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Fetal cerebral, circulatory, and metabolic responses during heart rate decelerations with umbilical cord compression
Fetal cerebral, circulatory, and metabolic responses during heart rate decelerations with umbilical cord compression Bryan S. Richardson, MD, Lesley Carmichael, BSc, Jacobus Homan, BSc, LauraJohnston, ACT, and Robert Gagnon, MD London, Ontario, Canada OBJECTIVE" The purpose of this study was to determine the cerebral, circulatory, and metabolic responses of the ovine fetus near term to umbilical cord compression with variable-type fetal heart rate decelerations. STUDY DESIGN" Nine fetal sheep, at 0.9 of gestation, were studied before, during, and after umbilical cord occlusion for 1-minute and again after repetitive 1-minute cord occlusions every 5 minutes for 1 hour, with resultant fetal heart rate decelerations of -90 beats/rain. Brachiocephalic arterial and sagittal venous blood was analyzed for oxygen content, blood gases and pH, glucose, and lactate. Cerebral and upper body blood flow was measured with the microsphere technique. RESULTS" Umbilical cord occlusion with moderate to severe variable-type fetal heart rate deceleration resulted in an immediate drop in arterial Po2 by -7 torr, an increase in P c o 2 by - 9 torr, and a small but significant increase in lactate levels. Cerebral oxidative metabolism was well maintained but required an increase in fractional oxygen extraction because the variable change in cerebral blood flow was insufficient to maintain oxygen delivery. A redistribution of upper body blood flow was evident, with that to the brain and heart variably maintained or increased whereas that to muscle tissue was markedly decreased. Repetitive umbilical cord occlusion over 1 hour resulted in a significant drop in fetal arterial pH, with the acidemia mixed as Pco2 increased - 6 torr, whereas lactate levels increased almost fourfold. CONCLUSION." Although cerebral oxidative metabolism appears to be well maintained during moderate to severe variable-type fetal heart rate decelerations with umbilical cord occlusion, the need to increase fractional oxygen extraction and the redistribution of blood flow from carcass tissues may contribute to an accumulation of lactic acid both within the brain and systemically when such an insult occurs repeatedly. (Am J Obstet Gynecol 1996;175:929-36.)
Key words: Fetal brain, cerebral metabolism, hypoxemia
Studies in the ovine fetus near term with sustained hypoxemia of several minutes to hours demonstrate an increase in brain blood flow in inverse relation to arterial oxygen content so that oxygen delivery and thus consumption are reasonably well maintained.l' 2 However, the ability of the fetal brain to increase its blood flow and maintain substrate consumption during short-term hypoxic events remains unknown. Such a study has an added importance given reports in the ovine fetus where frequent episodes of brief ischemia sensitize the brain to neuronal losss and intermittent umbilical cord occlusions result in selective white matter necrosis within the brain. 4
From the Departments of Obstetrics and Gynaecology and Physiology, Lawson Research Institute, St. Joseph's Health Centre, University of Western Ontario. Supported by grants from the Canadian Medical Research Council and the Lawson Research Institute Pooled Research Trust Fund. Presented at the Sixteenth Annual Meeting of the Society of Perinatal Obstetricians, Kamuela, Hawaii, February 4-10, 1996. Reprint requests: Bryan S. Richardson, MD, Department of Obstetrics and Gynaecology, St. Joseph's Health Centre, 268 Grosvenor St., London, Ontario, Canada N6A 4V2. Copyright 9 1996 by Mosto,-Year Book, Inc. 0002-9378/96 $5.00+ 0 6/6/75617
Indeed, ultrasonographic studies in the human newborn would indicate that apneic episodes complicated by severe bradycardia give rise to hypotension and a decrease in cerebral blood flow velocity.5' 6 This in turn may provide a mechanism by which the preterm infant with frequent apneic episodes is at increased risk for neurologic handicap. 7 Sustained hypoxemia in the ovine fetus also results in an increase in blood flow to the heart and adrenals whereas that to other fetal tissues is variously maintained or decreased depending on the severity of the insult and the means by which hypoxemia is induced. ~1~These studies may not predict the response during short-term hypoxic events, which will depend on the temporal interplay between changes to perfusion pressure and the local, neurally mediated, and circulating humoral factors affecting vascular resistance. Additionally, because heart rate largely determines cardiac output in the ovine fetus, H the associated bradycardia of short-term fetal hypoxemia may have a further impact on circulatory change. We therefore studied the metabolic and circulatory responses of the ovine fetus during moderate to severe fetal heart rate (FHR) decelerations with umbilical cord 929
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compression as a short-term hypoxic event that might be seen ante partum or repetitively intrapartum. We determined the cerebral metabolic response and the extent to which cerebral blood flow is increased and oxygen delivery and consumption are maintained. Blood flow to other upper body tissues was also determined as a measure of regional circulatory change. Blood gases and carbohydrate metabolites were additionally monitored as a measure of the systemic metabolic response to repeated umbilical cord compression.
Material and methods Surgical procedures. Nine near-term fetal sheep of mixed breed were surgically prepared for study between 129 and 132 days of gestation (term 147 days). The surgical procedures and postoperative care of the animals have previously been described. 2 Polyvinyl catheters were placed in the brachiocephalic artery and the sagittal sinus for sampling cerebral arteriovenous differences, in the inferior vena cava for injection of microspheres, in the other brachiocephalic artery for measurement of blood pressure, and in the amniotic cavity for measurement of amniotic pressure. Electrodes of Teflon-coated stainless steel wire (Cooner Wire, Chatsworth, Calif.) were implanted over the sternum for FHR recordings. A silicone rubber cuff with an inflatable balloon (In Vivo Metric, Healdsburg, Calif.) was additionally placed around the proximal portion of the umbilical cord. A polyvinyl catheter was also placed in the maternal femoral vein. Postoperatively animals were maintained in individual cages suitable for continuous monitoring and were allowed >3 days to recover from surgery before the experiments began. Animal care followed the guidelines of the Canadian Council on Animal Care. Physiologic measurements. A continuous strip chart recording was obtained for fetal arterial blood pressure, FHR as triggered from the pulse pressure, and amniotic fluid pressure, as previously described. 2 FHR was additionally monitored with electrocardiogram electrodes and a Sonicaid System 8000 (Oxford Sonicaid, Oxford, U.I~) to provide an on-line visual display of computerized FHR analysis. During the 2-hour experimental period intermittent umbilical cord occlusion was induced by inflating the cuff occluder over 15 seconds and maintaining the occlusion for 45 seconds thereafter, attempting to produce a moderate to severe FHR deceleration of -90 beats/min, as monitored by the Sonicaid System 8000 (Fig. 1). During the first hour umbilical cord occlusion was induced on three occasions -30 minutes apart. For the first and third occlusions brachiocephalic artery and sagittal vein paired blood samples were obtained beginning 1 minute before the occlusion, again at the nadir of the resultant FHR deceleration, and again 15 seconds after the occlusion was released. For the second occlusion radioactive-labeled microspheres were injected for blood
October 1996 AmJ ObstetGynecol
