A systematic review and meta-analysis of efficacy of vasopressin as a vasoconstrictive and uterotonic drug in laparoscopic myomectomy

Abstract

Introduction:

Laparoscopic myomectomy is a commonly performed operation with fast recovery and excellent results. However, haemorrhagic nature of the operation mandates us to use variety of vasoconstrictive and uterotonic agents. Amongst which, one of them is vasopressin. It is a synthetic antidiuretic hormone analogue which has been in common use as a vasoconstrictive agent in various surgical procedures including laparoscopic myomectomy.

Methods:

A meta-analysis of randomised controlled trials published from 2013 to 2023 (10 years) comparing the use of vasopressin against other drug or placebo or different doses of vasopressin was performed. The outcome measures were intraoperative blood loss, need for blood transfusion, difference in the haemoglobin (Hb) and haematocrit (Hct).

Results:

We identified 176 articles through the study search, amongst which 12 articles were included for the meta-analysis. There was a significant heterogeneity in the studies with moderate risk of bias in eight studies and low risk of bias in four studies. Compared to placebo, vasopressin showed significantly lower odds need of blood transfusion (odds ratio [OR] 0.28, 95% confidence interval [CI]: 0.13–0.61, P = 0.002) and significantly lower pre–post fall in Hb (OR −3.12, 95% CI: −4.63–−1.60, P < 0.0001). However, there was no statistically significant difference in intraoperative blood loss (OR −0.56 (95% CI: −2.04–0.92, P = 0.46) and pre–post fall in Hct (OR −0.94, 95% CI: −1.96–0.07, P > 0.05). Compared to other drug (epinephrine, misoprostol and octreotide acetate), vasopressin showed no significant superiority in controlling blood loss (P > 0.05). Even the two doses of vasopressin (dilute vs. concentrated) showed no statistically significant difference between surgical blood loss and need for blood transfusion (P > 0.05).

Conclusion:

Vasopressin is an efficacious drug to be used for controlling blood loss, decreasing blood transfusion requirement and maintaining Hb and Hct during laparoscopic myomectomy.

INTRODUCTION

Leiomyomas (derived from uterine smooth muscle cells) are amongst the most prevalent benign tumours of the female genital tract affecting 20%–40% women.[1,2] According to the 2019 Global Burden of Disease Study, there is an increase in the number of incident cases of uterine leiomyomas from 5,769,658 incidences in 1990–9,643,336.[1]

Although these remain asymptomatic, in as much as one-third of patients, they might cause adverse symptoms such as frequent urination, constipation, heavy menstrual bleeding and pelvic pain. Moreover, they can also lead to iron deficiency anaemia, obstetric complications and infertility.[3] Thus, the management becomes crucial. The first-line therapeutic approach for patients with symptomatic leiomyomas who do not experience success with expectant and medical treatment is surgery (hysterectomy or myomectomy). Myomectomy, particularly is the best surgical option for individuals who want to have childbearing in the future, especially with the newer advancement of laparoscopic myomectomy.[3]

Due to the leiomyomas being highly vascular, intraoperative bleeding and haemorrhage related complications (deranged haemostasis, circulatory shock and demise) are common, needing blood transfusion. Thus, to reduce morbidity and mortality, treatments to reduce bleeding and related complications during myomectomy are essential.[3]

In the literature, a number of pharmacologic medications have been evaluated to reduce blood loss and related morbidities during myomectomy. The vasoconstrictor vasopressin is one such example, which can reduce blood loss. It has been widely used in numerous gynaecological procedures to reduce the amount of intraoperative blood loss.[4,5]

Vasopressin is a synthetic analogue of the anti-diuretic hormone. It causes vasoconstriction through its action on V1 receptors and anti-diuresis through V2 receptors in the kidney. Intramyometrial injection of vasopressin causes vasoconstriction, stimulating the uterine contractions and reducing the surgical blood loss.[6,7]

The effectiveness and safety of perioperative vasopressin during myomectomy have been studied in numerous randomised controlled trials (RCTs) and non-RCTs (NCTs);[8,9,10,11,12,13,14,15,16,17,18,19,20] yet, the data on the subject are still inconclusive especially in regard to laparoscopic myomectomy.

Thus, the present systematic review and meta-analysis were conducted with an aim to analyse the results of various studies determining the efficacy and safety profile of vasopressin as a vasoconstricting agent during laparoscopic myomectomy in comparison to other drugs or placebo or different doses of vasopressin. The meta-analysis of the published studies may give us better evidence on the effectiveness of vasopressin for controlling blood loss in laparoscopic myomectomy – thus allowing for a frequent clinical use for better management of the patients.

