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The effect of reducing umbilical blood flow on fetal oxygenation
The effect of reducing umbilical blood flow on fetal oxygenation JOSEPH
ITSKOVITZ*
EDMUND
F. LAGAMMA
ABRAHAM
M.
RUDOLPH
San Francisco, California 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 btood 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 33.8% ? 4.8% to 87.7% 2 11.3% during 75% reduction of flow. (AM. J. OBSTET. GYNECOL. 145:813, 1983.)
DELIVERY OF OXYGEN fromtheplacentatothe fetus and oxygen uptake by the fetus have been shown to be affected by the magnitude of umbilical blood flow. The effect of changes in umbilical blood flow on fetal oxygenation was tested in mathematical models* and also acutely in exteriorized lamb fetuses.2, 3 Anesthesia, as well as exteriorization, may cause drastic changes in fetal metabolism and umbilical blood flow. In the study by Kiinzel and associates,2 for example, control values for umbilical blood flow in some fetuses were below 100 ml . min-’ . kg-’ fetal body weight. This is greatly reduced as compared with umbilical THE
From the Cardiovascular Research Institute and the Departments ?f Pediatrics, Physiology, and Obstetrics, Gynecology, and Reproductive Sciences, University of Culifornia (San Francisco). Supported by a grant from th United States Public Health Seruice, Program Project Grant HI24056 Receivtdfor Raised
publication
Jub 29, 1982.
September
28, 1982.
Accepted November
1, 1982.
Reprint requests: A. M. Rudolph, M.D., University of Calt~omia (San Francisco), California 94143. *National (TW02767)
Institutes from
I403-HSE, San Francisco,
of Health International Rambam Medical Center,
Fellow Haifa,
Israel.
blood flow values of about 200 ml min.-’ kg-’ measured in fetal lambs chronically instrumented in utero.4, 5 The purpose of our studies was IO determine the effects of acute reduction of umbilical blood flow in fetal lambs chronically instrumented in utero. We wished to examine the relationship between umbilical blood flow, oxygen delivery to the fetus, feral oxygen uptake, and the ability of the fetus to extract oxygen from fetal blood with its high oxygen affinity. Umbilical blood flow reduction was achieved by partial cord occlusion, which preferentially constricted the umbilical veins. Methods Animal preparation. We studied eight fetal lambs with known gestational ages of 120 to 128 days (term is about 147 days). A low spinal anesthetic was given to the ewe with 2 ml of 1% tetracaine hydrochloride. With the use of aseptic procedures, polyvinyl catheters were inserted into the maternal left pedal artery and vein and advanced to the descending aorta and abdominal inferior vena cava, respectively. The uterus was exposed through a midline abdominal incision and the fetal parts were identified. The uterus was incised ovel the fetal neck, and with local anesthesia with 0.5$% lidocaine hydrochloride catheters (0.8 mm inside di813
814
Itskovitz,
LaGamma,
April 1, iYXJ Am. J. Obstet. Gynecol.
and Rudolph
Qr 0
f -
l l
8
. .
80
.
:
l*
l .“cl
0
UV 0
UA IVC
O-
200 Flow Iml/min/kg)
120 Umbilical Blood
280
Fig. 1. Fetal blood 0, content before (open marks) and during (closed marks) partial cord occlusion. WV, Umbilical venous blood. UA, Descending aortic blood (Y = 5.23 log x -6.48 12 = 0.8C, p < 0.001). WC, Distal inferior vena caval blood (Y = 4.85 log x -7.46, r = 0.89, p < 0.001). Number of experiments as in Table I.
0 0 08
. .
. .
. /
/
y~0.09Xt0.70 r=0.97 p c o.oo/
.
I
I
120
40
Umbilical
Blood
1
4
200
280
Flow
(ml/min/kg)
Fig. 2. The correlation between umbilical blood flow and Oz delivery to the fetus before (open circles) and during (closed circles) partial cord occlusion.
