Fetal Responses to Reduced Oxygen Delivery

Fetal Responses to Reduced Oxygen Delivery Abraham M Rudolph Fetal Cardiology Symposium May 2016, Phoenix

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Oxygen Delivery Oxygen is transported to the placenta via the uterine circulation; it diffuses across the placenta and is delivered to the fetus by the umbilical veins

Combined Ventricular Output Distribution in Fetal Lamb In fetal lambs, umbilical-placental blood flow is about 200 ml/kg body weight/min. It is about 40 % of combined ventricular output. It falls only slightly in relation to fetal body weight in the latter part of gestation

Umbilical Venous Blood Flow Umbilical Blood Flow in Human Fetus In human fetuses, umbilical-placental blood flow falls markedly in relation to fetal body weight in the latter half of gestatioin Before 30 wk gestation Quv is about 140 ml/min/kg body weight or about 30 % of CVO After 30 wk gestation Quv is about 90 ml/min/kg body weight or about 20 % of CVO Kiserud T et al. Ultrasound Obstet Gynecol. 2006;28:126

Fetal Oxygen Delivery and Consumption Lamb Human Gestation dys /wks 70 140 20 40 Hemoglobin conc (g/dl) 8.0 9.0 10.0 16.0 Oxygen capacity (ml/dl) 10.8 12.2 13.4 21 UV oxygen saturation 80 80?80?80 UV oxygen content (ml/dl) 8.6 9.76 10.7 17.2 UA oxygen saturation % 50 50?50?50 UA oxygen content (ml/dl) 5.4 6.1 6.7 10.7

Fetal Oxygen Delivery and Consumption Lamb Human Gestation dys /wks 70 140 20 40 Umbilical blood flow (ml/min/kg) 200 180 140 90 Oxygen delivery (ml/min/kg) 17.2 17.6 15.0 15.4 Oxygen consumption (ml/min/kg) 6.5 6.6 5.6 5.9 Oxygen extraction (percent) 36 37 37 38

Decrease in Oxygen Delivery Reduced supply by uterine circulation Decreased oxygen content of maternal arterial blood (Hypoxemia) Decreased uterine blood flow Interference with placental transport Decreased placental area Placental pathology Reduced umbilical venous delivery Decreased umbilical blood flow Decreased umbilical venous oxygen content

Methods of Decreased Oxygen Supply Three methods were studied: Reducing oxygen content of maternal arterial blood hypoxemia ( Hypox ) Reducing uterine blood flow by constriction of the uterine arteries ( <Qu ) Reducing umbilical blood flow by constricting the umbilical cord ( <Qumb ) With each method, studies were performed with a 25 and a 50 percent reduction in oxygen delivery in lamb fetuses at about 120 dys gestation The method of reduced oxygen delivery may be associated with differences ln fetal response

Decreased Fetal Oxygen Delivery Percent Maternal Uterine Flow Umbilical Flow Change in Hypoxemia Reduction Reduction 25% 50% 25% 50% 25% 50% UV Po 2-36 - 45-8 - 20 Asc Ao Po 2-42 - 42-29 - 29-9 - 20 UV Pco 2 + 16 + 32 + 7 + 2 Asc Ao Pco 2 0 + 5 + 15 + 28 + 6 + 6

Decreased Fetal Oxygen Delivery UV Po 2 falls markedly with <Qut and presumably with Hypox, but not with < Qumb Asc Ao Po 2 falls markedly with Hypox, falls somewhat less with <Qut, but only slightly with <Qumb. UV blood, which remains well oxygenated preferentially crosses the foramen ovale to be distributed to the upper body UV Pco 2 increases with <Qut, but not with Hypox or presumably with <Qumb Asc Ao Pco 2 increases with <Qut but not with <Qumb or Hypox

Oxygen Delivery and Consumption < Uterine Flow < Umbilical Flow Cont 25% 50% Cont 25% 50% O 2 Delivery 20.9 14.7 15.6 22.4 16.5 12.0 ml/min/kg O 2 Consumption 6.4 5.9 6.2 7.5 7.0 6.1 ml/min/kg O 2 Extraction 30 40 42 34 44 51 percent Despite the fall in oxygen delivery, oxygen consumption is maintained as a result of an increase in extraction by the tissues

Oxygen Consumption with Graded Reduction of Umbilical Blood Flow Reduction of unbilical blood flow by up to 50% has little effect on oxygen consumption Further reduction results in a rapidly progressive fall in consumption Itskovitz J et al. Am J Obstet Gynecol.1983;145:813

