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The pre-ejection period of the fetal heart: Response to stress in the term fetal lamb
The pre-ejection period of the fetal heart: Response to stress in the term fetal lamb L.
W.
ORGAN,
J.
E.
MILLIGAN,
J.
W.
M.
J.
Toronto,
M.D., M.D.
GOODWIN, C.
BAIN,
Ontario,
B.A.Sc
M.D. M.B.
Canada
The fire-ejection period (PEP) of the cardiac cycle was studied in the mature lamb fetus exteriorized by cesarean section with the umbilical circulation intact. it was shown to be a reliable index of myocardial contractility. Changes in PEP and therefore in contractility during stress were studied. Fetal hypoxemia induced by a geriod of maternal anoxia consistently produced shortening of the PEP, whereas changes in the fetal heart rate over the same period were variable. The decrease in PEP was unexpected and was felt to result from catecholamines released by hyjroxic stimulation of the adrenal medulla. Umbilical cord occlusion produced lengthening of PEP during occlusion and shortening on release, effects most likely related to great changes in aortic diastolic pressure.
THE DEMONSTRATION that the preejection period (PEP) of the cardiac cycle can be detected in the human fetus near term and during labor’* 2 has created a stimulus for investigating the behavior of this parameter in the experimental animal under a variety of stresses. The PEP is the time from the onset of ventricular depolarization (QRS complex) to the onset of ejection from the left ventricle. Fig. 1 illustrates the position of the PEP and left ventricular ejection time (the systolic time intervals) within the cardiac cycle and shows that the PEP includes
From the Departments of Obstetrics Gynecology and of Physiology, University 5j Toronto, and the Women’s College Hospital. Supported Research Nos. MA Received Accepted 25, 1972.
the phase of isovolumetric contraction. Determination of the PEP requires the electrocardiogram plus an indicator of the onset of ventricular ejection, usually the beginning of the upstroke of the carotid arterial waveform. An alternative to this waveform is the tippler ultrasound technique of detecting the aortic valve opening, as used in both adult33 4 and fetus.‘, 2 Both of these techniques for determining the onset of ventricular ejection are noninvasive. The PEP is of interest because it is related to myocardial contractility and because of the possibility that knowledge of changes in myocardial contractility during labor may be used to complement or supplant some methods of fetal assessment presently being used. The relationship of the PEP to myocardial contractility is such that, provided major changes in left ventricular end diastolic pressure and aortic diastolic pressure do not occur, increases in contractility produce decreases in PEP and, conversely, decreases in contractility produce increases in PEP.5
and
in part by Medical Council of Canada Grants 2948 and MA 1843. for for
publication publication
October
9, 1972.
October
Reprint requests: Dr. L. W. Organ, Medical Sciences Building, University of Toronto, Toronto 181, Ontario, Canada. 377
378
Organ
et al. Am.
MC
AORTIC OR CAROTID PRESSURE ,
.M1 : : :
LEFT VENTRICLE PRESSURE ----
/-,.’ /’
ECG
PEP
LVET
Fig. 1. The systolic time intervals, consisting of PEP and left ventricular ejection time, LVET. Valvular motions are indicated by: MC, mitral closing ; Ao, aortic opening; AC, aortic closing; ZVC, isovolumetric contraction. The catheter in the common carotid artery is near the level of the aortic arch so aortic and carotid pressures are virtually identical.
Material and methods Thirteen fetal lambs, within 12 days of full gestation (term is 147 days), were exteriorized by cesareansection with umbilical circulation intact onto a heated table adjacent to the ewe. Further warming was provided by covering the fetus, after preparation, with surgical dressing pads and an overhead lamp. The section was performed under intravenous chloralose anesthesia (30 mg. per kilogram initially) and light anesthesiawas maintained with 10 mg. of chloralose per kilogram as required at one to 2 hour intervals. The ewe breathed 100 per cent oxygen spontaneously through a tracheostomy. The fetus was given sodium heparin, 100 U. per kilogram initially and at hourly intervals thereafter. The trachea was ligated with umbilical tape to prevent spontaneousrespiration. The right femoral artery of the fetus was catheterized to allow 1 ml. samplesof fetal blood for determination of pH, PO, and Pco, with an Instrumentation Laboratory Model 113 pH/gas analyzer.* Another cathe-
*Instrumentation chusetts.
Laboratory.
Inc.,
Lexington,
Massa-
Februaty J. Obstrt.
1, 1973 Gynecol.
