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Cardiovascular reactions to pitocin
CARDIOVASCULAR
REACTIONS
TO PITOCIN”
JAMES
R.
WILLIAM
(From
the Obstetric
Deportment,
Methodist
REINBERGER,
F.
MACKEY,
M.D., M.D.,
AND MEMPHIS,
TENN.
Hospital)
T
HE parenteral administration of posterior pituitary extracts for prevention or control of postpartum hemorrhage has been a routine procedure for almost half a century. This practice has been so successful that one now hesitates to leave the newly postpartum patient until one of the posterior pituitary extracts has been given. And yet this administration is not without danger. Reactions of unusual character vary from mild to severe, and sometimes fatal. Many mild reactions go unrecognized, and even severe ones are overshadowed by, or more often are attributed to, the operative procedure, blood loss, or the anesthetic. These reactions may result from a peculiar sensitivity to the drug or other component elements of the posterior pituitary gland solution. The manufacturers of posterior pituitary extract realize this fact, and have subsequently divided the extract of posterior lobe into more refined elements. They have separated a pressor element called Pitressin, and an oxytocic element, called Pitocin. They have also found that, regardless of the technique used in separating these elements, a small amount of each factor is present in each refined preparation. The U. S. Pharmacopeia permits such an assay at the present time. It is for this reason that the extract of the whole posterior pituitary lobe should not be used when a specific reaction is desired, especially in obstetrics where only the oxytocic element is desired. Pitocin is the drug of choice,gl I1 but even our use of Pitocin for induction of labor and control of postpartum hemorrhage has produced both mild and severe reactions. Pitocin reactions may be due to unusual sensitivity of the patient, to synergistic action with the anesthetic agent, and even to improper preparation and assay. These latter were reported in 1953 with certain lots of Pitocin having 18 pressor units per cubic centimeter rather than l/g unit or 1ess.3 These lots of Pitocin were recalled by the drug house but it is possible that the severe reactions which we report here could have been due to the pressor factor rather than the oxytocic element. Recently, a synthetic Pitocint has been made available which is said to be absolutely free of the pressor fact0r.l’ 2, * cians
*Presented at the Twenty-fifth Annual and Gynecologists, Omaha. Neb., Oct. ?Syntocinon, Sandoz Pharmaceuticals.
Meeting of the Central 24, 25, and 26. 1957.
Association
of Obstetri-
Volume Number
76 2
CARDIOVASCULAR
REACTIONS
TO
PITOCIN
‘28CI
Pharmacology of Pitocin.‘O -The effect of Pitocin on blood pressure is variable; occasionally, there is a rise. It increases cardiac output. Its effect. on the coronary arteries is theoretically nil, but actually they are constricted. The electrocardiogram is said by many authors not to be affected, but our case indicates that this may not always be true. The peripheral circulation is theoretically not affected, but actually shock has been reported. There ia no change in metabolism. Contraction of the pregnant uterus is immediatcb and intense. Cyclopropane gas is a parasympathetic stimulant. It, causes bronchial constriction which may precipitate an asthamtic attack in the susceptible patient. It also tends to produce cardiac arrhythmias with displacements of the rhythm centers. The range is bradycardia to ventricular fibrillation. Thf> combination of two parasympathetic stimulants, cyclopropane and pituitary extract, is most danger0us.l’ In the circulatory system, they have a synIt is ergistic tendency to produce hypertension and cardiac arrhythmias. important, therefort, never to use posterior pituitary extract when an oxytoc?ic is indicated in a patient under eyclopropane anesthesia. A survey of hospitals reveals that more attention should be directed to the type of posterior pituitary extract being used in the departments of obstetrics. The department of obstetrics should not have any surgical Pituitrin for this preparation should never be used as an oxytocic. The department of surgical gynecology should have both obstetrical and surgical Pituitrin and., if prescribed, the type of Pituitrin should be specifically ordered; otherwlsc. surgical Pituitrin could be given. Case Report Pnst History.-Appendectomy of pelvic adhesions were performed 1952, because of primary inertia.
