Uterine leiomyomata are the most frequent benign tumors affecting women. In fact, at least 20–25% of women of reproductive age are affected by uterine leiomyomata.1 Several medical treatments2 have been proposed to treat women with symptomatic uterine leiomyomata, but, at the present, none of these can be considered completely effective and safe. For this reason surgery still plays a pivotal role in the treatment of uterine leiomyomata. In fact, about one third of hysterectomies are performed in patients referred for uterine leiomyomata.1,3 Furthermore, in women who intend to conceive in the future, surgical treatment is usually considered the conservative approach.3
The laparoscopic myomectomy offers several advantages: a smaller and more cosmetic incision, better visibility of the operative field, minimal intraoperative blood loss and postoperative pain, less need of analgesia, a quicker recovery time, a shorter hospital stay, and an earlier return to work.4,5 In addition, the laparoscopic access results in a lower rate of adhesions in comparison with laparotomic access.6
Vasopressin (8-l-arginine vasopressin) causes vasospasm and is used during various gynecological surgical procedures to reduce blood loss.7–16 Specifically, previous studies have demonstrated that intraoperative infiltration of vasopressin is effective for reducing blood loss during abdominal myomectomy10,11 and hysterectomy.15 More recently, in a observational study, the effectiveness of dilute ornitin-vasopressin during laparoscopic myomectomy has been reported by Rossetti et al.14
There is not a wide consensus on the use of this agent because of serious side effects reported in literature,17–19 as well as the presence in the literature of only 2 randomized placebo-controlled trials on the effectiveness of the dilute vasopressin solution during gynecological surgery.12,15 In addition, in several countries, including Italy, vasopressin has not been commercialized because of its potential adverse effect on cardiovascular system.17–19
Our laparoscopic unit has used arbitrarily a vasoconstrictive solution composed of bupivacaine and epinephrine before myomectomy for at least 2 years with good clinical results in terms of blood loss and postoperative pain. However, its use was not supported by any scientific evidence. To evaluate the effectiveness of this vasoconstrictive solution of bupivacaine plus epinephrine before laparoscopic myomectomy, we performed the present prospective, randomized, double-blind, placebo-controlled study.
MATERIALS AND METHODS
Between March 2002 and December 2002, 60 premenopausal women with symptomatic uterine leiomyomata were initially enrolled in the study. The subjects were ambulatory patients enrolled after transabdominal or transvaginal ultrasonographic assessments. The inclusion criteria were history of infertility lasting more than 3 years, recurrent abortions during the first trimester, symptoms of increased vaginal bleeding, pelvic pressure and pain, urinary frequency, and constipation.
Women with liver disease, angina or ischemic heart disease, cardiomyopathy, congestive heart failure, hypertension, asthma, chronic obstructive pulmonary disease, dyslipidemia, diabetes, acute or recent vascular thrombosis, or known or suspected malignancy were excluded from the study. Other exclusion criteria were intramural largest leiomyoma with an ultrasonographic size less than 3 cm or more than 5 cm, more than 2 tumors, presence of ultrasonographically documented calcification or hypoechoic leiomyoma,13 submucosal fibroids as confirmed by hysteroscopy, pattern of hyperplasia with cytologic atypia in the endometrial biopsy performed because of menometrorrhagia, abnormal Papanicolaou test, or positive urine pregnancy test result. Women with anemia were also excluded and treated with gonadotropin-releasing hormone (GnRH) agonist 2 months before surgery.13
The procedures used were in accordance with the guidelines of the Helsinki Declaration on human experimentation. The study was approved by the Institutional Review Board of the University of Catanzaro. Before entering the study, the purpose of the protocol had been explained to the patients, and their written consent had been obtained.
Subjects were randomized into a double-blind, placebo-controlled study. Randomization was carried out by means of envelopes containing computer-generated numbers in single blocks. Each subject was assigned to 1 of the 2 treatment groups, with a total of 30 patients in each group. Upon entry, each woman's age, parity, and body mass index (BMI) were assessed, and a transvaginal ultrasonography and blood sampling were performed.
