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Cardiac output during ritodrine treatment in premature labor
Cardiac output during ritodrine treatment in premature labor JOSEPH
BIENIARZ,
M.D.
ANTHONY
IVANKOVICH,
ANTONIO
SCOMMEGNA,
M.D. M.D.
Chicago, Illinois Unlike other fi-mimetic drugs, ritodrine h),drochloride is able to inhibit uterine contractility in premature labor without producing hypotension. Based on previous studies, we have postulated that this homeostatic effect o[ ritodrine is caused by an increase in cardiac output. In 5 women in premature labor, the indicator dilution technique was used to check the increase in cardiac output. Arterial pressure, amniotic pressure, and heart rate were recorded electronically. The systolic blood prexsure increased 12 per cent during ritodrine infusion, while the diastolic pressure decreased 10 per cent. The mean blood pressure remained stable, but the pulse pressure increased significantly at 30 minutes o[ infusion. A consistent increase in cardiac output was [ound which reached the highest value, 56 per cent over the control, at 40 minutes. There was a slight decrease in cardiac output to 35 per cent aboz,e control at 60 minutes o[ in[usion, because of reduced venous return attributed to inhibition of uterine contractility. The significance of these findings is discussed.
SYMPATHOMIMETIC
AMINES
long
proposed for the treatment of premature labor because of its alleged selective action on the myometrium, without untoward cardiovascular effects. "-s In a previous study from this laboratory, we confirmed the marked inhibiting effect of ritodrine on uterine contractility without accompanying hypotension, but with a moderate increase in heart rateY In fact, systolic blood pressure rose to 109 per cent of control values while, concomitantly, the diastolic pressure decreased to 90 per cent of control. The resulting rise in pulse pressure suggested an increased stroke volume, 1° which along with the concomitant rise in heart rate conceivably could cause a significant increase in cardiac output during ritodrine treatment. This assumption is in good agreement with the fact that only fl-adrenergic receptors apparently are present in the inyocardium. These respond to stimulation with an inotropic effect, increase in the force of contraction, and a chronotropic effect, an increase in heart rate. The aim of the present study was to in-
have been recognized as potent inhibitors of uterine contractility. However, their usefulness in the treatment of premature labor has been limited because of their untoward effects on the cardiovascular system, such as marked hypotension and tachycardia which might reduce placental perfusion and endanger the fetus. 1-:' A new fl-mimetic-adrenergic compound, ritodrine hydrochloride (p-hydroxy phenylethyl p-hydroxy-norepinephrine ~) has been From the Laboratory o[ Uterine Physiology, Department o[ Obstetrics and Gynecology and the Department of Anesthesiology, Michael Reese Medical Center and the Pritzker School o[ Medicine of the University of Chicago. Received for publication July 5, 1973. Revised September 11, I973. Accepted September 24, 1973. Reprint requests: Dr. ]oseph Bieniarz, Department oJ Obstetrics and Gynecology, Michael Reese Medical Center, University o[ Chicago, Chicago, Illinois 60637. *N. V. Philips-Duphar, Weesp, the Netherlands.
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Cardiac output during ritodrine treatment 911
Number 7
vestigate the postulated effect of ritodrine on cardiac output with the use of the indicator dilution technique, as well as electronic recordings of arterial pressure and heart rate. This unrecognized circulatory action of ritodrine, if confirmed, could explain the stability of blood pressure during ritodrine treatment, as compared with hypotension usually observed with the use of other flmimetic drugs.
Material and methods Five patients in premature labor (twentysixth to thirty-sixth weeks of pregnancy) volunteered for this study. Uterine contractility was recorded through a thin polyethylene catheter inserted transparietally into the amniotic cavity. It was connected to a pressure transducer,* linked to an analogue recording system on one channel of a dynograph.J" Arterial pressure was recorded in a similar way through a catheter inserted into the radial artery, connected to a transducer,:~ and linked to a separate channel of the analogue recording system. The mean arterial blood pressure (MBP) was calculated from the recorded systolic (SBP) and diastolic (DBP) values: MBP
-
SBP - DBP + DBP. 3
The maternal heart rate was recorded with a cardiotachometer fed by the R wave of an electrocardiograph coupler circuit.§ The fetal heart rate was recorded through an external ultrasound transducer on one channel of a cardiotocograph.l[ Cardiac output was measured by a dye dilution technique. 1t-13 A catheter was inserted through the antecubital vein into the superior vena cava, and 5 rag. of indocyanine
*Model 23 BB, Statham Instruments, Inc., 2230 Statham Blvd., Oxnard, California 93030. "~Offner Type R, Beckman Instruments, Inc., 2500 Harbor Blvd., Fullerton, California 92634. SModel 23 Db, Statham Instruments, Inc. §Beckman Instruments, Inc. ]]Model 8021A, Hewlett-Packard Co., 1501 Page Mill Rd., Palo Alto, California 94304.
green* was injected, followed by a saline flush. Arterial blood was drawn with a pumpj" from the indwelling catheter, and photometric analysis was performed by a densitometer.:~ Dye curves were recorded directly, and the output signals were fed to a cardiac output computer§ which provided an immediate integration curve readout. This method has several advantages: There is no need for cumbersome calculations; there is no significant blood loss; oxygen saturation has no effect on the output curves; and the indicator is rapidly cleared from the blood by the liver, thus permitting repeated measurements without problem of a rising base line. Two to three measurements were performed for each cardiac output determination, and the mean _+ standard deviation was calculated, except if the value obtained in 10 minute intervals was of the same order as the preceding one. Peripheral resistance was calculated by dividing the mean blood pressure by cardiac output and was expressed in peripheral resistance units ( P R U ) : PRU =
136 x 950 dynes c m. 3
The stroke volume was calculated by dividing the cardiac output by the heart rate. All recordings and measurements were carried out with the patient in a supine position TM in stable conditions of rest and normal ambient temperature. The means of all factors under study were calculated, measured between uterine contractions during a 30 minute control period, and compared with the respective means calculated for 10 minute intervals during ritodrine infusion. The infusion started at 100 /xg per minute and was increased by 40 /zg at 10 minute intervals until complete uterine relaxation or un-
*Cardlo-Green, Hynson, Wescott & Dunning, Inc., Charles & Chase Sts., Baltimore, Maryland 21201. ~'Harvard Apparatus Co., 150 Dover Rd., Millis, Massachusetts 02054. SGilford Instrument Labs., Inc., 132 Artino Oberlin, Ohio 44074. §Model COC 5, Lexington Instruments Corp., Crescent St., Waltham, Mary]and 02154.
St., 241
912 Bieniarz, Ivankovich, and Scommegna
Ap,-il 1, 1974
Am. J Obstet. Gynecol.
