- Email: [email protected]
Cardiovascular effects of oxytocic drugs used post partum
Cardiovascular effects of oxytocic drugs used post partum CHARLES
H.
WILLIAM
E.
Chapel
Hill,
North
HENDRiICKS, BRENNER,
M.D. M.D.
Carolina
The almost routine use of oxytocin and/or ergot drugs post parturn for the prevention of or the control of postpartum hemorrhage is a widely accepted practice. It has been repeatedly demonstrated that the rapid intravenous administration of single large doses of either oxytocin or ergot preparation may haue profound effects upon cardiovascular system. The almost immediate development of profound hypotension following such administration of oxytocin and the relatively longer hypertension following administration of ergonovine and methylergonouine maleate have been demonstrated in human subjects.
used before the delivery of the child. The safety of oxytocin when used ante partum has been promoted by increasing recognition of its proper dosage and route of administration. Both classes of drugs are now very commonly administered for the prophylaxis and/ or control of postpartum bleeding. The principal complication from the use of ergot preparations in early puerperium appears to be that of hypertension. This factor is considered significant enough so that in many institutions ergonovine is not given to patients with pre-eclampsia, essential hypertensive disease, and cardiac abnormalities. The synthetic analoCgue, rnethylergonovine,* is reported to produce much less hypertension.8 With oxytocin pituitary extracts, various catastrophic events have been reported. By 1941g there began to appear in the American and European literature references to “pituitary shock,” occurring after the administration of pituitary products. An examination of 7 cases reporteds-l1 indicates that in the alleged cases of pituitary shock the patients usually had pre-existing hypertension, doses
OXYTOCIC AGENTS, long employed by midwives in the form of crude extracts of ergot, have been mentioned in European obstetric writings at least since 1668.l The principal changes in their use in the intervening two centuries have related to the identification of active principles,‘! 3 purifi+tion, standardization of dosage, and, finally, the synthesis of analogues useful for the promotion of uterine contractility. During the present century, the oxytocic properties of oxytocin have been identiiied,4 the drug and some of its analogues have been synthesized,5t 6 and its pharmacology has been studied.? It has been long recognized that either drug, when used before delivery, may endanger the fetus and possibly cause uterine rupture; this lesson has been so thoroughly learned that ergot preparations are no longer
From the Department of Obstetrics Gynecology, University of North Carolina School of Medicine.
and
Supported in part by Grant HD 04148-02 from the National Institute of Child Health and Human Development. Presented at the Ninety-third Annual Meeting of the American Gynecological Society, Hot Springs, Virginia, May 25-27, 1970.
“Methergine, Jersey.
751
Sandoz
Pharmaceuticals,
Hanover,
New
752
Hendricks
and Brenner
were given in grossly unphysiologic amounts to patients already hemorrhaging severely, and some of the untoward reactions may have been anaphylactoid in nature. (In at least 3 cases reported as “pituitary shock,” an ergot preparation was administered intravenously and/or intramuscularly concomitantly with the pituitary preparation.) In these latter cases it is not at all clear why oxytocin alone was incriminated as the causative agent instead of ergonovine, since it is already known that ergonovine may produce electrocardiographic changes compatible with those seen in myocardial ischemia.12 The most recent case of death allegedly due to oxytocin concerned a woman with congenital heart disease who was having therapeutic termination of pregnancy because of congestive heart failure in the first trimester. At the conclusion of the procedure, she was given a single intravenous injection of 10 I.U. of synthetic oxytocin, after which she promptly experienced circulatory collapse and died. At postmortem examination she was found to have an extensive concentric subendocardial infarction which had been present for an estimated 10 to 12 days.13 The major cardiovascular effects of oxytocin have been well documented. It is known that constant infusions of oxytocin within the physiologic dosage range (not exceeding 20 mu. per minute) have minimal or no effects upon the blood pressure, while constant infusions even of huge dosages result in only a slight elevation of the blood pressure which subsides as soon as the infusion is discontinued.14 Doses of oxytocin up to 10 I.U. administered either intramuscularly or subcutaneously have no demonstrable effect upon the cardiovascular system. When oxytocin is administered in a single intravenous dose, however, the effects upon the cardiovascular system are prompt and dramatic. Woodbury and associateP reported that synthetic oxytocin caused a 2 to 5 minute 30 to 50 mm. Hg decrease in arterial pressure associated with tachycardia within 2 to 5 minutes after intravenous injection. The response occurred
Amer.
November J. Obstet.
1, 1970 Gynec.