Ultrasonographic scans were performed by the same experienced operator using a Toshiba PowerVision 6000 (Toshiba Medical System, Rome, Italy) equipped with a 7.5 MHz transvaginal probe. The operator was unaware of treatment assignment. Uterine and leiomyoma sizes were evaluated by measuring the 3 main diameters (D1, D2, D3) and applying the formula of the ellipsoid (D1 × D2 × D3 × 0.52). An arithmetic mean of the sizes was used in cases of 2 leiomyomata.
Immediately before surgery, each patient received 2 g of intravenous cephalosporin (Curoxim 2; Glaxo SmithKline SpA, Verona, Italy) as antibiotic prophylaxis. As previously described,13,16 the same experienced operator (F.Z.) performed the laparoscopic myomectomies using a 10-mm scope (Karl Storz, Tuttlingen, Germany) with 2 or 3 ancillary ports. The first step was the infiltration of the serosa and/or myometrium overlying and just around the leiomyoma before uterine incision. In particular, in group A we used a solution composed of 50 mL of bupivacaine cloridrate 0.25% (Bupicain; Monico SpA., Mestre, Venice, Italy) and 0.5 mL of epinephrine ([1/2] vial of 1 mg/mL), whereas in group B (control group), a saline solution was injected. The solution was prepared by an assistant just before the procedure in a separate room in a 50-mL syringe with a 21-gauge needle. The syringe contained either vasoconstrictive solution or only saline solution. Before each infiltration of control or experimental solution, repeated aspirations were performed to prevent intravascular injection. Also, if the injection of experimental solution induced a greater blanching effect on the tissue than the control solution, the surgeon was unaware of which solution was used. Then a longitudinal, unipolar incision, possibly close to the midline, or a hook-scissors incision, was performed. After the identification of the cleavage plane, the leiomyoma was enucleated by means of adequate traction with a myoma drill or a strong grasper and countertraction maneuvers with Manhes forceps, scissors, or hydrodissection technique. Coagulation of significant bleeders was obtained with bipolar forceps, and the myometrial edges were reapproximated in 1 or 2 layers according to the depth of the uterine incision, by means of Vicryl CT 2–0 or PDS interrupted figure-of-eight sutures (Ethicon, Rome, Italy) using intracorporeal knots. In all cases the leiomyomas were removed with a 12-mm Steiner (Karl Storz, Tuttlingen, Germany) automatic morcellator. After washing the pelvis with saline solution, no adhesion barrier or saline dextrane macromolecular solutions were left in the peritoneal cavity. All operative samples were submitted for pathologic examination.
Just before and after (each 5 minutes for the successive 40 minutes) the intraoperative injection of vasoconstrictive or saline solution, systolic and diastolic blood pressure and heart rate were accurately recorded in each subject. During each surgical procedure, we noted the global operative time, the time of enucleation of all and of each tumor, and the time of suturing of uterine wall defect. The intraoperative blood loss was evaluated as the balance between the aspirated and the irrigated liquid. At the end of each procedure, the degree of surgical difficulty was evaluated subjectively by the same operator with the use of a visual analog scale (VAS), varying linearly from 1 (low difficulty) to 10 (high difficulty).
All patients received intravenous analgesics for the first 12 hours following the surgery. The pain drug consisted in tramadol (Prontalgin, GiEnne Pharma SpA, Milan, Italy), administered at a dose of 100 mg intravenously immediately after surgery, followed by patient-controlled analgesia, which consisted of tramadol 200 mg (2 vials) in 500 mL of saline solution.20,21 The number of vials of pain drug used during the hospital stay was carefully recorded.
At the end of the surgical procedure the postoperative pain was also evaluated using a VAS, and the severity of the pain was expressed as a score ranging from 0 to 10.22 Specifically, the postoperative pain was assessed in each group every 2 hours for the first 12 hours following the surgery and at 24 and 48 hours after the surgical procedure.