Fig. 1, In a primigravida 32 weeks pregnant and in premature labor, the arterial pressure of 112/56 ram. Hg descended transiently to 95/45 ram. Hg at the onset of ritodrine infusion but recovered rapidly and increased to 135/50 mrn. Hg. This remarkable increase in systolic and pulse pressure accompanied by an acceleration in the maternal heart rate from 98 to I34 beats per minute coincided with a rise in cardiac output from 5.0 to 6.1 L. per minute at l0 minutes of infusion, to 6.8 L. per minute at 30 minutes, and to 7.5 L. per minute at 40 minutes. Note the remarkable rise in pulse pressure and in cardiac output to 150 per cent of the control value. a c c e p t a b l e side effects o c c u r r e d . T h e signific a n c e of the d i f f e r e n c e b e t w e e n the g e n e r a l a v e r a g e v a l u e o b t a i n e d d u r i n g the control p e r i o d in all p a t i e n t s a n d the c o r r e s p o n d i n g a v e r a g e o b t a i n e d a f t e r 30 m i n u t e s of ritod r i n e infusion was assessed for e a c h f a c t o r u n d e r study w i t h the use of the t test for p a i r e d values, e a c h p a t i e n t a c t i n g as h e r o w n control.
Results T h e effects of r i t o d r i n e infusion on arterial blood pressure, h e a r t rate, c a r d i a c output, a n d uterine c o n t r a c t i l i t y in i n d i v i d u a l patients t r e a t e d for p r e m a t u r e l a b o r are illustrated in Figs. 1 to 3C. Arterial blood pressure. D u r i n g a 30 m i n ute control period, g e n e r a l a v e r a g e b l o o d pressure values w e r e as follows: systolic, 113
Cardiac output during ritodrine treatment 913
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Fig. 2. In a woman 33 weeks pregnant, gravida 2, para 1, ritodrine inhibited uterine contractility with a transient hypotension from 108/65 to 83/45 ram. Hg at 12 minutes of a rising infusion rate. In spite of progressive uterine relaxation, the blood pressure recovered to 112/55 ram. Hg at 30 minutes of infusion, accompanied by a rise in cardiac output from 3.8 to 5.5 L. per minute, 145 per cent of the control value.
T a b l e I. Arterial pressure values ( m e a n +_s t a n d a r d deviation) during ritodrine t r e a t m e n t in 5 w o m e n in p r e m a t u r e labor
Blood pressure
Control period
Systolic Diastolic Pulse Mean
113+6 61 +4 52±6 74+-4
Minutes of infusion I0 (lO0#g/ 20 (.142 #g/J30 (176#g/ 40 (218#g/JSO (208~g/ 60 (203#g/ min.) min.) I rain.) rain.) I rain.) rain.) 115+11 59 + 5 55+10 78 + 7
118+13 57± 4 61+12 79 + 8
123+11 55 + 5 67±11" 78 + 7
127+17 56 + 4 71±16" 79 + 8
125+-11 55 + 6 68±15" 77± 4
121+13 53 + 5 68-+16 * 76-+ 6
*p < 0.05.
mm. H g ; diastolic, 61 mm. H g ; pulse pressure, 52 mm. H g ; a n d m e a n blood pressure, 76 mm. Hg. These d a t a a n d changes observed d u r i n g t r e a t m e n t are presented in T a ble I a n d in Fig. 4. D u r i n g ritodrine treatment, the systolic blood pressure increased to a m a x i m u m of 127 mm. H g at 40 minutes a n d leveled off d u r i n g the following 20 minutes to 121 mm. Hg. T h e diastolic blood pressure decreased progressively from 61 to 53 mm. H g at 60 minutes. T h e m e a n blood pressure resulting from these changes of systolic a n d diastolic pressure in opposite directions r e m a i n e d rem a r k a b l y stable, between 76 a n d 79 ram.
Hg. O n the contrary, the pulse pressure increased significantly from 52 to 61 mm. H g at 30 minutes of infusion (P < 0.05), to a m a x i m u m of 71 mm. H g at 40 minutes, and decreased slightly to 68 mm. H g at 60 minutes. These changes could h a r d l y be attributed to chance ( T a b l e I and Fig. 4). M a t e r n a l h e a r t rate. T h e m a t e r n a l h e a r t rate of 92 beats p e r m i n u t e increased slightly during the first 10 minutes of ritodrine infusion to 95 beats per minute. T h e pulse accelerated significantly to 107 beats p e r m i n u t e at 20 minutes (P < 0.01) and increased further to 125 beats per m i n u t e at 60 minutes ( T a b l e I I a n d Fig. 5).
914
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Am. J. Obstet. Gynecoi+
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Fig. 3A. In a woman 33 weeks pregnant, gravida 2, para t, ritodrine, 100 to 150 #g per minute, accelerated the maternal heart rate, relaxed the uterus, and increased systolic pressure and cardiac output from 5.0 to 6.0 L. per minute, 120 per cent of the control value at 20 minutes of infusion. The fetal heart rate remained unchanged.
Fig. SB. Further increase in ritodrine infusion in the same patient a s in Fig. 3A during the next 20 minutes to 900 to 250 /zg per minute accelerated the maternal heart rate even more and increased systolic and pulse pressure with a concomitant decrease in diastolic pressure. Cardiac output increased to 8.7 L. per minute, 174 per cent of the control value at 40 minutes of infusion.
Volume118 Nwmber 7
Cardiac output during ritodrine treatment 915
Fig. 3(I. Same patient as Figs. 3A and 3B. During the next 20 minutes of ritodrine infusion, with the same rate (250 #g per minute), the maternal heart rate stayed high and stable, but blood pressure and cardiac output decreased, still remaining above the preinfusion values. The fetal heart rate increased slightly.
Cardiac output. Cardiac output of 3.92 L. per minute increased during ritodrine infusion to 5.70 L. per minute at 30 minutes (P < 0.05) and reached the maximum, 7.23 L. per minute, at 40 minutes. The cardiac output decreased eventually to 4.75 L. per minute at 60 minutes of infusion. Peripheral resistance. During the control period, 20.05 PRU decreased to 15.1 PRU at 10 minutes of infusion (P < 0.05) and to the lowest value of 10.97 PRU at 40 minutes of infusion. Partial recovery to 16.93 PRU occurred at 60 minutes. The change in peripheral resistance was the earliest significant change observed during ritodrine treatment. Stroke volume. From the control value of 42.6 ml. per minute, the stroke volume increased to 54.2 ml. per minute during the first 10 minutes of ritodrine infusion and decreased transiently when the maternal heart rate increased significantly. The highest stroke volume of 59.3 ml. per minute was reached at 40 minutes and decreased to 38 ml. per minute at 60 minutes of infusion.