flow determination beginning 1 minute before the occlusion, again at the nadir of the resultant FHR deceleration, and again 15 seconds after the occlusion was released. During the second hour umbilical cord occlusion was induced every 5 minutes with brachiocephalic artery and sagittal vein paired blood samples obtained immediately before the 30-minute occlusion and the last occlusion. All blood samples were analyzed for blood gases and pH; oxygen saturation; and hemoglobin, glucose, and lactate. With each paired blood sampling 1.0 ml of arterial blood and 1.0 ml of venous blood were withdrawn. Blood gases and pH were measured with an ABL-500 blood gas analyzer with temperature corrected to 39.5 ~ C (Radiometer, Copenhagen). Blood oxygen saturation and hemoglobin were measured in duplicate by an OSM 2 (Radiometer) hemoximeter. Oxygen content was then calculated with an oxygen capacity of 1.36 m l / g m hemoglobin. Whole blood glucose and lactate measurements were made in triplicate with m e m b r a n e - b o u n d glucose oxidase and D-lactate dehydrogenase, respectively (model YSI 2300 Stat Plus, Yellow Springs Instruments, Yellow Springs, Ohio). Regional blood flow was measured with 15 pm diameter microspheres (New England Nuclear, Boston) and labeled with one of four different radioisotopes (cerium 141, chromium 51, strontium 85, scandium 46) by methods previously described. 2 Reference samples were withdrawn from the brachiocephalic artery at a rate of 2.12 m l / m i n by a Harvard infusion-withdrawal pump. A single continuous reference withdrawal was used for the three microsphere injections beginning just before the first microsphere injection and ending 1 minute 45 seconds after the third microsphere injection. This resulted in the withdrawal of approximately 9 ml of arterial blood. On completion of each set of sequential arteriovenous blood samples and microsphere injections, the fetus was transfllsed with 8 ml of maternal blood. On completion of the studies the ewe and fetus were killed and an autopsy performed on the fetus to validate placement of the catheters. The fetus was then weighed, followed by removal and weighing of fetal organs and tissues. The fetal brain was fixed in formalin and subsequently dissected into the following regions: right and left cerebral cortex, subcortical structures, cerebellum, pons, medulla, pituitary, and choroid plexus. The muscle specimens were taken from the shoulders and the nuchal area of the neck. All tissues were weighed separately and analyzed for radioactivity (Compugamma model 1282, LKB Wallac Oy, Turku, Finland). Regional blood flow was then calculated as previously described by Makowski et al. 12 Data analysis. Results obtained from the nine animals before, during, and after occlusion during the first experimental hour and serially before occlusion during the second experimental hour are presented as grouped means + SEM. Means of brachiocephalic arterial and sag-
Volume 175, Number4, Part 1 AmJ ObstetGynecol
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Fig. 1. FHR recording with Sonicaid System 8000 with umbilical cord occlusion and associated FHR deceleration induced at 7 minutes and again at 46 minutes. ittal vein blood measurements for the two sets of sequential arteriovenous blood samples were determined to obtain one arterial and one venous value before, during, and after occlusion for each animal. Cerebral oxygen consumption values were calculated as the product of respective preocclusion, occlusion, and postocclusion arteriovenous differences and cerebral blood flow to the cerebral cortex because this is the region drained primarily by the sagittal sinus. Cerebral oxygen delivery was calculated as the product of corresponding arterial oxygen content and cerebral cortical flow values. Fractional oxygen extraction was calculated by dividing the arteriovenous difference by the arterial oxygen content. The glucose/oxygen molar quotient was calculated as six times the glucose arteriovenous difference divided by the oxygen arteriovenous difference, whereas the lactate/oxygen molar quotient was calculated as three times the lactate arteriovenous difference divided by the oxygen arteriovenous difference. The data reported were examined by analysis of variance for repeated measures, followed by post hoc paired t test with Bonferroni correction if a significantFratio was obtained (p < 0.05) (BMDP Statistical Software, Los Angeles). Significance for data that were not normally distributed was determined by a nonparametric test (Wilcoxon test).
Results Fetal cardiovascular and brachiocephalic arterial and sagittal vein blood measurements obtained before, during, and after occlusion for the first experimental hour are shown in Table I. Umbilical cord occlusion, as intended, resulted in a moderate to severe FHR deceleration o f - 9 0 beats/rain with the heart rate still significantly depressed when measured 15 seconds after occlusion (p< 0.05). Conversely, MAP was significantly elevated with cord occlusion and continued to be elevated when measured immediately after occlusion (p < 0.05). Umbili-
cal cord occlusion witll an associated FHR deceleration of -90 beats/rain resulted in an immediate drop in Po 2 by approximately 7 mm Hg (p < 0.01) and in oxygen saturation by approximately 18% (p < 0.01) and an increase in Pco 2 by approximately 7 m m Hg (p < 0.01), with the degree of change slightly greater for measurements from the brachiocephalic artery than from the sagittal vein. Fetal pH showed a small drop that was entirely respiratory in nature. Although returning toward preocclusion values, most of these blood gas and pH measurements continued to be significantly altered when sampled after occlusion. Although umbilical cord occlusion resulted in no immediate change in arterial glucose values, there was a small but significant increase in lactate values when measured after occlusion (p < 0.01), witl~ all nine animals showing an increase from preocclusion values. Cerebral metabolism. Blood flow to the cerebral cortex was variably changed from the preocclusion value of 184+ 17 ml per 100 g m / m i n to 2 2 0 + 2 4 ml per 100 g i n / r a i n when measured during cord occlusion (not significant) with five of the animals showing an increase, three a decrease, and one no change (Table II). When measured after occlusion, cerebral cortical blood flow was variably increased to 227_+ 12 mt per 100 gin/rain (p < 0.01) but with all animals now showing an increase compared with preocclusion values. Cerebral vascular resistance, which was calculated from the MAP and cerebral blood flow, assuming sagittal sinus pressure to be little changed, was marginally increased by 9% and then decreased by 4% when measured during cord occlusion and after occlusion, respectively, and compared with preocclusion values. Cerebral oxygen delivery was decreased by -25% during umbilical cord occlusion (p < 0.05) because the variable increase in cerebral blood flow was insufficient to compensate for the fall in fetal oxygenation (Table II). At this time, however, fractional oxygen extraction was significantly increased (p < 0.05) so that cerebral
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Table I. Cardiovascular and brachiocephalic artery and sagittal vein b l o o d m e a s u r e m e n t s before, during, and after occlusion during first e x p e r i m e n t a l h o u r
I
Preocclusion
Pao 2 (mm Hg) Pvo2 (mm Hg) Sao2 (%) Svo2 (%) Paco 2 (mm Hg) Pvco2 (ram Hg) Brachiocephalic artery pH Sagittal vein pH Brachiocephalic artery glucose (mmol/L) Brachiocephalic artery lactate (mmol/L) FHR (beats/min) MAP (ram Hg)
21.3 + 1.1 17.0 + 0.7 54.8 _+3.0 39.6 _+2.2 48.8 +_1.4 53.7 _+1.3 7.36 + 0.01 7.33 _+0.01 1.14 -+0.14 1.12 -+0.10 158 + 6 38 _+2
[
Occlusion
I
14.0 + 0.6* 11.3 +_0.9* 34.7 _+2.9* 23.7 + 2.2* 57.8 + 1.1" 59.2 + 1.0" 7.33 + 0.01" 7.32 +_0.01]1.02 -+ 0.13 1.19 +-0.11 67 _+4* 49 _+3]-
Postocclusion 18.0 + 0.3 t 15.3 + 0.4 42.0 + 1.6" 29.3 _+1.5" 55.9 _+1.0" 60.7 + 1.4" 7.34 + 0.01" 7.31 + 0.01" 1.13 _+0.14 1.37 _+0.12" 114 + 7]47 _+3]-
All data presented as mean _+SEM, n = 9. FHR and mean arterial pressure (MAP) values averaged for respective arteriovenous blood samples and blood flow determinations of first experimental hour. *p < 0.01. ]-p < 0.05.
Table II. Cerebral metabolic m e a s u r e m e n t s before, during, and after occlusion during first e x p e r i m e n t a l h o u r
Blood flow (ml/100 gm/min) Oxygen delivery (pmol/100 gm/min) Fractional oxygen extraction Oxygen consumption (pmol/100 gm/min) Glucose/oxygen quotient Lactate/oxygen quotient
Preocclusion
Occlusion
184 + 17 618 _+48 0.28 _+0.01 176 _+16 1.13 +_0.11 -0.01 _+0.09
220 +_24 470 _+30]0.35 +_0.03]165 _+19 1.13 _+0.12 0.08 + 0.08
I
Postocclusion 227 + 12" 655 _+39 0.30 _+0.03 189 _+22 1.55 + 0.17 -0.03 + 0.10
All data presented as mean _+SEM, n = 9. *p < 0.01. t-P < 0.05.
oxygen c o n s u m p t i o n r e m a i n e d u n c h a n g e d . W h e n measured after occlusion, n o n e of these values differed f r o m preocclusion values. T h e cerebral g l u c o s e / o x y g e n q u o tient, a l t h o u g h little different f r o m 1.0 before and d u r i n g cord occlusion, was increased after occlusion, although n o t significantly, suggesting a trend toward an increase in the cerebral uptake of glucose relative to oxygen at this time. T h e cerebral l a c t a t e / o x y g e n q u o t i e n t r e m a i n e d close to zero during all study measurements, indicating that lactate was n e i t h e r c o n s u m e d n o r p r o d u c e d by the brain. Regional blood flow. Regional differences in the effect of umbilical cord occlusion on brain b l o o d flow were evident (Fig. 2). T h e increase in brain b l o o d flow as a p e r c e n t of the preocclusion value was most p r o n o u n c e d in the subcortex, 152% + 19% and 152% + 15%, and the pons-medulla, 149% +_ 12% and 144% + 14%, w h e n measured d u r i n g cord occlusion and after occlusion, respectively. Conversely, b l o o d flow to the pituitary showed little change during cord occlusion, 109% + 12% and decreased after occlusion 55% +_ 7% (p< 0.05), whereas b l o o d flow to the c h o r o i d plexus decreased progressively, 55% + 10% and 16% + 4% (p< 0.01) during and after occlusion, respectively.
