Fluid and pharmacological agents for adhesion prevention ... · [Intervention Review] Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Gaity Ahmad

Fluid and pharmacological agents for adhesion prevention

after gynaecological surgery (Review)

Ahmad G, Mackie FL, Iles DA, O’Flynn H, Dias S, Metwally M, Watson A

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2014, Issue 7

http://www.thecochranelibrary.com

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review)

Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .

6BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Figure 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Figure 10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

22ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . .

32DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

36CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

83DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 1 Improvement in pelvic pain at

second-look laparoscopy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86

Analysis 1.2. Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 2 Live birth rate. . . . . 86

Analysis 1.3. Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 3 Improvement in adhesion score

at SLL. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

Analysis 1.4. Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 4 Number of participants with

worsening adhesion score. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

Analysis 1.5. Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 5 Number of participants with

adhesions at second-look laparoscopy. . . . . . . . . . . . . . . . . . . . . . . . . . 88

Analysis 1.6. Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 6 Mean adhesion score at second-

look laparoscopy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

Analysis 1.7. Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 7 Clinical pregnancy rate. . 90

Analysis 1.9. Comparison 1 Hydroflotation agent vs no hydroflotation agent, Outcome 9 Ectopic pregnancy rate (per

pregnancy). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

Analysis 2.3. Comparison 2 Gel agent vs no treatment, Outcome 3 Number of participants with improvement in adhesion

score. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

Analysis 2.4. Comparison 2 Gel agent vs no treatment, Outcome 4 Number of participants with worsening adhesion

score. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

Analysis 2.5. Comparison 2 Gel agent vs no treatment, Outcome 5 Number of participants with adhesions at second-look

laparoscopy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

Analysis 2.6. Comparison 2 Gel agent vs no treatment, Outcome 6 Mean adhesion score at second-look laparoscopy. 93

Analysis 3.3. Comparison 3 Gel agent vs hydroflotation agent when used as an instillant, Outcome 3 Number of participants

with improvement in adhesion score. . . . . . . . . . . . . . . . . . . . . . . . . . . 94


with worsening adhesion score. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

iFluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review)



with adhesions at second-look laparoscopy. . . . . . . . . . . . . . . . . . . . . . . . . 95

Analysis 3.6. Comparison 3 Gel agent vs hydroflotation agent when used as an instillant, Outcome 6 Mean adhesion score

at second-look laparoscopy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

Analysis 4.2. Comparison 4 Steroid (any route) vs no steroid, Outcome 2 Live birth rate. . . . . . . . . . . 96

Analysis 4.3. Comparison 4 Steroid (any route) vs no steroid, Outcome 3 Number of participants with improvement in

adhesion score. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

Analysis 4.4. Comparison 4 Steroid (any route) vs no steroid, Outcome 4 Number of participants with worsening adhesion

score. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

Analysis 4.7. Comparison 4 Steroid (any route) vs no steroid, Outcome 7 Clinical pregnancy rate. . . . . . . . 98

Analysis 4.9. Comparison 4 Steroid (any route) vs no steroid, Outcome 9 Ectopic pregnancy rate (per pregnancy). . 98

Analysis 5.4. Comparison 5 Intraperitoneal noxytioline vs no treatment, Outcome 4 Number of participants with worsening

adhesion score. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

Analysis 5.7. Comparison 5 Intraperitoneal noxytioline vs no treatment, Outcome 7 Clinical pregnancy rate. . . . 100

Analysis 5.9. Comparison 5 Intraperitoneal noxytioline vs no treatment, Outcome 9 Ectopic pregnancy rate (per

pregnancy). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

Analysis 6.3. Comparison 6 Intraperitoneal heparin solution vs no intraperitoneal heparin, Outcome 3 Number of

participants with improvement in adhesion score. . . . . . . . . . . . . . . . . . . . . . 101

Analysis 6.4. Comparison 6 Intraperitoneal heparin solution vs no intraperitoneal heparin, Outcome 4 Number of

participants with worsening adhesion score. . . . . . . . . . . . . . . . . . . . . . . . 101

Analysis 7.3. Comparison 7 Systemic promethazine vs no promethazine, Outcome 3 Number of participants with

improvement in adhesion score. . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

Analysis 7.4. Comparison 7 Systemic promethazine vs no promethazine, Outcome 4 Number of participants with

worsening adhesion score. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

103APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

109WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

110HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

110CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

110DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

111SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

111DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

111INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iiFluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review)


[Intervention Review]

Fluid and pharmacological agents for adhesion preventionafter gynaecological surgery

Gaity Ahmad1, Fiona L Mackie1, David A Iles2, Helena O’Flynn3, Sofia Dias4, Mostafa Metwally5, Andrew Watson6

1Obstetrics & Gynaecology, Pennine Acute NHS Trust, Manchester, UK. 2Obstetrics and Gynaecology, Blackpool Victoria Hospital,

Blackpool, UK. 3University Hospital of South Manchester, Manchester, UK. 4School of Social and Community Medicine, University

of Bristol, Bristol, UK. 5The Jessop Wing and Royal Hallamshire Hospital, Sheffield Teaching Hospitals, Sheffield, UK. 6Tameside &

Glossop Acute Services NHS Trust, Tameside General Hospital, Ashton-Under-Lyne, UK

Contact address: Gaity Ahmad, Obstetrics & Gynaecology, Pennine Acute NHS Trust, Manchester, UK. [email protected].

[email protected].

Editorial group: Cochrane Menstrual Disorders and Subfertility Group.

Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 7, 2014.

Review content assessed as up-to-date: 7 April 2014.

Citation: Ahmad G, Mackie FL, Iles DA, O’Flynn H, Dias S, Metwally M, Watson A. Fluid and pharmacological agents for

adhesion prevention after gynaecological surgery. Cochrane Database of Systematic Reviews 2014, Issue 7. Art. No.: CD001298. DOI:10.1002/14651858.CD001298.pub4.


A B S T R A C T

Background

Adhesions are fibrin bands that are a common consequence of gynaecological surgery. They are caused by various conditions including

pelvic inflammatory disease and endometriosis. Adhesions are associated with considerable co-morbidity, including pelvic pain, sub-

fertility and small bowel obstruction. Patients may require further surgery-a fact that has financial implications.

Objectives

To evaluate the role of fluid and pharmacological agents used as adjuvants in preventing formation of adhesions after gynaecological

surgery.

Search methods

The following databases were searched up to April 2014: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE,

EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and PsycINFO. Studies involving hydroflotation,

gel and such pharmacological agents as steroids, noxytioline, heparin, promethazine, N,O-carboxymethyl chitosan and gonadotrophin-releasing hormone agonists were evaluated.

Selection criteria

Randomised controlled trials investigating the use of fluid and pharmacological agents to prevent adhesions after gynaecological surgery.

Gels were defined as fluid agents.

Data collection and analysis

Three review authors independently assessed trials for eligibility, extracted data and evaluated risk of bias. Results were expressed as

odds ratios (ORs), mean differences (MDs) or standard mean differences (SMDs) as appropriate, with 95% confidence intervals (CIs).

