Intra-peritoneal prophylactic agents for preventing adhesions and adhesive intestinal obstruction after non-gynaecological abdominal surgery: Cochrane systematic review

Abstract

Assessed as up to date: 2008/08/02

Background

Intra-abdominal adhesions are common and challenge patients, surgeons and other healthcare providers. They are potentially preventable and several agents that act as barriers between adjacent peritoneal surfaces have been evaluated for prophylaxis. Efficacy, judged by systematic reviews, has only been undertaken in gynaecological surgery.

Objectives

To determine efficacy and safety of peritoneal adhesion prophylaxis on incidence, distribution and adhesion-related intestinal obstruction after non-gynaecological surgery.

Search strategy

The Cochrane Central Register of Controlled Trials, the Cochrane Colorectal Cancer Group specialised register, MEDLINE (1966-2008), and EMBASE (1971-2008) were searched.

Selection criteria

Blinded and non-blinded, randomised and quasi-randomised clinical trials were considered.

Data collection and analysis

Two authors individually conducted the searches and assessed the quality of studies for inclusion which were analysed using the Revman Analyses software 5.0.0 provided by the Cochrane collaboration. Meta-analysis used a random effects model.

Main results

Seven randomised trials were eligible; six compared hyaluronic acid/carboxymethyl membrane (HA/CMC) and one 0.5% ferric hyaluronate gel against controls.

HA/CMC reduced the incidence of adhesions (OR 0.15 (95% CI: 0.05, 0.43); p=0.0005) with reduced extent (WMD -25.9% (95% CI: -40.56, -11.26); p=0.0005) and severity. There was no reduction of intestinal obstruction needing surgical intervention (odds ratio: 0.84 (95% CI: 0.24, 2.7) with comparable overall morbidity and mortality.

The study of 0.5% ferric hyaluronate gel was prematurely terminated and no valid conclusions could be made but there was a higher incidence of overall morbidity (OR 5.04; 95% CI: 1.1, 22.9) and ileus (OR: 9.29; 95% CI: 1.57, 54.77; p=0.01).

Authors' conclusions

Implications for practice

There is evidence that the use of HA/CMC membrane reduces incidence, extent and severity of adhesions which may, theoretically, have implications in re-operative abdominal surgery. There is no evidence that the incidence of intestinal obstruction or need for operative intervention is reduced. HA/CMC appears to be safe but there may be a risk of leak when wrapped around an anastomoses. HA/CMC may be considered for intra-abdominal, adhesion prophylaxis at a surgeon’s discretion and clinical context.

Implications for research

Further research is needed to explore the effectiveness of other agents in abdominal surgery in general. Synergism, using agents which target different aspects of adhesiogenesis, with exploration effectiveness in a wide range of emergency and elective surgery should be considered. Longer term outcomes of recurrent intestinal obstruction and chronic pain, identification of high risk groups of patients with evaluation of cost-effectiveness are required.

Author(s)

Kumar Senthil, Wong Peng F, Leaper David J

Summary

The use of hyaluronic acid/carboxymethyl cellulose (HA/CMC) membrane, reduces the incidence, extent and severity of adhesions in the abdomen.

Adhesions in the abdomen cause abnormal bonding between adjacent peritoneal surfaces and are common after operations in the abdomen. They are composed of fibrous tissue but also contain blood vessels, fat and nerves. They result in a spectrum of problems that affect the patient (intestinal blockage, infertility and possibly pain); the surgeon (difficulties in access and dissection, prolongation of operative time, increase in blood loss, predisposition to bowel injury); the health care provider (increased cost due to readmissions and litigation). Prevention is the key. This review focus on the evaluation of the safety and efficacy of two preventive agents applied in the abdomen during general surgical operations, Hyaluronic acid /carboxymethyl cellulose membrane and 0.5% ferric hyaluronate gel.
There is evidence to suggest that use of Hyaluronic acid/carboxymethyl cellulose membrane reduces the incidence, severity and extent of adhesions.However, it does not reduce the incidence of subsequent intestinal obstruction or need for surgery to treat the obstruction, when it occurs. It appears to be safe with no significant increase in adverse effects or deaths when compared to control. There is limited data on 0.5% ferric hyaluronate gel with only one study available. This study did not report on the efficacy of the gel as it was prematurely terminated because of a significantly higher rate of adverse effects in the patients who were treated with this gel.

