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The effects of fetal exchange transfusion with a red blood cell substitute
The effects of fetal exchange transfusion with a red blood cell substitute Anthony Ambrose, M.D., Robert C. Cefalo, M.D., Ph.D., and Watson A. Bowes, M.D. Chapel Hill, North Carolina Isovolemic exchange transfusion in the fetal lamb in utero was performed with the use of Fluosol-DA (20%), a perfluorochemical erythrocyte substitute. With maternal hyperoxygenation, a physiologic P02 was maintained in the fetal lambs, although the total fetal oxygen content decreased as the hematocrit dropped. Because of the oxygen-carrying properties of the perfluorochemical emulsion, the fraction of fetal oxygen carried in the dissolved state increased significantly when compared with that in controls that received saline solution. (AM J OBSTET GYNECOL 1986;154:667-74.)
Key words: Fetal respiratory physiology, erythrocyte substitute, placental gas transfer
The safety and efficacy of perfluorochemicals in both improving oxygen delivery and maintaining circulation during conditions of acute blood loss have been demonstrated during in vivo studies of both nonpregnant laboratory animals and nonpregnant humans. I. 2 Recently, it was demonstrated that oxygen delivery to the fetal lamb was not impaired under conditions of neartotal maternal erythrocyte exchange with Fluosol-DA (20%), an acellular oxygen carrier. 3 Fluosol-DA (20%) is a milky white synthetic emulsion (Table I) consisting of electrolytes, starch, and the emulsified perfluorochemicals perfluorodecalin and perfluorotripropylamine. This report presents the results of a study of fetal cardiorespiratory effects of an isovolemic exchange transfusion of the near-term fetal lamb with Fluosol-DA (20%).
Material and methods Four groups of mixed-breed ewes between 135 and 142 days' gestation received ketamine hydrochloride (l mg/kg intramuscularly) premedication and then were anesthetized with ketamine by continuous intravenous drip at 7 to 9 mg/min after cut-down cannulation of a jugular vein. Each fetus then underwent isovolemic exchange transfusion, according to group, with either Fluosol-DA (20%) or normal saline solution, during which its mother breathed either room air or 100%
From the Division of Maternal and Fetal Medicine, Department of Obstetrics and Gynecology, and the School of Medicine, The University of North Carolina. Presented at the Annual Meeting of the Society of Perinatal Obstetricians, Las Vegas, Nevada, February 1,1985. Received for publication july 30, 1985; revised November 1, 1985; accepted November 5,1985. Reprint requests: Robert C. Cefalo, M.D., Ph.D., Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, 214 MacNider Building, 220H, The University of North Carolina, Chapel Hill, NC 27514.
Table I. Fluosol-DA (20%) emulsion composition after reconstitution Ingredient
Quantity (gm/dl)
Perfluorodecalin Perfluorotripropylamine Hydroxyethyl starch Pluoronic F-68 Glycerol Sodium chloride Egg yolk phospholipids Sodium bicarbonate Glucose Oleic acid Potassium chloride Calcium chloride Magnesium chloride Water for injection
14.0 6.0 3.0 2.7 0.8 0.6 0.4 0.21 0.18 0.04 0.03 0.02 0.02 q.s.
oxygen at I atmosphere pressure. Group I (n = 3) and group II (n = 3) ewes breathed room air throughout the procedure, while ewes of groups III (n = 3) and IV (n = 2) breathed near-l00% oxygen via a rebreathing bag inflated with 100% oxygen at a flow rate of greater than 6 Umin. Groups I and III fetal lambs underwent continuous isovolemic exchange transfusion of Fluosol-DA (20%) for whole blood via the jugular veins; groups II and IV lambs similarly underwent exchange of a normal saline solution for whole blood. A maternal femoral artery was catheterized to permit periodic blood collection and continuous systemic arterial pressure measurement with transducers (Hewlett-Packard Model 1280) and recording on a multichannel data recorder (Hewlett-Packard Model 7788A). After a laparotomy incision, a catheter was placed into a uterine vein draining the pregnant uterine horn to permit periodic sampling. The fetal head was then exteriorized with the amnion intact through a hysterotomy incision. Indwelling catheters were placed in each fetal jugular vein to permit exchange transfusion.
667
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Ambrose, Cefalo, and Bowes
March,1986 Am J Obstet Gynecol
Table II. Cardiorespiratory effects in group I of fetal exchange transfusion with fluosol-DA (20%) Fetal Hematocrit (%)
Baseline room air 15 min 30 min 45 min 60 min 75 min 90 min 105 min
41.5 37.5 34.2 30.0 27.0 25.0 23.0 20.7
± ± ± ± ± ± ± ±
3.6 0.4 0.2 3.6 2.9 1.4 2.2 2.6
Arterial (PH)
1.8 3.7 5.3 6.3 7.0 8.3 9.3
0 ± ± ± ± ± ± ±
0.8 0.6 1.2 1.9 1.7 1.2 1.2
23.3 19.5 19.5 19.8 19.5 19.0 18.5 19.5
± ± ± ± ± ± ± ±
0.2 0.7 1.2 1.5 2.0 1.6 1.4 2.5
7.376 7.366 7.363 7.342 7.307 7.265 7.212 7.182
± ± ± ± ± ± ± ±
0.034 0.047 0.035 0.018 0.019 0.046 0.083 0.100
f 38.8 42.1 40.3 40.5 44.7 47.5 47.3 50.3
± ± ± ± ± ± ± ±
4.1 4.1 6.9 6.7 4.8 4.8 8.5 6.9
[0, Ja;"t
0.074 0.072 0.082 0.092 0.097 0.098 0.013 0.114
± ± ± ± ± ± ± ±
0.001 0.002 0.005 0.007 0.010 0.010 0.008 0.014
f
[0, Jt,B:f:
9.052 6.588 5.978 5.421 4.760 4.331 3.871 3.705
± ± ± ± ± ± ± ±
0.805 0.056 0.059 0.666 0.492 0.270 0.364 0.443
*Volume percentage of perfluorochemicals centrifuged from blood. tMilliliters of oxygen per deciliter; oxygen content dissolved in aqueous and perfluorochemical phases, fetal arterial blood. tMilliliters of oxygen per deciliter; totla oxygen content, fetal arterial whole blood.
Table III. Cardiorespiratory effects in group II of fetal exchange transfusion with normal saline solution Fetal Hematocrit (%)
Baseline room air 15 min 30 min 45 min 60 min 75 min 90 min 105 min
44.7 43.3 41.1 38.8 35.3 31.7 34.3 30.5
± 7.4 ± 7.0 ± 6.8 ± 7.9 ± 7.6 ± 8.0 ± 6.8 ± 7.5
Arterial Po, (torr)
19.0 17.9 19.3 20.0 19.8 19.2 17.9 20.2
± 0.2 ± 1.1
± 1.1 ± 0.6
± 1.0 ± 0.2 ± 0.1
± 2.3
Arterial (PH)
7.306; 0.071 7.309 ± 0.069 7.276 ± 0.089 7.206 ± 0.094 7.131 ± 0.117 7.004 ± 0.188 7.018 ± 0.218 6.999 ± 0.199
Arterial Pea, (torr)
44.7 46.4 44.6 47.1 50.0 56.3 62.1 64.4
± 3.5 ± 3.8
± 3.9 ± 5.5 ± 5.8
± 10.7 ± 19.8 ± 19.1
f
[0 2 Ja;,,*
0.060 0.057 0.061 0.063 0.063 0.061 0.057 0.064
± ± ± ±
± ± ±
±
0.001 0.003 0.003 0.002 0.003 0.001 0.001 0.007
f[O,Jt,Bt 7.392 6.435 7.012 6.931 6.326 5.392 5.069 5.448
1.223 1.051 1.153 1.376 1.377 1.360 1.003 ± 1.326
± ± ± ± ± ± ±
Maternal arterial Po, (torr)
58.5 ± 7.5 61.6 ± 7.0 62.2 ± 7.8 64.7 ± 8.0 67.1 ± 8.5 63.3 ± 8.4 60.2 ± 10.2 54.0
*Milliliters of oxygen per deciliter; physically dissolved oxygen, fetal arterail blood. tMilliliters of oxygen per deciliter; total oxygen content, fetal arterial whole blood.
An indwelling catheter was likewise placed a distance of 4 to 8 em into a fetal carotid artery to allow periodic sampling and continuous pressure recording. After a postoperative stabilization period, exchange was accomplished via continuous infusion-withdrawal pumps at a rate of 5 to 10 mllmin during 75 to 105 minutes. Fluosol-DA (20%) or normal saline solution (391 ± 67 ml, 81 to 117 ml/kg) was infused, and whole blood (272 ± 48 ml, 56 to 80 mllkg) was removed. The target level of exchange was to achieve a fluorocrit of >6% and/or a reduction of hematocrit to half the original level. After these levels were reached or approximated, groups I and II ewes and lambs were put to death by intravenous injection of each with potassium chloride, while groups III and IV ewes were given 100% nitrogen to breathe. Data collected included continuous maternal femoral and fetal carotid arterial pressure, periodic (every 15 minutes) blood gases and pH from maternal and fetal arteries and from the maternal uterine vein, maternal hematocrits, and fetal hematocrits and fluorocrits. Hematocrits and fluorocrits (the volume percentage ofthe white bottom layer of perfluorochemical centrifuged
from the blood) were determined in capillary tubes that were centrifuged for 5 minutes at 10,000 rpm. Samples of blood for analysis of gases and pH were obtained simultaneously and drawn anaerobically. pH and the partial pressures of oxygen (Po,) and carbon dioxide (Peo2 ) were measured with an Instrument Laboratory No. 113 gas analyzer at 38° C. The total oxygen content of maternal arterial whole blood, M[02]~B' and uterine venous blood, M[02]WB' was calculated by adding the oxygen bound to hemoglobin to the oxygen in physical solution (M[02]WB = [02],bc + [02]d;,,), expressed in milliliters of oxygen per deciliter. The [02],bc was calculated by multiplying the hemoglobin concentration, the derived percentage of oxygen saturation from the sheep blood oxygen dissociation curve [02]d;,,, and the Hiifner coefficient (1.34 ml of oxygen per gram of hemoglobin per 100 ml). [02]d;" was calculated as the product of the partial pressure of oxygen and the Bunsen solubility coefficient of oxygen in plasma (0.0000316 X P02 X 100). Total oxygen content of fetal arterial blood in groups II and IV was calculated in an identical fashion, albeit with the use of the oxygen dissociation curve for fetal
Fetal exchange with Fluosol-OA 669
Volume 154 Number 3
(groups II and IV) for whole blood until fluorocrits of >6% and/or hematocrits of approximately half their original values were achieved; (4) continuous recording of maternal and fetal arterial blood pressure; (5) periodic (every 15 minutes during exchange) determinations of maternal arterial and uterine vein blood gases, pH, and hematocrit and fetal arterial blood gases, pH, hematocrit, and fluorocrit.