Fetal heart rate. The fetal heart rate of 157 beats per minute remained almost stable between 153 and 160 beats per minute. Comment Our results (Table I and Figs. 1 to 4) confirm previous reports that ritodrine, in contrast to other fl-mimetic drugs, does not produce marked hypotension. G-s There was a consistent decrease in diastolic pressure which did not produce hypotension except in two transient episodes which recovered spontaneously (Figs. 1 and 2). A tendency to hypotension was well compensated by an increase in systolic pressure and pulse pressure. A previous observation of a significant increase in pulse pressure coinciding with tachycardia during ritodrine treatment lead us to the contention that the alleged absence of hypotension is because of a compensatory elevation in cardiac output? This hitherto unrecognized effect of ritodrine on cardiac output has been confirmed by the results obtained in the present study (Table II and
916
Bieniarz, Ivankovich, and Scommegna
April 1, 1974 A m . J. Obstet. G y n e ~ l .
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120.
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Fig. 4. Effects of ritodrine on arterial blood pressure in 5 women in premature labor in the supine position expressed as mean + standard error of the preinfusion control value. The diastolic pressure decreased progressively while the systolic pressure increased during 40 minutes, resulting in a significant rise in pulse pressure, eventually leveling off slightly because of a decrease in systolic pressure (compare in Table I). Fig. 5). T h e marked increase in cardiac output deserves special attention as it occurs at a period during pregnancy when circulation is physiologically hyperkinetic and cardiac ouput is already 40 per cent elevated above the prepregnancy levels. O n the other hand, the markedly increased work load imposed on the circulatory system during ritodrine treatment requires caution in the use of this
drug in patients with heart disease. The increase in cardiac output is of the same order as that observed during moderate exercise? 3 We use Marsden's exercise test to check the tolerance to ritodrine of patients with potential stenocardia, chronic hypertension, or diabetes. If the test is positive, treatment with ritodrine is contraindicated. If circulatory insufficiency or signs of myocardial
Cardiac output during ritodrine treatment 917
Volume 118 Number 7
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Fig. 5. Average cardiac output and related hemodynamic factors + standard error obtained at 10 minute intervals during ritodrine treatment in 5 women in premature labor (compare in Table II). The decrease in peripheral resistance represented by the decrease in diastolic pressure (Fig. 4) is compensated by a rise in stroke volume during the first i0 minutes and eventually by an acceleration in the heart rate, resulting in a rise in cardiac output. These significant changes compensate for the decrease in diastolic pressure by a concomitant rise in systolic and pulse pressure, resulting in a remarkably stable mean arterial pressure, leveling off slightly after 40 minutes of infusion. ischemia develop unexpectedly during ritodrine treatment, we suggest immediate blocking of fl-mimetic effects by propranolol, 1 to 3 rag. intravenously in increments of 0.5 mg. with continuous monitoring of the electrocardiogram. Usually the recovery is rapid. Analysis of our results indicates that the effect of ritodrine on cardiac output occurs in three phases. T h e earliest effect was a significant decrease in peripheral resistance 10 minutes of ritodrine infusion. Beta mimetic compounds are known to lower peripheral resistance because of their relaxingleffects on all varieties of smooth muscle, including the vascular wall of resistance vessels. The lowered peripheral resistance, as manifested in the decrease in diastolic pressure, may facilitate venous return, resulting in a n increased stroke volume and rise in systolic and pulse pressure. T h e second phase of ritodrine effects was characterized by a significant acceleration in the maternal heart rate which contributed
at
to a further increase in cardiac output between the tenth and fortieth minutes of infusion (Table I I and Fig. 5). T h e chronotropic and inotropic effects of this fl-mimetic-adrenergic drug resulted in elevated cardiac output, systolic pressure, and pulse pressure, along with an increased venous return, which compensated for the decrease in peripheral resistance and diastolic pressure. T h e maximal cardiac output was observed at 40 minutes of ritodrine infusion when both the maternal heart rate and the stroke volume reached the highest levels. T h e third phase, between 40 and 60 minutes of ritodrine infusion, was characterized by a decrease in cardiac output and systolic and pulse pressure to levels still well above control values (Figs. 4 and 5). Blood pressure eventually remained at a similar level for several hours of ritodrine infusion and during oral treatment. Since the stroke volume decreased while the maternal heart rate remained high, this mild depression was
918
Bieniarz,
Ivankovich,
Table II. Cardiac
output
and
Apr it 1, 1974 Am. J. Obstet. Gynecol.
Scommegna
and related
hemodynamic
factors
Control period Maternal heart rate (beats/min.) Cardiac output (L./min.) Stroke volume (ml./min.) PRU Fetal heart rate (beats/mm.)
10
92k9 3.92 + 1.28 42.5 -e 10.47 20.05 t 5.7 157r13
(mean
(100 95 5.15 54.2 15.1 153+
i standard
pg/min.) 2 2 + 2
/
deviation)
20
9 1.37 4.35 3.0+ 16
(142
during
__pg/min.)
107+12+ 5.20 2 1.67 48.6 2 12.4 14.9 2 3.6” 155 + 13
*p < 0.01. tp
< 0.05.
probably caused by reduced venous return. Progressive inhibition of uterine contractility might be an important factor in reducing venous return. Each uterine contraction increases the venous pressure gradient, the driving force for venous return largely responsible for the increased cardiac output observed during uterine contraction. This force was evidently missing when uterine contractility was inhibited by ritodrine treatment. The consistent rise in cardiac output during this treatment might suggest that an increased tone of the venous bed maintained filling pressure and cardiac output when the uterus relaxed. Similar dissociation in the responses of capacitance vessels in which tone increases while resistance vessels relax is known to occur under various circumstances.l” Obstruction of the inferior vena cava by the relaxed uterus could be another possible cause of reduced venous return. The resulting supine hypotensive syndrome is characterized by peripheral blood pooling, bradycardia caused by vasovagal reflex, and immediate pressure recovery with changes in the patient’s position. This syndrome is not a likely cause of the observed moderate arterial depression. Tachycardia was present, not bradycardia, and peripheral pooling of blood seemed unlikely because of the elevated car-
disc output. Changes in the patient’s position did not influence blood pressure. This marked increase in cardiac output during ritodrine treatment also suggests one other possible mechanism of the inhibitory effect of this drug on uterine contractility, aside from the generally accepted effect on the myometrial cell. The Henry-Gauer reflex from the distended left auricle, consequent to an increase in cardiac output, might block the release of antidiuretic hormone and oxytocin from the neurohypophysis l6, I7 Changes in the fetal heart rate or signs of fetal distress were not observed during this treatment. The increased cardiac output with concomitant peripheral vasodilatation could increase regional placental perfusion. The rate of placental blood flow is the determinant factor in maternofetal interchanges. Chronic fetal distress in high-risk pregnancy is one of the major unresolved problems in obstetrics responsible for high perinatal mortality and morbidity rates. The therapeutic use of ritodrine with the resulting hyperkinetic circulation in patients with chronic fetal distress and intrauterine growth retardation might improve maternofetal interchanges and form an effective alternative to the very limited means of treatment of this condition currently available.
