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Effect of sparteine sulfate upon uterine activity in human pregnancy
volume
91
January
American
number I,
1
1965
of Obstetrics and Gynecology
Journal
OBSTETRICS
I
Effect of sparteine sulfate upon uterine activity CHARLES DAVID IAN LUIS Cleveland,
W. VAN A.
in human pregnancy
H.
HENDRICKS,
J.
REID,
PRAAGH, CIBILS,
M.D.
M.D. M.D.* M.D.
Ohio
S PART EI N E sulfate in recent years has achieved wide popularity for the purpose of the induction of labor and the enhancement of uterine activity. Among its “most outstanding” advantages are said to be the fact that it can be administered intramuscularly, does not require constant supervision, and that it has a wide margin of safety.l More recently, various reports have appeared in-
From the Department of Obstetrics and Gynecology, Western Reserve University School of Medicine. This investigation was supported in part by Grant No. HD 00264-09 from the National Institute of Child Health and Human Development, United States Public Health Service. *Postdoctoral Fellow under Grant 5TL GM-974-02, Reproductive Physiology Training Grant.
dicating that sparteine sulfate, like other oxytocic drugs, may be associated occasionally with obstetric catastrophes.2 The purpose of the present study has been to observe the effect of sparteine sulfate upon uterine activity in late human pregnancy in labor and in the early puerperium. If sparteine sulfate is to be used as an oxytocic drug, it is pertinent to compare its effects with the uterine activity seen in normal labor and also with the effects of oxytocin as it is being currently employed. Materials
and
methods
Thirty patients have been studied before, during, and after the administration of sparteine sulfate. Twenty-five received the medication intramuscularly, while 5 received intravenous infusion of the drug.
2
Hendricks
et al.
One to three intrauterine catheters were placed transabdominally to permit a continuous record of intrauterine pressure alterations? Most of the subjects also had a continuous arterial blood pressure record made from a catheter placed in the left femoral artery. Results
Sparteine sulfate administered intramuscularly. 1. When the pre-existing activity was already well coordinated sparteine sulfate appeared to exert a mild oxytocic effect in doses of 150 mg. intramuscularly. Under these conditions, the uterine activity appeared to remain essentially as well coordinated as it was before the administration of spartrine sulfate. The same statement holds true for instances in which multiple doses of
Fig. 1. Induction of labor. The well-coordinated tivity (Line A) was essentially unchanqed I hour of sparteine sulfate (Line B). The administration per minute resulted in active labor,
sparteine sulfate were administered intramuscularly. The well-coordinated pattern of spontaneous activity shown in Fig. 1 rcmained well coordinated after sparteine sulfate was given. although an intravenous infusion of osytocin was required to complete the labor. 2. When the spontaneous uterine activity was not well coordinated, the intramuscular administration of sparteine sulfate, if it increased uterine activity at all, usually increased the activity while leaving the preexisting degree of incoordination almost completely unaltered. Increased uterine activ,ity without improved coordination is well illustrated in Figs. 2 and 3. When labor is induced by the use of sparteine sulfate alone, and no supplementary oxytorin is employed. there may be a partial incoordination which continues through-
spontaneous uterine acafter the administration of oxytocin at 5 mu.
Volume Number
91 I
Sparteine
sulfate
and
uterine
activity
in pregnancy
3
Fig. 2. Induction
of labor at term. A large amount of spontaneous uterine activity was present, but the pattern was not well coordinated (top line). The administration of a single dose of sparteine sulfate intramuscularly was followed by increased uterine activity and also by bizarre changes in the pattern which persisted throughout the labor.