ter was positioned in the right common carotid artery for measurement of systemic blood pressure. In the last 5 fetal lambs, right ventricular pressure was measured by passing a catheter down the right jugular vein and through the superior vena cava and right atrium into the right ventricle. The position of the catheter tip was confirmed by the appearance of the ventricle pressurewave. Right ventricular pressurecan be used as a measurement of systemic blood pressure in the fetus because the right and left ventricles work in parallel since they are filled at approximately the samepressureand eject blood against equal pressures.@This circumvents the necessity of obtaining left ventricular pressure by ventricular puncture or passageof a catheter up through the aortic valve. Both carotid and ventricular pressures were recorded with Statham pressure transducers, Model P23 Gb.* Uninsulated clip electrodes were applied to the right upper and left lower extremities of the fetus to obtain the Lead II electrocardiogram (ECG) . Pressure and ECG signals were suitably amplified, monitored on a multichannel oscilloscope, and stored on magnetic tape (Precision Instrument tape recorder, Model 620t) for later analysis. The frequency responseof the combined electronics was direct current to an upper 3 db point of 100 Hz minimum. For calculating the maximum rate of change of ventricular pressure, a differentiator was built which was linear to over 1,000 Hz. Fig. 2A, is an oscilloscope photograph of the raw data from the fetal lamb--right ventricular pressure, carotid artery pressure, fetal ECG, and the rate of change of right ventricular pressure, dp/dt. The PEP was calculated by increasing the oscilloscopesweepspeedand measuring between the points as shown in Fig. 2B. Note that the maximum rate of change [ (dp/dt ) maX]occurs just before ventricular ejection, as indicated by the upstroke of the carotid pressure curve. A Tektronix Model 564 storage
oscilloscope$
was used
playing these tracings. *Statham
Instruments,
tPrecision
Instrument
$Tektmnix,
Inc.,
Inc., Co.,
Beaverton,
Oxnard, Palo
Alto,
Oregon.
California. California.
for dis-
Volume Number
115 3
Pre-ejection
period:
response
to stress
379
RV
Fig. 2A. Oscilloscope photograph of raw data obtained from fetal lamb. From below upward: right ventricular pressure, RV; carotid artery pressure, CA; ECG; rate of change of right ventricular pressure, dp/dt.
d b?t ECG
CA
RV
Fig. 2B. Photograph of same data at times 5 sweep speed. The PEP is obtained by measuring between the arrows indicated on the ECG and CA tracings. The arrow in the top tracing indicates (dp/dt) 148Xwhich occurs just before aortic valve opening. To produce fetal hypoxemia, the 100 per cent oxygen supply to the ewe was replaced with 100 per cent nitrogen for 1’/2 minutes. Serial samples of fetal pH, Paz and Pcop were taken at oneminute intervals. For umbilical cord occlusion, umbilical tape was gently looped around the cord, then tightened just sufficiently to produce complete occlusion for 30 seconds. Again, serial samples of pH and blood gases were taken. In other experiments, assessment of PEP as an index of myocardial contractili-
ty was obtained by recording and comparing the response of PEP and a more direct indicator of myocardial contractility, the maximum rate of ventricular pressure rise, to injections of isoproterenol and propranolol. The former is commonly used experimentally to increase myocardial contractility, and the latter, to depress it. These drugs were administered into the inferior vena cava through a catheter passed up the right femoral vein. Priorities were established so that no ex-
380
Organ
February 1, lsi:? .4m. J. Obstet. Gynecol.
et al.
Analysis
66
PEP msec
” 58
1
1
1
1
1
1
’
fi
IW IW’WO aaoa40160 aw FHR
beats/min
Fig. 3. Relationship between initial control values in each of the 13 experiments of PEP versus FHR. The linear regression line PEP = -0.15 FHR + 97 msec. is drawn.
Table I. Average initial control values in this study on 13 term fetal lambs. Blood pressure was measured in the common carotid artery, and pH and blood gaseswere determined from samplescollected from the femoral artery
PEP (msec.) FHR (heats/min. ) Blood pressure (mm. Hg) Systolic Diastolic PH b-m. Hg) Po2 (mm. Hg) PcoI (mm. Hg)
Auerage
Standard deviafian
65 214
8 37
78 49 7.30 23 46
9 8 0.07 5 9
periment followed a nitrogen experiment unless the pH and blood gasesreturned to or near to normal control values; cord occlusion experiments were generally not followed by other procedures becauseof the ease of spasmof the umbilical vessels.No experiments followed injection of isoproterenol and propranolol. Before each experimenta stress, fetal heart rate and blood pressure were followed for about 20 minutes to ensure stability of the lamb; fetal arterial pH, PO, and Pco, were measured one minute before each stress, as well as at varying intervals after its application.
of data
and
results
For each of the 13 fetal lambs, control values of PEP, fetal heart rate (FHR), arterial blood pressure, pH, PO, and PCO, were determined before any experimental procedure was performed. Average values are listed in Table I. There is an inverse relationship between PEP and FHR, with a correlation coefficient of -0.79. This finding is compatible with a similar relationship in the infant’ and adult* human subject. The linear regressionof PEP on FHR ii PEP = -0.15 FHR + 97 msec. and is shown plotted in Fig. 3. Ewe breathing 100 per cent nitrogen. A total of 17 trials of hypoxemia were imposed on 11 fetusesby replacing the maternal oxygen supply with 100per cent nitrogen for 1y2 minutes. After a latency of about one minute, there were changes in the PEP and FHR in 16 of the 17 trials. The one case which showed no change in PEP or FHR had the least decrease in fetal PO,. In the other 16 cases,PEP invariably shortened ( 16 of 16)) followed by a late prolongation in 38 per cent (6 of 16). FHR decreasedinitially in 55 per cent (9 of 16) and increased initially in the other 45 per cent. Fifty-five per cent (5 of 9) which decreased initially showed a later increase; 14 per cent (one of 7) which increased initially showed a late decrease.Examples of the effects of mild and severe hypoxemia are shown in Figs. 4 and 5, respectively. As can be seen by the initial and minimum values of PO,, the base-line status of the fetal lamb of Fig. 4 was better and the severity of the hypoxemia was less than for the lamb of Fig. 5. In these examples and in general, the magnitude and duration of the decrease in PEP was directly related to the severity of fetal compromise. For FHR, small
decreases
in PO, usually
caused
initial
acceleration, whereas larger decreasesusually produced initial deceIerations. Changes in fetal Pco, were inconsistent, at times increasing or decreasing or remaining constant dur-
ing the nitrogen experiment. In summary, fetal hypoxemia produces an invariable
shortening
of PEP, with
the mag-
nitude of the decrease proportional to the
Volunw Number
115 3
Pre-ejection
period:
response
to stress
381
PEP msec
80-
BP ” mm Hg60504Or
PO, "7mWl
132
20
-1
1
13 2
20
3minutes”
25
27 5
Ewe breathinglOO~N,
Fig.