Maternal Uterine vein P02
Arterial P02
Uterine vein Peo2
(torr)
(torr)
(torr)
42.9 40.7 41.1 40.7 39.7 39.8 40.6 42.5
± 1.9 ± 1.8
± 0.8 ± 2.1 ± ± ± ±
1.5 2.0 1.2 3.3
59.4 ± 15.3 71.8 ± 2.0 77.1 ± 4.8 75.9 ± 5.2 71.1 ± 5.6 70.3 ± 4.0 71.5 ± 2.7 78.3 ± 4.0
35.4 33.2 32.9 32.0 36.2 34.2 35.4 33.7
± 2.6 ± 2.7 ± 2.5
5.8 2.6 1.8 ± 0.6 ± 0.9 ±
± ±
Results
lamb blood. Since the blood of groups I and III lambs had a third oxygen-carrying phase (the perfluorochemical emulsion), total oxygen content was determined with the use of the calculation of the whole blood-perfluorochemical emulsion mixture oxygen content by means of Henry's law (volume = pressure X solubility coefficient) applied to the perfluorochemical and aqueous phases of the whole blood mixture. 4 Oxygen carried by the perfluorochemical phase, f[02]prc> was determined by the formula [02]prc = (lpr,
X
~~~ X
fluorocrit
X
0.000318
X
P02
X
fluorocrit.
Oxygen carried in the aqueous phase, [02].q", was determined by the formula [02].qu = (l.qu
X
~~~
X
(l00 - fluorocrit) = 0.0000316 X Po, X (100 - fluorocrit). These two quantities together compose the dissolved phase, f[02]di" = f[02]pfc + f[02].qu, and thus the total oxygen content of fetal arterial blood during exchange with Fluosol-DA (20%) is f[02]wB = f[02]'oc + f[02]di" = f[02]'OC + f[02]pk + f[02].qu. Fluosol-DA (20%) was supplied by Alpha Therapeutic Corporation, Los Angeles, California, as manufactured by Green Cross Corporation, Osaka, Japan. The contents of the perfluorochemical emulsion are listed in Table 1. It has the appearance and consistency of skim milk, a pH of 7.40, an osmolarity of 41 0 mOsm, oncotic pressure of 380 to 395 mm H 2 0, and the average particle size of the perfluorochemical compound is 0.2 f.Lm. The experimental protocol consisted of: (1) a postoperative stabilization period of 15 to 30 minutes, during which the ewes of all groups breathed room air and during which maternal and fetal arterial pressures were recorded continuously, with intermittent determinations of blood gases, pH, and hematocrit from the fetal carotid artery and maternal femoral artery and uterine vein; (2) a second stabilization phase during which groups III and IV ewes breathed 100% oxygen and during which similar recording and sampling were accomplished; (3) isovolemic fetal exchange of FluosolDA (20%) (groups I and III) or normal saline solution
Relevant cardiorespiratory data are listed in Tables II to V. In groups I and III (the Fluosol-DA (20%)exchanged lambs), fetal lambs weighed 4031 ± 844 gm, and their calculated blood volume was 363 ± 76 m\. Therefore, each fetus underwent a 74% exchange with Fluosol-DA (20%) during 75 to 105 minutes. Baseline hematocrits were 41.1% ± 2.7%, and by the end of the exchange period hematocrits had decreased to 21.3% ± 5.4%, a drop to 52% of their original levels. Maximum fluorocrits achieved were 8.4% ± 1.6%. The fetuses in groups II and IV, which received normal saline solution, weighed 4155 ± 672 gm. The calculated blood volume was 374 ± 61 ml, and they underwent 80% exchange. The hematocrits dropped from41.4% ± 7.2% to 23.9% ± 1.7%,58%oftheoriginal levels. Fetal and maternal arterial pressures remained stable during the test period in all preparations. Oxygen. In the lambs that underwent exchange transfusion with F1uosol-DA (20%), fetal arterial P0 2 was able to be maintained at physiologic levels (30.9 ± 3.3 torr) (Fig. 1) under conditions of maternal hyperoxygenation, even as the fetal hematocrit decreased almost to half of its original value. Moreover, in these group III fetuses, the fraction of total fetal oxygen in the dissolved state (f[02Li") increased significantly relative to that in controls (Fig. 2) (Student's t distribution, one-sided, (l = 0.05). Carbon dioxide. Under the conditions of the study, the Pco2 of fetal arterial blood in all four groups increased significantly from 46.5 ± 5.2 to 62.0 ± 7.4 torr during the exchange, and the pH of fetal arterial blood decreased from 7.305 ± 0.046 to 7.084 ± 0.081. There was no difference in this behavior between the Fluosol-DA (20%)-exchanged groups and the saline solution-exchanged groups, nor did maternal hyperoxygenation make a difference. These trends began early in the exchange and persisted throughout.
Comment Perfluorochemical emulsions used as red blood cell substitutes have been shown in clinical use to directly increase the delivery of oxygen to tissues by maintaining perfusion and transporting oxygen and carbon dioxide.'· 2 F1uosol-DA (20%) transports oxygen and carbon dioxide by direct solubility, and the volumes of
670
Ambrose, Cefalo, and Bowes
March, 1986 Am J Obstet Gynecol
Table IV. Cardiorespiratory effects in group III of fetal exchange transfusion with fluosol-DA (20%) Fetal
Baseline room air 100% oxygen 15 min 30 min 45 min 60 min 75 min
Hematocrit
Fluorocrit*
(%)
(%)
40.7 40.7 35.7 32.7 28.1 26.3 24.5
± ± ± ± ± ± ±
1.2 1.7 0.8 1.3 1.3 2.1 1.5
1.7 3.0 3.8 5.2 7.2
0 0 ± ± ± ± ±
0.6 0.4 0.5 0.8 0.8
Arterial P0 2 (torr)
24.1 36.4 34.6 29.3 28.6 28.1 28.3
± ± ± ± ± ± ±
Arterial (PH)
2.8 5.5 5.3 2.9 2.2 1.8 2.3
7.248 7.205 7.195 7.184 7.184 7.167 7.146
± ± ± ± ± ± ±
Arterial Peo 2 (torr)
0.049 0.034 0.024 0.011 0.025 0.032 0.046
49.8 52.6 56.1 58.4 60.8 62.9 62.5
± ± ± ± ± ± ±
1.0 2.7 3.5 4.6 3.8 5.2 4.5
f
[02Ja,,,t
0.076 0.115 0.126 0.118 0.122 0.130 0.137
± ± ± ± ± ± ±
0.009 0.017 0.019 0.012 0.010 0.008 0.011
f[ 0 2JWBt 9.380 14.509 12.454 9.967 8.414 7.647 7.230
± ± ± ± ± ± ±
0.293 0.566 0.341 0.387 0.374 0.627 0.460
*Volume percentage of perfluorochemicals centrifuged from blood. tMilliliters of oxygen per deciliter; oxygen content dissolved in aqueous and perfluorochemical phases, fetal arterial blood. tMilliliters of oxygen per deciliter; total oxygen content, fetal arterial whole blood.
Table V. Cardiorespiratory effects in group IV of fetal exchange transfusion with normal saline solution Fetal Hematocrit Fetal
Baseline room air 100% oxygen 15 min 30 min 45 min 60 min 75 min 90 min 105 min
(%)
36.5 36.3 34.0 32.8 30.5 28.8 26.3 23.5 23.5
± 3.0 ± 2.8 ± 3.0 ± 2.8 ± 1.5 ± 1.3 ± 1.8 ± 1.0 ± 1.0
Arterial P0 2 (torr)
22.4 29.5 28.1 27.2 26.7 25.6 25.7 24.5 23.9
± 0.6
± 1.5 ± 0.9 ± 1.2
± 0.7 ± 1.4 ± 2.4 ± 2.3 ± 3.2
Arterial (PH)
7.288 7.256 7.242 7.240 7.221 7.191 7.137 7.073 7.010
Arterial Peo 2 (torr)
± 0.013 ± 0.024
± 0.038 ± 0.033 ± 0.019
± 0.030 ± 0.003 ± 0.003 ± 0.010
52.5 53.5 56.5 58.0 57.3 57.3 59.3 71.5 70.6
± 1.5 ± 0.1 ± 2.0 ± 1.6
1.8 3.8 0.8 1.0 ± 0.6
± ± ± ±
f
[0 2Ja,,,*
0.071 0.093 0.089 0.086 0.084 0.081 0.081 0.077 0.076
± 0.002
± 0.005
± 0.003 ± 0.004 ± 0.002 ± 0.004 ± 0.007 ± 0.007 ± 0.010
f[ 0 2JWB t 7.661 11.068 9.817 9.035 8.226 7.434 6.915 5.678 5.168
± ± ± ± ±
± ± ± ±
0.645 0.943 0.887 0.848 0.417 0.320 0.489 0.228 0.211
*Milliliters of oxygen per deciliter; physically dissolved oxygen, fetal arterial blood. tMilliliters of oxygen per deciliter; total oxygen content, fetal arterial whole blood.
the gases vary linearly with their partial pressures, according to Henry's law. Physical considerations limit the maximum concentrations of perfluorochemicals contained in the emulsion. The fluorocrit of Fluosol-DA (20%) has been measured as 14.63% ± 0.06%; in our study we were able to achieve a fluorocrit of 8.4% ± 1.6%, which is 57% of the fluorocritofthe pure emulsion, uncontaminated by blood. At oxygen tensions achieved by the adult breathing room air, FluosolDA (20%) has only a limited capacity to carry oxygen and serves primarily as a volume expander. At Po 2s achieved by breathing 100% oxygen, however, FluosolDA (20%) can carry 5.6 ml of oxygen per deciliter, approximately one third that of whole blood. In the presence of a whole blood-Fluosol-DA (20%) mixture, oxygen will be carried in three phases: chemically combined with hemoglobin, dissolved in plasma, and dissolved in the perfluorochemical emulsion. Methods for calculating these volumes, as well as for assessing their delivery and consumption have been described.' The tissues will obtain most of their oxygen from the dissolved phase before any is provided by hemoglobin.