out labor (Fig. 2). In Fig. 2 the uterine contractions appear to have become even less coordinated than previously after the administration of sparteine sulfate, and in the third and fourth lines small incomplete contractions of great frequency begin to ap-’ pear. These are somewhat reminiscent of what is seen in response to the administration of ergot preparations post partum. An almost equally bizarre response appears at the end of labor in the tracing shown in Fig. 3. Sparteine sulfate administered intravenousIy. Five intravenous infusions were carried out under laboratory conditions. First, it was elected to explore the dosage of 2.5 mg. per minute for 1 hour periods to see how it compared with the previously suggested dosage of 150 mg. administered intramuscularly at intervals not more frequent than every 1 hour. Fig. 4 shows the modest response resulting from a 1 hour adminis-
tration in an antepartum patient. In this individual, while the coordination of the uterine contractions did not definitely improve, neither did it become significantly worse. Immediately after the baby was born, however, the observations being continued, another infusion of sparteine sulfate was begun, this time at the rate of 5 mg. per minute by constant pump infusion. A grossly abnormal response continued throughout the administration of the drug at this dosage rate. The pattern resembled the type of response sometimes seen with the administration of ergot preparations post partum. Half an hour after the infusion was discontinued, however, the pattern had returned to what we consider to be nearer a normal postpartum pattern. A final example shows a poorly coordinated type of spontaneous uterine activity (Fig. 6). The uterine activity was increased, and appeared to become temporarily par-
4
Jammy
Hendricks et al.
Am. J. Ohst. &
tially coordinated by the infusion of sparteine sulfate at 2.5 mg. per minute, intravenously by constant pump infusion. After lJ/2 hours of the infusion, however, the response became extremely bizarre and, as may be seen in Fig. 7, Line G, the pattern resembled that seen after the administration of ergot preparations. The marked dysrhythmia continued until the end of labor. The
TIME
1, 1%5 Gynec.
actual progress in labor, while not excellent, was relatively rapid once it got underway. Comparison between the action of sparteine sulfate an ergot preparation
and
Fig. 8 illustrates what a small dosage of crgonovine infused intravenously can do to the previously well-coordinated action of the
(MINUTES)
Fig. 3. Induction of labor at term. The spontaneous uterine activity was only partially coordinated with the patient either in the supine or lateral position (Line A). A single dose of sparteine sulfate (150 mg intramuscularly) was followed by increased uterine activity (Lines B, C, and D ) Bizarre changes in the activity pattern appeared about 1% hours after the administration of the drug (Line E). in spite of the fact that amniotomy had been done. Some aspects of the dysrhythmia remained throughout the rest of labor (Line F).
Volume Number
91 1
Sparteine
sulfate
TIME
and
uterine
activity
in
pregnancy
5
(MINUTES)
Fig. 4. Induction of labor at 42% weeks’ gestation. The spontaneous uterine activity of prelabor was already well coordinated (Line A). An intravenous infusion of sparteine sulfate at the rate of 2.5 mg. per minute over a 1 hour period increased uterine activity (Lines B and C). During a 1 hour infusion of oxytocin at 2 mu. per minute, the uterine activity further increased (Line D), but subsided somewhat after the oxytocin was discontinued (Line E) .
uterus post partum. The total dose employed during 1 hour (84 micrograms) was less than half the usual single postpartum dose which is given either intramuscularly or at a single intravenous injection postpartum in many places in this country. We have recorded similar responses in postpartum patients after the oral administration of 0.2 mg. (200 micrograms) of ergonovine maleate. Similar bizarre manifestations have been pointed out in the cases presented here in which sparteine sulfate was used. In addition to the similarity of their observed effects upon uterine activity, sparteine sulfate and ergonovine are similar in the duration of the observed response. Ergo-
novine is l-mown to be a long-acting oxytocic agent, as compared to oxytocin. In a number of cases studied the action of 150 mg. sparteine sulfate intramuscularly is evident nearly 4 hours later. Any variations in arterial blood pressure in this series were only reflections of those changes induced in uterine contractility*; no direct vascular changes were seen to result from the administration of sparteine sulfate by either the intramuscular or the intravenous route. Comment
It has become customary in assessing alterations in uterine activity during the course
6
Hendricks
January I. I%l, Am. J. Ohs. & Cynec.
et al.
