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Abstract

This review will focus on the dynamic changes of the fetal circulation, the distribution of organ blood flow during normoxemia, and that during hypoxia and asphyxia caused by various experimental perturbations. Furthermore, the relation between oxygen delivery and tissue metabolism during oxygen lack as well as evidence to support a new concept will be presented along with the principal cardiovascular mechanisms involved. Finally, blood flow and oxygen delivery to the principal fetal organ will be examined and discussed in relation to organ function. The fetal circulatory response to hypoxaemia and asphyxia is a rapid centralization of blood flow in favour of the brain, heart, and adrenals and at the expense of almost all peripheral organs, particularly of the lungs, carcass, skin and scalp. This response is qualitatively similar but quantitatively different under various experimental conditions. However, at the nadir of severe acute asphyxia the circulatory centralization cannot be maintained. Then there is circulatory de-centralization, and the fetus will experience severe brain damage if not expire unless immediate resuscitation occurs. Future work in this field will have to concentrate on the important questions, what factors determine this collapse of circulatory compensating mechanisms in the fetus, how does it relate to neuronal damage, and how can the fetal brain be pharmacologically protected against the adverse effects of asphyxia?
... La vasoconstriction périphérique est accentuée par l'action directe de l'hypoxémie sur les cellules de la paroi des vaisseaux et par la stimulation de la surrénale par action sympathique (19)(20)(21). Cela entraîne une production de catécholamines responsable d'un effet vasoconstricteur (14,18,22). Ces effets contrebalancent l'effet chronotrope négatif induit par le système parasympathique et impactent ainsi la balance du SNA (23). ...
... Le premier est la baisse de la résistance vasculaire par l'effet local vasodilatateur du CO2 (99,100). Un autre est lié à la redistribution vasculaire vers les organes dits nobles du sang oxygéné par notamment une hausse du débit cardiaque induits par les décharges du système sympathique et des catécholamines circulantes (22). Enfin, on note une augmentation de la pression artérielle systémique due à la vasoconstriction périphérique. ...
Thesis
Introduction : La prévention de l’encéphalopathie anoxo-ischémique (EAI) pendant le travail est une préoccupation majeure en salle de naissance. Une acidose néonatale sévère est un des critères pour définir une asphyxie foetale. Elle est associée à un risque de lésions cérébrales. Actuellement les moyens de surveillance pendant le travail ne permettent pas de dépister correctement ces situations à risque d’hypoxie et/ou de lésions cérébrales. L’analyse de la variabilité de la fréquence cardiaque (VFC) foetale semble être une piste intéressante pour le dépistage de ces situations. Notre équipe a développé un marqueur d’analyse de la VFC, le Fetal Stress Index (FSI). L’objectif de ce travail était en première partie d’évaluer l’utilisation des différents marqueurs du rythme cardiaque foetal dans des systèmes automatisés (machine learning) pour mieux prédire l’acidose foetale, et en deuxième partie d’évaluer l’utilisation de la VFC dans le dépistage des lésions d’EAI.Matériel et Méthodes : Nous avons réalisé une étude expérimentale chez le foetus de brebis à terme. Des occlusions du cordon ombilical totales (OCT) répétées étaient réalisées selon différentes phases (phase A, B et C) pour obtenir une acidose foetale sévère. Les paramètres hémodynamiques, l’ECG et les gaz du sang étaient analysés. L’ECG permettait l’analyse des paramètres de la VFC. Le gold standard utilisé pour classer l’hypoxie était le pH artériel foetal (pH<7,10). Une analyse anatomopathologique des cerveaux des foetus de brebis était réalisée 48h après les manipulations pour l’évaluation des lésions cérébrales. Les méthodes statistiques de machine learning utilisées pour le dépistage de l’acidose étaient la régression logistique et les arbres décisionnels. L’association entre les lésions cérébrales et les différents paramètres était étudiée selon les différentes phases d’occlusion à l'aide d'un test rho de Spearman.Résultats : 21 agneaux ont été instrumentés. 