ameter, 1.2 mm outside diameter) were inserted into a carotid artery and an external jugular vein. A second uterine incision was made over the fetal hind limbs which were extracted from the uterus. Catheters (0.8 mm inside diameter, 1.2 mm outside diameter) were inserted into both pedal arteries and advanced to the descending aorta or the external iliac artery. Similar catheters were inserted into the pedal veins and advanced to the external iliac vein or to the inferior vena cava distal to the origin of the renal veins. A polyvinyl catheter was inserted into a cotyledonary branch of the umbilical vein and advanced to the main
umbilical vein. The uterine incision was extended and the lamb was extracted further to expose the lower abdomen and flanks. A cuff-type electromagnetic flow transducer that had been precalibrated in vitro was placed around the common unbilical artery, as previously describedj The fetus was then extracted further to the level of the umbilical ring, and a silicone rubber cuff with an inflatable balloon was placed around the proximal portion of the umbilical cord. The fetus was returned to the uterus and a catheter was placed in the amniotic fluid cavity. Amniotic fluid was replaced with 0.9% saline, and the uterine incision was closed. The catheters and the flow transducer cable were passed through the abdominal wall to the flank of the ewe and protected by a pouch sewn to the skin. On the day of operation and each day thereafter, the ewe received two million units of penicillin G and 800 mg of kanamycin, half intravenously and half into the amniotic cavity. Experimental protocol. The experiments were carried out on the second to fifth postoperative days, while the ewe stood in a stall with free access to alfalfa pellets and water. Fetal aortic, umbilical venous, and intrauterine pressures were measured by Statham P23Db pressure transducers; mean umbilical blood flow was measured with a Statham SP2202 electromagnetic flowmeter. Fetal heart rate was recorded by means of a cardiotachometer triggered by the arterial pulse pressure. All pressures, umbilical blood flow, and heart rate were recorded continuously on a Beckman direct-writing recorder. Fetal arterial and umbilical venous pressures were measured with amniotic cavity pressure as zero reference. Umbilical blood flow was reduced by inflation of the balloon occluder around the umbilical cord for 3 to 4 minutes. Blood samples (0.7 to 0.8 ml) were obtained before and at the end of cord occlusion from the umbilical vein, descending aorta, and inferior vena cava for the determination of blood gases, pH, hemoglobin concentration, and percent oxygen saturation of hemoglobin. Each fetus was studied at normal umbilical blood flow and at two or three different levels of umbilical blood flow (approximately 25%, n = 5; 50%, n = 8; or 75%, n = 5). At least 1 hour of recovery was allowed between each occlusion. At the end of the study, the animals were killed with an overdose of sodium pentobarbital, and the positions of all catheters were confirmed. Measurements and calculations. Oxygen delivery to the fetus was calculated by multiplying umbilical blood flow by umbilical venous oxygen content. Fetal oxygen consumption was calculated by multiplying umbilical blood flow by umbilical venous-arterial oxygen content difference. The proportion of oxygen extracted by the
Volume Number
I-t5 7
Effect
Table I. The effect of umbilical blood flow reduction aortic and umbilical venous blood pressures
on fetal pH, blood
Urnbikal
of reducing
umbilical
blood
flow
815
gases, and heart race and on mean
blood flow
reductions
Parameter Descending aorta: PH PO, Pco, (tort-) Heart rate (bpm) Mean aortic pressure (torr) Mean umbilical venous pressure Data are means + SD. *p < 0.005 when compared tp < 0.02 when compared
7.39 21 44 182 45 14
(ton-)
with controls with controls
(paired (paired
” c 2 2 -t *
0.02 1 2 13 5 5
7.38 18 45 178 48 25
2 c t -t T ‘-
0.02 2+ 1 17 8 7t
7.36 I7 47 156 47 27
? + + _’ 2 i
0.02* 2* 3t 14* 5 6*
7.33 15 4%) I(!8 IX :ii,
2 c f f ‘r f
0.04t 2: 41 20* 7 j*
t test). t test).
Table II. The effect of changes in umbilical blood flow on total oxygen delivery to the fetus, oxygen consumption, and oxygen extraction by the fetus as a whole and oxygen extraction by the lower trutlk of the fetus -_IUmbilical Parameter
Control
Umbilical blood flow (ml/min/kg) O2 delivery (ml/mm/kg) O2 consumption Fetal O2 extraction (%) Lower trunk O2 extraction (%) Data *p < tp < $p <
fetus blood
are means -t SD. 0.01 when compared 0.002 when compared 0.02 when compared
241 22.43 7.49 33.6 31.2
with controls with controls with controls
2 k ” k 2
(paired (paired (paired
from the total delivered by umbilical was calculated from the ratio:
V,,iO,
Del = [ Q&UV,, = [ UV,,
- UA,,)]/(Quv
39 2.15 0.90 4.8 7.8
blood $ow
reductions
25%
(n = 5)
50%
(n = 8)
75% (II = 5)
189 16.50 7.04 43.8 35.1
t t 2 2 r
128 12.01 6.12 53.0 4i.5
2 ‘k t lr
Cl 5.x.5 3.92 67.7 53.7
22* 2.14* 0.62 5.8$ 4.5*
21t 1.91t 0.86t 8.lt 8.9$
f t t t f
14t 1.59t 1. lot 11.3t 7.R$
t test). t test). t test).
venous
x UV,,,)
- UA,, ]/UVo,,
where i:,, is fetal oxygen consumption, 0, Del is the amount of oxygen delivered to the fetus from the placenta, Q[.r is umbilical blood flow, UVo, is umbilical venous oxygen content, and UA., is umbilical arterial (descending aortic) oxygen content. Similarly, the proportion of oxygen extracted by the lower trunk of the fetus was calculated as follows: UA,j., - IVC&JAor, where WC,, is distal inferior vena caval oxygen content. Umbilical-placental vascular resistance was calculated by dividing umbilical arterial minus umbilical venous mean pressure by umbilical blood flow. Blood PO,, Pco,, and pH were determined on a Radiometer blood gas analyzer (HM73, London Company) at 39” C. Blood hemoglobin concentration and hemoglobin oxygen saturation were determined
in duplicate on a Radiometer hemoximeter (Model OSM2). Oxygen content was calculated according to the formula: content
(mlidl)
Dissolved
oxygen
0,
= hemoglobin concentration (gm/dl) x 1.34 x 0, satnration/lOO. was considered
as negligible.