REFERENCES
1. 2.
3.
Bishop, E. H., and Woutersz, T. B.: J. A. M. A. 178: 812, 1961. Hendricks, C. H., Cibils, L. A., Pose, S. V., and Eskes, T. IL: AM. J. OBSTET. GYNECOL. 82: 1064, 1961. Pose, S. V., Cibils, L. A., and Zuspan, F. P.:
AM.
4.
5. 6.
J.
OBSTET.
GYNECOL. 84: 297, 1962. Barden, T. P., Thompson, R., and Werts, C. E.: AM.
Stander, R. J. F., Pugh,
W., W.
J.
GYNECOL.
OBSTET.
89:
792,
1964.
Barden, T. P., and Stander, R. W.: J. OBSTET. GYNECOL. 96: 1069, 1966. Baumgarten, K., Frohlich, H., Seidl,
AIN. A.,
V~me 118
Cardiac output during ritodrine treatment
Number 7
919
todrine treatment in 5 w o m e n in p r e m a t u r e labor
Minutes o[ in[usion 30 (176 #g/min.) I 40 (218 #g/min.) 114 + *
5.70 + 1.29t 50.0 + 10.44 13.7 -+2.0* 155 +_13
I
50 (208 #g/min.)
122-+ 13"
121 --+18"
7.23 + 1.55 59.3 + 7.59 10.97 -+ 1.44" 157 + 12
160 + 12
Rachmat, F., and Sokol, K.: Wien. Klin. Wochenschr. 81: 102, 1969. 7. Wesselius-deCasparis, A., Thierry, M., Yo Le Sian, A., Baumgarten, K., Brossens, T., Gamisans, O., Stolk, T. G., and Vivier, W.: Br. Med. J. 3: 144, 1971. 8. Flynn, M. J.: A Report on the Human Pharmacological Studies with Ritodrine in Premature Labor, N.V. Philips-Duphar, Weesp, The Netherlands, 1971, Report No. 56638/
636/V650/71. 9. Bieniarz, J., Motew, M., and Scommegna, A.: Obstet. Gynecol. 40: 65, 1972. 10. Hendricks, C. H., and Quilligan, E. J.: AM. J. OBSTET. GYNECOL. 71: 953, 1956. 11. Fox, T. J., Brooker, L. G. S., Heseltine, D., Essex, H. E., and Wood, E. H.: Mayo Clin. Proc. 32: 18, 1957.
Discussion DR. SUZAr~NE OPAmL, Chicago, Illinois. This study demonstrates a marked effect of ritodrine hydrochloride on cardiac output in pregnant women during premature labor. The observation is of great importance because ritodrine previously was considered to have a selective action on myometrium. The cardiovascular side eitects shown in this study, if confirmed by further investigation, would limit the use of the drug in patients with heart disease. It should be emphasized that careful attention should be given to volume repletion in patients receiving ritodrine therapy. S~nce the drug is a potent vasodilator, hypovolemia and hypotension otherwise might ensue. Although only 5 patients were studied, all showed increases in cardiac output, and the difference between control and treatment outputs was significant at the 0.05 level. The inotropic and chronotropic effects of the drug appear to be caused by peripheral vasodilatation, with reflex cardioacceleration and increased stroke volume appearing as a secondary change. It is of interest that this beta-active agent has such a profound peripheral vasodilating effect on the
I
60 (203 #g/min.) 125 --- lOt 4.75 + 1.23 38.0 + 5.75 16.93 -+ 1.18t 155 + 11
12. Lees, M. B., Taylor, S. H., Scott, D. B., and Kerr, M. G.: J. Obstet. Gynaecol. Brit. Commonw. 74: 319, 1967. 13. Weland, K., Novy, M. J., Peterson, E. N., and Metcalfe, J.: AM. J. OBSTET. GYNECOL. 104" 856, 1969. 14. Quilligan, E. J., and Tyler, C.: AM. J. OBSTET. GVNECOL. 78: 465, 1959. 15. Epstein, T. E., Stampfer, M., and Beiser, G. D.: Circulation :}7: 524, 1968. 16. Henry, J. P., Gauer, O. H., and Reeves, J. L.: Circ. Res. 4: 85, 1956. 17. Bieniarz, J., Burd, L., Motew, M., and Seommegna, A.: AM. J. OBSTET. GYNECOL. 111: 874, 1971.
pregnant patient near term, as these patients already have lowered peripheral resistance. It would be of great practical interest to see if the changes noted in this paper persist through prolonged periods of ritodrine infusion. The present study was terminated after 60 minutes of infusin, whereas one might expect therapeutic administration of the drug to last for several hours. Similarly, it would be useful to see whether the drug affects cardiac output when administered orally. Studies of this kind might make it possible to arrive at a dosage and route of administration at which uterine effects are preserved while cardiovascular side effects are minimized. The authors' point about the importance of posture as a determinant of blood pressure and cardiac output in the pregnant patient at term deserves emphasis. There is now good documentation for the view that cardiac output in pregnancy remains substantially elevated above prepregnant levels until term. Many of the early observations of decreasing output in the third trimester were artifactual because of compression of the gravid uterus on the inferior vena cava, and consequent depression of the venous return produced an increase in cardiac output
920
Bieniarz, Ivankovich, and Scommegna
even in supine patients. It would be of great physiologic interest to see if this effect were exaggerated in patients in the left lateral decubitus position, DR. BIENIARZ (Closing) I wish to thank Dr. Oparil for her comments and constructive criticism. I fully agree that ritodrine cannot be considered as a selective inhibitor of myometrium. Like all other fl-mimetic drugs, ritodrine is a potent vasodilator; however, hypotension common to all of these compounds is not apparent during ritodrine treatment because of the increase in cardiac output. The increased compliance of the vascular sys-
April 1, 1974
Am. J. Obstet. Gynecol.
tern and stimulation of the heart impose such a work load upon the cardiovascular system that caution is indicated during ritodrine treatment in patients with heart disease. We use an electrocardiogram exercise test before ritodrine treatment to reveal coronary insufficiency in patients with chronic hypertension or diabetes. The slight decrease in cardiac output and blood pressure observed after maximal values are reached at 40 minutes of infusion indicates the need for studies over longer periods to ascertain whether cardiac output, similar to blood pressure, remains stable during prolonged intravenous or oral treatment.
BIENIARZ,
M.D.
ANTHONY
IVANKOVICH,
ANTONIO
SCOMMEGNA,
M.D. M.D.