of spontaneous labor or as the result of the administration of oxytocin to characterize the uterine response in terms of alterations in intensity or frequency of the contractions. This method of assessment of uterine activity has served very well for describing quantitative alterations in uterine activity. From the study reported here, however, the authors have come to the conclusion that the most characteristic alteration of uterine activity induced by sparteine sulfate is not a quantitative one, but rather a qualitative change. Thus, the charting of quantitative alterations of frequencyand intensity of
TIME
contractions is, at best, of limited value in describing changes in uterine activity resulting from the use of this drug. It is for this reason that detailed summary charts dealing with alterations in intensity and frequency are not included here. A word should be said about the question of “tonus” which is brought up so often in studies such as this. Tonus is ordinarily considered to be the “resting pressure” when the uterus is not in the active part of its contraction cycle. Hypertonus, by definition, is an elevation of this resting pressure. The words tonus and hypertonus and their mis-
(MINUTES)
Fig. 5. Same case as Fig. 18. Postpartum record. After the birth of baby at 2:37 P.M., the infusion of sparteine sulfate was resumed, but time at the rate of 5 mg. per minute, with the production of grossly normal uterine activity (Lines F, G, and H) Half an hour after the fusion was discontinued, the activity was becoming much better coordinated (Lines I, 1, and K) .
the this abin-
Sparteine
Fig. 6. Induction of labor at term. The spontaneous uterine activity was poorly coordinated (Lines A, B, and C). The infusion of sparteine sulfate at the rate of 2.5 mg. per minute brought about an increase in the uterine activity, but failed to coordinate the contractility pattern.
n
sulfate
“) 11:22AM supirr *tart Sp;rrtamr 2 5 ml,min
and
uterine
activity
in pregnancy
7
I\’
,, -r1 la’s: .*I.4 sop>re rrtcr l,L Hr sparmne
TIME (MINUTES)
0
Fig. 7. Same
case as Fig. 6. The contractility pattern remained poorly coordinated until late labor (Lines F, G, and ff). When the infusion rate was increased to 5 mg. per minute for the final 18 minutes of labor, the pattern remained most bizarre, even though the uterine activity increased (Lines I and 1).
1) 2.21 PM Supxne .4mniatomy 232 PM lncrrase Sparteme to 5 mg. ,I”,“.
50
0~
I I I I I r Jb 2:36 PM supine sparteim 5 mg.
I I End Of Labor
I
TIME (MINUTES)
I
I
I
I
I
r
8
Hendricks
et al. Am.
uses have led to great confusion and misinterpretation in the study of many drugs. Careful perusal of the individual tracings reproduced here should help to clarify this problem. We have not been able to show any hypertonus, as such, except in very rare instances in our laboratory. What most often passes for hypertonus is not a change in the resting phase of the contraction cycle, but rather an alteration in the contraction cycle itself which, if it breaks up into enough
January 1, l!X5 J. Obst. & Gynec.
components, may result in the failure to return to the so-called “resting pressure” over a period of time. The relative decreases in pressure when a series or a “complex” of such incomplete contractions occur are often called “the tonus,” and because those pressures are above the so-called normal resting pressure of the uterus, “hypertonus” is said to be present. This problem goes far beyond a mere semantic argument, because it involves the basic understanding by clin-
Fig. 8. Normal spontaneous labor at term (Lines A and B) was followed by a normal postpartum pattern of spontaneous uterine activity (Line C), no oxytocic agent having been employed in any stage of labor. The infusion of 0.084 mg. of ergonovine during a 1 hour period resulted in bizarre changes in the pattern of uterine activity (Lines D, E, and F).
Volume Number
91 1
icians of the mechanism ulated labor and action
Sparteine
of normal and stimof various drugs.
Summary
Sparteine sulfate administered intramuscularly in doses of 150 mg. has a mildly oxytocic effect on uterine contractility. The effect is enhanced by repeated intramuscular administration or by the intravenous administration of the drug at 2.5 mg. per minute over a sufficiently long period of
REFERENCES
1. 2.
Plentl, A. A., Friedman, E. A., and Gray, M. J.: AM. J. OBST. & GYNEC. 82: 1332, 1961. Kaminetsky, H. A.: Obst. & Gynec. 21: 512, 1963.
sulfate
and
uterine
activity
in pregnancy
9
time. It does not tend to improve the coordination of a uterine contractility pattern where the uterine contractility pattern is incoordinate prior to its administration. Under certain conditions it may produce an increasingly uncoordinated pattern of uterine activity. In its duration of action, and in its effect upon uterine contractility, sparteine sulfate resembles the ergot preparations more than it resembles oxytocin preparations.
3.
4.
Hendricks, Saameli, 1962. Hendricks, 76: 969,
K.:
C. H., Eskes, AM. J. OBST.
C. 1958.
H.:
AM.
T.
K.
A.
& GYNEC.
J.
OBST.