Results A 25% reduction of umbilical blood How resulted in a small decrease in descending aortic blood 1’0, and no significant changes in pH, Pco,, Ietal heart rate, and arterial pressure (Table I). Reducing umbilical blood flow by 50% and 75% of control values caused a fall in pH and PO, and a rise in Pcos in descending aortic blood. Fetal heart rate fell with 50c4 and 75% reduction, but mean aortic blood pressure was not significantly affected. There were no significant changes in umbilical venous PO,, pH, or Pcos. Compression of the cord resulted in a progressive increase in distal umbilical venous pressure, from a control of 14 + 5 torr to 32 t 5 tot-r during 754 reduction of trmhilical blood
816
Itskovitz,
LaGamma,
and Rudolph
y= -276~90;
f 8.49
80-
rzO.84
Y' - 58f8 I' -0.91 PCOOOf
p < o.oo/
.
72 s ‘Z ::. P
l &&=i=
w
. .
.+
log x+/73.44
60-
40-
0"
/
+ t
l
-75%
-50%
-25%
40
120 Umbilical
-75 %
c ,
I
L
200 Blood
Flaw
-50%
t
1
40
280
-25%
I
120 Umbilical
(ml/min/kg)
Blood
c 6
I
200
280
Flow (ml/min/kg)
80-
. 2
y= -36.03 F-O 78
60-
hgxt
/z/5
P c ooo/
E .o 5L tB.38
?I
40-
0"
p
20-75% 4
-50% 1 12
t 02
Delivery
-25% I 20
-75%
C I 28
@
(ml/min/kgl
-50%
-25%
I I20
t 40 Umbilical
c
I 200 Blood
Flow
I 280
Lml/min/kgl
Fig. 3. The correlation of umbilical blood flow with fetal O2 consumption (A) and 0, delivery (B) before (@en circles) and during (closed circles) partial cord occlusion.
Fig. 4. Fetal 0, extraction (A) and (B) before (open circles) and during
flow (Table I). The mean arterial-venous pressure differences across the umbilical-placental circulation decreased from 31 torr during control to 23 torr during 25% reduction, 20 during 50% reduction, and 16 during 75% reduction of umbilical blood flow. The effects of umbilical blood flow reduction on umbilical venous, descending aortic, and inferior vena caval oxygen content are shown in Fig. 1. During cord occlusion, umbilical venous blood oxygen content was maintained and descending aortic blood oxygen content was decreased. Thus, the venoarterial difference of blood oxygen content across the placenta increased with progressive reduction of umbilical blood flow. Distal inferior vena caval blood oxygen content showed a change similar to that in the descending aortic blood oxygen content. Since umbilical venous blood oxygen content was
maintained during cord occlusion, the amount of oxygen delivered to the fetus was linearly correlated (r = 0.97) with umbilical blood flow (Fig. 2 and Table II). Fetal oxygen consumption was 7.49 & 0.90 ml/mini kg during the control period and did not change significantly with a 25% reduction of the umbilical blood flow. Oxygen consumption decreased to 6.12 2 0.86 (p < 0.002) during 50% reduction and to 3.92 t 1.10 ml/min/kg (p < 0.001) during 75% reduction (Table II, Fig. 3). Similarly, a 25% reduction in the amount of oxygen delivered to the fetus resulted in no significant effect on fetal oxygen consumption, but 50% and 75% reductions resulted in a decrease in oxygen consumption (Table II, Fig. 3). The difference in oxygen saturation between umbilical venous and descending aortic blood increased progressively with umbilical occlusion, from 30.4 to 51.8. However, oxygen saturation differ-
lower carcass 0, extraction (closed circb) partial cord
occlusion.
Effect
ence between descending aortic and inferior vena caval bloods fell from 17.0 to 12.6 during progressive occlusion. During the control period, 33.6% + 4.8% of the total amount of oxygen delivered to the fetus from the placenta was extracted by the fetus (Table II, Fig. 4). During a 25% reduction of the umbilical blood flow, oxygen extraction increased to 43.8% f 5.8% (p < 0.02). With 50% and 75Q reductions, oxygen extraction further increased to 52.0% t 8.1% (p < 0.001) and to 67.5V 5 1 1.3% (1’ < O.OOl), respectively. The ability of the fetal peripheral circulation to extract oxygen is shown in Table II and Fig. 4. Normally, 31.2 ‘7r t 7.8% of the amount of oxygen delivered to the lower carcass is extracted. With falling umbilical blood flow, oxygen extraction by the lower carcass progressively increased (r = -0.78, J) < 0.001).
