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					   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
Adhesions after colorectal surgery
     Do we need to prevent?


              Yes
      Do we need to treat?
          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
Formation of Adhesions
                          Influencing
            Injury      factors during
                            surgery
                          • Ischaemia
                          •
    Bleeding              • Infection
                          •
Inflammation              • GI contents
                          •
             Fibrin       • Abrasion
                          •
           deposition     • Desiccation
                          •
                          • Heat
                          •
                          • Light
                          •
                          • Electrocautery
                          •
                          • Sutures
                          •
         Adhesions        • Fibres
                          •
                          • Glove powder
                          •
Protection against adhesions
          Injury   Steps to reduce adhesions
                        during surgery
                       • Increase vascular permeability
    Bleeding           • Reduce infection risk
inflammation           • Avoid GI contamination
            Fibrin     • Minimise tissue handling
          deposition        • Careful technique
                            • Microsurgery
                       • Reduce drying of tissues
                            • Lubrication
                       • Limit use of cautery
                       • Limit use of sutures
         Adhesions     • Avoid materials with fibres
                       • Use starch-free gloves
   Adhesion reduction strategies

• Careful surgical technique

• Minimise Inflammatory response

• Augmentation of fibrinolysis

• Adhesion-reduction agents
                                    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
                Adhesion Reduction Agents:
                           The ideal agent
According to recent surveys of surgeons the four key
attributes are:
     • Safety                         • Efficacy
                                        – Operation site
     • Easy to use                      – Throughout the
         – General surgery                cavity
         – Gynaecological
           surgery                    • Economical
         – Open
         – Laparoscopic

ESHRE 2002 Survey, EACP 2002 Survey
Adhesion Reduction Agents
 Key issues

 •   Toxicity
 •   Handling
 •   Limited efficacy
 •   Clinical outcomes
 •   Cost
                       Adhesion Reduction Agents
Site Specific
Preclude*      expanded polytetrafluoroethylene Gore-Tex sheet         Generally unavailable

Interceed      oxidised regenerated cellulose fabric
Seprafilm      hyaluronic acid carboxymethylcellulose film
SprayGel       polyethylene glycol hydrogel
SurgiWrap      copolymer 70:30 Poly(L-lactide-co-D, L-lactide) sheet


Broad Coverage
Crystalloids     Ringer’s lactate/saline +/- Heparin
Hyskon         32% dextran 70 solution                                 Generally unavailable
Sepracoat      0.04% hyaluronic acid-phosphate-buffered saline                   Withdrawn
Intergel       0.5% ferric hyaluronate gel                                       Withdrawn
Adept          icodextrin 4% solution



* Withdrawn from US market
           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!
                               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!
                                         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
                                           SprayGel
                   (Polyethylene Glycol Polymer, Confluent)
• Polymerization




• Methylene blue to show where it is used
                    SprayGel

Laparoscopic Kit
                      Requires
                      specialised air
                      pump

 Open Surgery Kit
                                               SprayGel




       5 kits needed for complete peritoneal coverage!!!*



*Korell Adhesions News & Views 2004 in press
                                     SprayGel
Limitations
•   complex set-up
•   time consuming
•   limited efficacy & safety data
•   US regulatory study halted
•   cost……
                                               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
                                       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!!
                                  ®
                           Adept
New solution to adhesion reduction?
        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’
            Adept hydroflotation mechanism
                Residual Volume in Abdomen
     2500

     2000

     1500
                                                       4% icodextrin
ml                                                     Saline
     1000                                              Glucose

      500

        0
            0   20     40        60   80   100   120

                        Time (hours)


Hosie et al Drug Delivery 2001
Adept use
- Irrigation - minimum 100mls/30mins
              - Laparoscopy through the scope
              - Laparotomy via a syringe

- Instillation - 1000ml at closure

               Laparoscopy                      Laparotomy
                                                 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
   Surgical procedures and adjuvant use
                  Adhesion                    Fertility Surgery                     Gynaecology                  General
                    Type                                                                                         Surgery
                 De         Reform         Open          Laparoscope             Open              Scope       Open   Scope
                novo

                                     Uterus   Adnexa   Uterus     Adnexa   Uterus   Adnexa   Uterus   Adnexa

Site
Specific
Preclude         +++         +++       √          X      X          X        √          X      X           X    √      X

Interceed        +++         +++       √          √      √          √        √          √      √           √    O      O

Seprafilm        +++         +++       √          X      X          X        √          X      X           X    √      X

SprayGel         +++         +++       √          √      √          √        √          √      √           √    ?      ?

SurgiWrap         ?           ?        ?          ?      ?          ?        ?          ?      ?           ?    ?      ?