Women were allowed to eat and drink the morning after the surgery and could ambulate as soon as they felt comfortable. The urinary catheter was withdrawn the evening the surgery. Twenty-four hours after surgery, a blood sample was performed, and the variation of hemoglobin (δ Hb) levels was calculated for each woman. All intra- and postoperative complications were recorded. A 3-month postoperative follow-up was done.
Our primary end-point was the intraoperative blood loss. Based on previous data11,16 and on the assumption that the intraoperative blood loss is 200 mL in the control group (laparoscopic myomectomy without use of any vasoconstrictive solution, group B) and 165 mL in the cases group (laparoscopic myomectomy with the use of vasoconstrictive solution, group A), with a mean difference of 35 mL and a common within-group standard deviation of 47 mL, we needed to enroll 30 patients for each group to define statistical significance between the groups with an α = 0.05 and a β = 0.20.
The Student t test for unpaired data was used to compare all data between the groups except the time of enucleation of tumors, the total blood loss, and the vials of analgesic, which were evaluated with the Mann-Whitney U test. The difference between and within groups in systolic and diastolic blood pressure, heart rate, and VAS scores for postoperative pain were analyzed using repeated measures analysis of variance (ANOVA). Fisher exact test was used to compare the incidence of complications between groups. The data were analyzed using the intention-to-treat method. The statistical analysis was performed with the SPSS 11.0 software package (SPSS Inc, Chicago, IL). Statistical significance was set at P < .05. The normal distribution of data was evaluated with the Kolmogrov-Smirnov test. Data were expressed as mean ± standard deviation.
Figure 1 shows the flow diagram of the clinical trial. The demographic characteristics of the subjects are shown in Table 1. After randomization, the 2 study groups were similar for age, parity, and BMI. Uterine and leiomyoma volume, number of leiomyoma, volume of largest leiomyoma were not significantly different between groups at the baseline. In all cases the estimated sizes of the leiomyomas measured by ultrasonography reflected the real size of the tumors removed, and the histopathological examination confirmed the ultrasonographic diagnosis of uterine leiomyomata. Four subjects (2 for each group) were excluded because of additional surgical procedures (endometriosis) that were performed.
No significant intra- or postoperative complications were observed in either group. All myomectomies were completed laparoscopically. Fifty-three women were discharged 2 days after surgery, whereas 1 patient in group A and 2 patients in group B were discharged after 4 days because of fever (temperatures > 38°C).
After the injection of vasoconstrictive solution, transient and not significant increases in systolic and diastolic blood pressure (Fig. 2) and heart rate were observed (Fig. 3).
The global operative time and the enucleation time were statistically (P < .05) shorter in group A than in group B. No difference was observed between groups in suturing time of the hysterotomy (Table 2). The intraoperative blood loss and the δ Hb were significantly (P < .05) lower in group A in comparison with group B (Table 2). Blood transfusion was required in none of the cases. A significantly (P < .05) lower mean degree of surgical difficulty was detected in group A than in group B (Table 2).
Figure 4 shows the VAS scores for postoperative pain. No significant difference was detected during the first 12 hours postoperatively. A value of VAS significantly (P < .05) lower in group A than in group B was observed 24 hours after surgery. At 48 hours after surgery, the difference in VAS for postoperative pain was not statistically significant.
The number of vials of pain drug used was significantly (P < .05) lower in group A than in group B (Table 2). After 3 months of follow-up, the presence of symptomatic leiomyoma was detected in none of the subjects.
Previous studies10,11,14 have demonstrated that the intraoperative infiltration of vasopressin is effective for reducing blood loss during abdominal and laparoscopic myomectomy. However, in several countries vasopressin is not commercialized because of the potentially serious side effects on the cardiovascular system.17–19 A significant reduction in intraoperative blood loss was detected in the present study with the injection of our experimental solution before the laparoscopic myomectomy. The reduction in blood loss also induced a significantly lower δ Hb in the experimental group compared with the control group. The minimal intraoperative bleeding decreased the use of bipolar forceps to obtain an adequate hemostasis and, therefore, the global operative time and the time of leiomyoma enucleation. Our data are very similar to those obtained with the use of vasopressin.10,11,14 Furthermore, at present, no other study has evaluated the subjective degree of surgical difficulty. After the laparoscopic myomectomies, in fact, the surgeon expressed a value of surgical difficulty significantly lower in the group treated with experimental solution in comparison with the control group. The reduced difficulty was probably due to a better visualization of the dissection planes because of the reduction in bleeding. Also, we cannot exclude an easier enucleation due to myometrial contraction around the tumor.