in both males and females, and the degree of hypotension was dependent upon the size of the dose. Administration of large doses intravenously (in excess of 2 I.U.) was followed by electrocardiographic changes consistent with those found with hypoxia. Mayes working with synthetic and Shearman,ls oxytocin, reported that single intravenous doses of 2 or more I.U. of oxytocin would bring about flattening or inversion of the T wave. Similar results were reported by others.17 Despite the careful documentation in the literature indicating the disadvantages and potential dangers of the rapid administration of oxytocin in a single intravenous dose, the drug continues to be thus administered by a significant number of American obstetricians, sometimes in doses as high as 10 I.U. This unfortunate practice may be perpetuated because severe reactions to toxic dosages are relatively rare or misinterpreted, while milder reactions are dismissed as of little or no consequence. Most American textbooks now recommend that oxytocin be given by another route or, if it is to be given intravenously, as a dilute slow infusion. Some, however, are not at all clear on this point. Because of the hiatus between curre t physiologic knowledge and clinical practi Pe, it seemed worthwhile to offer this short report. It is proposed to illustrate the typical cardiovascular response to oxytocin and ergot preparations in dosages still being commonly used by some obstetric services for the prevention of postpartum bleeding, and to place this knowledge in proper perspective in relation to postpartum hemostasis. Materials
and
methods
All observations were made either in the delivery suites of MacDonald House at the University Hospitals of Cleveland, Ohio, or at Memorial Hospital of the University of North Carolina, Chapel Hill. Gravid and postpartum women and a healthy male volunteer were studied. Two subjects had therapeutic abortions induced by hypertonic saline with postpartum recordings. Intrauterine pressure was measured
Volume Number
108 5
Cardiovascular
Fig. 1. The Manic flow line),
effects
of oxytocic
rapid injection of 5 I.U. of oxytocin intravenously was followed promptly of uterine contraction (top line), a significant alteration in relative uterine (second line), a dramatic fall in the arterial blood pressure from 115/60 to 72/38 and an equally pronounced transient increase in the heart rate (bottom line). type
by an open-end catheter inserted transabdominally into the uterine cavity.l* Arterial blood pressure was measured directly in the femoral artery with open-end catheter. Heart rate was obtained with a digital cardiotachometer. Relative uterine blood flow as noted in Fig. 1 was measured with a thermister needle embedded in the cervix but will not be discussed in this report. Mean arterial blood pressure was calculated as l/s the difference between systolic and diastolic pressure above the diastolic blood pressure. Intravenous injections were administered rapidly in a planned sequence through an intravenous catheter followed by a saline flush. Placebo injections were given to demonstrate that no alteration in blood pressure would be elicited by saline alone. Results A typical response to the rapid intravenous administration of oxytocin is shown in Fig. 1. Two hours post partum, with the patient
drugs
753
by a blood (thi70’
supine, 5 I.U. of oxytocin was given. The blood pressure, previously well stabilized at 115/60, began to decrease within 20 seconds and within 35 seconds had declined to 72/38. The precipitous decrease was followed by recovery during the following three minutes and a small “overshoot” to a level higher than the original pressure, returning to its preinjection level within 10 minutes after injection. The heart rate increased rapidly from an initial rate of 70 to a peak of 110 beats per minute as the blood pressure decreased. During the blood pressure recovery lleriod, the heart rate decreased but had not returned to its original level ten minutes after injection. The usual postpartum contraction pattern was converted to a tetanic type. The pattern of blood pressure decrease and recovery is always the same. The extent of the decrease and the recovery time,, however, are always directly proportional to the size of the dose of oxytocin given. We have
754
Hendricks
and
Brenner Amer.
November J. Obstet.
1, 19X Gynec.
PS 12/24/69 SUPINE OXYTOCIN
r
100 cr,
IN IU
SYSTOLIC
20-
\ \ 50, ,5==-.10.0
-/,:--I---
32
56
DIASTOLIC
IO1
0
8
16
24
TIME
Fig. 2. Blood pressure injection of oxytocin amount of reduction of the dose given.
40
48
64
72
80
INJECTION
AFTER
104 II2
120 128 136 142
IN SECONDS
T E. 11110/61 SUPINE OXYTOCIN IN fig/K9
E
E 1
96
response to oxytocin post partum. In this postpartum patient, the rapid in doses between 0.5 and 10.0 I.U. was followed by hypotension, the in both systolic and diastolic pressures being proportionate to the size
I” z
88
110
100
c g
90
8 2
80
2&
70
k % 60 5 g
50
TIME
IN SECONDS
Fig. 3. Mean arterial blood pressure response to oxytocin. A reduction in mean arterial blood pressure in a healthy male subject was demonstrated at a level of 0.003 pg per kilogram of body weight. At the largest dose used (0.100 pg per kilogram, or 3.15 I.U.), the mean arterial blood pressure was reduced by 46 per cent.
observed in one subject a significant transient decrease in pressure to doses as small as 0.1 I.U. In Fig. 2, the relationship between the size of the dose and the degree of blood pressure depression is shown. In this case, a small reduction in blood pressure was observed with 0.5 I.U., but no significant response was elicited by a dose of 0.25 I.U. With doses of 1.0, 5.0, and 10.0 I.U., the blood pressure reduction was proportionally
greater and of longer duration as the size of the dose of oxytocin was increased. The hypotensive response is illustrated in terms of the reduction in the mean arterial blood pressure when oxytocin injections were administered to a healthy male subject (Fig. 3). In this subject, doses as small as 0.003 rg per kilogram of body weight were followed by hypotension. Again, the reduction in mean arterial blood pressure and the
Volume Number
108 5
Cardiovascular
effects
----
PS. FEMALE
-TE.
MALE
of
oxytocic
5.0
drugs
755
IU
3 15 IU
~~
0
0
8
16
24
TIME
32
40
IN
SECONDS
48
56
64
72
AFTER
80
88
96
104
II2
120
INJECTION
Fig. 4. Sexual difference in cardiovascular effect. The response in the began to be evident approximately 16 seconds after injection, while (Fig. 2) the response did not begin to be evident until approximately jection.
male subject (Fig. 3) in the female subject 32 seconds after in-
Fig. 5. Effect partum), ministration significant
In Patient B. G. (18 minutes posl of oxytocin in postpartum hemorrhage. already hemorrhaging and with blood pressure approaching shock levels, the adof 5 I.U. of oxytocin in a single intravenous dose brought about a brief but additional further depression of the blood pressure to a level of 44/26.
of recovery time may be seen to be dose dependent. At the largest dose employed, 0.100 ng. per kilogram (3.15 I.U.) , the mean arterial blood pressure was reduced by 46 per cent. There is one notable difference in the response time between this male subject and the pregnant or postpartum woman. In the latter subjects, onset of the blood pressure reduction was not apparent until 24 to 28 seconds after injection, while slowness
in the male subject the blood pressure reduction began to become evident within 12 to 16 seconds. This difference in response time is shown both in the blood pressure and in the reduction of the level of the dicrotic notch (Fig. 4). A practical demonstration of the fruitlessness and possible danger of giving large intravenous stat doses of oxytocin to a patient whose blood pressure already is at shock
756
Hendricks
Fig. line) line)
and
Brenner
Amer.
November J. Obstct.
1, 1970 Gynec.