Blood flow changes to o t h e r u p p e r body tissues in response to umbilical cord occlusion and the time course for such was also variable (Fig. 3). Blood flow to the heart as a p e r c e n t of the preocclusion value was also increased w h e n m e a s u r e d d u r i n g cord occlusion, 151% + 39%, and after occlusion, 121% + 30%, but with greater variability than that of the brain, so that n o n e of these changes were significant. Conversely, b l o o d flow to the thyroid and thymus were variably decreased w h e n m e a s u r e d during cord occlusion, 81% _+ 16% and 66% + 16% (not significant), respectively, and after occlusion 78%-+ 8% and 69% + 9% (p< 0.05), respectively. Blood flow to u p p e r body muscle decreased progressively, 35% + 22% (p < 0.05) and 16% _+ 7% (p< 0.01), during and after occlusion, respectively. Serial preocelusion metabolic measurements. Repetitive umbilical cord occlusions every 5 minutes over 1 hour, with an associated d r o p in FHR of approximately 90 beats/rain, resulted in a significant c h a n g e in fetal metabolite concentrations (Fig. 4). A l t h o u g h fetal arterial Po 2 was only marginally decreased, oxygen saturation was variably decreased w h e n m e a s u r e d after 30 minutes, 43.7% + 3.8% (not significant), and after 60 minutes, 45.2% + 4.7% (not significant), of repetitive F H R decel-
Volume 175, Number 4, Part 1 Am J Obstet Gynecol
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L_~ 1200
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~Post-occlusion
oN~ 900 ~600
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Fig. 2. Regional blood flow changes within brain before, during, and after umbilical cord occlusion during first experimental hour. Data presented as means ___SEM, n = 9. Asterisk, p< 0.01; daggo;p< 0.05.
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Fig. 3. Regional blood flow changes to upper body tissues before, during, and after umbilical cord occlusion during first experimental hour. Data presented as means -+ SEM, n = 9. Aste~'isk,p < 0.01; dagg~ p < 0.05. erations. Arterial p H was likewise variably decreased, m e a s u r i n g 7.26 +_ 0.02 (p < 0.01) after 60 m i n u t e s o f repetitive F H R d e c e l e r a t i o ~s ( r a n g e 7.35 to 7.15), with t h e a c i d e m i a m i x e d as Pco 2 i n c r e a s e d to 54.1 _+ 1.3 m m H g (p < 0.05), w h e r e a s lactate levels i n c r e a s e d to 4.00 _+ 0.63 m m o l / L ( p < 0.01) (Fig. 4). Fetal p l a s m a glucose levels were also i n c r e a s e d f r o m t h e p r e o c c l u s i o n values o f t h e first e x p e r i m e n t a l h o u r at 1.14_+0.14 m m o l / L , to
1.53 _+ 0.20 m m o l / L (p < 0.01) after 60 m i n u t e s of repetitive c o r d occlusion.
Comment Umbilical c o r d occlusion r e s u l t e d in m o d e r a t e - t o - s e vere F H R d e c e l e r a t i o n s o f - 9 0 b e a t s / r a i n , r e s e m b l i n g variable-type F H R d e c e l e r a t i o n s as m i g h t b e s e e n episodically a n t e p a r t u m o r repetitively with u t e r i n e c o n t r a c t i o n s
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24
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Fig. 4. Metabolic measurements obtained before occlusion during first and second experimental hours. Solid circles,Three umbilical cord occlusions during first experimental hour and repetitive mnbilical cord occlusions during second experimental hour. Data presented as means _+SEM, n ---9. Asterisk, p < 0.01; dagg~ p < 0.05.
intrapartum. As r e p o r t e d by Itskovitz et al., aa the change in heart rate with cord occlusion varies directly with the i n d u c e d change in umbilical b l o o d flow and appears to be primarily m e d i a t e d t h r o u g h c h e m o r e c e p t o r mechanisms. By extrapolation f r o m their findings, the d e g r e e of h e a r t rate deceleration in the c u r r e n t study would be in keeping with an i n d u c e d r e d u c t i o n in umbilical b l o o d flow of 75% to 100% (i.e., c o m p l e t e occlusion). T h e significant increase in arterial b l o o d pressure, b o t h during and after umbilical cord occlusion, was also n o t e d by ltskovitz et al) a and was felt to be reflex m e d i a t e d ( c h e m o r e c e p t o r or baroreceptor), at least in part, given the timing of b l o o d pressure change. Blood gas changes with this degree of umbilical cord occlusion and associated variable type F H R deceleration were likewise similar to that r e p o r t e d by ltskovitz et al., 1~ with m o d e r a t e fetal h y p o x e m i a and hypercapnia w h e n m e a s u r e d at the nadir of the h e a r t rate deceleration. O f note, umbilical cord occlusion acutely i n d u c e d f o r 1 m i n u t e was sufficient to cause a small increase in b l o o d lactate levels in all animals studied, possibly in response to an associated rise in catec h o l a m i n e levels ~4 or the onset of anaerobic metabolism by some fetal tissues. Blood flow to the cerebral cortex was variably c h a n g e d w h e n m e a s u r e d d u r i n g cord occlusion, which may reflect in part m e t h o d o l o g i c issues but also the temporal interplay between the well-known local factors and possibly n e u r o g e n i c or circulating h u m o r a l factors affecting the cerebral vasculature) ~ This variable b l o o d flow response by the brain to i n d u c e d short-term h y p o x e m i a has also b e e n r e p o r t e d by J e n s e n et al. 1~ with arrest of uterine
blood flow and would suggest that initially vasoconstrictor mechanisms, possibly c h e m o r e c e p t o r mediated, 17 override vasodilator mechanisms. W h e n b l o o d flow was measured after occlusion, all animals d e m o n s t r a t e d an increase in brain b l o o d flow, indicating a p r e d o m i n a n c e in vasodilator mechanisms at this time and in keeping with the well-described increase in b l o o d flow by the ovine fetal brain with sustained h y p o x i a ) ' 2 T h e variable change in brain b l o o d flow during acute umbilical cord occlusion resulted in an overall decrease in oxygen delivery to the brain. At this time fractional oxygen extraction was increased so that oxygen c o n s u m p tion by the brain r e m a i n e d little changed. However, the n e e d to increase fractional oxygen extraction will result in a further r e d u c t i o n in sagittal venous P % and ultimately tissue P o 2 within the fetal brain. This is again in contrast to the response to sustained hypoxemia, where the increase in cerebral b l o o d flow maintains oxygen delivery and thus c o n s u m p t i o n with no n e e d to increase fractional oxygen extraction)' 2 O f interest, there was a trend toward an increase in the cerebral uptake of glucose relative to oxygen w h e n m e a s u r e d after occlusion. Similar findings r e p o r t e d by H o h i m e r et al) s with acutely i n d u c e d m a t e r n a l h y p o x e m i a would suggest that the ovine fetal brain during hypoxic conditions anaerobically metabolizes glucose to lactate. A l t h o u g h there was no measurable efflux of lactate f r o m the brain after occlusion, this may be due to blood-brain barrier constraints ~8 or the associated increase in b l o o d lactate levels and thus no actual brain to b l o o d g r a d i e n t for lactate. A redistribution of blood flow within the brain was
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evident both during cord occlusion and after occlusion, with all animals showing an increase in flow to subcortical and brain stem structures relative to that of cortical structures. This hierarchy of regional blood flow change, which has also been reported byJensen et al. 16with shortterm asphyxia, is similar to that seen in response to sustained hypoxemia 2 and may be attributed to regional differences in sympathetic vascular control 19or metabolic activity2 within the ovine fetal brain. Conversely, arterial blood flow to the pituitary was relatively decreased compared with other cerebral structures both during cord occlusion and after occlusion, suggesting that hypoxic regulatory mechanisms again differ, as previously reported for adult dogs. 2~ The immediate and profound decrease in blood flow to the choroid plexus with umbilical cord occlusion likewise noted byJensen et al. 16 with short-term restrictions in uterine blood flow would indicate that in response to short-term hypoxic events there is intense vasoconstriction, suggesting a predominance in vasoconstrictive mechanisms with little in the way of counterbalancing vasodilatory mechanisms. The distribution of blood flow to upper body tissues in response to umbilical cord occlusion with variable-type FHR decelerations was such that flow to the brain and heart was variously maintained or increased and that to the thyroid and thymus variously decreased whereas that to upper body muscle was markedly decreased. These blood flow changes would suggest a generalized vasoconstrictive reflex mechanism of rapid onset, possibly involving the sympathetics and chemoreceptor mediated, 21 on which are superimposed local vasoactive control mechanisms. For the myocardium such local mechanisms will involve the well-known increase in blood flow in response to hypoxia ~1~ and possibly a decrease in blood flow in response to the decrease in FHR given the association between heart rate and cardiac work and, in turn, metabolic needs and blood flow. 2~ The marked decrease in muscle blood flow with umbilical cord occlusion would indicate an intense vasoconstriction in lieu of the increase in arterial blood pressure, presumably reflecting the generalized increase in sympathetic tone and an attempt to redistribute cardiac output to so called vital organs. The decrease in blood flow was such that oxygen delivery to muscle tended toward zero, as would oxygen consumption, which may account in part for the small but significant increase in circulating lactate levels after occlusion. Repetitive umbilical cord occlusion with moderate-tosevere variable type FHR decelerations over 1 hour resulted in a variable decrease in fetal oxygenation and pH. Because fetal arterial P o 2 w a s little changed when measured before occlusion at 60 minutes, the modest fall in arterial oxygen saturation can instead be largely attributed to the associated fetal acidemia and a rightward shift
Richardson et al.
