Doi:10.1016/j.ijgo.2007.05.050

International Journal of Gynecology and Obstetrics (2008) 100, 4–9 a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m w w w. e l s e v i e r. c o m / l o c a t e / i j g o A systematic review of randomized controlled trials toreduce hemorrhage during myomectomy foruterine fibroids ☆ E.J. Kongnyuy a,⁎, N. van den Broek a, C.S. Wiysonge b a Child and Reproductive Health Group, Liverpool School of Tropical Medicine, Liverpool, UK b South African Cochrane Centre, South African Medical Research Council, Cape Town, South Africa Received 8 May 2007; accepted 13 May 2007 Objective: To assess the effectiveness and safety of interventions to reduce blood loss during myomectomy. Methods: Electronic searches of the Cochrane Library, MEDLINE, and EMBASE, between 1966 and 2006 for randomized controlled trials (RCTs). Results: We found significant reductions in blood loss with vaginal misoprostol (weighted mean difference [WMD] −149.00 mL, 95% confidence interval [CI] −229.24 to −68.76); intramyometrial vasopressin and analogues (WMD −298.72 mL, 95% CI −593.10 to −4.34); intramyometrial bupivacaine plus epinephrine(WMD −68.60 mL, 95% CI −93.69 to −43.51); and pericervical tourniquet (WMD −1870.00 mL, 95%CI −2547.16 to −1192.84). There was no evidence of effect in blood loss with myoma enucleationby morcellation and oxytocin. Conclusion: There is limited evidence from a few RCTs that someinterventions may reduce bleeding during myomectomy. There is need for adequately poweredRCTs to shed more light on the effectiveness, safety, and cost of different interventions to reduceblood loss during myomectomy.
2007 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd.
All rights reserved.
☆ This paper is based on a Cochrane Review published in The The standard treatment of symptomatic leiomyomas (myo- mas or fibroids) is hysterectomy for women who have information). Cochrane Reviews are regularly updated as new completed childbearing and myomectomy for women who evidence emerges and in response to feedback, and The Cochrane wish to preserve fertility. Myomectomy can be accomplished Library should be consulted for the most recent version of the by laparotomy, laparoscopy, or hysteroscopy. Massive blood loss associated with the dissection of huge fibroids renders ⁎ Corresponding author. Liverpool School of Tropical Medicine, L3 5QA, Liverpool, UK. Tel.: +44 151 705 3705; fax: +44 151 705 3329.
myomectomy a more technically challenging procedure than hysterectomy. A requirement for transfusion in up to 20% of 0020-7292/$ - see front matter 2007 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd.
All rights reserved.
A systematic review of randomized controlled trials cases following abdominal myomectomy has been reported omy (laparotomy, laparoscopy, or hysteroscopy) for uterine in the literature, and in 2% of cases there is need for fibroids for any reason. Only interventions performed during conversion of myomectomy to hysterectomy surgery, immediately before surgery, or within 24 h prior to A number of interventions have been introduced to surgery were considered for this review.
reduce bleeding during myomectomy. Three categories of The primary outcome measures were estimated blood loss in interventions can be identified: (a) interventions on uterine milliliters and need for blood transfusion. Secondary outcomes arteries such as laparoscopic uterine artery dissection, included duration of operation, intraoperative hysterectomy, uterine artery embolization, pericervical mechanical tourni- conversions from laparoscopy to laparotomy, other intraopera- quet and hormonal tourniquets such as vasopressin and tive complications, duration of hospital stay in days, post- terlipressin; (b) uterotonics such as ergometrine, oxytocin, operative morbidity, post-operative hemoglobin and hematocrit, misoprostol, and sulprostone; and (c) myoma dissection abdominal revisions for hemoperitoneum or pelvic hematoma, techniques which include the use of laser and chemical post-operative recurrence of myomas, pregnancy (if pregnancy dissectors such as sodium-2-mercaptoethanesulfonate desired), treatment adherence, adverse events and cost (total cost, and cost of the intervention).