6. The administration of 0.2 mg. of ergonovine maleate intravenously was followed (top by a substantial rise in the blood pressure within 3 minutes after injection and (bottom an enormous increase in uterine contractility.
levels is given in Fig. 5. This is a segment of the record of a patient who was delivered of the second of twins 18 minutes previously. The placenta had been delivered 15 minutes previously, at which time the bIood pressure was stable at 104/58, and there was good postpartum uterine contractility. Nevertheless, the patient continued to bleed from the uterine cavity. Initial manual exploration of the uterus failed to reveal any cause for the bleeding, and after an estimated blood loss of 1,000 ml., the patient’s pressure had decreased to 70/42. At the point indicated on the record, 5 I.U. of oxytocin was given rapidly intravenously. The blood pressure decreased transiently to 44/26 within 30 seconds after injection, and the patient, who had been somewhat lethargic, became unresponsive until the blood pressure returned to 90/54 after the rapid intravenous administration of 500 ml. of physiologic saline. Repeat manual exploration of the uterus revealed a small adherent placental fragment. The uterine bleeding promptly subsided after removal of the retained fragment. Twenty seconds after the injection of oxytocin, the uterus began a contraction which persisted for 3vz minutes, The cardiovascular and uterine response to the injection of a “routine” intravenous dosage (0.2 mg. of ergonovine) in a normotensive postpartum patient is presented in Fig. 6. Within 2 minutes, uterine activity increased and persisted with increased tone, frequency, and intensity during the period
of observation after an initial tetanic-like contraction. Arterial pressure increased from 110/50 to 130/70 within 3 minutes after injection. This hypertension persisted throughout the period of observation and no unusual signs or symptoms were noted in the patient. Some have advocated the simultaneous administration of oxytocin and an ergot preparation. The cardiovascular effect of the rapid intravenous injection of such a combination is illustrated in Fig. 7. In this patient, 2 hours post partum, 10 I.U. of oxytocin and 0.2 mg. of methylergonovine were administered. The first response was typical of that seen after oxytocin. Both the systolic and diastolic blood pressures were reduced by about 40 per cent, while the heart rate rose by 20 beats per minute. Then, approximately If/2 minutes after injection, the blood pressure rose above the base-line level, and the heart rate had increased by about 30 beats per minute over the base-line level. At this point, the patient began to vomit. The blood pressure and heart rate returned nearly to the preinjection levels after about only six minutes. Comment
The foregoing illustrations principally serve to confirm the observations recorded by careful workers in previous studies. The precise mechanism whereby large doses of intravenous oxytocin induce hypotension has been the matter of debate for years. In their original work, Woodbury
758
Hendricks
and Brenner
Amer.
arterial blood pressure records, even though the blood pressure was recorded for hours following the administration of oxytocin. This seems only logical in view of the fact that oxytocin is a very rapidly metabolized drug, the biologic half-time being only in the range of 2v2 to 3 minutesZ3 Actually, the majority of patients after normal delivery would get along well without the use of any oxytocic at a1LZ4 In our own studies, we have found that after easy normal spontantous delivery there may be only minimal bleeding, even in cases in which there has not been early delivery of the placenta, fundal massage, or the use of any oxytocic. Furthermore, despite the fact that there may be adequate hemostasis, we have observed that the postpartum uterine tonus, i.e., lowest pressure between contractions, is no higher than it was before delivery and that contractions may not occur spontaneously more than once every 15 minutes.25 Nevertheless, in certain cases, it appears that the prophylactive use of oxytocics post partum is indicated. Such instances would include cases in which the uterus had been overdistended (polyhydramnios, twins, large infant), or in which there had been a par-
November J. Obstet.
1, 1970 Gynec.
titularly long or difficult labor, or in cases in which partial abruptio placentae or placenta previa had been present. But perhaps the most common reason why oxytocic agents are needed in modern obstetrics is because the uterus does not contract well immediately post partum when the patient is under general anesthesia. Thus, if the obstetrician administers general anesthesia to his patient, he may also need to administer an oxytocic post partum to counteract the effects of the general anesthesia. This brings us back to the primary point of this paper: If oxytocic agents are to be used post partum, they should be used correctly. Ergot preparations should be used only intramuscularly. Oxytocin, if it is to be used, should be administered either intramuscularly or, if a prolonged effect is desired, as a dilute intravenous drip. Used within physiologic limits, oxytocin can progood prophylaxis against excessive vide hemorrhage and be effective in the control of postpartum hemorrhage due to uterine “atony.” Given intravenously in grossly toxic doses, oxytocin, like any other agent given in grossly toxic quantities, invites disastrous consequences.
REFERENCES
1.
Condie, D. F., editor: Churchill’s
Theory and
Practice of Midwifery, New American Edition, Philadelphia, 1866, Henry C. Lea, p. 262. 2. Moir, J. C.: Brit. Med. J. 1: 1119, 1932. 3. Davis, M. E., Adair, F. L., Rogers, G., Kharasch, M. S., and Legault, R. E.: AMER. J. OBSTET. GYNEC. 29: 155, 1935. Dale, H. H.: J. Physiol. (Lond.) 34: 163, 1906. DuVigneaud, V., Ressler, C., and Trippett, S.: J. Biol. Chem. 205: 949, 1953. Rudinger, J., Honzl, .J., and Zoaral, M.: Coll. Trav. Chim. Tchecosl. 21: 770, 1956. Caldevro-Barcia. R.. Sica-Blanco. Y.. Poseiro. J. J., Gonzalez-Panizza, V., Mendez-Bauer, C., Fielitz, C., Alvarez, H., Pose, S. V., and Hendricks, C. H.: J. Pharmacol. Exp. Ther. 121: 18: 1957. 8. Shane, F.: AMER. J. OBSTET. GYNEC. 61: 188, 1951. ,
I
,
,
9. Adelman, 10. 11. 12. 13. 14. 15.
I
16. 17. 18.