The low viscosity of the emulsion and small size of the fluorocarbon particles (0.2 fLm) support flow through small or constricted vessels, thus improving delivery to the tissues. 2 Oxygen. Since the classic work of Huggett' in 1927, it has been accepted that oxygen crosses the placental membrane by a process of simple diffusion along a concentration gradient; normal P0 2 values of 27 torr for the umbilical vein and 15 torr for the umbilical artery have been calculated by Longo. Further work by a number of investigators has shown that the rate and volume of oxygen transfer across the placenta are affected by many factors, including differences in maternal and fetal Po2 , maternal and fetal intervillous blood flow, placental permeability, and differences in maternal and fetal PC0 2 • 6 Moreover, during pregnancy, intraerythrocytotic concentrations of 2, 3-diphosphoglycerate increase by 30%, causing a shift of the oxygen dissociation curve to the right and enhancing the release of oxygen across the placenta to the fetus. Fetal oxygen uptake is favored by a high concentration of hemoglobin. Moreover, Battaglia et aU dem-
Fetal exchange with Fluosol-OA 671
Volume 154 Number 3
40
Maternal
'" 35
:I:
Uterine vein P0 2 (torr)
48.4 ± 7.9 82.9 ± 19.3 115.1±34.7 88.3 ± 27.7 91.0 ± 31.0 86.7 ± 26.7 64.6 ± 1.6
Arterial P0 2 (torr)
69.5 334.3 306.7 296.0 298.0 311.0 211.0
± ± ± ± ± ± ±
9.1 59.3 63.3 48.0 36.0 39.0 69.0
E E
Uterine vein Peo z (torr)
43.5 47.6 44.0 51.6 49.5 50.1 52.6
± ± ± ± ± ± ±
2.2 0.6 5.3 3.9 0.8 2.3 4.2
o o
30
o
iii 25 ...J
~
20
w ~
~ 15
t
...J
W
10
u..
t
Hypero)(ygenation Groups m and
IlZ:
Room Air
ON 5
a.
o 30 60 90 TIME (MINUTES) SINCE EXOiANGE STARTED
Maternal Uterine vein P0 2 (torr)
Arterial P0 2 (torr)
Uterine vein Peo2 (torr)
65.0 51.5 61.0 64.9 52.8 44.0 47.0 52.3 75.8
73.5 337.5 ± 7.5 320.0 ± 96.2 320.0 ± 5.0 302.5 ± 17.5 304.5 ± 7.5 302.5 ± 17.5 300.0 ± 1.0 298.0 ± 8.0
40.0 48.3 49.5 47.5 44.8 50.0 52.5 52.3 53.0
onstrated that fetal erythrocytes have a much higher affinity for oxygen than adult red blood cells. Fetal hemoglobin can thus be saturated with oxygen at lower partial pressures than adult hemoglobin. Under normal conditions the transfer of oxygen is not thought to be limited by resistance to diffusion at the placental membrane but is flow limited. The force that drives oxygen across the placenta is the gradient in the partial pressure of the physically dissolved gas between maternal and fetal blood.' When the mother is breathing room air, according to Henry's law, 0.3 ml of oxygen per deciliter is physically dissolved in the plasma, and 15 to 17 ml of oxygen per deciliter is bound to the hemoglobin. As the physically dissolved oxygen diffuses across the placenta, additional oxygen is released from the maternal hemoglobin. On the fetal side, the opposite occurs: After diffusion across the placenta in the dissolved phase, the gas enters the fetal circulation where it is quickly absorbed by the fetal hemoglobin with its high oxygen affinity. The oxyhemoglobin dissociation curves of human maternal and fetal blood at pH = 7.4 illustrate that at a given oxygen tension, fetal hemoglobin will be significantly more saturated with oxygen than adult he-
120
Fig. 1. Partial pressure of oxygen in fetal arterial blood in group I (room air, Fluosol-exchanged) lambs (A-A-A), group II (room air, saline solution-exchanged) lambs (6.-6.-6.), group III (hyperoxygenation, Fluosol-exchanged) lambs (...........-.), and group IV (hyperoxygenation, saline solution-exchanged) lambs (0--0--0).
moglobin, and the position and steepness of the fetal curve at usual fetal oxygen tensions demonstrate that the oxygen content of fetal blood may be greatly affected by small changes of fetal Po 2 • Yet it has been demonstrated that major increases in maternal arterial oxygen tension have resulted in only modest elevations of fetal Po2 • Only by hyperbaric oxygen administration to the mother, as shown by Assali et al.," can fetal Po 2 s in excess of 100 mm Hg be achieved. Meschia 9 explained that the large P0 2 differences between maternal arterial blood and umbilical venous blood is primarily the result of the structural characteristics of the placenta and oxygen consumption by the placenta; flow, consequently, resembles that of a concurrent system, in which the oxygen tension of fetal blood at the placental interface may not exceed that of the venous side of the donor stream. Whereas this results in fetal blood having a relatively low oxygen tension, umbilical venous and arterial blood normally contain large amounts of oxygen, because of the high affinity of fetal erythrocytes for oxygen. Because of this, for example, an increase of 5 torr in the arterial P0 2 of the fetus may increase its total blood oxygen content as much as a 500 tOfr increase in the arterial P0 2 of the mother. 9 . 10 Under conditions of maternal hyperoxygenation, perfluorochemical emulsion-exchanged fetuses (group III) did not demonstrate a greater affinity for oxygen than saline solution-exchanged controls (group IV) in that there was no significant increase in total oxygen content in the perfluorochemical emulsion-exchanged fetuses; they were apparently unable to attract increased quantities of oxygen across the placenta (Fig. 3). The group IV fetuses (saline solution, hyperoxy-
672 Ambrose, Cefalo, and Bowes
March, 1986
Am J Obstet Gynecol
16 14 '0
.....
12
E IZ W
IZ
8 ~
t
Hyperoxygenatioo Groups m and Ill:
10
8
6
N
~4 2
t Room
Hyperoxygenotion Groups mand Ill:
Air
o 30 60 90 TIME (MINUTES) SINCE EXCHANGE STARTED
o 30 60 90 TIME (MINUTES) SINCE EXCHANGE STARTED
Fig. 2. Oxygen content dissolved in a queous and perftuorochemical phases, fetal arterial blood, in group I (room air, Fluosol-exchanged) lambs (A-A-A), group II (room air, saline solution-exchanged) lambs (6-6-6), group III (hyperoxygenation, Fluosol-exchanged) lambs (.____.), and group IV (hyperoxygenation, saline solution-exchanged) lambs (0-0-0).
Fig. 3. Total oxygen content of fetal whole blood in group I (room air, Fluosol-exchanged) lambs (A-A-A), group II (room air, saline solution-exchanged) lambs (6-6-6), group III (hyperoxygenation, Fluosol-exchanged) lambs (.____.), and group IV (hyperoxygenation, saline solutionexchanged) lambs (0-0-0).