&
B., and 83: 890, GYNEC.
91
January
American
number I,
1
1965
of Obstetrics and Gynecology
Journal
OBSTETRICS
I
Effect of sparteine sulfate upon uterine activity CHARLES DAVID IAN LUIS Cleveland,
W. VAN A.
in human pregnancy
H.
HENDRICKS,
J.
REID,
PRAAGH, CIBILS,
M.D.
M.D. M.D.* M.D.
Ohio
S PART EI N E sulfate in recent years has achieved wide popularity for the purpose of the induction of labor and the enhancement of uterine activity. Among its “most outstanding” advantages are said to be the fact that it can be administered intramuscularly, does not require constant supervision, and that it has a wide margin of safety.l More recently, various reports have appeared in-
From the Department of Obstetrics and Gynecology, Western Reserve University School of Medicine. This investigation was supported in part by Grant No. HD 00264-09 from the National Institute of Child Health and Human Development, United States Public Health Service. *Postdoctoral Fellow under Grant 5TL GM-974-02, Reproductive Physiology Training Grant.
dicating that sparteine sulfate, like other oxytocic drugs, may be associated occasionally with obstetric catastrophes.2 The purpose of the present study has been to observe the effect of sparteine sulfate upon uterine activity in late human pregnancy in labor and in the early puerperium. If sparteine sulfate is to be used as an oxytocic drug, it is pertinent to compare its effects with the uterine activity seen in normal labor and also with the effects of oxytocin as it is being currently employed. Materials
and
methods
Thirty patients have been studied before, during, and after the administration of sparteine sulfate. Twenty-five received the medication intramuscularly, while 5 received intravenous infusion of the drug.
2
Hendricks
et al.
One to three intrauterine catheters were placed transabdominally to permit a continuous record of intrauterine pressure alterations? Most of the subjects also had a continuous arterial blood pressure record made from a catheter placed in the left femoral artery. Results
Sparteine sulfate administered intramuscularly. 1. When the pre-existing activity was already well coordinated sparteine sulfate appeared to exert a mild oxytocic effect in doses of 150 mg. intramuscularly. Under these conditions, the uterine activity appeared to remain essentially as well coordinated as it was before the administration of spartrine sulfate. The same statement holds true for instances in which multiple doses of
Fig. 1. Induction of labor. The well-coordinated tivity (Line A) was essentially unchanqed I hour of sparteine sulfate (Line B). The administration per minute resulted in active labor,
sparteine sulfate were administered intramuscularly. The well-coordinated pattern of spontaneous activity shown in Fig. 1 rcmained well coordinated after sparteine sulfate was given. although an intravenous infusion of osytocin was required to complete the labor. 2. When the spontaneous uterine activity was not well coordinated, the intramuscular administration of sparteine sulfate, if it increased uterine activity at all, usually increased the activity while leaving the preexisting degree of incoordination almost completely unaltered. Increased uterine activ,ity without improved coordination is well illustrated in Figs. 2 and 3. When labor is induced by the use of sparteine sulfate alone, and no supplementary oxytorin is employed. there may be a partial incoordination which continues through-
spontaneous uterine acafter the administration of oxytocin at 5 mu.
Volume Number
91 I
Sparteine
sulfate
and
uterine
activity
in pregnancy
3
Fig. 2. Induction
of labor at term. A large amount of spontaneous uterine activity was present, but the pattern was not well coordinated (top line). The administration of a single dose of sparteine sulfate intramuscularly was followed by increased uterine activity and also by bizarre changes in the pattern which persisted throughout the labor.
