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Circulatory shock in pregnant sheep
Circulatory shock in pregnant sheep 1. Effects umbilical
of endotoxin circulation
on uteroplacental
P.
BECH-JANSEN,
C.
R.
BRINKMAN
III,
G.
H.
JOHNSON,
M.D.**
N.
S.
ASSALI,
Los Angeles,
and fetal
M.D.* M.D.
M.D.
California
The response of the uteroplacental and fetal circulations and oxygen transfer to injection of E. coli endotoxininto the pregnant sheep was investigated. Endotoxin injection into the mother wnf comprised of three distinct phases: First came a precipitous fall in arterial pressureand uteroplacental blood flow with an increase in uteroplacental vascular resistance. This phase was followed by a progressive recovery period during which flow, pressure, and resistance returned to control values. A third phase occurred during which arterial pressure and uteroplacental blood flow decreased until death of the animal. Despite the marked changes in uteroplacental hemodynamics and a decrease in uteroplacental oxygen transfer, the fetal circulation did not show any major alteration until the terminal phase of shock, when arterial pressure and umbilical flow decreased. There was a fall in fetal oxygen content difference.
N u M ERo u s studies have been carried out on the hemodynamic and metabolic alterations produced by endotoxin shock in the nonpregnant animal.lm6Not much attention, however, has been given to the effects of endotoxin shock in the pregnant animal, particularly with reference to the alterations in the uteroplacental and fetal circulation.
Since bacteremic shock is relatively frequent in obstetrics, we thought it of importance to investigate the responseof the uteroplacental, fetal, and neonatal circulation to experimentally induced endotoxin shock. The experimental animal chosen for this project was the sheep, mainly becauseof the wealth of information available on the circulatory and metabolic functions in the pregnant ewe, the fetus, and the neonate in this animal species.6’7 The present report deals with data on the responseof the uteroplacental and fetal circulation, uteroplacental oxygen transfer, and fetal oxygen consumption to injection of E. coli endotoxin into the mother. The report to follow will deal with the fetal and neonatal responses when endotoxin is introduced directly into the fetal and neonatal circulation.
From the Department of Obstetrics and Gynecology and the Department of Physiology, University of California Los Angeles Medical School. These studies were from The National
supported Institutes
by grants of Health.
f;;;ived
for
publication
December
3,
f;;;pted
for publication
December
16,
Reprint requests: Dr. C. R. Brinkman III, Dept. of Ob./Gyn., UCLA, Los Angeles, California 90024. *Present address: Bispebjerg Hospital, Copenhagen, Denmark. **Present address: Department of Obstetrics and Gynecology, University Utah, Salt Lake City, Utah.
Material
and
methods
Experiments were carried out on 12 nearterm pregnant ewes of mixed breed, ranging
of 1084
Circulatory shock in pregnant sheep. I 1085
Volume 112 Number 8
in weight from 46 to 75 kilograms, and their fetuses who ranged in weight from 2.5 to 4.6 kilograms. With the use of local anesthesia, one carotid artery and one jugular vein were cannulated. The carotid cannula served to monitor arterial pressure and to collect arterial blood samples anaerobically. Through the venous catheter, sodium pentobarbital was given in an initial dose of 10 mg. per kilogram, supplemented by intermittent doses as needed. A tracheostomy was performed, and the ewe’s respirations were assisted with a Bird respirator, with either compressed air or 95 per cent O,, both with 5 per cent CO, added. Through bilateral inguinal incisions, the main left and right uterine arteries were exposed; the adventitia of a segment of the artery was infiltrated with a mixture of hexylcaine* and phenoxybenzaminet to prevent spasm. Each artery was then fitted with a balanced-field electromagnetic flow transducer. An indwelling catheter was placed into a major uterine vein tributary and served for anaerobic collection of uterine vein blood samples. The pregnant uterine horn was then exposed through a midline incision and was marsupialized to the abdominal wall to prevent evisceration. The fetus was delivered and marsupialized to the edges of the uterine walls to protect the umbilical circulation. The head was covered with a saline-filled glove to prevent breathing. An indwelling catheter was placed into an intercotyledonary branch of the umbilical vein and served for anaerobic collection of umbilical vein blood samples and umbilical vein pressure recording. The fetal left femoral artery and vein were cannulated; the femoral arterial catheter served for collections of blood samples and for monitoring the fetal arterial pressure. The venous catheter served for replacing blood collected for blood gases with like volumes of maternal blood withdrawn prior “Cyclaine, vania. tDibenzyline, Permsylvania.
Merck, Smith,
Sharp Kline
& Dohme, & French
West Labs.,
Point,
Pennsyl-
Philadelphia,
to the administration of endotoxin. The main umbilical vein was exposed in the fetal abdomen and was fitted with an electromagnetic flow transducer to measure fetal umbilical blood flow. Technical details of these procedures have been published elsewhere.“, lo The experimental protocol comprised a control period lasting about 30 to 60 minutes during which phasic and mean (electronic integrated) pressures and flows were continuously monitored. Maternal and fetal blood respiratory gases and pH were analyzed two to three times. The control period was followed by the intravenous injection of endotoxin (Difco lipopolysaccharide) , (1.2 to 0.5 mg. per kilogram of ewe’s weight. Maternal and fetal blood pressures and uterine and umbilical blood flows were monitored continuously; blood respiratory gases and PH were analyzed at frequent intervals. Observations on the effects of endotoxin continued for 1 to 2 hours after the injection or until the death of the animal. Maternal and fetal arterial and venous blood samples were collected anaerobically in 2 C.C. syringes in which the dead space was filled with heparin. Blood POT, PC+> pH, hemoglobin, per cent of saturation, and 0: content were each analyzed independently by standard techniques.‘l Pressures were measured with Statham P-23 strain gauges calibrated to a common zero base line, and blood flows were measured with the balanced-field type of electromagnetic flowmeter.8 Uterine vascular resistance (UVK) was calculated from the ratio of pressure and flow (the uterine vein pressure was assumed to be very close to zero and, therefore, negtigible) ; umbilicoplacental vascular resistance (PVR) was calculated from the formula: arterial pressure minus umbilical vein pressure divided by umbilical vein Aow ; uteroplacental oxygen transfer (UiQ) was calculated from the product of the total uterine blood flow and the arteriovenous oxygen content *difference. Fetal oxygen consumption (FVO,) was calcuIated from the product of the umbilical vein blood flow and the
1086
Beth-Jansen
April Am. J. Ohstrt.
et a(.
15, 1972 Gynerol.