Comment Compression of the umbilical cord is a common cause of’fetal asphyxia. We have assessed the effects on fetal oxygenation of graded compression of the cord in fetal lambs, to produce measured changes in umbilical blood flow. This form of fetal stress differs from that produced by maternal hypoxemia. Administration of a low-oxygen gas mixture to pregnant ewes results in a decrease in umbilical venous oxygen content, but umbilical blood flow is maintained.6 With cord compression, umbilical venous oxygen content is maintained, but umbilical blood flow is reduced. We have shown that following acute fetal hemorrhage there is a decrease in both umbilical blood Row and umbilical venous oxygen content.” The umbilical venous oxygen content did not change significantly during cord compression. This is of considerable interest because, in association with reduced flow rate through the placenta with longer transit time and presumably no change in uterine blood flow, it is possible that umbilical venous PO* would have increased progressively as flow fell. Furthermore, a rise in umbilical venous pressure could increase the placental blood volume and placental vascular volume, thereby increasing the area for oxygen diffusion. The lack of a significant increase in umbilical venous oxygen content could be related to the decrease in umbilical arterial oxygen content and PO,. It is also possible, however, that the placental vessels in the site of gas exchange are not
of reducing
umbilical
blood
flow
817
easily distended and that the main change occults in the very compliant major umbilical \;essels. Because umbilical oxygen content does not change, fetal oxygen delivery is linearly related to umbilical blood flow over a wide range. However, Iimbilical blood flow and, thus, oxygen delivery can be reduced acutely to about half of control values without influencing fetal body oxygen consumption. Maintenance of oxygen consumption during a small or moderate reduction of umbilical blood flow and oxygen delivery was achieved by increasing the amount of oxygen extracted by the fetus. Our studies show that the fetus normally extracts about S4Z of’ the oxygen that is delivered from the placenta. This level of‘ oxygen extraction is similar to that in the rlewborn lamb soon after birth and at 8 weeks after birth, at which time almost all fetal hemoglobin has been replaced bv the adult type.’ The high affinity of fetal hemoglobin for oxygen is considered to be disadvantageous in the neonatal period in regard to oxygen extraction. AI the high PO, levels in the postnatal period, a greater quantity of oxygen is extracted from blood with adult-type as compared with fetal hemoglobin. However, at the low PO? levels in the fetus, oxygen extraction is similar to that in the adult. Faced with a reduced amount of oxygen availability, the fetus is able to increase markedly the level of oxygen extraction. With a 75’;; reduction of the umbilical blood flow and oxygen delivery, up to 80% ot the total amount of oxygen delivered to the fetus was extracted.
It is not
clear
what
the
capability
is for
dif-
ferent organs to increase oxygen extraction. In this study we calculated the amount of‘ oxygen extracted 1~2 the fetal carcass; we assumed that the oxygen content of the blood samples obtained from the distal inferior vena cava OJ the iliac vein represents the true mixed venous blood of the lower carcass. The f&al lower carcass was able to increase its oxygen extraction from a control level of about 3 1% to 5-R when umbilical blood flow and oxygen delivery were reduced by 7.5%. The factors and mechanisms regulating the ability of individual fetal organs to extract oxvgen under various types of stress are not known. This is of considerable importance since the ability of the fetus 10 regulate the amount of oxygen extraction appears to be a prominent feature of fetal adjustment to stress
REFERENCES
1. Longo. L. D., Hill, E. P., and Power, G. G.: Theoretical analysis of factors affecting placental O2 transfer, Am. J. Physiol. 222:730, 1972.
2. Kiinzel, W., Mann, L. J., Bhakthavathsalan, A.. Airomlooi, J., and Liu, M.: The effect of umbilical vein occlusion on fetal oxygenation, cardiovascular parameters, and fetal
818
Itskovitz,
LaGamma,
and Rudolph
electroencephalogram, AM. J. OBSTET. GYNECOL. 128:201, 1977. 3. Dawes, G. 3, and Mott, J. C.: Changes in O2 distribution and consumption in foetal lambs with variations in umbilical blood flow, J. Physiol. 170:524, 1964. 4. Itskovitz, J., Go&man, B. W., and Rudolph, A. M.: Effects of hemorrhage on umbilical venous return and oxygen delivery in fetal lambs, Am. J. Physiol. 242:H543, 1982. 5. Berman, W. Jr., W., Goodlin, R. C., Heymann, M. A., and Rudolph, A. M.: Measurement of umbilical blood flow in fetal lambs in utero, J. Appl. Physiol. 39:1056, 1975.
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orders.
6. Cohn, H. E., Sacks, E. J., Heymann, M. A., and Rudolph, A. M.: Cardiovascular responses to hypoxemia and acidemia in fetal lambs, AM. J. OBSTET. GYNECOL. 120:817. 1974. 7. Lister, G., Walter, T. K., Versmold, H. T., Dallman, P. R., and Rudolph, A. M.: Oxygen delivery in lambs: Cardiovascular and hematologic development, Am. J. Physiol. 237: H668, 1979.