Myocardial and Cerebral Oxygen Consumption Reduction of ascending aortic Po 2 from 23 to 14 mm Hg and coronary sinus Po 2 from 13 to 7 mm Hg by maternal hypoxemia did not affect myocardial oxygen consumption in fetal lambs. Before hypoxemia it was 8.9 ml/min/100g and during hypoxemia it was 9.4 ml/min/100g Fisher DJ et al. Am J Physiol. 1972:242;H657 Over the range of cerebral arterial Po 2 of 14-36 mm Hg cerebral venous Po 2 of 9-25 mm Hg, cerebral oxygen consumption did not change in fetal lambs; the fall in oxygen content was associated with an increase in cerebral blood flow Jones MD Jr et al. J Appl Physiol 1977, 43:1080

Effects of Decreased Fetal Oxygen Delivery on the Circulation Percent Maternal Uterine Flow Umbilical Flow Change in Hypoxemia Reduction Reduction 25% 50% 25% 50% 25% 50% Heart Rate - 42-42 - 14-16 - 4-10 CVO - 5-18 - 6-12 - 2-18 Placental Flow Quv + 11 + 8 + 6-2 - 21-50 Body Q - 16-35 - 19-20 + 14 + 11

Decreased Fetal Oxygen Delivery Fetal heart rate falls markedly with Hypox, moderately with <Qut, but does not change significantly with <Qumb. This difference in response is related to the fact that Asc Ao Po 2 does not fall with <Qumb and thus chemoreceptors are not stimulated Combined ventricular output does not change significantly Umbilical blood flow falls by design with <Qumb; it increases slightly with Hypox and does not change with <Qut Blood flow to the fetal body falls with Hypox and <Qut as a result of vasoconstriction with increased resistance. With <Qumb, body flow increases. Umbilical vascular resistance is increased as a result of cord compression and resistance in the peripheral circulation does not change significantly. Thus blood flows to the body preferentially

Effects of Decreased Fetal Oxygen Delivery on the Circulation Percent Maternal Uterine Flow Umbilical Flow Change in Hypoxemia Reduction Reduction Organ Flows 25% 50% 25% 50% 25% 50% Brain Q + 75 + 93 + 74 + 77 + 29 + 40 Heart Q + 150 + 169 + 69 + 125 + 8 + 40 Lungs - 55-47 - 57-35 - 19-50 Periph Circ - 30-70 - 25-40 + 24 + 19

Effects of Decreased Fetal Oxygen Delivery on the Circulation Blood flow to the brain is increased considerably with Hypox and <Qut, associated with the fall in Asc Ao Po 2. The increase is less significant with <Qumb, because Po 2 falls only modestly Similarly myocardial blood flow increases markedly with Hypox, modestly with <Qut, but much less with <Qumb Pulmonary blood flow falls with all three modes of reduced oxygen delivery; the lung is perfused with blood from the right ventricle

Effects of Decreased Fetal Oxygen Delivery on the Circulation Decreased arterial oxygen saturation induces relaxation of vascular smooth muscle, except in the pulmonary circulation Blood flow to the peripheral circulation (as well as to the gastrointestinal tract) falls dramatically with Hypox, modestly with <Qut. The decreased flow is related to chemoreflex stimulation with vasoconstriction. The less dramatic vasoconstriction with <Out could be related to the rise in Pco 2, which exerts some dilatory effect The increase in peripheral flow with <Quv is related to lack of significant chemoreflex response and also to the induced high umbilical placental vascular resistance

Gestational Differences in Response to Maternal Hypoxemia Percent Change in ~120 d gest ~90 d gest Art Po 2-42 - 41 Art Pco 2 + 5-6 Heart Rate - 42 + 6 CVO ml/min/kg - 18-14 Placental Flow Quv + 8-35 Body Q - 35 + 8 Organ Flows ml/min/100g Brain Q + 93 + 38 Heart Q + 169 + 178 Lungs - 55-51 Periph Circ - 70 + 4 Iwamoto HS et al. Am J Physiol. 1989: 256; H613

Hormonal Responses to Reduced Oxygen Delivery In Fetal Lamb Norepinephrine In lambs ~90 d gest Control 900 pg/ml Hypoxemia 1800 pg/ml In lambs ~120 d gest Control 450 pg/ml Hypoxemia 4500 pg/ml Vasopressin In lambs ~90 d gest Control 2 pg/ml Hypoxemia 13 pg/ml In lambs ~120 d gest Control 3 pg/ml Hypoxemia 35 pg/ml ACTH and cortisol concentrations increase Angiotensin concentration is not affected

Gestational Differences in Response to Maternal Hypoxemia A similar decrease in arterial Po 2 was associated with; A fall in heart rate at 0.8 g, but no change at 0.6g A marked decrease in fetal body flow at 0.8g, but little change at 0.6g No change in umbilical flow at 0.8g, but a fall at 0.6g A marked increase in cerebral flow at 0.8g, but only a modest increase at 0.6g A marked decrease in flow to the peripheral circulation at 0.8g, but no change at 0.6g A marked increase in norepinephrine concentration at 0.8g, but only a modest increase at 0.6g