Our study-population comprised 60 patients randomized into 2 groups with characteristics of high homogeneity. In fact, to obtain a homogeneous series of cases with comparable surgical difficulty, we selected only cases with 1 or 2 leiomyomata, in which the largest leiomyomata were intramural and reconstruction of the uterine walls with sutures was necessary, and we excluded women pretreated with GnRH agonist, as well as those with hypoechoic or calcified leiomyomata.13,16 In fact, in hypoechoic or calcified leiomyomata, the operating time is significantly longer because of difficulties in grasping the tumor.13
Epinephrine induces a vasoconstrictive effect on tissue that lasts longer than that of vasopressin (5–6 hours versus 17–35 minutes) (Hutchins FL. A randomized comparison of vasopressin and tourniquet as hemostatic agents during myomectomy [letter]. Obstet Gynecol 1996;88:639).23–24 Two hypothetical risks may result from this pharmacological action. Firstly, it is possible that the vasoconstrictive action is not dissipated during the surgery, and an inaccurate hemostasis may be performed with an occulted postoperative bleeding. Secondly, the long duration of vasoconstriction could induce tissue damage, as observed with the epinephrine use during vaginal hysterectomy.23
Notwithstanding these 2 potential risks of using epinephrine, no significant intra- and postoperative complications were observed in our series, and only 2 women were discharged later than 48 hours after surgery. Furthermore, during the surgery a particular attention was given to performing the suture of the hysterotomy. Specifically, we performed a complete reapproximation of the uterine wall to close all dead spaces in 1 or 2 layers according to the depth of the incision (Hutchins, Obstet Gynecol). In addition, we do not know the real duration of the vasoconstriction with the use of our experimental solution. In fact, it is well know24 that bupivacaine induces a local vasodilatation that could partially counterbalance the vasoconstrictive effect of epinephrine.
During the surgical procedures, we carefully assessed the safety of the use of diluted epinephrine. No particular side effect was detected during surgery after vasoconstrictive solution injection, and only transient and not significant increases in blood pressure and heart rate were observed. Moreover, we emphasize the importance of selecting the patients carefully and of avoiding the intravascular injection of the solution. Adhering to these precautions, the use of diluted epinephrine may be considered safe.
The findings regarding postoperative pain are probably more surprising. In fact, our data show that the intraoperative injection of bupivacaine induces a significant reduction in postoperative pain for a period of at least 24 hours. Indeed, we detected, just after surgery, a VAS value for postoperative pain significantly lower in the experimental group than in the control group. As expected, after the start of the patient-controlled analgesia, no significant difference in VAS score was detected between groups during the first 12 hours after surgery. On the contrary, the number of vials of pain drug used was still significantly lower in the experimental group than in the control group. Twenty-four hours after surgery, when patient-controlled analgesia was stopped, a significant difference in subjective postoperative pain was again detected.
In conclusion, in the present study we demonstrate that the injection of a solution composed of bupivacaine and epinephrine before laparoscopic myomectomy reduces the blood loss, the global operative and enucleation times, the subjective surgical difficulty, and the postoperative pain.
1. Stewart EA. Uterine fibroids. Lancet 2001;357:293–8.
2. De Leo V, Morgante G, La Marca A, Musacchio MC, Sorace M, Cavicchioli C, et al. A benefit-risk assessment of medical treatment for uterine leiomyomas. Drug Saf 2002;25:759–79.
3. Falcone T, Bedaiwy MA. Minimally invasive management of uterine fibroids. Curr Opin Obstet Gynecol 2002;14:401–7.
4. Dubuisson JB, Fauconnier A, Babaki-Fard K, Chapron C. Laparoscopic myomectomy: a current view. Hum Reprod Update 2000;6:588–94.