METHODS

Study design and search strategy

An extensive literature search was performed by two primary investigators for published studies over a period of the past 10 years from 1^st January 2013 to January 2023. The databases include for the search were EmBase, Medline, DOAJ, PubMed and Elsevier.

The key words used for the search were ‘vasopressin AND laparoscopic myomectomy’. Two reviewers independently screened the abstract and titles of the articles which were retrieved during the search excluding the duplicates. The studies which were found to be eligible for the present systematic review were included for further assessment and downloaded (full text). Even, the bibliographies of the downloaded studies were searched for any articles which were missed out during the search.

Inclusion criteria

• RCT published over the period of the past 10 years

• Studies done only on humans

• Studies published only in the English language

• Studies whose full text was available on free basis

• Studies where trial outcomes were given and they matched the study objectives

• Studies done only on laparoscopic myomectomy.

Exclusion criteria

• NCT (review articles, cross-sectional observational studies)

• Studies reporting the safety and efficacy of vasopressin in open myomectomies

• Studies done on animals.

Outcome measures

The primary outcome measures included intraoperative blood loss, need for blood transfusion, difference in the haemoglobin (Hb) and haematocrit (Hct). The secondary outcomes were any side effects of vasopressin and patients’ mortality.

Data extraction

The data extraction was done by two independent reviewers which were then cross-checked, and any discrepancies, were further removed by the other two reviewers. The information was extracted from the studies and noted down in Microsoft Excel tables which comprised of author name, year of publication, the dose and number of patients enrolled in vasopressin group, the dose and number of patients enrolled in placebo group or the other drug group, the outcomes of the surgery-intraoperative blood loss in both the groups, need for blood transfusion for individual groups, pre–post Hb difference for individual groups, pre–post Hct difference for individual groups, drug associated complications and mortality.

Risk bias assessment

ROBINS-I tool was used for assessing the risk of bias, wherein seven parameters were analysed, which include selection bias, measurement bias, confounding bias, outcome reporting bias, attrition bias and performance bias. Then, the overall risk was calculated and categorised into low, high and moderate based on the scores, with low having score of 0–1, moderate having score of 2–5 and high having score of 6 or more [Table 1].

Table 1.

Risk of bias assessment

Name of the author	Confounding bias	Selection bias	Measurement on interventions bias	Intended interventions (performance bias)	Attrition bias	Measurement bias	Outcome reporting bias	Overall risk of bias
Soliman et al.[13]	−	+	+	+	−	−	+	Moderate
Elgendy et al.[11]	−	−	−	−	−	−	−	Low
Kode et al.[17]	−	+	−	−	+	−	−	Moderate
Matasariu et al.[15]	−	+	−	−	+	−	−	Moderate
Isah et al.[12]	−	−	−	−	−	−	−	Low
Protopapas et al.[19]	+	−	+	+	−	−	+	Moderate
Protopapas et al.[4]	−	+	−	−	+	−	−	Moderate
Srivastava et al.[20]	+	−	−	+	+	−	+	Moderate
Cohen et al.[10]	−	−	−	−	−	−	−	Low
Badawy[8]	−	−	+	+	−	−	+	Moderate
Thiek et al.[14]	+	−	−	+	+	−	+	Moderate
Song et al.[9]	−	−	−	−	−	+	−	Low

+: Present, -: Absent

Statistical analysis

The statistical analysis was performed by two independent reviewers by STATA version 13.0 (Stata Corp., College Station, TX) and Review Manager (RevMan)version 5.4 (Cochrane, London, UK). Odds ratio (OR) and standardised mean difference of outcomes were calculated with 95% confidence interval (CI). Random-effects model was used to synthesise the data for the relevant outcomes. Heterogeneity was evaluated using I² statistic. Forest plots visually showed the effect estimates of the included studies. Funnel plots and Egger’s test were used to evaluate the potential publication bias. A two-tailed P < 0.05 was considered statistically significant.

RESULTS

Study selection

We identified 176 articles through the study search, amongst which 70 duplicates were removed. A total of 106 articles were screened and 12 articles were included for the meta-analysis. The Preferred Reporting Items for Systematic Reviews and Meta-analyses flowchart is shown in Figure 1.

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart

The data extraction was done from the included studies and is tabulated in Table 2. Amongst 12 studies, seven studies compared vasopressin against placebo, three studies compared vasopressin against other drugs (epinephrine, misoprostol and octreotide acetate) one study compared two doses of vasopressin and one study compared the three groups – vasopressin versus placebo versus another drug.

Table 2.