Lennon, B. B.: AMER. 41: 652, -1941. E.. and Klawan. A. H.: AMER. J. OB.&ET GY~EC. 56: 366, i948. Martmer, M. J., Barland, S., and Sacca, J.: AMER. J. OBSTET. GYNEC. 64: 686, 1952. Stein, I., and Weinstein, J.: J. Lab. Clin. Med. 36: 66, 1950. Robinson, M., Newman, N., and Creevy, D.: J. A. M. A. 200: 108, 1967. Caldeyro-Barcia, R.: Acta Endocr. (Copenhagen) 34: (Suppl. 50) 41, 1960. Woodbury, R. A., Hamilton, W. F., Volpitto, P. P., Abreu, B. E., and Harper, H. T.: J. Pharmacol. 81: 95, 1944. Mayes, B. T., and Shearman, R. P.: J. Obstet. Gynaec. Brit. Comm. 63: 812, 1956. Bergquist, J. R., and Kaiser, I. H.: Obstet. Gynec. 13: 360, 1959. Alvarez, H., and Caldeyro-Barcia, R.: Surg. Gynec. Obstet. 91: 1, 1950.
J. OBST~T. Kanter. A.
M.
H.,
GY~EC.
and
Volume 108 Number 5
19. Pickford, M.: In Caldeyro-Barcia, R., and Heller, H., editors: Oxytocin, Oxford, 1961, Pergamon Press, Inc. 20. Kitchin, A. H., Lloyd, S. M., and Pickford, M.: Clin. Sci. 18: 399, 1959. 2 1. Nakano, J., and Fisher, R. D.: J. Pharmacol. Exp. Ther. 142: 206, 1963. 22. Bonica, J. J.: In Principles and Practice of
Cardiovascular
effects
of oxytocic
drugs
759
Obstetric Analgesia and Anesthesia, Philadelphia, 1969, F. A. Davis Company, p. 320. 23. Saameli, K.: AMER. J. OBSTET. GYNEL 85: 186, 1963. 24. Crisp, W. E.: Obstet. Gynec. 7: 470, 1956. 25. Hendricks, C. H., Eskes, T. K. A. R., and Saameli, K.: AMER. J. OBSTET. GYIL.K. 83: 890,
1962.
Discussion CHARLES P. MCCARTNEY, Chicago, Illinois. During the past two decades, there has been a plethora of reports evaluating the cardiovascular effects of oxytocics administered for the prevention and management of postpartum hemorrhage. Dr. Hendrick’s excellently designed study emphasizes the inadequacies of the majority of these reports and sets the standard for clinical investigation in this field. The essayist accurately defines the population evaluated and employs valid criteria that are precisely asessed. His data, therefore, enhance our knowledge of the acute cardiovascular effects of oxytocin and ergonovine under the conditions that he specifies and places oxytocin administered by intravenous drip in physiologic doses in the position to challenge the derivatives of ergot as the preferred agent for the management of the placental stage of labor. The adverse cardiovascular effects of both classes of oxytocics are mediated by variables that include the biologic aberations of abnormal pregnant states, as well as those introduced by the physician when he administers anesthetics, narcotics, diuretics, and antihypertensives. In evaluating the relative merits of oxytocin and the derivatives of ergot, a definitive assessment of these variables is desirable. It is hoped that Dr. Hendricks and his group will conduct these studies. The alkaloids of ergot have contributed significantly to obstetric management during the past 40 years. If the superiority of oxytocin for the prevention and management of postpartum hemorrhage is established they can be retired with honor. DR. ROBERT A. MUNSICK, Albuquerque, New Mexico. I would like to commend Drs. Hendricks and Brenner on bringing this to our attention.. The immediate vasodepressor effect of oxytocin in posterior pituitary preparations was, of course, described as long ago as 1912 by Paton and Watson in ducks. Coon described an assay DR.
of oxytocin utilizing this “avian depressor“ response in chickens in 1930. This assay is still used by the United States Pharmacopeia for standardizing oxytocin injection. The clear documentation by Hendricks and Brenner that oxytocin causes a vasodepressor response in women, too, should alert obstetricians to possible untoward side effects of rapid, bolus injections of this peptide. In my opinion, oxytotin should never be administered in this manner. DR. FRITZ F. FUCHS, New York, New York. I wonder, Dr. Hendricks, if your observation that very large doses of oxytocin are followed by nausea could result in a secondary release of vasopressin which could compound thr effect on the cardiovascular system? DR. BRENNER (Closing). The major cardiovascular effects of the rapid intravenous injection of oxytocin, as Dr. Munsick has pointed out? have been known for a long time. Yet, many obstetricians continue to administer these oxytocics in grossly unphysiologic amounts. The magnitude of the cardiovascular effect is dependent upon the dosage used. Both men and postpartal women respond with progressively more marked tachycardia and hypotension to increasing doses of oxytocin. In postpartum hemorrhage with shock, when one feels he desparatcly needs increased uterine activity for hemostasis, the rapid injection of oxytocin results in a further decrease in blood pressure. Administration of oxytocin intramuscularly, subcutaneously, or by dilute infusion rapidly increases uteritte activity without any accompanying cardiovascular response. Injection of ergonovine or methylergonovine may result in a prolonged elevation of blood pressure. Cardiovascular effects of oxytocin and methylergonovine in combination do not cancel one another, but the hypotension from oxytocin is merely followed by the hvpertension from methylergonovine. To answer Dr. Fuchs’ question, essentially nothing is known about the release of vasopres-
760
Hendricks
and
Brenner
sin resulting from the rapid infusion of oxytocin. This has not been studied. Although nausea and vomiting are observed after administration of intravenous oxytocin, it is more common following ergot preparations. We did not wish to give the impression that methylergonovine or ergono-
Amer.
November J. Obstet.
1, 1970 Gynec.
vine maleate should not be &ken under any circumstance in the postpartum state or that it should be replaced by oxytocin for all postparturn patients. We only wished to say that none of these drugs should be given by intravenous stat doses.