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in the oxyhemoglobin dissociation curve. The fall in arterial pH with repetitive cord occlusion was due to both a respiratory and a metabolic acidosis because arterial Pco 2 and lactate levels were both significantly increased when measured before occlusion at 60 minutes. The increase in carbon dioxide levels would suggest a residual decrease in umbilical blood flow or a failure to completely clear the build-up of carbon dioxide with each cord occlusion. The almost fourfold increase in lactate levels presumably reflects the cumulative increase in lactate after each cord occlusion, as already noted. O f interest, fetal glucose levels were also significantly increased in response to 1 hour of repetitive cord occlusion, likely reflecting an increase in fetal glycogenolysis as previously reported in the ovine fetus with sustained hypoxemia and a rise in catecholamine levels.~s In the current study we have determined the fetal cerebral, circulatory and metabolic responses to umbilical cord compression with variable-type FHR decelerations. Although cerebral oxidative metabolism appeared to be well maintained, there was a transient decrease in tissue oxygenation within the brain that was enhanced by the need to increase fractional oxygen extraction, and an alteration in carbohydrate metabolism was suggested. Although unlikely to be detrimental in the short term, with time repetitive insults with transient decreases in tissue oxygenation could give rise to a cumulative increase in lactate levels within the brain. Such lactate accumulation may be an important factor in subsequent brain injury, as suggested by the studies of Myers et al. 24 where tissue accumulation of lactate above a critical level was found to correlate with histologic evidence for neuronal damage. It is of interest that, within the brain, blood flow to the choroid plexus was markedly decreased with umbilical occlusion. This, in turn, may give rise to hypoxic damage to this vasculature and, given the fragile nature of these vessels during early development, 25 provide a mechanism by which the preterm infant with frequent apneic episodes is at increased risk for periventricular hemorrhage. 7 As such, the human fetus with preterm labor and frequent variable type heart rate decelerations suggesting cord occlusion may be at increased risk for the same. The maintenance of oxidative metabolism by the fetal brain with acute umbilical cord occlusion is supported in part by a redistribution of regional blood flow with a marked decrease in that to muscle and presumably all carcass tissues. Although protective of the brain, this blood flow redistribution may give rise to anaerobic glycolysis by these tissues and lactate production. With repetitive umbilical cord occlusion and moderate-to-severe variabletype FHR decelerations, such lactate production can give rise to progressive metabolism acidosis as in the current study, which may not be predicted by changes to fetal oxygen levels.
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We t h a n k Mrs. P. M c C a l l u m a n d Mr. J. R i c h a r d s o n for t e c h n i c a l assistance a n d Drs. A. B o c k i n g a n d R. Natale for t h e i r i n t e r e s t in this work. REFERENCES
1. Jones MD, Sheldon RE, Peeters LL, Meschia G, Battaglia FC, Makowski EL. Fetal cerebral oxygen consumption at different levels of oxygenation. J Appl Physiol Respir Environ Exercise Physiol 1977;43:1080-4. 2. Richardson BS, Rurak D, PatrickJE, HomanJ, Carmichael L. Cerebral oxidative metabolism during sustained hypoxemia in fetal sheep. J Dev Physiol 1989;11:3%43. 3. Mallard EC, Williams CE, Gunn AJ, Gunning MI, Gluckman PD. Frequent episodes of brief ischemia sensitize the fetal sheep brain to neuronal loss and induce striatal injury. Pediatr Res 1993;33:61-5. 4. ClappJE, Peress NS, Wesley M, Mann LL Brain damage after intermittent partial cord occlusion in the chronically instrumented fetal lamb. A m J Obstet Gynecol 1988;159:504-9. 5. Girling DJ. Changes in heart rate, blood pressure and pulse pressure during apneic attacks in newborn babies. Arch Dis Child 1972;47:405-10. 6. Perlman JM, Volpe JJ. Episode of apnea and bradycardia in the preterm newborn: impact on cerebral circulation. Pediatrics 1985;76:333-8. 7. Sinha SK, Davies JM, Sims DG, Chiswick ML. Relation between periventricular haemorrhage and ischaemic brain lesions diagnosed by ultrasound in very preterm infants. Lancet 1985;2:1154-5. 8. Cohn HE, Sacks EJ, Heyman MA, Rudolph AM. Cardiovascular responses to hypoxemia and acidemia in fetal lambs. A m J Obstet Gynecol 1974;120:817-24. 9. Itskovitz J, La Gamma EF, Rudolph AM. Effects of cord compression on fetal blood flow distribution and O 2 delivery. A m J Physiol 1987;252:H100-9. 10. Peeters LLH, Sheldon RE, Jones MDJr, Makowski EL, Meschia G. Blood flow to fetal organs as a function of arterial oxygen content. A m J Obstet Gynecol 1979;135:637-46. 11. Anderson PAW, Glick KL, Killam AP, Mainwaring RD. The effect of heart rate on in utero left ventricular output in the fetal sheep. J Physiol 1986;372:557-73. 12. Makowski EL, Schneider JM, Tsoulos NG, Colwill JR, Battaglia FC, Meschia G. Cerebral blood flow, oxygen consumption and glucose utilization of fetal lambs in utero. Am J Obstet Gyuecol 1972;114:292-301.
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13. ItskovitzJ, LaGamma EF, Rudolph AM. Heart rate and blood pressure responses to umbilical cord compression in fetal lambs with special reference to the mechanism of variable deceleration. A m J Obstet Gynecol 1983;147:451-7. 14. Jones CT, RitchieJWK. The metabolic and endocrine effects of circulating catecholamine in fetal sheep. J Physiol Lond 1978;285:395-408. 15. Kontos HA. Regulation of the cerebral circulation. Ann Rev Physiol 1981;43:397-407. 16. Jensen A, H o h m a n n M, Kunzel W. Dynamic changes in organ blood flow and oxygen consumption during acute asphyxia in fetal sheep. J Dev Physiol 1987;9:543-59. 17. Vatner SE Priano LL, RutherfordJD, Maslders WT. Sympathetic regulation of the cerebral circulation by the carotid chemoreceptor reflex. A m J Physiol 1980;238:H594-8. 18. Hohimer AR, Chao CR, Bissonnette JM. The effect of combined hypoxemia and cephalic hypotension on fetal cerebral blood flow and metabolism. J Cereb Blood Flow Metab 1991;11:99-105. 19. Licata RH, Olson DR, Mack EW. Cholinergic and adrenergic innervation of cerebral vessels. In: Langfitt TW, McHenry LC, Reivich M, Wollmann H, editors. Cerebral circulation and metabolism. Berlin: Springer-Verlag, 1975:466-9. 20. Hanley DE Wilson DA, Traystman RJ. Effect of hypoxia and hypercapnia on neuropophyseal blood flow. Am J Physiol 1986;250:H7-15. 21. Dawes GS, Lewis BV, Milligan JE, Roach MR, Talner NS. Vasomotor responses in the hind limbs of foetal and newborn lambs to asphyxia and aortic chemoreceptor stimulation. J Physiol 1968;195:55-81. 22. Berne RM, galabb RM, Ely SW, Rnbio R. Adenosine in the local regulation of blood flow: a brief overview. Fed Proc 1983;42:3136-42. 23. Gn W, Jones CT, Parer JT. Metabolic and cardiovascular effects on fetal sheep of sustained reduction of uterine blood flow. J Physiol 1985;368:109-29. 24. Myers RE, de Courten-Myers GM, Wagner KR. The effects of asphyxia on the fetal brain. In: Beard RW, Nathanielsz P, editors. In: Fetal physiology in medicine. New York: Dekker, 1984:419-58. 25. Pape KE, Wigglesworth JS. The clinico-pathological relationship and aetiological aspects of intraventricular haemorrhage: haemorrhage, ischaemia and the perinatal brain. In: Clinics in developmental medicine. Spastics. Suffolk (UK): Lippincott, 1979:133-48.