132 couples analyse du rythme cardiaque foetal / pH foetal ont été obtenus dont 29 dans le groupe acidose et 103 dans le groupe non acidose. Un modèle de régression logistique, avec une sélection « backward » des variables, permettait d’obtenir une AUC de 0.73 avec une sensibilité à 0,59 et une spécificité à 0,83. Par cette méthode, seule la variable FSI était sélectionnée. Aucun seuil permettant de prédire l’acidose n’a pu être déterminé. En utilisant les arbres décisionnels, on obtenait une spécificité de 0,96 à 0,99 et une sensibilité de 0,56 à 0,59. La première variable sélectionnée pour classer les enregistrements en acidose ou non acidose était le FSI.Dans la seconde partie du travail, 9 cerveaux ont été analysés. Des lésions cérébrales d’EAI étaient présentes chez 7/9 foetus avec des lésions du tronc cérébral observées chez 3/9 foetus. Le FSI, la variabilité à long terme (VLT) et la variabilité à court terme (VCT) étaient significativement corrélés au nombre de lésions du tronc cérébral en phase C pour le FSI (r=-0,784 ; p=0,021) et en phase B pour la VLT (r=-0,677 ; p=0,045) et la VCT (r=-0,837 ; p=0,005). On retrouvait une corrélation significative entre les lésions cérébrales et les variations de pression artérielle moyenne durant les occlusions. Il n'y avait pas de corrélation significative entre les lésions cérébrales et les autres marqueurs de la VFC ainsi qu’avec les marqueurs gazométriques dont le pH.Conclusion : Les modèles de machine learning ne semblaient pas améliorer le dépistage de l’acidose foetale. Les variables principales sélectionnées automatiquement dans ces modèles étaient celles de la VFC dont le FSI comme variable d’entrée dans les modèles. L’acidose foetale n’était pas corrélée aux lésions d’EAI. Seuls certains paramètres de la VFC (FSI, VCT, VLT) étaient corrélés aux lésions d’EAI. Ainsi la VFC ne permettrait pas une bonne prédiction de l’acidose foetale mais permettrait le dépistage des situations à risque d’EAI.
... Hypoxic ischemic encephalopathy (HIE) due to perinatal asphyxia is an important cause of neurodevelopmental abnormalities in childhood, and is estimated to occur in 1-6 per 1000 live births [1]. The rationale for studying multi-organ dysfunction (MOD) in the context of perinatal asphyxia stems from the diving reflex, a physiologic response to oxygen deprivation in which blood is shunted from nonvital organs to preserve perfusion of vital organs such as the brain [2][3][4]. In neonates who exhibit encephalopathy secondary to perinatal asphyxia, brain perfusion has been compromised despite this reflex, suggesting that other end-organs may have similarly experienced a hypoxic ischemic insult. ...
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Objective To evaluate multi-organ dysfunction (MOD) in newborns treated with therapeutic hypothermia (TH) for hypoxic ischemic encephalopathy (HIE), and to compare MOD in those with normal/mild magnetic resonance imaging (MRI) findings to those with moderate to severe MRI findings or death. Study design Retrospective single-center observational study of infants treated with TH. A total of 16 parameters across 7 organ systems were analyzed. Primary outcome was death or moderate to severe brain injury on MRI. Result Of 157 infants treated with TH, 77% had ≥2 organ systems with dysfunction. The number of organ systems with dysfunction was strongly associated with death or moderate-to-severe brain injury (p < 0.0001). Hematologic (68%) and hepatic (65%) dysfunction were most common. Neurologic and renal dysfunction were most strongly associated with the primary outcome (OR 13.5 [6.1–29.8] and 11.2 [4.1–30.3], respectively), while pulmonary hypertension was not. Conclusion MOD is prevalent in infants undergoing TH for HIE, and the association between MOD and adverse outcomes may impact clinical care and counseling.
... During oxygen deprivation in the event of fetal hypoxia-ischemia, compensatory mechanisms are responsible for redistributing cardiac output, centralization of blood flow to vital organs, and reducing oxygen consumption [57]. Although hypoxia-ischemia can affect other tissues and systems, such as the renal (transient renal failure), pulmonary (pulmonary hypertension, meconium aspiration), hepatic (transient transaminase elevation), and gastrointestinal (food intolerance, necrotizing enterocolitis) systems, the heart and the kidneys are the two most critical extracerebral organs involved [56,58]. ...
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Perinatal asphyxia is caused by lack of oxygen delivery (hypoxia) to end organs due to an hypoxemic or ischemic insult occurring in temporal proximity to labor (peripartum) or delivery (intrapartum). Hypoxic–ischemic encephalopathy is the clinical manifestation of hypoxic injury to the brain and is usually graded as mild, moderate, or severe. The search for useful biomarkers to precisely predict the severity of lesions in perinatal asphyxia and hypoxic–ischemic encephalopathy (HIE) is a field of increasing interest. As pathophysiology is not fully comprehended, the gold standard for treatment remains an active area of research. Hypothermia has proven to be an effective neuroprotective strategy and has been implemented in clinical routine. Current studies are exploring various add-on therapies, including erythropoietin, xenon, topiramate, melatonin, and stem cells. This review aims to perform an updated integration of the pathophysiological processes after perinatal asphyxia in humans and animal models to allow us to answer some questions and provide an interim update on progress in this field.