Gestational Differences in Response to Maternal Hypoxemia The differences in response of the younger fetuses could be explained by an immaturity of the chemoreceptor response to decreased arterial oxygen content The marked increase in peripheral vascular resistance, with a fall in peripheral blood flow in the older fetuses, could account for the maintenance of umbilical blood flow. In the younger fetuses, blood flow to the peripheral circulation is maintained, but umbilical flow falls

Catecholamine Response to Reduced Arterial Oxygen Saturation Reduction of carotid arterial O 2 saturation from a control of about 65% to levels of about 25% is associated with small increases of norepinephrine concentration Below about 25%, a small fall in O 2 sat is associated with a dramatic increase in norepinephrine concentration Sola A, Rudolph AM et al

Role of Chemoreflex in Response to Decreased Oxygen Delivery Postnatally, stimulatiion of chemoreceptors predominantly affects respiration with an increase in depth and rate of breathing. Heart rate increases, but inhibition of the increased respiratory response induces bradycardia In the fetus the predominant effect of chemoreceptor stimulation is bradycardia and perhaps a few gasps, but no significant respiratory effect The magnitude of the bradycardia response is related to resting carotid arterial oxygen saturation; the lower the saturation, the greater is the response to the same degree of fall in saturation

Heart Rate Response to Decreased Ascending Aortic Oxygen Content Hypoxemia induces a fall in heart rate The bradycardia is the result of parasympathetic stimulation via the vagus nerve; it is blocked by atropine The bradycardia is related to chemorecepior stimulation; sino-aortic denervation inhibits the bradycardia response Control Sino-aortic denervation Sino-aortic denervation Control Itskovitz J, Rudolph AM. Am J Physiol. 1982;242:H916

Role of Chemoreceptors in Catecholamine Response to Hypoxemia At carotid arterial O 2 saturation above about 25%, inhibition of chemoreceptors induces only a small decrease in catecholamine response At saturations below about 25%, chemoreceptor blockade almost completely inhibits the response to further reduction in O 2 sat Chemoreceptor stimulation is very important in the increase in norepinephrine concentations with hypoxia, especially when O 2 sat is < 25% (Po 2 < 15-16 torr) Sola A, Rudolph AM et al.

Role of Chemoreceptors in Hormonal Responses The dramatic increase in fetal plasma norepinephrine concentrations resulting from reduced ascending aortic oxygen content is markedly limited by inhibition of chemoreceptors Peripheral chemoreceptor inhibition has no effect on the increase in vasopressin concentrations associated with reduced O 2 content Raff H et al Am J Physiol. 1991;260:R1077 To determine which chemoreceptors are involved in the norepinephrine response, we selectively blocked carotid and aortic receptor either by surgical denervation or by blockade

Carotid vs Aortic Chemoreceptors Bartelds B et al. 1993;34:51

Carotid vs Aortic Chemoreceptors Bartelds B et al. 1993;34:51

Fetal Responses to Reduced Oxygen Delivery (Summation) Compared with the lamb, the human fetus has a progressive fall in umbilical blood flow related to fetal weight. Oxygen delivery is facilitated by an increase in hemoglobin concentration The effects of reduced oxygen delivery differ, dependent on the mechanism responsible for decreased delivery A decrease in oxygen concentration of perfusing blood induces vascular smooth muscle relaxation. This accounts for the increased blood flow in the brain and to the myocardium Pulmonary blood flow falls as a result of the lowered oxygen content of blood perfusing the lungs it is derived from the right ventricle

Summation The peripheral chemoreceptors are influenced by oxygen content of ascending aortic blood. This falls considerably with maternal hypoxia and reduced uterine blood flow, but not with decreased umbilical blood flow Chemoreceptor stimulation is responsible for the bradycardia through parasympatheic mechanisms. It also induces the marked increase in plasma norepinephrine concentrations. This causes vasoconstriction of the peripheral circulation and the fall of body blood flow with maternal hypoxia and reduced uterine blood flow The carotid rather than aortic chemoreceptor is responsible for these effects

Summation The responses to reduced oxygen delivery are related to gestational age. Chemoreceptor responsiveness increases beyond about 0.75 gestation in the lamb fetus, but the pattern of development of responsiveness in the human fetus is not known. Possibly the response of the peripheral circulation to alphaadrenergic stimulatioin by norepinephrine is also not fully developed in younger fetuses

Glucose Delivery Is reduced oxygen delivery the most important factor in fetal distress? In the fetus, all energy substrates, as well as oxygen, are delivered via the placenta Glucose delivery would be reduced by interference with uterine blood flow, umbilical blood flow and by placental dysfunction Maternal hypoxemia would not affect glucose delivery We need to consider the possibility that some of the adverse effects that we have ascribed to inadequate oxygenation could be the result of reduced energy substrate supply