Key words: Fetal brain, cerebral metabolism, hypoxemia
Studies in the ovine fetus near term with sustained hypoxemia of several minutes to hours demonstrate an increase in brain blood flow in inverse relation to arterial oxygen content so that oxygen delivery and thus consumption are reasonably well maintained.l' 2 However, the ability of the fetal brain to increase its blood flow and maintain substrate consumption during short-term hypoxic events remains unknown. Such a study has an added importance given reports in the ovine fetus where frequent episodes of brief ischemia sensitize the brain to neuronal losss and intermittent umbilical cord occlusions result in selective white matter necrosis within the brain. 4
From the Departments of Obstetrics and Gynaecology and Physiology, Lawson Research Institute, St. Joseph's Health Centre, University of Western Ontario. Supported by grants from the Canadian Medical Research Council and the Lawson Research Institute Pooled Research Trust Fund. Presented at the Sixteenth Annual Meeting of the Society of Perinatal Obstetricians, Kamuela, Hawaii, February 4-10, 1996. Reprint requests: Bryan S. Richardson, MD, Department of Obstetrics and Gynaecology, St. Joseph's Health Centre, 268 Grosvenor St., London, Ontario, Canada N6A 4V2. Copyright 9 1996 by Mosto,-Year Book, Inc. 0002-9378/96 $5.00+ 0 6/6/75617
Indeed, ultrasonographic studies in the human newborn would indicate that apneic episodes complicated by severe bradycardia give rise to hypotension and a decrease in cerebral blood flow velocity.5' 6 This in turn may provide a mechanism by which the preterm infant with frequent apneic episodes is at increased risk for neurologic handicap. 7 Sustained hypoxemia in the ovine fetus also results in an increase in blood flow to the heart and adrenals whereas that to other fetal tissues is variously maintained or decreased depending on the severity of the insult and the means by which hypoxemia is induced. ~1~These studies may not predict the response during short-term hypoxic events, which will depend on the temporal interplay between changes to perfusion pressure and the local, neurally mediated, and circulating humoral factors affecting vascular resistance. Additionally, because heart rate largely determines cardiac output in the ovine fetus, H the associated bradycardia of short-term fetal hypoxemia may have a further impact on circulatory change. We therefore studied the metabolic and circulatory responses of the ovine fetus during moderate to severe fetal heart rate (FHR) decelerations with umbilical cord 929
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compression as a short-term hypoxic event that might be seen ante partum or repetitively intrapartum. We determined the cerebral metabolic response and the extent to which cerebral blood flow is increased and oxygen delivery and consumption are maintained. Blood flow to other upper body tissues was also determined as a measure of regional circulatory change. Blood gases and carbohydrate metabolites were additionally monitored as a measure of the systemic metabolic response to repeated umbilical cord compression.
Material and methods Surgical procedures. Nine near-term fetal sheep of mixed breed were surgically prepared for study between 129 and 132 days of gestation (term 147 days). The surgical procedures and postoperative care of the animals have previously been described. 2 Polyvinyl catheters were placed in the brachiocephalic artery and the sagittal sinus for sampling cerebral arteriovenous differences, in the inferior vena cava for injection of microspheres, in the other brachiocephalic artery for measurement of blood pressure, and in the amniotic cavity for measurement of amniotic pressure. Electrodes of Teflon-coated stainless steel wire (Cooner Wire, Chatsworth, Calif.) were implanted over the sternum for FHR recordings. A silicone rubber cuff with an inflatable balloon (In Vivo Metric, Healdsburg, Calif.) was additionally placed around the proximal portion of the umbilical cord. A polyvinyl catheter was also placed in the maternal femoral vein. Postoperatively animals were maintained in individual cages suitable for continuous monitoring and were allowed >3 days to recover from surgery before the experiments began. Animal care followed the guidelines of the Canadian Council on Animal Care. Physiologic measurements. A continuous strip chart recording was obtained for fetal arterial blood pressure, FHR as triggered from the pulse pressure, and amniotic fluid pressure, as previously described. 2 FHR was additionally monitored with electrocardiogram electrodes and a Sonicaid System 8000 (Oxford Sonicaid, Oxford, U.I~) to provide an on-line visual display of computerized FHR analysis. During the 2-hour experimental period intermittent umbilical cord occlusion was induced by inflating the cuff occluder over 15 seconds and maintaining the occlusion for 45 seconds thereafter, attempting to produce a moderate to severe FHR deceleration of -90 beats/min, as monitored by the Sonicaid System 8000 (Fig. 1). During the first hour umbilical cord occlusion was induced on three occasions -30 minutes apart. For the first and third occlusions brachiocephalic artery and sagittal vein paired blood samples were obtained beginning 1 minute before the occlusion, again at the nadir of the resultant FHR deceleration, and again 15 seconds after the occlusion was released. For the second occlusion radioactive-labeled microspheres were injected for blood
October 1996 AmJ ObstetGynecol
flow determination beginning 1 minute before the occlusion, again at the nadir of the resultant FHR deceleration, and again 15 seconds after the occlusion was released. During the second hour umbilical cord occlusion was induced every 5 minutes with brachiocephalic artery and sagittal vein paired blood samples obtained immediately before the 30-minute occlusion and the last occlusion. All blood samples were analyzed for blood gases and pH; oxygen saturation; and hemoglobin, glucose, and lactate. With each paired blood sampling 1.0 ml of arterial blood and 1.0 ml of venous blood were withdrawn. Blood gases and pH were measured with an ABL-500 blood gas analyzer with temperature corrected to 39.5 ~ C (Radiometer, Copenhagen). Blood oxygen saturation and hemoglobin were measured in duplicate by an OSM 2 (Radiometer) hemoximeter. Oxygen content was then calculated with an oxygen capacity of 1.36 m l / g m hemoglobin. Whole blood glucose and lactate measurements were made in triplicate with m e m b r a n e - b o u n d glucose oxidase and D-lactate dehydrogenase, respectively (model YSI 2300 Stat Plus, Yellow Springs Instruments, Yellow Springs, Ohio). Regional blood flow was measured with 15 pm diameter microspheres (New England Nuclear, Boston) and labeled with one of four different radioisotopes (cerium 141, chromium 51, strontium 85, scandium 46) by methods previously described. 2 Reference samples were withdrawn from the brachiocephalic artery at a rate of 2.12 m l / m i n by a Harvard infusion-withdrawal pump. A single continuous reference withdrawal was used for the three microsphere injections beginning just before the first microsphere injection and ending 1 minute 45 seconds after the third microsphere injection. This resulted in the withdrawal of approximately 9 ml of arterial blood. On completion of each set of sequential arteriovenous blood samples and microsphere injections, the fetus was transfllsed with 8 ml of maternal blood. On completion of the studies the ewe and fetus were killed and an autopsy performed on the fetus to validate placement of the catheters. The fetus was then weighed, followed by removal and weighing of fetal organs and tissues. The fetal brain was fixed in formalin and subsequently dissected into the following regions: right and left cerebral cortex, subcortical structures, cerebellum, pons, medulla, pituitary, and choroid plexus. The muscle specimens were taken from the shoulders and the nuchal area of the neck. All tissues were weighed separately and analyzed for radioactivity (Compugamma model 1282, LKB Wallac Oy, Turku, Finland). Regional blood flow was then calculated as previously described by Makowski et al. 12 Data analysis. Results obtained from the nine animals before, during, and after occlusion during the first experimental hour and serially before occlusion during the second experimental hour are presented as grouped means + SEM. Means of brachiocephalic arterial and sag-
Volume 175, Number4, Part 1 AmJ ObstetGynecol
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Fig. 1. FHR recording with Sonicaid System 8000 with umbilical cord occlusion and associated FHR deceleration induced at 7 minutes and again at 46 minutes. ittal vein blood measurements for the two sets of sequential arteriovenous blood samples were determined to obtain one arterial and one venous value before, during, and after occlusion for each animal. Cerebral oxygen consumption values were calculated as the product of respective preocclusion, occlusion, and postocclusion arteriovenous differences and cerebral blood flow to the cerebral cortex because this is the region drained primarily by the sagittal sinus. Cerebral oxygen delivery was calculated as the product of corresponding arterial oxygen content and cerebral cortical flow values. Fractional oxygen extraction was calculated by dividing the arteriovenous difference by the arterial oxygen content. The glucose/oxygen molar quotient was calculated as six times the glucose arteriovenous difference divided by the oxygen arteriovenous difference, whereas the lactate/oxygen molar quotient was calculated as three times the lactate arteriovenous difference divided by the oxygen arteriovenous difference. The data reported were examined by analysis of variance for repeated measures, followed by post hoc paired t test with Bonferroni correction if a significantFratio was obtained (p < 0.05) (BMDP Statistical Software, Los Angeles). Significance for data that were not normally distributed was determined by a nonparametric test (Wilcoxon test).