1Fluid and pharmacological agents for adhesion prevention after gynaecological surgery (Review)


mailto:[email protected]:[email protected]

Main results

Twenty-nine trials were included (3227 participants), and nine were excluded. One study examined pelvic pain and found no evidence

of a difference between use of hydroflotation agents and no treatment. We found no evidence that any of the antiadhesion agents

significantly affected the live birth rate. When gels were compared with no treatment or with hydroflotation agents at second-look

laparoscopy (SLL), fewer participants who received a gel showed a worsening adhesion score when compared with those who received

no treatment (OR 0.16, 95% CI 0.04 to 0.57, P value 0.005, two studies, 58 women, I2 = 0%, moderate-quality evidence) and with

those given hydroflotation agents (OR 0.28, 95% CI 0.12 to 0.66, P value 0.003, two studies, 342 women, I2 = 0%, high-quality

evidence). Participants who received steroids were less likely to have a worsening adhesion score (OR 0.27, 95% CI 0.12 to 0.58, P

value 0.0008, two studies, 182 women, I2 = 0%, low-quality evidence). Participants were less likely to have adhesions at SLL if they

received a hydroflotation agent or gel than if they received no treatment (OR 0.34, 95% CI 0.22 to 0.55, P value < 0.00001, four

studies, 566 participants, I2 = 0%, high-quality evidence; OR 0.25, 95% CI 0.11 to 0.56, P value 0.0006, four studies, 134 women, I2

= 0%, high-quality evidence, respectively). When gels were compared with hydroflotation agents, participants who received a gel were

less likely to have adhesions at SLL than those who received a hydroflotation agent (OR 0.36, 95% CI 0.19 to 0.67, P value 0.001, two

studies, 342 women, I2 = 0%, high-quality evidence). No studies evaluated quality of life. In all studies apart from one, investigators

stated that they were going to assess serious adverse outcomes associated with treatment agents, and no adverse effects were reported.

Results suggest that for a woman with a 77% risk of developing adhesions without treatment, the risk of developing adhesions after use

of a gel would be between 26% and 65%. For a woman with an 83% risk of worsening of adhesions after no treatment at initial surgery,

the chance when a gel is used would be between 16% and 73%. Similarly, for hydroflotation fluids for a woman with an 84% chance

of developing adhesions with no treatment, the risk of developing adhesions when hydroflotation fluid is used would be between 53%

and 73%.

Several of the included studies could not be included in a meta-analysis: The findings of these studies broadly agreed with the findings

of the meta-analyses.

The quality of the evidence, which was assessed using the GRADE approach, ranged from low to high. The main reasons for downgrading

of evidence included imprecision (small sample sizes and wide confidence intervals) and poor reporting of study methods.

Authors’ conclusions

Gels and hydroflotation agents appear to be effective adhesion prevention agents for use during gynaecological surgery, but no evidence

indicates that they improve fertility outcomes or pelvic pain, and further research is required in this area. Future studies should measure

outcomes in a uniform manner, using the modified American Fertility Society (mAFS) score. Statistical findings should be reported in

full.

P L A I N L A N G U A G E S U M M A R Y

Use of fluids and pharmacological agents (medicinal drugs) to prevent the formation of adhesions (scar tissue) after surgery of

the female pelvis

Review question: This Cochrane systematic review evaluated all fluid and pharmacological agents that aim to prevent adhesion

formation after gynaecological surgery (gels were defined as fluid agents).

Background: Adhesions are defined as internal scar tissue that may form as part of the body’s healing process after surgery. They can

also be caused by pelvic infection and endometriosis. Adhesions join together tissues and organs that are not normally connected. They

are common after gynaecological surgery and can cause pelvic pain, infertility and bowel obstruction. Women with adhesions may need

further surgery, which is more difficult and can lead to additional complications. The fluid agents are placed inside the pelvic cavity

(which contains all female reproductive organs) during surgery and physically prevent raw, healing tissues from touching. These fluids

can be broken down into hydroflotation agents or gels; hydroflotation agents are fluids placed in large volumes (usually around a litre);

gels are directly applied to the internal surgical site. Pharmacological agents act by changing part of the healing process.

Study characteristics: We included 29 randomised controlled trials in the review (3227 participants). Of these, results of 18 trials were

pooled (2740 participants). Results from the remaining 11 trials could not be used in the meta-analysis because investigators did not

use a way of measuring adhesions that would allow findings to be pooled with other data, or because important statistical information

was not reported. We searched all evidence up to April 2014.



Key results: Only one study evaluated pelvic pain and provided no evidence that the adhesion prevention agent made a difference. No

evidence suggests that any of the investigated agents affected live birth rate. Regarding adhesions, participants given a fluid agent during

surgery were less likely to form adhesions than participants who did not receive a fluid agent. When fluids and gels were compared

with each other, gels appeared to perform better than fluids. No pharmacological agents showed good evidence of causing a significant

effect on adhesions. No studies looked at differences in quality of life. All studies apart from one stated that investigators were going

to assess serious adverse outcomes associated with the agents, and no adverse effects were reported.

For gels, results suggest that for a woman with a 77% risk of developing adhesions without treatment, the risk of developing adhesions

after a gel is used would be between 26% and 65%. For a woman with an 83% risk of worsening of adhesions after no treatment at

initial surgery, the chance when a gel is used would be between 16% and 73%. Similarly, for hydroflotation fluids in a woman with an

84% chance of developing adhesions with no treatment, the risk of developing adhesions when hydroflotation fluid is used would be

between 53% and 73%.

Fluids and gels appear to be effective in reducing adhesions, but more information is needed to determine whether this affects pelvic

pain, live birth rate, quality of life and long-term complications such as bowel obstruction. Further large, high-quality studies should

be conducted in which investigators use the standard way of measuring adhesions as developed by the American Fertility Society (the

modified AFS score).

Quality of the evidence: The quality of the evidence ranged from low to high. The main reasons for downgrading of evidence were

imprecision (small sample sizes and wide confidence intervals) and poor reporting of study methods.



S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Hydroflotation agents vs no hydroflotation agents for adhesion prevention after gynaecological surgery

Patient or population: women after gynaecological surgery

Settings: postsurgical

Intervention: hydroflotation agents vs no hydroflotation agents

Outcomes Illustrative comparative risks* (95% CI) Relative effect

(95% CI)

No. of participants

(studies)

Quality of the evidence

(GRADE)

Comments

Assumed risk Corresponding risk

No hydroflotation agents Hydroflotation agents

Improvement in pelvic

pain in participants with

a primary diagnosis of

pelvic pain, at second-

look laparoscopy

806 per 1000 730 per 1000

(606-826)

OR 0.65

(0.37-1.14)

286

(1 study)

⊕⊕⊕©

moderate1

Live birth rate 140 per 1000 98 per 1000

(45-205)

OR 0.67

(0.29-1.58)

208

(2 studies)

⊕⊕⊕©

moderate1

Improvement in adhe-

sion score

437 per 1000 496 per 1000

(380-614)

OR 1.27

(0.79-2.05)

665

(4 studies)

⊕⊕⊕©

moderate1,2

Number of participants

withworseningadhesion

score

308 per 1000 111 per 1000

(30-350)

OR 0.28

(0.07-1.21)

53

(1 study)

⊕⊕⊕©

moderate1,3


with adhesions at sec-

ond-look laparoscopy

836 per 1000 635 per 1000

(529-738)

OR 0.34

(0.22-0.55)

566

(4 studies)

⊕⊕⊕⊕

high

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Mean adhesion score

at second-look la-

paroscopy

The mean adhesion

score at second-look la-

paroscopy in the interven-

tion groups was

0.06 standard deviations

lower

(0.2 lower-0.09 higher)

722

(4 studies)

⊕⊕⊕⊕

high

SMD -0.06 (-0.2 to 0.09)4

Clinical pregnancy rate 234 per 1000 163 per 1000

(99-258)

OR 0.64

(0.36-1.14)

310

(3 studies)

⊕⊕⊕©

moderate1

*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison

group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; OR: Odds ratio.