genation) had a small apparent but not significant decrease in P0 2 relative to the perfluorochemical emulsion-exchanged fetal lambs (Fig. 1). The group III ewes (perfluorochemical emulsion, hyperoxygenation) likewise had an apparent but not significant increase in maternal uterine vein P0 2 compared to the mothers of the saline solution-exchanged fetuses. When these values were combined, however, the approximate P0 2 gradient, that is, maternal uterine vein P0 2 minus fetal arterial Po 2, was significantly lower in the saline solution-exchanged preparations than in those in which a Fluosol-DA (20%) exchange was performed. The fact that we were unable to raise fetal arterial P0 2 levels above maternal uterine vein P0 2 levels in spite of the high affinity of the perfluorochemicals for oxygen and even though uterine vein P0 2 levels in the perfluorochemical emulsion-exchanged group appeared to be higher than in the saline solution-exchanged group, is in agreement with the findings of Meschia and lends further support to his theory of concurrent flow,"' 10 The fetal arterial oxygen tension, on the other hand, was able to be maintained at physiologic levels during the hyperoxygenation tests with induced anemia; the perfluorochemical emulsion-exchanged fetal lambs' P0 2 levels were apparently but not significantly higher than those exchanged with saline solution (Fig. 1). Barcroft ll measured the oxygen consumption of the fetal lamb as 4.8 ± 0.6 ml of oxygen per kilogram per minute; Meschia accurately measured umbilical blood flow at approximately 100 mllkg/minute. With use of these data, one can calculate a critical oxygen content of fetal umbilical blood of 4.8 ± 0.6 ml of oxygen per
deciliter, below which the oxygen needs of the fetus, at least in theory, will not be met. In our study, the fetal lambs of groups I, II, and IV all approached or dropped below that critical level (Fig. 3). In the group III fetuses (perfluorochemical emulsion, hyperoxygenation), however, even in the presence of the physiologic but relatively low P0 2 available on the fetal side of the placenta, there was apparently more oxygen available to fetal tissues than in the saline solution-exchanged controls. In these fetal lambs, as a level of half the original hematocrit was approached, the f[02]~B was still 7.23 ± 0.46 ml of oxygen per deciliter-well above the critical level of 4.2 to 5.4 mlldl theoretically required to provide sufficient oxygen for the lamb's physiologic needs. If the hematocrit were to continue to decrease, however, the f[02l~B would eventually reach this critical level, because of the nature of the FluosolDA (20%), whose oxygen-carrying properties, albeit having 10 times the oxygen-carrying capacity of plasma per volume percent, depend on a high oxygen tension. With use of the calculations of Rosen, a fetus with absolutely no hemoglobin completely exchanged with Fluosol-DA (20%) would be able to achieve a f[02]~B of 4.8 ml of oxygen per deciliter, but to do so would require an umbilical vein P0 2 of more than 600 torr, a level reached experimentally only under hyperbaric conditions. At modest oxygen tensions, such as the 27 torr usually seen in the umbilical vein, perfluorochemicals have only a small capacity to carry oxygen, and the emulsion acts primarily as a volume expander! On the other hand, achieving a fluorocrit of 8% to 10% in an anemic fetus with a P0 2 of 35 to 40 torr and a hF-
Fetal exchange with Fluosol-OA 673
Volume 154 Number 3
matocrit of lO% to 15% might provide the additional oxygen necessary to allow survival, especially considering that the small size of the perfluorochemical emulsion particle allows it to deliver oxygen to tissues that might otherwise be inaccessible because of vasospasm. Carbon dioxide. Carbon dioxide crosses the placenta by simple diffusion along a gradient mainly as dissolved carbon dixoide rather than as bicarbonate, as shown by Longo, Hill, and others. 12• 13 The rate and volume of carbon dioxide exchange across the placenta is influenced by umbilical and uterine artery P02 values, umbilical and uterine blood flow rates, the hemoglobin buffering capacity, and the hemoglobin concentration. 12• 13 Under normal conditions the P0 2 on the fetal side (43 and 48 mm Hg, respectively, for the umbilical vein and artery)IO is greater than that on the maternal side, probably because of anatomic and physiologic shunting as well as placental production of Co 2 , The ability of perfluorochemical emulsions to transport carbon dioxide has been amply demonstrated. In vitro, carbon dioxide is extremely soluble in perf1uorochemical emulsions, more so than any other gas. The easy uptake and loss of carbon dioxide by FluosolDA (20%) facilitates exchange with the surrounding environment, and depends only on the partial pressure of the gas. 11 During studies involving massively bled dogs which then received perfluorochemical emulsion transfusions, it was established that perfluorochemical emulsions were capable of carrying carbon dioxide as well as oxygen in vivo. IS The rate of carbon dioxide uptake and release in perfluorochemical particles was investigated kinetically with use of stopped flow spectrophotometry; it took only a few milliseconds for the particles to complete carbon dioxide transfer. ln The pH of fetal arterial blood in most mammalian species, including the sheep and the human, is about 0.1 less and the Peo 2 10 to 15 torr higher than that of maternal arterial blood. Nevertheless, a relative respiratory acidosis was observed in the fetal lambs in this study, and various etiologic possibilities were entertained to explain it. It is very unlikely that the increase in Peo 2 and decrease in pH observed was due to interference with carbonic anhydrase activity, as it has been determined that this is not influenced by FluosolDA (20%). It was hypothesized that the increased Peo 2 observed in the perfluorochemical emulsion-exchanged fetuses might be due to an excess of bicarbonate in the annex solution, which contains 0.21 gm/dl of sodium bicarbonate. However, it has been shown that bicarbonate is a necessary component of erythrocyte substitute preparations; in its absence, the pH decreases and the carbon dioxide increases to an extent dependent on the quantity of hemoglobin remaining in the circulation. 14 Cefalo et aJ.3 showed that fetal pH and Peo2 did not
change during maternal exchange transfusion with Fluosol-DA (20%) in intubated ewes breathing 100% oxygen in a carbon dioxide-absorbing system, which suggests that perfluorochemicals on the maternal side of the placenta represent no barrier to carbon dioxide diffusion. In the current study, however, it is apparent that at least part of the observed fetal hypercapnia and acidosis in groups III and IV was related to the significant maternal hypercapnia that was observed, in spite of high oxygen flow rates through the rebreathing bags. The mean maternal arterial and uterine vein Peo 2 values were 32.9 and 34.0 torr, respectively, in the ewes which breathed room air and 45.9 and 48.6 torr, respectively, in the ewes using rebreathing bags. The ewes in groups III and IV, therefore, spent the study period in a state of partially compensated respiratory acidosis caused by their rebreathing significant amounts of their expired carbon dioxide, and this was obviously reflected in their fetuses. Other possibilities considered in attempts to explain the fetal respiratory acidosis included the occasional uterine contractions commonly observed in such acute preparations, as well as the fact that we simply may have been witnessing and documenting deteriorating preparations. Since the total oxygen content of the fetal lambs was observed to be decreasing during the study, a portion of the decrease in pH may have been due to an uncompensated metabolic acidosis caused by anaerobic metabolism by the fetus and accumulation of lactate. In summary, under the conditions of our study, the efficacy ofFluosol-DA (20%) as a volume expander during an isovolemic exchange transfusion in the fetal lamb in utero was demonstrated, since fetal blood pressure was maintained despite an almost 50% acute drop in fetal hematocrit. In the presence of maternal hyperoxygenation, fetal lambs so exchanged were able to maintain a physiologic Po., although the total fetal oxygen content decreased as the hematocrit dropped. Because of the oxygen-carrying properties of the perfluorochemical emulsion, the fraction of fetal oxygen carried in the dissolved state increased significantly compared to saline solution-exchanged controls. REFERENCES I. Tremper KK, Lapin R, Levine E, Friedman A, Shoemaker we. Hemodynamic and oxygen transport effects of a perfluorochemical blood substitute, Fluosol-DA(20%). Crit Care Med 1980;8:738. 2. Tremper KK, Friedman AE, Levine EM, Lapin R, Camarillo D. The preoperative treatment of severely anemic patients with a perfluorochemical oxygen transport fluid, Fluosol-DA(20%). N Engl j Med 1982;307:277. 3. Cefalo RC, Seeds JW, Proctor Hj, Baker VV. Maternal and fetal effects of exchange transfusion with a red blood cell substitute. AM] OBSTET GYNECOL 1984;148:859. 4. Rosen AL, Sehgal LR, Gould SA, et al. Fluorocarbon emulsions: methodology to assess efficacy. Crit Care Med 1982;10:149.
Ambrose, Cefalo, and Bowes
5. Huggett ASG. Fetal blood gas tension and gas transfusion through the placenta of a goat.] Physiol. (Lond) 1927; 52:373. 6. Meschia G. Evolution of thinking in fetal respiratory physiology. AM] OBSTET GYNECOL 1978;132:806. 7. Battaglia FC, Bowes WA, McGaughey HR, Makowski EL, Meschia G. The effect of fetal exchange transfusions with adult blood upon fetal oxygenation. Pediatr Res 1969; 3:60. 8. Assali NS, Kirschbaum TH, Dilts PV. Effects of hyperbaric oxygen on utero placental and fetal circulation. Circ Res 1968;22:573. 9. Meschia G. Supply of oxygen to fetus. ] Reprod Med 1979;23: 160. 10. Meschia G, Battaglia Fe. Acute changes of oxygen pressure and the regulation of uterine blood flow. In: Barcroft Symposium. Fetal and neonatal physiology, New York: Cambridge University Press, 1973. 11. Barcroft]. Researches on prenatal life. Oxford: Blackwell Scientific, 1946:286.
March, 1986 Am J Obstet Gynecol
12. Longo LD, Papadapoulos MD, Forster RH. Placental CO2 transfer after fetal carbonic anhydrase inhibition. Am ] Physiol 1974;226:703. 13. Power GG, Hill EP, Longo LD. A mathematical model of CO 2 transfer in the placenta. In: Longo LD, Bartels H, eds. Respiratory gas exchange and blood flow in the placenta. Bethesda, Maryland: Department of Health, Education, and Welfare, 1972; DHEW publication no. 73361:395. 14. Geyer RP. The design of artificial blood substitutes. In: Ariens E], ed. Drug design. London: Academic Press, 1976. 15. Sekita M. Blood gas transport of fluorocarbon emulsion and its effect on the metabolism in peripheral tissue. ]pn ] Surg 1973;3:184. 16. Ohyanagi HT, Itoh T, Sekita M, Okamoto M, Mitsuno T. Kinetic studies of O 2 and CO 2 transport into or from PFC particles. Tokyo: International Congress on Artificial Organs, first annual meeting, 1977.
Oxygen consumption in fetal lambs after maternal administration of sodium pentobarbital D. W. Rurak, D.Phil., and S. M. Taylor, A.H.T. Vancouver, British Columbia, Canada To determine whether anesthesia lowers fetal oxygen consumption, sodium pentobarbital (10 mg/kg) was given intravenously to seven chronically instrumented pregnant ewes (123 to 144 days' gestation). Oxygen consumption fell by 23% in association with a rise in fetal vascular Po2 • Fetal breathing movements were abolished for 50.5 minutes, while the number of fetal heart rate accelerations fell by 80% in the first 30 minutes after pentobarbital injection. It is concluded that anesthesia reduces fetal oxygen consumption, probably by abolishing skeletal muscle activity, and perhaps also by reducing cerebral metabolic rate. (AM J OSSTET GYNECOL 1986;154:674-8.)
Key words: Fetal lamb, oxygen consumption, anesthesia Although there have been many reports on various effects of anesthetic agents in the fetal and neonatal periods, I there is a lack of information on the effects of general anesthetic agents on fetal oxygen uptake. Since such agents generally readily cross the placenta, they cause anesthesia in the fetus. This might be expected to reduce fetal oxygen consumption by abolishing fetal body movements and breathing activity;' 3 and perhaps by reducing cerebral metabolism.· Alternatively fetal oxygen transfer could be reduced by perFrom the Department of Obstetrics and Gynaecology, Centre for Developmental Medicine, Faculty of Medicine, University of British Columbia. This work was supported by funds from the Medical Research Council of Canada. Received for publication August 19, 1985; revised October 18, 1985; accepted November 5, 1985. Reprint requests: Dr. D. W. Rurak, The Research Center, 950 West 28th Ave., Vancouver, British Columbia, Canada V5Z 4H4.