Results Fetal cardiovascular and brachiocephalic arterial and sagittal vein blood measurements obtained before, during, and after occlusion for the first experimental hour are shown in Table I. Umbilical cord occlusion, as intended, resulted in a moderate to severe FHR deceleration o f - 9 0 beats/rain with the heart rate still significantly depressed when measured 15 seconds after occlusion (p< 0.05). Conversely, MAP was significantly elevated with cord occlusion and continued to be elevated when measured immediately after occlusion (p < 0.05). Umbili-
cal cord occlusion witll an associated FHR deceleration of -90 beats/rain resulted in an immediate drop in Po 2 by approximately 7 mm Hg (p < 0.01) and in oxygen saturation by approximately 18% (p < 0.01) and an increase in Pco 2 by approximately 7 m m Hg (p < 0.01), with the degree of change slightly greater for measurements from the brachiocephalic artery than from the sagittal vein. Fetal pH showed a small drop that was entirely respiratory in nature. Although returning toward preocclusion values, most of these blood gas and pH measurements continued to be significantly altered when sampled after occlusion. Although umbilical cord occlusion resulted in no immediate change in arterial glucose values, there was a small but significant increase in lactate values when measured after occlusion (p < 0.01), witl~ all nine animals showing an increase from preocclusion values. Cerebral metabolism. Blood flow to the cerebral cortex was variably changed from the preocclusion value of 184+ 17 ml per 100 g m / m i n to 2 2 0 + 2 4 ml per 100 g i n / r a i n when measured during cord occlusion (not significant) with five of the animals showing an increase, three a decrease, and one no change (Table II). When measured after occlusion, cerebral cortical blood flow was variably increased to 227_+ 12 mt per 100 gin/rain (p < 0.01) but with all animals now showing an increase compared with preocclusion values. Cerebral vascular resistance, which was calculated from the MAP and cerebral blood flow, assuming sagittal sinus pressure to be little changed, was marginally increased by 9% and then decreased by 4% when measured during cord occlusion and after occlusion, respectively, and compared with preocclusion values. Cerebral oxygen delivery was decreased by -25% during umbilical cord occlusion (p < 0.05) because the variable increase in cerebral blood flow was insufficient to compensate for the fall in fetal oxygenation (Table II). At this time, however, fractional oxygen extraction was significantly increased (p < 0.05) so that cerebral
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Table I. Cardiovascular and brachiocephalic artery and sagittal vein b l o o d m e a s u r e m e n t s before, during, and after occlusion during first e x p e r i m e n t a l h o u r
I
Preocclusion
Pao 2 (mm Hg) Pvo2 (mm Hg) Sao2 (%) Svo2 (%) Paco 2 (mm Hg) Pvco2 (ram Hg) Brachiocephalic artery pH Sagittal vein pH Brachiocephalic artery glucose (mmol/L) Brachiocephalic artery lactate (mmol/L) FHR (beats/min) MAP (ram Hg)
21.3 + 1.1 17.0 + 0.7 54.8 _+3.0 39.6 _+2.2 48.8 +_1.4 53.7 _+1.3 7.36 + 0.01 7.33 _+0.01 1.14 -+0.14 1.12 -+0.10 158 + 6 38 _+2
[
Occlusion
I
14.0 + 0.6* 11.3 +_0.9* 34.7 _+2.9* 23.7 + 2.2* 57.8 + 1.1" 59.2 + 1.0" 7.33 + 0.01" 7.32 +_0.01]1.02 -+ 0.13 1.19 +-0.11 67 _+4* 49 _+3]-
Postocclusion 18.0 + 0.3 t 15.3 + 0.4 42.0 + 1.6" 29.3 _+1.5" 55.9 _+1.0" 60.7 + 1.4" 7.34 + 0.01" 7.31 + 0.01" 1.13 _+0.14 1.37 _+0.12" 114 + 7]47 _+3]-
All data presented as mean _+SEM, n = 9. FHR and mean arterial pressure (MAP) values averaged for respective arteriovenous blood samples and blood flow determinations of first experimental hour. *p < 0.01. ]-p < 0.05.
Table II. Cerebral metabolic m e a s u r e m e n t s before, during, and after occlusion during first e x p e r i m e n t a l h o u r
Blood flow (ml/100 gm/min) Oxygen delivery (pmol/100 gm/min) Fractional oxygen extraction Oxygen consumption (pmol/100 gm/min) Glucose/oxygen quotient Lactate/oxygen quotient
Preocclusion
Occlusion
184 + 17 618 _+48 0.28 _+0.01 176 _+16 1.13 +_0.11 -0.01 _+0.09
220 +_24 470 _+30]0.35 +_0.03]165 _+19 1.13 _+0.12 0.08 + 0.08
I
Postocclusion 227 + 12" 655 _+39 0.30 _+0.03 189 _+22 1.55 + 0.17 -0.03 + 0.10
All data presented as mean _+SEM, n = 9. *p < 0.01. t-P < 0.05.
oxygen c o n s u m p t i o n r e m a i n e d u n c h a n g e d . W h e n measured after occlusion, n o n e of these values differed f r o m preocclusion values. T h e cerebral g l u c o s e / o x y g e n q u o tient, a l t h o u g h little different f r o m 1.0 before and d u r i n g cord occlusion, was increased after occlusion, although n o t significantly, suggesting a trend toward an increase in the cerebral uptake of glucose relative to oxygen at this time. T h e cerebral l a c t a t e / o x y g e n q u o t i e n t r e m a i n e d close to zero during all study measurements, indicating that lactate was n e i t h e r c o n s u m e d n o r p r o d u c e d by the brain. Regional blood flow. Regional differences in the effect of umbilical cord occlusion on brain b l o o d flow were evident (Fig. 2). T h e increase in brain b l o o d flow as a p e r c e n t of the preocclusion value was most p r o n o u n c e d in the subcortex, 152% + 19% and 152% + 15%, and the pons-medulla, 149% +_ 12% and 144% + 14%, w h e n measured d u r i n g cord occlusion and after occlusion, respectively. Conversely, b l o o d flow to the pituitary showed little change during cord occlusion, 109% + 12% and decreased after occlusion 55% +_ 7% (p< 0.05), whereas b l o o d flow to the c h o r o i d plexus decreased progressively, 55% + 10% and 16% + 4% (p< 0.01) during and after occlusion, respectively.
