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Vasopressin During Abdominal Hysterectomy: A Randomized Controlled Trial

From the University of Pittsburgh, Magee-Women’s Hospital, Pittsburgh, Pennsylvania.

Address reprint requests to: Richard S. Guido, MD Department of Obstetrics, Gynecology and Reproductive Sciences Magee-Women’s Hospital of the UPMC Health System 300 Halket Street Pittsburgh, PA 15213 E-mail: rguido{at}mail.magee.edu

	Abstract

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Objective: To investigate if the use of vasopressin during abdominal hysterectomy would decrease blood loss.

Methods: Fifty-one patients undergoing abdominal hysterectomy with the diagnosis of leiomyomatous uterus were randomized and received either vasopressin 10 units/10 mL of normal saline or 10 mL of normal saline, injected 5 mL bilaterally, 1 cm medial to the uterine vessels into the lower uterine segment. The sample size was determined assuming a one-third reduction in total blood loss would be clinically relevant. A power analysis determined that 25 patients would be required in each group to assure a power of 0.80, at the .05 significance level.

Results: Overall, the two groups were very similar with regard to their demographics, preoperative diagnosis, and relevant findings at the time of surgery. The mean total blood loss in the vasopressin and placebo groups was 445.41 mL and 748.42 mL, respectively. Total blood loss was significantly decreased by 40% in the vasopressin group compared with the placebo group (P < .001). There was no statistically significant difference between the two groups with respect to possible confounding variables or surgical complications.

Conclusion: Injection of vasopressin into the uterus at the time of abdominal hysterectomy significantly reduces blood loss without increasing morbidity. We have shown that it is a useful adjunct during abdominal hysterectomy.

It is estimated that 544,000 hysterectomies are performed annually in the United States, approximately 75% of these abdominally.¹ The morbidity associated with abdominal hysterectomy ranges from 25% to 42.8%.^2,3 One of the most commonly cited complications is hemorrhage requiring a transfusion, which is superseded only by fever.² Two large prospective studies list leiomyoma as the most frequent indication for abdominal hysterectomy.^2,3 Leiomyomas of the uterus may be associated with menorrhagia causing preoperative anemia or excessive blood loss at the time of surgery leading to symptomatic anemia or blood transfusion.

Vasopressin (8-L-arginine vasopressin, American Regent Laboratories, Inc., Shirley, NY) is a drug that causes vasospasm. In the gynecologic literature, it has been used intraoperatively during myomectomies, dilation, evacuation and curettage, and hysteroscopy to reduce blood loss.^4–6 There are also case reports of using vasopressin during conservative management for control of hemorrhage caused by accreta at the time of cesarean.⁷ Its ability to decrease blood loss at the time of abdominal hysterectomy has not been studied.

This prospective randomized double-masked placebo controlled trial was designed to investigate if the use of vasopressin during abdominal hysterectomy would decrease intraoperative blood loss.

	Materials and Methods

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The study was approved by the Institutional Review Board of Magee-Women’s Hospital in Pittsburgh, Pennsylvania. Magee-Women’s Hospital is a private teaching institution affiliated with University of Pittsburgh Medical Center. Recruitment took place between April 1999 and May 2000.

All patients at Magee-Women’s Hospital 18 years or older scheduled for total abdominal hysterectomy (TAH) with or without bilateral salpingo-oophorectomy with the diagnosis of leiomyomatous uterus were identified as possible participants in the study. Patients from the private and clinical faculty offices, as well as the residents’ continuity clinics, were asked to participate.

The sample size was determined using total blood loss as the main outcome variable. To ensure that the study was designed with a power of at least 0.80, at the .05 significance level, a random chart review of patients admitted for TAHs for leiomyomatous uterus was performed. The mean blood loss of this sample of 20 patients was 510 mL (±214 mL). The goal of the trial was to obtain at least a one-third decrease in blood loss. This review indicated that to show that a decrease in blood loss by at least one-third was significant, it was necessary to include 25 patients in each arm.

The study excluded patients with a medical history of angina, myocardial infarction, cardiomyopathy, congestive heart failure, uncontrolled hypertension, migraine, asthma, severe chronic obstructive pulmonary disease, or known or suspected malignancy of a pelvic organ. Individuals scheduled to undergo major concomitant surgical repair with the exception of bilateral salpingo-oophorectomy were also excluded from the study.

One hundred three patients were approached to participate in this research protocol of which 16 were ineligible, 22 declined, and 65 patients consented to participate. A total of 51 evaluable patients completed the protocol. Seven patients were never randomized. Of the seven, two did not undergo TAH. One patient, after having consented, declined to participate. One patient was excluded secondary to asthma. One surgeon declined to participate after the patient had consented. Two patients were not randomized because of lack of research personnel at the scheduled time of surgery.