out labor (Fig. 2). In Fig. 2 the uterine contractions appear to have become even less coordinated than previously after the administration of sparteine sulfate, and in the third and fourth lines small incomplete contractions of great frequency begin to ap-’ pear. These are somewhat reminiscent of what is seen in response to the administration of ergot preparations post partum. An almost equally bizarre response appears at the end of labor in the tracing shown in Fig. 3. Sparteine sulfate administered intravenousIy. Five intravenous infusions were carried out under laboratory conditions. First, it was elected to explore the dosage of 2.5 mg. per minute for 1 hour periods to see how it compared with the previously suggested dosage of 150 mg. administered intramuscularly at intervals not more frequent than every 1 hour. Fig. 4 shows the modest response resulting from a 1 hour adminis-
tration in an antepartum patient. In this individual, while the coordination of the uterine contractions did not definitely improve, neither did it become significantly worse. Immediately after the baby was born, however, the observations being continued, another infusion of sparteine sulfate was begun, this time at the rate of 5 mg. per minute by constant pump infusion. A grossly abnormal response continued throughout the administration of the drug at this dosage rate. The pattern resembled the type of response sometimes seen with the administration of ergot preparations post partum. Half an hour after the infusion was discontinued, however, the pattern had returned to what we consider to be nearer a normal postpartum pattern. A final example shows a poorly coordinated type of spontaneous uterine activity (Fig. 6). The uterine activity was increased, and appeared to become temporarily par-
4
Jammy
Hendricks et al.
Am. J. Ohst. &
tially coordinated by the infusion of sparteine sulfate at 2.5 mg. per minute, intravenously by constant pump infusion. After lJ/2 hours of the infusion, however, the response became extremely bizarre and, as may be seen in Fig. 7, Line G, the pattern resembled that seen after the administration of ergot preparations. The marked dysrhythmia continued until the end of labor. The
TIME
1, 1%5 Gynec.
actual progress in labor, while not excellent, was relatively rapid once it got underway. Comparison between the action of sparteine sulfate an ergot preparation
and
Fig. 8 illustrates what a small dosage of crgonovine infused intravenously can do to the previously well-coordinated action of the
(MINUTES)
Fig. 3. Induction of labor at term. The spontaneous uterine activity was only partially coordinated with the patient either in the supine or lateral position (Line A). A single dose of sparteine sulfate (150 mg intramuscularly) was followed by increased uterine activity (Lines B, C, and D ) Bizarre changes in the activity pattern appeared about 1% hours after the administration of the drug (Line E). in spite of the fact that amniotomy had been done. Some aspects of the dysrhythmia remained throughout the rest of labor (Line F).
Volume Number
91 1
Sparteine
sulfate
TIME
and
uterine
activity
in
pregnancy
5
(MINUTES)
Fig. 4. Induction of labor at 42% weeks’ gestation. The spontaneous uterine activity of prelabor was already well coordinated (Line A). An intravenous infusion of sparteine sulfate at the rate of 2.5 mg. per minute over a 1 hour period increased uterine activity (Lines B and C). During a 1 hour infusion of oxytocin at 2 mu. per minute, the uterine activity further increased (Line D), but subsided somewhat after the oxytocin was discontinued (Line E) .
uterus post partum. The total dose employed during 1 hour (84 micrograms) was less than half the usual single postpartum dose which is given either intramuscularly or at a single intravenous injection postpartum in many places in this country. We have recorded similar responses in postpartum patients after the oral administration of 0.2 mg. (200 micrograms) of ergonovine maleate. Similar bizarre manifestations have been pointed out in the cases presented here in which sparteine sulfate was used. In addition to the similarity of their observed effects upon uterine activity, sparteine sulfate and ergonovine are similar in the duration of the observed response. Ergo-
novine is l-mown to be a long-acting oxytocic agent, as compared to oxytocin. In a number of cases studied the action of 150 mg. sparteine sulfate intramuscularly is evident nearly 4 hours later. Any variations in arterial blood pressure in this series were only reflections of those changes induced in uterine contractility*; no direct vascular changes were seen to result from the administration of sparteine sulfate by either the intramuscular or the intravenous route. Comment
It has become customary in assessing alterations in uterine activity during the course
6
Hendricks
January I. I%l, Am. J. Ohs. & Cynec.
et al.
of spontaneous labor or as the result of the administration of oxytocin to characterize the uterine response in terms of alterations in intensity or frequency of the contractions. This method of assessment of uterine activity has served very well for describing quantitative alterations in uterine activity. From the study reported here, however, the authors have come to the conclusion that the most characteristic alteration of uterine activity induced by sparteine sulfate is not a quantitative one, but rather a qualitative change. Thus, the charting of quantitative alterations of frequencyand intensity of
TIME
contractions is, at best, of limited value in describing changes in uterine activity resulting from the use of this drug. It is for this reason that detailed summary charts dealing with alterations in intensity and frequency are not included here. A word should be said about the question of “tonus” which is brought up so often in studies such as this. Tonus is ordinarily considered to be the “resting pressure” when the uterus is not in the active part of its contraction cycle. Hypertonus, by definition, is an elevation of this resting pressure. The words tonus and hypertonus and their mis-
(MINUTES)
Fig. 5. Same case as Fig. 18. Postpartum record. After the birth of baby at 2:37 P.M., the infusion of sparteine sulfate was resumed, but time at the rate of 5 mg. per minute, with the production of grossly normal uterine activity (Lines F, G, and H) Half an hour after the fusion was discontinued, the activity was becoming much better coordinated (Lines I, 1, and K) .