Chicago, Illinois Unlike other fi-mimetic drugs, ritodrine h),drochloride is able to inhibit uterine contractility in premature labor without producing hypotension. Based on previous studies, we have postulated that this homeostatic effect o[ ritodrine is caused by an increase in cardiac output. In 5 women in premature labor, the indicator dilution technique was used to check the increase in cardiac output. Arterial pressure, amniotic pressure, and heart rate were recorded electronically. The systolic blood prexsure increased 12 per cent during ritodrine infusion, while the diastolic pressure decreased 10 per cent. The mean blood pressure remained stable, but the pulse pressure increased significantly at 30 minutes o[ infusion. A consistent increase in cardiac output was [ound which reached the highest value, 56 per cent over the control, at 40 minutes. There was a slight decrease in cardiac output to 35 per cent aboz,e control at 60 minutes o[ in[usion, because of reduced venous return attributed to inhibition of uterine contractility. The significance of these findings is discussed.
SYMPATHOMIMETIC
AMINES
long
proposed for the treatment of premature labor because of its alleged selective action on the myometrium, without untoward cardiovascular effects. "-s In a previous study from this laboratory, we confirmed the marked inhibiting effect of ritodrine on uterine contractility without accompanying hypotension, but with a moderate increase in heart rateY In fact, systolic blood pressure rose to 109 per cent of control values while, concomitantly, the diastolic pressure decreased to 90 per cent of control. The resulting rise in pulse pressure suggested an increased stroke volume, 1° which along with the concomitant rise in heart rate conceivably could cause a significant increase in cardiac output during ritodrine treatment. This assumption is in good agreement with the fact that only fl-adrenergic receptors apparently are present in the inyocardium. These respond to stimulation with an inotropic effect, increase in the force of contraction, and a chronotropic effect, an increase in heart rate. The aim of the present study was to in-
have been recognized as potent inhibitors of uterine contractility. However, their usefulness in the treatment of premature labor has been limited because of their untoward effects on the cardiovascular system, such as marked hypotension and tachycardia which might reduce placental perfusion and endanger the fetus. 1-:' A new fl-mimetic-adrenergic compound, ritodrine hydrochloride (p-hydroxy phenylethyl p-hydroxy-norepinephrine ~) has been From the Laboratory o[ Uterine Physiology, Department o[ Obstetrics and Gynecology and the Department of Anesthesiology, Michael Reese Medical Center and the Pritzker School o[ Medicine of the University of Chicago. Received for publication July 5, 1973. Revised September 11, I973. Accepted September 24, 1973. Reprint requests: Dr. ]oseph Bieniarz, Department oJ Obstetrics and Gynecology, Michael Reese Medical Center, University o[ Chicago, Chicago, Illinois 60637. *N. V. Philips-Duphar, Weesp, the Netherlands.
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Cardiac output during ritodrine treatment 911
Number 7
vestigate the postulated effect of ritodrine on cardiac output with the use of the indicator dilution technique, as well as electronic recordings of arterial pressure and heart rate. This unrecognized circulatory action of ritodrine, if confirmed, could explain the stability of blood pressure during ritodrine treatment, as compared with hypotension usually observed with the use of other flmimetic drugs.
Material and methods Five patients in premature labor (twentysixth to thirty-sixth weeks of pregnancy) volunteered for this study. Uterine contractility was recorded through a thin polyethylene catheter inserted transparietally into the amniotic cavity. It was connected to a pressure transducer,* linked to an analogue recording system on one channel of a dynograph.J" Arterial pressure was recorded in a similar way through a catheter inserted into the radial artery, connected to a transducer,:~ and linked to a separate channel of the analogue recording system. The mean arterial blood pressure (MBP) was calculated from the recorded systolic (SBP) and diastolic (DBP) values: MBP
-
SBP - DBP + DBP. 3
The maternal heart rate was recorded with a cardiotachometer fed by the R wave of an electrocardiograph coupler circuit.§ The fetal heart rate was recorded through an external ultrasound transducer on one channel of a cardiotocograph.l[ Cardiac output was measured by a dye dilution technique. 1t-13 A catheter was inserted through the antecubital vein into the superior vena cava, and 5 rag. of indocyanine
*Model 23 BB, Statham Instruments, Inc., 2230 Statham Blvd., Oxnard, California 93030. "~Offner Type R, Beckman Instruments, Inc., 2500 Harbor Blvd., Fullerton, California 92634. SModel 23 Db, Statham Instruments, Inc. §Beckman Instruments, Inc. ]]Model 8021A, Hewlett-Packard Co., 1501 Page Mill Rd., Palo Alto, California 94304.
green* was injected, followed by a saline flush. Arterial blood was drawn with a pumpj" from the indwelling catheter, and photometric analysis was performed by a densitometer.:~ Dye curves were recorded directly, and the output signals were fed to a cardiac output computer§ which provided an immediate integration curve readout. This method has several advantages: There is no need for cumbersome calculations; there is no significant blood loss; oxygen saturation has no effect on the output curves; and the indicator is rapidly cleared from the blood by the liver, thus permitting repeated measurements without problem of a rising base line. Two to three measurements were performed for each cardiac output determination, and the mean _+ standard deviation was calculated, except if the value obtained in 10 minute intervals was of the same order as the preceding one. Peripheral resistance was calculated by dividing the mean blood pressure by cardiac output and was expressed in peripheral resistance units ( P R U ) : PRU =
136 x 950 dynes c m. 3
The stroke volume was calculated by dividing the cardiac output by the heart rate. All recordings and measurements were carried out with the patient in a supine position TM in stable conditions of rest and normal ambient temperature. The means of all factors under study were calculated, measured between uterine contractions during a 30 minute control period, and compared with the respective means calculated for 10 minute intervals during ritodrine infusion. The infusion started at 100 /xg per minute and was increased by 40 /zg at 10 minute intervals until complete uterine relaxation or un-
*Cardlo-Green, Hynson, Wescott & Dunning, Inc., Charles & Chase Sts., Baltimore, Maryland 21201. ~'Harvard Apparatus Co., 150 Dover Rd., Millis, Massachusetts 02054. SGilford Instrument Labs., Inc., 132 Artino Oberlin, Ohio 44074. §Model COC 5, Lexington Instruments Corp., Crescent St., Waltham, Mary]and 02154.
St., 241
912 Bieniarz, Ivankovich, and Scommegna
Ap,-il 1, 1974
Am. J Obstet. Gynecol.
