Intra‐peritoneal prophylactic agents for preventing adhesions and adhesive intestinal obstruction after non‐gynaecological abdominal surgery
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
Primary objective:
To determine the efficacy of intra‐peritoneal prophylactic agents in reducing the incidence, distribution and severity of adhesions in non‐gynaecological abdominal surgery.
Secondary objectives:
To determine the effect of intra‐peritoneal prophylactic agents on the incidence and outcome of adhesion related intestinal obstruction.
To determine the safety and adverse effect profile of intra‐peritoneal prophylactic agents in non‐gynaecological intra‐abdominal surgery.
To detect any changes in health related quality of life from the use of intra‐peritoneal prophylactic agents in this subset of patients.
Background
Intra‐abdominal adhesions are usually iatrogenic, affect both genders and all ages. They may occur in up to 95% of patients who had undergone a previous laparotomy (Ellis 1997). This contrasts with a 10% incidence in patients without a prior laparotomy (Menzies 1990).Pelvic adhesions that follow trans‐abdominal gynaecological surgery have long been implicated in causing pain and infertility. Similarly, patients presenting to the general surgeon display a spectrum of adhesion related problems or morbidity. The treating surgeon often faces difficulties with access and obscured normal anatomy which may lead either to an inability to apply minimal access surgery, prolongation of operative time (Coleman 2000) or result in potentially serious organ injury such as inadvertent enterotomy (Van der krabben 2000). Adhesions are estimated to account for about a third of all bowel obstructions and two‐thirds of small bowel obstructions in the western world (Menzies 1992; Menzies 1993).
Certain surgical operations have been reported to carry a higher than usual risk of adhesion‐related complications. A 25 % incidence of adhesive obstruction has been reported in a series of 1005 ileo‐anal pouch procedures (Fazio 1995). Total or subtotal colectomy (Lockhart‐Mummery1967; Nieuwenhuijzen 1998) and appendicectomy (Cox 1993) are other high risk procedures in terms of their propensity to lead to adhesive intestinal obstruction. In neonates, surgery for gastroschisis and malrotation are reported to carry a 15% risk of post‐operative adhesive intestinal obstruction (Wilkins 1986). Managing adhesions and adhesion related complications is expensive in terms of time (Menzies 2001; Parker 2001), effort and finances (Ray 1998; Jeckel 1997; Menzies 2001; Wilson 1998) and impacts not only on the patient and the treating physician but also the health care system at large. The prolongation in hospital stay, re‐admissions, repeated surgical interventions and litigation impose an enormous burden on the health care systems globally, making adhesion prevention an important area of health care intervention research.
As once established, adhesions follow an unpredictable temporal course, which is attended by a lifetime risk of recurrent symptoms, complications, re‐admissions and repeat surgery, prevention seems to be the most viable strategy yet. Peritoneal injury, the attendant inflammation, imbalance in plasmin system and proximity of injured surfaces are the crucial elements in adhesion formation. Hence, preventive strategies have been designed targeting these steps individually or in combination. Injury limitation, a vital aspect of prophylaxis is largely a surgical endeavour achieved by meticulous attention to operative technique and tissue handling. However, as injury can only be minimised and not completely abolished, adjuncts to injury limitation techniques are necessary to reduce the risk of adhesions. Systemic and intraperitoneal pharmacological strategies like anti‐inflammatories, anticoagulants, agents targeting the plasmin cascade and hormones have not met with much success clinically (diZerega 1994; Risberg 1997).
A number of fluid and solid phase (membranes, sheets) agents that primarily act as barriers to contact between two adjacent peritoneal surfaces, have been evaluated clinically for their potential for adhesion prophylaxis. Examples of fluid agents include 4% Icodextrin (Adept®, ML laboratories plc.,UK) and Hyaluronic acid‐phosphate buffered saline (Sepracoat®, Genzyme Corp., USA). Examples of solid phase agents include, Hyaluronic acid /Carboxymethyl cellulose membrane (Seprafilm®, Genzyme Corp., USA), Oxidised regenerated cellulose (Interceed®, Johnson&Johnson medical Inc., USA), and expanded Polytetrafluoroethylene (Gore‐tex®, WL Gore& Associates, USA ). These agents differ in their chemical composition, biodegradability, tissue interactions and hence the adverse effect profiles.
An intervention such as adhesion prophylaxis, that is likely to have a wide impact on day to day surgical practice and on the health care economics needs to be scrutinised for safety and efficacy with specific reference to the context in which it is used and in relation to relevant outcomes.Barrier and non‐barrier agents in prophylaxis of adhesions have been evaluated for efficacy by systematic reviews, but only in the context of gynaecological surgery, with respect to their effect on fertility rates and pain (Farquhar 2004).