5. Mais V, Ajossa S, Guerriero S, Mascia M, Solla E, Melis GB. Laparoscopic versus laparotomic myomectomy: a prospective randomized trial to evaluate benefits in early outcome. Am J Obstet Gynecol 1996;174:654–8.
6. Takeuchi H, Kinoshita K. Evaluation of adhesion formation after laparoscopic myomectomy by systematic second-look microlaparoscopy. J Am Assoc Gynecol Laparosc 2002;9:442–6.
7. Schulz KF, Grimes DA, Christensen DD. Vasopressin reduces blood loss from second-trimester dilatation and evacuation abortion. Lancet 1985;2:353–6.
8. Townsend DE. Vasopressin pack for treatment of bleeding after myoma resection. Am J Obstet Gynecol 1991;165:1405–7.
9. Corson SL, Brooks PG, Serden SP, Batazer FR, Gocial B. Effects of vasopressin administration during hysteroscopic surgery. J Reprod Med 1994;39:419–23.
10. Frederick J, Fletcher H, Simeon D, Mullings A, Hardie M. Intramyometrial vasopressin as a haemostatic agent during myomectomy. Br J Obstet Gynaecol 1994;101:435–7.
11. 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.
12. Phillips DR, Nathanson HG, Milim SJ, Haselkorn JS, Khapra A, Ross PL. The effect of dilute vasopressin solution on blood loss during operative hysteroscopy: a randomized controlled trial. Obstet Gynecol 1996;88:761–6.
13. Zullo F, Pellicano M, De Stefano R, Zupi E, Mastrantonio P. A prospective randomized study to evaluate leuprolide acetate treatment before laparoscopic myomectomy: efficacy and ultrasonographic predictors. Am J Obstet Gynecol 1998;178:108–12.
14. Rossetti A, Paccosi M, Sizzi O, Zulli S, Mancuso S, Lanzone A. Dilute ornitin vasopressin and a myoma drill for laparoscopic myomectomy. J Am Assoc Gynecol Laparosc 1999;6:189–93.
15. Okin CR, Guido RS, Meyn LA, Ramanathan S. Vasopressin during abdominal hysterectomy: a randomized controlled trial. Obstet Gynecol 2001;97:867–72.
16. Palomba S, Pellicano M, Affinito P, Di Carlo C, Zullo F, Nappi C. Effectiveness of short-term administration of tibolone plus gonadotropin-releasing hormone analogue on the surgical outcome of laparoscopic myomectomy. Fertil Steril 2001;75:429–33.
17. Nezhat F, Admon D, Nezhat CH, Dicorpo JE, Nezhat C. Life-threatening hypotension after vasopressin injection during operative laparoscopy, followed by uneventful repeat laparoscopy. J Am Assoc Gynecol Laparosc 1994;2:83–6.
18. Tulandi T, Beique F, Kimia M. Pulmonary edema: a complication of local injection of vasopressin at laparoscopy. Fertil Steril 1996;66:478–80.
19. Lurie S, Mamet Y. Transient myocardial ischemia may occur following subendometrial vasopressin infiltration. Eur J Obstet Gynecol Reprod Biol 2000;91:87–9.
20. Jin F, Chung F. Multimodal analgesia for postoperative pain control. J Clin Anesth 2001;13:524–39.
21. Dolin SJ, Cashman JN, Bland JM. Effectiveness of acute postoperative pain management. I. Evidence from published data. Br J Anaesth 2002;89:409–23.
22. Pellicano M, Zullo F, Di Carlo C, Zupi E, Nappi C. Postoperative pain control after microlaparoscopy in patients with infertility: a prospective randomized study. Fertil Steril 1998;70:289–92.
23. England GT, Randall HW, Graves WL. Impairment of tissue defenses by vasoconstrictors in vaginal hysterectomies. Obstet Gynecol 1983;61:271–4.
24. McClellan KJ, Spencer CM. Levobupivacaine. Drugs 1998;56:355–62.