was performed in 1944. in 1949. A cesarean
Right section
oophorectomy was performed
and @is July 4>
Hospital Course.-The patient was admitted to Methodist HospitaI in November, 1954, at 38 weeks’ gestation for elective cesarean section. The blood pressure was llZ/iO; hematocrit, 44; and urinalysis, negative. il spinal anesthetic was given by a doctoranesthetist. An incision was made, removing the old scar. Omental adhesions hatL to btX released before the pregnant uterus could be exposed. The uterus was then opened arrll a normal male infant was extracted. The infant weighed 6 pounds, 9 ounces, and crird immediately. The placenta and membranes were removed. Pitocin, 1 cc., was then injected into the uterine muscle. The patient, who had been perfectly calm and composed, then complained immediately of severe pain in the chest, associated with shortness 11f breath. This reaction was associated with a rapidly rising pulse rate from 55 to 1% per minute. This pulse elevation lasted about 30 minutes. At the time the procedure The was finished (1 to lys hours), the pulse was 95 per minute, blood pressure 90/60. patient was sent to her room awake, talking, and in excellent condition. Postoperative Course.-An electrocardiogram was ordered 3 hours after operation This was ordered for two reasons: first, because of the unusual reaction of this patient, after injection of Pitocin into the uterus and, second, because several months previousIS an unusually severe similar reaction had occurred in another patient but, unfortunately, no electrocardiogram was obtained. The electrocardiogram was interpreted by Dr. J. B. Witherington as an abnormal tracing showing coronary spasm, probably due to the administration of Pitocin into the uterus at the time of cesarean section. The first postoperative days were stormy, with oxygen necessary for dyspnea, and Wangensteen suction for distention. Blood transfusions and general supportive measures were given. During these 3 days the pulse would rise to 150 per minute at times and would skip every third beat. Ry the third postoperative day, however, a repeat electrocardiogram showed
290
REINBER,GER
AND
.4m. J. Obst. & Gyrm. August, IO58
MACKEY
“a normal tracing; the abnormalities previously present may have been due to coronary The insufficiency or acute pulmonary embolism,” as interpreted by Dr. Warren Kyle. blood pressure was 110/70 and pulse 80 on the third postoperative day. From then on, recovery was rapid and the patient was discharged home on the tenth postoperative day. Follow-Up Examinations.-For the first 2 years there were no significant findings except that at times the patient’s pulse would drop to 30 or 40 per minute. These attacks At the last visit, 3 years postoperatively, were associated with some distress and weakness. in October, 1957, there were no complaints or abnormalities.
Comment We have now discontinued the use of Pitocin or any drug in the uterus at the time of cesarean section. Since we are not injecting any drug into the uterus, we have found that we really do not need any oxytocics in most cases. If an oxytocic is needed, it can be given intramuscularly by the anesthetist. Intravenous Pitocin after normal delivery has just lately been shown to cause a more frequent and higher rise in blood pressure than either This is very important, especially since it implies Ergotrate or Methergine.4 that Pitocin is dangerous in toxemia.12 We do not completely agree with the statement of Dr. Eastman5 in the “It is probable that intramuscular Pitocin eleventh edition of his textbook: has no place in the first or second stages of labor in modern obstetrics.” We do, however, heartily agree with his words of caution as to the use of an intravenous drip of Pitocin. He contends that intravenous-drip Pitocin is safer than its intramuscular use; yet, to our knowledge, in Memphis, 3 cesarean sections have been done recently because of tetanic uteri and fetal distress following Pitocin infusions. Also, 3 ruptures of the uterus have occurred in Memphis, caused by the use of intravenous-drip Pitocin. Other tragic accidents, even death, have been reported elsewhere.‘j We cannot recall such cases following intramuscular Pitocin, even in 1 cc. doses.
Summary A case of coronary
constriction during a cesarean section under spinal anesthesia has been reported. It is believed that this complication was due to the injection of Pitocin into the uterus.