GRADE Working Group grades of evidence.

High quality: Further research is very unlikely to change our confidence in the estimate of effect.

Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low quality: We are very uncertain about the estimate.

1Wide 95% CI.2Moderate heterogeneity.3Small number of events.4Scale: mean of the ‘ ‘ mean adhesion score’’ used. A lower mean ‘ ‘ mean adhesion score’’ represents an improvement in adhesion

disease. A variety of adhesion scoring systems were used (e.g. Hulka, mAFS or system developed by authors for purpose of study);

therefore for comparison, standardised mean difference was calculated.

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B A C K G R O U N D

Description of the condition

Adhesions are fibrin bands that form as the result of aberrant

peritoneal healing (Cheong 2001). Normally, peritoneal damage

causes an inflammatory response; this activates the coagulation cas-

cade, and a fibrin plug is formed over the damaged mesothelium,

which is then broken down to reveal regenerated peritoneum.

However, in adhesion formation, fibrinolysis of the fibrin plug is

decreased and, consequently, a fibrin matrix develops. Adhesions

may be defined as ‘de novo,’ meaning that they have formed at a

location that was previously free from adhesions, or ‘re-formed,’

which describes adhesions that recur post adhesiolysis. A variety of

factors influence the extent of adhesion formation, including type

of surgery performed (i.e. laparoscopic or open), haemostasis and

the presence of endometriosis and infection, particularly pelvic

inflammatory disease (Diamond 2001). Although the aetiologies

are different, the basic pathogenesis is similar.

Description of the intervention

Adhesion prevention agents can be divided into three types: fluid,

pharmacological and barrier. This review will examine fluid and

pharmacological agents. A separate review evaluates barrier agents.

Fluid agents include both hydroflotation products and gels. Exam-

ples of hydroflotation devices are 4% icodextrin solution (Adept,

Baxter, Berkshire, UK), an iso-osmolar and non-viscous high

molecular weight glucose polymer, and 32% dextran (Hyskon

Pharmacia, Uppsala, Sweden), a polysaccharide-containing solu-

tion that is no longer approved for use as an antiadhesion agent.

Both agents can be used as intraperitoneal irrigants and/or instil-

lants.

Derivatives of hyaluronic acid form the basis of a number of antiad-

hesion gels. Hyaluronic acid is a linear polysaccharide with repeat-

ing disaccharide units composed of sodium D-glucuronate and N-acetyl-D-glucosamine. SepraSpray (Genzyme Corporation, Cam-

bridge, MA, USA) contains hyaluronic acid in addition to car-

boxymethylcellulose powder and is applied to relevant tissues with

the use of a preloaded delivery device. SepraCoat (Genzyme Cor-

poration) is a dilute hyaluronic acid solution that is applied be-

fore and after surgery. Hyalobarrier gel (Nordic Pharma, Read-

ing, UK) contains auto-cross-linked hyaluronic acid. Intergel (Gy-

necare, Lifecore Biomedical, Chaska, MN, USA) contains ferrous

hyaluronic acid, although it has been withdrawn from the market.

N,O-carboxymethyl chitosan is a derivative of chitin and is simi-lar in structure to hyaluronic acid and carboxymethylcellulose. It

is formed when the gel and solution components are combined.

Polyethylene glycol (PEG)-based gels are also available. CoSeal

(Baxter) is formed by mixing a powder and a liquid intraopera-

tively, both of which contain PEG and are then applied as a gel

to relevant surfaces using a specific instrument. SprayGel (Con-

fluent Surgical Inc., Waltham, MA, USA) is formed by two PEG-

containing liquid precursors, which create a cross-linked gel when

combined. Intercoat (FzioMed, San Luis Obispo, CA, USA) is

an Oxiplex/AP viscoelastic gel composed of polyethylene oxide

(PEO), which is very similar to PEG but has a different molecular

weight, and carboxymethylcellulose.

Steroids have been used to prevent adhesions and can be adminis-

tered in a number of ways, including systemically before, during

and after surgery; intraperitoneally during surgery; and via hy-

drotubation postoperatively. Other pharmacological agents used

to prevent adhesions include noxytioline, an antibacterial agent;

promethazine, an antihistamine; and reteplase, a thrombolytic

drug, all of which are instilled intraperitoneally; as well as hep-

arin, an anticoagulant used for intraoperative irrigation. A nasal

gonadotrophin-releasing hormone agonist (GnRHa) has also been

used preoperatively and postoperatively.

How the intervention might work

Hyaluronic acid is a major component of many body tissues and

fluids, where it provides physically supportive and mechanically

protective roles (Johns 2001). PEG is a polymer; when the two

PEG-containing liquids are sprayed simultaneously, they form a

cross-linked gel. Gels are thought to decrease adhesion formation

mainly by preventing denuded tissues from touching.

Steroids and antihistamines (e.g. promethazine) act as im-

munomodulating agents and were used in the belief that they pro-

mote fibrinolysis during healing, without hindering the healing

process. GnRHa may work by decreasing oestrogen-related growth

factors and promoting fibroblasts. Fluid agents such as icodex-

trin and dextran work through the act of hydroflotation, whereby

the fluid separates raw opposing surfaces until the healing process

has been completed. Fluid agents are believed to remain in the

peritoneal cavity for several days, which is considered a sufficient

length of time, given that adhesions form within eight days of

surgery (Diamond 2001; Hosie 2001).

Why it is important to do this review

Adhesiolysis is the only available treatment for adhesions, although

controversy regarding its efficacy is ongoing (Hammoud 2004).

The focus of adhesion management is now prevention. Intraperi-

toneal adhesions are associated with considerable co-morbidity

and have large economic and public health repercussions. They are

the most common complication of gynaecological surgery, form-

ing in 50% to 100% of women (diZerega 1994). Women present

with the secondary effects of adhesions including dyspareunia,

subfertility, bowel obstruction and chronic pelvic pain, although

the latter has a controversial association with adhesions, as no cor-

relation with extent of adhesions and severity of pain is apparent.



Nevertheless, these consequences can greatly decrease a woman’s

well-being and require further surgery. Subsequent surgery in

women with adhesions is more difficult, often takes longer and is

associated with a higher complication rate. It is estimated that in

the first year after lower abdominal surgery, the cost of adhesion-

related readmissions in the UK is £24.2 million, which increases to

£95.2 million over the subsequent nine years (Wilson 2002). The

Surgical and Clinical Adhesions Research (SCAR) study found

that 5% (n = 245) of readmissions 10 years after open gynaecolog-

ical surgery were due to adhesions (Lower 2000; Lower 2004). An

English study estimated that the National Health Service (NHS)

could save £700,000 per year if an antiadhesion agent that reduced

adhesions by 25% and cost £110 was used or, at worst, that this

approach would be cost-neutral (Cheong 2011).

O B J E C T I V E S

To evaluate the role of fluid and pharmacological agents used as

adjuvants in preventing formation of adhesions after gynaecolog-

ical surgery.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Published and unpublished randomised controlled trials (RCTs)

investigating the use of fluid and pharmacological agents to prevent

adhesion formation after gynaecological surgery were eligible for

inclusion. Non-randomised trials and those considered to be at

high risk of bias for sequence generation or allocation concealment

were excluded. Studies using a cross-over design were excluded.