Table I. Data on maternal and fetal arterial and umbilical vein pressures (MAP, FAP, UVP) , resistances (UVR and PVR), uteroplacental 0, transfer (UVO,), and fetal 0, consumption
I
Maternal
data 1JVR
Period Control
MAP (mm. ff.d 127 + 5
Minutes after intravenous endotoxin 1 902 8 ‘)3 153 107 +t 17 12 4 5 10 20 30 40
166 -+ 150+ 111 t 107k 98 + 86 k
11 8 7 9 10 10
&JA (ml./min.) 965 k 166
(S) 0.16 2 0.03
lJt0, (mUmin.) 30.6 + 6.3
535 + 167 +_ 141 370 431 zi 158
0.27 t 0.07 1.26 1.15 2+ 0.74 0.58
10.2 +- 6.5
478 485 607 61.5 459 378
0.67 0.45 0.23 0.22 0.28 0.28
arteriovenous oxygen content difference (umbilical vein-umbilical artery) . Details of these calculations have been published elsewhere.6pI1 Results Effects of the experimental procedure on the animals. The effects of the preparatory operation and anesthesia were no different than those previously reported.6, lo* l2 A transient decreasein arterial pressure and blood flows was noted with each supplemental dose of sodium pentobarbital. Control maternal and fetal blood respiratory gases,pressures and flows were within the range of values previously reported.6l 9 Chaqes in uteroplacental hemodynamics and oxygen transfer. Of the first 10 animals studied, 3 died within 15 to 20 minutes after endotoxin injection. The remaining 7 animals were killed at the end of the experimental period (about 2 hours after the injection of endotoxin). The results in these two groups of animals are presented separately. In Table I are presented the data on the effects of endotoxin administration on mother and fetus in the group of 7 animals that survived for 2 hours. Fig. 1 illustrates the pattern of the mean changes in this group of animals. The maternal responseto endotoxin com-
2 + + t ++
120 97 105 121 114 108
2 2 + + t +
0.29 0.12 0.03 0.04 0.06 0.06
21.6 + 6.4 19.9 2 6.9 18.0 !I 5.0
prised three distinct phases (Fig. 1, Table I). The first phase occurred 1 to 3 minutes after endotoxin injection and was characterized by a precipitous fall in mean arterial blood pressureand uteroplacental blood flow. The flow decreased considerably more than the pressure. Therefore, during this phase which lasted about 2 minutes, the uterine vascular resistance rose strikingly. The peak increase in vascular resistance averaged about 700 per cent over control values (Fig. 1, Table I). Uteroplacental oxygen transfer during this period decreased to about one third of the control values; the decreasewas related to the marked fall in uterine blood flow (Fig. 1, Table I). The arteriovenous oxygen content difference increased but the increment was not enough to compensate for the marked decreasein blood flow. The second phase, which followed immediately, was characterized by a progressive recovery in arterial pressure and uterine blood flow. The degree of recovery was variable from one animal to another; but, in general, the mean arterial pressure rose to levels above control values (Fig. 1, Table I). Uterine blood flow also increased, but the increment was lessthan that of the arterial pressure with the uterine flow never retuming to control levels. Uterine vascular resistance tended to return toward control values. Although uterine oxygen transfer was more
ute$ne (FVO,)
Volume
112
Number
8
and umbilical in 7 animals
Circulatory
blood flows that survived
(QUA and GUV), for 2 hours (figures
shock in pregnant
uterine placental and are means + 1 SE.)
sheep. I
umbilical
FAP (mm. Hg) fj:! -L 2 6:1 63 62 64 64 62
51 i: + + 2 t 60 -t 60 * 61 t
2 2 2 2 I! 2 ” 3 4
UVP (mm. Hg)
___
cjvv
4
258
+ 37
0.20
+ 0.03
19 19 “0 21 20 la 16 13 12
4 4 4 5 5 4 4 5 4
259 244 248 245 244 226 225 224 231
? t + + + k + +_ +
0.20 0.20 0.20 021 0.22 0.20 0.24 0.24 0.28
+ 5 2 + + t i: It +
than double the values observed during the first phase of shock, it remained below control levels. This second phase of shock lasted about 10 minutes (Fig. 1, Table I). The third phase of endotoxin shock was characterized by a progressive and equivalent decline in both the arterial pressure and uteroplacental blood flow; uterine vascular resistance remained close to control values, while uteroplacental oxygen transfer remained below control values. This phase lasted for about 2 hours, at the end of which the animal’s condition had deteriorated, requiring termination of the experiment (Fig. 1, Table I). In Table IV are presented the data on the effects of endotoxin on mother and fetus in the group of 3 animals that died within 15 to 20 minutes after endotoxin injection. Fig. 2 illustrates a representative example of this group. The pattern of response to endotoxin injection in this group was qualitatively similar to that of the group already discussed. However, the degree of blood pressure fall in this group was more pronounced during Phase 1. The uteroplacental blood flow also decreased, and uterine vascular resistance increased (Fig. 2, Table IV). The duration of the recovery period (Phase 2) in these animals was considerably shorter than the previous group, and both the arterial pressure and uterine flow never showed
-_ .- -
FVO, (ml./min.)
(mUmin.)
19 t
t 2 + 5 + f +_ f ?
vascular ---...-
Fetal data
_I__--
1087
35 27 32 31 31 22 33 34 49
0.03 0.03 0.03 0.05 0.04 0.03 0.06 0.02 0.05
6.’
f 0.5
4.6 t
1.1
6.1 + 0.8
3.4 i
1.6
a significant recovery from the low values reached in the first phase. Following this short recovery period (about 2 minutes), the pressure and Aow rapidly deteriorated, and within 20 minutes the animals were dead. Uteroplacental oxygen transfer fell strikingly during the shock period. During endotoxin shock, the maternal arterial hemoglobin concentration progressively increased from a control value of I 1 .I Gm. per 100 ml. to 13.6 Gm. 40 minutes after the administration of endotoxin (Table II). The increase at 40 minutes was statistically significant, while those at 2 and 10 minutes were of borderline significance. The fetal arterial and umbilical vein hemoglobin concentrations remained stable throughout the entire duration of the experiment.
Maternal responseto endotoxin in animals primed with phenoxybenzamine. In order to assess the degree of adrenergic stimulation produced by endotoxin shock, the following experimental protocol was used in two experiments (Table III). After a control period similar to that described under Methods, the ewe was given an intravenous injection of 0.5 mg. per kilogram of phenoxybenzamine. The effectiveness of the adrenergic blockade was tested by administering 0.5 pg per kilogram of norepinephrine, which did not alter the flow and pressure appreciably (this dose produces
1088
Beth-Jansen
April Am. J. Obstet.
et al.
ENDOTOXIN
15, 1972 Gynecol.
i.v.
MAP mm Hg
bUA ml/mln
UVR mm ml/min
FAP mm Hg UMB VP mm Hg ~k?n~n”
260 220
PVR
t -30.
I -25
x)-z5
I -20
I -15
1 -10
1 -5 TIME
111110 5 IN MINUTES
15-5
2-5 TIME
1 IO
5-15
I 15
. 20
15-20
I 25
I 30
I 35
I 40
309
IN MINUTES
Fig. 1. Effects of endotoxin injected into the ewe on maternal arterial pressure (MAP), total uterine blood flow (QUA), uterine vascular resistance (UVR), fetal arterial pressure (FAP), umbilical vein pressure (Umb VP), total umbilical blood flow ((iUmbV), and umbilicoplacental vascular resistance (PVR). Figures represent mean of 7 animals (see text). Note the marked .fall in maternal pressure and uteroplacental blood flow and the striking increase in uterine vascular resistance after endotoxin injection, Arterial pressure rebounded to higher than control values and uterine flow recovered somewhat thereafter. Note the stability of the fetal circulation during the various phases of maternal shock. Note also the decrease in uteroplacental oxygen transfer (l&O,) and fetal oxygen consumption (FVO,) after endotoxin injection. a marked increased uterine vascular resistance in normal animaF2). When no response to norepinephrine was observed, endotoxin was injected into the maternal jugular vein. Table III shows that the maternal arterial pressure and flow fell somewhat after phenoxybenzamine; this is consistent with the ef-
fects of adrenergic blockade. During endotoxin shock, both pressure and flow fell simultaneously; the fall in pressure was close to the critical closing pressure previously observed for the uteroplacental circulation.12 The blood flow fell and the uterine vascular resistance increased (Table III). Such an increase was, however, considerably less than
Volume Number
112 8
Circulatory
shock
in pregnant
EWE FETUS
sheep.
I
1089
w!. 65kg wt. 2.98 kg
EXPERIMENT
# 8
400 bUA ml/min
200 o-
FAP mmHg Bi: UMB
VPmmHg
Iq----4w----*
IO] 8-
UoOz
ml/minm
6-
F002
mUmin%
420-a\ , -20 -15 -CONTROL------I
I -10
-5
1 0
I
TIME
I 5
I IO
I 15
1 20
IN MINUTES
Fig. 2. Illustrative example of an experiment in which the ewe died about 20 minutes after endotoxin injection. Note the rapid deterioration in maternal and fetal circulatory parameters and oxygen transfer. (For explanation of symbols, see legend for Fig. 1.)
that observed in animals with intact adrenergic system.This increase in uterine vascular resistance at such a low pressure is most likely related to collapse of the vesselsat the critical closing pressure. The recovery period in the animals with adrenergic blockade was shorter and the deterioration was more rapid than in the animals not receiving an adrenergic-blocking agent. Changes in fetal hemodynamics and oxy-
gen
consumption. Despite the marked changes in uteroplacental hemodynamics and oxygen transfers during the three phases of shock, the fetal circulation did not reflect any major
aIteration
except
in the terminal
phase of shock. In the animals included in the first group, fetal arterial and umbilical vein pressures, umbilical vein flow, and umbilicoplacental vascular resistance remained stable and at control levels throughout the first and second
1090
Beth-Jansen
Apd Am. J. Ohstet.
et al.