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11830
in place of
ITSKOVITZ*
EDMUND
F. LAGAMMA
ABRAHAM
M.
RUDOLPH
San Francisco, California 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 btood 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 33.8% ? 4.8% to 87.7% 2 11.3% during 75% reduction of flow. (AM. J. OBSTET. GYNECOL. 145:813, 1983.)
DELIVERY OF OXYGEN fromtheplacentatothe fetus and oxygen uptake by the fetus have been shown to be affected by the magnitude of umbilical blood flow. The effect of changes in umbilical blood flow on fetal oxygenation was tested in mathematical models* and also acutely in exteriorized lamb fetuses.2, 3 Anesthesia, as well as exteriorization, may cause drastic changes in fetal metabolism and umbilical blood flow. In the study by Kiinzel and associates,2 for example, control values for umbilical blood flow in some fetuses were below 100 ml . min-’ . kg-’ fetal body weight. This is greatly reduced as compared with umbilical THE
From the Cardiovascular Research Institute and the Departments ?f Pediatrics, Physiology, and Obstetrics, Gynecology, and Reproductive Sciences, University of Culifornia (San Francisco). Supported by a grant from th United States Public Health Seruice, Program Project Grant HI24056 Receivtdfor Raised
publication
Jub 29, 1982.
September
28, 1982.
Accepted November
1, 1982.
Reprint requests: A. M. Rudolph, M.D., University of Calt~omia (San Francisco), California 94143. *National (TW02767)
Institutes from
I403-HSE, San Francisco,
of Health International Rambam Medical Center,
Fellow Haifa,
Israel.
blood flow values of about 200 ml min.-’ kg-’ measured in fetal lambs chronically instrumented in utero.4, 5 The purpose of our studies was IO determine the effects of acute reduction of umbilical blood flow in fetal lambs chronically instrumented in utero. We wished to examine the relationship between umbilical blood flow, oxygen delivery to the fetus, feral oxygen uptake, and the ability of the fetus to extract oxygen from fetal blood with its high oxygen affinity. Umbilical blood flow reduction was achieved by partial cord occlusion, which preferentially constricted the umbilical veins. Methods Animal preparation. We studied eight fetal lambs with known gestational ages of 120 to 128 days (term is about 147 days). A low spinal anesthetic was given to the ewe with 2 ml of 1% tetracaine hydrochloride. With the use of aseptic procedures, polyvinyl catheters were inserted into the maternal left pedal artery and vein and advanced to the descending aorta and abdominal inferior vena cava, respectively. The uterus was exposed through a midline abdominal incision and the fetal parts were identified. The uterus was incised ovel the fetal neck, and with local anesthesia with 0.5$% lidocaine hydrochloride catheters (0.8 mm inside di813
814
Itskovitz,
LaGamma,
April 1, iYXJ Am. J. Obstet. Gynecol.
and Rudolph
Qr 0
f -
l l
8
. .
80
.
:
l*
l .“cl
0
UV 0
UA IVC
O-
200 Flow Iml/min/kg)
120 Umbilical Blood
280
Fig. 1. Fetal blood 0, content before (open marks) and during (closed marks) partial cord occlusion. WV, Umbilical venous blood. UA, Descending aortic blood (Y = 5.23 log x -6.48 12 = 0.8C, p < 0.001). WC, Distal inferior vena caval blood (Y = 4.85 log x -7.46, r = 0.89, p < 0.001). Number of experiments as in Table I.
0 0 08
. .
. .
. /
/
y~0.09Xt0.70 r=0.97 p c o.oo/
.
I
I
120
40
Umbilical
Blood
1
4
200
280
Flow
(ml/min/kg)
Fig. 2. The correlation between umbilical blood flow and Oz delivery to the fetus before (open circles) and during (closed circles) partial cord occlusion.