Fifty-eight patients were randomized. One patient was withdrawn by the surgeon after receiving the solution. This patient required vasopressin to perform a myomectomy to facilitate the hysterectomy. She had been randomized in the placebo arm.

The six patients who were randomized, but not evaluable, did not receive the intrauterine injection. Three of these patients were in the vasopressin arm and three were in the placebo arm. Two patients were withdrawn during surgery by the surgeon because of the difficulty of the case; one patient was withdrawn because of suspicion for cancer before beginning the surgery; one patient was withdrawn because her surgery was cancelled and it was never rescheduled; one patient was withdrawn because she cancelled her surgery, then no longer desired to participate in the study; and one surgery was missed because of lack of research personnel.

The participants were randomized to either vasopressin or normal saline using a permuted block design with a block size of six created using a table of random permutations and digits.⁸ The solution was prepared by the pharmacy in a 10-mL syringe with a 21-gauge needle so that the operating room personnel were masked to their contents. The syringe contained either 10 mL of normal saline or 10 units of vasopressin in 10 mL of normal saline.

The dosage of 10 units of vasopressin was established after reviewing the literature to determine what had been used for the other gynecologic procedures studied. The American Medical Association Drug Evaluations, Fifth edition, 1983, states that with dosages of 20 units of vasopressin, angina, myocardial ischemia, and myocardial infarction have been reported.

Before beginning the actual hysterectomy, the solution was injected 5 mL bilaterally, 1 cm medial to the uterine vessels in the most distal area of the lower uterine segment that did not compromise the bladder. This area was chosen because it is accessible and close to entry of the uterine vessels. If this site was obstructed, for example, by a fibroid, the alternative site was midline at the fundus.

In addition to routine operative monitoring, blood pressure (BP) and heart rate were recorded for analysis at the time of injection and then every minute for the following 5 minutes. One patient in each arm had missing data points for BP and pulse during the uterine injections and the following 5 minutes.

Blood loss was measured and recorded throughout the surgical procedure by a designated research assistant. Specifically, the two recorded variables were blood loss before injection and total blood loss. This allowed for a calculated value of blood loss associated with the hysterectomy portion of the procedure.

Blood loss was estimated using both the canisters containing suctioned blood, minus irrigant, as well as blood absorbed in the lap sponges. Before each operation, moist and dry weights of the sponges were obtained; after use, they were reweighed. The weight of the bloody sponges minus the weight of the dry or moist sponges divided by 1.06 g/1 mL gave milliliters of blood loss absorbed in the sponges.

The surgeon was asked to announce the times of skin incision, uterine injection, cuff closure, and skin closure. The physician was also asked to make an estimate of uterine size in weeks.

The patient charts were reviewed, on average, 2 to 4 weeks after discharge to ascertain the postoperative course, the pathology report including uterine weight and any readmissions. Two specimens in the vasopressin arm and one specimen in the placebo arm were weighed with normal appearing adnexa. One specimen in the placebo arm was never weighed. Routine preoperative hemoglobin and postoperative day 1 hemoglobin were used to calculate a change in hemoglobin.

The main outcome variable analyzed was total blood loss. Additional analyses evaluated the effect of vasopressin on blood loss for the hysterectomy, change in hemoglobin, and the rate of transfusion. The potential for adverse side effects of the injection was assessed by analyzing the risk of adverse drug reactions, postoperative fever, cellulitis, and the need for readmission.

Possible confounding variables included patient race, age, medical/surgical history, medications including GnRH-agonists, and body mass index. Other possible confounding variables analyzed were total operating time, type of skin incision, uterine size in weeks, uterine mass on final pathology report, and findings at time of surgery.

All statistical analyses were performed using SPSS statistical software version 9.0 (SPSS Inc., Chicago, IL). Comparisons between the vasopressin and placebo arms were evaluated using Fisher exact, ², or Student t test where appropriate. Associations of the independent variables with total blood loss, blood loss related to the hysterectomy, and change in hemoglobin were evaluated using Student t test or linear regression where appropriate. Multivariable linear regression models were developed to identify the factors that were independently associated with total blood loss and hysterectomy-related blood loss.

	Results

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Overall, there were 51 evaluable patients; 27 participants were randomized to the vasopressin arm, and 24 were randomized to the placebo arm (Table 1). The demographics of the two groups were very similar with the exception of race. All nine black women in the study were randomized to the placebo arm. Because of the strict exclusion criteria of the established Institutional Review Board protocol, the study population was healthy. None of the patients had a history of cardiac disease, uncontrolled hypertension, or asthma; one patient had a history of noninsulin-dependent diabetes. Patients taking medications that could affect blood loss such as nonsteroidal anti-inflammatory drugs or aspirin were equally distributed with two in each group.