Fig. 1, In a primigravida 32 weeks pregnant and in premature labor, the arterial pressure of 112/56 ram. Hg descended transiently to 95/45 ram. Hg at the onset of ritodrine infusion but recovered rapidly and increased to 135/50 mrn. Hg. This remarkable increase in systolic and pulse pressure accompanied by an acceleration in the maternal heart rate from 98 to I34 beats per minute coincided with a rise in cardiac output from 5.0 to 6.1 L. per minute at l0 minutes of infusion, to 6.8 L. per minute at 30 minutes, and to 7.5 L. per minute at 40 minutes. Note the remarkable rise in pulse pressure and in cardiac output to 150 per cent of the control value. a c c e p t a b l e side effects o c c u r r e d . T h e signific a n c e of the d i f f e r e n c e b e t w e e n the g e n e r a l a v e r a g e v a l u e o b t a i n e d d u r i n g the control p e r i o d in all p a t i e n t s a n d the c o r r e s p o n d i n g a v e r a g e o b t a i n e d a f t e r 30 m i n u t e s of ritod r i n e infusion was assessed for e a c h f a c t o r u n d e r study w i t h the use of the t test for p a i r e d values, e a c h p a t i e n t a c t i n g as h e r o w n control.
Results T h e effects of r i t o d r i n e infusion on arterial blood pressure, h e a r t rate, c a r d i a c output, a n d uterine c o n t r a c t i l i t y in i n d i v i d u a l patients t r e a t e d for p r e m a t u r e l a b o r are illustrated in Figs. 1 to 3C. Arterial blood pressure. D u r i n g a 30 m i n ute control period, g e n e r a l a v e r a g e b l o o d pressure values w e r e as follows: systolic, 113
Cardiac output during ritodrine treatment 913
Volv,me 118 Number 7
Fig. 2. In a woman 33 weeks pregnant, gravida 2, para 1, ritodrine inhibited uterine contractility with a transient hypotension from 108/65 to 83/45 ram. Hg at 12 minutes of a rising infusion rate. In spite of progressive uterine relaxation, the blood pressure recovered to 112/55 ram. Hg at 30 minutes of infusion, accompanied by a rise in cardiac output from 3.8 to 5.5 L. per minute, 145 per cent of the control value.
T a b l e I. Arterial pressure values ( m e a n +_s t a n d a r d deviation) during ritodrine t r e a t m e n t in 5 w o m e n in p r e m a t u r e labor
Blood pressure
Control period
Systolic Diastolic Pulse Mean
113+6 61 +4 52±6 74+-4
Minutes of infusion I0 (lO0#g/ 20 (.142 #g/J30 (176#g/ 40 (218#g/JSO (208~g/ 60 (203#g/ min.) min.) I rain.) rain.) I rain.) rain.) 115+11 59 + 5 55+10 78 + 7
118+13 57± 4 61+12 79 + 8
123+11 55 + 5 67±11" 78 + 7
127+17 56 + 4 71±16" 79 + 8
125+-11 55 + 6 68±15" 77± 4
121+13 53 + 5 68-+16 * 76-+ 6
*p < 0.05.
mm. H g ; diastolic, 61 mm. H g ; pulse pressure, 52 mm. H g ; a n d m e a n blood pressure, 76 mm. Hg. These d a t a a n d changes observed d u r i n g t r e a t m e n t are presented in T a ble I a n d in Fig. 4. D u r i n g ritodrine treatment, the systolic blood pressure increased to a m a x i m u m of 127 mm. H g at 40 minutes a n d leveled off d u r i n g the following 20 minutes to 121 mm. Hg. T h e diastolic blood pressure decreased progressively from 61 to 53 mm. H g at 60 minutes. T h e m e a n blood pressure resulting from these changes of systolic a n d diastolic pressure in opposite directions r e m a i n e d rem a r k a b l y stable, between 76 a n d 79 ram.
Hg. O n the contrary, the pulse pressure increased significantly from 52 to 61 mm. H g at 30 minutes of infusion (P < 0.05), to a m a x i m u m of 71 mm. H g at 40 minutes, and decreased slightly to 68 mm. H g at 60 minutes. These changes could h a r d l y be attributed to chance ( T a b l e I and Fig. 4). M a t e r n a l h e a r t rate. T h e m a t e r n a l h e a r t rate of 92 beats p e r m i n u t e increased slightly during the first 10 minutes of ritodrine infusion to 95 beats per minute. T h e pulse accelerated significantly to 107 beats p e r m i n u t e at 20 minutes (P < 0.01) and increased further to 125 beats per m i n u t e at 60 minutes ( T a b l e I I a n d Fig. 5).
914
Bieniarz, [vankovich, and Scommegna
April 1, 1974
Am. J. Obstet. Gynecoi+
- 0,0
Fig. 3A. In a woman 33 weeks pregnant, gravida 2, para t, ritodrine, 100 to 150 #g per minute, accelerated the maternal heart rate, relaxed the uterus, and increased systolic pressure and cardiac output from 5.0 to 6.0 L. per minute, 120 per cent of the control value at 20 minutes of infusion. The fetal heart rate remained unchanged.
Fig. SB. Further increase in ritodrine infusion in the same patient a s in Fig. 3A during the next 20 minutes to 900 to 250 /zg per minute accelerated the maternal heart rate even more and increased systolic and pulse pressure with a concomitant decrease in diastolic pressure. Cardiac output increased to 8.7 L. per minute, 174 per cent of the control value at 40 minutes of infusion.
Volume118 Nwmber 7
Cardiac output during ritodrine treatment 915
Fig. 3(I. Same patient as Figs. 3A and 3B. During the next 20 minutes of ritodrine infusion, with the same rate (250 #g per minute), the maternal heart rate stayed high and stable, but blood pressure and cardiac output decreased, still remaining above the preinfusion values. The fetal heart rate increased slightly.
Cardiac output. Cardiac output of 3.92 L. per minute increased during ritodrine infusion to 5.70 L. per minute at 30 minutes (P < 0.05) and reached the maximum, 7.23 L. per minute, at 40 minutes. The cardiac output decreased eventually to 4.75 L. per minute at 60 minutes of infusion. Peripheral resistance. During the control period, 20.05 PRU decreased to 15.1 PRU at 10 minutes of infusion (P < 0.05) and to the lowest value of 10.97 PRU at 40 minutes of infusion. Partial recovery to 16.93 PRU occurred at 60 minutes. The change in peripheral resistance was the earliest significant change observed during ritodrine treatment. Stroke volume. From the control value of 42.6 ml. per minute, the stroke volume increased to 54.2 ml. per minute during the first 10 minutes of ritodrine infusion and decreased transiently when the maternal heart rate increased significantly. The highest stroke volume of 59.3 ml. per minute was reached at 40 minutes and decreased to 38 ml. per minute at 60 minutes of infusion.