Types of participants

Female participants in any age group who underwent pelvic

surgery (by laparoscopy or laparotomy). Studies investigating ad-

hesion prevention in non-gynaecological specialities were not in-

cluded.

Types of interventions

Interventions were grouped together for meta-analysis according

to physical state and main mechanism of action: hydroflotation

agents (including dextran, 4% icodextrin solution), gel agents (in-

cluding SepraSpray, SepraCoat, Hyalobarrier gel, Intergel, CoSeal,

SprayGel and Intercoat) and pharmacological agents. The follow-

ing comparisons were made.

1. Hydroflotation agent versus no hydroflotation agent.

2. Gel agent versus no treatment.

3. Gel agent versus hydroflotation agent when used as an

instillant.

4. Steroid (including systemic, intraperitoneal, preoperative

and postoperative) versus no steroid (or placebo).

5. Intraperitoneal noxytioline versus no noxytioline (or

placebo).

6. Intraperitoneal heparin versus no heparin (or placebo).

7. Systemic promethazine versus no promethazine (or

placebo).

8. GnRHa versus no GnRHa (or placebo).

9. Reteplase plasminogen activator versus no reteplase

plasminogen activator (or placebo).

10. N,O-carboxymethyl chitosan versus no N,O-carboxymethylchitosan (or placebo).

Types of outcome measures

We decided to alter outcomes slightly from the previous version

of the review, so that the primary outcomes focus on what is most

important to the participants rather than on adhesion formation,

which has little correlation with symptoms experienced. A variety

of adhesion assessment measures were included as secondary out-

comes to enable maximum study inclusion.

Primary outcomes

1. Pelvic pain (improvement/worsening/no change in pain at sec-

ond-look laparoscopy (SLL)), independent of the method used to

assess pelvic pain.

2. Live birth rate, as defined by the individual study.

Secondary outcomes

3. Improvement in adhesion score at SLL, recorded on whichever

scale the study authors used, but with preference given to the

modified American Fertility Society (mAFS) score.

4. Worsening in adhesion score at SLL, recorded on whichever

scale the study authors used, but with preference given to the

mAFS score.

5. Adhesions at SLL.

6. Mean adhesion score at SLL per participant, recorded on

whichever scale the study authors used, but with preference given

to the mAFS score.

7. Clinical pregnancy rate as defined by the individual study.

8. Miscarriage rate, defined as loss of pregnancy before 24 weeks’

gestation.

9. Ectopic pregnancy rate.

10. Improvement in quality of life (QoL) at SLL, recorded on

whichever scale the study authors used, but with preference given

to Short Form (SF)-36.



11. Adverse outcomes, local and systemic, thought to be due to the

antiadhesion agent, in studies stating this as one of their outcomes,

as opposed to observation.

Articles were included independent of the adhesion scoring

method used. Articles that met the inclusion criteria but did not

report any of the outcomes considered within this review were

included within the qualitative analysis.

Search methods for identification of studies

This is an update of the review by Metwally et al. published in

2006. The Menstrual Disorders and Subfertility Group (MDSG)

Specialised Register of Controlled Trials, the Cochrane Central

Register of Controlled Trials (CENTRAL) and citation indexes

were searched using a search strategy designed by the MDSG Trials

Search Co-ordinator. No restriction on language was applied. See

the Review Group module for additional details on the make-up

of the Specialised Register.

Electronic searches

Electronic databases were searched using Ovid software: MED-

LINE (1950 to April 2014), MDSG database (inception to April

2014), EMBASE (1980 to April 2014), CENTRAL (inception to

April 2014), PsycINFO (1806 to April 2014) and the Cumulative

Index to Nursing and Allied Health Literature (CINAHL) (1982

to April 2014). The clinical trials databases International Clini-

cal Trials Registry Platform (ICTRP) and clinicaltrials.gov were

searched from inception to February 2013.

See Appendix 1; Appendix 2; Appendix 3; Appendix 4; Appendix

5; Appendix 6; Appendix 7; and Appendix 8,

Searching other resources

Grey literature was handsearched, specifically, abstracts presented

at meetings of the British Society of Gynaecological Endoscopy,

the European Society of Gynaecological Endoscopy, the American

Association of Gynecological Laparoscopists and the British Fer-

tility Society. Reference lists of included studies were also searched.

Data collection and analysis

Selection of studies

Three review authors (GA, FM, DI) independently performed an

initial screen of titles and abstracts to assess trials for suitability of

inclusion in accordance with the eligibility criteria. FM and DI

independently examined the full-text articles and abstracts to con-

firm eligibility. If necessary, investigators were contacted to obtain

further information. Discrepancies were settled by consensus by

GA and AW.

Data extraction and management

Two review authors (FM, DI) independently extracted the data.

Data were transcribed onto a Microsoft Word data collection form

designed for this review before they were entered into RevMan.

The statistical package Metaview of RevMan 5.1, provided by The

Cochrane Collaboration, was used to analyse and synthesise data.

Study authors were contacted for further information as required.

If no reply was received and the information was related to bias, this

was denoted as unclear; if the information required was statistical

and prevented inclusion in the meta-analysis, the study was not

included in that outcome analysis, although it was still considered

an “included study.” Disagreements were resolved by consensus

by GA and AW.

Assessment of risk of bias in included studies

The risk of bias of all studies deemed eligible was assessed indepen-

dently by two review authors (FM, DI). These included allocation

(random sequence generation and allocation concealment); blind-

ing of participants, personnel and outcome assessors; incomplete

outcome data; selective reporting and other biases. Disagreements

regarding interpretation of data were settled by consensus by GA

and AW. The quality of trials was assessed as recommended by the

risk of bias tool in the Cochrane Handbook for Systematic Reviewsof Interventions (Higgins 2011) and was entered into the risk ofbias table.

Measures of treatment effect

The odds ratio (OR) was used for dichotomous data (e.g. number

of women with worsening adhesion score). The standardised mean

difference (SMD) was used for continuous measures that used

different scales (e.g. mean adhesion score at SLL). When the same

scale was used, the mean difference (MD) on this specific scale

was used. We presented 95% confidence intervals (CIs) for all

outcomes.

Unit of analysis issues

The included primary studies were analysed per woman. Studies

that used an internal control were excluded and have been listed

as such.

Dealing with missing data

Investigators were contacted to request missing data. If data were

insufficient for inclusion of the study in a particular analysis, it

was not included.

Assessment of heterogeneity

The Chi2 test was performed and the I2 statistic calculated to

determine significant heterogeneity. An I2 measurement > 30%



was considered moderate heterogeneity, > 50% substantial hetero-

geneity and > 70% high heterogeneity.

Assessment of reporting biases

In consideration of the difficulty of detecting and correcting pub-

lication bias and other reporting bias, we aimed to minimise the

impact by ensuring that a robust and comprehensive search was

performed. We planned to create a funnel plot to assess the risk

of reporting bias if 10 or more studies were included in a meta-

analysis.

Data synthesis

Statistical analysis was performed in accordance with guidelines

developed by The Cochrane Collaboration. Data from the primary

studies were combined in RevMan using the fixed-effect model.

An increase in OR or SMD or MD was indicated to the right

of the central line of the forest plot; a decrease was indicated to

the left of the central line. Whether this favoured treatment or no

treatment depended on the outcome analysed, but the axes were

labelled accordingly.