Despite these procedures excessive hemorrhage during myomectomy remains a major challenge to gynecologic surgeons The effects of these procedures on blood lossduring myomectomy, as reported by previous non-rando- Data were analyzed using RevMan 4.2 according to standard mized studies, have been inconsistent . Moreover, the Cochrane guidelines ; analyzing trial participants in groups to types of these interventions are so varied that there is need which they were randomized, regardless of whether they to identify those procedures that are most effective and have actually received the treatment assigned. For dichotomous the least adverse effects to help the gynecologic surgeon to data, we expressed study results as odds ratios (OR) with 95% confidence intervals (CI). We were not able to assess for The aim of this review was to assess, using the best heterogeneity because of insufficient number of trials in the 7 available evidence, the effectiveness and safety of interven- comparisons (intervention vs placebo/no treatment) considered tions to reduce blood loss during myomectomy for uterine in this review. Planned subgroup analyses based on the fibroids. The use of pre-operative gonadotrophin releasing technique of myomectomy (laparotomy, laparoscopy, or hys- hormone (GnRH) analogues was not considered in this review teroscopy), type of comparison group (placebo or no treatment), because their effectiveness has previously been examined in and ethnic background (black or white) were not performed for For continuous data, we recorded the means and their stand- ard deviations for each arm of the trial and expressed studyresults as weighted mean differences (WMD) with 95% CI. Where only the median was reported, we assumed that the mean wasequal to the median (after checking for skewness) and estimated Electronic searches were conducted in the Cochrane Menstrual the standard deviation from the range (range × 0.95/4). Only one Disorders and Subfertilty Group specialized register, Cochrane comparison, hormonal tourniquet vs placebo or no treatment, Central Register of Controlled Trials (Cochrane Library Issue 1, had two trials. There was significant statistical heterogeneity 2006), MEDLINE (1966 to March 2006), EMBASE (1980 to March between the study results (P b 0.00001, I2 = 98.8%). Thus, we used 2006), Current Contents (1993 to March 2006), the National the random effects method to pool the data and investigated the Research Register, and the National Library of Medicine's Clinical Trial Register (up to March 2006), by combining search terms forthe health condition (myoma⁎, fibroids, leiomyoma) and the interventions (myomectomy OR laparotomy, laparoscop⁎, hys-teroscop⁎, uterotonic⁎, misoprostol, sulprostone, ergometrin⁎, We identified 17 potentially eligible studies, from which we tourniquet, vasopressin, terlipressin, uterine artery ligation, excluded 4 because further investigation revealed that there was uterine artery dissection, uterine artery emboli⁎, mesna, no randomization , and 5 because the control group was chemical dissection, laser dissection, uterine fibroid emboli⁎) another active intervention rather than a placebo or no treat- followed by standardized methodological filters for identifying The remaining 8 randomized controlled trials with 371 parti- In addition, the above searches were supplemented by cipants met our inclusion criteria: two trials with 58 participants contacting experts in the field of myomectomy (for unpublished on a hormonal tourniquet, vasopressin ; one trial on the data) and a hand search of specialist journals, conference uterotonic effect of misoprostol one on oxytocin ; one abstracts, relevant review articles, and reference lists of iden- on pericervical tourniquet one on chemical dissection with tified trials. There were no language restrictions to the search.
mesna ; one on the vasoconstrictor effect of bupivacaine plusepinephrine ; and one on the enucleation of myoma by morcellation while it is attached to the uterus We did notidentify a randomized controlled trial that assessed the effect of Our inclusion criteria were randomized controlled trials (RCTs) uterine artery ligation or laser dissection of the myoma. In 5 that compared the effect of interventions with placebo or no studies, myomectomy was carried out by laparotomy and in 2 treatment to reduce blood loss during myomectomy. Study studies it was by laparoscopy. Both laparotomy and participants were premenopausal women undergoing myomect- vaginal routes were used in one trial .