Study characteristics

Study	Year	Vasopressin (dose, n)	Placebo (n)	Other drug (dose, n)	Intraop blood loss - Groups I, II, III (mean±SD); P	Need of BT - Groups I, II, III (n, %); P	Pre- and post-Hb difference - Groups I, II, III (mean±SD); P	Pre- and post-Hct difference - Groups I, II, III (mean±SD); P
Soliman et al.[13]	2021	Diluted as 0.1 unit/mL and 15 mL was injected, 97	97	-	615.20 mL, 690.50 mL; 0.001	15.46% versus 29.89%; 0.025	0.75±0.20 g/dL, 0.67±0.20 g/dL; 0.152	-
Elgendy et al.[11]	2021	Terlipressin (glypressin, Ferring, Egypt) diluted with saline as 1 unit for every 200 mL of saline Maximum used dose: 1 unit/200 mL saline, 30	30	-	826.67±185.94 mL versus 115.53±23.17 mL; <0.001	0%/50%	0.08±0.22 g/dl, 1.38±0.14 g/dL	2.48±0.5% versus 5.23±−2.52%
Kode et al.[17]	2021	20 units vasopressin in 200 mL normal saline as 0.1 unit/mL, then 15 mL was injected, n=30	30	-	411.11±89.70 mL versus 545.44±72.23 mL; 0.001	16.67% versus 36.67%; 0.021	1.98±1.25 g/dL versus 2.51±1.57 g/dL; 0.045	Significant fall (values not specified)
Matasariu et al.[15]	2021	5-mL intramyometrial injection of glypressin 0.2 mg/mL, n=64	124	-	-	-	1.14±0.83 g/dL versus 1.56±0.79 g/dL; 0.001	3.23±2.65% versus 4.49±2.82%; 0.001
Isah et al.[12]	2020	20 IU (1 mL) of vasopressin in 19 mL of normal saline, n=62	63	-	503.2 mL versus 841.3 mL; <0.001	12.9% versus 42.9%; <0.001	-	Post-operative Hct was higher in the vasopressin group
Protopapas et al.[19]	2020	Dilute vasopressin (20 IU/100 mL normal saline), n=100	50	Vaginal misoprostol 400 µg, n=50	147.8±171.8 mL versus 321.8±246.0 mL (P=0.793) versus 179.7±200.0 mL (P<0.001)	-	-	-
Protopapas et al.[4]	2019	Intramyometrial injection of dilute vasopressin (20 IU/100 mL normal saline), n=100	100	-	147.8±171.8 versus 321.8±246.0 mL; <0.001	6% versus 4%, 0.795	-	-
Srivastava et al.[20]	2018	Intramyometrial vasopressin alone (20 units of vasopressin diluted in 100 mL of normal saline), n=30	-	Intramyometrial vasopressin plus rectal misoprostol (600 µg), n=30	206±101.2 mL versus 139±96.7 mL; 0.008	-	1.9±0.2 g/dL versus 0.7±0.1 g/dL; 0.001	-
Cohen et al.[10]	2017	200 mL of diluted vasopressin solution (20 U in 400 mL normal saline), n=76	-	30 mL of concentrated vasopressin solution (20 U in 60 mL normal saline, n=76	178 mL versus 198 mL; 0.65	2.6% versus 2.6%; 0.99		No significant change in both groups
Badawy[8]	2017	20 IU (1 mL) diluted in 20 mL saline (in a dilution of 1:20), n=20	20	Octreotide acetate: 0.050 mg (1 mL) diluted in 20 mL saline (in a dilution of 1:10), n=20	113±37.43 mL versus 820.5±203.19 mL versus 279±148.28 mL; 0.0001	0% versus 45% versus 5%; 0.001	0.18±−0.01 g/dL versus 1.44±−0.125 g/dL versus 0.41±0.07 g/dL; <0.05	-
Thiek et al.[14]	2016	Intramyometrial injection of vasopressin, n=35	35	-	206 mL versus 493.14 mL; <0.0001	5.71% versus 22.8%; <0.05	0.6±−0.361 g/dL versus 1.9±0.411 g/dL; <0.05	-
Song et al.[9]	2015			0.5 mg of epinephrine (1/2 vial of 1 mg/mL concentration) in 50 mL of saline solution, n=30	150.1 mL versus 146.2 mL; 0.853	3% versus 10%; 0.612	1.7±0.9 mg/dL versus 1.8±1.0 mg/dL; 0.798

Hb: Haemoglobin, SD: Standard deviation, Hct: Haematocrit, BT: Blood transfusion

Outcome measures results

Vasopressin versus placebo

Need for blood transfusion

For this, seven studies compared vasopressin against placebo. Amongst them, only Protopapas et al.[4] study favoured placebo in comparison to vasopressin, although it was statistically insignificant (P > 0.05). Apart from that, all other six studies favoured vasopressin for decreasing the need of blood transfusion. Overall, it showed that vasopressin was significant in decreasing the need for blood transfusion, with odd ratio of 0.28 (95% CI: 0.13–0.61, P = 0.002). There was significant heterogeneity with I² statistics equal to 59% Funnel plot showed significant publication bias with Egger test P = 0.05 [Figure 2a and b].