H.
WILLIAM
E.
Chapel
Hill,
North
HENDRiICKS, BRENNER,
M.D. M.D.
Carolina
The almost routine use of oxytocin and/or ergot drugs post parturn for the prevention of or the control of postpartum hemorrhage is a widely accepted practice. It has been repeatedly demonstrated that the rapid intravenous administration of single large doses of either oxytocin or ergot preparation may haue profound effects upon cardiovascular system. The almost immediate development of profound hypotension following such administration of oxytocin and the relatively longer hypertension following administration of ergonovine and methylergonouine maleate have been demonstrated in human subjects.
used before the delivery of the child. The safety of oxytocin when used ante partum has been promoted by increasing recognition of its proper dosage and route of administration. Both classes of drugs are now very commonly administered for the prophylaxis and/ or control of postpartum bleeding. The principal complication from the use of ergot preparations in early puerperium appears to be that of hypertension. This factor is considered significant enough so that in many institutions ergonovine is not given to patients with pre-eclampsia, essential hypertensive disease, and cardiac abnormalities. The synthetic analoCgue, rnethylergonovine,* is reported to produce much less hypertension.8 With oxytocin pituitary extracts, various catastrophic events have been reported. By 1941g there began to appear in the American and European literature references to “pituitary shock,” occurring after the administration of pituitary products. An examination of 7 cases reporteds-l1 indicates that in the alleged cases of pituitary shock the patients usually had pre-existing hypertension, doses
OXYTOCIC AGENTS, long employed by midwives in the form of crude extracts of ergot, have been mentioned in European obstetric writings at least since 1668.l The principal changes in their use in the intervening two centuries have related to the identification of active principles,‘! 3 purifi+tion, standardization of dosage, and, finally, the synthesis of analogues useful for the promotion of uterine contractility. During the present century, the oxytocic properties of oxytocin have been identiiied,4 the drug and some of its analogues have been synthesized,5t 6 and its pharmacology has been studied.? It has been long recognized that either drug, when used before delivery, may endanger the fetus and possibly cause uterine rupture; this lesson has been so thoroughly learned that ergot preparations are no longer
From the Department of Obstetrics Gynecology, University of North Carolina School of Medicine.
and
Supported in part by Grant HD 04148-02 from the National Institute of Child Health and Human Development. Presented at the Ninety-third Annual Meeting of the American Gynecological Society, Hot Springs, Virginia, May 25-27, 1970.
“Methergine, Jersey.
751
Sandoz
Pharmaceuticals,
Hanover,
New
752
Hendricks
and Brenner
were given in grossly unphysiologic amounts to patients already hemorrhaging severely, and some of the untoward reactions may have been anaphylactoid in nature. (In at least 3 cases reported as “pituitary shock,” an ergot preparation was administered intravenously and/or intramuscularly concomitantly with the pituitary preparation.) In these latter cases it is not at all clear why oxytocin alone was incriminated as the causative agent instead of ergonovine, since it is already known that ergonovine may produce electrocardiographic changes compatible with those seen in myocardial ischemia.12 The most recent case of death allegedly due to oxytocin concerned a woman with congenital heart disease who was having therapeutic termination of pregnancy because of congestive heart failure in the first trimester. At the conclusion of the procedure, she was given a single intravenous injection of 10 I.U. of synthetic oxytocin, after which she promptly experienced circulatory collapse and died. At postmortem examination she was found to have an extensive concentric subendocardial infarction which had been present for an estimated 10 to 12 days.13 The major cardiovascular effects of oxytocin have been well documented. It is known that constant infusions of oxytocin within the physiologic dosage range (not exceeding 20 mu. per minute) have minimal or no effects upon the blood pressure, while constant infusions even of huge dosages result in only a slight elevation of the blood pressure which subsides as soon as the infusion is discontinued.14 Doses of oxytocin up to 10 I.U. administered either intramuscularly or subcutaneously have no demonstrable effect upon the cardiovascular system. When oxytocin is administered in a single intravenous dose, however, the effects upon the cardiovascular system are prompt and dramatic. Woodbury and associateP reported that synthetic oxytocin caused a 2 to 5 minute 30 to 50 mm. Hg decrease in arterial pressure associated with tachycardia within 2 to 5 minutes after intravenous injection. The response occurred
Amer.
November J. Obstet.
1, 1970 Gynec.