The purpose of the current review is to provide an evidence based appraisal of the safety and efficacy of intra‐peritoneal agents in general surgical operations from randomised controlled trials that have assessed adhesion reformation (severity, distribution and frequency) and /or adhesion related intestinal obstruction as the main outcome measure.
Objectives
Primary objective:
To determine the efficacy of intra‐peritoneal prophylactic agents in reducing the incidence, distribution and severity of adhesions in non‐gynaecological abdominal surgery.
Secondary objectives:
To determine the effect of intra‐peritoneal prophylactic agents on the incidence and outcome of adhesion related intestinal obstruction.
To determine the safety and adverse effect profile of intra‐peritoneal prophylactic agents in non‐gynaecological intra‐abdominal surgery.
To detect any changes in health related quality of life from the use of intra‐peritoneal prophylactic agents in this subset of patients.
Methods
Criteria for considering studies for this review
Types of studies
Inclusion criteria:
Randomised and Quasi‐randomised clinical trials addressing the safety and/or efficacy of prophylactic intraperitoneal agents in prevention of adhesions and adhesion related complications would be included.
Both blinded and non‐blinded studies would be considered.
Only parallel group and factorial designs would be considered.
Only studies involving non‐gynaecological abdominal surgery involving the peritoneal contents would be evaluated for inclusion.
In studies reporting on efficacy, the patients should have had the intra‐peritoneal adhesions assessed at a second operation ‐ either open or laparoscopic.
In studies reporting on incidence of adhesion related re‐admission and intestinal obstruction, patients should have been followed‐up for at least 5 years. The study should have used explicitly defined criteria prospectively to measure the morbidity attributable to adhesions.
In studies reporting on safety of intraperitoneal agents, patients should have been followed up for at least a year.
Types of participants
Inclusion criteria:
Patients of all ages and both genders will be included.
Patients should have undergone a non‐gynaecological abdominal surgery either open or laparoscopic, involving the use of a prophylactic intra‐peritoneal agent for adhesion prevention, during the course of the surgery.
Exclusion criteria:
Patients undergoing primarily a transabdominal gynaecological surgery .This would be defined for the purpose of this review as any transabdominal primary operative intervention on the female reproductive tract. However, patients who had a primary general surgical operation but also had to undergo a surgical procedure on the female reproductive tract during the course of the operation would be included in the review.
Types of interventions
Intra‐operative intra‐peritoneal incorporation or instillation of a solid phase agent (membranes or sheets) or a fluid agent respectively, with a view to prevent intra‐abdominal adhesions and adhesion related complications.
The prophylactic agent studied should have been compared with either no intervention or against a placebo or against another prophylctic agent.
Both open and minimal access surgeries involving the intraperitoneal contents and employing the interventions would be considered.
There would be no restriction as to the grade or level of experience of the operating surgeon performing the interventions.
Types of outcome measures
Primary outcome measure:
1.The incidence, distribution and severity of adhesions assessed during the course of a second open surgical or laparoscopic operation
Secondary outcome measures:
1.The incidence and outcome of adhesion‐related intestinal obstruction.
2.Incidence and outcome of adhesion related re‐admissions
3.Local, regional and systemic complications arising from the use of fluid and membrane agents
4.Patient reported health related quality of life recorded by a validated generic or specific quality of life assessment tool.
Exclusion criteria:
1.Main outcome measure is pain
2.Main outcome measure is fertility
Search methods for identification of studies
The following bibliographic electronic medical databases will be searched for publications addressing the above clinical problem
1.The cochrane central register of controlled trials (CENTRAL)
2.The Cochrane colorectal cancer group specialist register (SR‐COLOCA)
3.MEDLINE from 1966 to 2004
4.EMBASE from 1971 to 2004
Two authors would individually conduct the searches.The following search strings would be used where appropriate, without language restrictions.
Strategy A:
1.Adhesi$ ‐ LIMIT to human studies
2.Abdo$ OR Intraabdominal
3.Peritoneal OR Intraperitoneal
4.COMBINE 2 OR 3
5.COMBINE 1AND 4
6.Prevent$ OR Prophyla$
7.COMBINE 5 AND 6
The titles and abstracts when available would be scrutinised to select relevant controlled studies addressing the safety and efficacy of the use of these agents in non‐gynaecological abdominal surgery.