Further details about the study participants, interventions, trials with 58 participants: WMD [random] − 298.72 mL, 95% type of myomectomy, quality of included studies, and outcomes CI − 593.10 to − 4.34) (. Though the two trials of vasopressin showed significant reduction in blood loss,there was significant heterogeneity between them (P b 0.00001, I2 = 98.7%), presumably due to use of differenttypes of vasopressin: natural vasopressin (1 trial with 20 participants: WMD − 450.00 mL, 95% CI − 507.49 to − 392.51) and synthetic vasopressin (1 trial with 38 We found no evidence of a difference between oxytocin and participants: WMD − 149.60, 95% CI − 178.22 to − 120.98).
placebo in blood loss (1 trial with 94 participants: WMD However, we found no evidence that vasopressin has an 57.00 mL, 95% CI −129.22 to 243.22), need for blood trans- effect on the need for blood transfusion (1 trial with 20 fusion (OR 1.99, 95% CI 0.88–4.54), and duration of surgery participants: OR 0.05, 95% CI 0.00–1.03), duration of (WMD 4.00 min, 95% CI −1.49 to 9.49).
surgery (1 trial with 38 participants: WMD − 28.50 min, 95%CI − 61.76 to 4.76), duration of hospital stay (1 trial with 38 participants: WMD 0.55 days, 95% CI − 0.10 to 1.20), post-operative adhesions to the bowel/omentum (1 trial with 38 Compared to placebo, misoprostol significantly reduced participants: OR 2.02, 95% CI 0.54–7.49), post-operative blood loss (1 trial with 25 participants: WMD −149.00 mL, adnexal adhesions (1 trial with 38 participants: OR 1.87, 95% CI −229.24 to −68.76), shortened duration of surgery 95% CI 0.39–8.93), and occurrence of pregnancy one year (WMD −9.50 min, 95% CI −15.90 to −3.10) and increased after myomectomy (1 trial with 38 participants: OR 0.64, post-operative hemoglobin (WMD 0.80 g/dL, 95% CI 0.33– 1.27). However, there was no evidence of effect on the needfor blood transfusion (OR 0.36, 95% CI 0.05–2.50), duration ofhospital stay (WMD 0.00 days, 95% CI −0.82 to 0.82), and febrile morbidity (OR 1.25, 95% CI 0.24–6.44).
Compared to placebo, bupivacaine plus epinephrine signifi- 3.3. Vasopressin and analogues of vasopressin cantly reduced blood loss (1 trial with 60 participants: WMD − 68.60 mL, 95% CI −93.69 to −43.51) and duration of surgery Compared to participants on placebo, those on vasopressin (WMD −30.50 min, 95% CI −37.68 to −23.32). No patient and analogues had a significant reduction in blood loss (2 Characteristics of trials included in the review 15 IU oxytocin IV infusion vs physiological serum Laparotomy Pre-operative blood loss, blood transfusion, Laparotomy Pre-operative blood loss, operation time, hospital stay, adhesions and pregnancyoutcome Laparotomy Post-operative hemoglobin and hematocrit, for chemical dissection of myoma vs saline for duration of operation, hospital stay, and post- 400 μg misoprostol vaginally 1 h before surgery Laparotomy Pre-operative blood loss, post-operativevs identical placebo.
hemoglobin, operation time, blood transfusion,hospital stay, and post-operative morbidity.
Laparotomy Pre-operative blood loss and blood transfusion.
vasopressin during surgery vs injection ofplacebo Enucleation of myoma by morcellation while Laparoscopy Pre-operative blood loss, hospital stay, and technique of complete enucleation followed bymorcellation.
Laparotomy Pre-operative blood loss, need for blood 50 mL of bupivacaine cloridrate 0.25% + 0.5 mL Laparoscopy Pre-operative blood loss and operation time.
of epinephrine infiltrated into myometriumaround the myoma before incision vsinfiltration of normal saline A systematic review of randomized controlled trials Comparison of blood loss (mL): vasopressin and analogues vs placebo or no treatment.