1. Dieckmann? W. J., and Fugo, .N. W.: Exhibit, Experimental Biology, Chicago, April, 1957. 2. Bishop, E. N.: To be published. 3. Jackson, R. L.: Personal communication. West. J. Surg. 64: 22, 1956. 4. MeGinty, L. B.: Williams Obstetrics, ed. 11, 5. Eastman, N. J.: Crofts, Inc., p. 831. 6. Bamo, Alex, Freeman, D. W., and Belleville, T. 7. Passloe, C. P., Morris, L. B., and Orth, Sidney 8. Boissonnas, I&. N., Guttmann, S., Juguerowd, P. acta 36: 491, 1955. 9. Hellman, L. M., Kohl, S. G., and Schechter, N.
Federation
New P.: 0.:
H.,
York,
States,
Fifteenth
1956,
Obst. Jr Gynec. Anesthesiology and Wailer, J.
R.:
1957. 10. Pharmacopeia of the United 11. Belinkoff, Stanton: AM. J. 12. Jackson, R. L., and Decker,
of American
Revision,
Societies
Appleton-Century9: 336, 1957. 11: 76, 1950. P.: Helvet. them.
AM. J. OBST. & GYNEC. 73: 507, 1955, p. 494.
OBST. & GYNEC.~~: 109,1944. D.
Q.:
Proc.
Staff
Meet.,
for
Mayo
Clin.
28:
20, 1953.
Volume Nrlmber
76 2
CARDIOVASCULAR
REACTIONS
TO
PITOCIN
29 1
Discussion DR. J. L. JACKSON, III, Wichita Falls, Texas.-Many reports attest the danger of the combined use of cyclopropane anesthesia and pituitary extracts. However, the type of shock described by Dr. Mackey following the administration of Pitocin is, per, haps, not so well recognized. After I discussed the contents of Dr. Mackey’s paper with my colleagues in Wichita Falls, Dr. Richard Bates recalled a similar case which occurred at Southwestern Medical Center, in Dallas, Texas, during his residency. While Dr. Bates was performing a cesarean section, 1 C.C. of pituitary extract was injected into the uterine muscle. Within a few moments, the patient went into profound shock and failed to respond to the usual forms of therapy. Later she received digitalis and it was only t,hen that she began t,o respond. It was approximately 48 hours before she was considered out of danger. After a review of almost 12,000 deliveries at the Wichita General Hospital, Wichita Falls, Texas, since 1949, only one case was found which could possibly be called Pitocin shock. of a 9 pound, 1 ounce, Mrs. M. W., aged 23, para ii, gravida iii, was delivered stillborn fetus after a moderately difficult midforceps delivery. A few minutes following the supposed administration of intravenous Ergotrate and intramuscular Pitocin, the patient went into profound shock. She failed to respond to the administ.ration of’ Only after digitoxin did she begin to respontl. Coramine, oxygen, and intravenous fluids. It was 24 hours before she was considered out of serious danger. No cause for thi:: ili cident was apparent at the time. Dr. Bates also recalled 3 additional cases at Southwestern Medical School which were designated as Pitocin shock. These cases presented a picture similar to that of Dr Mackey’s case except that the shock occurred following a vaginal delivery. In every case. 1 C.C. of Pitocin was accidentally administered intravenously. These 3 patients presented a similar shocklike syndrome which responded following the administration of some digi, talis preparation. Combining the information obtained from these 5 eases, and Dr. Mackey’s ease, it appears that this syndrome of Pitocin shock occurs following the accidental administration of a whole cubic centimeter of Pitocin intravenously. It is rn? opinion that in both Dr. Mackey’s case and in Dr. Bates’s cesarean section, the pituitary extract was inadvertently administered intravenously rather than into the uterine musculature. In Dr. Bates’s other 3 cases accidental administration of 1 C.C. of Pitocin intra venously was definitely considered to be the cause of the shock syndrome. In the ease reported that the patient received of accident would precipitate
from the Wichita Pitocin intravenously the shock syndrome
General Hospital I would and ergot intramuscularly, that this patient showed.
like
to for
surmise this type
To add emphasis to the belief that shock follows the accidental administration of large doses of Pitocin intravenously, in the 12,000 cases reviewed at the Wichita General Hospital it was discovered that 75 per cent of the patients received Pitooin in one form or another. Among the cases reviewed, there was no suggestion of shock following the administration of Pitocin in small doses intravenousI>or large doses intramuscularly.