4. Effect
well as PEP
of mild and heart
fetal hypoxemia on PEP and FHR. Values for PO* and blood pressure. as rate,
refer
to the fetus,
severity of hypoxemia. The initial change in FHR during the same period is variable, with an increase being more likely with mild hypoxemia and a decrease more likely with severe hypoxemia. Umbilical cord occlusion. Seven umbilical cord occlusions lasting 30 seconds were performed on 6 fetal lambs. The PEP usually became prolonged during occlusion (5 of 7, other 2 no change) and shortened below control upon release (5 of 7). The FHR usually decreased during occlusion (5 of 7, with 2 no change) and occasionally increased beyond control upon release (3 of 7) . These changes were associated with a marked rise in systolic and diastolic blood pressure, as shown in Fig. 6. Maximum rate of rise of ventricular pressure [ (dp/dt) ,,,J. An additional parameter, the rate of rise of ventricular pressure
(dp/dt) was computed by electronically differentiating the right ventricular wave form in 23 experiments in 5 fetuses. The maximum rate of rise of ventricular pressure [ (dp/dt) ,,,;tX] has been shown to be a good index of myocardial contractility.9* lo When isoproterenol, an activator of beta adrenergic myocardial receptor sites, was injected into the inferior vena cava, (dp/dt) mRx, PEP, FHR, and blood pressure responded as shown in Fig. 7. The positive inotropic (increased contractility) and chronotropic effects of this drug can be seen by the increase in (dp/dt),,, and heart rate, respectively. [Note that (dp/dt) max is plotted so that increasmg values proceed in the negative Y-axis direction.] The relative lack of vascular smooth muscle stimulation by isoproterenol is reflected by the essentially constant diastolic blood pressure. Propranolol, 2 mg. into the inferior
382
Organ
et al. Am.
February 1, 1973 J. Obstet. Gynecol.
270. 260. 250. 240. 230-
FHR vmn
t
:;; 200 170. 160-
msec
62. 5854. 50.
80.
BP 7o mmHg60 50,
m n-lmHg_
19 -1
16
6
15
12
minutes4
u2
3
Ewe bmthing
18 5
6
7
8
roo%N,
Fig. 5. Effect of severefetal hypoxemiaon PEPand FHR. vena cava, caused a slight decrease in (dp/dt) ma and a slight increase in PEP and, when injected before isoproterenol, delayed and substantially decreased the stimulatory effect. But of most interest is the confirmation of the inverse relationship of PEP to (dp/dt)man. This relationship is maintained during experimental stress,as shown in Fig. 8, a trial of nitrogen-induced hypoxemia. Comment
These results show that the PEP is a sensitive and consistent indicator of fetal hypoxemia, progressively decreasing as the hypoxemia becomesmore severe. The usual effect of umbiliCa1cord occlusion is a prolongation of PEP during occlusion and a shortening on release, effects most likely due to the great increase observed in aortic diastolic pressure with occlusion. This lengthens the
time required for the isovolumetrically contracting left ventricle to exceed aortic diastolic pressure and open the aortic valve. Therefore, the isovolumetric contraction time and, consequently, the PEP are prolonged. There is little or no change in myocardial contractility. In the adult human subject arteriosclerotic heart diseaseproduces a prolonged PEP,4 and acute myocardial ischemia in the experimental animal produces a decreased (dp/dt) .ll The prolonged PEP and decreased (dp/dt) reflect a decreasein myocardial contractility, as would be expected with myocardial hypoxia. It was therefore unexpected that the fetal hypoxemia in the nitrogen experiments causedthe PEP to shorten and (dp/dt)max to increase. This suggested that either fetal myocardium responds entirely differently from adult myocardium to
Volume Number3
113
Pre-ejection
FHli beats min
250
\
240
-
period:
response
to
stress
383
230220-
72 70-
6a66 64
-
621 60-
PO2
11
22
r;unHg
16
19
-1 Ot
minutes
'
umbilical
cord
occluded
Fig. 6. Effect of umbilicalcord occlusionon PEP and FHR. hypoxia, i.e., the contractility of the former increasesand the latter decreases,or, what is more likely, there was another mechanism present which was more dominant than the direct effect of hypoxia. The experiments of Comline and associates12on the effects of asphyxia on the adrenal medulla of fetal lambs can be used to develop a hypothesisfor this mechanism. They found that hypoxia is a strong direct stimulus on the adrenal medulla for the release of both epinephrine and norepinephrine. Both catechol-
amines were secreted in increasing amounts as the PO, fell, with a fall to 12 to 16 mm. Hg required for a detectable increase in rate of release of norepinephrine and to 8 mm. Hg for epinephrine. Increasing Pcop did not have a significant effect, and it did not potentiate the effect of decreasingPO,. These results are especially meaningful when considered together with Fig. 9, taken from our nitrogen experiments, which shows the relationship between the change in PEP and the minimum PO, produced during the
384
Organ
February 1, 19i3 Am. J. Obstet. Gynecol.
et al.