ameter, 1.2 mm outside diameter) were inserted into a carotid artery and an external jugular vein. A second uterine incision was made over the fetal hind limbs which were extracted from the uterus. Catheters (0.8 mm inside diameter, 1.2 mm outside diameter) were inserted into both pedal arteries and advanced to the descending aorta or the external iliac artery. Similar catheters were inserted into the pedal veins and advanced to the external iliac vein or to the inferior vena cava distal to the origin of the renal veins. A polyvinyl catheter was inserted into a cotyledonary branch of the umbilical vein and advanced to the main
umbilical vein. The uterine incision was extended and the lamb was extracted further to expose the lower abdomen and flanks. A cuff-type electromagnetic flow transducer that had been precalibrated in vitro was placed around the common unbilical artery, as previously describedj The fetus was then extracted further to the level of the umbilical ring, and a silicone rubber cuff with an inflatable balloon was placed around the proximal portion of the umbilical cord. The fetus was returned to the uterus and a catheter was placed in the amniotic fluid cavity. Amniotic fluid was replaced with 0.9% saline, and the uterine incision was closed. The catheters and the flow transducer cable were passed through the abdominal wall to the flank of the ewe and protected by a pouch sewn to the skin. On the day of operation and each day thereafter, the ewe received two million units of penicillin G and 800 mg of kanamycin, half intravenously and half into the amniotic cavity. Experimental protocol. The experiments were carried out on the second to fifth postoperative days, while the ewe stood in a stall with free access to alfalfa pellets and water. Fetal aortic, umbilical venous, and intrauterine pressures were measured by Statham P23Db pressure transducers; mean umbilical blood flow was measured with a Statham SP2202 electromagnetic flowmeter. Fetal heart rate was recorded by means of a cardiotachometer triggered by the arterial pulse pressure. All pressures, umbilical blood flow, and heart rate were recorded continuously on a Beckman direct-writing recorder. Fetal arterial and umbilical venous pressures were measured with amniotic cavity pressure as zero reference. Umbilical blood flow was reduced by inflation of the balloon occluder around the umbilical cord for 3 to 4 minutes. Blood samples (0.7 to 0.8 ml) were obtained before and at the end of cord occlusion from the umbilical vein, descending aorta, and inferior vena cava for the determination of blood gases, pH, hemoglobin concentration, and percent oxygen saturation of hemoglobin. Each fetus was studied at normal umbilical blood flow and at two or three different levels of umbilical blood flow (approximately 25%, n = 5; 50%, n = 8; or 75%, n = 5). At least 1 hour of recovery was allowed between each occlusion. At the end of the study, the animals were killed with an overdose of sodium pentobarbital, and the positions of all catheters were confirmed. Measurements and calculations. Oxygen delivery to the fetus was calculated by multiplying umbilical blood flow by umbilical venous oxygen content. Fetal oxygen consumption was calculated by multiplying umbilical blood flow by umbilical venous-arterial oxygen content difference. The proportion of oxygen extracted by the
Volume Number
I-t5 7
Effect
Table I. The effect of umbilical blood flow reduction aortic and umbilical venous blood pressures
on fetal pH, blood
Urnbikal
of reducing
umbilical
blood
flow
815
gases, and heart race and on mean
blood flow
reductions
Parameter Descending aorta: PH PO, Pco, (tort-) Heart rate (bpm) Mean aortic pressure (torr) Mean umbilical venous pressure Data are means + SD. *p < 0.005 when compared tp < 0.02 when compared
7.39 21 44 182 45 14
(ton-)
with controls with controls
(paired (paired
” c 2 2 -t *
0.02 1 2 13 5 5
7.38 18 45 178 48 25
2 c t -t T ‘-
0.02 2+ 1 17 8 7t
7.36 I7 47 156 47 27
? + + _’ 2 i
0.02* 2* 3t 14* 5 6*
7.33 15 4%) I(!8 IX :ii,
2 c f f ‘r f
0.04t 2: 41 20* 7 j*
t test). t test).
Table II. The effect of changes in umbilical blood flow on total oxygen delivery to the fetus, oxygen consumption, and oxygen extraction by the fetus as a whole and oxygen extraction by the lower trutlk of the fetus -_IUmbilical Parameter
Control
Umbilical blood flow (ml/min/kg) O2 delivery (ml/mm/kg) O2 consumption Fetal O2 extraction (%) Lower trunk O2 extraction (%) Data *p < tp < $p <
fetus blood
are means -t SD. 0.01 when compared 0.002 when compared 0.02 when compared
241 22.43 7.49 33.6 31.2
with controls with controls with controls
2 k ” k 2
(paired (paired (paired
from the total delivered by umbilical was calculated from the ratio:
V,,iO,
Del = [ Q&UV,, = [ UV,,
- UA,,)]/(Quv
39 2.15 0.90 4.8 7.8
blood $ow
reductions
25%
(n = 5)
50%
(n = 8)
75% (II = 5)
189 16.50 7.04 43.8 35.1
t t 2 2 r
128 12.01 6.12 53.0 4i.5
2 ‘k t lr
Cl 5.x.5 3.92 67.7 53.7
22* 2.14* 0.62 5.8$ 4.5*
21t 1.91t 0.86t 8.lt 8.9$
f t t t f
14t 1.59t 1. lot 11.3t 7.R$
t test). t test). t test).
venous
x UV,,,)
- UA,, ]/UVo,,
where i:,, is fetal oxygen consumption, 0, Del is the amount of oxygen delivered to the fetus from the placenta, Q[.r is umbilical blood flow, UVo, is umbilical venous oxygen content, and UA., is umbilical arterial (descending aortic) oxygen content. Similarly, the proportion of oxygen extracted by the lower trunk of the fetus was calculated as follows: UA,j., - IVC&JAor, where WC,, is distal inferior vena caval oxygen content. Umbilical-placental vascular resistance was calculated by dividing umbilical arterial minus umbilical venous mean pressure by umbilical blood flow. Blood PO,, Pco,, and pH were determined on a Radiometer blood gas analyzer (HM73, London Company) at 39” C. Blood hemoglobin concentration and hemoglobin oxygen saturation were determined
in duplicate on a Radiometer hemoximeter (Model OSM2). Oxygen content was calculated according to the formula: content
(mlidl)
Dissolved
oxygen
0,
= hemoglobin concentration (gm/dl) x 1.34 x 0, satnration/lOO. was considered
as negligible.
