = 0.049, p = 0.015, respectively). As compared with control perfused cotyledon, the inflammatory stimuli significantly increased the vasoconstriction response to ATII in fetal placental blood vessels, as expressed by increased AUC - median (IQR): 555 (235-1184) vs. 133 (118-207), respectively, p = 0.017. The time to maximal constriction and the relaxation factor did not differ between the groups.Discussion: Inflammatory stimuli but not acidosis impact fetal-placental vasculature in response to ATII, suggesting that inflammation can compromise vascular function.

•The dual-perfused single cotyledon model enables us to study placental vessels reactivity. •Low dose aspirin induced lower feto-placental vasculature reactivity in response to angiotensin. •Low dose aspirin directly attenuates placental blood vessel reactivity.

Fetal growth restriction (FGR) is one of the major contributors to adverse perinatal outcome. However, the diagnostic tools used for the assessment of fetal well-being are limited due to the great variability among fetuses. The purpose of this study was to estimate the dynamics of fetal circulation during the advanced stages of the gestational period. A methodology for estimating fetal hemodynamic parameters is presented. The method combines a mathematical model of the fetal circulation, optimization algorithm, and measurements of power-Doppler ultrasound. The model estimates fetal indices of the fetal circulation that are not accessible for direct measurement, aimed at the identification of the degree of circulatory compromise in fetuses diagnosed as FGR. The method was tested on a cohort of 20 normal and 22 growth-restricted fetuses. Model predictions indicated significant changes in the circulation of FGR fetuses compared to normal fetuses. Cardiac output was significantly lower in the FGR group compared to the control group (330 ± 52 mL min−1 kg−1 compared to 396 ± 52 mL min−1 kg−1, p < 0.001). Furthermore, placental blood flow was lower for the FGR group (145 ± 49 mL min−1 kg−1 compared to 181 ± 31 mL min−1 kg−1, p < 0.01). In the FGR fetuses with adverse outcome, both indices were reduced even further (297 ± 56 mL min−1 kg−1, p < 0.001 and 97 ± 46 mL min−1 kg−1, p < 0.001, respectively). In the adverse outcome group the model indicated also significant increase in cardiac output distribution towards the brain (9.6 ± 0.7%, compared to 8.0 ± 1.6%, p < 0.01) and an increase in the ratio of blood shunted by the ductus venosus (60.6 ± 17.7%, compared to 39.7 ± 14.8%, p < 0.01), indicating a severe brain sparing effect in these fetuses. In conclusion, patient-specific modeling may provide a reliable estimate of the important hemodynamic indices of the fetal circulation which may be clinically relevant for the management of FGR pregnancies.

Fetal growth restriction (FGR) is one of the major contributors to adverse perinatal outcome. However, the diagnostic tools currently used for estimating the fetal hemodynamic status are still limited. In this study we developed a methodology for estimating fetal hemodynamic parameters. The method is based on a mathematical model of the fetal circulation, an optimization algorithm and measurements of power-Doppler ultrasound. The model estimates parameters of the fetal circulation that are not possible for direct measurement. The method was tested on a cohort of 20 normal and 22 growth-restricted fetuses. In each fetus, power-Doppler velocity waveforms were measured in large number of sites of the fetal circulation. Three-dimensional volume-flow measurements were performed in the placenta to evaluate its resistance to blood flow. Model predictions indicated significant changes in the circulation of FGR fetuses compared to normal fetuses. In the FGR group, the model predicted significant reduction in fetal cardiac output and decreased cardiac output distribution towards the placenta. In FGR fetuses that showed adverse outcome, the model indicated significant increase in cardiac output distribution towards the brain and in the degree of blood shunted by the ductus venosus, indicating severe brainsparing state in these fetuses. We conclude that patientspecific modeling may be useful in personalizing and optimizing the treatment options in pregnancies complicated by fetal growth-restriction.

OBJECTIVE:The authors aimed to study the contractility responses of normal and fetal growth restriction (FGR) placentas to prostaglandin E(2) (PGE(2) ) and to correlate the results to subsequent placental histological analysis. METHOD:A dual-perfused single cotyledon model was used. Placentas from pregnancies complicated by FGR and from normal pregnancies were obtained. Selected cotyledons were cannulated and dually perfused. Following stabilization, three concentrations of PGE(2) (0.05, 0.1, and 0.15 mg/mL) were administered to the fetal arterial side causing contraction/relaxation response. Fetal perfusion pressure was measured continuously during these contraction and relaxation phases. Following the perfusion experiments, the placentas were analyzed for fetal or maternal origin vascular lesions. RESULTS:A total of 21 complete experiments were performed (16 normal, 5 FGR). In response to PGE(2) , FGR placentas exhibited lower change in the perfusion pressure and lower relaxation time constant. Basal perfusion pressure did not differ significantly between the two groups. Placental histopathology lesions, fetal or maternal origin, were more common in the FGR compared with the controls placentas, 80% versus 25%, respectively, P=  0.047. CONCLUSIONS:The lower vascular reactivity in response to PGE(2) and the presence of fetal and maternal vascular placental lesions suggest a mechanism explaining the altered vascular supply in FGR.