2200 2400 2600 2800 3000
PEP msec
66 62 58
3 isaprohnnol
Ipg/min
4 minutes5
6
7
I.V.
Fig. 7. Effect of isoproterenol on myocardial contractility as measured by the maximum rate of rise of ventricular pressure [(dp/dt),..] and the relationship of PEP to (dp/dt) n,.r. Note that (dp/dt),.. is plotted with k&easing values proceeding downward to facilitate comparison with PEP.
set 1
PEP msec
66 63 -
-2
28
25
mmHg
16
i’t Ewe Fig.
8. Relationship
between
20
Lutes breathing PEP
and
’
lOO%N, (dp/dt)
mar during
fetal
hypoxemia.
8
Vollmc Number
113 3
Pre-ejection
period:
response
1OOL
h
88.
L B
84
E'
no-
-
l . b
7672
-
6%
-
64
-
60
-
l
.
.
.
.
I
,
1
I
I
I
,
I
,
.
,
,
,
,
6
7
8
9
10
11
12
13
14
IS
16
17
18
19
min in
. .
.
.
5
Fig. 9. Change hypoxemia.
PEP
as a function
PO,
of the
hypoxemia. In the range of 12 to 16 mm. Hg, the PEP begins to shorten ; below this range, the degree of shortening is more pronounced. This leads to the following interpretation of our experimental results. Fetal hypoxemia stresses both the myocardium and the adrenal medulla. The effect on the myocardium would be to decrease contractility, but this effect is minimal except with continued or profound hypoxia because anaerobic metabolism from the relatively great glycogen stores in the fetal myocardium increases its resistance to asphyxia.13 On the other hand, the release of catecholamines from the adrenal medulla causes a marked positive inotropic effect on the myocardium, so contractility is increased and PEP is shortened. The variability of response of the FHR can be explained by the coexistence of several factors, any of which may become dominant. For example, the chronotropic effect of catecholamines increases the heart rate, but their additional effect of raising blood pressure by increasing peripheral resistance can produce a reflex bradycardia through the baroreceptors. A variable heart rate response, REFERENCES
1. Murata, AM.
mm
GYNECOL.
H., and Kurachi, K.: 111: 287, 1971.
20
Hg
minimum
PO* produced
during
the
period
of
bradycardia and/or tachycardia, has also been found with experimental peripheral chemoreceptor stimulation by either sodium cyanideI or hypoxemia.l” Since PEP is inversely proportional to the heart rate of the unstressed fetal lamb, as it is in the human subject, it does not appear that comparison of base-line PEP for an individual subject with the group average would be useful, unless perhaps correction is made for heart rate with the regression equation. However, as has been demonstrated, it is the change in a given subject relative to its own control that is most meaningful, Since PEP is a function of heart rate it might be argued that since heart rate also changes with hypoxemia at least some of the observed change in PEP is related to heart rate changes. But this cannot be a signi6cant factor because, as was seen, fetal heart rate was almost as likely to increase as to decrease with hypoxemia, whereas PEP consistently decreased. We should like to thank F. W. Unger, MSc., for assistance and advice on the electronic aspects of this work and also Miss Daria Sydor for technical assistance. 2.
Y., Takemura,
J. OBSTET.
385
l
0 -
to stress
Organ, L. W., Bernstein, A., Rowe, I. H., and Smith, K. C.: AM. J. OBSTET. GYNECOL. 115: 369, 1973.
386
3.
4.
5.
6.
7. 8.
Organ
Frhrua, .4m. J. Obstet.
et al.
Yoshida, T., Mori, M., Nimura, Y., Hikita, G., Takagishi, S., Nakanishi K., and Satomura, S.: Am. Heart J. 61: 61, 1961. Nimura, Y., Matsuo, h., Mochizuki, S., Aoki, K.. Wada. 0.. and Abe H.: Am. Heart Y1. 75; 49, 1968. ’ Metzger, C. C., Chough, C. B., Kroetz, F. W., and Leonard, J. J.: Am. J. Cardiol. 25: 434, 1970. Dawes, G. S.: Foetal and Neonatal Physiology, Chicago, 1968, Year Book Medical Publishers, Inc., p. 94. Golde, D., and Burstin, L.: Circulation 42: 1029, 1970. Weissler, A. M., Harris, W. S., and Schoen-
9. 10. 11. 12. 13. 14.
15.
y 1. 1973 Gynecol.
feld, C. D.: Am. J. Cardiol. 23: 577, 1969. GIeason, W. L., and Braunwald, E.: J. Clin. Invest. 41: 80, 1962. Mason, D. T.: Am. J. Cardiol. 23: 516, 1969. Wiggers, C. J.: Circulation 5: 321, 1952. Comline, R. S., Silver, I. A., and Silver, M.: J. Physiol. 178: 211, 1965. Dawes, G. S.: Arch. Dis. Child. 34: 281, 1959. Dawes, G. S., Lewis, B. V., Milligan, J. E., Roach, M. R., and Talner, N. S.: J. Physiol. 195: 55, 1968. Dawes, G. S., Duncan, S. L. B., Lewis, B. V., Merlet, C. L., Owen-Thomas, J. B., and Reeves, J. T.: J. Physiol. 201: 105, 1969.