3.5. Mesna (sodium-2-mercaptoethanesulfonate) the conclusion that blood loss was significantly lower withvasopressin vs placebo is valid. However, more trials are Chemical dissection with mesna significantly reduced the needed to quantify the actual estimate of benefit from duration of surgery (1 trial with 58 participants: WMD vasopressin. Heterogeneity was thought to be due to the −20.00 min, 95% CI −28.60 to −11.36) and hospital stay (WMD differences in blinding of outcome assessors and the fact that −1.00 day, 95% CI −1.12 to −0.88). Post-operative hemoglobin one study used natural vasopressin, while the other study (WMD 0.50 g/dL, 95% CI 0.42–0.58) and hematocrit (WMD used ornithine vasopressin (ornipressin), a synthetic analo- 1.90 g/dL, 95% CI 1.30–2.50) were also significantly increased gue of vasopressin in which ornithine is found in position 8 of with mesna compared to placebo, but there was no evidence of effect on the incidence of post-operative fever (OR 0.14, 95% The injection of bupivacaine plus epinephrine into the myometrium overlying the myoma was evaluated in one studyand the result showed evidence of reduction in blood loss, although this might not be useful clinically (68.6 mL). Vaso-pressin and bupivacaine plus epinephrine are known localvasoconstrictors and may reduce local blood flow when Occlusion of the uterine and ovarian arteries signifi- injected around the myoma. The study on the effect of che- cantly reduced blood loss (1 trial with 28 participants: mical dissection of the myoma with mesna did not directly WMD − 1870.00 mL, 95% CI −2547.16 to −1192.84) and the evaluate blood loss, but showed a significant gain in post- need for blood transfusion (OR 0.02, 95% CI 0.00–0.23).
operative hemoglobin. Mesna is a lytic agent that can disrupt However, the procedure had no evidence of effect on the connections between tissue layers and may thus operating time (WMD −4.00 min, 95% CI −29.28 to 21.28).
The largest effect on blood loss during myomectomy was recorded by the study that combined the occlusion of theuterine arteries and ovarian arteries using tourniquets prior Myoma enucleation by morcellation during laparoscopic to myoma enucleation. The uterus receives blood supply myomectomy reduced the operating time (1 trial with 48 primarily from the uterine artery and secondarily from the participants: WMD −25.30 min, 95% CI −44.23 to −6.37), but ovarian artery. Misoprostol, a prostaglandin E2 analogue, was there was no evidence of effect on blood loss (WMD equally shown to significantly reduce blood loss, probably by 65.40 mL, 95% CI −36.47 to 167.27) and duration of hospital causing uterine contraction and reducing uterine blood flow.
stay (WMD −0.07 days, 95% CI −0.18 to 0.04).
Other interventions have not been able to demonstrate the expected effect on blood loss that was theoretically postulated. The trial on oxytocin, a known uterotonic agent,showed no evidence of effect on blood loss during myomect- This review evaluated the effect of different interventions omy. This is consistent with other evidence that the myo- on blood loss during myomectomy for uterine fibroids. We metrial concentration of oxytocin receptors is very low in identified 8 well designed randomized trials that have non-pregnant uteri . Similarly, myoma enucleation by assessed the effect of each intervention on blood loss. All morcellation showed no evidence of reducing blood loss during myomectomy. This could partly be due to the small Some of the interventions showed promising effects on reducing blood loss during myomectomy. Significant reduc- One way of evaluating difficulty encountered during tion of intraoperative blood loss (298.72 mL) was noted when myomectomy was by measuring operation time. The trials vasopressin is injected into the uterine muscles overlying the on misoprostol, bupivacaine plus epinephrine, mesna, and myoma during myomectomy. Inspection of the data shows myoma enucleation by morcellation all recorded a signifi- that the WMD was less than zero in each of the two studies cant reduction in operation time. The use of oxytocin, peri- that assessed the effect of vasopressin on blood loss; cervical tourniquet, and vasopressin showed no evidence of however, the confidence intervals did not overlap suggesting highly significant heterogeneity (P b 0.00001, I2 = 98.8%).
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Source: http://t.www.britishfibroidtrust.org.uk/journals/bft_Kongnyuy.pdf