ABSTRACTObjectivesTo investigate the role of three‐dimensional (3D) power Doppler ultrasonography in the assessment of fetal growth‐restriction (FGR) with various degrees of severity and onset, and compare the results with the analysis of two‐dimensional (2D) Doppler.Study designVascular indices extracted from 3D Doppler measurements of the placenta were compared with indices of flow‐velocity waveforms extracted from 2D Doppler measurements of the major sites of the fetal circulation between FGR (study group) and uncomplicated pregnancies (control group) from 25 to 38 weeks’ gestation.ResultsThree‐dimensional indices were significantly lower in pregnancies complicated by FGR compared with uncomplicated pregnancies. When measured in placental periphery, vascularization index was 9.4 ± 9.6 in FGR pregnancies compared with 16 ± 14.7, P = 0.04. Flow index was 33.9 ± 6.9 compared with 38.7 ± 4.9, P = 0.03 and the vascularization‐flow index was 3.8 ± 4.3 compared with 6.5 ± 6, respectively, P = 0.03. Among the conventional 2D indices, umbilical artery and middle cerebral artery pulsatility indices were not significantly different between the FGR and control groups. Higher rate of maternal or fetal compartment vascular lesions were detected in the FGR group.ConclusionsThree‐dimensional Doppler was found to be more strongly associated with placental vascular compromise than conventional 2D Doppler, regardless of severity and onset of fetal growth restriction. © 2012 John Wiley & Sons, Ltd.

Investigate the possible contribution of the fetal vs. maternal placental vascular abnormality in fetal growth restriction (FGR) with a component of placental insufficiency. The influence of prostaglandin E2 (PGE2) on fetal arterial perfusion pressure was compared between normal term (control) and FGR placentas, using the dual perfused single cotyledon model. Selected cotyledons were cannulated and perfused with constant flow of 6 ml/min and 12 ml/min in the fetal and maternal sides, respectively. PGE2 at concentrations of 0.05 mg/ml, 0.1 mg/ml and 0.15 mg/ml were added to the fetal arterial side. Fetal perfusion pressure was measured continuously and was used as an index of fetal vessel reactivity during the contraction and relaxation phases. At the end of the experiments placentas were sent to histopathologic examination. Nine placentas were retrieved from the control group, with mean birth weight of 3031±314 grams and 3 from the FGR group, with mean birth weight of 2140±45 grams, p<0.001. Placental mean weight was 269±50 grams in the FGR compared to 441±90 grams in the control group, p<0.01. Decreased reactivity to PGE2 was observed in the FGRcompared to the control group. This was pronounced during the relaxation phase of the contraction, and expressed by higher time constants (calculated by exponential fit of the pressure signals) of the fetal perfusion pressure, 1.32±0.08 at 0.05 mg/ml, 1.0±0.17 at 0.1 mg/ml and 0.72±0.31 at 0.15 mg/ml PGE2 concentrations, compared to 0.57±0.47, 0.42±0.38, 0.33±0.25, respectively (Figure). Histopathologic analysis revealed normal histologic appearance in the control placentas compared with lesions consistent with maternal underperfusion, in the FGR placentas. Reduced reactivity was measured in the fetal compartment in placentas from growth-restricted pregnancies in response to PGE2, suggesting either placental vascular abnormalities or altered endothelial dysfunction in fetal vessels.

Fetal growth restriction (FGR) elicits hemodynamic compensatory mechanisms in the fetal circulation. These mechanisms are complex and their effect on the cerebral oxygen availability is not fully understood. To quantify the contribution of each compensatory mechanism to the fetal cerebral oxygen availability, a mathematical model of the fetal circulation was developed. The model was based on cardiac-output distribution in the fetal circulation. The compensatory mechanisms of FGR were simulated and their effects on cerebral oxygen availability were analyzed. The mathematical analysis included the effects of cerebral vasodilation, placental resistance to blood flow, degree of blood shunting by the ductus venosus and the effect of maternal-originated placental insufficiency. The model indicated a unimodal dependency between placental blood flow and cerebral oxygen availability. Optimal cerebral oxygen availability was achieved when the placental blood flow was mildly reduced compared to the normal flow. This optimal ratio was found to increase as the hypoxic state of FGR worsens. The model indicated that cerebral oxygen availability is increasingly dependent on the cardiac output distribution as the fetus gains weight.

Elevated maternal blood pressure (BP) is common in pregnancies complicated by hypertensive disorders. In response, increased production and accumulation of elastin occurs in the feto-placental blood vessels. This results in increased vascular wall stiffness that increases the resistance to flow. To study the interaction between the stiffness of the fetoplacental blood vessels, fetoplacental blood flow and BP, a mathematical model of the fetoplacental vascular tree was developed. The model describes an elastic structure exposed to external pressure. Model results indicate that increased vascular stiffness in the fetal blood vessels may contribute to optimizing fetoplacental blood flow in hypertensive pregnancies. According to model predictions, uncontrolled lowering of BP following vascular adaptation may adversely affect fetoplacental blood flow.