Fetal heart rate. The fetal heart rate of 157 beats per minute remained almost stable between 153 and 160 beats per minute. Comment Our results (Table I and Figs. 1 to 4) confirm previous reports that ritodrine, in contrast to other fl-mimetic drugs, does not produce marked hypotension. G-s There was a consistent decrease in diastolic pressure which did not produce hypotension except in two transient episodes which recovered spontaneously (Figs. 1 and 2). A tendency to hypotension was well compensated by an increase in systolic pressure and pulse pressure. A previous observation of a significant increase in pulse pressure coinciding with tachycardia during ritodrine treatment lead us to the contention that the alleged absence of hypotension is because of a compensatory elevation in cardiac output? This hitherto unrecognized effect of ritodrine on cardiac output has been confirmed by the results obtained in the present study (Table II and
916
Bieniarz, Ivankovich, and Scommegna
April 1, 1974 A m . J. Obstet. G y n e ~ l .
beats/rain
(k I o , ' ~ .
120.
•
•
110.
1000
SO-
i...... c¢ • 100
!
-'...... . o I°
"SO
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-30
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F'
20" ",.. %
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....°,,o,.
...,.....,."*""
"Y t -'-
i
~ ii
,
,
.liMP
Fig. 4. Effects of ritodrine on arterial blood pressure in 5 women in premature labor in the supine position expressed as mean + standard error of the preinfusion control value. The diastolic pressure decreased progressively while the systolic pressure increased during 40 minutes, resulting in a significant rise in pulse pressure, eventually leveling off slightly because of a decrease in systolic pressure (compare in Table I). Fig. 5). T h e marked increase in cardiac output deserves special attention as it occurs at a period during pregnancy when circulation is physiologically hyperkinetic and cardiac ouput is already 40 per cent elevated above the prepregnancy levels. O n the other hand, the markedly increased work load imposed on the circulatory system during ritodrine treatment requires caution in the use of this
drug in patients with heart disease. The increase in cardiac output is of the same order as that observed during moderate exercise? 3 We use Marsden's exercise test to check the tolerance to ritodrine of patients with potential stenocardia, chronic hypertension, or diabetes. If the test is positive, treatment with ritodrine is contraindicated. If circulatory insufficiency or signs of myocardial
Cardiac output during ritodrine treatment 917
Volume 118 Number 7
12@
i
........... t ............ } ............. t ....
+. ~.
1o<
............. ~"............ {.. °'4Srot,e ,=tssu.t
........ -+........... i----
........t..............!
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I
20
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I
30
40
I
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mcK/min
Fig. 5. Average cardiac output and related hemodynamic factors + standard error obtained at 10 minute intervals during ritodrine treatment in 5 women in premature labor (compare in Table II). The decrease in peripheral resistance represented by the decrease in diastolic pressure (Fig. 4) is compensated by a rise in stroke volume during the first i0 minutes and eventually by an acceleration in the heart rate, resulting in a rise in cardiac output. These significant changes compensate for the decrease in diastolic pressure by a concomitant rise in systolic and pulse pressure, resulting in a remarkably stable mean arterial pressure, leveling off slightly after 40 minutes of infusion. ischemia develop unexpectedly during ritodrine treatment, we suggest immediate blocking of fl-mimetic effects by propranolol, 1 to 3 rag. intravenously in increments of 0.5 mg. with continuous monitoring of the electrocardiogram. Usually the recovery is rapid. Analysis of our results indicates that the effect of ritodrine on cardiac output occurs in three phases. T h e earliest effect was a significant decrease in peripheral resistance 10 minutes of ritodrine infusion. Beta mimetic compounds are known to lower peripheral resistance because of their relaxingleffects on all varieties of smooth muscle, including the vascular wall of resistance vessels. The lowered peripheral resistance, as manifested in the decrease in diastolic pressure, may facilitate venous return, resulting in a n increased stroke volume and rise in systolic and pulse pressure. T h e second phase of ritodrine effects was characterized by a significant acceleration in the maternal heart rate which contributed
at
to a further increase in cardiac output between the tenth and fortieth minutes of infusion (Table I I and Fig. 5). T h e chronotropic and inotropic effects of this fl-mimetic-adrenergic drug resulted in elevated cardiac output, systolic pressure, and pulse pressure, along with an increased venous return, which compensated for the decrease in peripheral resistance and diastolic pressure. T h e maximal cardiac output was observed at 40 minutes of ritodrine infusion when both the maternal heart rate and the stroke volume reached the highest levels. T h e third phase, between 40 and 60 minutes of ritodrine infusion, was characterized by a decrease in cardiac output and systolic and pulse pressure to levels still well above control values (Figs. 4 and 5). Blood pressure eventually remained at a similar level for several hours of ritodrine infusion and during oral treatment. Since the stroke volume decreased while the maternal heart rate remained high, this mild depression was
918
Bieniarz,
Ivankovich,
Table II. Cardiac
output
and
Apr it 1, 1974 Am. J. Obstet. Gynecol.
Scommegna
and related
hemodynamic
factors
Control period Maternal heart rate (beats/min.) Cardiac output (L./min.) Stroke volume (ml./min.) PRU Fetal heart rate (beats/mm.)
10
92k9 3.92 + 1.28 42.5 -e 10.47 20.05 t 5.7 157r13
(mean
(100 95 5.15 54.2 15.1 153+
i standard
pg/min.) 2 2 + 2
/
deviation)
20
9 1.37 4.35 3.0+ 16
(142
during
__pg/min.)
107+12+ 5.20 2 1.67 48.6 2 12.4 14.9 2 3.6” 155 + 13
*p < 0.01. tp
< 0.05.
probably caused by reduced venous return. Progressive inhibition of uterine contractility might be an important factor in reducing venous return. Each uterine contraction increases the venous pressure gradient, the driving force for venous return largely responsible for the increased cardiac output observed during uterine contraction. This force was evidently missing when uterine contractility was inhibited by ritodrine treatment. The consistent rise in cardiac output during this treatment might suggest that an increased tone of the venous bed maintained filling pressure and cardiac output when the uterus relaxed. Similar dissociation in the responses of capacitance vessels in which tone increases while resistance vessels relax is known to occur under various circumstances.l” Obstruction of the inferior vena cava by the relaxed uterus could be another possible cause of reduced venous return. The resulting supine hypotensive syndrome is characterized by peripheral blood pooling, bradycardia caused by vasovagal reflex, and immediate pressure recovery with changes in the patient’s position. This syndrome is not a likely cause of the observed moderate arterial depression. Tachycardia was present, not bradycardia, and peripheral pooling of blood seemed unlikely because of the elevated car-
disc output. Changes in the patient’s position did not influence blood pressure. This marked increase in cardiac output during ritodrine treatment also suggests one other possible mechanism of the inhibitory effect of this drug on uterine contractility, aside from the generally accepted effect on the myometrial cell. The Henry-Gauer reflex from the distended left auricle, consequent to an increase in cardiac output, might block the release of antidiuretic hormone and oxytocin from the neurohypophysis l6, I7 Changes in the fetal heart rate or signs of fetal distress were not observed during this treatment. The increased cardiac output with concomitant peripheral vasodilatation could increase regional placental perfusion. The rate of placental blood flow is the determinant factor in maternofetal interchanges. Chronic fetal distress in high-risk pregnancy is one of the major unresolved problems in obstetrics responsible for high perinatal mortality and morbidity rates. The therapeutic use of ritodrine with the resulting hyperkinetic circulation in patients with chronic fetal distress and intrauterine growth retardation might improve maternofetal interchanges and form an effective alternative to the very limited means of treatment of this condition currently available.