REACTIONS
TO PITOCIN”
JAMES
R.
WILLIAM
(From
the Obstetric
Deportment,
Methodist
REINBERGER,
F.
MACKEY,
M.D., M.D.,
AND MEMPHIS,
TENN.
Hospital)
T
HE parenteral administration of posterior pituitary extracts for prevention or control of postpartum hemorrhage has been a routine procedure for almost half a century. This practice has been so successful that one now hesitates to leave the newly postpartum patient until one of the posterior pituitary extracts has been given. And yet this administration is not without danger. Reactions of unusual character vary from mild to severe, and sometimes fatal. Many mild reactions go unrecognized, and even severe ones are overshadowed by, or more often are attributed to, the operative procedure, blood loss, or the anesthetic. These reactions may result from a peculiar sensitivity to the drug or other component elements of the posterior pituitary gland solution. The manufacturers of posterior pituitary extract realize this fact, and have subsequently divided the extract of posterior lobe into more refined elements. They have separated a pressor element called Pitressin, and an oxytocic element, called Pitocin. They have also found that, regardless of the technique used in separating these elements, a small amount of each factor is present in each refined preparation. The U. S. Pharmacopeia permits such an assay at the present time. It is for this reason that the extract of the whole posterior pituitary lobe should not be used when a specific reaction is desired, especially in obstetrics where only the oxytocic element is desired. Pitocin is the drug of choice,gl I1 but even our use of Pitocin for induction of labor and control of postpartum hemorrhage has produced both mild and severe reactions. Pitocin reactions may be due to unusual sensitivity of the patient, to synergistic action with the anesthetic agent, and even to improper preparation and assay. These latter were reported in 1953 with certain lots of Pitocin having 18 pressor units per cubic centimeter rather than l/g unit or 1ess.3 These lots of Pitocin were recalled by the drug house but it is possible that the severe reactions which we report here could have been due to the pressor factor rather than the oxytocic element. Recently, a synthetic Pitocint has been made available which is said to be absolutely free of the pressor fact0r.l’ 2, * cians
*Presented at the Twenty-fifth Annual and Gynecologists, Omaha. Neb., Oct. ?Syntocinon, Sandoz Pharmaceuticals.
Meeting of the Central 24, 25, and 26. 1957.
Association
of Obstetri-
Volume Number
76 2
CARDIOVASCULAR
REACTIONS
TO
PITOCIN
‘28CI
Pharmacology of Pitocin.‘O -The effect of Pitocin on blood pressure is variable; occasionally, there is a rise. It increases cardiac output. Its effect. on the coronary arteries is theoretically nil, but actually they are constricted. The electrocardiogram is said by many authors not to be affected, but our case indicates that this may not always be true. The peripheral circulation is theoretically not affected, but actually shock has been reported. There ia no change in metabolism. Contraction of the pregnant uterus is immediatcb and intense. Cyclopropane gas is a parasympathetic stimulant. It, causes bronchial constriction which may precipitate an asthamtic attack in the susceptible patient. It also tends to produce cardiac arrhythmias with displacements of the rhythm centers. The range is bradycardia to ventricular fibrillation. Thf> combination of two parasympathetic stimulants, cyclopropane and pituitary extract, is most danger0us.l’ In the circulatory system, they have a synIt is ergistic tendency to produce hypertension and cardiac arrhythmias. important, therefort, never to use posterior pituitary extract when an oxytoc?ic is indicated in a patient under eyclopropane anesthesia. A survey of hospitals reveals that more attention should be directed to the type of posterior pituitary extract being used in the departments of obstetrics. The department of obstetrics should not have any surgical Pituitrin for this preparation should never be used as an oxytocic. The department of surgical gynecology should have both obstetrical and surgical Pituitrin and., if prescribed, the type of Pituitrin should be specifically ordered; otherwlsc. surgical Pituitrin could be given. Case Report Pnst History.-Appendectomy of pelvic adhesions were performed 1952, because of primary inertia.