Subgroup analysis and investigation of heterogeneity

When significant heterogeneity was identified, the cause was ex-

plored, and a sensitivity analysis was performed using the random-

effects model. This was highlighted in the results section, and any

variation in the direction of effect was noted. A subanalysis com-

paring the effects of antiadhesion agents on de novo adhesions ver-

sus re-formed adhesions would have been performed if sufficient

data were available.

Sensitivity analysis

Sensitivity analysis was performed to determine whether the results

were robust to decisions made regarding eligibility of the studies

and analysis. If a study was considered to have a high risk of bias,

or an apparent outlier was identified, the reason for the significant

heterogeneity was investigated, as to whether this was believed

to be clinical or methodological, and analysis was conducted to

evaluate whether inclusion of the study significantly affected the

results. Results of the sensitivity analysis are reported in the Risk

of bias in included studies subsection of the results section.

R E S U L T S

Description of studies

Results of the search

Forty-four studies were identified as potentially eligible for inclu-

sion. Twenty-nine studies were included. For a summary of each

included study, see the section Characteristics of included studies.

Reasons for study exclusion are detailed in the Characteristics of

excluded studies section. For details of the screening and selection

process, see Figure 1.



Figure 1. Study flow diagram.

Included studies

Study design and setting

Of the 29 included studies, 19 were conducted at multiple centres

and 10 at a single centre. Nine were conducted in the USA, six

in Europe, two in the USA/Europe, two in the Netherlands, three

in Australia, one in Sweden, two in Italy and one in Germany/

Canada/Netherlands/Antilles; three studies did not state their lo-

cation.

Results of nine of the included trials could not be entered into the

meta-analysis because the data were not reported in an appropriate

format. In some cases, the study authors used different ways of

assessing adhesions, such as reporting only individual sections of

the mAFS, as in Hellebrekers 2009 and Diamond 2003, or the

adhesion area (cm2), as in Coddington 2009. Another reason why

studies could not be entered was that complete statistical data were

not published, for example, Thornton 1998 and Rosenberg 1984

did not report standard deviations (SDs) or standard errors of the

mean (SEMs), and although Fossum 2011 reported the outcomes

we were examining, results were displayed on a graph without ac-

tual numbers stated at any point in the text. DiZerega 2007 was

not entered into the meta-analysis, as investigators reported only

the effect that the antiadhesion agent had on AFS endometriosis

score, and as the results were presented per adnexa, not per par-

ticipant. Thus 20 trials were involved in the meta-analysis.

Fifteen studies stated that they received commercial funding.

Participants

A wide variety was noted in the number of participants in each

study, with participant numbers ranging from 10 to 203 in the

intervention group and from 10 to 199 in the control group. All



participants were women undergoing a gynaecological procedure

who had had a second-look laparoscopy. Reasons for surgery in-

cluded pelvic inflammatory disease (PID), endometriosis, adhe-

sions, fibroids, pelvic pain, pelvic mass, endometrioid cysts and

infertility assessment and treatment (e.g. tubal surgery).

Interventions

The numbers of studies entered into the meta-analysis for each

comparison are as follows.

1. Seven studies compared hydroflotation agents versus no

hydroflotation agents. A distinction was made between

hydroflotation agents (e.g. dextran, 4% icodextrin, SepraCoat)

designed as antiadhesion agents and liquids such as saline, which

was often used as a control and is not considered a

hydroflotation agent in this review.

2. Five studies compared gel agents versus no gel agents.

3. Two studies compared hydroflotation agents versus gel

agents.

4. Four studies compared steroids versus no steroids.

5. One study compared noxytioline versus no noxytioline.

6. One study compared heparin versus no heparin.

7. One study compared promethazine versus no

promethazine.

No studies that evaluated GnRHa, reteplase plasminogen activator

or N,O-carboxymethyl chitosan could be included in the meta-analysis.

Outcomes

Two studies did not assess adhesions (Rose 1991; Sites 1997).

DiZerega 2007 and Lundorff 2005 presented the results per ad-

nexa.

Primary outcomes

One of 29 studies examined pelvic pain (Brown 2007).

Three of 29 studies examined live birth rate (Jansen 1985; Larsson

1985; Rock 1984).

Secondary outcomes

Of 29 studies, 11 examined improvement in adhesion score at SLL

(Adhesion SG 1983; Brown 2007; diZerega 2002; Jansen 1985;

Jansen 1988; Jansen 1990; Johns 2001; Larsson 1985; Lundorff

2001; Mettler 2004; Young 2005).

Of 29 studies, nine examined the number of participants with

worsening adhesion score at SLL (diZerega 2002; Jansen 1985;

Jansen 1988; Jansen 1990; Johns 2001; Lundorff 2001; Mettler

2004; Querleu 1989; Young 2005).

Of 29 studies, 10 examined adhesions at SLL (Adhesion SG

1983; Diamond 1998; diZerega 2002; Jansen 1985; Johns 2001;

Lundorff 2001; Mais 2006; Mettler 2004; Pellicano 2003; Ten

Broek 2012).

Of 29 studies, seven examined the mean adhesion score at SLL

per participant (Adhesion SG 1983; Brown 2007; Larsson 1985;

Lundorff 2001; Mais 2006; Ten Broek 2012; Trew 2011).

Of 29 studies, five examined the clinical pregnancy rate. All par-

ticipants in these studies were actively seeking pregnancy during

the study time period (Adhesion SG 1983; Jansen 1985; Larsson

1985; Querleu 1989; Rock 1984).

None of the 29 studies examined the miscarriage rate.

Of 29 studies, four examined the ectopic pregnancy rate (Jansen

1985; Larsson 1985; Querleu 1989; Rock 1984).

None of the 29 studies examined QoL.

Of 29 studies, 28 examined adverse outcomes. Rosenberg 1984

was the only study that did not examine adverse outcomes.

Excluded studies

Nine studies were excluded. Johns 2003 used an internal control.

Diamond 2011 and Tulandi 1991 used internal controls, which

was not explicitly stated in the abstract. Two studies were interim

reports (Mettler 2003(a); Mettler 2003(b)) and the final report

was included. One trial was not randomised (Tsuji 2005), and

one study did not state that it was randomised (Pellicano 2005),

although it appeared to include the same study group as was used

in Pellicano 2003. This was not explicitly stated in the methods,

nor was the fact that the study was randomised. Thus Pellicano

2005 was excluded. One study was excluded because it was quasi-

randomised (Swolin 1967). Tulandi 1985 reported the effect of the

agent on blood indices, not on adhesions. This study was included

in the original review but has been excluded because investigators

used an external control.

Studies awaiting classification

Three studies sit in the awaiting classification section (Hudecek

2012; Litta 2013; Tchartchian 2009) pending publication of suf-

ficient data to allow their inclusion.

Risk of bias in included studies

The risk of bias for each included study can be seen in the

Characteristics of included studies section. Figure 2 presents a

summary of risk of bias of all included studies. Figure 3 depicts

the proportions of studies within each judgement for each risk of

bias element.



Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included

study.



Figure 3. Risk of bias graph: review authors’ judgements about each risk of bias item presented as

percentages across all included studies.

Allocation

Sequence generation

No studies were at high risk of sequence generation bias. Seventeen

studies adequately explained an appropriate method of sequence

generation and were thus deemed at low risk. Twelve studies de-

scribed the methods of random sequence generation inadequately

and were at unclear risk.

Allocation concealment

No studies were at high risk of allocation concealment bias. Eleven

studies were at low risk of allocation concealment bias, as the au-

thors described an acceptable method of allocation concealment.