Broad
Coverage
Hyskon            ++         ++        O          O      O          O        O          O      O           O    O      O

Sepracoat         ++         ++                                              Withdrawn

Intergel         +++         +++                                             Withdrawn

Adept            +++         +++       √          √      √          √        √          √      √           √    √      √


 O = not used/recommended
            Adhesion reduction agents status
                   Approved     Safety profile       Limitations            Clinical    Cost
                                                                            Studies
                                                                         (ongoing and
                                                                           complete)
                 Europe   US
Site Specific

Preclude           √      No          √            Suture in place               2      ££(£)

Interceed          √      √           √          Blood incompatibility        24+        £

Seprafilm          √      √     Anastomosis           Handling                4+        ££(£)
                                                  Complex & capital       2 – pivotal
SprayGel           √      No          ?                                  stopped poor   £££
                                                    equipment               efficacy
                                                 Suture in place, but
SurgiWrap          √      No         No          dissolves in 1 year             0      ££(£)
Broad Coverage

Hyskon            No      No    Anaphylaxis            Toxicity                  3       £

Sepracoat                      Withdrawn – FDA did not approve - poor efficacy

Intergel                          Withdrawn – late onset postoperative pain
                                38,000 patient
Adept              √      No                     Main studies ongoing            4       £
                               years 7.5% soln
                                     Cost comparison*
             Interceed (per sheet)                   £90 (€135)

           Intergel (300ml bottle)                        £110 (€165)

Spraygel (per kit excl airpump)                                            £200
                                                                          (€300)
            Seprafilm (per sheet)                        £99 (€149)

              Adept (1.5 litre bag)           £44 (€66)

                      Adept (1 litre)        £35 (€53)

                                        £0   £50    £100      £150      £200   £250

  SurgiWrap estimate ~£150 (€225)/sheet
  *UK sterling prices € equivalent
                                     Cost comparison*
           Interceed (per sheet)             £90 (€135)

         Intergel (300ml bottle)              £110 (€165)
                                                                                £1000
Spraygel (5 kits excl airpump)
                                                                               (€1500)
          Seprafilm (4.4 sheets)                           £436 (€654)

             Adept (1.5 litre bag)          £44 (€66)

                     Adept (1 litre)        £35 (€53)

                                       £0     £200      £400   £600   £800 £1,000 £1,200

  SurgiWrap estimate ~£150 (€225)/sheet
  *UK sterling prices € equivalent
        Prophylaxis?

 Adoption of routine prophylaxis
depends on impact of strategy on
 adhesion-related readmissions
      and cost of strategy
                                           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
                                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
                     Cumulative cost of adhesion-related readmissions
                           following lower abdominal surgery
Cumulative cost/100 patients




                               £70,000

                               £60,000                 64%                                Control

                               £50,000

                               £40,000                                                    £200

                               £30,000

                               £20,000

                               £10,000

                                   £0
                                         0   1   2     3     4      5     6   7   8   9
                                                        Years since surgery
                    Wilson et al Colorectal Dis 2002
                     Cumulative cost of adhesion-related readmissions
                           following lower abdominal surgery
Cumulative cost/100 patients




                               £70,000

                                                     16%                                 Control
                               £60,000
                                                                                         £50
                               £50,000

                               £40,000

                               £30,000

                               £20,000

                               £10,000

                                   £0
                                         0   1   2     3     4     5    6    7   8   9

                                                       Years since surgery
                    Wilson et al Colorectal Dis 2002
                            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
                                             Modeled cumulative cost savings in the UK
                                        Lower abdominal surgery (158,000 ops per year) SCAR
                                     £150
                                     £125
Cumulative cost savings (Millions)




                                     £100
                                                      £50 product (assume 25% efficacy) Saving £71m
                                      £75
                                      £50
                                      £25
                                       £0
                                     -£25
                                     -£50
                                     -£75
                                     -£100
                                     -£125
                                 -£150
                                                1       2       3       4       5        6       7       8       9

                                                    £200 product (assume 25% efficacy) Loss £142m
                                      Time since start of adhesion-reduction treatment policy with product (years)
         Use of anti-adhesion agents
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


            Or do nothing???
         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?
                                                 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
                              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
                            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
                          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
Adopt use of anti-adhesion agents in
                  ‘High Risk’ surgery
•   Adhesiolysis
•   Small bowel resection
•   Formation of stoma
•   Hartmann’s procedure
•   Anterior resection
•   Abdomino-perineal excision
•   Colectomy
•   Surgical treatment of peritonitis & fistulae
                                 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
Thank you

				
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