674
turbations in uterine blood flow. I To address this question, oxygen consumption, blood gas tensions, and pH were measured in chronically catheterized lambs before and after the intravenous administration of sodium pentobarbital to the ewe.
Methods Preparation of animals. Experiments were performed on seven pregnant sheep. At 116 to 131 days' gestation, surgery was performed under halothane anesthesia, following induction with Pentothal. The uterus was exposed through a midline abdominal incision, and after opening the uterus, silicone rubber catheters were placed in a fetal femoral artery, lateral tarsal vein, the common umbilical vein, trachea, and amniotic cavity. In one fetus an electromagnetic blood flow transducer (C & C Instruments, Culver City, California) was placed on the common umbilical artery.'
Key words: Fetal respiratory physiology, erythrocyte substitute, placental gas transfer
The safety and efficacy of perfluorochemicals in both improving oxygen delivery and maintaining circulation during conditions of acute blood loss have been demonstrated during in vivo studies of both nonpregnant laboratory animals and nonpregnant humans. I. 2 Recently, it was demonstrated that oxygen delivery to the fetal lamb was not impaired under conditions of neartotal maternal erythrocyte exchange with Fluosol-DA (20%), an acellular oxygen carrier. 3 Fluosol-DA (20%) is a milky white synthetic emulsion (Table I) consisting of electrolytes, starch, and the emulsified perfluorochemicals perfluorodecalin and perfluorotripropylamine. This report presents the results of a study of fetal cardiorespiratory effects of an isovolemic exchange transfusion of the near-term fetal lamb with Fluosol-DA (20%).
Material and methods Four groups of mixed-breed ewes between 135 and 142 days' gestation received ketamine hydrochloride (l mg/kg intramuscularly) premedication and then were anesthetized with ketamine by continuous intravenous drip at 7 to 9 mg/min after cut-down cannulation of a jugular vein. Each fetus then underwent isovolemic exchange transfusion, according to group, with either Fluosol-DA (20%) or normal saline solution, during which its mother breathed either room air or 100%
From the Division of Maternal and Fetal Medicine, Department of Obstetrics and Gynecology, and the School of Medicine, The University of North Carolina. Presented at the Annual Meeting of the Society of Perinatal Obstetricians, Las Vegas, Nevada, February 1,1985. Received for publication july 30, 1985; revised November 1, 1985; accepted November 5,1985. Reprint requests: Robert C. Cefalo, M.D., Ph.D., Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, 214 MacNider Building, 220H, The University of North Carolina, Chapel Hill, NC 27514.
Table I. Fluosol-DA (20%) emulsion composition after reconstitution Ingredient
Quantity (gm/dl)
Perfluorodecalin Perfluorotripropylamine Hydroxyethyl starch Pluoronic F-68 Glycerol Sodium chloride Egg yolk phospholipids Sodium bicarbonate Glucose Oleic acid Potassium chloride Calcium chloride Magnesium chloride Water for injection
14.0 6.0 3.0 2.7 0.8 0.6 0.4 0.21 0.18 0.04 0.03 0.02 0.02 q.s.
oxygen at I atmosphere pressure. Group I (n = 3) and group II (n = 3) ewes breathed room air throughout the procedure, while ewes of groups III (n = 3) and IV (n = 2) breathed near-l00% oxygen via a rebreathing bag inflated with 100% oxygen at a flow rate of greater than 6 Umin. Groups I and III fetal lambs underwent continuous isovolemic exchange transfusion of Fluosol-DA (20%) for whole blood via the jugular veins; groups II and IV lambs similarly underwent exchange of a normal saline solution for whole blood. A maternal femoral artery was catheterized to permit periodic blood collection and continuous systemic arterial pressure measurement with transducers (Hewlett-Packard Model 1280) and recording on a multichannel data recorder (Hewlett-Packard Model 7788A). After a laparotomy incision, a catheter was placed into a uterine vein draining the pregnant uterine horn to permit periodic sampling. The fetal head was then exteriorized with the amnion intact through a hysterotomy incision. Indwelling catheters were placed in each fetal jugular vein to permit exchange transfusion.
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March,1986 Am J Obstet Gynecol
Table II. Cardiorespiratory effects in group I of fetal exchange transfusion with fluosol-DA (20%) Fetal Hematocrit (%)
Baseline room air 15 min 30 min 45 min 60 min 75 min 90 min 105 min
41.5 37.5 34.2 30.0 27.0 25.0 23.0 20.7
± ± ± ± ± ± ± ±
3.6 0.4 0.2 3.6 2.9 1.4 2.2 2.6
Arterial (PH)
1.8 3.7 5.3 6.3 7.0 8.3 9.3
0 ± ± ± ± ± ± ±
0.8 0.6 1.2 1.9 1.7 1.2 1.2
23.3 19.5 19.5 19.8 19.5 19.0 18.5 19.5
± ± ± ± ± ± ± ±
0.2 0.7 1.2 1.5 2.0 1.6 1.4 2.5
7.376 7.366 7.363 7.342 7.307 7.265 7.212 7.182
± ± ± ± ± ± ± ±
0.034 0.047 0.035 0.018 0.019 0.046 0.083 0.100
f 38.8 42.1 40.3 40.5 44.7 47.5 47.3 50.3
± ± ± ± ± ± ± ±
4.1 4.1 6.9 6.7 4.8 4.8 8.5 6.9
[0, Ja;"t
0.074 0.072 0.082 0.092 0.097 0.098 0.013 0.114
± ± ± ± ± ± ± ±
0.001 0.002 0.005 0.007 0.010 0.010 0.008 0.014
f
[0, Jt,B:f:
9.052 6.588 5.978 5.421 4.760 4.331 3.871 3.705
± ± ± ± ± ± ± ±
0.805 0.056 0.059 0.666 0.492 0.270 0.364 0.443
*Volume percentage of perfluorochemicals centrifuged from blood. tMilliliters of oxygen per deciliter; oxygen content dissolved in aqueous and perfluorochemical phases, fetal arterial blood. tMilliliters of oxygen per deciliter; totla oxygen content, fetal arterial whole blood.
Table III. Cardiorespiratory effects in group II of fetal exchange transfusion with normal saline solution Fetal Hematocrit (%)
Baseline room air 15 min 30 min 45 min 60 min 75 min 90 min 105 min
44.7 43.3 41.1 38.8 35.3 31.7 34.3 30.5
± 7.4 ± 7.0 ± 6.8 ± 7.9 ± 7.6 ± 8.0 ± 6.8 ± 7.5
Arterial Po, (torr)
19.0 17.9 19.3 20.0 19.8 19.2 17.9 20.2
± 0.2 ± 1.1
± 1.1 ± 0.6
± 1.0 ± 0.2 ± 0.1
± 2.3
Arterial (PH)
7.306; 0.071 7.309 ± 0.069 7.276 ± 0.089 7.206 ± 0.094 7.131 ± 0.117 7.004 ± 0.188 7.018 ± 0.218 6.999 ± 0.199
Arterial Pea, (torr)
44.7 46.4 44.6 47.1 50.0 56.3 62.1 64.4
± 3.5 ± 3.8
± 3.9 ± 5.5 ± 5.8
± 10.7 ± 19.8 ± 19.1
f
[0 2 Ja;,,*
0.060 0.057 0.061 0.063 0.063 0.061 0.057 0.064
± ± ± ±
± ± ±
±
0.001 0.003 0.003 0.002 0.003 0.001 0.001 0.007
f[O,Jt,Bt 7.392 6.435 7.012 6.931 6.326 5.392 5.069 5.448
1.223 1.051 1.153 1.376 1.377 1.360 1.003 ± 1.326
± ± ± ± ± ± ±
Maternal arterial Po, (torr)
58.5 ± 7.5 61.6 ± 7.0 62.2 ± 7.8 64.7 ± 8.0 67.1 ± 8.5 63.3 ± 8.4 60.2 ± 10.2 54.0
*Milliliters of oxygen per deciliter; physically dissolved oxygen, fetal arterail blood. tMilliliters of oxygen per deciliter; total oxygen content, fetal arterial whole blood.
An indwelling catheter was likewise placed a distance of 4 to 8 em into a fetal carotid artery to allow periodic sampling and continuous pressure recording. After a postoperative stabilization period, exchange was accomplished via continuous infusion-withdrawal pumps at a rate of 5 to 10 mllmin during 75 to 105 minutes. Fluosol-DA (20%) or normal saline solution (391 ± 67 ml, 81 to 117 ml/kg) was infused, and whole blood (272 ± 48 ml, 56 to 80 mllkg) was removed. The target level of exchange was to achieve a fluorocrit of >6% and/or a reduction of hematocrit to half the original level. After these levels were reached or approximated, groups I and II ewes and lambs were put to death by intravenous injection of each with potassium chloride, while groups III and IV ewes were given 100% nitrogen to breathe. Data collected included continuous maternal femoral and fetal carotid arterial pressure, periodic (every 15 minutes) blood gases and pH from maternal and fetal arteries and from the maternal uterine vein, maternal hematocrits, and fetal hematocrits and fluorocrits. Hematocrits and fluorocrits (the volume percentage ofthe white bottom layer of perfluorochemical centrifuged
from the blood) were determined in capillary tubes that were centrifuged for 5 minutes at 10,000 rpm. Samples of blood for analysis of gases and pH were obtained simultaneously and drawn anaerobically. pH and the partial pressures of oxygen (Po,) and carbon dioxide (Peo2 ) were measured with an Instrument Laboratory No. 113 gas analyzer at 38° C. The total oxygen content of maternal arterial whole blood, M[02]~B' and uterine venous blood, M[02]WB' was calculated by adding the oxygen bound to hemoglobin to the oxygen in physical solution (M[02]WB = [02],bc + [02]d;,,), expressed in milliliters of oxygen per deciliter. The [02],bc was calculated by multiplying the hemoglobin concentration, the derived percentage of oxygen saturation from the sheep blood oxygen dissociation curve [02]d;,,, and the Hiifner coefficient (1.34 ml of oxygen per gram of hemoglobin per 100 ml). [02]d;" was calculated as the product of the partial pressure of oxygen and the Bunsen solubility coefficient of oxygen in plasma (0.0000316 X P02 X 100). Total oxygen content of fetal arterial blood in groups II and IV was calculated in an identical fashion, albeit with the use of the oxygen dissociation curve for fetal
Fetal exchange with Fluosol-OA 669
Volume 154 Number 3
(groups II and IV) for whole blood until fluorocrits of >6% and/or hematocrits of approximately half their original values were achieved; (4) continuous recording of maternal and fetal arterial blood pressure; (5) periodic (every 15 minutes during exchange) determinations of maternal arterial and uterine vein blood gases, pH, and hematocrit and fetal arterial blood gases, pH, hematocrit, and fluorocrit.