... The placenta is the main interface between the mother and the fetus, and its development and placental oxygen consumption also affect fetal oxygen supply. In addition, changes in maternal pO 2 and/or abnormal placental development or metabolism may reduce pO 2 in the fetal arteries and lead to fetal hypoxia (Jensen et al., 1999;Myatt, 2006). ...
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The fetal origins of adult disease (FOAD) hypothesis, which was proposed by David Barker in the United Kingdom in the late 1980s, posited that adult chronic diseases originated from various adverse stimuli in early fetal development. FOAD is associated with a wide range of adult chronic diseases, including cardiovascular disease, cancer, type 2 diabetes and neurological disorders such as schizophrenia, depression, anxiety, and autism. Intrauterine hypoxia/prenatal hypoxia is one of the most common complications of obstetrics and could lead to alterations in brain structure and function; therefore, it is strongly associated with neurological disorders such as cognitive impairment and anxiety. However, how fetal hypoxia results in neurological disorders remains unclear. According to the existing literature, we have summarized the causes of prenatal hypoxia, the effects of prenatal hypoxia on brain development and behavioral phenotypes, and the possible molecular mechanisms.
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Increased fetal heart rate variability (FHRV) in intrapartum cardiotocographic recording has been variably defined and poorly understood, limiting its clinical utility. Both preclinical (animal) and clinical (human) evidence support that increased FHRV is observed in the early stage of intrapartum fetal hypoxaemia but can also be observed in a subset of fetuses during the preterminal stage of repeated hypoxaemia. This review of available evidence provides data and expert opinion on (1.) pathophysiology of increased FHRV, (2.) its clinical significance, and (3.) a stepwise approach regarding the management of this pattern and (4.) propose recommendations for standardisation of related terminology.
Article
Introduction: The aim of the study was to identify the obstetric risk factors for hypoxic-ischemic encephalopathy (HIE) in infants with asphyxia at birth. Material and methods: This multicenter case-control study covered the 5-year period from 2014 through 2018 and included newborns ≥36 weeks of gestation with an umbilical pH at birth ≤7.0. Cases were newborns who developed moderate or severe HIE; they were matched with controls with pH ≤7.0 at birth over the same period without moderate or severe HIE. The factors studied were maternal, gestational, intrapartum, delivery-related, and neonatal characteristics. A multivariable analysis was performed to study the maternal, obstetric, and neonatal factors independently associated with moderate or severe HIE. Results: Our review of the records identified 41 cases and 98 controls. Compared with controls, children with moderate or severe HIE had a lower 5-min Apgar score, lower umbilical artery pH, and higher cord lactate levels at birth and at 1 h of life. Obstetric factors associated with moderate or severe HIE were the occurrence of an acute event (adjusted odds ratio [aOR] 6.4; 95% confidence interval [CI] 1.8-22.5), maternal fever (aOR 3.5; 95% CI 1.0-11.9), and thick meconium during labor (aOR 2.9; 95% CI 1.0-8.6). Conclusions: HIE is associated with a lower 5-min Apgar score and with the severity of acidosis at birth and at 1 h of life. In newborns with a pH <7.0 at birth, the occurrence of an acute obstetric event, maternal fever, and thick meconium are independent factors associated with moderate or severe HIE.
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Objectives: to assess labour characteristics in relation to the occurrence of Composite Adverse neonatal Outcome (CAO) within a cohort of fetuses with metabolic acidaemia. Design: retrospective cohort study. Setting: 3 Italian tertiary maternity units. Population: 431 neonates born with acidaemia ≥36 weeks. Methods: Intrapartum CTG traces were assigned to one of these four types of labour hypoxia: acute, subacute, gradually evolving and chronic hypoxia. The presence of CAO was defined by the occurrence of at least one of the following: Sarnat Score grade ≥2, seizures, hypothermia and death <7 days from birth. Main outcome measures: to compare the type of hypoxia on the intrapartum CTG traces among the acidaemic neonates with and without CAO. Results: The occurrence of a CAO was recorded in 15.1% of neonates. At logistic regression analysis, the duration of the hypoxia was the only parameter associated with CAO in case of acute and subacute pattern (OR 1.3; 95% CI 1.02-1.6 and OR 1.04; 95% CI 1.0-1.1), while the duration of the hypoxic insult and the time from PROM to delivery were both associated with CAO in those with gradually evolving pattern (OR 1.13; 95% CI 1.01-1.3 and OR 1.04; 95% CI 1.0-1.7). The incidence of CAO was higher in fetuses with chronic antepartum hypoxia compared to those showing CTG features of intrapartum hypoxia (64.7 vs. 13.0%; p<0.001). Conclusions: The frequency of CAO seems related to the duration and the type of the hypoxic injury being higher in fetuses showing CTG features of antepartum chronic hypoxia.