Table II. Maternal and fetal hemoglobin shock (figures are mean -I 1 SE.)
concentration
during control and endotoxin
Minutes Control
15, 192 Gynrcol.
after
intravenous
2
endotoxin
10
40
Maternal arterial (Gm./lOO ml.)
11.1
+ 0.3
11.5
2 0.3*
12.4
F 0.6”
13.6
+ 0.4t
FetaI arterial (Gm./lOO
ml.)
14.4
+ 0.7
14.8
2 0.7
14.0
f
0.7
13.8
+ 06
vein ml.)
14.7
+_ 0.6
i5.0
? 0.7
14.3
t 0.7
14.4
rt 0.8
Umbilical (Gm./lOO “P < 0.05
> 0.02.
tP < 0.m.
phase of shock; fetal heart rate decreased slightly in some animals while in others it did not change. These various circulatory functions began to change only at the end of the third phase of shock when the mother’s condition was deteriorating (Fig. 1, Table I); during this phase, heart rate, arterial pressure, and umbilical flow decreased. Fetal oxygen consumption fell initially but recovered during the second phase of shock; it fell again during the third phase. Since the umbilical blood flow did not change during the first phase of shock, the decrease in fetal oxygen consumption was related to a fall in the arteriovenous oxygen content difference; the fall during the third phase was caused by a decrease in both flow arteriovenous 0, and content difference. The fetuses included in the second group showed a more pronounced response particularly as the animal deteriorated rapidly. Hypotension, bradycardia, and decreased umbilical flow were more severe than in the first group (Table IV), Changes in maternal and fetal blood respiratory gases and PH. Table V shows the values on maternal and fetal blood PO, Pco~, and pH in both groups of animals. The values for the control periods for both mother and fetus (Group 1) lie within the ranges previously found in this laboratory.Q* lo The large standard error in the maternal PO, values is due to the fact that some animals required lung ventilation with 95 per cent 0, to counteract effects of decreased ventilation due to atelectasis.
In Group 1, a slight decrease in maternal arterial PO, and increase in Pcoz occurred during endotoxin shock; maternal blood pH did not change significantly. The administration of 95 per cent 0, to some ewes might have prevented a greater decrease in maternal blood PO, and pH. Fetal blood PO,, however, decreased significantly during endotoxin shock regardless of whether one looks at the umbilical vein or the femoral artery blood. Fetal blood Pco, increased and fetal blood pH decreased in this group of animals (Table V). In Group 2, despite the severity of the circulatory shock which led to a rapid death of the mother, the maternal Paz, Pcoz, and pH were not significantly different from those of Group 1, both in the control and shock periods. Here again, lung ventilation with 100 per cent 0, probably prevented changes in the maternal blood respiratory gases and pH. On the other hand, control values for fetal blood Paz and pH (in both the umbihcal vein and artery) were lower than those of the other group; both parameters fell profoundly during the endotoxin shock (Table III). Control Pcoz was higher than the other group and increased further during shock (Table V) . Comment
Maternal hemodynamics. The classical pattern of hemodynamic response to acute injection of E. coli endotoxin, as observed in the dog, consists of the following three phases1-5 : an acute hypotensive phase, dur-
Volume 1I:! Number 8
Circulatory
Table III. Effects of endotoxin by phenoxybenzamine++ -.---
in a sheep whose adrenergic
shock in pregnant
sheep. I
1091
system had been blocked
-.-UV’K
Time Control After intravenous benzamine Minutes after intravenous
&JAt
MAP (mm. W
(mUmin.)
108
257
0.37
88
166
0.40
114 108 50 48 54 72 65
221 ‘1’11 -33 13 26 14 39
0.46 0.43 1.06 2.08 1.23 0.89 I.31
phenozy0.3 mg./Kg. endotoxin
of
1 ‘) 3 4 5 1.5 2.5 ‘For explanation of abbreviations, +One uterine artery.
see caption for Table
.-.__
I.
ing which cardiac output and regional blood flows fall and systemic and regional resistances increase ; a recovery phase during which pressure and flows recover and vascular resistances return toward normal values. During this phase, the renin-angiotensin-aldosterone system is activated and the secretion of these hormones is increased.13 A deteriorating phase follows during which flows and pressure fall gradually, the vascular resistances are within the normal range, and the activities of the renin-angiotensin-aldosterone system returns to normal ending with the death of the animal.13 The mechanisms by which these three phases are produced are hotly debated. Some authors believe that in the dog at least the adrenergic system is overstimulated by the shock state; others believe that the stimulation of this system is transitory and occurs only in the initial phase of shock when the vascular resistances increase. In the nonpregnant sheep, the few studies that have been made indicate that pulmonary hypertension is the prominent feature in the response to endotoxin shock.l4 But variable degrees of hypotension and a decrease in the cardiac output were also observed. These studies noted that some animals collapsed and died rapidly while others survived longer when given 0.3 mg. per kilogram of endotoxin.14
The present data obtained from pregnant sheep show that qualitatively the maternal circulatory response to endotoxin is not a great deal different from that observed in the dog or in the nonpregnant sheep. The initial hypotensive phase was definitely accompanied by an over stimulation of the adrenergic system. Since the increase in uterine vascular resistance characteristic of this phase was blocked by phenoxybenzamine, this overstimulation was responsible for the greater decrease in uterine blood flow than arterial pressure and for the striking increase in uterine vascular resistance. Previous studie3”* I5 have shown that active uterine vasoconstriction in the normal sheep can only be induced by adrenergic stimulation. Under any other circumstances, including shock produced by autonomic blockade with spinal anesthesia, the flow depends on the perfusion pressure.12~ I6 We believe that the adrenergic overstimulation was responsible for the “overshoot” which returned the pressure and flows to near control values during the second phase of shock. Whether the renin-angiotensin-aldosterone system played any role in this phase, as it does in the dog, cannot be stated from these studies. We do not have an explanation for the mechanisms of the third and terminal phase. Neither do we have a precise explanation
1092
Beth-Jansen
April 15, 1972 Am. J. Obstet. Gynerol.
et al.
Table IV. Data on the 3 animals that died 15 to 20 minutes after endotoxin injection* Maternal
data UVR
&JA Period Control
107 +
Minutes
after
intravenous
explanation
UtiO, ml./min.
cz3
6
539
t
39
0.21
t 0.01
425 54 2 54 + 52 It 48 ?r 34 +
9 21 21 22 18 16
163 188 174 173 163 150
f 2 t t ?I +
35 114 122 115 111 94
0.29 0.40 0.50 0.43 0.46 0.32
+ 0.09 t 0.11 + 0.13 2 0.09 + 0.12 +- 0.10
and
units,
of Table
I.
14.2
?: 1.5
endotonin
1 2 3 4 5 10 ‘For
(mUmin.)