Maternal Uterine vein P02
Arterial P02
Uterine vein Peo2
(torr)
(torr)
(torr)
42.9 40.7 41.1 40.7 39.7 39.8 40.6 42.5
± 1.9 ± 1.8
± 0.8 ± 2.1 ± ± ± ±
1.5 2.0 1.2 3.3
59.4 ± 15.3 71.8 ± 2.0 77.1 ± 4.8 75.9 ± 5.2 71.1 ± 5.6 70.3 ± 4.0 71.5 ± 2.7 78.3 ± 4.0
35.4 33.2 32.9 32.0 36.2 34.2 35.4 33.7
± 2.6 ± 2.7 ± 2.5
5.8 2.6 1.8 ± 0.6 ± 0.9 ±
± ±
Results
lamb blood. Since the blood of groups I and III lambs had a third oxygen-carrying phase (the perfluorochemical emulsion), total oxygen content was determined with the use of the calculation of the whole blood-perfluorochemical emulsion mixture oxygen content by means of Henry's law (volume = pressure X solubility coefficient) applied to the perfluorochemical and aqueous phases of the whole blood mixture. 4 Oxygen carried by the perfluorochemical phase, f[02]prc> was determined by the formula [02]prc = (lpr,
X
~~~ X
fluorocrit
X
0.000318
X
P02
X
fluorocrit.
Oxygen carried in the aqueous phase, [02].q", was determined by the formula [02].qu = (l.qu
X
~~~
X
(l00 - fluorocrit) = 0.0000316 X Po, X (100 - fluorocrit). These two quantities together compose the dissolved phase, f[02]di" = f[02]pfc + f[02].qu, and thus the total oxygen content of fetal arterial blood during exchange with Fluosol-DA (20%) is f[02]wB = f[02]'oc + f[02]di" = f[02]'OC + f[02]pk + f[02].qu. Fluosol-DA (20%) was supplied by Alpha Therapeutic Corporation, Los Angeles, California, as manufactured by Green Cross Corporation, Osaka, Japan. The contents of the perfluorochemical emulsion are listed in Table 1. It has the appearance and consistency of skim milk, a pH of 7.40, an osmolarity of 41 0 mOsm, oncotic pressure of 380 to 395 mm H 2 0, and the average particle size of the perfluorochemical compound is 0.2 f.Lm. The experimental protocol consisted of: (1) a postoperative stabilization period of 15 to 30 minutes, during which the ewes of all groups breathed room air and during which maternal and fetal arterial pressures were recorded continuously, with intermittent determinations of blood gases, pH, and hematocrit from the fetal carotid artery and maternal femoral artery and uterine vein; (2) a second stabilization phase during which groups III and IV ewes breathed 100% oxygen and during which similar recording and sampling were accomplished; (3) isovolemic fetal exchange of FluosolDA (20%) (groups I and III) or normal saline solution
Relevant cardiorespiratory data are listed in Tables II to V. In groups I and III (the Fluosol-DA (20%)exchanged lambs), fetal lambs weighed 4031 ± 844 gm, and their calculated blood volume was 363 ± 76 m\. Therefore, each fetus underwent a 74% exchange with Fluosol-DA (20%) during 75 to 105 minutes. Baseline hematocrits were 41.1% ± 2.7%, and by the end of the exchange period hematocrits had decreased to 21.3% ± 5.4%, a drop to 52% of their original levels. Maximum fluorocrits achieved were 8.4% ± 1.6%. The fetuses in groups II and IV, which received normal saline solution, weighed 4155 ± 672 gm. The calculated blood volume was 374 ± 61 ml, and they underwent 80% exchange. The hematocrits dropped from41.4% ± 7.2% to 23.9% ± 1.7%,58%oftheoriginal levels. Fetal and maternal arterial pressures remained stable during the test period in all preparations. Oxygen. In the lambs that underwent exchange transfusion with F1uosol-DA (20%), fetal arterial P0 2 was able to be maintained at physiologic levels (30.9 ± 3.3 torr) (Fig. 1) under conditions of maternal hyperoxygenation, even as the fetal hematocrit decreased almost to half of its original value. Moreover, in these group III fetuses, the fraction of total fetal oxygen in the dissolved state (f[02Li") increased significantly relative to that in controls (Fig. 2) (Student's t distribution, one-sided, (l = 0.05). Carbon dioxide. Under the conditions of the study, the Pco2 of fetal arterial blood in all four groups increased significantly from 46.5 ± 5.2 to 62.0 ± 7.4 torr during the exchange, and the pH of fetal arterial blood decreased from 7.305 ± 0.046 to 7.084 ± 0.081. There was no difference in this behavior between the Fluosol-DA (20%)-exchanged groups and the saline solution-exchanged groups, nor did maternal hyperoxygenation make a difference. These trends began early in the exchange and persisted throughout.
Comment Perfluorochemical emulsions used as red blood cell substitutes have been shown in clinical use to directly increase the delivery of oxygen to tissues by maintaining perfusion and transporting oxygen and carbon dioxide.'· 2 F1uosol-DA (20%) transports oxygen and carbon dioxide by direct solubility, and the volumes of
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March, 1986 Am J Obstet Gynecol
Table IV. Cardiorespiratory effects in group III of fetal exchange transfusion with fluosol-DA (20%) Fetal
Baseline room air 100% oxygen 15 min 30 min 45 min 60 min 75 min
Hematocrit
Fluorocrit*
(%)
(%)
40.7 40.7 35.7 32.7 28.1 26.3 24.5
± ± ± ± ± ± ±
1.2 1.7 0.8 1.3 1.3 2.1 1.5
1.7 3.0 3.8 5.2 7.2
0 0 ± ± ± ± ±
0.6 0.4 0.5 0.8 0.8
Arterial P0 2 (torr)
24.1 36.4 34.6 29.3 28.6 28.1 28.3
± ± ± ± ± ± ±
Arterial (PH)
2.8 5.5 5.3 2.9 2.2 1.8 2.3
7.248 7.205 7.195 7.184 7.184 7.167 7.146
± ± ± ± ± ± ±
Arterial Peo 2 (torr)
0.049 0.034 0.024 0.011 0.025 0.032 0.046
49.8 52.6 56.1 58.4 60.8 62.9 62.5
± ± ± ± ± ± ±
1.0 2.7 3.5 4.6 3.8 5.2 4.5
f
[02Ja,,,t
0.076 0.115 0.126 0.118 0.122 0.130 0.137
± ± ± ± ± ± ±
0.009 0.017 0.019 0.012 0.010 0.008 0.011
f[ 0 2JWBt 9.380 14.509 12.454 9.967 8.414 7.647 7.230
± ± ± ± ± ± ±
0.293 0.566 0.341 0.387 0.374 0.627 0.460
*Volume percentage of perfluorochemicals centrifuged from blood. tMilliliters of oxygen per deciliter; oxygen content dissolved in aqueous and perfluorochemical phases, fetal arterial blood. tMilliliters of oxygen per deciliter; total oxygen content, fetal arterial whole blood.
Table V. Cardiorespiratory effects in group IV of fetal exchange transfusion with normal saline solution Fetal Hematocrit Fetal
Baseline room air 100% oxygen 15 min 30 min 45 min 60 min 75 min 90 min 105 min
(%)
36.5 36.3 34.0 32.8 30.5 28.8 26.3 23.5 23.5
± 3.0 ± 2.8 ± 3.0 ± 2.8 ± 1.5 ± 1.3 ± 1.8 ± 1.0 ± 1.0
Arterial P0 2 (torr)
22.4 29.5 28.1 27.2 26.7 25.6 25.7 24.5 23.9
± 0.6
± 1.5 ± 0.9 ± 1.2
± 0.7 ± 1.4 ± 2.4 ± 2.3 ± 3.2
Arterial (PH)
7.288 7.256 7.242 7.240 7.221 7.191 7.137 7.073 7.010
Arterial Peo 2 (torr)
± 0.013 ± 0.024
± 0.038 ± 0.033 ± 0.019
± 0.030 ± 0.003 ± 0.003 ± 0.010
52.5 53.5 56.5 58.0 57.3 57.3 59.3 71.5 70.6
± 1.5 ± 0.1 ± 2.0 ± 1.6
1.8 3.8 0.8 1.0 ± 0.6
± ± ± ±
f
[0 2Ja,,,*
0.071 0.093 0.089 0.086 0.084 0.081 0.081 0.077 0.076
± 0.002
± 0.005
± 0.003 ± 0.004 ± 0.002 ± 0.004 ± 0.007 ± 0.007 ± 0.010
f[ 0 2JWB t 7.661 11.068 9.817 9.035 8.226 7.434 6.915 5.678 5.168
± ± ± ± ±
± ± ± ±
0.645 0.943 0.887 0.848 0.417 0.320 0.489 0.228 0.211
*Milliliters of oxygen per deciliter; physically dissolved oxygen, fetal arterial blood. tMilliliters of oxygen per deciliter; total oxygen content, fetal arterial whole blood.
the gases vary linearly with their partial pressures, according to Henry's law. Physical considerations limit the maximum concentrations of perfluorochemicals contained in the emulsion. The fluorocrit of Fluosol-DA (20%) has been measured as 14.63% ± 0.06%; in our study we were able to achieve a fluorocrit of 8.4% ± 1.6%, which is 57% of the fluorocritofthe pure emulsion, uncontaminated by blood. At oxygen tensions achieved by the adult breathing room air, FluosolDA (20%) has only a limited capacity to carry oxygen and serves primarily as a volume expander. At Po 2s achieved by breathing 100% oxygen, however, FluosolDA (20%) can carry 5.6 ml of oxygen per deciliter, approximately one third that of whole blood. In the presence of a whole blood-Fluosol-DA (20%) mixture, oxygen will be carried in three phases: chemically combined with hemoglobin, dissolved in plasma, and dissolved in the perfluorochemical emulsion. Methods for calculating these volumes, as well as for assessing their delivery and consumption have been described.' The tissues will obtain most of their oxygen from the dissolved phase before any is provided by hemoglobin.
