Prevention and Management of Pelvic Adhesions

Tommaso Falcone, M.D.Professor and ChairDepartment of Obstetrics & Gynecology

Definition

• Adhesion: abnormal joining of anatomical structures at sites where no such anatomical attachment should exist

• Categories– De novo ( at operative site/other site)– Reformation (operative site/other site-other

adhesiolysis)

• Scoring system– Location, vascularity, type (thickness)

Complications of adhesions

• Within 1 year of laparotomy- 1 % develop adhesion related intestinal obstruction & 12 % will suffer a recurrence

• Variation in incidence– Cause

Complications of adhesions

• Intestinal obstruction– Early 20 th century: primary cause

strangulated external hernias– Now in western society-adhesions

• Secondary to surgery colon & rectum, appendectomies, and gyn procedures

Complications of adhesions

• 17-29% of intestinal obstruction occur within 1 month of surgery

• Recurrence increases with number of prior episodes– Recurrence 81 % with 4 or more admissions– Recurrence within 5 years

Pain

• Adhesions contain nerve fibers– Confounding variables

• Restriction of free organ movement

• 20-50 % patients with chronic pain have pelvic adhesions

• No relationship between the extent of adhesions and severity of the pain

Pelvic Pain & Adhesions

• Consensus:– Adhesions may be the cause of pain in some

but in others adhesions may be an incidental finding

Laparoscopy & Adhesion formation

• Laparoscopic adhesiolysis ( Diamond et al 1991)– Adhesion reformation noted in 66/68 subjects ( 97%)– Extent of pelvic adhesions reduced by half– De novo adhesion development in 12 %

• Introduction of laparoscopy for abdominal procedures not associated with reduction of hospitalization rates for adhesive bowel obstruction

Diamond et al. 1991 62 67% tube 23% pelvic80% ovary

Canis et al. 1992 42 82% adnexa 21% adnexa

Lundorff et al. 1991 31 60% tube 17% tube

Study Year N Reformed De Novo

Adhesion Reformation and De Novo Adhesion Formation Following

Operative Laparoscopy- slide from Dr.Diamond

Surgery for Chronic Pain

• Peters et al BJOG 1992• RCT: surgery ( by laparotomy) versus no

surgery• Netherlands• Control( N=24) and Surgery group (N=24)• Evaluation at 12 months no significant

difference in pain scores– Patients with vascularized and dense

adhesions involving bowel had relief

Surgery for Chronic Pain

• Swank et al Lancet 2003• RCT ( double blinded) diagnostic scope and

laparoscopic adhesiolysis– N=100– 1 year follow up– No change or worsened pain

• Control group: 58%• Study group: 43 %

– More complications adhesiolysis group– No endometriosis patients

Surgery for Infertility

• One RCT-laparotomy (Tulandi et al 1990)

• Salpingo-ovariolysis

• CPR 24 months– Treated - 32 % & 45 % at 12 & 24 months

compared with 11% and 16 % in controls.

Summary

• Adhesions cause morbidity & mortality• Surgical management unproven benefit

– High Complication rate

• Adhesions are caused by surgery ( laparotomy or laparoscopy)

• Adhesion Prevention should be the goal

Abnormal Repair ?

• Inhibition of fibrinolysis

• Fibroblasts invade fibrin matrix

Risk Factors

• Previous surgery– Ischemia– Thermal injury– Infection– Foreign body– Radiation

Consensus Statements

• “Adhesion prevention strategies should employed during all abdominal or pelvic surgery”– Royal College of Obstetrricians &

Gynaecologists of the UK-2004

Prevention

• Surgical technique– Reduce infection risk

• Antibiotics administered before the surgery starts

– Excellent hemostasis– Gentle tissue handling– Use of irrigation to avoid desiccation

Prevention

– Limit use of cautery– Tissue approximation

• Avoidance of ischemic suturing• Use fine non-reactive sutures

– Peritoneal closure avoided• Controversial• C/S may be less adhesions with closure

– Minimal exposure to foreign body

Energy source

• Energy & Adhesion formation– Laser– Bipolar– Unipolar– Harmonic scalpel

• None have been shown to be superior

Classes of Anti-adhesions

• Pharmacologic Agents– Anti-inflammatory Agents (questionable

efficacy)• NSAIDS• Corticosteroids• Antihistamines

– Antibiotics

Pharmacologic agents

– Fibrinolytic Agents

– Anticoagulants• Heparin added to peritoneal irrigation• Jansen et al 1988

– RCT –no benefit

Mechanical Separation

• Separate traumatized peritoneal surfaces between day 3 & 5.