was performed in 1944. in 1949. A cesarean
Right section
oophorectomy was performed
and @is July 4>
Hospital Course.-The patient was admitted to Methodist HospitaI in November, 1954, at 38 weeks’ gestation for elective cesarean section. The blood pressure was llZ/iO; hematocrit, 44; and urinalysis, negative. il spinal anesthetic was given by a doctoranesthetist. An incision was made, removing the old scar. Omental adhesions hatL to btX released before the pregnant uterus could be exposed. The uterus was then opened arrll a normal male infant was extracted. The infant weighed 6 pounds, 9 ounces, and crird immediately. The placenta and membranes were removed. Pitocin, 1 cc., was then injected into the uterine muscle. The patient, who had been perfectly calm and composed, then complained immediately of severe pain in the chest, associated with shortness 11f breath. This reaction was associated with a rapidly rising pulse rate from 55 to 1% per minute. This pulse elevation lasted about 30 minutes. At the time the procedure The was finished (1 to lys hours), the pulse was 95 per minute, blood pressure 90/60. patient was sent to her room awake, talking, and in excellent condition. Postoperative Course.-An electrocardiogram was ordered 3 hours after operation This was ordered for two reasons: first, because of the unusual reaction of this patient, after injection of Pitocin into the uterus and, second, because several months previousIS an unusually severe similar reaction had occurred in another patient but, unfortunately, no electrocardiogram was obtained. The electrocardiogram was interpreted by Dr. J. B. Witherington as an abnormal tracing showing coronary spasm, probably due to the administration of Pitocin into the uterus at the time of cesarean section. The first postoperative days were stormy, with oxygen necessary for dyspnea, and Wangensteen suction for distention. Blood transfusions and general supportive measures were given. During these 3 days the pulse would rise to 150 per minute at times and would skip every third beat. Ry the third postoperative day, however, a repeat electrocardiogram showed
290
REINBER,GER
AND
.4m. J. Obst. & Gyrm. August, IO58
MACKEY
“a normal tracing; the abnormalities previously present may have been due to coronary The insufficiency or acute pulmonary embolism,” as interpreted by Dr. Warren Kyle. blood pressure was 110/70 and pulse 80 on the third postoperative day. From then on, recovery was rapid and the patient was discharged home on the tenth postoperative day. Follow-Up Examinations.-For the first 2 years there were no significant findings except that at times the patient’s pulse would drop to 30 or 40 per minute. These attacks At the last visit, 3 years postoperatively, were associated with some distress and weakness. in October, 1957, there were no complaints or abnormalities.
Comment We have now discontinued the use of Pitocin or any drug in the uterus at the time of cesarean section. Since we are not injecting any drug into the uterus, we have found that we really do not need any oxytocics in most cases. If an oxytocic is needed, it can be given intramuscularly by the anesthetist. Intravenous Pitocin after normal delivery has just lately been shown to cause a more frequent and higher rise in blood pressure than either This is very important, especially since it implies Ergotrate or Methergine.4 that Pitocin is dangerous in toxemia.12 We do not completely agree with the statement of Dr. Eastman5 in the “It is probable that intramuscular Pitocin eleventh edition of his textbook: has no place in the first or second stages of labor in modern obstetrics.” We do, however, heartily agree with his words of caution as to the use of an intravenous drip of Pitocin. He contends that intravenous-drip Pitocin is safer than its intramuscular use; yet, to our knowledge, in Memphis, 3 cesarean sections have been done recently because of tetanic uteri and fetal distress following Pitocin infusions. Also, 3 ruptures of the uterus have occurred in Memphis, caused by the use of intravenous-drip Pitocin. Other tragic accidents, even death, have been reported elsewhere.‘j We cannot recall such cases following intramuscular Pitocin, even in 1 cc. doses.
Summary A case of coronary
constriction during a cesarean section under spinal anesthesia has been reported. It is believed that this complication was due to the injection of Pitocin into the uterus.