MAP
of abbreviations
see caption
2.5 + 0.2
Table V. Maternal and fetal blood gasesand pH* Fetal
Maternal
arterial blood Group Groug
Control
(
Umbilical
Shock
Control
vein 1
blood Shock
Femoral Control
artery (
blood Shock
I
PO? (mm. Hg) Pco* (mm. Hg) PH
126 A- 16 24 + 1 7.48 + 0.02
92 + 18 29 It 3 7.40 + 0.02
34 ? 2 27 ” 2 7.41 2 0.02
22 1 3 39 -c 7 7.31 t 0.03
23 2 1 28 5 1 7.38 2 0.02
19 + 2 40 + 6 7.30 + 0.03
Group 2 PO? (mm. Hg) Pco3 (mm. Hg) PH
98 ” 39 31 + 4 7.40 k 0.06
104 + 45 31 + 9 7.39 51 10
23 + 2 41 t 5 7.30 -+ 0.07
951 70 + 9 7.15 ?: 0.03
16 2 2 44 5 5 7.28 5 0.07
851 68 t 10 7.12 + 0.07
*Group I is comprised of the 7 sheep that survived for 2 hours. Group 2 is comprised of the 3 sheep that died 15 to 20 minutes. AI1 values are presented as means + 1 SE. Control values represent the average of all determinations to endotoxin injection. Shock values in Group 1 represent the average values observed 30 to 60 minutes after endotoxin; in Group 2, average values 5 minutes after injection.
why some animals died within 15 to 20 minutes, while others lived longer. The maternal blood respiratory gases and pH of both groups were within the normal range, while in the fetus the Paz and pH were lower in Group 2. An underlying circulatory dysfunction in the second group of animals is possible in view of their lower arterial pressure and uterine blood flow during the control period. At any rate, in the dog, the third and terminal phase of endotoxin shock has been attributed by some to the development of hypoxia and metabolic acidosis.ll2r5 But in the present seriesof experiments, maternal hypoxia and acidosis did not occur, even in the animals that died rapidly, probably because of supported lung ventilation with oxygen-enriched mixtures. Yet, despite the normal blood oxygenation and acid-basepic-
within prior and,
ture, the circulatory deterioration occurred invariably which led to the death of the animal. These findings strongly indicate that the use of the blood respiratory gasesand pH may be misleading in assessingthe severity of endotoxin shock. Uteroplacental oxygen transfer. The present data show clearly that, despite maintenance of normal blood oxygenation in the mother, uteroplacental oxygen transfer decreased markedly during endotoxin shock. The decrease was roughly proportional to the decreasein uterine blood flow. Although the hemoglobin concentration of maternal blood increased progressively, causing an increase in the arteriovenous oxygen content difference, the increment was not sufficient to compensate for the marked decrease in uterine blood flow. These data favor the
Vohlme II2 Numher8
Circulatory
Fetal
shock in pregnant
sheep. I
1093
data PVR
FAP (mm. Hd 64%
UVP (mm. Hg) 2
64+ 6 622 6 60+ 8 575 8 58 + 10 41% - 7
&JV
FtiOz (mUmin.)
(mUmin.)
(Z>
15 2 1
188 + 18
0.34
5 0.04
12 14 14 15 16 11
176 178 144 130 113 61
0.35 0.32 0.48 0.42 0.46 0.95
+ t + t 2 t
t t t 2 2 ?r
4 5 6 6 7 4
f + k 2 + +
hypothesis advanced by various authors that the transfer of oxygen between mother and fetus is flow dependent.17,I8 Fetal circulation and oxygen consumption. The behavior of the fetal circulation, when the mother was in a state of endotoxin shock, is remarkable. Despite the profound changes in the uteroplacental circulation and oxygen transfer, the fetal vascular pressuresand umbilical blood flow remain stable. The only exception was a slight and transitory bradycardia which occurred in some animals. These circulatory parameters only began to fall in the terminal stage of maternal shock. The transitory fall in fetal oxygen consumption in the early phase of shock was IargeIy related to the sharp fall in ~rteroplacental oxygen transfer and the decreasein fetal blood PO,. Such a stability of fetal circulatory dynamics in the presence of maternal shock has been reported from this laboratory in relation to spinal shock and to maternal hypotension caused by hydralazine.lel I9 It shows that the fetal circulation can tolerate marked changes in the maternal circulation without any ill effects. True, the state of maternal shock decreased the delivery of oxygen to the fetus and this led to the fall in fetal blood PO,. The decrease in fetal blood pH could be
41 40 42 32 29 26
0.13 0.12 0.27 0.21 0.19 0.59
3.8 t
1.2
1.1 + 0.8 ---
related to : (1) the decrease in fetal blood oxygenation and the increase in Pco~, or (2) the impairment of excretion of acids through the altered placental circulation. At any rate, despite the marked fall in fetal blood PO? and the frank acidosis, the fetal circulatory dynamics was not affected. This fact showsclearly the lack of any correlation between the status of fetal circulation and the level of blood PO, and pH. It further points out the difficulties in interpreting blood pH changesand their relation to fetal distress. It is not possibleto state from the present set of experiments whether endotoxin crossed the placenta from the maternal to the fetal side. The absence of hemodynamic alterations in the fetus during maternal shock does not rule out placental transfer of endotoxin. Studies in this laboratory (see following report) show that the fetus tolerates several times the dose of endotoxin given to the mother per kilogram of the body weight before showing any cardiovascular response. Similar tolerance of the fetal lamb to vasoactive stimuli has been observed previously.6lI9 The reasonsfor this tolerance are currently being investigated. We would assistance and Della
like of Dave Fuller.
to acknowledge the technical Huntsman, Helena Martinek,
REFERENCES
1. 2.
Morris, S.: AN. Gilbert,
J. A., Smith, R. W., and Assali, N. J. OBSTET. GYNECOL. 91: 491, 1965. R.: Physiol. Review 40: 245, 1959.
3.
Fine, J.: Hamilton, W., editor: Handbook of Physiology, Washington, D. C., 1965, American Physiological Society, p. 2073.
1094
4.
Beth-Jansen
April 15, 1972 Am. J. Obstet. Cynecol.
et al.
Hershey, S. G., editor: Shock, Boston, 1964, Little, Brown & Company. M., and Braun, W., editors: Bac5. Landy, terial Endotoxins, New Brunswick, New Jersey, 1964, Rutgers University Institute of Microbiology Press. N. S., editor: Biology of Gestation, 6. Assali, New York, 1968, ~01s. 1 and 2, Academic Press, Inc. 7. Dawes, G.: Fetal and Neonatal Circulation, Chicago, 1968, Year Book Medical Publishers, Inc. 8. Westersten, A., Rice, E., Brinkman, C. R., III, and Assali, N. S.: J. Appl. Fhysiol. 28: 497, 1969. 9. Johnson, G. H., Kirschbaum, T. H., Brinkman. Cl. R.. III. and Assali. N. S.: Am. 1. Physiol. 226 1748, 1971, ’ 10. Brinkman, C. R., III, Weston, P. V., Kirschbaum, T. H., and Assali, N. S.: AM. J. OBSET. GYNECOL. 108: 288, 1970. 11. Kirschbaum, T. H., Brinkman, C. R., III, and Assali, N. S.: AMER. J. OBSTET. GYNECOL. 110: 190, 1971.
12.
13. 14. 15. 16. 17.
18.
19.
20.
Ladner, C., Brinkman, C. R., III, Weston, P. V., and Assali, N. S.: Am. J. Physiol. 218: 257, 1970. White, F. N., Gold, E. M., and Vaughn, D. L.: Am. J. Physiol. 212: 1195, 1967. Halmagyi, D. F. J., Starzecki, B., and Horner, G. J.: J. Appl. Physiol. 18: 544, 1963. Greiss, F., and Gobble, F.: AM. J. OBSTET. GYNECOL. 97: 962, 1967. Lucas, W. E., Kirschbaum, T. H., and Assali, N. S.: Biol. Neonate 10: 166. 1966. Power, G. G., Longo, L. D:, Wagner, H. N., Jr., Kuhl, D. E., and Forster, R. E., III: J. Clin. Invest. 46: 2053, 1967. Meschia, G., Cotter, J. R., Makowski, E. L., and Barron, D. H.: J. Exp. Physiol. 52: 1, 1967. Ladner, C., Weston, P. V., Brinkman, Cl. R., III, and Assali, N. S.: AM. J. OBSTET. GYNECOL. 108: 375, 1970. Dilts, P. V., Jr., Brinkman, Cl. R., III, Kirschbaum, T. H., and Assali, N. S.: AM. J. OBSTET. GYNECOL. 103: 138, 1969.
of endotoxin circulation
on uteroplacental
P.