The low viscosity of the emulsion and small size of the fluorocarbon particles (0.2 fLm) support flow through small or constricted vessels, thus improving delivery to the tissues. 2 Oxygen. Since the classic work of Huggett' in 1927, it has been accepted that oxygen crosses the placental membrane by a process of simple diffusion along a concentration gradient; normal P0 2 values of 27 torr for the umbilical vein and 15 torr for the umbilical artery have been calculated by Longo. Further work by a number of investigators has shown that the rate and volume of oxygen transfer across the placenta are affected by many factors, including differences in maternal and fetal Po2 , maternal and fetal intervillous blood flow, placental permeability, and differences in maternal and fetal PC0 2 • 6 Moreover, during pregnancy, intraerythrocytotic concentrations of 2, 3-diphosphoglycerate increase by 30%, causing a shift of the oxygen dissociation curve to the right and enhancing the release of oxygen across the placenta to the fetus. Fetal oxygen uptake is favored by a high concentration of hemoglobin. Moreover, Battaglia et aU dem-
Fetal exchange with Fluosol-OA 671
Volume 154 Number 3
40
Maternal
'" 35
:I:
Uterine vein P0 2 (torr)
48.4 ± 7.9 82.9 ± 19.3 115.1±34.7 88.3 ± 27.7 91.0 ± 31.0 86.7 ± 26.7 64.6 ± 1.6
Arterial P0 2 (torr)
69.5 334.3 306.7 296.0 298.0 311.0 211.0
± ± ± ± ± ± ±
9.1 59.3 63.3 48.0 36.0 39.0 69.0
E E
Uterine vein Peo z (torr)
43.5 47.6 44.0 51.6 49.5 50.1 52.6
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Maternal Uterine vein P0 2 (torr)
Arterial P0 2 (torr)
Uterine vein Peo2 (torr)
65.0 51.5 61.0 64.9 52.8 44.0 47.0 52.3 75.8
73.5 337.5 ± 7.5 320.0 ± 96.2 320.0 ± 5.0 302.5 ± 17.5 304.5 ± 7.5 302.5 ± 17.5 300.0 ± 1.0 298.0 ± 8.0
40.0 48.3 49.5 47.5 44.8 50.0 52.5 52.3 53.0
onstrated that fetal erythrocytes have a much higher affinity for oxygen than adult red blood cells. Fetal hemoglobin can thus be saturated with oxygen at lower partial pressures than adult hemoglobin. Under normal conditions the transfer of oxygen is not thought to be limited by resistance to diffusion at the placental membrane but is flow limited. The force that drives oxygen across the placenta is the gradient in the partial pressure of the physically dissolved gas between maternal and fetal blood.' When the mother is breathing room air, according to Henry's law, 0.3 ml of oxygen per deciliter is physically dissolved in the plasma, and 15 to 17 ml of oxygen per deciliter is bound to the hemoglobin. As the physically dissolved oxygen diffuses across the placenta, additional oxygen is released from the maternal hemoglobin. On the fetal side, the opposite occurs: After diffusion across the placenta in the dissolved phase, the gas enters the fetal circulation where it is quickly absorbed by the fetal hemoglobin with its high oxygen affinity. The oxyhemoglobin dissociation curves of human maternal and fetal blood at pH = 7.4 illustrate that at a given oxygen tension, fetal hemoglobin will be significantly more saturated with oxygen than adult he-
120
Fig. 1. Partial pressure of oxygen in fetal arterial blood in group I (room air, Fluosol-exchanged) lambs (A-A-A), group II (room air, saline solution-exchanged) lambs (6.-6.-6.), group III (hyperoxygenation, Fluosol-exchanged) lambs (...........-.), and group IV (hyperoxygenation, saline solution-exchanged) lambs (0--0--0).
moglobin, and the position and steepness of the fetal curve at usual fetal oxygen tensions demonstrate that the oxygen content of fetal blood may be greatly affected by small changes of fetal Po 2 • Yet it has been demonstrated that major increases in maternal arterial oxygen tension have resulted in only modest elevations of fetal Po2 • Only by hyperbaric oxygen administration to the mother, as shown by Assali et al.," can fetal Po 2 s in excess of 100 mm Hg be achieved. Meschia 9 explained that the large P0 2 differences between maternal arterial blood and umbilical venous blood is primarily the result of the structural characteristics of the placenta and oxygen consumption by the placenta; flow, consequently, resembles that of a concurrent system, in which the oxygen tension of fetal blood at the placental interface may not exceed that of the venous side of the donor stream. Whereas this results in fetal blood having a relatively low oxygen tension, umbilical venous and arterial blood normally contain large amounts of oxygen, because of the high affinity of fetal erythrocytes for oxygen. Because of this, for example, an increase of 5 torr in the arterial P0 2 of the fetus may increase its total blood oxygen content as much as a 500 tOfr increase in the arterial P0 2 of the mother. 9 . 10 Under conditions of maternal hyperoxygenation, perfluorochemical emulsion-exchanged fetuses (group III) did not demonstrate a greater affinity for oxygen than saline solution-exchanged controls (group IV) in that there was no significant increase in total oxygen content in the perfluorochemical emulsion-exchanged fetuses; they were apparently unable to attract increased quantities of oxygen across the placenta (Fig. 3). The group IV fetuses (saline solution, hyperoxy-
672 Ambrose, Cefalo, and Bowes
March, 1986
Am J Obstet Gynecol
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o 30 60 90 TIME (MINUTES) SINCE EXCHANGE STARTED
Fig. 2. Oxygen content dissolved in a queous and perftuorochemical phases, fetal arterial blood, in group I (room air, Fluosol-exchanged) lambs (A-A-A), group II (room air, saline solution-exchanged) lambs (6-6-6), group III (hyperoxygenation, Fluosol-exchanged) lambs (.____.), and group IV (hyperoxygenation, saline solution-exchanged) lambs (0-0-0).
Fig. 3. Total oxygen content of fetal whole blood in group I (room air, Fluosol-exchanged) lambs (A-A-A), group II (room air, saline solution-exchanged) lambs (6-6-6), group III (hyperoxygenation, Fluosol-exchanged) lambs (.____.), and group IV (hyperoxygenation, saline solutionexchanged) lambs (0-0-0).
genation) had a small apparent but not significant decrease in P0 2 relative to the perfluorochemical emulsion-exchanged fetal lambs (Fig. 1). The group III ewes (perfluorochemical emulsion, hyperoxygenation) likewise had an apparent but not significant increase in maternal uterine vein P0 2 compared to the mothers of the saline solution-exchanged fetuses. When these values were combined, however, the approximate P0 2 gradient, that is, maternal uterine vein P0 2 minus fetal arterial Po 2, was significantly lower in the saline solution-exchanged preparations than in those in which a Fluosol-DA (20%) exchange was performed. The fact that we were unable to raise fetal arterial P0 2 levels above maternal uterine vein P0 2 levels in spite of the high affinity of the perfluorochemicals for oxygen and even though uterine vein P0 2 levels in the perfluorochemical emulsion-exchanged group appeared to be higher than in the saline solution-exchanged group, is in agreement with the findings of Meschia and lends further support to his theory of concurrent flow,"' 10 The fetal arterial oxygen tension, on the other hand, was able to be maintained at physiologic levels during the hyperoxygenation tests with induced anemia; the perfluorochemical emulsion-exchanged fetal lambs' P0 2 levels were apparently but not significantly higher than those exchanged with saline solution (Fig. 1). Barcroft ll measured the oxygen consumption of the fetal lamb as 4.8 ± 0.6 ml of oxygen per kilogram per minute; Meschia accurately measured umbilical blood flow at approximately 100 mllkg/minute. With use of these data, one can calculate a critical oxygen content of fetal umbilical blood of 4.8 ± 0.6 ml of oxygen per
deciliter, below which the oxygen needs of the fetus, at least in theory, will not be met. In our study, the fetal lambs of groups I, II, and IV all approached or dropped below that critical level (Fig. 3). In the group III fetuses (perfluorochemical emulsion, hyperoxygenation), however, even in the presence of the physiologic but relatively low P0 2 available on the fetal side of the placenta, there was apparently more oxygen available to fetal tissues than in the saline solution-exchanged controls. In these fetal lambs, as a level of half the original hematocrit was approached, the f[02]~B was still 7.23 ± 0.46 ml of oxygen per deciliter-well above the critical level of 4.2 to 5.4 mlldl theoretically required to provide sufficient oxygen for the lamb's physiologic needs. If the hematocrit were to continue to decrease, however, the f[02l~B would eventually reach this critical level, because of the nature of the FluosolDA (20%), whose oxygen-carrying properties, albeit having 10 times the oxygen-carrying capacity of plasma per volume percent, depend on a high oxygen tension. With use of the calculations of Rosen, a fetus with absolutely no hemoglobin completely exchanged with Fluosol-DA (20%) would be able to achieve a f[02]~B of 4.8 ml of oxygen per deciliter, but to do so would require an umbilical vein P0 2 of more than 600 torr, a level reached experimentally only under hyperbaric conditions. At modest oxygen tensions, such as the 27 torr usually seen in the umbilical vein, perfluorochemicals have only a small capacity to carry oxygen, and the emulsion acts primarily as a volume expander! On the other hand, achieving a fluorocrit of 8% to 10% in an anemic fetus with a P0 2 of 35 to 40 torr and a hF-
Fetal exchange with Fluosol-OA 673
Volume 154 Number 3