Article
Background: Queensland introduced a colour-coded cardiotocograph (CTG) classification system (green, blue, yellow and red) to complement the Royal Australian and New Zealand College of Obstetricians and Gynaecologists prose-based classification system of 'low, unlikely, maybe or likely' fetal compromise. Aims: The aim of the study was to determine the clinical impact of the introduction of the colour-coded CTG classification system compared to the prose-based system. We hypothesised there would be no change in the rate of operative delivery for intrapartum fetal compromise (OD-IFC). Materials and methods: This retrospective non-inferiority study from November 2014 to May 2018 used routinely collected data from the Mater Mother's Hospital. Non-insured women with a singleton, non-anomalous, cephalic fetus at term, attempting a vaginal birth with continuous intrapartum CTG were included. The primary outcome was OD-IFC. Secondary outcomes included various obstetric and perinatal outcomes. Non-inferiority analysis was performed with a pre-specified non-inferiority margin of 2% risk difference. Results: Eleven thousand seven hundred and twenty-seven participants were included. The OD-IFC rate was similar across the study groups (prose-based 15.1% vs colour-coded 15.3%, adjusted odds ratio (aOR) 1.02, 95% CI 0.93-1.13) with the adjusted risk difference of 0.29% (95% CI -0.98 to 1.56), which did not exceed the inferiority margin. There were more spontaneous (aOR 1.11, 95% CI 1.04-1.19) and fewer instrumental (aOR 0.87, 95% CI 0.80-0.95) vaginal births in the colour-coded cohort. There were no differences in neonatal outcomes. Conclusions: Reassuringly, the colour-coded CTG classification system was non-inferior to the prose-based system, did not influence OD-IFC but was associated with more spontaneous vaginal deliveries.
Chapter
The fetus can be at risk of perinatal asphyxia by different pathophysiological processes, so the effectiveness of the various fetal tests depends on the underlying pathophysiological condition. The processes that can be related to fetal death or damage are decreased uteroplacental blood flow, decreased gas exchange at the level of the trophoblastic membrane, metabolic processes, fetal sepsis, fetal anemia, fetal heart failure, and umbilical cord accidents. Different ways and diseases lead the fetus to chronic fetal distress process, requiring, as a consequence, different obstetric procedures, according to each pattern of involvement of the fetus. Each of these is involved in one of the models of chronic fetal distress and requires a specific pattern of maternal-fetal surveillance for each condition in order to avoid perinatal morbidity and mortality.
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Maternal cardiovascular disease is a leading cause of maternal death worldwide and recently, maternal mortality has increased secondary to cardiovascular causes. Maternal admissions to critical care encompass 1-2% of all critical care admissions, and while not common, the management of the critically ill pregnant patient is complex. Caring for the critically ill pregnant cardiac patient requires integration of pregnancy associated physiologic changes, understanding pathophysiologic disease states unique to pregnancy and a multidisciplinary approach to timing around delivery as well as antenatal and postpartum care. Herein we describe cardiorespiratory changes that occur during pregnancy and the differential diagnosis for cardiorespiratory failure in pregnancy. Cardiorespiratory diseases that are either associated or exacerbated by pregnancy are highlighted with emphasis on perturbations secondary to pregnancy and appropriate management strategies. Finally, we describe general management of the pregnant cardiac patient admitted to critical care.
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To improve the understanding of fetal responses to labour, we have ascertained whether reduced fetal skin blood flow after asphyxia reflects redistribution of the circulation, and if so, whether this can be detected by transcutaneous PO2 monitoring. We also studied the relation between plasma concentrations of catecholamines and organ blood flow. Eight experiments were conducted on 8 acutely-prepared fetal sheep in utero between 125 and 135 days of gestation. In each fetus 11 episodes of asphyxia were induced within 33 min by intermittent arrest of uterine blood flow for 90 s. The distribution of blood flow was measured before and after asphyxia (at 35.5 min) by the isotope-labelled microsphere method. Blood samples were drawn at 0, 33 (i.e. after 90 s recovery), and 40 min to determine blood gases, acid-base balance, and catecholamine concentrations. Fetal transcutaneous PO2, heart rate, arterial blood pressure, and arterial O2 saturation were recorded continuously. Repeated fetal asphyxia increased plasma catecholamine concentrations and caused a circulatory redistribution to the brain (181% change), adrenals (116% change), and lungs (105% change) at the expense of many peripheral organs, particularly of the skin (-61% change). The pattern of these changes was different from that observed by others in persistent hypoxia or asphyxia. The decrease in skin blood flow, which depressed transcutaneous PO2 and increased the arterial-transcutaneous PO2 difference, correlated with the decrease in blood flow to other peripheral organs and with an increase in blood flow to the brain stem. We conclude that reduced blood flow to the fetal skin after repeated episodes of asphyxia indicates circulatory redistribution, which can be detected by transcutaneous PO2 measurements. We suggest that monitoring of variables that depend on skin blood flow may improve fetal surveillance during complicated labour.