• Site specific

• Broad coverage

Interceed

• Fabric composed of oxidized, regenerated cellulose • Preclinical studies with Interceed demonstrated:

– Negligible tissue response– Absorption from the peritoneal cavity in <28 days– Reduction of extent and severity of postsurgical

adhesions in standardized animal models

Interceed: How to use it ?

• Operative site perfect hemostasis

• Remove all fluid

• Completely cover the affected site

• DO NOT wrap tube and ovary together– Adhesions increase

Pivotal study-Interceed

• Azziz, R, and the INTERCEED (TC7) Adhesion Barrier Study Group II. Microsurgery Alone or With INTERCEED Absorbable Adhesion Barrier for Pelvic Sidewall Adhesion Re-Formation. Surg. Gynecol. Obstet.,1993; 177: 135-139 – Increased number of patients from 74 to 134– Increased number of centers from 9 to 13

Results: Absence or presence of adhesions

• Significantly fewer sidewalls were observed with adhesions when treated with Interceed (66 versus 102)

Seprafilm

• Seprafilm is composed of sodium hyaluronate and carboxymethylcellulose

• Provides physical separation of damaged tissue during early wound repair

• Resorbs from peritoneal cavity in 7 days, excreted within 28 days

• Effective in animal models prior to this study

Hyaluronic acid and carboxymethylcellulose (Seprafilm)

– Between bowel and anterior abdominal wall– Substantial literature– Difficult to apply by laparoscopy– Mean of 4.5 sheets per patient

Seprafilm

• Colorectal procedures (Becker et al 1996)

• Separate the bowel from anterior abdominal wall

• 51 % of treated women were adhesion free at follow up compared to 6 %

• Extent decreased

• Dense adhesions present in 15 % of the treated and 58 % of controls

• Diamond, Michael P. The Seprafilm Adhesion Study Group. Reduction of adhesions after uterine myomectomy by Seprafilm membrane (HAL-F): a blinded, prospective, randomized, multicenter clinical study. Fertility and Sterility 1996. Vol 66, No 6; 904-10.

In patients with at least one anterior incision: incidence of patients with no adhesions

• to anterior uterine surface was 39% in Seprafilm group; 6% in no treatment group

• To the posterior uterine surface: 13% versus 8%(NS)

Broad Coverage

• Adept (4 % icodextrin) solution– Glucose polymer– Used for intraperitoneal dialysis– Recently approved in the USA– Has been used >100,000 patients– Hydroflotation ( constant fluid barrier)– Long intraperitoneal residence-3-4 days– Absorbed, metabolized and excreted by the

kidney

Stucture of Icodextrin

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OH

OH

H O

OH

OH

O

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OH

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OH y

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Icodextrin solution (Adept 4 %)

• 1 L or 1.5 L bags

• Handles like normal saline

• Isosmolar

• Irrigate with fluid (100ml) every 30 minutes and leave 1 liter in the pelvis

• Pilot study- approximately 2 liters were used for irrigation during the procedure

Icodextrin solution (Adept 4 %)

• No difference in healing of incision sites

• Fluid leaking from port sites: 13 %

Icodextrin solution (Adept 4 %)

• CID– Allergy to cornstarch– Infection– Laparotomy– Bowel resection/repair, appendectomy

• Rare hypersensitivity reactions, pulmonary edema

• Vulvar swelling

Icodextrin solution (Adept 4 %)

• No data on fertility outcomes• Pain data-shows no short term difference

compared with RL

Clinical study

• Adept (icodextrin 4% solution) reduces adhesions after laparoscopic surgery for adhesiolysis: a double-blind, randomized, controlled studyBy Brown et al. Fertility and Sterility Vol. 88, November 2007, 1413-1426.