Figure 2.

(a) Forest plot for need of BT (vasopressin vs. placebo). (b) Funnel plot of need of BT (vasopressin vs. placebo), Egger’s test P = 0.05. OR: Odds ratio, CI: Confidence interval, BT: Blood transfusion

Intraoperative blood loss

For this, five studies compared vasopressin against placebo. Amongst them, only Elgendy et al.’s[11] study favoured placebo in comparison to vasopressin, which was statistically significant (P < 0.05). Apart from that, all other four studies favoured vasopressin in controlling intraoperative blood loss. Overall, it showed that vasopressin was not significant in decreasing the intraoperative blood loss, with odd ratio of −0.56 (95% CI: −2.04–0.92, P = 0.46). There was significant heterogeneity with I² statistics equal to 98%. Funnel plot showed significant publication bias with Egger test P = 0.002 [Figure 3a and b].

Figure 3.

(a) Forest plot of intraoperative blood loss (vasopressin vs. placebo). (b) Funnel plot of intraoperative blood loss (vasopressin vs. placebo), Egger’s test P = 0.002. SD: Standard deviation, CI: Confidence interval, SMD: Standardized mean difference, SE(SMD): Standard error of the standardized mean difference

Pre–post haemoglobin difference

For this, six studies compared vasopressin against placebo. Amongst them, only Soliman et al.’s[13] study favoured placebo in comparison to vasopressin, and it was statistically significant (P < 0.05). Apart from that, all other five studies favoured vasopressin for lower decrease in Hb. Overall, it showed that vasopressin had significantly lower fall in Hb during the surgery with odd ratio of −3.12 (95% CI: −4.63–−1.60, P < 0.0001. There was significant heterogeneity with I² statistics equal to 98% (P < 0.05). Funnel plot showed a significant publication bias with Egger’s test P < 0.0001 [Figure 4a and b].

Figure 4.

(a) Forest plot of pre-post haemoglobin (Hb) difference (vasopressin vs. placebo). (b) Funnel plot of pre–post Hb difference (vasopressin vs. placebo), egger test P < 0.0001. SD: Standard deviation, CI: Confidence interval, SMD: Standardized mean difference, SE(SMD): Standard error of the standardized mean difference

Pre-post haematocrit difference

For this, two studies compared vasopressin against placebo. Amongst them, both studies favoured vasopressin in comparison to placebo (P < 0.05). Compared to placebo, vasopressin showed lesser odds of decrease in Hct with odd ratio of −0.94 (95% CI: –1.96–0.07); however, the difference was statistically insignificant (P > 0.05). There was significant heterogeneity with I² statistics equal to 90% (P < 0.05) [Figure 5a and b].

Figure 5.

(a) Forest plot of pre–post haematocrit (Hct) difference (vasopressin vs. placebo). (b) Funnel plot of pre–post Hct difference (vasopressin vs. placebo). SD: Standard deviation, CI: Confidence interval, SMD: Standardized mean difference, SE(SMD): Standard error of the standardized mean difference

Vasopressin versus other drug

Intra-operative blood loss

For this, two studies compared vasopressin against other drugs. Amongst them, both studies favoured vasopressin in comparison to other drugs with lower intraoperative blood loss in vasopressin. Although odds of intraoperative blood loss were lower in vasopressin in comparison to other drugs with OR of −0.80 (−2.10–0.50), it showed no significant difference in intraoperative blood loss, with P = 0.23. There was significant heterogeneity with I² statistics equal to 91% (P > 0.05) [Figure 6a and b].

Figure 6.

(a) Forest plot of intraoperative blood loss (vasopressin vs. other drug). (b) Funnel plot of intraoperative blood loss (vasopressin vs. other drug). SD: Standard deviation, CI: Confidence interval, SMD: Standardized mean difference, SE(SMD): Standard error of the standardized mean difference

Need of blood transfusion

For this, two studies compared vasopressin against other drugs. Amongst them, both studies favoured vasopressin in comparison to other drugs with less proportion of patients needed blood transfusion in vasopressin. Although odds of need of blood transfusion were lower in vasopressin in comparison to other drugs with OR of 0.31 (0.05–2.07), it showed no significant difference, with P = 0.23. There was non-significant heterogeneity with I² statistics equal to 0% (P > 0.05) [Figure 7a and b].