Eighteen studies did not provide sufficient information on alloca-

tion to permit a judgement.

Blinding

Six studies did not provide sufficient information on blinding to

permit a judgement. Three studies blinded only the participant

(Coddington 2009; Mettler 2008; Rose 1991). Five studies were

double-blinded (i.e. both participant and operating surgeon were

blinded) (Brown 2007; Mettler 2004; Pellicano 2003; Querleu

1989; Rosenberg 1984). Ten Broek 2012 stated that the study was

single-blinded (participant), although the surgeon performing the

initial surgery was unaware of allocation until the end of the initial

procedure after the adhesions were scored, and the second-look la-

paroscopy surgeon was blinded. The remaining 14 studies blinded

the participant and the operating surgeon and used an independent

blinded reviewer to assess videos or diagrams obtained through

the second-look laparoscopy (Diamond 1998; Diamond 2003;

diZerega 2002; DiZerega 2007; Fossum 2011; Hellebrekers 2009;

Jansen 1985; Jansen 1988; Johns 2001; Larsson 1985; Lundorff

2001; Mais 2006; Trew 2011; Young 2005).

Incomplete outcome data

Two studies (Rosenberg 1984; Thornton 1998) were considered

at high risk of attrition bias, as neither study reported SDs or

SEMs. Twenty-two studies were at low risk for attrition bias. Five

studies did not provide sufficient information to reveal attrition

bias; consequently the risk of attrition bias was unclear.

Selective reporting

One study (Mettler 2008) was at high risk for reporting bias. The

authors of the study decided “in hindsight” to change the primary

outcome scoring method from the total mAFS score, as stated

in the original protocol, to the mAFS of the posterior uterus, as

discussed during data analysis. Consequently, a sensitivity analysis

was conducted and found that excluding Mettler 2008 made no

difference to the direction of treatment effect. Thus the study

was excluded from analysis. Twenty-five studies were at low risk

for reporting bias, and three studies did not provide sufficient

information to allow judgement on reporting bias risk.



Other potential sources of bias

Two studies were identified as having other sources of bias that

were unclear (Jansen 1988; Ten Broek 2012). A potential source

of bias in Jansen 1988 was that the practice of adding hydrocor-

tisone sodium succinate to the irrigation solution was stopped af-

ter 46 participants had received it because a possible detrimental

effect was reported in an earlier study. These 46 participants were

still included in the analysis. The study by Ten Broek 2012 was

“prematurely ended due to financial and organizational reasons.

During the conduct of the study, the clinical trial insurance unex-

pectedly required a separate fee for both laparoscopic procedures

in each patient”; this study was still included. No potential sources

of bias were identified in the other 27 included studies.

Effects of interventions

See: Summary of findings for the main comparison

Hydroflotation agents vs no hydroflotation agents for adhesion

prevention after gynaecological surgery; Summary of findings

2 Gel agents vs no treatment for adhesion prevention after

gynaecological surgery; Summary of findings 3 Gel agents

compared with hydroflotation agents when used as an instillant

for adhesion prevention after gynaecological surgery; Summary

of findings 4 Steroids (any route) vs no steroids for adhesion


5 Intraperitoneal noxytioline vs no treatment for adhesion


6 Intraperitoneal heparin solution vs no intraperitoneal heparin

for adhesion prevention after gynaecological surgery; Summary

of findings 7 Systemic promethazine vs no promethazine for

adhesion prevention after gynaecological surgery

1. Hydroflotation agents versus no treatment

Primary outcomes

1.1 Pelvic pain

One study (Brown 2007) examined the effect of a hydroflotation

agent (4% icodextrin) on pelvic pain and found no evidence of

a difference compared with saline (OR 0.65, 95% CI 0.37 to

1.14, P value 0.13, one study, 286 participants, moderate-quality

evidence). See Analysis 1.1.

1.2 Live birth rate

No evidence of a difference between groups was seen (OR 0.67,

95% CI 0.29 to 1.58, P value 0.36, two studies, 208 participants,

I2 = 0%, moderate-quality evidence) (Jansen 1985: dextran vs

Hartmann’s; Larsson 1985: dextran vs saline). See Analysis 1.2 and

Figure 4.

Figure 4. Forest plot of comparison: 1 Hydroflotation agent vs no hydroflotation agent, outcome: 1.2 Live

birth rate.

Secondary outcomes

1.3 Improvement in adhesion score at SLL


95% CI 0.79 to 2.05, P value 0.32, four studies, 665 participants,

I2 = 38%, moderate heterogeneity, moderate-quality evidence)

(Adhesion SG 1983: dextran vs saline; Brown 2007: 4% icodextrin

vs saline; diZerega 2002: 4% icodextrin vs saline; Jansen 1985:

dextran vs Hartmann’s). Heterogeneity was reduced to I2 = 0%

when Jansen 1985 was removed, which consequently meant that

a significant difference between groups was seen (OR 1.47, 95%

CI 1.03 to 2.10, P value 0.03, three studies, 546 participants);



however a cause for the heterogeneity was not elucidated, and thus

the study remained in the meta-analysis. The only difference that

we could discern was the use of Hartmann’s as a control as opposed

to saline by Jansen 1985; however, the review authors believed this

difference to be unlikely to cause significant heterogeneity, as the

solutions are so similar in composition. See Analysis 1.3.

1.4 Worsening in adhesion score at SLL


95% CI 0.07 to 1.21, P value 0.09, one study, 53 participants,

moderate-quality evidence) (diZerega 2002: 4% icodextrin vs

saline). With the addition of Jansen 1985, heterogeneity was high

in the analysis of worsening adhesion score (I2 = 79%). As this

outcome was poorly defined in Jansen 1985, this study was re-

moved from the analysis; this did not affect the results, as they

remained not statistically significant. See Analysis 1.4.

1.5 Adhesions at SLL

Meta-analysis demonstrated a significant difference in adhesions

at SLL, with participants less likely to have adhesions at SLL if

they received a hydroflotation agent (OR 0.34, 95% CI 0.22 to

0.55, P value < 0.00001, four studies, 566 participants, I2 = 0%,

high-quality evidence) (Adhesion SG 1983: dextran vs saline;

Diamond 1998: SepraCoat vs phosphate-buffered saline (PBS);

diZerega 2002: 4% icodextrin vs saline; Jansen 1985: dextran vs

Hartmann’s). See Analysis 1.5 and Figure 5.

Figure 5. Forest plot of comparison: 1 Hydroflotation agent vs no hydroflotation agent, outcome: 1.5

Number of participants with adhesions at second-look laparoscopy.

1.6 Mean adhesion score at SLL per participant

No evidence of a difference between groups was seen (OR -0.06,

95% CI -0.20 to 0.09, P value 0.44, four studies, 722 participants,

I2 = 0%, high-quality evidence) (Adhesion SG 1983: dextran vs

saline; Brown 2007: 4% icodextrin vs saline; Larsson 1985: dextran

vs saline; Trew 2011: 4% icodextrin vs saline). See Analysis 1.6.

1.7 Clinical pregnancy rate


95% CI 0.36 to 1.14, P value 0.13, three studies, 310 participants,

I2 = 0%, moderate-quality evidence) (Adhesion SG 1983: dextran

vs saline; Jansen 1985: dextran vs Hartmann’s; Larsson 1985: dex-

tran vs saline). See Analysis 1.7.

1.8 Miscarriage rate

This was not assessed by any study.