• Iso-osmotic biodegradable starch– Residual time-

• Safety and Effectiveness data-1 liter cleared between 18-50 hours

• Report says 4 days

Methods• Design- Multicenter, prospective, randomized, double-blind

study to test the efficacy and safety of Adept (icodextrin 4% Solution)

• Patient Population- – All patients 18 y.o. or older– Pre-Op Exclusion criteria- use of concomitant use systemic

steroids, antineoplastic agents, radiation therapy, pregnancy, active pelvic or abdominal infection, cancer, allergy to starch based polymers

– Intra-op Exclusion criteria- unplanned surgery, surgery necessitating opening the bowel, (excluding appendectomy), any laparotomy procedure, use of another adhesion barrier.

– Adhesion site exclusion- patients having fewer than 3 available anatomical study sites with adhesions, if fewer than 3 adhesions were lysed, removal of any anatomical sites being scored for the study, inability to clearly visualize all available anatomical score sites

Patient Population (cont.)

• Laparoscopic surgery was planned for a gynecologic procedure that included adhesiolysis

• Second look surgery follow up was to occur 4-8 weeks later

• 410 patients were to complete study• 205 patients received Adept• 205 patients received Lactated Ringers

Methods ( cont.)

• Conducted at 16 referral centers• Double blinded study of anti-adhesion device

– Double blinding possible because adept and lactated ringers (control) are both clear and odorless solutions with similar viscosities

– Computer generated randomization on 1:1 basis– Solution bags were presented in identical

packages– Outer wrap contained the study code and patient

number on an identification label

Methods ( cont.)

• Study procedures– First laparoscopic procedure took place. Confirmation

of no intraop exclusion criteria then lead to randomization.

• 23 or all available anatomical sites for adhesion scoring were videotaped during the surgery

• The presence or absence and extent of adhesions at all anatomical sites recorded

• Throughout procedure abdomen was irrigated with a min. of 100ml of study soln. every 30 minutes

• No limit of volume for irrigation, total volume recorded at end of case• All remaining soln. irrigated out at end of procedure, then and 1000

ml of the study soln. was instilled from a fresh bag.• Patients given diary to record any adverse events and meds

Methods (cont.)

• Patient scheduled for f/u Lsx surgery in 4-8 weeks– second Lsx surgery took place with video

taping and scoring of all available anatomical sites.

Methods (cont.)

• Adhesion scoring- 23 available anatomical sites: anterior peritoneum (caudal anterior, cephalad anterior right, cephalad anterior left), small bowel, anterior uterus, posterior uterus, omentum, large bowel (left and right), rectosigmoid, cul-de-sac (posterior), right pelvic sidewall, left pelvic sidewall, right ovary ( lateral, medial, fossa), left ovary ( lateral, medial, fossa), right Fallopian tube, right ampulla, left Fallopian tube, left ampulla

Methods (cont.)

• Scoring- each site-AFS score used • Extent defined as:

– Localized: less than 1/3 of the adhesion site covered.

– Moderate: 1/3-2/3 of the adhesion site covered– Extensive: more than 2/3 of the adhesion site

coveredSeverity of adhesions defined as:

- Mild: filmy and avascular adhesions- Severe: dense, cohesive, or vascular adhesions

Minimum of three adhesions had to be lyzed at initial surgery and the sites recorded

Video Review Process

• Used to ensure consistency of adhesion scoring between study sites

• All investigators trained on adhesion assessment process

• 1st three videos of each investigator were reviewed by an independent reviewer, if deemed acceptable, then one in every five subsequent videos were reviewed.

• If any video found unacceptable, videos for next three patients reviewed until 3 consecutive videos acceptable- no mention how these recordings were included in the study

Study Measures and Assessments

• Clinical adhesion reduction success- determined “in a discussion with FDA” as a reduction of adhesions of 30% of sites lysed between initial surgery and f/u lsx second look for each individual patient

• Incidence, extent, and severity of adhesions were assessed at both surgeries at all 23 sites.– Comparisons of mean scores, % of patients with an increase

or decrease in incidence, extent, and severity were undertaken.