in both males and females, and the degree of hypotension was dependent upon the size of the dose. Administration of large doses intravenously (in excess of 2 I.U.) was followed by electrocardiographic changes consistent with those found with hypoxia. Mayes working with synthetic and Shearman,ls oxytocin, reported that single intravenous doses of 2 or more I.U. of oxytocin would bring about flattening or inversion of the T wave. Similar results were reported by others.17 Despite the careful documentation in the literature indicating the disadvantages and potential dangers of the rapid administration of oxytocin in a single intravenous dose, the drug continues to be thus administered by a significant number of American obstetricians, sometimes in doses as high as 10 I.U. This unfortunate practice may be perpetuated because severe reactions to toxic dosages are relatively rare or misinterpreted, while milder reactions are dismissed as of little or no consequence. Most American textbooks now recommend that oxytocin be given by another route or, if it is to be given intravenously, as a dilute slow infusion. Some, however, are not at all clear on this point. Because of the hiatus between curre t physiologic knowledge and clinical practi Pe, it seemed worthwhile to offer this short report. It is proposed to illustrate the typical cardiovascular response to oxytocin and ergot preparations in dosages still being commonly used by some obstetric services for the prevention of postpartum bleeding, and to place this knowledge in proper perspective in relation to postpartum hemostasis. Materials
and
methods
All observations were made either in the delivery suites of MacDonald House at the University Hospitals of Cleveland, Ohio, or at Memorial Hospital of the University of North Carolina, Chapel Hill. Gravid and postpartum women and a healthy male volunteer were studied. Two subjects had therapeutic abortions induced by hypertonic saline with postpartum recordings. Intrauterine pressure was measured
Volume Number
108 5
Cardiovascular
Fig. 1. The Manic flow line),
effects
of oxytocic
rapid injection of 5 I.U. of oxytocin intravenously was followed promptly of uterine contraction (top line), a significant alteration in relative uterine (second line), a dramatic fall in the arterial blood pressure from 115/60 to 72/38 and an equally pronounced transient increase in the heart rate (bottom line). type
by an open-end catheter inserted transabdominally into the uterine cavity.l* Arterial blood pressure was measured directly in the femoral artery with open-end catheter. Heart rate was obtained with a digital cardiotachometer. Relative uterine blood flow as noted in Fig. 1 was measured with a thermister needle embedded in the cervix but will not be discussed in this report. Mean arterial blood pressure was calculated as l/s the difference between systolic and diastolic pressure above the diastolic blood pressure. Intravenous injections were administered rapidly in a planned sequence through an intravenous catheter followed by a saline flush. Placebo injections were given to demonstrate that no alteration in blood pressure would be elicited by saline alone. Results A typical response to the rapid intravenous administration of oxytocin is shown in Fig. 1. Two hours post partum, with the patient
drugs
753
by a blood (thi70’
supine, 5 I.U. of oxytocin was given. The blood pressure, previously well stabilized at 115/60, began to decrease within 20 seconds and within 35 seconds had declined to 72/38. The precipitous decrease was followed by recovery during the following three minutes and a small “overshoot” to a level higher than the original pressure, returning to its preinjection level within 10 minutes after injection. The heart rate increased rapidly from an initial rate of 70 to a peak of 110 beats per minute as the blood pressure decreased. During the blood pressure recovery lleriod, the heart rate decreased but had not returned to its original level ten minutes after injection. The usual postpartum contraction pattern was converted to a tetanic type. The pattern of blood pressure decrease and recovery is always the same. The extent of the decrease and the recovery time,, however, are always directly proportional to the size of the dose of oxytocin given. We have
754
Hendricks
and
Brenner Amer.
November J. Obstet.
1, 19X Gynec.
PS 12/24/69 SUPINE OXYTOCIN
r
100 cr,
IN IU
SYSTOLIC
20-
\ \ 50, ,5==-.10.0
-/,:--I---
32
56
DIASTOLIC
IO1
0
8
16
24
TIME
Fig. 2. Blood pressure injection of oxytocin amount of reduction of the dose given.
40
48
64
72
80
INJECTION
AFTER
104 II2
120 128 136 142
IN SECONDS
T E. 11110/61 SUPINE OXYTOCIN IN fig/K9
E
E 1
96
response to oxytocin post partum. In this postpartum patient, the rapid in doses between 0.5 and 10.0 I.U. was followed by hypotension, the in both systolic and diastolic pressures being proportionate to the size
I” z
88
110
100
c g
90
8 2
80
2&
70
k % 60 5 g
50
TIME
IN SECONDS
Fig. 3. Mean arterial blood pressure response to oxytocin. A reduction in mean arterial blood pressure in a healthy male subject was demonstrated at a level of 0.003 pg per kilogram of body weight. At the largest dose used (0.100 pg per kilogram, or 3.15 I.U.), the mean arterial blood pressure was reduced by 46 per cent.
observed in one subject a significant transient decrease in pressure to doses as small as 0.1 I.U. In Fig. 2, the relationship between the size of the dose and the degree of blood pressure depression is shown. In this case, a small reduction in blood pressure was observed with 0.5 I.U., but no significant response was elicited by a dose of 0.25 I.U. With doses of 1.0, 5.0, and 10.0 I.U., the blood pressure reduction was proportionally
greater and of longer duration as the size of the dose of oxytocin was increased. The hypotensive response is illustrated in terms of the reduction in the mean arterial blood pressure when oxytocin injections were administered to a healthy male subject (Fig. 3). In this subject, doses as small as 0.003 rg per kilogram of body weight were followed by hypotension. Again, the reduction in mean arterial blood pressure and the
Volume Number
108 5
Cardiovascular
effects
----
PS. FEMALE
-TE.
MALE
of
oxytocic
5.0
drugs
755
IU
3 15 IU
~~
0
0
8
16
24
TIME
32
40
IN
SECONDS
48
56
64
72
AFTER
80
88
96
104
II2
120
INJECTION
Fig. 4. Sexual difference in cardiovascular effect. The response in the began to be evident approximately 16 seconds after injection, while (Fig. 2) the response did not begin to be evident until approximately jection.
male subject (Fig. 3) in the female subject 32 seconds after in-
Fig. 5. Effect partum), ministration significant
In Patient B. G. (18 minutes posl of oxytocin in postpartum hemorrhage. already hemorrhaging and with blood pressure approaching shock levels, the adof 5 I.U. of oxytocin in a single intravenous dose brought about a brief but additional further depression of the blood pressure to a level of 44/26.
of recovery time may be seen to be dose dependent. At the largest dose employed, 0.100 ng. per kilogram (3.15 I.U.) , the mean arterial blood pressure was reduced by 46 per cent. There is one notable difference in the response time between this male subject and the pregnant or postpartum woman. In the latter subjects, onset of the blood pressure reduction was not apparent until 24 to 28 seconds after injection, while slowness
in the male subject the blood pressure reduction began to become evident within 12 to 16 seconds. This difference in response time is shown both in the blood pressure and in the reduction of the level of the dicrotic notch (Fig. 4). A practical demonstration of the fruitlessness and possible danger of giving large intravenous stat doses of oxytocin to a patient whose blood pressure already is at shock
756
Hendricks
Fig. line) line)
and
Brenner
Amer.
November J. Obstct.
1, 1970 Gynec.