1.9 Ectopic pregnancy rate



I2 = 5%) (Jansen 1985: dextran vs Hartmann’s; Larsson 1985:

dextran vs saline). See Analysis 1.9.

1.10 Quality of life


1.11 Adverse outcomes

No adverse outcomes were reported.

2. Gel agents versus no treatment

Primary outcomes



2.1 Pelvic pain


2.2 Live birth rate


Secondary outcomes




I2 = 0%, moderate-quality evidence) (Mettler 2004: SprayGel vs

no treatment; Young 2005: Oxiplex/AP gel vs no treatment). The

95% CI is very wide though, which was believed to be related

to the small number of participants that could be included in

this analysis. Irrespective, the result remains not significant. See

Analysis 2.3.


A significant difference was seen, with fewer participants who had

received a gel showing worsening in adhesion score at SLL com-

pared with those who received no treatment (OR 0.16, 95% CI

0.04 to 0.57, P value 0.005, two studies, 58 participants, I2 = 0%,

moderate-quality evidence) (Mettler 2004: SprayGel vs no treat-

ment; Young 2005: Oxiplex/AP gel vs no treatment). See Analysis

2.4.


Participants who received a gel were significantly less likely to have

adhesions at SLL compared with those who received no adhesion

prevention agent (OR 0.25, 95% CI 0.11 to 0.56, P value 0.0006,

four studies, 134 participants, I2 = 0%, high-quality evidence)

(Mais 2006: Hyalobarrier vs no treatment; Mettler 2004: SprayGel

vs no treatment; Pellicano 2003: auto-cross-linked hyaluronic acid

gel vs no treatment; Ten Broek 2012: SepraSpray vs no treatment).

See Analysis 2.5 and Figure 6.

Figure 6. Forest plot of comparison: 2 Gel agent vs no treatment, outcome: 2.5 Number of participants

with adhesions at second-look laparoscopy.


No evidence of a difference between groups was seen (SMD -0.13,

95% CI -0.65 to 0.39, P value 0.63, two studies, 58 participants,

I2 = 0%, moderate-quality evidence) (Mais 2006: Hyalobarrier vs

no treatment; Ten Broek 2012: SepraSpray vs no treatment). See

Analysis 2.6 and Figure 7.



Figure 7. Forest plot of comparison: 2 Gel agent vs no treatment, outcome: 2.6 Mean adhesion score at

second-look laparoscopy.











Data that could not be included in a meta-analysis but were con-

sidered in the review are outlined here. Mettler 2008 (hydrogel vs

saline), Rosenberg 1984 (dextran vs saline) and Thornton 1998

(0.5% ferric hyaluronate vs saline) found that participants who

did not receive the antiadhesion agent had a significantly worse

adhesion score at SLL than participants who had received the anti-

adhesion agent. Diamond 2003 (N,O-carboxymethyl chitosan vssaline) found no significant difference in adhesion scores between

participants who received an antiadhesion agent and those who did

not. Lundorff 2005 (Oxiplex/AP gel) found a significant differ-

ence in adhesions at SLL, with adnexae that had not been treated

with Oxiplex/AP gel having significantly worse adhesions at SLL

than adnexae that had been treated. See Analysis 2.2; Analysis 2.7;

and Analysis 2.8.

3. Gel agents versus hydroflotation agents when used

as an instillant

Primary outcomes

3.1 Pelvic pain


3.2 Live birth rate


Secondary outcomes



95% CI 0.82 to 2.92, P value 0.17, two studies, 342 partici-

pants, I2 = 0%, moderate-quality evidence) (both Johns 2001 and

Lundorff 2001 examined Intergel vs saline). See Analysis 3.3.

Fossum 2011 (Sepraspray vs no SepraSpray) found no significant

difference in adhesion scores between participants who received

an antiadhesion agent and those who did not. These data could

not be included in the meta-analysis.


Participants who received a gel (Intergel) were less likely to have a

worsening adhesion score at SLL compared with participants who

received saline (OR 0.28, 95% CI 0.12 to 0.66, P value 0.003, two

studies, 342 participants, I2 = 0%, high-quality evidence) (Johns

2001; Lundorff 2001). See Figure 8.



Figure 8. Forest plot of comparison: 3 Gel agent vs hydroflotation agent when used as an instillant,

outcome: 3.4 Number of participants with worsening adhesion score.


Participants who received a gel (Intergel) were significantly less

likely to have adhesions at SLL (OR 0.36, 95% CI 0.19 to 0.67, P

value 0.001, two studies, 342 participants, I2 = 0%, high-quality

evidence) (Johns 2001; Lundorff 2001) compared with partici-

pants who had received no gel but were given a hydroflotation

agent (saline) as an instillant. See Figure 9.

Figure 9. Forest plot of comparison: 3 Gel agent vs hydroflotation agent when used as an instillant,

outcome: 3.5 Number of participants with adhesions at second-look laparoscopy.


Lundorff 2001 reported a lower adhesion score at SLL in par-

ticipants who received Intergel compared with those given saline

(MD -0.79, 95% CI -0.79 to -0.79, P value < 0.00001, one study,

77 participants, moderate-quality evidence); however as the SD

appears very precise for a study that included only 38 participants

in each arm, the study authors advise caution in interpreting these

results.











4. Steroids (including systemic, intraperitoneal,

preoperative and postoperative) versus no steroids

(or placebo)



Primary outcomes

4.1 Pelvic pain


4.2 Live birth rate

No significant difference was seen (OR 0.65, 95% CI 0.26 to

1.62, P value 0.35, two studies, 223 participants, I2 = 0%) (Jansen

1985: intraperitoneal hydrocortisone, IV dexamethasone and PO

prednisolone vs no steroids; Rock 1984: intraperitoneal hydrocor-

tisone vs saline). See Figure 10.

Figure 10. Forest plot of comparison: 4 Steroid (any route) vs no steroid, outcome: 4.2 Live birth rate.

Secondary outcomes


A significant difference was demonstrated by the only study that

measured this outcome (OR 4.83, 95% CI 1.71 to 13.65, P value

0.003, one study, 75 participants, low-quality evidence) (Jansen

1990: IV dexamethasone and PO prednisolone vs no steroids).

The data from this study are taken from the previous version of

this review; data are unpublished and were supplied by the study

author along with little information about the characteristics of

the study. Thus caution is urged in interpreting this result. See

Analysis 4.3.


Fewer participants who received steroids showed worsening in

adhesion score compared with participants who did not receive

steroids (OR 0.27, 95% CI 0.12 to 0.58, P value 0.0008, two stud-

ies, 187 participants, I2 = 0%, low-quality evidence) (Jansen 1990:

IV dexamethasone and PO prednisolone vs no steroids; Querleu

1989: IM dexamethasone vs no steroids). See Analysis 4.4.








I2 = 0%, moderate-quality evidence) (Jansen 1985: intraperitoneal

hydrocortisone, IV dexamethasone and PO prednisolone vs no

steroids; Querleu 1989: IM dexamethasone vs no steroids; Rock

1984: intraperitoneal hydrocortisone vs saline). See Analysis 4.7.








I2 = 60%, substantial heterogeneity, moderate-quality evidence)

(Jansen 1985: intraperitoneal hydrocortisone, IV dexamethasone

and PO prednisolone vs no steroids; Querleu 1989: IM dexam-

ethasone vs no steroids; Rock 1984: intraperitoneal hydrocorti-

sone vs saline). See Analysis 4.9.