Figure 7.

(a) Forest plot of need of BT (vasopressin vs. other drug). (b) Funnel plot of need of BT (vasopressin vs. other drug). OR: Odds ratio, CI: Confidence interval

Pre–post haemoglobin difference

For this, two studies compared vasopressin against other drugs. Both of them favoured vasopressin in comparison to other drugs with lower fall in Hb in vasopressin. Odds of fall in Hb was significantly lower in vasopressin in comparison to other drugs with OR of −2.23 (−6.63–2.18) but with non-significant P = 0.32. There was significant heterogeneity with I² statistics equal to 98% (P < 0.05) [Figure 8a and b].

Figure 8.

(a) Forest plot of pre-post haemoglobin (Hb) difference (vasopressin vs. other drug). (b) Funnel plot of pre–post Hb difference (vasopressin vs. other drug). SD: Standard deviation, CI: Confidence interval, SMD: Standardized mean difference, SE(SMD): Standard error of the standardized mean difference

Specifically comparing two doses of vasopressin (dilute vs. concentrated), Cohen et al.[10] found that there was no significant difference between surgical blood loss and need for blood transfusion (P > 0.05).

Risk of bias

In four studies, the risk of bias was low and in remaining, i.e., eight studies, moderate risk of bias was present [Table 2].

DISCUSSION

The present meta-analysis is one of the first analysis of studies determining the efficacy of vasopressin in controlling the blood loss and maintaining Hb and Hct in women undergoing laparoscopic myomectomy. Myomectomy is usually done in elderlies and in such female patients that need to maintain the blood Hb and Hct levels as it may have adverse outcomes. Laparoscopy has become the surgery of choice in women undergoing myomectomy and those studies have analysed the efficacy of vasopressin in open myomectomies, but specifically for laparoscopic myomectomies, the evidence remains still the enigma. Moreover, the dose whether concentrated or diluted vasopressin should be used in comparison to placebo or other drugs demands a thorough review of various studies conducted in various places.

Myomectomy is an extensive surgery and controlling the blood loss obviously decreases the need of the blood transfusion and it was found that studies by Soliman et al.,[13] Elgendy et al.[11] Kode et al.[17] Isah et al.[12] Badawy[8] Thiek et al.[14] and Song et al.[9] showed that vasopressin was effective in significantly reducing the blood transfusion. This adds an additional benefit in controlling the mean Hb and mean Hct after the surgery where the studies showed that the differences was significantly reduced (Badawy,[8] Elgendy et al.,[11] Thiek et al.,[14] Srivastava et al.[20] Matasariu et al.[15] Kode et al.[17]). However, it had no significant impact on reducing the hospital stay and mortality amongst such patients.[4,9,10,14,15]

The present meta-analysis found that vasopressin was effective in controlling the blood loss in comparison to placebo.[4,8,11,12,13,14,19] However, in comparison to other drugs such as vaginal misoprostol,[19] intramyometrial vasopressin plus rectal misoprostol,[20] octreotide acetate[8] and epinephrine,[9] there was no statistical superiority. This might be because all of the uterotonic agents work under the same principle on vasoconstriction and cause similar effect in controlling surgical blood loss.[5]

Specifically, the studies that compared dilute and concentrated vasopressin were Cohen et al.[10] and it found no significant difference in the studied outcomes. There were negligible side effects with vasopressin making it effective and safe for using in laparoscopic myomectomy.

The study holds strength in regard to the analysis of various outcomes and providing a clinical utility of the application of vasopressin for controlling blood loss in myomectomy. This allows the laparoscopic approach to be safe with the use of vasopressin in a wider age group of females.

Limitations

The study results must be interpreted under the heterogeneity that existed in the enrolled studies. Another limitation is that different studies compared different groups like vasopressin comparing with placebo or other drugs or dilute versus concentrated vasopressin. Last, the studies using vasopressin in open myomectomies was not assessed.

CONCLUSION

Vasopressin is an efficacious drug to be used for controlling blood loss, decreasing blood transfusion requirement, and maintaining Hb and Hct during surgery without a significant fall in the post-operative period in comparison to other drugs-making it one of the drug of choice for use in laparoscopic myomectomy.

It is recommended that further reports are published on the use of vasopressin with concentrated and dilute dose so that further analysis can be done and a better clinical approach could be made in view of the use of vasopressin use in laparoscopic myomectomy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.