Strategy B:
The following text words would be used individually to identify studies reporting results from the specific use of the respective products
1."SEPRAFILM"
2."SEPRACOAT"
3."INTERCEED"
4."ADEPT"
5."ICODEXTRIN"
6."GORETEX"
7. "SURGIWRAP"
8. "DEXTRAN"
9. "HYSCON"
10. "CARBOXYMETHYLCELLULOSE"
11. " HYALURONAN"
12. " HYALURONIC ACID"
13. " POLYTETRAFLUOROETHYLENE"
14. " OXIDISED REGENERATED CELLULOSE"
15. " PHOSPHATIDYLCHOLINE"
16.COMBINE 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15.
17.Adhesi$
18.COMBINE 16 AND 17
The search would be limited to human studies
The titles and abstracts when available would be scrutinised to select relevant controlled studies addressing the safety and efficacy of the use of these agents in non‐gynaecological abdominal surgery.
Strategy C:
1.Adhes$ LIMIT to human studies
2.Intestinal obstruction OR Bowel obstruction
3.COMBINE 1 and 2
4.Complications
5.COMBINE 1 and 4
6 COMBINE 3 OR 5, avoid duplicates
7.Prevent$ OR Prophyl$
8.COMBINE 6 AND 7.
The titles and abstracts when available would be scrutinised to select relevant controlled studies addressing the safety and efficacy of the use of these agents in non‐gynaecological abdominal surgery.
Reference lists of retrieved full text articles would be searched for relevant additional studies.
Principal authors of published trials would be contacted to acquire information about any other published trials known to them that could be of relevance.
The manufacturers of the prophylactic agents mentioned above would be contacted to acquire information about any published trials known to them that could be of relevance.
The health technology assessment database and its related websites would also be searched for relevant publications.
Data collection and analysis
STUDY SELECTION
Two reviewers (SK and PFW) will conduct a methodical search of the electronic bibliographic medical databases and other sources as outlined in the search strategy. Trials will be considered for inclusion in the review if they fulfil the following criteria:
1. Prospective randomised or quasi‐randomised controlled trials in humans.
2.The procedure performed should be an intra‐peritoneal non‐gynaecological surgery either open or laparoscopic.
3.The trial should compare an agent against either no treatment or an appropriate placebo or against another prophylactic agent.
4.Trial should address the safety and/or efficacy of the intra‐peritoneal prophylactic agents.
The title and abstract would initially be screened to see if the study satisfies the above criteria. A third reviewer (DJL) would then assess the studies that do not fully meet the criteria to independently justify their exclusion. Any disagrement among the reviewers as to the suitability of a particular study would be resolved by discussion and consensus.
The full‐text article of the studies would be retrieved in the following situations:
1.Study fulfils criteria on initial screening of the abstract and title
2.Study may potentially fulfil criteria but there is not enough information in the abstract alone to justify inclusion.
3.No abstract is available but the title suggests a potential that the study may fulfil criteria.
An english translation of a non‐english language publication would be performed with the help of an appropriate translator, if there is a suggestion that the study might fulfil criteria based on the information contained in the english abstract or based on the opinion of a third party ( usually a senior author or researcher in the field) who is aware of such a study.
The full text article would then be scrutinised independently by two reviewers to confirm that the study justifies inclusion. A specifically designed structured flow chart with a set of check lists incorporated would be used in the selection procedure. This would be useful to resolve any conflicts of opinion between reviewers as well as serve as a record for future reference and clarifications, if necessary. The third reviewer would scrutinise the included studies independently before data extraction.
QUALITY ASSESSMENT:
Two reviewers will independently assess the quality of included trials. Quality assessment would be by a component based system incorporating aspects of internal validity outlined below. Composite scoring systems for quality assessment will not be used.The domains considered towards quality assessment, would seek to detect any potential for selection bias, detection bias and attrition bias.
The studies would be scrutinised for details regarding the following components:
1. Randomisation:
Good quality: True randomisation ( Computer generated random number sequences, sequences from validated random number tables, coin tossing, casting dice, shuffling cards or similar methods )
Poor quality: Quasi‐randomisation (based on date of birth, hospital number, date of admission, alternating sequence or similar methods ).
2.Allocation concealment:
Good quality: sequentially labelled sealed, opaque envelopes; Centralised randomisation revealed by telephoning before assignment or similar methods.
Poor quality: unsealed or non‐opaque envelopes, open allocation schedule, all procedures based on quasi‐randomisation.
3.Blinding:
Good quality: Assessor or observer is blinded to the intervention that the patient has had.
Poor quality: Assessor not blinded; Only the patient and or the surgeon applying the intervention is blinded ; No blinding used.
4.Handling of attrition:
Good quality: Analysis on an intention to treat basis; patients lost to follow‐up, drop outs, protocol violations reported and causes discussed; proportion of patient attrition < 15% (Chalmers 1981).