5. Intraperitoneal noxytioline versus no noxytioline

(or placebo)

Noxytioline was examined by only one study: Querleu 1989.

Primary outcomes

5.1 Pelvic pain


5.2 Live birth rate


Secondary outcomes




No evidence of a difference was seen between participants who

received intraperitoneal noxytioline and those who did not (OR

0.55, 95% CI 0.17 to 1.76, P value 0.32, one study, 87 partic-

ipants, moderate-quality evidence) (Querleu 1989). See Analysis

5.4.








0.66, 95% CI 0.30 to 1.47, P value 0.31, one study, 126 partic-

ipants, moderate-quality evidence) (Querleu 1989). See Analysis

5.7.






4.91, 95% CI 0.45 to 53.27, P value 0.19, one study, 33 partici-

pants, low-quality evidence) (Querleu 1989). See Analysis 5.9.





6. Intraperitoneal heparin versus no heparin (or

placebo)

Heparin was examined by only one study: Jansen 1988.

Primary outcomes

6.1 Pelvic pain


6.2 Live birth rate




Secondary outcomes



received intraperitoneal heparin and those who did not (OR 0.87,


low-quality evidence) (Jansen 1988). See Analysis 6.3.



received intraperitoneal heparin and those who did not (OR 1.27,


low-quality evidence) (Jansen 1988). See Analysis 6.4.















7. Systemic promethazine versus no promethazine

(or placebo)

Promethazine was examined by only one study: Jansen 1990.

Primary outcomes

7.1 Pelvic pain


7.2 Live birth rate


Secondary outcomes


No significant difference was seen between participants who re-

ceived promethazine and those who did not (OR 0.56, 95% CI

0.22 to 1.43, P value 0.22, one study, 75 participants, low-quality

evidence) (Jansen 1990).



received promethazine and those who did not (OR 0.59, 95% CI

0.25 to 1.42, P value 0.24, one study, 93 participants, low-quality

evidence) (Jansen 1990). See Analysis 7.4.

















8. GnRHa versus no GnRHa (or placebo)

This was not assessed by any study eligible for inclusion in the

meta-analysis. Coddington 2009 (GnRHa vs no GnRHa) found

no evidence of a difference in adhesion scores between participants

who received an antiadhesion agent and those who did not. Data

from this study could not be included in the meta-analysis. See

Analysis 8.1.

9. Reteplase plasminogen activator versus no

reteplase plasminogen activator (or placebo)

This was not assessed by any study that could be used in the

meta-analysis. Fossum 2011 (SepraSpray vs no SepraSpray) and

Hellebrekers 2009 (reteplase vs saline) found no evidence of a

difference in adhesion scores between participants who received

an antiadhesion agent and those who did not. See Analysis 9.1.

10. N,O-carboxymethyl chitosan versus no N,O-

carboxymethyl chitosan (or placebo)

This was not assessed by any study that could be used in the meta-

analysis.

The only included study that did not examine adverse outcomes

was Rosenberg 1984. None of the included studies reported any

adverse effects that the study authors believed to be due to antiad-

hesion agents; however new evidence has come to light since the

publication of these studies that led to the withdrawal of Intergel.



A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]

Gel agents vs no treatment for adhesion prevention after gynaecological surgery



Intervention: gel agents vs no treatment


(95% CI)

No. of participants

(studies)


(GRADE)

Comments


No treatment Gel agents


with improvement in ad-

hesion score

43 per 1000 147 per 1000

(27-515)

OR 3.78

(0.61-23.32)

58

(2 studies)

⊕⊕⊕©

moderate1



score

826 per 1000 432 per 1000

(160-730)

OR 0.16

(0.04-0.57)

58

(2 studies)

⊕⊕⊕©

moderate2




766 per 1000 450 per 1000

(264-647)

OR 0.25

(0.11-0.56)

134

(4 studies)

⊕⊕⊕⊕

high

Mean adhesion score

at second-look la-

paroscopy

Mean adhesion score at

second-look laparoscopy

in the intervention groups

was

0.13 standard deviations

lower

(0.65 lower-0.39 higher)

58

(2 studies)

⊕⊕⊕©

moderate3SMD -0.13 (-0.65 to 0.

39)4



CI: Confidence interval; OR: Odds ratio.23F

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http://www.thecochranelibrary.com/view/0/SummaryFindings.html






1Large 95% confidence interval-small number of participants able to be included in analysis.2Low number of events.3Small population size.4Scale: mean of the ‘ ‘ mean adhesion score’’ used. A lower mean ‘ ‘ mean adhesion score’’ represents an improvement in the adhesion

disease. A variety of adhesion scoring systems were used (e.g. Hulka, mAFS, system developed by trial authors for purpose of study);

therefore for comparison standardised mean difference was calculated.

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Gel agents compared with hydroflotation agents when used as an instillant for adhesion prevention after gynaecological surgery



Intervention: gel agents

Comparison: hydroflotation agents when used as an instillant


(95% CI)

No. of participants

(studies)


(GRADE)

Comments


Hydroflotation agents

when used as an instil-

lant

Gel agents



hesion score

110 per 1000 161 per 1000

(92-265)

OR 1.55

(0.82-2.92)

342

(2 studies)

⊕⊕⊕©

moderate1



score

139 per 1000 43 per 1000

(19-96)

OR 0.28

(0.12-0.66)

342

(2 studies)

⊕⊕⊕⊕

high




225 per 1000 95 per 1000

(52-163)

OR 0.36

(0.19-0.67)

342

(2 studies)

⊕⊕⊕⊕

high

Mean adhesion score

at second-look la-

paroscopy

Mean adhesion score at

second-look laparoscopy

in the intervention groups

was

0.79 lower

(0.79-0.79 lower)

77

(1 study)

⊕⊕⊕©

moderate2

3

25

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1Wide 95% CI.2Study authors advise caution in interpreting result; SD appears very precise for study with only 38 participants in each arm.3Scale: mean of the ‘ ‘ mean adhesion score’’ used. A lower mean ‘ ‘ mean adhesion score’’ represents an improvement in the adhesion

disease. A variety of adhesion scoring systems were used (e.g. Hulka, mAFS, system developed by authors for purpose of study);

therefore for comparison, standardised mean difference was calculated.

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Steroids (any route) vs no steroids for adhesion prevention after gynaecological surgery



Intervention: steroids (any route) vs no steroids


(95% CI)

No. of participants

(studies)


(GRADE)

Comments


No steroids Steroids (any route)

Live birth rate 112 per 1000 76 per 1000

(32-170)

OR 0.65

(0.26-1.62)

223

(2 studies)

⊕⊕⊕©

moderate2



hesion score

462 per 1000 805 per 1000

(594-921)

OR 4.83

(1.71-13.65)

75

(1 study)

⊕⊕©©

low14



score

343 per 1000 124 per 1000

(59-233)

OR 0.27

(0.12-0.58)

176

(2 studies)

⊕⊕©©

low1,24

Clinical pregnancy rate 297 per 1000 299 per 1000

(218-396)

OR 1.01

(0.66-1.55)

410

(3 studies)

⊕⊕⊕©

moderate1,2

Ectopic rate (per preg-

nancy)

195 per 1000 140 per 1000

(19-580)

OR 0.67

(0.08-5.7)

83

(3 studies)

⊕⊕⊕©

moderate3




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Fluid and pharmacological agents for adhesion prevention ... · [Intervention Review] Fluid and pharmacological agents for adhesion prevention after gynaecological surgery Gaity Ahmad

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