6. The administration of 0.2 mg. of ergonovine maleate intravenously was followed (top by a substantial rise in the blood pressure within 3 minutes after injection and (bottom an enormous increase in uterine contractility.
levels is given in Fig. 5. This is a segment of the record of a patient who was delivered of the second of twins 18 minutes previously. The placenta had been delivered 15 minutes previously, at which time the bIood pressure was stable at 104/58, and there was good postpartum uterine contractility. Nevertheless, the patient continued to bleed from the uterine cavity. Initial manual exploration of the uterus failed to reveal any cause for the bleeding, and after an estimated blood loss of 1,000 ml., the patient’s pressure had decreased to 70/42. At the point indicated on the record, 5 I.U. of oxytocin was given rapidly intravenously. The blood pressure decreased transiently to 44/26 within 30 seconds after injection, and the patient, who had been somewhat lethargic, became unresponsive until the blood pressure returned to 90/54 after the rapid intravenous administration of 500 ml. of physiologic saline. Repeat manual exploration of the uterus revealed a small adherent placental fragment. The uterine bleeding promptly subsided after removal of the retained fragment. Twenty seconds after the injection of oxytocin, the uterus began a contraction which persisted for 3vz minutes, The cardiovascular and uterine response to the injection of a “routine” intravenous dosage (0.2 mg. of ergonovine) in a normotensive postpartum patient is presented in Fig. 6. Within 2 minutes, uterine activity increased and persisted with increased tone, frequency, and intensity during the period
of observation after an initial tetanic-like contraction. Arterial pressure increased from 110/50 to 130/70 within 3 minutes after injection. This hypertension persisted throughout the period of observation and no unusual signs or symptoms were noted in the patient. Some have advocated the simultaneous administration of oxytocin and an ergot preparation. The cardiovascular effect of the rapid intravenous injection of such a combination is illustrated in Fig. 7. In this patient, 2 hours post partum, 10 I.U. of oxytocin and 0.2 mg. of methylergonovine were administered. The first response was typical of that seen after oxytocin. Both the systolic and diastolic blood pressures were reduced by about 40 per cent, while the heart rate rose by 20 beats per minute. Then, approximately If/2 minutes after injection, the blood pressure rose above the base-line level, and the heart rate had increased by about 30 beats per minute over the base-line level. At this point, the patient began to vomit. The blood pressure and heart rate returned nearly to the preinjection levels after about only six minutes. Comment
The foregoing illustrations principally serve to confirm the observations recorded by careful workers in previous studies. The precise mechanism whereby large doses of intravenous oxytocin induce hypotension has been the matter of debate for years. In their original work, Woodbury
758
Hendricks
and Brenner
Amer.
arterial blood pressure records, even though the blood pressure was recorded for hours following the administration of oxytocin. This seems only logical in view of the fact that oxytocin is a very rapidly metabolized drug, the biologic half-time being only in the range of 2v2 to 3 minutesZ3 Actually, the majority of patients after normal delivery would get along well without the use of any oxytocic at a1LZ4 In our own studies, we have found that after easy normal spontantous delivery there may be only minimal bleeding, even in cases in which there has not been early delivery of the placenta, fundal massage, or the use of any oxytocic. Furthermore, despite the fact that there may be adequate hemostasis, we have observed that the postpartum uterine tonus, i.e., lowest pressure between contractions, is no higher than it was before delivery and that contractions may not occur spontaneously more than once every 15 minutes.25 Nevertheless, in certain cases, it appears that the prophylactive use of oxytocics post partum is indicated. Such instances would include cases in which the uterus had been overdistended (polyhydramnios, twins, large infant), or in which there had been a par-
November J. Obstet.
1, 1970 Gynec.
titularly long or difficult labor, or in cases in which partial abruptio placentae or placenta previa had been present. But perhaps the most common reason why oxytocic agents are needed in modern obstetrics is because the uterus does not contract well immediately post partum when the patient is under general anesthesia. Thus, if the obstetrician administers general anesthesia to his patient, he may also need to administer an oxytocic post partum to counteract the effects of the general anesthesia. This brings us back to the primary point of this paper: If oxytocic agents are to be used post partum, they should be used correctly. Ergot preparations should be used only intramuscularly. Oxytocin, if it is to be used, should be administered either intramuscularly or, if a prolonged effect is desired, as a dilute intravenous drip. Used within physiologic limits, oxytocin can progood prophylaxis against excessive vide hemorrhage and be effective in the control of postpartum hemorrhage due to uterine “atony.” Given intravenously in grossly toxic doses, oxytocin, like any other agent given in grossly toxic quantities, invites disastrous consequences.
REFERENCES
1.
Condie, D. F., editor: Churchill’s
Theory and
Practice of Midwifery, New American Edition, Philadelphia, 1866, Henry C. Lea, p. 262. 2. Moir, J. C.: Brit. Med. J. 1: 1119, 1932. 3. Davis, M. E., Adair, F. L., Rogers, G., Kharasch, M. S., and Legault, R. E.: AMER. J. OBSTET. GYNEC. 29: 155, 1935. Dale, H. H.: J. Physiol. (Lond.) 34: 163, 1906. DuVigneaud, V., Ressler, C., and Trippett, S.: J. Biol. Chem. 205: 949, 1953. Rudinger, J., Honzl, .J., and Zoaral, M.: Coll. Trav. Chim. Tchecosl. 21: 770, 1956. Caldevro-Barcia. R.. Sica-Blanco. Y.. Poseiro. J. J., Gonzalez-Panizza, V., Mendez-Bauer, C., Fielitz, C., Alvarez, H., Pose, S. V., and Hendricks, C. H.: J. Pharmacol. Exp. Ther. 121: 18: 1957. 8. Shane, F.: AMER. J. OBSTET. GYNEC. 61: 188, 1951. ,
I
,
,
9. Adelman, 10. 11. 12. 13. 14. 15.
I
16. 17. 18.