BECH-JANSEN,
C.
R.
BRINKMAN
III,
G.
H.
JOHNSON,
M.D.**
N.
S.
ASSALI,
Los Angeles,
and fetal
M.D.* M.D.
M.D.
California
The response of the uteroplacental and fetal circulations and oxygen transfer to injection of E. coli endotoxininto the pregnant sheep was investigated. Endotoxin injection into the mother wnf comprised of three distinct phases: First came a precipitous fall in arterial pressureand uteroplacental blood flow with an increase in uteroplacental vascular resistance. This phase was followed by a progressive recovery period during which flow, pressure, and resistance returned to control values. A third phase occurred during which arterial pressure and uteroplacental blood flow decreased until death of the animal. Despite the marked changes in uteroplacental hemodynamics and a decrease in uteroplacental oxygen transfer, the fetal circulation did not show any major alteration until the terminal phase of shock, when arterial pressure and umbilical flow decreased. There was a fall in fetal oxygen content difference.
N u M ERo u s studies have been carried out on the hemodynamic and metabolic alterations produced by endotoxin shock in the nonpregnant animal.lm6Not much attention, however, has been given to the effects of endotoxin shock in the pregnant animal, particularly with reference to the alterations in the uteroplacental and fetal circulation.
Since bacteremic shock is relatively frequent in obstetrics, we thought it of importance to investigate the responseof the uteroplacental, fetal, and neonatal circulation to experimentally induced endotoxin shock. The experimental animal chosen for this project was the sheep, mainly becauseof the wealth of information available on the circulatory and metabolic functions in the pregnant ewe, the fetus, and the neonate in this animal species.6’7 The present report deals with data on the responseof the uteroplacental and fetal circulation, uteroplacental oxygen transfer, and fetal oxygen consumption to injection of E. coli endotoxin into the mother. The report to follow will deal with the fetal and neonatal responses when endotoxin is introduced directly into the fetal and neonatal circulation.
From the Department of Obstetrics and Gynecology and the Department of Physiology, University of California Los Angeles Medical School. These studies were from The National
supported Institutes
by grants of Health.
f;;;ived
for
publication
December
3,
f;;;pted
for publication
December
16,
Reprint requests: Dr. C. R. Brinkman III, Dept. of Ob./Gyn., UCLA, Los Angeles, California 90024. *Present address: Bispebjerg Hospital, Copenhagen, Denmark. **Present address: Department of Obstetrics and Gynecology, University Utah, Salt Lake City, Utah.
Material
and
methods
Experiments were carried out on 12 nearterm pregnant ewes of mixed breed, ranging
of 1084
Circulatory shock in pregnant sheep. I 1085
Volume 112 Number 8
in weight from 46 to 75 kilograms, and their fetuses who ranged in weight from 2.5 to 4.6 kilograms. With the use of local anesthesia, one carotid artery and one jugular vein were cannulated. The carotid cannula served to monitor arterial pressure and to collect arterial blood samples anaerobically. Through the venous catheter, sodium pentobarbital was given in an initial dose of 10 mg. per kilogram, supplemented by intermittent doses as needed. A tracheostomy was performed, and the ewe’s respirations were assisted with a Bird respirator, with either compressed air or 95 per cent O,, both with 5 per cent CO, added. Through bilateral inguinal incisions, the main left and right uterine arteries were exposed; the adventitia of a segment of the artery was infiltrated with a mixture of hexylcaine* and phenoxybenzaminet to prevent spasm. Each artery was then fitted with a balanced-field electromagnetic flow transducer. An indwelling catheter was placed into a major uterine vein tributary and served for anaerobic collection of uterine vein blood samples. The pregnant uterine horn was then exposed through a midline incision and was marsupialized to the abdominal wall to prevent evisceration. The fetus was delivered and marsupialized to the edges of the uterine walls to protect the umbilical circulation. The head was covered with a saline-filled glove to prevent breathing. An indwelling catheter was placed into an intercotyledonary branch of the umbilical vein and served for anaerobic collection of umbilical vein blood samples and umbilical vein pressure recording. The fetal left femoral artery and vein were cannulated; the femoral arterial catheter served for collections of blood samples and for monitoring the fetal arterial pressure. The venous catheter served for replacing blood collected for blood gases with like volumes of maternal blood withdrawn prior “Cyclaine, vania. tDibenzyline, Permsylvania.
Merck, Smith,
Sharp Kline
& Dohme, & French
West Labs.,
Point,
Pennsyl-
Philadelphia,
to the administration of endotoxin. The main umbilical vein was exposed in the fetal abdomen and was fitted with an electromagnetic flow transducer to measure fetal umbilical blood flow. Technical details of these procedures have been published elsewhere.“, lo The experimental protocol comprised a control period lasting about 30 to 60 minutes during which phasic and mean (electronic integrated) pressures and flows were continuously monitored. Maternal and fetal blood respiratory gases and pH were analyzed two to three times. The control period was followed by the intravenous injection of endotoxin (Difco lipopolysaccharide) , (1.2 to 0.5 mg. per kilogram of ewe’s weight. Maternal and fetal blood pressures and uterine and umbilical blood flows were monitored continuously; blood respiratory gases and PH were analyzed at frequent intervals. Observations on the effects of endotoxin continued for 1 to 2 hours after the injection or until the death of the animal. Maternal and fetal arterial and venous blood samples were collected anaerobically in 2 C.C. syringes in which the dead space was filled with heparin. Blood POT, PC+> pH, hemoglobin, per cent of saturation, and 0: content were each analyzed independently by standard techniques.‘l Pressures were measured with Statham P-23 strain gauges calibrated to a common zero base line, and blood flows were measured with the balanced-field type of electromagnetic flowmeter.8 Uterine vascular resistance (UVK) was calculated from the ratio of pressure and flow (the uterine vein pressure was assumed to be very close to zero and, therefore, negtigible) ; umbilicoplacental vascular resistance (PVR) was calculated from the formula: arterial pressure minus umbilical vein pressure divided by umbilical vein Aow ; uteroplacental oxygen transfer (UiQ) was calculated from the product of the total uterine blood flow and the arteriovenous oxygen content *difference. Fetal oxygen consumption (FVO,) was calcuIated from the product of the umbilical vein blood flow and the
1086
Beth-Jansen
April Am. J. Ohstrt.
et a(.
15, 1972 Gynerol.
