The Modern Management of Adhesions

1. The Modern Management of Adhesions Michael C Parker BSc MS FRCS FRCS(Ed) Darent Valley Hospital Dartford, Kent, UK SCAR Panel Member Hungary 24th April 2004

2. Adhesions after colorectal surgery Do we need to prevent? Yes Do we need to treat?

3. Paradox of surgery… • …the method proposed to treat adhesions is the one that induces adhesions Need for clinical & cost-effective agents to reduce adhesion development

4. Influencing factorsduring surgery Injury • Ischaemia • • Infection • • GI contents • Bleeding • Abrasion • Inflammation • Desiccation • Fibrin • Heat • deposition • Light • • Electrocautery • • Sutures • • Fibres • • Glove powder • Adhesions Formation of Adhesions

5. Steps to reduce adhesions during surgery • Increase vascular permeability • Reduce infection risk • Avoid GI contamination • Minimise tissue handling • Careful technique • Microsurgery • Reduce drying of tissues • Lubrication • Limit use of cautery • Limit use of sutures • Avoid materials with fibres • Use starch-free gloves Protection against adhesions Injury Bleeding inflammation Fibrin deposition Adhesions

6. Adhesion reduction strategies • Careful surgical technique • Minimise Inflammatory response • Augmentation of fibrinolysis • Adhesion-reduction agents

7. Applying adjuvants:solutions/drugs NSAIDs • Most widely studied; clinical efficacy is questionable Corticosteroids • Poor efficacy; associated with immunosuppression and delayed wound healing Fibrinolytics • Risk of impaired wound healing and/or bleeding Risberg B. Eur J Surg Suppl. 1997

8. Safety Easy to use General surgery Gynaecological surgery Open Laparoscopic Efficacy Operation site Throughout the cavity Economical Adhesion Reduction Agents: The ideal agent According to recent surveys of surgeons the four key attributes are: ESHRE 2002 Survey, EACP 2002 Survey

10. Adhesion Reduction Agents Key issues • Toxicity • Handling • Limited efficacy • Clinical outcomes • Cost

11. Adhesion Reduction Agents * Withdrawn from US market

12. Most Widely Used Adhesion Prevention Adjuvants • Crystalloid instillates • Lactated Ringer’s • Saline • Hartmann’s Solution • Limitations: • Absorbed within 24 hours • They don’t prevent adhesions!

13. Interceed Barrier(Oxidized Cellulose, Gynecare) First FDA approved adhesion reduction adjuvant Most clinical studies (24) Widely applicable all intraperitoneal locations all surgical procedures Compatible with laparoscopy Limited use in colorectal surgery Limitations: Blood oozing renders it ineffective Irrigants must be removed Technical application challenges!

14. Seprafilm Membrane (HA+CMC, Genzyme) Widely applicable covers all intraperitoneal locations all surgical procedures Used in general surgery Limitations: Handling Residual irrigation fluid must be removed Cannot be used via laparoscopy Cannot use at site of anastomosis Cost!! need mean 4.4 sheets in colorectal surgery!!!* Beck et al Dis Colon Rectum 2003;46:1310-1319

15. SprayGel(Polyethylene Glycol Polymer, Confluent) • Polymerization • Methylene blue to show where it is used

16. SprayGel Laparoscopic Kit Requires specialised air pump Open Surgery Kit

17. SprayGel • 5 kits needed for complete peritoneal coverage!!!* *Korell Adhesions News & Views 2004 in press

18. SprayGel Limitations • complex set-up • time consuming • limited efficacy & safety data • US regulatory study halted • cost……

19. SprayGel Limitations • complex set-up • time consuming • limited efficacy & safety data • US regulatory study halted • cost…… • particularly 5 kits!* *Korell Adhesions News & Views 2004 in press

20. SurgiWrap (polylactide copolymer film, Macropore) Peritoneal replacement film Suture in place Remains for ~6 months Excreted through lungs Limitations: Data – limited safety and efficacy Handling?? Cost!!

21. Adept®New solution to adhesion reduction?

22. Adept - icodextrin 4% solution •  1,4 linked glucose polymer • Icodextrin 4% solution • isosmolar • biocompatible • well-established safety profile at 7.5% concentration • >36,000 patient years safety data from renal use • ~50,000 patients treated with Adept • persists in peritoneal cavity • reduces adhesion formation through physical action • ‘hydroflotation’

23. Adept hydroflotation mechanism Hosie et al Drug Delivery 2001

24. Adept use- Irrigation- minimum 100mls/30mins - Laparoscopy through the scope - Laparotomy via a syringe Laparoscopy Laparotomy - Instillation- 1000ml at closure

25. Adept (Icodextrin 4%, Shire Pharmaceuticals) Used as an irrigant and an instillate Covers all intraperitoneal locations Easy to use laparoscopic clinical studies laparotomy registry feedback Not constrained by oozing Residual irrigation solution is not a problem Extensive safety experience at 7.5% ARIEL Registry of routine use in >4,600 patients feedback of use and safety good Promising early results Modest cost Limitations: Limited clinical data at present – extensive work in progress

26. Surgical procedures and adjuvant use O = not used/recommended

27. Adhesion reduction agents status

28. Cost comparison* SurgiWrap estimate ~£150 (€225)/sheet *UK sterling prices € equivalent

29. Cost comparison* SurgiWrap estimate ~£150 (€225)/sheet *UK sterling prices € equivalent

30. Prophylaxis? Adoption of routine prophylaxis depends on impact of strategy on adhesion-related readmissions and cost of strategy