Lennon, B. B.: AMER. 41: 652, -1941. E.. and Klawan. A. H.: AMER. J. OB.&ET GY~EC. 56: 366, i948. Martmer, M. J., Barland, S., and Sacca, J.: AMER. J. OBSTET. GYNEC. 64: 686, 1952. Stein, I., and Weinstein, J.: J. Lab. Clin. Med. 36: 66, 1950. Robinson, M., Newman, N., and Creevy, D.: J. A. M. A. 200: 108, 1967. Caldeyro-Barcia, R.: Acta Endocr. (Copenhagen) 34: (Suppl. 50) 41, 1960. Woodbury, R. A., Hamilton, W. F., Volpitto, P. P., Abreu, B. E., and Harper, H. T.: J. Pharmacol. 81: 95, 1944. Mayes, B. T., and Shearman, R. P.: J. Obstet. Gynaec. Brit. Comm. 63: 812, 1956. Bergquist, J. R., and Kaiser, I. H.: Obstet. Gynec. 13: 360, 1959. Alvarez, H., and Caldeyro-Barcia, R.: Surg. Gynec. Obstet. 91: 1, 1950.
J. OBST~T. Kanter. A.
M.
H.,
GY~EC.
and
Volume 108 Number 5
19. Pickford, M.: In Caldeyro-Barcia, R., and Heller, H., editors: Oxytocin, Oxford, 1961, Pergamon Press, Inc. 20. Kitchin, A. H., Lloyd, S. M., and Pickford, M.: Clin. Sci. 18: 399, 1959. 2 1. Nakano, J., and Fisher, R. D.: J. Pharmacol. Exp. Ther. 142: 206, 1963. 22. Bonica, J. J.: In Principles and Practice of
Cardiovascular
effects
of oxytocic
drugs
759
Obstetric Analgesia and Anesthesia, Philadelphia, 1969, F. A. Davis Company, p. 320. 23. Saameli, K.: AMER. J. OBSTET. GYNEL 85: 186, 1963. 24. Crisp, W. E.: Obstet. Gynec. 7: 470, 1956. 25. Hendricks, C. H., Eskes, T. K. A. R., and Saameli, K.: AMER. J. OBSTET. GYIL.K. 83: 890,
1962.
Discussion CHARLES P. MCCARTNEY, Chicago, Illinois. During the past two decades, there has been a plethora of reports evaluating the cardiovascular effects of oxytocics administered for the prevention and management of postpartum hemorrhage. Dr. Hendrick’s excellently designed study emphasizes the inadequacies of the majority of these reports and sets the standard for clinical investigation in this field. The essayist accurately defines the population evaluated and employs valid criteria that are precisely asessed. His data, therefore, enhance our knowledge of the acute cardiovascular effects of oxytocin and ergonovine under the conditions that he specifies and places oxytocin administered by intravenous drip in physiologic doses in the position to challenge the derivatives of ergot as the preferred agent for the management of the placental stage of labor. The adverse cardiovascular effects of both classes of oxytocics are mediated by variables that include the biologic aberations of abnormal pregnant states, as well as those introduced by the physician when he administers anesthetics, narcotics, diuretics, and antihypertensives. In evaluating the relative merits of oxytocin and the derivatives of ergot, a definitive assessment of these variables is desirable. It is hoped that Dr. Hendricks and his group will conduct these studies. The alkaloids of ergot have contributed significantly to obstetric management during the past 40 years. If the superiority of oxytocin for the prevention and management of postpartum hemorrhage is established they can be retired with honor. DR. ROBERT A. MUNSICK, Albuquerque, New Mexico. I would like to commend Drs. Hendricks and Brenner on bringing this to our attention.. The immediate vasodepressor effect of oxytocin in posterior pituitary preparations was, of course, described as long ago as 1912 by Paton and Watson in ducks. Coon described an assay DR.
of oxytocin utilizing this “avian depressor“ response in chickens in 1930. This assay is still used by the United States Pharmacopeia for standardizing oxytocin injection. The clear documentation by Hendricks and Brenner that oxytocin causes a vasodepressor response in women, too, should alert obstetricians to possible untoward side effects of rapid, bolus injections of this peptide. In my opinion, oxytotin should never be administered in this manner. DR. FRITZ F. FUCHS, New York, New York. I wonder, Dr. Hendricks, if your observation that very large doses of oxytocin are followed by nausea could result in a secondary release of vasopressin which could compound thr effect on the cardiovascular system? DR. BRENNER (Closing). The major cardiovascular effects of the rapid intravenous injection of oxytocin, as Dr. Munsick has pointed out? have been known for a long time. Yet, many obstetricians continue to administer these oxytocics in grossly unphysiologic amounts. The magnitude of the cardiovascular effect is dependent upon the dosage used. Both men and postpartal women respond with progressively more marked tachycardia and hypotension to increasing doses of oxytocin. In postpartum hemorrhage with shock, when one feels he desparatcly needs increased uterine activity for hemostasis, the rapid injection of oxytocin results in a further decrease in blood pressure. Administration of oxytocin intramuscularly, subcutaneously, or by dilute infusion rapidly increases uteritte activity without any accompanying cardiovascular response. Injection of ergonovine or methylergonovine may result in a prolonged elevation of blood pressure. Cardiovascular effects of oxytocin and methylergonovine in combination do not cancel one another, but the hypotension from oxytocin is merely followed by the hvpertension from methylergonovine. To answer Dr. Fuchs’ question, essentially nothing is known about the release of vasopres-
760
Hendricks
and
Brenner
sin resulting from the rapid infusion of oxytocin. This has not been studied. Although nausea and vomiting are observed after administration of intravenous oxytocin, it is more common following ergot preparations. We did not wish to give the impression that methylergonovine or ergono-
Amer.
November J. Obstet.
1, 1970 Gynec.
vine maleate should not be &ken under any circumstance in the postpartum state or that it should be replaced by oxytocin for all postparturn patients. We only wished to say that none of these drugs should be given by intravenous stat doses.