Results A 25% reduction of umbilical blood How resulted in a small decrease in descending aortic blood 1’0, and no significant changes in pH, Pco,, Ietal heart rate, and arterial pressure (Table I). Reducing umbilical blood flow by 50% and 75% of control values caused a fall in pH and PO, and a rise in Pcos in descending aortic blood. Fetal heart rate fell with 50c4 and 75% reduction, but mean aortic blood pressure was not significantly affected. There were no significant changes in umbilical venous PO,, pH, or Pcos. Compression of the cord resulted in a progressive increase in distal umbilical venous pressure, from a control of 14 + 5 torr to 32 t 5 tot-r during 754 reduction of trmhilical blood
816
Itskovitz,
LaGamma,
and Rudolph
y= -276~90;
f 8.49
80-
rzO.84
Y' - 58f8 I' -0.91 PCOOOf
p < o.oo/
.
72 s ‘Z ::. P
l &&=i=
w
. .
.+
log x+/73.44
60-
40-
0"
/
+ t
l
-75%
-50%
-25%
40
120 Umbilical
-75 %
c ,
I
L
200 Blood
Flaw
-50%
t
1
40
280
-25%
I
120 Umbilical
(ml/min/kg)
Blood
c 6
I
200
280
Flow (ml/min/kg)
80-
. 2
y= -36.03 F-O 78
60-
hgxt
/z/5
P c ooo/
E .o 5L tB.38
?I
40-
0"
p
20-75% 4
-50% 1 12
t 02
Delivery
-25% I 20
-75%
C I 28
@
(ml/min/kgl
-50%
-25%
I I20
t 40 Umbilical
c
I 200 Blood
Flow
I 280
Lml/min/kgl
Fig. 3. The correlation of umbilical blood flow with fetal O2 consumption (A) and 0, delivery (B) before (@en circles) and during (closed circles) partial cord occlusion.
Fig. 4. Fetal 0, extraction (A) and (B) before (open circles) and during
flow (Table I). The mean arterial-venous pressure differences across the umbilical-placental circulation decreased from 31 torr during control to 23 torr during 25% reduction, 20 during 50% reduction, and 16 during 75% reduction of umbilical blood flow. The effects of umbilical blood flow reduction on umbilical venous, descending aortic, and inferior vena caval oxygen content are shown in Fig. 1. During cord occlusion, umbilical venous blood oxygen content was maintained and descending aortic blood oxygen content was decreased. Thus, the venoarterial difference of blood oxygen content across the placenta increased with progressive reduction of umbilical blood flow. Distal inferior vena caval blood oxygen content showed a change similar to that in the descending aortic blood oxygen content. Since umbilical venous blood oxygen content was
maintained during cord occlusion, the amount of oxygen delivered to the fetus was linearly correlated (r = 0.97) with umbilical blood flow (Fig. 2 and Table II). Fetal oxygen consumption was 7.49 & 0.90 ml/mini kg during the control period and did not change significantly with a 25% reduction of the umbilical blood flow. Oxygen consumption decreased to 6.12 2 0.86 (p < 0.002) during 50% reduction and to 3.92 t 1.10 ml/min/kg (p < 0.001) during 75% reduction (Table II, Fig. 3). Similarly, a 25% reduction in the amount of oxygen delivered to the fetus resulted in no significant effect on fetal oxygen consumption, but 50% and 75% reductions resulted in a decrease in oxygen consumption (Table II, Fig. 3). The difference in oxygen saturation between umbilical venous and descending aortic blood increased progressively with umbilical occlusion, from 30.4 to 51.8. However, oxygen saturation differ-
lower carcass 0, extraction (closed circb) partial cord
occlusion.
Effect
ence between descending aortic and inferior vena caval bloods fell from 17.0 to 12.6 during progressive occlusion. During the control period, 33.6% + 4.8% of the total amount of oxygen delivered to the fetus from the placenta was extracted by the fetus (Table II, Fig. 4). During a 25% reduction of the umbilical blood flow, oxygen extraction increased to 43.8% f 5.8% (p < 0.02). With 50% and 75Q reductions, oxygen extraction further increased to 52.0% t 8.1% (p < 0.001) and to 67.5V 5 1 1.3% (1’ < O.OOl), respectively. The ability of the fetal peripheral circulation to extract oxygen is shown in Table II and Fig. 4. Normally, 31.2 ‘7r t 7.8% of the amount of oxygen delivered to the lower carcass is extracted. With falling umbilical blood flow, oxygen extraction by the lower carcass progressively increased (r = -0.78, J) < 0.001).