Table I. Data on maternal and fetal arterial and umbilical vein pressures (MAP, FAP, UVP) , resistances (UVR and PVR), uteroplacental 0, transfer (UVO,), and fetal 0, consumption
I
Maternal
data 1JVR
Period Control
MAP (mm. ff.d 127 + 5
Minutes after intravenous endotoxin 1 902 8 ‘)3 153 107 +t 17 12 4 5 10 20 30 40
166 -+ 150+ 111 t 107k 98 + 86 k
11 8 7 9 10 10
&JA (ml./min.) 965 k 166
(S) 0.16 2 0.03
lJt0, (mUmin.) 30.6 + 6.3
535 + 167 +_ 141 370 431 zi 158
0.27 t 0.07 1.26 1.15 2+ 0.74 0.58
10.2 +- 6.5
478 485 607 61.5 459 378
0.67 0.45 0.23 0.22 0.28 0.28
arteriovenous oxygen content difference (umbilical vein-umbilical artery) . Details of these calculations have been published elsewhere.6pI1 Results Effects of the experimental procedure on the animals. The effects of the preparatory operation and anesthesia were no different than those previously reported.6, lo* l2 A transient decreasein arterial pressure and blood flows was noted with each supplemental dose of sodium pentobarbital. Control maternal and fetal blood respiratory gases,pressures and flows were within the range of values previously reported.6l 9 Chaqes in uteroplacental hemodynamics and oxygen transfer. Of the first 10 animals studied, 3 died within 15 to 20 minutes after endotoxin injection. The remaining 7 animals were killed at the end of the experimental period (about 2 hours after the injection of endotoxin). The results in these two groups of animals are presented separately. In Table I are presented the data on the effects of endotoxin administration on mother and fetus in the group of 7 animals that survived for 2 hours. Fig. 1 illustrates the pattern of the mean changes in this group of animals. The maternal responseto endotoxin com-
2 + + t ++
120 97 105 121 114 108
2 2 + + t +
0.29 0.12 0.03 0.04 0.06 0.06
21.6 + 6.4 19.9 2 6.9 18.0 !I 5.0
prised three distinct phases (Fig. 1, Table I). The first phase occurred 1 to 3 minutes after endotoxin injection and was characterized by a precipitous fall in mean arterial blood pressureand uteroplacental blood flow. The flow decreased considerably more than the pressure. Therefore, during this phase which lasted about 2 minutes, the uterine vascular resistance rose strikingly. The peak increase in vascular resistance averaged about 700 per cent over control values (Fig. 1, Table I). Uteroplacental oxygen transfer during this period decreased to about one third of the control values; the decreasewas related to the marked fall in uterine blood flow (Fig. 1, Table I). The arteriovenous oxygen content difference increased but the increment was not enough to compensate for the marked decreasein blood flow. The second phase, which followed immediately, was characterized by a progressive recovery in arterial pressure and uterine blood flow. The degree of recovery was variable from one animal to another; but, in general, the mean arterial pressure rose to levels above control values (Fig. 1, Table I). Uterine blood flow also increased, but the increment was lessthan that of the arterial pressure with the uterine flow never retuming to control levels. Uterine vascular resistance tended to return toward control values. Although uterine oxygen transfer was more
ute$ne (FVO,)
Volume
112
Number
8
and umbilical in 7 animals
Circulatory
blood flows that survived
(QUA and GUV), for 2 hours (figures
shock in pregnant
uterine placental and are means + 1 SE.)
sheep. I
umbilical
FAP (mm. Hg) fj:! -L 2 6:1 63 62 64 64 62
51 i: + + 2 t 60 -t 60 * 61 t
2 2 2 2 I! 2 ” 3 4
UVP (mm. Hg)
___
cjvv
4
258
+ 37
0.20
+ 0.03
19 19 “0 21 20 la 16 13 12
4 4 4 5 5 4 4 5 4
259 244 248 245 244 226 225 224 231
? t + + + k + +_ +
0.20 0.20 0.20 021 0.22 0.20 0.24 0.24 0.28
+ 5 2 + + t i: It +
than double the values observed during the first phase of shock, it remained below control levels. This second phase of shock lasted about 10 minutes (Fig. 1, Table I). The third phase of endotoxin shock was characterized by a progressive and equivalent decline in both the arterial pressure and uteroplacental blood flow; uterine vascular resistance remained close to control values, while uteroplacental oxygen transfer remained below control values. This phase lasted for about 2 hours, at the end of which the animal’s condition had deteriorated, requiring termination of the experiment (Fig. 1, Table I). In Table IV are presented the data on the effects of endotoxin on mother and fetus in the group of 3 animals that died within 15 to 20 minutes after endotoxin injection. Fig. 2 illustrates a representative example of this group. The pattern of response to endotoxin injection in this group was qualitatively similar to that of the group already discussed. However, the degree of blood pressure fall in this group was more pronounced during Phase 1. The uteroplacental blood flow also decreased, and uterine vascular resistance increased (Fig. 2, Table IV). The duration of the recovery period (Phase 2) in these animals was considerably shorter than the previous group, and both the arterial pressure and uterine flow never showed
-_ .- -
FVO, (ml./min.)
(mUmin.)
19 t
t 2 + 5 + f +_ f ?
vascular ---...-
Fetal data
_I__--
1087
35 27 32 31 31 22 33 34 49
0.03 0.03 0.03 0.05 0.04 0.03 0.06 0.02 0.05
6.’
f 0.5
4.6 t
1.1
6.1 + 0.8
3.4 i
1.6
a significant recovery from the low values reached in the first phase. Following this short recovery period (about 2 minutes), the pressure and Aow rapidly deteriorated, and within 20 minutes the animals were dead. Uteroplacental oxygen transfer fell strikingly during the shock period. During endotoxin shock, the maternal arterial hemoglobin concentration progressively increased from a control value of I 1 .I Gm. per 100 ml. to 13.6 Gm. 40 minutes after the administration of endotoxin (Table II). The increase at 40 minutes was statistically significant, while those at 2 and 10 minutes were of borderline significance. The fetal arterial and umbilical vein hemoglobin concentrations remained stable throughout the entire duration of the experiment.
Maternal responseto endotoxin in animals primed with phenoxybenzamine. In order to assess the degree of adrenergic stimulation produced by endotoxin shock, the following experimental protocol was used in two experiments (Table III). After a control period similar to that described under Methods, the ewe was given an intravenous injection of 0.5 mg. per kilogram of phenoxybenzamine. The effectiveness of the adrenergic blockade was tested by administering 0.5 pg per kilogram of norepinephrine, which did not alter the flow and pressure appreciably (this dose produces
1088
Beth-Jansen
April Am. J. Obstet.
et al.
ENDOTOXIN
15, 1972 Gynecol.
i.v.
MAP mm Hg
bUA ml/mln
UVR mm ml/min
FAP mm Hg UMB VP mm Hg ~k?n~n”
260 220
PVR
t -30.
I -25
x)-z5
I -20
I -15
1 -10
1 -5 TIME
111110 5 IN MINUTES
15-5
2-5 TIME
1 IO
5-15
I 15
. 20
15-20
I 25
I 30
I 35
I 40
309
IN MINUTES
Fig. 1. Effects of endotoxin injected into the ewe on maternal arterial pressure (MAP), total uterine blood flow (QUA), uterine vascular resistance (UVR), fetal arterial pressure (FAP), umbilical vein pressure (Umb VP), total umbilical blood flow ((iUmbV), and umbilicoplacental vascular resistance (PVR). Figures represent mean of 7 animals (see text). Note the marked .fall in maternal pressure and uteroplacental blood flow and the striking increase in uterine vascular resistance after endotoxin injection, Arterial pressure rebounded to higher than control values and uterine flow recovered somewhat thereafter. Note the stability of the fetal circulation during the various phases of maternal shock. Note also the decrease in uteroplacental oxygen transfer (l&O,) and fetal oxygen consumption (FVO,) after endotoxin injection. a marked increased uterine vascular resistance in normal animaF2). When no response to norepinephrine was observed, endotoxin was injected into the maternal jugular vein. Table III shows that the maternal arterial pressure and flow fell somewhat after phenoxybenzamine; this is consistent with the ef-
fects of adrenergic blockade. During endotoxin shock, both pressure and flow fell simultaneously; the fall in pressure was close to the critical closing pressure previously observed for the uteroplacental circulation.12 The blood flow fell and the uterine vascular resistance increased (Table III). Such an increase was, however, considerably less than
Volume Number
112 8
Circulatory
shock
in pregnant
EWE FETUS
sheep.
I
1089
w!. 65kg wt. 2.98 kg
EXPERIMENT
# 8
400 bUA ml/min
200 o-
FAP mmHg Bi: UMB
VPmmHg
Iq----4w----*
IO] 8-
UoOz
ml/minm
6-
F002
mUmin%
420-a\ , -20 -15 -CONTROL------I
I -10
-5
1 0
I
TIME
I 5
I IO
I 15
1 20
IN MINUTES
Fig. 2. Illustrative example of an experiment in which the ewe died about 20 minutes after endotoxin injection. Note the rapid deterioration in maternal and fetal circulatory parameters and oxygen transfer. (For explanation of symbols, see legend for Fig. 1.)
that observed in animals with intact adrenergic system.This increase in uterine vascular resistance at such a low pressure is most likely related to collapse of the vesselsat the critical closing pressure. The recovery period in the animals with adrenergic blockade was shorter and the deterioration was more rapid than in the animals not receiving an adrenergic-blocking agent. Changes in fetal hemodynamics and oxy-
gen
consumption. Despite the marked changes in uteroplacental hemodynamics and oxygen transfers during the three phases of shock, the fetal circulation did not reflect any major
aIteration
except
in the terminal
phase of shock. In the animals included in the first group, fetal arterial and umbilical vein pressures, umbilical vein flow, and umbilicoplacental vascular resistance remained stable and at control levels throughout the first and second
1090
Beth-Jansen
Apd Am. J. Ohstet.
et al.