Reviewer's Conclusions

Implications for practice

Based on the currently available data considered in this systematic review, there is evidence that the use of HA/CMC membrane, reduces the incidence, extent and severity of adhesions. This may have implications in re-operative abdominal surgery in terms of time, ease of access, blood loss, visceral injury and cost, but these outcomes were beyond the remit of this review. With respect to symptomatic long term outcomes, however, there is currently no evidence that use of HA/CMC membrane, reduces the incidence of intestinal obstruction or the need for operative intervention in adhesive intestinal obstruction in the first few years following the index abdominal surgery. HA/CMC membrane appears to be safe, though there are concerns that it may increase the risk of anastomotic leak when wrapped around the anastomosis. Hence, in the absence of an ideal or alternative agent of proven efficacy in general surgical patients, HA/CMC may be considered in the prophylaxis of intra-peritoneal adhesions, at the discretion of the surgeon, tailored to the individual clinical context.

0.5% Ferric hyaluranate gel, has an unacceptably high morbidity, based on the limited data available, and hence cannot be recommended.

Implications for research

a. Evidence on effectiveness of other agents in general surgery
Currently Hyaluronic acid/Carboxymethylcellulose (HA/CMC) membrane remains the only agent on which evidence of effectiveness as an anti-adhesio genesic agent is available in general surgical patients. However, HA/CMC has certain shortcomings. It is suitable only for open surgery and it needs to be applied with some degree of precision on to the raw surfaces to be effective. It does not prevent adhesions in regions of the peritoneum which may harbour areas of injury not be macroscopically visible, areas which therefore, are not protected. Fluid agents such as 4% icodextrin circumvent many of these problems and there is evidence from at least one study in gynaecological surgery of its efficacy in preventing adhesions. Studies in general surgical operations are ongoing and would perhaps clarify its role in future. A plethora of other pharmacological and physical (membrane and fluid) agents have been shown to be effective in pre-clinical animal experiments, but only a selected few have been tested in human studies. Even fewer agents have been tried in randomised clinical trials, mostly in gynaecological surgery. Adequately powered, prospective, blinded, randomised controlled clinical trials in general surgical patients using agents which have proven efficacy in preclinical studies, may potentially uncover useful therapeutic options.
b. Evidence of synergism
The potential for synergistic effects of a combination of different types of adhesion prevention strategies, such as anti-inflammatory strategies, fibrinolytic strategies and barrier agents applied together has been demonstrated in animal experiments. The clinical value of using a combination of strategies in general surgical patients undergoing laparotomy may be worth investigating.
c. Evidence on other clinically important effects
Though it is evident that film barrier agents reduce the incidence and severity of adhesions, currently there is lack of evidence that this translates to a reduction in symptomatic long term outcomes such as incidence of intestinal obstruction and the proportion needing surgical intervention for adhesive obstruction. If there was indeed a small benefit from the barrier agents, which was missed in the available studies (type II error), then this will need a large, adequately powered study to uncover the effect. As adhesive disease is common, even small risk reductions have the potential to translate to significant benefits when applied on a global scale.The other clinically significant long term outcome is chronic pain, on which there is no data available at present on the efficacy of prophylactic agents in general surgical patients.
d. Evidence of effectiveness in a range of operations
Generalised peritonitis results in a higher incidence of adhesion related re-admission and re-operation. Data on safety and efficacy of anti-adhesio genetic agents used in the context of pathologies leading to generalised peritonitis is worth pursuing. Similarly use of prophylactic agents in other types of surgery such as small bowel resections for Crohns disease and a range of laparoscopic surgical procedures would be valuable. If noninvasive tools for evaluation of adhesions such as magnetic resonance imaging are validated in assessing adhesions then a broader range of surgical interventions and consequently a larger subgroup of patients could be studied.
e. Identification of high risk groups
It is known that adhesions and adhesion related complications are more frequent after certain types of surgery such as pelvic surgery. However, at present there is no validated system to identify individual patients with an increased risk of adhesions and related complications during the perioperative period. Future studies should focus on collecting good quality, prospective data (epidemiological, clinical, biochemical, cellular and biomolecular) which may then be used to predict the risk in individual patients. Risk prediction may help in prognostication, planning service needs and targeting anti-adhesive therapy.
f. Cost effectiveness
Economic analysis in the field of peritoneal adhesion prevention is understandably difficult for many reasons including controlling for the number of potential confounding factors in the perioperative period, the difficulty in measuring the economic impact accurately and the length of follow up required. Nevertheless as economic analysis may be useful in resource planning it is perhaps worthwhile exploring the cost effectiveness in a carefully chosen index procedure which is amenable to standardisation.

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