W.
ORGAN,
J.
E.
MILLIGAN,
J.
W.
M.
J.
Toronto,
M.D., M.D.
GOODWIN, C.
BAIN,
Ontario,
B.A.Sc
M.D. M.B.
Canada
The fire-ejection period (PEP) of the cardiac cycle was studied in the mature lamb fetus exteriorized by cesarean section with the umbilical circulation intact. it was shown to be a reliable index of myocardial contractility. Changes in PEP and therefore in contractility during stress were studied. Fetal hypoxemia induced by a geriod of maternal anoxia consistently produced shortening of the PEP, whereas changes in the fetal heart rate over the same period were variable. The decrease in PEP was unexpected and was felt to result from catecholamines released by hyjroxic stimulation of the adrenal medulla. Umbilical cord occlusion produced lengthening of PEP during occlusion and shortening on release, effects most likely related to great changes in aortic diastolic pressure.
THE DEMONSTRATION that the preejection period (PEP) of the cardiac cycle can be detected in the human fetus near term and during labor’* 2 has created a stimulus for investigating the behavior of this parameter in the experimental animal under a variety of stresses. The PEP is the time from the onset of ventricular depolarization (QRS complex) to the onset of ejection from the left ventricle. Fig. 1 illustrates the position of the PEP and left ventricular ejection time (the systolic time intervals) within the cardiac cycle and shows that the PEP includes
From the Departments of Obstetrics Gynecology and of Physiology, University 5j Toronto, and the Women’s College Hospital. Supported Research Nos. MA Received Accepted 25, 1972.
the phase of isovolumetric contraction. Determination of the PEP requires the electrocardiogram plus an indicator of the onset of ventricular ejection, usually the beginning of the upstroke of the carotid arterial waveform. An alternative to this waveform is the tippler ultrasound technique of detecting the aortic valve opening, as used in both adult33 4 and fetus.‘, 2 Both of these techniques for determining the onset of ventricular ejection are noninvasive. The PEP is of interest because it is related to myocardial contractility and because of the possibility that knowledge of changes in myocardial contractility during labor may be used to complement or supplant some methods of fetal assessment presently being used. The relationship of the PEP to myocardial contractility is such that, provided major changes in left ventricular end diastolic pressure and aortic diastolic pressure do not occur, increases in contractility produce decreases in PEP and, conversely, decreases in contractility produce increases in PEP.5
and
in part by Medical Council of Canada Grants 2948 and MA 1843. for for
publication publication
October
9, 1972.
October
Reprint requests: Dr. L. W. Organ, Medical Sciences Building, University of Toronto, Toronto 181, Ontario, Canada. 377
378
Organ
et al. Am.
MC
AORTIC OR CAROTID PRESSURE ,
.M1 : : :
LEFT VENTRICLE PRESSURE ----
/-,.’ /’
ECG
PEP
LVET
Fig. 1. The systolic time intervals, consisting of PEP and left ventricular ejection time, LVET. Valvular motions are indicated by: MC, mitral closing ; Ao, aortic opening; AC, aortic closing; ZVC, isovolumetric contraction. The catheter in the common carotid artery is near the level of the aortic arch so aortic and carotid pressures are virtually identical.
Material and methods Thirteen fetal lambs, within 12 days of full gestation (term is 147 days), were exteriorized by cesareansection with umbilical circulation intact onto a heated table adjacent to the ewe. Further warming was provided by covering the fetus, after preparation, with surgical dressing pads and an overhead lamp. The section was performed under intravenous chloralose anesthesia (30 mg. per kilogram initially) and light anesthesiawas maintained with 10 mg. of chloralose per kilogram as required at one to 2 hour intervals. The ewe breathed 100 per cent oxygen spontaneously through a tracheostomy. The fetus was given sodium heparin, 100 U. per kilogram initially and at hourly intervals thereafter. The trachea was ligated with umbilical tape to prevent spontaneousrespiration. The right femoral artery of the fetus was catheterized to allow 1 ml. samplesof fetal blood for determination of pH, PO, and Pco, with an Instrumentation Laboratory Model 113 pH/gas analyzer.* Another cathe-
*Instrumentation chusetts.
Laboratory.
Inc.,
Lexington,
Massa-
Februaty J. Obstrt.
1, 1973 Gynecol.