Table II. Maternal and fetal hemoglobin shock (figures are mean -I 1 SE.)
concentration
during control and endotoxin
Minutes Control
15, 192 Gynrcol.
after
intravenous
2
endotoxin
10
40
Maternal arterial (Gm./lOO ml.)
11.1
+ 0.3
11.5
2 0.3*
12.4
F 0.6”
13.6
+ 0.4t
FetaI arterial (Gm./lOO
ml.)
14.4
+ 0.7
14.8
2 0.7
14.0
f
0.7
13.8
+ 06
vein ml.)
14.7
+_ 0.6
i5.0
? 0.7
14.3
t 0.7
14.4
rt 0.8
Umbilical (Gm./lOO “P < 0.05
> 0.02.
tP < 0.m.
phase of shock; fetal heart rate decreased slightly in some animals while in others it did not change. These various circulatory functions began to change only at the end of the third phase of shock when the mother’s condition was deteriorating (Fig. 1, Table I); during this phase, heart rate, arterial pressure, and umbilical flow decreased. Fetal oxygen consumption fell initially but recovered during the second phase of shock; it fell again during the third phase. Since the umbilical blood flow did not change during the first phase of shock, the decrease in fetal oxygen consumption was related to a fall in the arteriovenous oxygen content difference; the fall during the third phase was caused by a decrease in both flow arteriovenous 0, and content difference. The fetuses included in the second group showed a more pronounced response particularly as the animal deteriorated rapidly. Hypotension, bradycardia, and decreased umbilical flow were more severe than in the first group (Table IV), Changes in maternal and fetal blood respiratory gases and PH. Table V shows the values on maternal and fetal blood PO, Pco~, and pH in both groups of animals. The values for the control periods for both mother and fetus (Group 1) lie within the ranges previously found in this laboratory.Q* lo The large standard error in the maternal PO, values is due to the fact that some animals required lung ventilation with 95 per cent 0, to counteract effects of decreased ventilation due to atelectasis.
In Group 1, a slight decrease in maternal arterial PO, and increase in Pcoz occurred during endotoxin shock; maternal blood pH did not change significantly. The administration of 95 per cent 0, to some ewes might have prevented a greater decrease in maternal blood PO, and pH. Fetal blood PO,, however, decreased significantly during endotoxin shock regardless of whether one looks at the umbilical vein or the femoral artery blood. Fetal blood Pco, increased and fetal blood pH decreased in this group of animals (Table V). In Group 2, despite the severity of the circulatory shock which led to a rapid death of the mother, the maternal Paz, Pcoz, and pH were not significantly different from those of Group 1, both in the control and shock periods. Here again, lung ventilation with 100 per cent 0, probably prevented changes in the maternal blood respiratory gases and pH. On the other hand, control values for fetal blood Paz and pH (in both the umbihcal vein and artery) were lower than those of the other group; both parameters fell profoundly during the endotoxin shock (Table III). Control Pcoz was higher than the other group and increased further during shock (Table V) . Comment
Maternal hemodynamics. The classical pattern of hemodynamic response to acute injection of E. coli endotoxin, as observed in the dog, consists of the following three phases1-5 : an acute hypotensive phase, dur-
Volume 1I:! Number 8
Circulatory
Table III. Effects of endotoxin by phenoxybenzamine++ -.---
in a sheep whose adrenergic
shock in pregnant
sheep. I
1091
system had been blocked
-.-UV’K
Time Control After intravenous benzamine Minutes after intravenous
&JAt
MAP (mm. W
(mUmin.)
108
257
0.37
88
166
0.40
114 108 50 48 54 72 65
221 ‘1’11 -33 13 26 14 39
0.46 0.43 1.06 2.08 1.23 0.89 I.31
phenozy0.3 mg./Kg. endotoxin
of
1 ‘) 3 4 5 1.5 2.5 ‘For explanation of abbreviations, +One uterine artery.
see caption for Table
.-.__
I.
ing which cardiac output and regional blood flows fall and systemic and regional resistances increase ; a recovery phase during which pressure and flows recover and vascular resistances return toward normal values. During this phase, the renin-angiotensin-aldosterone system is activated and the secretion of these hormones is increased.13 A deteriorating phase follows during which flows and pressure fall gradually, the vascular resistances are within the normal range, and the activities of the renin-angiotensin-aldosterone system returns to normal ending with the death of the animal.13 The mechanisms by which these three phases are produced are hotly debated. Some authors believe that in the dog at least the adrenergic system is overstimulated by the shock state; others believe that the stimulation of this system is transitory and occurs only in the initial phase of shock when the vascular resistances increase. In the nonpregnant sheep, the few studies that have been made indicate that pulmonary hypertension is the prominent feature in the response to endotoxin shock.l4 But variable degrees of hypotension and a decrease in the cardiac output were also observed. These studies noted that some animals collapsed and died rapidly while others survived longer when given 0.3 mg. per kilogram of endotoxin.14
The present data obtained from pregnant sheep show that qualitatively the maternal circulatory response to endotoxin is not a great deal different from that observed in the dog or in the nonpregnant sheep. The initial hypotensive phase was definitely accompanied by an over stimulation of the adrenergic system. Since the increase in uterine vascular resistance characteristic of this phase was blocked by phenoxybenzamine, this overstimulation was responsible for the greater decrease in uterine blood flow than arterial pressure and for the striking increase in uterine vascular resistance. Previous studie3”* I5 have shown that active uterine vasoconstriction in the normal sheep can only be induced by adrenergic stimulation. Under any other circumstances, including shock produced by autonomic blockade with spinal anesthesia, the flow depends on the perfusion pressure.12~ I6 We believe that the adrenergic overstimulation was responsible for the “overshoot” which returned the pressure and flows to near control values during the second phase of shock. Whether the renin-angiotensin-aldosterone system played any role in this phase, as it does in the dog, cannot be stated from these studies. We do not have an explanation for the mechanisms of the third and terminal phase. Neither do we have a precise explanation
1092
Beth-Jansen
April 15, 1972 Am. J. Obstet. Gynerol.
et al.
Table IV. Data on the 3 animals that died 15 to 20 minutes after endotoxin injection* Maternal
data UVR
&JA Period Control
107 +
Minutes
after
intravenous
explanation
UtiO, ml./min.
cz3
6
539
t
39
0.21
t 0.01
425 54 2 54 + 52 It 48 ?r 34 +
9 21 21 22 18 16
163 188 174 173 163 150
f 2 t t ?I +
35 114 122 115 111 94
0.29 0.40 0.50 0.43 0.46 0.32
+ 0.09 t 0.11 + 0.13 2 0.09 + 0.12 +- 0.10
and
units,
of Table
I.
14.2
?: 1.5
endotonin
1 2 3 4 5 10 ‘For
(mUmin.)