Blood flow changes to o t h e r u p p e r body tissues in response to umbilical cord occlusion and the time course for such was also variable (Fig. 3). Blood flow to the heart as a p e r c e n t of the preocclusion value was also increased w h e n m e a s u r e d d u r i n g cord occlusion, 151% + 39%, and after occlusion, 121% + 30%, but with greater variability than that of the brain, so that n o n e of these changes were significant. Conversely, b l o o d flow to the thyroid and thymus were variably decreased w h e n m e a s u r e d during cord occlusion, 81% _+ 16% and 66% + 16% (not significant), respectively, and after occlusion 78%-+ 8% and 69% + 9% (p< 0.05), respectively. Blood flow to u p p e r body muscle decreased progressively, 35% + 22% (p < 0.05) and 16% _+ 7% (p< 0.01), during and after occlusion, respectively. Serial preocelusion metabolic measurements. Repetitive umbilical cord occlusions every 5 minutes over 1 hour, with an associated d r o p in FHR of approximately 90 beats/rain, resulted in a significant c h a n g e in fetal metabolite concentrations (Fig. 4). A l t h o u g h fetal arterial Po 2 was only marginally decreased, oxygen saturation was variably decreased w h e n m e a s u r e d after 30 minutes, 43.7% + 3.8% (not significant), and after 60 minutes, 45.2% + 4.7% (not significant), of repetitive F H R decel-
Volume 175, Number 4, Part 1 Am J Obstet Gynecol
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L_~ 1200
933
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~Post-occlusion
oN~ 900 ~600
14-
~ 400 2OO 0
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Fig. 2. Regional blood flow changes within brain before, during, and after umbilical cord occlusion during first experimental hour. Data presented as means ___SEM, n = 9. Asterisk, p< 0.01; daggo;p< 0.05.
500
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Fig. 3. Regional blood flow changes to upper body tissues before, during, and after umbilical cord occlusion during first experimental hour. Data presented as means -+ SEM, n = 9. Aste~'isk,p < 0.01; dagg~ p < 0.05. erations. Arterial p H was likewise variably decreased, m e a s u r i n g 7.26 +_ 0.02 (p < 0.01) after 60 m i n u t e s o f repetitive F H R d e c e l e r a t i o ~s ( r a n g e 7.35 to 7.15), with t h e a c i d e m i a m i x e d as Pco 2 i n c r e a s e d to 54.1 _+ 1.3 m m H g (p < 0.05), w h e r e a s lactate levels i n c r e a s e d to 4.00 _+ 0.63 m m o l / L ( p < 0.01) (Fig. 4). Fetal p l a s m a glucose levels were also i n c r e a s e d f r o m t h e p r e o c c l u s i o n values o f t h e first e x p e r i m e n t a l h o u r at 1.14_+0.14 m m o l / L , to
1.53 _+ 0.20 m m o l / L (p < 0.01) after 60 m i n u t e s of repetitive c o r d occlusion.
Comment Umbilical c o r d occlusion r e s u l t e d in m o d e r a t e - t o - s e vere F H R d e c e l e r a t i o n s o f - 9 0 b e a t s / r a i n , r e s e m b l i n g variable-type F H R d e c e l e r a t i o n s as m i g h t b e s e e n episodically a n t e p a r t u m o r repetitively with u t e r i n e c o n t r a c t i o n s
934
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October 1996 AmJ Obstet Gynecol
24
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Fig. 4. Metabolic measurements obtained before occlusion during first and second experimental hours. Solid circles,Three umbilical cord occlusions during first experimental hour and repetitive mnbilical cord occlusions during second experimental hour. Data presented as means _+SEM, n ---9. Asterisk, p < 0.01; dagg~ p < 0.05.
intrapartum. As r e p o r t e d by Itskovitz et al., aa the change in heart rate with cord occlusion varies directly with the i n d u c e d change in umbilical b l o o d flow and appears to be primarily m e d i a t e d t h r o u g h c h e m o r e c e p t o r mechanisms. By extrapolation f r o m their findings, the d e g r e e of h e a r t rate deceleration in the c u r r e n t study would be in keeping with an i n d u c e d r e d u c t i o n in umbilical b l o o d flow of 75% to 100% (i.e., c o m p l e t e occlusion). T h e significant increase in arterial b l o o d pressure, b o t h during and after umbilical cord occlusion, was also n o t e d by ltskovitz et al) a and was felt to be reflex m e d i a t e d ( c h e m o r e c e p t o r or baroreceptor), at least in part, given the timing of b l o o d pressure change. Blood gas changes with this degree of umbilical cord occlusion and associated variable type F H R deceleration were likewise similar to that r e p o r t e d by ltskovitz et al., 1~ with m o d e r a t e fetal h y p o x e m i a and hypercapnia w h e n m e a s u r e d at the nadir of the h e a r t rate deceleration. O f note, umbilical cord occlusion acutely i n d u c e d f o r 1 m i n u t e was sufficient to cause a small increase in b l o o d lactate levels in all animals studied, possibly in response to an associated rise in catec h o l a m i n e levels ~4 or the onset of anaerobic metabolism by some fetal tissues. Blood flow to the cerebral cortex was variably c h a n g e d w h e n m e a s u r e d d u r i n g cord occlusion, which may reflect in part m e t h o d o l o g i c issues but also the temporal interplay between the well-known local factors and possibly n e u r o g e n i c or circulating h u m o r a l factors affecting the cerebral vasculature) ~ This variable b l o o d flow response by the brain to i n d u c e d short-term h y p o x e m i a has also b e e n r e p o r t e d by J e n s e n et al. 1~ with arrest of uterine
blood flow and would suggest that initially vasoconstrictor mechanisms, possibly c h e m o r e c e p t o r mediated, 17 override vasodilator mechanisms. W h e n b l o o d flow was measured after occlusion, all animals d e m o n s t r a t e d an increase in brain b l o o d flow, indicating a p r e d o m i n a n c e in vasodilator mechanisms at this time and in keeping with the well-described increase in b l o o d flow by the ovine fetal brain with sustained h y p o x i a ) ' 2 T h e variable change in brain b l o o d flow during acute umbilical cord occlusion resulted in an overall decrease in oxygen delivery to the brain. At this time fractional oxygen extraction was increased so that oxygen c o n s u m p tion by the brain r e m a i n e d little changed. However, the n e e d to increase fractional oxygen extraction will result in a further r e d u c t i o n in sagittal venous P % and ultimately tissue P o 2 within the fetal brain. This is again in contrast to the response to sustained hypoxemia, where the increase in cerebral b l o o d flow maintains oxygen delivery and thus c o n s u m p t i o n with no n e e d to increase fractional oxygen extraction)' 2 O f interest, there was a trend toward an increase in the cerebral uptake of glucose relative to oxygen w h e n m e a s u r e d after occlusion. Similar findings r e p o r t e d by H o h i m e r et al) s with acutely i n d u c e d m a t e r n a l h y p o x e m i a would suggest that the ovine fetal brain during hypoxic conditions anaerobically metabolizes glucose to lactate. A l t h o u g h there was no measurable efflux of lactate f r o m the brain after occlusion, this may be due to blood-brain barrier constraints ~8 or the associated increase in b l o o d lactate levels and thus no actual brain to b l o o d g r a d i e n t for lactate. A redistribution of blood flow within the brain was
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evident both during cord occlusion and after occlusion, with all animals showing an increase in flow to subcortical and brain stem structures relative to that of cortical structures. This hierarchy of regional blood flow change, which has also been reported byJensen et al. 16with shortterm asphyxia, is similar to that seen in response to sustained hypoxemia 2 and may be attributed to regional differences in sympathetic vascular control 19or metabolic activity2 within the ovine fetal brain. Conversely, arterial blood flow to the pituitary was relatively decreased compared with other cerebral structures both during cord occlusion and after occlusion, suggesting that hypoxic regulatory mechanisms again differ, as previously reported for adult dogs. 2~ The immediate and profound decrease in blood flow to the choroid plexus with umbilical cord occlusion likewise noted byJensen et al. 16 with short-term restrictions in uterine blood flow would indicate that in response to short-term hypoxic events there is intense vasoconstriction, suggesting a predominance in vasoconstrictive mechanisms with little in the way of counterbalancing vasodilatory mechanisms. The distribution of blood flow to upper body tissues in response to umbilical cord occlusion with variable-type FHR decelerations was such that flow to the brain and heart was variously maintained or increased and that to the thyroid and thymus variously decreased whereas that to upper body muscle was markedly decreased. These blood flow changes would suggest a generalized vasoconstrictive reflex mechanism of