Poor quality: Participant attrition poorly described or analysed. Attrition rate > 15% of total recruited.
Studies would be assigned an overall grade as follows: A (All criteria for good quality are met, low risk of bias; would be classified as a good quality study), B (One or more criteria of good quality only partly met, moderate risk of bias; would be classified as an intermediate quality study), C (One or more criteria for good quality not met, high risk of bias; would be classified as a poor quality study).
The grading would be used for sensitivity analysis which would be done including and excluding studies of grade B (intermediate quality) and grade C (poor quality) to observe their effect on the meta‐analysis.
The grading however would not be used to weight the summary outcomes in the event of a meta‐analysis.
DATA COLLECTION :
Data extraction from the studies would be standardised by specially designed forms and would be double checked by a second reviewer independently. Reviewers would be blinded to the source of the articles (authors, institution, journal, funding) wherever appropriate. The data collected would be in relation to the following characteristics:
Methods:
‐Setting: Geographical location; single centre or multicenter
‐Type of randomisation: True, Quasi‐.
‐Method of randomisation : Generation of sequence; allocation concealment.
‐Extent of blinding: Patient; surgeon employing the intervention; observer; non‐blinded; unclear; not stated.
‐Power calculations: Not applicable; not stated; unclear; provided; if provided then statement of power.
‐Size of the study: Total patients recruited; total included in analysis; whether size appropriate to a priori statement of study size.
‐Methods employed to deal with attrition and missing data
‐Type of adhesion assessment: second look laparoscopy; second look laparotomy.
‐Time of adhesion assessment in relation to the index surgery.
‐Duration of the study.
‐Duration of follow‐up.
Participants:
‐Age and gender distribution.
‐Type of underlying abdominal pathology (peritonitis or not; benign or malignant; Inflammatory or non‐inflammatory bowel pathology ; Mixed, unclear; not stated).
Intervention:
‐Setting: Type of surgery‐ laparoscopic or open; emergency or elective; mixed.
‐Agent(s) used and comparator: agent Vs none; agent Vs placebo; agent Vs agent.
‐Dose or size of agent used.
‐Area of application: General peritoneal cavity; all surgical sites; identified raw areas or peritoneal defects; around anastamosis; under the laparotomy wound; unclear; not stated.
Outcome measures and results:
1.Incidence of adhesions
2.Distribution/ extent of adhesions.
3.Severity/type of adhesions
4.Adhesion scores
5.Incidence of morbidity attributable to adhesions or intervention.
6.Incidence of mortality attributable to adhesion or intervention.
7.Incidence of re‐admissions
8.Incidence of clinical bowel obstruction.
9.Incidence of operative intervention attributable to adhesions.
10.Quality of life scores
11.Numbers needed to treat
DATA ANALYSIS AND SYNTHESIS:
The statistical package Metaview of Revman 4.2.6, provided by the Cochrane collaboration will be used to analyse and synthesise data. For dichotomous data such as presence or absence of adhesions, incidence of morbidity and mortality attributable to adhesions, incidence of intestinal obstruction and incidence of re‐admissions , the impact of the intervention would be expressed as an odds ratio with 95% confidence intervals. Continuous data such as quality of life scores and extent of adhesions measured as absolute area (square millimetres or square centimetres) or as a proportion or percentage of wound area, the effect size would be compared by computing the weighted mean difference with 95% confidence intervals. If different scales are used in different studies then a standardised mean difference will be calculated using Glass's Delta method.
The individual outcomes would be tabled separately for each agent‐control combination stratified into open and laparoscopic surgery where appropriate. The tables of comparison would be for the following outcomes:
1.Incidence of adhesions
2.Extent of adhesions (absolute area; area differential; proportion or percentage)
3.Severity of adhesions
4.Adhesion scores
5.Incidence of morbidity
6.Incidence of mortality
7.Incidence of re‐admissions
8.Incidence of intestinal obstruction
9.Incidence of operative intervention for complications
10.Quality of life scores.
A meta‐analysis would be performed if appropriate. The potential of a publication bias would be explored by a funnel plot of sample size plotted against the odds ratio of primary outcome. Statistical heterogeneity would be tested by inspection of the forest plot and computation of the chi square statistic for heterogeneity with the probability of a type I error set at 10% ( P value <0.1 would be considered significant). If significant heterogeneity is detected then causes for this would be explored and explained. A subgroup analysis will be considered at this stage as necessary.
Where a meta‐analysis is considered appropriate, a random effects model would be used to pool effect sizes using the Dersimonian and Laird method. Sensitivity analysis would be done including and excluding studies of the quality category B and C to observe their effects on the meta‐analysis.