– Visceral, abdominal wall, de novo, and reformed adhesions were also evaluated

– AFS (American Fertility Society) classifications for adnexal adhesions were recorded in all patients with ovaries and tubes

– Final AFS scores was calculated by summing component scores from the right and left side separately and taking the lower of the two values.

Study Populations

• Safety assessed in the intent- to- treat population which included all patients who had the study solution instilled

• Efficacy results present for the per protocol population

• Patients undergoing surgery with infertility as a primary diagnosis were assessed as an infertility subgroup with AFS scores

Statistical Analysis

• All tests were two- tailed determined at the 5% level

• All comparisons were recorded with 95% confidence intervals for the difference

• Continuous variables were assessed used a two-way analysis of covariance (ANCOVA) when looking for differences between the two treatment groups.

• Logistic regressions used for categorical data

Validity

• Randomized with a concealed randomization list• Treatment groups were both similar at baseline• Patients were analyzed in the groups which they

were randomized • Patients and Clinicians were both blinded• Groups were almost treated identically• The group definitely describes our general

gynecology population

Results• 777 patients screened, 449 patients were randomized with

227 patients receiving Adept and 222 patients receiving LRS• 29 patients withdrawn from study

– 9 pregnancy or pain resolution after first surgery– 12 patients declined second surgery– 1 patient (LRS group) withdrew because of bowel perforation– 4 patients (2 in each group) were lost to follow up– 1 Adept patient had her right Fallopian tube removed during

surgery– 1 Adept patient moved before the second surgery– 1 LRS patient had hysterectomy6.6% of patients in Adept group withdrew vs. 6.3% of patients in

the LRS group (P=.90)420 patients completed the trial, of these, 18 patients had major

protocol violations leaving 402 patients in the protocol population

Results (cont.)

• Subanalysis of the protocol population for subgroups as follows:– Infertility as primary diagnosis ( Adept 102,

LRS 112)– Patients with endometriosis (Adept 124, of

whom 56 also had infertility, LRS 119 patients, of whom 61 had infertility

– Patients with diagnosis of infertility and pelvic pain (Adept 45 patients, LRS 48 patients).

Adept 4 %: Primary Effectiveness endpoint

1. “clinical success”-individual decrease in adhesions sites of at least 30 % between baseline and SLL .

• 45.4 % cases & 35.6 % controls • Difference in % success 9.8 -95 % CI (0.7, 18.9)• Lower bound was a pre-specified 5% target

• OR: 1.64 ( 1.09-2.46)• P value for treatment- 0.016

Clinical success. The percentage of patients inwhom the number of sites with adhesions decreasedby at least three or 30% of the number of sites lyzed

(Per Protocol population).Brown.

Adept 4 %: Primary Effectiveness endpoint

2.Number of adhesion sites:

• First look : 10 sites for both cases & controls

• Second look: 7.8 for the cases and 8.4 for the controls. Difference in scope means

– -0.62 ( -1.24, -0.004); P value for treatment= 0.047

Adept 4 %: Primary Effectiveness endpoint

3. Number of sites with dense adhesions

• First look: 6 sites for both cases & controls

• Second look: 5 sites for both P= 0.73

Secondary effectiveness-at 23 sites

• Incidence of sites with adhesions- Adept vs. LRS– % of patients with reduction-76 % vs. 69 % P=.12– Shift analysis- P= 0.17

• Severity of sites with adhesions-– % of patients with reduction- 72 % vs. 69 % P= 0.44

• Extent of sites with adhesions-– % of patients with reduction-77 % vs. 69 % P= 0.08

Percentage of patients free of de novo adhesions inthe Adept and LRS treatment groups at second

laparoscopy (PP= per Protocol population).