matocrit of lO% to 15% might provide the additional oxygen necessary to allow survival, especially considering that the small size of the perfluorochemical emulsion particle allows it to deliver oxygen to tissues that might otherwise be inaccessible because of vasospasm. Carbon dioxide. Carbon dioxide crosses the placenta by simple diffusion along a gradient mainly as dissolved carbon dixoide rather than as bicarbonate, as shown by Longo, Hill, and others. 12• 13 The rate and volume of carbon dioxide exchange across the placenta is influenced by umbilical and uterine artery P02 values, umbilical and uterine blood flow rates, the hemoglobin buffering capacity, and the hemoglobin concentration. 12• 13 Under normal conditions the P0 2 on the fetal side (43 and 48 mm Hg, respectively, for the umbilical vein and artery)IO is greater than that on the maternal side, probably because of anatomic and physiologic shunting as well as placental production of Co 2 , The ability of perfluorochemical emulsions to transport carbon dioxide has been amply demonstrated. In vitro, carbon dioxide is extremely soluble in perf1uorochemical emulsions, more so than any other gas. The easy uptake and loss of carbon dioxide by FluosolDA (20%) facilitates exchange with the surrounding environment, and depends only on the partial pressure of the gas. 11 During studies involving massively bled dogs which then received perfluorochemical emulsion transfusions, it was established that perfluorochemical emulsions were capable of carrying carbon dioxide as well as oxygen in vivo. IS The rate of carbon dioxide uptake and release in perfluorochemical particles was investigated kinetically with use of stopped flow spectrophotometry; it took only a few milliseconds for the particles to complete carbon dioxide transfer. ln The pH of fetal arterial blood in most mammalian species, including the sheep and the human, is about 0.1 less and the Peo 2 10 to 15 torr higher than that of maternal arterial blood. Nevertheless, a relative respiratory acidosis was observed in the fetal lambs in this study, and various etiologic possibilities were entertained to explain it. It is very unlikely that the increase in Peo 2 and decrease in pH observed was due to interference with carbonic anhydrase activity, as it has been determined that this is not influenced by FluosolDA (20%). It was hypothesized that the increased Peo 2 observed in the perfluorochemical emulsion-exchanged fetuses might be due to an excess of bicarbonate in the annex solution, which contains 0.21 gm/dl of sodium bicarbonate. However, it has been shown that bicarbonate is a necessary component of erythrocyte substitute preparations; in its absence, the pH decreases and the carbon dioxide increases to an extent dependent on the quantity of hemoglobin remaining in the circulation. 14 Cefalo et aJ.3 showed that fetal pH and Peo2 did not
change during maternal exchange transfusion with Fluosol-DA (20%) in intubated ewes breathing 100% oxygen in a carbon dioxide-absorbing system, which suggests that perfluorochemicals on the maternal side of the placenta represent no barrier to carbon dioxide diffusion. In the current study, however, it is apparent that at least part of the observed fetal hypercapnia and acidosis in groups III and IV was related to the significant maternal hypercapnia that was observed, in spite of high oxygen flow rates through the rebreathing bags. The mean maternal arterial and uterine vein Peo 2 values were 32.9 and 34.0 torr, respectively, in the ewes which breathed room air and 45.9 and 48.6 torr, respectively, in the ewes using rebreathing bags. The ewes in groups III and IV, therefore, spent the study period in a state of partially compensated respiratory acidosis caused by their rebreathing significant amounts of their expired carbon dioxide, and this was obviously reflected in their fetuses. Other possibilities considered in attempts to explain the fetal respiratory acidosis included the occasional uterine contractions commonly observed in such acute preparations, as well as the fact that we simply may have been witnessing and documenting deteriorating preparations. Since the total oxygen content of the fetal lambs was observed to be decreasing during the study, a portion of the decrease in pH may have been due to an uncompensated metabolic acidosis caused by anaerobic metabolism by the fetus and accumulation of lactate. In summary, under the conditions of our study, the efficacy ofFluosol-DA (20%) as a volume expander during an isovolemic exchange transfusion in the fetal lamb in utero was demonstrated, since fetal blood pressure was maintained despite an almost 50% acute drop in fetal hematocrit. In the presence of maternal hyperoxygenation, fetal lambs so exchanged were able to maintain a physiologic Po., although the total fetal oxygen content decreased as the hematocrit dropped. Because of the oxygen-carrying properties of the perfluorochemical emulsion, the fraction of fetal oxygen carried in the dissolved state increased significantly compared to saline solution-exchanged controls. REFERENCES I. Tremper KK, Lapin R, Levine E, Friedman A, Shoemaker we. Hemodynamic and oxygen transport effects of a perfluorochemical blood substitute, Fluosol-DA(20%). Crit Care Med 1980;8:738. 2. Tremper KK, Friedman AE, Levine EM, Lapin R, Camarillo D. The preoperative treatment of severely anemic patients with a perfluorochemical oxygen transport fluid, Fluosol-DA(20%). N Engl j Med 1982;307:277. 3. Cefalo RC, Seeds JW, Proctor Hj, Baker VV. Maternal and fetal effects of exchange transfusion with a red blood cell substitute. AM] OBSTET GYNECOL 1984;148:859. 4. Rosen AL, Sehgal LR, Gould SA, et al. Fluorocarbon emulsions: methodology to assess efficacy. Crit Care Med 1982;10:149.
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5. Huggett ASG. Fetal blood gas tension and gas transfusion through the placenta of a goat.] Physiol. (Lond) 1927; 52:373. 6. Meschia G. Evolution of thinking in fetal respiratory physiology. AM] OBSTET GYNECOL 1978;132:806. 7. Battaglia FC, Bowes WA, McGaughey HR, Makowski EL, Meschia G. The effect of fetal exchange transfusions with adult blood upon fetal oxygenation. Pediatr Res 1969; 3:60. 8. Assali NS, Kirschbaum TH, Dilts PV. Effects of hyperbaric oxygen on utero placental and fetal circulation. Circ Res 1968;22:573. 9. Meschia G. Supply of oxygen to fetus. ] Reprod Med 1979;23: 160. 10. Meschia G, Battaglia Fe. Acute changes of oxygen pressure and the regulation of uterine blood flow. In: Barcroft Symposium. Fetal and neonatal physiology, New York: Cambridge University Press, 1973. 11. Barcroft]. Researches on prenatal life. Oxford: Blackwell Scientific, 1946:286.
March, 1986 Am J Obstet Gynecol
12. Longo LD, Papadapoulos MD, Forster RH. Placental CO2 transfer after fetal carbonic anhydrase inhibition. Am ] Physiol 1974;226:703. 13. Power GG, Hill EP, Longo LD. A mathematical model of CO 2 transfer in the placenta. In: Longo LD, Bartels H, eds. Respiratory gas exchange and blood flow in the placenta. Bethesda, Maryland: Department of Health, Education, and Welfare, 1972; DHEW publication no. 73361:395. 14. Geyer RP. The design of artificial blood substitutes. In: Ariens E], ed. Drug design. London: Academic Press, 1976. 15. Sekita M. Blood gas transport of fluorocarbon emulsion and its effect on the metabolism in peripheral tissue. ]pn ] Surg 1973;3:184. 16. Ohyanagi HT, Itoh T, Sekita M, Okamoto M, Mitsuno T. Kinetic studies of O 2 and CO 2 transport into or from PFC particles. Tokyo: International Congress on Artificial Organs, first annual meeting, 1977.
Oxygen consumption in fetal lambs after maternal administration of sodium pentobarbital D. W. Rurak, D.Phil., and S. M. Taylor, A.H.T. Vancouver, British Columbia, Canada To determine whether anesthesia lowers fetal oxygen consumption, sodium pentobarbital (10 mg/kg) was given intravenously to seven chronically instrumented pregnant ewes (123 to 144 days' gestation). Oxygen consumption fell by 23% in association with a rise in fetal vascular Po2 • Fetal breathing movements were abolished for 50.5 minutes, while the number of fetal heart rate accelerations fell by 80% in the first 30 minutes after pentobarbital injection. It is concluded that anesthesia reduces fetal oxygen consumption, probably by abolishing skeletal muscle activity, and perhaps also by reducing cerebral metabolic rate. (AM J OSSTET GYNECOL 1986;154:674-8.)
Key words: Fetal lamb, oxygen consumption, anesthesia Although there have been many reports on various effects of anesthetic agents in the fetal and neonatal periods, I there is a lack of information on the effects of general anesthetic agents on fetal oxygen uptake. Since such agents generally readily cross the placenta, they cause anesthesia in the fetus. This might be expected to reduce fetal oxygen consumption by abolishing fetal body movements and breathing activity;' 3 and perhaps by reducing cerebral metabolism.· Alternatively fetal oxygen transfer could be reduced by perFrom the Department of Obstetrics and Gynaecology, Centre for Developmental Medicine, Faculty of Medicine, University of British Columbia. This work was supported by funds from the Medical Research Council of Canada. Received for publication August 19, 1985; revised October 18, 1985; accepted November 5, 1985. Reprint requests: Dr. D. W. Rurak, The Research Center, 950 West 28th Ave., Vancouver, British Columbia, Canada V5Z 4H4.
674
turbations in uterine blood flow. I To address this question, oxygen consumption, blood gas tensions, and pH were measured in chronically catheterized lambs before and after the intravenous administration of sodium pentobarbital to the ewe.
Methods Preparation of animals. Experiments were performed on seven pregnant sheep. At 116 to 131 days' gestation, surgery was performed under halothane anesthesia, following induction with Pentothal. The uterus was exposed through a midline abdominal incision, and after opening the uterus, silicone rubber catheters were placed in a fetal femoral artery, lateral tarsal vein, the common umbilical vein, trachea, and amniotic cavity. In one fetus an electromagnetic blood flow transducer (C & C Instruments, Culver City, California) was placed on the common umbilical artery.'