There were no statistically significant differences between the two groups with respect to the other outcome variables examined. One patient in each group received a blood transfusion. The patient in the placebo group had a preoperative hemoglobin of 8.8 and an estimated blood loss of 1504 mL. The vasopressin patient had a preoperative hemoglobin of 6.0 and an estimated blood loss of 950 mL.

Vasopressin produced little to no effect on the cardiovascular parameters of the study patients. Five patients in the vasopressin group had a transient elevation of blood pressure to 140/90 compared to no patients in the control group (P = .052). No patients in either group had an elevation of blood pressure above 140/90. Six patients in the vasopressin group had a transient reduction in their heart rate of 15 beats/minute as compared to two in the control group (P = .23).

No statistically significant differences existed between the groups with regard to postoperative infection or hospital readmissions. One patient in the placebo group did not receive preoperative antibiotics; she had no postoperative fevers. However, five patients in each arm had postoperative fevers to 101.3. All but two of the fevers were attributed to atelectasis. One patient in the placebo group had a postoperative fever on day 1 and was treated for a urinary tract infection. One patient in the placebo group had a fever on postoperative days 1 and 2; she received antibiotics, but no source of infection was identified. This patient also had an extended stay to 4 days for additional observation. One patient in the placebo group had a slow return of gastrointestinal function and stayed to day 4. A third placebo patient stayed to postoperative day 4 for social issues. Two vasopressin patients were readmitted. One patient, who also had had atelectasis, was readmitted for a partial small bowel obstruction that resolved with conservative management. Another patient, one with a previous history of domestic violence, was readmitted for a sexual assault/cuff cellulitis.

	Discussion

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The use of vasopressin as a medical means to decrease blood loss has been studied in the gynecologic literature. When examining myomectomy, Frederick et al showed a decrease in median blood loss from 675 mL in the placebo group to median blood loss of 225 mL in the vasopressin arm (P < .001).⁴ One study concerning dilation and evaluation abortion elicited a 50% decrease in blood loss in the vasopressin arm.⁵ Corson et al evaluated the use of vasopressin in hysteroscopic procedures; when vasopressin was injected intracervically, bleeding was minimal 81% of the time compared with 42% of the time in the placebo group.⁶ Lurie et al reported six patients with uncontrollable hemorrhage caused by placenta accreta at the time of cesarean in which they successfully controlled the bleeding and salvaged the uterus using vasopressin injected subendometrially (5 units/19 mL of saline). This agent was used after failed hemostasis with conventional uterotonic drugs including oxytocin, methergine, and hemobate.⁷

Our study, in agreement with previous studies looking at other gynecologic procedures, demonstrated that vasopressin significantly reduced blood loss without increasing the risk of serious complications.

Vasopressin causes vasospasm and uterine muscle contractions. The half-life of this agent is 10–20 minutes (American Regent Laboratories Inc., Shirley, NY, Package insert, 2/96). The main risks associated with local vasopressin injection include transient increase in BP, bleeding from the site of injection, and inadvertent intravascular infiltration.

An extensive literature search, specifically addressing the use of vasopressin intraoperatively for gynecologic procedures, found the following: one case report of pulmonary edema after uterine wall injection of vasopressin (5 units) during laparoscopy.⁹ There has also been one case report of intraoperative myocardial infarction after paracervical vasopressin (20 units) for a cold-knife cone biopsy that was immediately preceded by a laparoscopic tubal ligation.¹⁰ Although the patients in the vasopressin group had a trend toward a mild elevation in blood pressure, there were no patients who experienced significant or sustained blood pressure elevation or heart rate changes as a result of the medication. Vasopressin has been safely used at higher doses (20 units) during myomectomy with no reported increase in mean arterial blood pressure.^11,12 It is important that the surgeon avoid intravascular injection of vasopressin as this has been associated with severe hypotension secondary to coronary artery spasm.¹³

One concern is that using a vasoconstrictive agent may increase cuff cellulitis. England et al showed a relative risk of 5.5 for development of cuff cellulitis in vaginal hysterectomy after using epinephrine compared with normal saline to decrease blood loss. This drug has a vasoconstrictive effect on tissue for 5 to 6 hours.¹⁴ Vasopressin, unlike epinepherine, has a much shorter half-life, and therefore produces its vasoconstriction action during the surgery, but the effect is dissipated by the time the field is examined for bleeding pedicles. In our study, there was only one reported case of cuff cellulitis and although it was in the vasopressin group, it was not statistically significant, and the patient had been sexually assaulted within days of her surgery.