31. Cost-effectiveness • Costs of adhesion-related Small Bowel Obstruction • Conservatively treated £1,606 (mean stay 7 days) • Surgically treated £4,677 (mean stay 16 days) • Adhesion reduction technologies may reduce costs Menzies, Parker et al. Ann Roy Coll Surg Engl. 2001

32. Modelling cost effectiveness- lower abdominal surgery If adhesion-related readmissions are reduced by the routine use of an adhesion reduction agent, what’s the cost impact? • Assume agent costs £200 • Assume agent costs £50 • What efficacy is required to payback the cost of using an anti-adhesion agent at 3 years??? Wilson et al. Colorectal Dis. 2002

34. £70,000 Control 64% £60,000 £50,000 £200 £40,000 £30,000 £20,000 £10,000 £0 1 2 3 4 5 6 7 8 9 0 Years since surgery Cumulative cost of adhesion-related readmissions following lower abdominal surgery Cumulative cost/100 patients Wilson et al Colorectal Dis 2002

35. Cumulative cost of adhesion-related readmissions following lower abdominal surgery £70,000 Control 16% £60,000 £50 £50,000 Cumulative cost/100 patients £40,000 £30,000 £20,000 £10,000 £0 1 2 3 4 5 6 7 8 9 0 Years since surgery Wilson et al Colorectal Dis 2002

36. Modelling cost effectiveness- lower abdominal surgery Routine use of an anti-adhesion agent costing £50 will payback the investment cost if it reduces adhesion-related readmissions by only 16% after 3 years Agents costing £200 or more are unlikely to payback the costs of usage Wilson et al. Colorectal Dis. 2002

37. Modeled cumulative cost savingsin the UK Lower abdominal surgery (158,000 ops per year) SCAR £150 £125 £50 product (assume 25% efficacy) Saving £71m £100 £75 £50 £25 Cumulative cost savings (Millions) £0 -£25 -£50 -£75 -£100 -£125 -£150 1 2 3 4 5 6 7 8 9 Loss £142m £200 product (assume 25% efficacy) Time since start of adhesion-reduction treatment policy with product (years)

38. Routine prophylaxis vs ‘High Risk’ Surgery Adhesiolysis Small bowel resection Formation of stoma Hartmann’s procedure Anterior resection Abdomino-perineal excision Colectomy Surgical treatment of peritonitis & fistulae Use of anti-adhesion agents Or do nothing???

39. Implications of doing nothing • Adhesions are inevitable • High risk of adhesion-related problems • Small bowel obstruction • Female infertility • Chronic and debilitating pelvic pain • Reoperative complications Do we tell our patients when we obtain consent?

40. Informed consent International Adhesions Society Patient Survey* • In only 10.4% of cases adhesions mentioned as part of informed consent process • 14.4% adhesions discussed but not part of consent • Adhesiolysis patients • 54% given some information before surgery • 46% given specific information about anti-adhesion agents • In non-adhesiolysis procedures only 10% patients advised about adhesions • Only 6% given information on anti-adhesion agents Wiseman, Adhesions News & Views 4 2003 and PAX Meeting 2003

41. Medico-legal consequences Most common claims • Failure to diagnose / delay in diagnosis • Failure to take precautions to prevent • Bowel damage at adhesiolysis • Infertility / risk of infertility • Chronic abdominal / pelvic pain • Starch granuloma (gloves) 1995-1999 UK MDU received 77 adhesion-related claims • Average settlements £50,765 Before SCAR Before we knew the real extent of the problem Before we had newer anti-adhesion agents Ellis H, Journal of the Royal Society of Medicine 2001

42. Where are we now? • Adhesions continue to be a significant burden • For the patient: • pain, SBO, infertility, re-operative complications • For the surgeon • increased workload, lengthy and complex procedures, medicolegal consequences • For the healthcare system • increased workloads, costs, bed stay

43. Where are we now? • Any advances in surgery have had little impact • Action on adhesions has received low priority • even in high risk procedures • New developments in anti-adhesion agents • not all are difficult or costly to use • emerging evidence of efficacy

44. Adhesiolysis Small bowel resection Formation of stoma Hartmann’s procedure Anterior resection Abdomino-perineal excision Colectomy Surgical treatment of peritonitis & fistulae Adopt use of anti-adhesion agents in ‘High Risk’ surgery

46. Acknowledgments Fellow SCAR Panel Members Prof Harold Ellis, UMDS, London Malcolm Wilson, Christie Hospital, Manchester Don Menzies, Colchester Hospital, Colchester Jeremy Thompson, Chelsea & Westminster Hospital, London Brendan Moran, North Hampshire Hospital, Hampshire Adrian Lower, St Bartholomew's Hospital, London Rob Hawthorn, Southern General Hospital, Glasgow Prof Alastair McGuire, City University, London Graham Sunderland, Southern General Hospital, Glasgow David Clark, James Boyd, Alan Finlayson, ISD, NHS Scotland, Edinburgh Prof Ian Ford, Robertson Centre Biostatistics, Glasgow Alastair Knight & Alison Crowe, Corvus Shire Pharmaceuticals Group plc

47. Thank you