the this abin-
Sparteine
Fig. 6. Induction of labor at term. The spontaneous uterine activity was poorly coordinated (Lines A, B, and C). The infusion of sparteine sulfate at the rate of 2.5 mg. per minute brought about an increase in the uterine activity, but failed to coordinate the contractility pattern.
n
sulfate
“) 11:22AM supirr *tart Sp;rrtamr 2 5 ml,min
and
uterine
activity
in pregnancy
7
I\’
,, -r1 la’s: .*I.4 sop>re rrtcr l,L Hr sparmne
TIME (MINUTES)
0
Fig. 7. Same
case as Fig. 6. The contractility pattern remained poorly coordinated until late labor (Lines F, G, and ff). When the infusion rate was increased to 5 mg. per minute for the final 18 minutes of labor, the pattern remained most bizarre, even though the uterine activity increased (Lines I and 1).
1) 2.21 PM Supxne .4mniatomy 232 PM lncrrase Sparteme to 5 mg. ,I”,“.
50
0~
I I I I I r Jb 2:36 PM supine sparteim 5 mg.
I I End Of Labor
I
TIME (MINUTES)
I
I
I
I
I
r
8
Hendricks
et al. Am.
uses have led to great confusion and misinterpretation in the study of many drugs. Careful perusal of the individual tracings reproduced here should help to clarify this problem. We have not been able to show any hypertonus, as such, except in very rare instances in our laboratory. What most often passes for hypertonus is not a change in the resting phase of the contraction cycle, but rather an alteration in the contraction cycle itself which, if it breaks up into enough
January 1, l!X5 J. Obst. & Gynec.
components, may result in the failure to return to the so-called “resting pressure” over a period of time. The relative decreases in pressure when a series or a “complex” of such incomplete contractions occur are often called “the tonus,” and because those pressures are above the so-called normal resting pressure of the uterus, “hypertonus” is said to be present. This problem goes far beyond a mere semantic argument, because it involves the basic understanding by clin-
Fig. 8. Normal spontaneous labor at term (Lines A and B) was followed by a normal postpartum pattern of spontaneous uterine activity (Line C), no oxytocic agent having been employed in any stage of labor. The infusion of 0.084 mg. of ergonovine during a 1 hour period resulted in bizarre changes in the pattern of uterine activity (Lines D, E, and F).
Volume Number
91 1
icians of the mechanism ulated labor and action
Sparteine
of normal and stimof various drugs.
Summary
Sparteine sulfate administered intramuscularly in doses of 150 mg. has a mildly oxytocic effect on uterine contractility. The effect is enhanced by repeated intramuscular administration or by the intravenous administration of the drug at 2.5 mg. per minute over a sufficiently long period of
REFERENCES
1. 2.
Plentl, A. A., Friedman, E. A., and Gray, M. J.: AM. J. OBST. & GYNEC. 82: 1332, 1961. Kaminetsky, H. A.: Obst. & Gynec. 21: 512, 1963.
sulfate
and
uterine
activity
in pregnancy
9
time. It does not tend to improve the coordination of a uterine contractility pattern where the uterine contractility pattern is incoordinate prior to its administration. Under certain conditions it may produce an increasingly uncoordinated pattern of uterine activity. In its duration of action, and in its effect upon uterine contractility, sparteine sulfate resembles the ergot preparations more than it resembles oxytocin preparations.
3.
4.
Hendricks, Saameli, 1962. Hendricks, 76: 969,
K.:
C. H., Eskes, AM. J. OBST.
C. 1958.
H.:
AM.
T.
K.
A.
& GYNEC.
J.
OBST.
&
B., and 83: 890, GYNEC.