1. Dieckmann? W. J., and Fugo, .N. W.: Exhibit, Experimental Biology, Chicago, April, 1957. 2. Bishop, E. N.: To be published. 3. Jackson, R. L.: Personal communication. West. J. Surg. 64: 22, 1956. 4. MeGinty, L. B.: Williams Obstetrics, ed. 11, 5. Eastman, N. J.: Crofts, Inc., p. 831. 6. Bamo, Alex, Freeman, D. W., and Belleville, T. 7. Passloe, C. P., Morris, L. B., and Orth, Sidney 8. Boissonnas, I&. N., Guttmann, S., Juguerowd, P. acta 36: 491, 1955. 9. Hellman, L. M., Kohl, S. G., and Schechter, N.
Federation
New P.: 0.:
H.,
York,
States,
Fifteenth
1956,
Obst. Jr Gynec. Anesthesiology and Wailer, J.
R.:
1957. 10. Pharmacopeia of the United 11. Belinkoff, Stanton: AM. J. 12. Jackson, R. L., and Decker,
of American
Revision,
Societies
Appleton-Century9: 336, 1957. 11: 76, 1950. P.: Helvet. them.
AM. J. OBST. & GYNEC. 73: 507, 1955, p. 494.
OBST. & GYNEC.~~: 109,1944. D.
Q.:
Proc.
Staff
Meet.,
for
Mayo
Clin.
28:
20, 1953.
Volume Nrlmber
76 2
CARDIOVASCULAR
REACTIONS
TO
PITOCIN
29 1
Discussion DR. J. L. JACKSON, III, Wichita Falls, Texas.-Many reports attest the danger of the combined use of cyclopropane anesthesia and pituitary extracts. However, the type of shock described by Dr. Mackey following the administration of Pitocin is, per, haps, not so well recognized. After I discussed the contents of Dr. Mackey’s paper with my colleagues in Wichita Falls, Dr. Richard Bates recalled a similar case which occurred at Southwestern Medical Center, in Dallas, Texas, during his residency. While Dr. Bates was performing a cesarean section, 1 C.C. of pituitary extract was injected into the uterine muscle. Within a few moments, the patient went into profound shock and failed to respond to the usual forms of therapy. Later she received digitalis and it was only t,hen that she began t,o respond. It was approximately 48 hours before she was considered out of danger. After a review of almost 12,000 deliveries at the Wichita General Hospital, Wichita Falls, Texas, since 1949, only one case was found which could possibly be called Pitocin shock. of a 9 pound, 1 ounce, Mrs. M. W., aged 23, para ii, gravida iii, was delivered stillborn fetus after a moderately difficult midforceps delivery. A few minutes following the supposed administration of intravenous Ergotrate and intramuscular Pitocin, the patient went into profound shock. She failed to respond to the administ.ration of’ Only after digitoxin did she begin to respontl. Coramine, oxygen, and intravenous fluids. It was 24 hours before she was considered out of serious danger. No cause for thi:: ili cident was apparent at the time. Dr. Bates also recalled 3 additional cases at Southwestern Medical School which were designated as Pitocin shock. These cases presented a picture similar to that of Dr Mackey’s case except that the shock occurred following a vaginal delivery. In every case. 1 C.C. of Pitocin was accidentally administered intravenously. These 3 patients presented a similar shocklike syndrome which responded following the administration of some digi, talis preparation. Combining the information obtained from these 5 eases, and Dr. Mackey’s ease, it appears that this syndrome of Pitocin shock occurs following the accidental administration of a whole cubic centimeter of Pitocin intravenously. It is rn? opinion that in both Dr. Mackey’s case and in Dr. Bates’s cesarean section, the pituitary extract was inadvertently administered intravenously rather than into the uterine musculature. In Dr. Bates’s other 3 cases accidental administration of 1 C.C. of Pitocin intra venously was definitely considered to be the cause of the shock syndrome. In the ease reported that the patient received of accident would precipitate
from the Wichita Pitocin intravenously the shock syndrome
General Hospital I would and ergot intramuscularly, that this patient showed.
like
to for
surmise this type
To add emphasis to the belief that shock follows the accidental administration of large doses of Pitocin intravenously, in the 12,000 cases reviewed at the Wichita General Hospital it was discovered that 75 per cent of the patients received Pitooin in one form or another. Among the cases reviewed, there was no suggestion of shock following the administration of Pitocin in small doses intravenousI>or large doses intramuscularly.