Comment Compression of the umbilical cord is a common cause of’fetal asphyxia. We have assessed the effects on fetal oxygenation of graded compression of the cord in fetal lambs, to produce measured changes in umbilical blood flow. This form of fetal stress differs from that produced by maternal hypoxemia. Administration of a low-oxygen gas mixture to pregnant ewes results in a decrease in umbilical venous oxygen content, but umbilical blood flow is maintained.6 With cord compression, umbilical venous oxygen content is maintained, but umbilical blood flow is reduced. We have shown that following acute fetal hemorrhage there is a decrease in both umbilical blood Row and umbilical venous oxygen content.” The umbilical venous oxygen content did not change significantly during cord compression. This is of considerable interest because, in association with reduced flow rate through the placenta with longer transit time and presumably no change in uterine blood flow, it is possible that umbilical venous PO* would have increased progressively as flow fell. Furthermore, a rise in umbilical venous pressure could increase the placental blood volume and placental vascular volume, thereby increasing the area for oxygen diffusion. The lack of a significant increase in umbilical venous oxygen content could be related to the decrease in umbilical arterial oxygen content and PO,. It is also possible, however, that the placental vessels in the site of gas exchange are not
of reducing
umbilical
blood
flow
817
easily distended and that the main change occults in the very compliant major umbilical \;essels. Because umbilical oxygen content does not change, fetal oxygen delivery is linearly related to umbilical blood flow over a wide range. However, Iimbilical blood flow and, thus, oxygen delivery can be reduced acutely to about half of control values without influencing fetal body oxygen consumption. Maintenance of oxygen consumption during a small or moderate reduction of umbilical blood flow and oxygen delivery was achieved by increasing the amount of oxygen extracted by the fetus. Our studies show that the fetus normally extracts about S4Z of’ the oxygen that is delivered from the placenta. This level of‘ oxygen extraction is similar to that in the rlewborn lamb soon after birth and at 8 weeks after birth, at which time almost all fetal hemoglobin has been replaced bv the adult type.’ The high affinity of fetal hemoglobin for oxygen is considered to be disadvantageous in the neonatal period in regard to oxygen extraction. AI the high PO, levels in the postnatal period, a greater quantity of oxygen is extracted from blood with adult-type as compared with fetal hemoglobin. However, at the low PO? levels in the fetus, oxygen extraction is similar to that in the adult. Faced with a reduced amount of oxygen availability, the fetus is able to increase markedly the level of oxygen extraction. With a 75’;; reduction of the umbilical blood flow and oxygen delivery, up to 80% ot the total amount of oxygen delivered to the fetus was extracted.
It is not
clear
what
the
capability
is for
dif-
ferent organs to increase oxygen extraction. In this study we calculated the amount of‘ oxygen extracted 1~2 the fetal carcass; we assumed that the oxygen content of the blood samples obtained from the distal inferior vena cava OJ the iliac vein represents the true mixed venous blood of the lower carcass. The f&al lower carcass was able to increase its oxygen extraction from a control level of about 3 1% to 5-R when umbilical blood flow and oxygen delivery were reduced by 7.5%. The factors and mechanisms regulating the ability of individual fetal organs to extract oxvgen under various types of stress are not known. This is of considerable importance since the ability of the fetus 10 regulate the amount of oxygen extraction appears to be a prominent feature of fetal adjustment to stress
REFERENCES
1. Longo. L. D., Hill, E. P., and Power, G. G.: Theoretical analysis of factors affecting placental O2 transfer, Am. J. Physiol. 222:730, 1972.
2. Kiinzel, W., Mann, L. J., Bhakthavathsalan, A.. Airomlooi, J., and Liu, M.: The effect of umbilical vein occlusion on fetal oxygenation, cardiovascular parameters, and fetal
818
Itskovitz,
LaGamma,
and Rudolph
electroencephalogram, AM. J. OBSTET. GYNECOL. 128:201, 1977. 3. Dawes, G. 3, and Mott, J. C.: Changes in O2 distribution and consumption in foetal lambs with variations in umbilical blood flow, J. Physiol. 170:524, 1964. 4. Itskovitz, J., Go&man, B. W., and Rudolph, A. M.: Effects of hemorrhage on umbilical venous return and oxygen delivery in fetal lambs, Am. J. Physiol. 242:H543, 1982. 5. Berman, W. Jr., W., Goodlin, R. C., Heymann, M. A., and Rudolph, A. M.: Measurement of umbilical blood flow in fetal lambs in utero, J. Appl. Physiol. 39:1056, 1975.
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6. Cohn, H. E., Sacks, E. J., Heymann, M. A., and Rudolph, A. M.: Cardiovascular responses to hypoxemia and acidemia in fetal lambs, AM. J. OBSTET. GYNECOL. 120:817. 1974. 7. Lister, G., Walter, T. K., Versmold, H. T., Dallman, P. R., and Rudolph, A. M.: Oxygen delivery in lambs: Cardiovascular and hematologic development, Am. J. Physiol. 237: H668, 1979.
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