ter was positioned in the right common carotid artery for measurement of systemic blood pressure. In the last 5 fetal lambs, right ventricular pressure was measured by passing a catheter down the right jugular vein and through the superior vena cava and right atrium into the right ventricle. The position of the catheter tip was confirmed by the appearance of the ventricle pressurewave. Right ventricular pressurecan be used as a measurement of systemic blood pressure in the fetus because the right and left ventricles work in parallel since they are filled at approximately the samepressureand eject blood against equal pressures.@This circumvents the necessity of obtaining left ventricular pressure by ventricular puncture or passageof a catheter up through the aortic valve. Both carotid and ventricular pressures were recorded with Statham pressure transducers, Model P23 Gb.* Uninsulated clip electrodes were applied to the right upper and left lower extremities of the fetus to obtain the Lead II electrocardiogram (ECG) . Pressure and ECG signals were suitably amplified, monitored on a multichannel oscilloscope, and stored on magnetic tape (Precision Instrument tape recorder, Model 620t) for later analysis. The frequency responseof the combined electronics was direct current to an upper 3 db point of 100 Hz minimum. For calculating the maximum rate of change of ventricular pressure, a differentiator was built which was linear to over 1,000 Hz. Fig. 2A, is an oscilloscope photograph of the raw data from the fetal lamb--right ventricular pressure, carotid artery pressure, fetal ECG, and the rate of change of right ventricular pressure, dp/dt. The PEP was calculated by increasing the oscilloscopesweepspeedand measuring between the points as shown in Fig. 2B. Note that the maximum rate of change [ (dp/dt ) maX]occurs just before ventricular ejection, as indicated by the upstroke of the carotid pressure curve. A Tektronix Model 564 storage
oscilloscope$
was used
playing these tracings. *Statham
Instruments,
tPrecision
Instrument
$Tektmnix,
Inc.,
Inc., Co.,
Beaverton,
Oxnard, Palo
Alto,
Oregon.
California. California.
for dis-
Volume Number
115 3
Pre-ejection
period:
response
to stress
379
RV
Fig. 2A. Oscilloscope photograph of raw data obtained from fetal lamb. From below upward: right ventricular pressure, RV; carotid artery pressure, CA; ECG; rate of change of right ventricular pressure, dp/dt.
d b?t ECG
CA
RV
Fig. 2B. Photograph of same data at times 5 sweep speed. The PEP is obtained by measuring between the arrows indicated on the ECG and CA tracings. The arrow in the top tracing indicates (dp/dt) 148Xwhich occurs just before aortic valve opening. To produce fetal hypoxemia, the 100 per cent oxygen supply to the ewe was replaced with 100 per cent nitrogen for 1’/2 minutes. Serial samples of fetal pH, Paz and Pcop were taken at oneminute intervals. For umbilical cord occlusion, umbilical tape was gently looped around the cord, then tightened just sufficiently to produce complete occlusion for 30 seconds. Again, serial samples of pH and blood gases were taken. In other experiments, assessment of PEP as an index of myocardial contractili-
ty was obtained by recording and comparing the response of PEP and a more direct indicator of myocardial contractility, the maximum rate of ventricular pressure rise, to injections of isoproterenol and propranolol. The former is commonly used experimentally to increase myocardial contractility, and the latter, to depress it. These drugs were administered into the inferior vena cava through a catheter passed up the right femoral vein. Priorities were established so that no ex-
380
Organ
February 1, lsi:? .4m. J. Obstet. Gynecol.
et al.
Analysis
66
PEP msec
” 58
1
1
1
1
1
1
’
fi
IW IW’WO aaoa40160 aw FHR
beats/min
Fig. 3. Relationship between initial control values in each of the 13 experiments of PEP versus FHR. The linear regression line PEP = -0.15 FHR + 97 msec. is drawn.
Table I. Average initial control values in this study on 13 term fetal lambs. Blood pressure was measured in the common carotid artery, and pH and blood gaseswere determined from samplescollected from the femoral artery
PEP (msec.) FHR (heats/min. ) Blood pressure (mm. Hg) Systolic Diastolic PH b-m. Hg) Po2 (mm. Hg) PcoI (mm. Hg)
Auerage
Standard deviafian
65 214
8 37
78 49 7.30 23 46
9 8 0.07 5 9
periment followed a nitrogen experiment unless the pH and blood gasesreturned to or near to normal control values; cord occlusion experiments were generally not followed by other procedures becauseof the ease of spasmof the umbilical vessels.No experiments followed injection of isoproterenol and propranolol. Before each experimenta stress, fetal heart rate and blood pressure were followed for about 20 minutes to ensure stability of the lamb; fetal arterial pH, PO, and Pco, were measured one minute before each stress, as well as at varying intervals after its application.
of data
and
results
For each of the 13 fetal lambs, control values of PEP, fetal heart rate (FHR), arterial blood pressure, pH, PO, and PCO, were determined before any experimental procedure was performed. Average values are listed in Table I. There is an inverse relationship between PEP and FHR, with a correlation coefficient of -0.79. This finding is compatible with a similar relationship in the infant’ and adult* human subject. The linear regressionof PEP on FHR ii PEP = -0.15 FHR + 97 msec. and is shown plotted in Fig. 3. Ewe breathing 100 per cent nitrogen. A total of 17 trials of hypoxemia were imposed on 11 fetusesby replacing the maternal oxygen supply with 100per cent nitrogen for 1y2 minutes. After a latency of about one minute, there were changes in the PEP and FHR in 16 of the 17 trials. The one case which showed no change in PEP or FHR had the least decrease in fetal PO,. In the other 16 cases,PEP invariably shortened ( 16 of 16)) followed by a late prolongation in 38 per cent (6 of 16). FHR decreasedinitially in 55 per cent (9 of 16) and increased initially in the other 45 per cent. Fifty-five per cent (5 of 9) which decreased initially showed a later increase; 14 per cent (one of 7) which increased initially showed a late decrease.Examples of the effects of mild and severe hypoxemia are shown in Figs. 4 and 5, respectively. As can be seen by the initial and minimum values of PO,, the base-line status of the fetal lamb of Fig. 4 was better and the severity of the hypoxemia was less than for the lamb of Fig. 5. In these examples and in general, the magnitude and duration of the decrease in PEP was directly related to the severity of fetal compromise. For FHR, small
decreases
in PO, usually
caused
initial
acceleration, whereas larger decreasesusually produced initial deceIerations. Changes in fetal Pco, were inconsistent, at times increasing or decreasing or remaining constant dur-
ing the nitrogen experiment. In summary, fetal hypoxemia produces an invariable
shortening
of PEP, with
the mag-
nitude of the decrease proportional to the
Volunw Number
115 3
Pre-ejection
period:
response
to stress
381
PEP msec
80-
BP ” mm Hg60504Or
PO, "7mWl
132
20
-1
1
13 2
20
3minutes”
25
27 5
Ewe breathinglOO~N,
Fig.