Although there was a significant decrease in estimated blood loss in the vasopressin group, this did not appear to affect the postoperative hemoglobin or change in hemoglobin. This may result from our inability to control for such things as the variability of the time between preoperative evaluation and the time to surgery or the amount of fluid the patient received during the operation and in the postoperative period.

Because of the risk of communicable diseases that exist with all blood transfusions and the healthy population that was examined, transfusions in both groups were very limited. Transfusion is the second leading morbidity associated with abdominal hysterectomy, superceded only by infection.² It is possible that in an individual with little hemoglobin reserve the use of vasopressin may reduce the blood loss to a degree that would prevent the necessity for blood transfusion.

This study may be limited in its generalizability because only patients who were previously healthy were able to participate. One bias may have been introduced by the exclusion of seven patients after randomization; however, four were in the placebo and three were in the vasopressin group, and the randomization remained masked until all data points had been entered. Furthermore, the demographics of the two groups evaluated were very similar.

The use of vasopressin in this randomized double-masked placebo controlled trial comparing blood loss during abdominal hysterectomy showed a statistically significant benefit to using the drug. There was no significant morbidity associated with the drug. We have shown that it is a useful adjunct to abdominal hysterectomy in conservation of blood loss and its subsequent risk of symptomatic anemia or transfusion.

	Footnotes

 
Funded by the Department of Obstetrics, Gynecology, and Reproductive Sciences.

PII S0029-7844(01)01353-9

Received September 11, 2000. Received in revised form January 4, 2001. Accepted January 31, 2001.

	References

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1. Stovall TG. Hysterectomy. In: Berek JS, ed. Novak’s gynecology. 12th ed. Baltimore: Williams and Wilkins, 1996:727–67.

2. Dicker RC, Greenspan JR, Strauss LT, Cowart MR, Scally MJ, Peters HB, et al. Complications of abdominal and vaginal hysterectomy among women of reproductive age in the United States. The collaborative review of sterilization. Am J Obstet Gynecol 1982;144:841–8.[Medline]

3. Gambone JC, Reiter RC, Lench JB. Quality assurance indicators and short-term outcome of hysterectomy. Obstet Gynecol 1990;76: 841–5.[Medline]

4. Frederick J, Fletcher H, Simeon D, Mullings A, Hardie M. Intramyometrial vasopressin: A haemostatic agent during myomectomy. Br J Obstet Gynaecol 1994;101:435–7.[Medline]

5. Schulz KF, Grimes DA, Christensen DD. Vasopressin reduces blood loss from second-trimester dilatation and evacuation abortion. Lancet 1985;17:353–6.

6. Corson SL, Brooks PG, Serden SP, Batzer FR, Gocial B. Effects of vasopressin administration during hysteroscopic surgery. J Reprod Med 1994;39:419–23.[Medline]

7. Lurie S, Appleman Z, Katz Z. Subendometrial vasopressin to control intractable placental bleeding. Lancet 1997;349:698–9.[Medline]

8. Pocock SJ, ed. Clinical trials: A practical approach. New York: John Wiley & Sons, 1983.

9. Tulandi T, Beique F, Kimia M. Pulmonary edema: A complication of local injection of vasopressin at laparoscopy. Fertil Steril 1996; 66:478–80.[Medline]

10. Martin JD, Shenk LG. Intraoperative myocardial infarction after paracervical vasopressin infiltration. Anesth Analg 1994;79:1201–2.[Free Full Text]

11. Ginsburg ES, Benson CB, Garfield JM, Gleason RE, Friedman AJ.The effect of operative technique and uterine size on blood loss during myomectomy: A prospective randomized study. Fertil Steril 1993;60:956–62.[Medline]

12. Fletcher H, Frederick J, Hardie M, Simeon D. A randomized comparison of vasopressin and tourniquet as hemostatic agents during myomectomy. Obstet Gynecol 1996;87:1014–8.[Abstract]

13. Nezhat F, Admon D, Nezhat CH, Dicorpo JE, Nezhat C. Lifethreatening hypotension after vasopressin injection during operative laparoscopy, followed by uneventful repeat laparoscopy. J Am Assoc Gynecol Laparosc 1994;2:83–6.[Medline]

14. England GT, Randall HW, Graves WL. Impairment of tissue defenses by vasocontrictors in vaginal hysterectomies. Obstet Gynecol 1983;61:271–4.[Abstract/Free Full Text]

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