REFERENCES
1. 2.
3.
Bishop, E. H., and Woutersz, T. B.: J. A. M. A. 178: 812, 1961. Hendricks, C. H., Cibils, L. A., Pose, S. V., and Eskes, T. IL: AM. J. OBSTET. GYNECOL. 82: 1064, 1961. Pose, S. V., Cibils, L. A., and Zuspan, F. P.:
AM.
4.
5. 6.
J.
OBSTET.
GYNECOL. 84: 297, 1962. Barden, T. P., Thompson, R., and Werts, C. E.: AM.
Stander, R. J. F., Pugh,
W., W.
J.
GYNECOL.
OBSTET.
89:
792,
1964.
Barden, T. P., and Stander, R. W.: J. OBSTET. GYNECOL. 96: 1069, 1966. Baumgarten, K., Frohlich, H., Seidl,
AIN. A.,
V~me 118
Cardiac output during ritodrine treatment
Number 7
919
todrine treatment in 5 w o m e n in p r e m a t u r e labor
Minutes o[ in[usion 30 (176 #g/min.) I 40 (218 #g/min.) 114 + *
5.70 + 1.29t 50.0 + 10.44 13.7 -+2.0* 155 +_13
I
50 (208 #g/min.)
122-+ 13"
121 --+18"
7.23 + 1.55 59.3 + 7.59 10.97 -+ 1.44" 157 + 12
160 + 12
Rachmat, F., and Sokol, K.: Wien. Klin. Wochenschr. 81: 102, 1969. 7. Wesselius-deCasparis, A., Thierry, M., Yo Le Sian, A., Baumgarten, K., Brossens, T., Gamisans, O., Stolk, T. G., and Vivier, W.: Br. Med. J. 3: 144, 1971. 8. Flynn, M. J.: A Report on the Human Pharmacological Studies with Ritodrine in Premature Labor, N.V. Philips-Duphar, Weesp, The Netherlands, 1971, Report No. 56638/
636/V650/71. 9. Bieniarz, J., Motew, M., and Scommegna, A.: Obstet. Gynecol. 40: 65, 1972. 10. Hendricks, C. H., and Quilligan, E. J.: AM. J. OBSTET. GYNECOL. 71: 953, 1956. 11. Fox, T. J., Brooker, L. G. S., Heseltine, D., Essex, H. E., and Wood, E. H.: Mayo Clin. Proc. 32: 18, 1957.
Discussion DR. SUZAr~NE OPAmL, Chicago, Illinois. This study demonstrates a marked effect of ritodrine hydrochloride on cardiac output in pregnant women during premature labor. The observation is of great importance because ritodrine previously was considered to have a selective action on myometrium. The cardiovascular side eitects shown in this study, if confirmed by further investigation, would limit the use of the drug in patients with heart disease. It should be emphasized that careful attention should be given to volume repletion in patients receiving ritodrine therapy. S~nce the drug is a potent vasodilator, hypovolemia and hypotension otherwise might ensue. Although only 5 patients were studied, all showed increases in cardiac output, and the difference between control and treatment outputs was significant at the 0.05 level. The inotropic and chronotropic effects of the drug appear to be caused by peripheral vasodilatation, with reflex cardioacceleration and increased stroke volume appearing as a secondary change. It is of interest that this beta-active agent has such a profound peripheral vasodilating effect on the
I
60 (203 #g/min.) 125 --- lOt 4.75 + 1.23 38.0 + 5.75 16.93 -+ 1.18t 155 + 11
12. Lees, M. B., Taylor, S. H., Scott, D. B., and Kerr, M. G.: J. Obstet. Gynaecol. Brit. Commonw. 74: 319, 1967. 13. Weland, K., Novy, M. J., Peterson, E. N., and Metcalfe, J.: AM. J. OBSTET. GYNECOL. 104" 856, 1969. 14. Quilligan, E. J., and Tyler, C.: AM. J. OBSTET. GVNECOL. 78: 465, 1959. 15. Epstein, T. E., Stampfer, M., and Beiser, G. D.: Circulation :}7: 524, 1968. 16. Henry, J. P., Gauer, O. H., and Reeves, J. L.: Circ. Res. 4: 85, 1956. 17. Bieniarz, J., Burd, L., Motew, M., and Seommegna, A.: AM. J. OBSTET. GYNECOL. 111: 874, 1971.
pregnant patient near term, as these patients already have lowered peripheral resistance. It would be of great practical interest to see if the changes noted in this paper persist through prolonged periods of ritodrine infusion. The present study was terminated after 60 minutes of infusin, whereas one might expect therapeutic administration of the drug to last for several hours. Similarly, it would be useful to see whether the drug affects cardiac output when administered orally. Studies of this kind might make it possible to arrive at a dosage and route of administration at which uterine effects are preserved while cardiovascular side effects are minimized. The authors' point about the importance of posture as a determinant of blood pressure and cardiac output in the pregnant patient at term deserves emphasis. There is now good documentation for the view that cardiac output in pregnancy remains substantially elevated above prepregnant levels until term. Many of the early observations of decreasing output in the third trimester were artifactual because of compression of the gravid uterus on the inferior vena cava, and consequent depression of the venous return produced an increase in cardiac output
920
Bieniarz, Ivankovich, and Scommegna
even in supine patients. It would be of great physiologic interest to see if this effect were exaggerated in patients in the left lateral decubitus position, DR. BIENIARZ (Closing) I wish to thank Dr. Oparil for her comments and constructive criticism. I fully agree that ritodrine cannot be considered as a selective inhibitor of myometrium. Like all other fl-mimetic drugs, ritodrine is a potent vasodilator; however, hypotension common to all of these compounds is not apparent during ritodrine treatment because of the increase in cardiac output. The increased compliance of the vascular sys-
April 1, 1974
Am. J. Obstet. Gynecol.
tern and stimulation of the heart impose such a work load upon the cardiovascular system that caution is indicated during ritodrine treatment in patients with heart disease. We use an electrocardiogram exercise test before ritodrine treatment to reveal coronary insufficiency in patients with chronic hypertension or diabetes. The slight decrease in cardiac output and blood pressure observed after maximal values are reached at 40 minutes of infusion indicates the need for studies over longer periods to ascertain whether cardiac output, similar to blood pressure, remains stable during prolonged intravenous or oral treatment.