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The responses of fetal heart rate and blood pressure to a transient reduction in uterine blood flow were studied in normoxemic and chronically hypoxemic lambs. In normoxemic fetuses, a reduction in uterine blood flow, if prolonged sufficiently, produced reflex bradycardia mediated through chemoreceptors and was associated with a decrease in carotid arterial Po 2 to below 20 torr. The bradycardia was associated with a marked decrease in left ventricular output as measured by electromagnetic flowmeter; both were abolished by atropine. In chronically hypoxemic fetuses, a reduction in uterine blood flow produced a delayed deceleration of the heart rate which consisted of three components: reflex bradycardia due to chemoreceptor stimulation; baroreceptor-mediated reflex bradycardia which involved the slow and late recovery of the heart rate; and nonreflex bradycardia which was probably secondary to hypoxic myocardial depression. Quantitative analysis revealed a relationship between the components of delayed deceleration and the status of fetal oxygenation prior to the reduction in uterine blood flow. The lower the carotid arterial Po 2 , the shorter was the delay in the onset of bradycardia, the greater the decrease in heart rate, and the more prolonged the duration of bradycardia. The conclusion is that the response of fetal heart rate to a transient reduction in uterine blood flow is related to the duration of the reduction and to the status of fetal oxygenation prior to the decrease in uterine blood flow.
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We examined heart rate and blood pressure responses to umbilical cord compression in fetal lambs. Fetal heart rate (FHR) responses resembling variable deceleration occurred only after umbilical blood flow was reduced by at least 50%. These changes during partial cord occlusion varied directly with the reduced umbilical blood flow and were abolished by atropine; no significant changes in arterial pressure were observed. Complete cord occlusion caused severe bradycardia, a progressive increase in arterial pressure, and delayed recovery of FHR. With partial cord occlusion, the bradycardia was of chemoreceptor origin and was vagally mediated; with complete occlusion the bradycardia may have resulted from both chemoreceptor and baroreceptor stimulation. During prolonged partial cord occlusion, FHR decreased initially, then recovered to above control value; this occurred in the face of a significant acidosis. Thus, FHR responses to cord compression are dependent on the actual percentage of reduction in umbilical blood flow and on its duration.
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To assess the effect of various degrees of umbilical cord compression on fetal oxygenation, we instrumented fetal lambs at 120 to 128 days' gestation. An electromagnetic flow transducer was placed around the common umbilical artery to record umbilical blood flow continuously. Catheters were passed into an umbilical vein and a hind limb artery and vein, and a balloon occluder was placed around the umbilical cord. After recovery from operation, umbilical blood flow was reduced to 75%, 50%, and 25% of control values by controlled cord occlusion. Umbilical venous oxygen content did not change during cord compression; thus, oxygen delivery was linearly related to umbilical blood flow. Oxygen consumption of the fetus was maintained with reduction of umbilical blood flow to about 50% of control values; further reductions were associated with a progressive fall in fetal oxygen consumption. With reduced umbilical flow, there was a progressive increase in oxygen extraction from a control of 33.6% ± 4.8% to 67.7% ± 11.3% during 75% reduction of flow.
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The depletion of glycogen, creatine phosphate and ATP in the fetal heart, liver and brain was studied in 40 mature guinea pig fetuses acutely exteriorized and submitted to a graded hypoxia. A strong linear correlation was found between an ECG scoring system, taking the severity of the ST-T changes into account, and the depletion of heart glycogen and creatine-P. ATP was unaffected until glycogen was almost depleted (25 &percnt; of initial value). At this point, brain and liver glycogen were also severely affected. Bradycardia (AV-block, type II) was strongly correlated to failing myocardial metabolism. It is concluded that the changes in the fetal ECG pattern could be regarded as a sign of myocardial glycolysis and early hypoxic stress.Copyright © 1976 S. Karger AG, Basel