During high-frequency oscillatory ventilation (HFOV), the primary variable affecting lung volume is the mean airway pressure (MAP). To effectively maintain lung recruitment and optimal gas exchange without overstretching (or collapsing) the lung, MAP should be set between the lower and upper inflection points of the pressure-volume curve of the lung. At present, there is no efficacious means that allows the neonatologist to determine the MAP (optimal MAP) which attains optimal lung expansion and avoids overdistension. Thus, MAP is usually adjusted by trial and error or by clinical experience of the user. In this study, we investigated the acoustic properties of the neonate lung in six newborns undergoing high frequency oscillatory ventilation, to assess its usefulness as a means for determining optimal mean air- way pressure. We found that the shape of the acoustic reflection-pressure curve was similar to the shape of the known pressure-volume curve. In all subjects, the estimated range of MAP was in congruence with the pressure chosen by the neonatologist. The acoustic measurements indicated of an increase in lung volume following administration of exogenous surfactant. Hysteresis in the amplitude of acoustic reflection was measured as expected. Our results indicate that the acoustic technique provides useful information about the state of lung recruitment during HFOV and may be helpful in identifying the adequate MAP for optimal lung expansion without overdistension.

The relationship between instantaneous changes in fetal head station and cervical dilatation within the individual contraction during the active stage of labor were studied and an index of labor progress was suggested. Cervix dilatation and fetal head station were measured continuously in 30 nullipara women (mean age 27.5, standard deviation 4.8). The continuous measurements enabled the analysis of each variable and the analysis of the relations between these two variables. The relationship between the head station and the cervical dilatation were demonstrated by plotting one against the other during a contraction. This led to the definition of a contraction vector that integrates the interaction between the two variables. The angle of this vector, that indicates this relation, was plotted against mean head station to demonstrate change along the delivery process regardless of time to normalize the progress and allow comparison between different women with different labor durations. This plot showed a sharp change from almost zero into a steep curve at about zero head station. A zero angle indicates that the cervix dilates during a contraction with little effect on head station while a steep angle indicates a significant effect of cervical dilatation on head station during the contraction. The contraction-vector angle reflects the changing intra-contraction relationship between head station and cervical dilatation. The angle of this vector may serve as an indicator of labor progress.

Ventilation using high-frequency oscillation (HFO) has become a standard care for the ventilatory management of critically ill newborns. In recent years, there has been growing recognition that maintenance of an optimal lung volume during high-frequency oscillation plays an important role in minimizing ventilator-induced lung injury. The primary variable affecting lung volume is the mean airway pressure (MAP). To effectively maintain lung recruitment and optimal gas exchange without overstretching (or collapsing) the lung, MAP should be set between two well defined points in the pressure-volume curve of the lung. To determine optimal MAP during high frequency ventilation, an acoustic monitoring system was developed and tested. The system was based on transmission of audible acoustic bursts and reception of echoes from the lungs. The results suggest that these acoustic measurements reflect the mechanical properties of the lungs. The acoustic measurements indicated an increase in lung volume following the administration of exogenous surfactant into the lungs as expected. Hysteresis in the amplitude of acoustic reflection was also measured as expected. Despite the fact that we had no "gold standard" to compare with, our results suggest that acoustic properties of the lung as measured by our system, have the potential to indicate the degree of lung recruitment during HFO and to define the optimal region of MAP.

A non-linear mathematical model of the oesophagus was developed to study the effects of non-invasive ventilation variables on the severity of gastric inflation. The model was based on the non-linear physical characteristics of biological tissue. The model simulated oesophageal mechanical function during non-invasive ventilation in cardiac arrest (2:30 ventilations/chest compressions cycles) and respiratory arrest (1:5 ventilations/s) as recommended by the European Resuscitation Council (ERC) in its 2005 guidelines for adult basic and advanced life support. Model predictions establish a strong correlation between the expiratory time and the occurrence of gastric inflation. For cardiac arrest, when using ventilation pressure lower than 12 cmH2O, expiratory time between consequent ventilations and time until the occurrence of gastric inflation were linearly dependent (r = 0.98). This linear correlation changed abruptly when airway pressure exceeded the threshold pressure of 12 cmH2O, indicating that air had entered the stomach during the first ventilation. The interval at which the pressure at the distal section of the oesophagus was above the lower oesophageal sphincter (LES) opening pressure was significantly prolonged in the model of cardiac arrest (approximately 5.5 s compared to 3 s in respiratory arrest), thus allowing a greater amount of air to enter the stomach at relatively low airway pressures. During cardiac arrest, the mean pressure at the distal section of the oesophagus and the amplitude of air backflow were higher compared to the mean pressure and amplitude during respiratory arrest. This is also due to the shorter expiratory intervals in the 2:30 ventilations/chest compressions technique. The model indicates that the time required for the air trapped in the oesophagus to completely deflate is approximately 2 s. This may be longer than the expiratory time recommended by the 2005 guidelines. Model predictions support the 2005 guidelines regarding the decrease in the tidal volume and in the inspiratory pressure in an effort to minimise gastric inflation.