MAP
of abbreviations
see caption
2.5 + 0.2
Table V. Maternal and fetal blood gasesand pH* Fetal
Maternal
arterial blood Group Groug
Control
(
Umbilical
Shock
Control
vein 1
blood Shock
Femoral Control
artery (
blood Shock
I
PO? (mm. Hg) Pco* (mm. Hg) PH
126 A- 16 24 + 1 7.48 + 0.02
92 + 18 29 It 3 7.40 + 0.02
34 ? 2 27 ” 2 7.41 2 0.02
22 1 3 39 -c 7 7.31 t 0.03
23 2 1 28 5 1 7.38 2 0.02
19 + 2 40 + 6 7.30 + 0.03
Group 2 PO? (mm. Hg) Pco3 (mm. Hg) PH
98 ” 39 31 + 4 7.40 k 0.06
104 + 45 31 + 9 7.39 51 10
23 + 2 41 t 5 7.30 -+ 0.07
951 70 + 9 7.15 ?: 0.03
16 2 2 44 5 5 7.28 5 0.07
851 68 t 10 7.12 + 0.07
*Group I is comprised of the 7 sheep that survived for 2 hours. Group 2 is comprised of the 3 sheep that died 15 to 20 minutes. AI1 values are presented as means + 1 SE. Control values represent the average of all determinations to endotoxin injection. Shock values in Group 1 represent the average values observed 30 to 60 minutes after endotoxin; in Group 2, average values 5 minutes after injection.
why some animals died within 15 to 20 minutes, while others lived longer. The maternal blood respiratory gases and pH of both groups were within the normal range, while in the fetus the Paz and pH were lower in Group 2. An underlying circulatory dysfunction in the second group of animals is possible in view of their lower arterial pressure and uterine blood flow during the control period. At any rate, in the dog, the third and terminal phase of endotoxin shock has been attributed by some to the development of hypoxia and metabolic acidosis.ll2r5 But in the present seriesof experiments, maternal hypoxia and acidosis did not occur, even in the animals that died rapidly, probably because of supported lung ventilation with oxygen-enriched mixtures. Yet, despite the normal blood oxygenation and acid-basepic-
within prior and,
ture, the circulatory deterioration occurred invariably which led to the death of the animal. These findings strongly indicate that the use of the blood respiratory gasesand pH may be misleading in assessingthe severity of endotoxin shock. Uteroplacental oxygen transfer. The present data show clearly that, despite maintenance of normal blood oxygenation in the mother, uteroplacental oxygen transfer decreased markedly during endotoxin shock. The decrease was roughly proportional to the decreasein uterine blood flow. Although the hemoglobin concentration of maternal blood increased progressively, causing an increase in the arteriovenous oxygen content difference, the increment was not sufficient to compensate for the marked decrease in uterine blood flow. These data favor the
Vohlme II2 Numher8
Circulatory
Fetal
shock in pregnant
sheep. I
1093
data PVR
FAP (mm. Hd 64%
UVP (mm. Hg) 2
64+ 6 622 6 60+ 8 575 8 58 + 10 41% - 7
&JV
FtiOz (mUmin.)
(mUmin.)
(Z>
15 2 1
188 + 18
0.34
5 0.04
12 14 14 15 16 11
176 178 144 130 113 61
0.35 0.32 0.48 0.42 0.46 0.95
+ t + t 2 t
t t t 2 2 ?r
4 5 6 6 7 4
f + k 2 + +
hypothesis advanced by various authors that the transfer of oxygen between mother and fetus is flow dependent.17,I8 Fetal circulation and oxygen consumption. The behavior of the fetal circulation, when the mother was in a state of endotoxin shock, is remarkable. Despite the profound changes in the uteroplacental circulation and oxygen transfer, the fetal vascular pressuresand umbilical blood flow remain stable. The only exception was a slight and transitory bradycardia which occurred in some animals. These circulatory parameters only began to fall in the terminal stage of maternal shock. The transitory fall in fetal oxygen consumption in the early phase of shock was IargeIy related to the sharp fall in ~rteroplacental oxygen transfer and the decreasein fetal blood PO,. Such a stability of fetal circulatory dynamics in the presence of maternal shock has been reported from this laboratory in relation to spinal shock and to maternal hypotension caused by hydralazine.lel I9 It shows that the fetal circulation can tolerate marked changes in the maternal circulation without any ill effects. True, the state of maternal shock decreased the delivery of oxygen to the fetus and this led to the fall in fetal blood PO,. The decrease in fetal blood pH could be
41 40 42 32 29 26
0.13 0.12 0.27 0.21 0.19 0.59
3.8 t
1.2
1.1 + 0.8 ---
related to : (1) the decrease in fetal blood oxygenation and the increase in Pco~, or (2) the impairment of excretion of acids through the altered placental circulation. At any rate, despite the marked fall in fetal blood PO? and the frank acidosis, the fetal circulatory dynamics was not affected. This fact showsclearly the lack of any correlation between the status of fetal circulation and the level of blood PO, and pH. It further points out the difficulties in interpreting blood pH changesand their relation to fetal distress. It is not possibleto state from the present set of experiments whether endotoxin crossed the placenta from the maternal to the fetal side. The absence of hemodynamic alterations in the fetus during maternal shock does not rule out placental transfer of endotoxin. Studies in this laboratory (see following report) show that the fetus tolerates several times the dose of endotoxin given to the mother per kilogram of the body weight before showing any cardiovascular response. Similar tolerance of the fetal lamb to vasoactive stimuli has been observed previously.6lI9 The reasonsfor this tolerance are currently being investigated. We would assistance and Della
like of Dave Fuller.
to acknowledge the technical Huntsman, Helena Martinek,
REFERENCES
1. 2.
Morris, S.: AN. Gilbert,
J. A., Smith, R. W., and Assali, N. J. OBSTET. GYNECOL. 91: 491, 1965. R.: Physiol. Review 40: 245, 1959.
3.
Fine, J.: Hamilton, W., editor: Handbook of Physiology, Washington, D. C., 1965, American Physiological Society, p. 2073.
1094
4.
Beth-Jansen
April 15, 1972 Am. J. Obstet. Cynecol.
et al.
Hershey, S. G., editor: Shock, Boston, 1964, Little, Brown & Company. M., and Braun, W., editors: Bac5. Landy, terial Endotoxins, New Brunswick, New Jersey, 1964, Rutgers University Institute of Microbiology Press. N. S., editor: Biology of Gestation, 6. Assali, New York, 1968, ~01s. 1 and 2, Academic Press, Inc. 7. Dawes, G.: Fetal and Neonatal Circulation, Chicago, 1968, Year Book Medical Publishers, Inc. 8. Westersten, A., Rice, E., Brinkman, C. R., III, and Assali, N. S.: J. Appl. Fhysiol. 28: 497, 1969. 9. Johnson, G. H., Kirschbaum, T. H., Brinkman. Cl. R.. III. and Assali. N. S.: Am. 1. Physiol. 226 1748, 1971, ’ 10. Brinkman, C. R., III, Weston, P. V., Kirschbaum, T. H., and Assali, N. S.: AM. J. OBSET. GYNECOL. 108: 288, 1970. 11. Kirschbaum, T. H., Brinkman, C. R., III, and Assali, N. S.: AMER. J. OBSTET. GYNECOL. 110: 190, 1971.
12.
13. 14. 15. 16. 17.
18.
19.
20.
Ladner, C., Brinkman, C. R., III, Weston, P. V., and Assali, N. S.: Am. J. Physiol. 218: 257, 1970. White, F. N., Gold, E. M., and Vaughn, D. L.: Am. J. Physiol. 212: 1195, 1967. Halmagyi, D. F. J., Starzecki, B., and Horner, G. J.: J. Appl. Physiol. 18: 544, 1963. Greiss, F., and Gobble, F.: AM. J. OBSTET. GYNECOL. 97: 962, 1967. Lucas, W. E., Kirschbaum, T. H., and Assali, N. S.: Biol. Neonate 10: 166. 1966. Power, G. G., Longo, L. D:, Wagner, H. N., Jr., Kuhl, D. E., and Forster, R. E., III: J. Clin. Invest. 46: 2053, 1967. Meschia, G., Cotter, J. R., Makowski, E. L., and Barron, D. H.: J. Exp. Physiol. 52: 1, 1967. Ladner, C., Weston, P. V., Brinkman, Cl. R., III, and Assali, N. S.: AM. J. OBSTET. GYNECOL. 108: 375, 1970. Dilts, P. V., Jr., Brinkman, Cl. R., III, Kirschbaum, T. H., and Assali, N. S.: AM. J. OBSTET. GYNECOL. 103: 138, 1969.