4. Effect
well as PEP
of mild and heart
fetal hypoxemia on PEP and FHR. Values for PO* and blood pressure. as rate,
refer
to the fetus,
severity of hypoxemia. The initial change in FHR during the same period is variable, with an increase being more likely with mild hypoxemia and a decrease more likely with severe hypoxemia. Umbilical cord occlusion. Seven umbilical cord occlusions lasting 30 seconds were performed on 6 fetal lambs. The PEP usually became prolonged during occlusion (5 of 7, other 2 no change) and shortened below control upon release (5 of 7). The FHR usually decreased during occlusion (5 of 7, with 2 no change) and occasionally increased beyond control upon release (3 of 7) . These changes were associated with a marked rise in systolic and diastolic blood pressure, as shown in Fig. 6. Maximum rate of rise of ventricular pressure [ (dp/dt) ,,,J. An additional parameter, the rate of rise of ventricular pressure
(dp/dt) was computed by electronically differentiating the right ventricular wave form in 23 experiments in 5 fetuses. The maximum rate of rise of ventricular pressure [ (dp/dt) ,,,;tX] has been shown to be a good index of myocardial contractility.9* lo When isoproterenol, an activator of beta adrenergic myocardial receptor sites, was injected into the inferior vena cava, (dp/dt) mRx, PEP, FHR, and blood pressure responded as shown in Fig. 7. The positive inotropic (increased contractility) and chronotropic effects of this drug can be seen by the increase in (dp/dt),,, and heart rate, respectively. [Note that (dp/dt) max is plotted so that increasmg values proceed in the negative Y-axis direction.] The relative lack of vascular smooth muscle stimulation by isoproterenol is reflected by the essentially constant diastolic blood pressure. Propranolol, 2 mg. into the inferior
382
Organ
et al. Am.
February 1, 1973 J. Obstet. Gynecol.
270. 260. 250. 240. 230-
FHR vmn
t
:;; 200 170. 160-
msec
62. 5854. 50.
80.
BP 7o mmHg60 50,
m n-lmHg_
19 -1
16
6
15
12
minutes4
u2
3
Ewe bmthing
18 5
6
7
8
roo%N,
Fig. 5. Effect of severefetal hypoxemiaon PEPand FHR. vena cava, caused a slight decrease in (dp/dt) ma and a slight increase in PEP and, when injected before isoproterenol, delayed and substantially decreased the stimulatory effect. But of most interest is the confirmation of the inverse relationship of PEP to (dp/dt)man. This relationship is maintained during experimental stress,as shown in Fig. 8, a trial of nitrogen-induced hypoxemia. Comment
These results show that the PEP is a sensitive and consistent indicator of fetal hypoxemia, progressively decreasing as the hypoxemia becomesmore severe. The usual effect of umbiliCa1cord occlusion is a prolongation of PEP during occlusion and a shortening on release, effects most likely due to the great increase observed in aortic diastolic pressure with occlusion. This lengthens the
time required for the isovolumetrically contracting left ventricle to exceed aortic diastolic pressure and open the aortic valve. Therefore, the isovolumetric contraction time and, consequently, the PEP are prolonged. There is little or no change in myocardial contractility. In the adult human subject arteriosclerotic heart diseaseproduces a prolonged PEP,4 and acute myocardial ischemia in the experimental animal produces a decreased (dp/dt) .ll The prolonged PEP and decreased (dp/dt) reflect a decreasein myocardial contractility, as would be expected with myocardial hypoxia. It was therefore unexpected that the fetal hypoxemia in the nitrogen experiments causedthe PEP to shorten and (dp/dt)max to increase. This suggested that either fetal myocardium responds entirely differently from adult myocardium to
Volume Number3
113
Pre-ejection
FHli beats min
250
\
240
-
period:
response
to
stress
383
230220-
72 70-
6a66 64
-
621 60-
PO2
11
22
r;unHg
16
19
-1 Ot
minutes
'
umbilical
cord
occluded
Fig. 6. Effect of umbilicalcord occlusionon PEP and FHR. hypoxia, i.e., the contractility of the former increasesand the latter decreases,or, what is more likely, there was another mechanism present which was more dominant than the direct effect of hypoxia. The experiments of Comline and associates12on the effects of asphyxia on the adrenal medulla of fetal lambs can be used to develop a hypothesisfor this mechanism. They found that hypoxia is a strong direct stimulus on the adrenal medulla for the release of both epinephrine and norepinephrine. Both catechol-
amines were secreted in increasing amounts as the PO, fell, with a fall to 12 to 16 mm. Hg required for a detectable increase in rate of release of norepinephrine and to 8 mm. Hg for epinephrine. Increasing Pcop did not have a significant effect, and it did not potentiate the effect of decreasingPO,. These results are especially meaningful when considered together with Fig. 9, taken from our nitrogen experiments, which shows the relationship between the change in PEP and the minimum PO, produced during the
384
Organ
February 1, 19i3 Am. J. Obstet. Gynecol.
et al.