rapid onset, possibly involving the sympathetics and chemoreceptor mediated, 21 on which are superimposed local vasoactive control mechanisms. For the myocardium such local mechanisms will involve the well-known increase in blood flow in response to hypoxia ~1~ and possibly a decrease in blood flow in response to the decrease in FHR given the association between heart rate and cardiac work and, in turn, metabolic needs and blood flow. 2~ The marked decrease in muscle blood flow with umbilical cord occlusion would indicate an intense vasoconstriction in lieu of the increase in arterial blood pressure, presumably reflecting the generalized increase in sympathetic tone and an attempt to redistribute cardiac output to so called vital organs. The decrease in blood flow was such that oxygen delivery to muscle tended toward zero, as would oxygen consumption, which may account in part for the small but significant increase in circulating lactate levels after occlusion. Repetitive umbilical cord occlusion with moderate-tosevere variable type FHR decelerations over 1 hour resulted in a variable decrease in fetal oxygenation and pH. Because fetal arterial P o 2 w a s little changed when measured before occlusion at 60 minutes, the modest fall in arterial oxygen saturation can instead be largely attributed to the associated fetal acidemia and a rightward shift
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in the oxyhemoglobin dissociation curve. The fall in arterial pH with repetitive cord occlusion was due to both a respiratory and a metabolic acidosis because arterial Pco 2 and lactate levels were both significantly increased when measured before occlusion at 60 minutes. The increase in carbon dioxide levels would suggest a residual decrease in umbilical blood flow or a failure to completely clear the build-up of carbon dioxide with each cord occlusion. The almost fourfold increase in lactate levels presumably reflects the cumulative increase in lactate after each cord occlusion, as already noted. O f interest, fetal glucose levels were also significantly increased in response to 1 hour of repetitive cord occlusion, likely reflecting an increase in fetal glycogenolysis as previously reported in the ovine fetus with sustained hypoxemia and a rise in catecholamine levels.~s In the current study we have determined the fetal cerebral, circulatory and metabolic responses to umbilical cord compression with variable-type FHR decelerations. Although cerebral oxidative metabolism appeared to be well maintained, there was a transient decrease in tissue oxygenation within the brain that was enhanced by the need to increase fractional oxygen extraction, and an alteration in carbohydrate metabolism was suggested. Although unlikely to be detrimental in the short term, with time repetitive insults with transient decreases in tissue oxygenation could give rise to a cumulative increase in lactate levels within the brain. Such lactate accumulation may be an important factor in subsequent brain injury, as suggested by the studies of Myers et al. 24 where tissue accumulation of lactate above a critical level was found to correlate with histologic evidence for neuronal damage. It is of interest that, within the brain, blood flow to the choroid plexus was markedly decreased with umbilical occlusion. This, in turn, may give rise to hypoxic damage to this vasculature and, given the fragile nature of these vessels during early development, 25 provide a mechanism by which the preterm infant with frequent apneic episodes is at increased risk for periventricular hemorrhage. 7 As such, the human fetus with preterm labor and frequent variable type heart rate decelerations suggesting cord occlusion may be at increased risk for the same. The maintenance of oxidative metabolism by the fetal brain with acute umbilical cord occlusion is supported in part by a redistribution of regional blood flow with a marked decrease in that to muscle and presumably all carcass tissues. Although protective of the brain, this blood flow redistribution may give rise to anaerobic glycolysis by these tissues and lactate production. With repetitive umbilical cord occlusion and moderate-to-severe variabletype FHR decelerations, such lactate production can give rise to progressive metabolism acidosis as in the current study, which may not be predicted by changes to fetal oxygen levels.
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We t h a n k Mrs. P. M c C a l l u m a n d Mr. J. R i c h a r d s o n for t e c h n i c a l assistance a n d Drs. A. B o c k i n g a n d R. Natale for t h e i r i n t e r e s t in this work. REFERENCES
1. Jones MD, Sheldon RE, Peeters LL, Meschia G, Battaglia FC, Makowski EL. Fetal cerebral oxygen consumption at different levels of oxygenation. J Appl Physiol Respir Environ Exercise Physiol 1977;43:1080-4. 2. Richardson BS, Rurak D, PatrickJE, HomanJ, Carmichael L. Cerebral oxidative metabolism during sustained hypoxemia in fetal sheep. J Dev Physiol 1989;11:3%43. 3. Mallard EC, Williams CE, Gunn AJ, Gunning MI, Gluckman PD. Frequent episodes of brief ischemia sensitize the fetal sheep brain to neuronal loss and induce striatal injury. Pediatr Res 1993;33:61-5. 4. ClappJE, Peress NS, Wesley M, Mann LL Brain damage after intermittent partial cord occlusion in the chronically instrumented fetal lamb. A m J Obstet Gynecol 1988;159:504-9. 5. Girling DJ. Changes in heart rate, blood pressure and pulse pressure during apneic attacks in newborn babies. Arch Dis Child 1972;47:405-10. 6. Perlman JM, Volpe JJ. Episode of apnea and bradycardia in the preterm newborn: impact on cerebral circulation. Pediatrics 1985;76:333-8. 7. Sinha SK, Davies JM, Sims DG, Chiswick ML. Relation between periventricular haemorrhage and ischaemic brain lesions diagnosed by ultrasound in very preterm infants. Lancet 1985;2:1154-5. 8. Cohn HE, Sacks EJ, Heyman MA, Rudolph AM. Cardiovascular responses to hypoxemia and acidemia in fetal lambs. A m J Obstet Gynecol 1974;120:817-24. 9. Itskovitz J, La Gamma EF, Rudolph AM. Effects of cord compression on fetal blood flow distribution and O 2 delivery. A m J Physiol 1987;252:H100-9. 10. Peeters LLH, Sheldon RE, Jones MDJr, Makowski EL, Meschia G. Blood flow to fetal organs as a function of arterial oxygen content. A m J Obstet Gynecol 1979;135:637-46. 11. Anderson PAW, Glick KL, Killam AP, Mainwaring RD. The effect of heart rate on in utero left ventricular output in the fetal sheep. J Physiol 1986;372:557-73. 12. Makowski EL, Schneider JM, Tsoulos NG, Colwill JR, Battaglia FC, Meschia G. Cerebral blood flow, oxygen consumption and glucose utilization of fetal lambs in utero. Am J Obstet Gyuecol 1972;114:292-301.
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13. ItskovitzJ, LaGamma EF, Rudolph AM. Heart rate and blood pressure responses to umbilical cord compression in fetal lambs with special reference to the mechanism of variable deceleration. A m J Obstet Gynecol 1983;147:451-7. 14. Jones CT, RitchieJWK. The metabolic and endocrine effects of circulating catecholamine in fetal sheep. J Physiol Lond 1978;285:395-408. 15. Kontos HA. Regulation of the cerebral circulation. Ann Rev Physiol 1981;43:397-407. 16. Jensen A, H o h m a n n M, Kunzel W. Dynamic changes in organ blood flow and oxygen consumption during acute asphyxia in fetal sheep. J Dev Physiol 1987;9:543-59. 17. Vatner SE Priano LL, RutherfordJD, Maslders WT. Sympathetic regulation of the cerebral circulation by the carotid chemoreceptor reflex. A m J Physiol 1980;238:H594-8. 18. Hohimer AR, Chao CR, Bissonnette JM. The effect of combined hypoxemia and cephalic hypotension on fetal cerebral blood flow and metabolism. J Cereb Blood Flow Metab 1991;11:99-105. 19. Licata RH, Olson DR, Mack EW. Cholinergic and adrenergic innervation of cerebral vessels. In: Langfitt TW, McHenry LC, Reivich M, Wollmann H, editors. Cerebral circulation and metabolism. Berlin: Springer-Verlag, 1975:466-9. 20. Hanley DE Wilson DA, Traystman RJ. Effect of hypoxia and hypercapnia on neuropophyseal blood flow. Am J Physiol 1986;250:H7-15. 21. Dawes GS, Lewis BV, Milligan JE, Roach MR, Talner NS. Vasomotor responses in the hind limbs of foetal and newborn lambs to asphyxia and aortic chemoreceptor stimulation. J Physiol 1968;195:55-81. 22. Berne RM, galabb RM, Ely SW, Rnbio R. Adenosine in the local regulation of blood flow: a brief overview. Fed Proc 1983;42:3136-42. 23. Gn W, Jones CT, Parer JT. Metabolic and cardiovascular effects on fetal sheep of sustained reduction of uterine blood flow. J Physiol 1985;368:109-29. 24. Myers RE, de Courten-Myers GM, Wagner KR. The effects of asphyxia on the fetal brain. In: Beard RW, Nathanielsz P, editors. In: Fetal physiology in medicine. New York: Dekker, 1984:419-58. 25. Pape KE, Wigglesworth JS. The clinico-pathological relationship and aetiological aspects of intraventricular haemorrhage: haemorrhage, ischaemia and the perinatal brain. In: Clinics in developmental medicine. Spastics. Suffolk (UK): Lippincott, 1979:133-48.