Clinical Success in infertility patients-

Infertility Patients-all groups

• AFS scores• 43% of all Adept patients had reduction in AFS

adnexal adhesion score at f/u compared with 35% of LRS patient ( mean reduction 2.7 + 6.1 vs. 1.2 + 5.9; P=.065)

• Of the 57 patients in Adept treatment group and 55 patients in LRS group with mod/severe AFS scores at initial surgery, 29 (51%) Adept and 19 (35%) LRS patients demonstrated improvements in AFS score by moving to minimal/mild category-no P value given

• Patients with min/mild AFS scores at initial surgery 131/134 (98%) in the Adept group and 137/144 (95%) in the LRS group had AFS scores that remained the same

AFS Score (Infertility only Patients)

• Adnexal adhesions

• Adept treated infertility patients had a 53 % reduction in AFS score on second look compared with LRS group-30% (P=.001)- mean reduction of 3.4 vs.1.1

Infertility & ……

• Endometriosis Patients- 54% of patients treated with Adept had decreased AFS scores on second look vs. 25% treated with LRS (P=.003)

• Pelvic pain patients- 51% patients treated with Adept had reduction in AFS score on second look vs. 23% of LRS treated patients (P=.006)

Strengths of Study

Double blinded

No investigator bias

Randomized

Showed decreased AFS score for multiple scenarios

Multiple ways to assess adhesions (Video, AFS score)

Similar safety profiles for both Adept and LRS

Largest study of its kind

Weaknesses of Study

• No cost effectiveness data- irrigate and 1 liter left in

• “Success” in only one co-primary endpoint

• Also saw reduction of adhesions in the LRS group, which was contrary to other literature, so is it meaningful?

• If any video found unacceptable, videos for next three patients reviewed until 3 consecutive videos acceptable- so were they included in the study?

Final Recommendation

• Limited to laparoscopic surgery patients undergoing adhesiolysis

Cochrane Database

• Ahmad et al Barrier agents for adhesion prevention after gynecologic surgery– Cochrane Library 2008 CD 000475

• 16 RCT– 6 with laparoscopy– 10 with laparotomy– 11 assessed Interceed vs. no treatment– 2 assessed interceed vs. Gore-Tex– 1 assessed Gore-Tex vs. no treatment– 1 assessed fibrin sheet vs. no treatment– 1 assessed Seprafilm vs. no treatment

Cochrane Database-direct quotes

• Interceed reduces the incidence of adhesion formation following laparoscopy and laprotomy

• Gore-Tex may be superior to Interceed

• There was no evidence of effectiveness of Seprafilm and fibrin sheet in preventing adhesion formation

Mechanical Separation

• SurgiWrap biodegradable polymer film• Biodegradable polymer film polylactide

– Approved in Europe reduction of postop adhesions– In USA “tissue separation”– Long absorption time

• 6 months

– Need to suture the sheet in place– Lack of published data showing efficacy

• 2 reports- none show efficacy

Mechanical Separation

• Expanded polytetrafluoroethylene (Gore-tex surgical membrane) – Not approved by the FDA for preventing pelvic

adhesions– Not biodegradable– Requires suturing– Requires removal ?

Broad Coverage

• Ringer’s lactate– Not approved by the FDA for preventing

adhesions– No studies showing human efficacy– Rapidly absorbed 35-65 ml/hr

Broad Coverage

• Dextran-70 ( 32 %)– Dextrose polymer– Shown in RCT to be ineffective

• Larsson et al 1985

– Not-FDA approved for preventing adhesions• Reabsorbed by the third postop day

– Significant complications such as coagulopathy & anaphylaxis

Broad Coverage

• Intergel ( hyaluronic acid crossed linked with ferric chloride)– Withdrawn for late onset postop pain

Broad Coverage

• Spraygel– Two water based synthetic polyethyelene

glycol solutions-one clear and one colored– Complex set up and application– When sprayed together they form a hydrogel

film that provides a physical barrier that remains in place for 7 days

– Approved in Europe but study stopped in USA because of lack of efficacy

Surgery in Patients with Adhesions

• Longer operation time

• Enterotomy risk– 19 % open cases– 10-25 % laparoscopy cases

• Strategy for laparoscopic cases– Open laparoscopy– LUQ primary site