2200 2400 2600 2800 3000
PEP msec
66 62 58
3 isaprohnnol
Ipg/min
4 minutes5
6
7
I.V.
Fig. 7. Effect of isoproterenol on myocardial contractility as measured by the maximum rate of rise of ventricular pressure [(dp/dt),..] and the relationship of PEP to (dp/dt) n,.r. Note that (dp/dt),.. is plotted with k&easing values proceeding downward to facilitate comparison with PEP.
set 1
PEP msec
66 63 -
-2
28
25
mmHg
16
i’t Ewe Fig.
8. Relationship
between
20
Lutes breathing PEP
and
’
lOO%N, (dp/dt)
mar during
fetal
hypoxemia.
8
Vollmc Number
113 3
Pre-ejection
period:
response
1OOL
h
88.
L B
84
E'
no-
-
l . b
7672
-
6%
-
64
-
60
-
l
.
.
.
.
I
,
1
I
I
I
,
I
,
.
,
,
,
,
6
7
8
9
10
11
12
13
14
IS
16
17
18
19
min in
. .
.
.
5
Fig. 9. Change hypoxemia.
PEP
as a function
PO,
of the
hypoxemia. In the range of 12 to 16 mm. Hg, the PEP begins to shorten ; below this range, the degree of shortening is more pronounced. This leads to the following interpretation of our experimental results. Fetal hypoxemia stresses both the myocardium and the adrenal medulla. The effect on the myocardium would be to decrease contractility, but this effect is minimal except with continued or profound hypoxia because anaerobic metabolism from the relatively great glycogen stores in the fetal myocardium increases its resistance to asphyxia.13 On the other hand, the release of catecholamines from the adrenal medulla causes a marked positive inotropic effect on the myocardium, so contractility is increased and PEP is shortened. The variability of response of the FHR can be explained by the coexistence of several factors, any of which may become dominant. For example, the chronotropic effect of catecholamines increases the heart rate, but their additional effect of raising blood pressure by increasing peripheral resistance can produce a reflex bradycardia through the baroreceptors. A variable heart rate response, REFERENCES
1. Murata, AM.
mm
GYNECOL.
H., and Kurachi, K.: 111: 287, 1971.
20
Hg
minimum
PO* produced
during
the
period
of
bradycardia and/or tachycardia, has also been found with experimental peripheral chemoreceptor stimulation by either sodium cyanideI or hypoxemia.l” Since PEP is inversely proportional to the heart rate of the unstressed fetal lamb, as it is in the human subject, it does not appear that comparison of base-line PEP for an individual subject with the group average would be useful, unless perhaps correction is made for heart rate with the regression equation. However, as has been demonstrated, it is the change in a given subject relative to its own control that is most meaningful, Since PEP is a function of heart rate it might be argued that since heart rate also changes with hypoxemia at least some of the observed change in PEP is related to heart rate changes. But this cannot be a signi6cant factor because, as was seen, fetal heart rate was almost as likely to increase as to decrease with hypoxemia, whereas PEP consistently decreased. We should like to thank F. W. Unger, MSc., for assistance and advice on the electronic aspects of this work and also Miss Daria Sydor for technical assistance. 2.
Y., Takemura,
J. OBSTET.
385
l
0 -
to stress
Organ, L. W., Bernstein, A., Rowe, I. H., and Smith, K. C.: AM. J. OBSTET. GYNECOL. 115: 369, 1973.
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Yoshida, T., Mori, M., Nimura, Y., Hikita, G., Takagishi, S., Nakanishi K., and Satomura, S.: Am. Heart J. 61: 61, 1961. Nimura, Y., Matsuo, h., Mochizuki, S., Aoki, K.. Wada. 0.. and Abe H.: Am. Heart Y1. 75; 49, 1968. ’ Metzger, C. C., Chough, C. B., Kroetz, F. W., and Leonard, J. J.: Am. J. Cardiol. 25: 434, 1970. Dawes, G. S.: Foetal and Neonatal Physiology, Chicago, 1968, Year Book Medical Publishers, Inc., p. 94. Golde, D., and Burstin, L.: Circulation 42: 1029, 1970. Weissler, A. M., Harris, W. S., and Schoen-
9. 10. 11. 12. 13. 14.
15.
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feld, C. D.: Am. J. Cardiol. 23: 577, 1969. GIeason, W. L., and Braunwald, E.: J. Clin. Invest. 41: 80, 1962. Mason, D. T.: Am. J. Cardiol. 23: 516, 1969. Wiggers, C. J.: Circulation 5: 321, 1952. Comline, R. S., Silver, I. A., and Silver, M.: J. Physiol. 178: 211, 1965. Dawes, G. S.: Arch. Dis. Child. 34: 281, 1959. Dawes, G. S., Lewis, B. V., Milligan, J. E., Roach, M. R., and Talner, N. S.: J. Physiol. 195: 55, 1968. Dawes, G. S., Duncan, S. L. B., Lewis, B. V., Merlet, C. L., Owen-Thomas, J. B., and Reeves, J. T.: J. Physiol. 201: 105, 1969.