1 University of Southern California Keck School of Medicine, Los Angeles, 2 IGO Medical Group, 3 San Diego Fertility Center, San Diego, CA, 4 Private Practice, Memphis, TN, 5 Allegheny General Hospital, Pittsburgh, PA, USA and 6 ML Laboratories PLC, Leicester, UK
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Abstract |
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Key words: glucose polymer/icodextrin/laparoscopic surgery/peritoneal adhesions/post-surgical adhesions
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Introduction |
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Adhesion prevention adjuvants became available to practising surgeons in 1990 with the introduction of Interceed® absorbable adhesion barrier (Gynecare, Somerville, NJ, USA) [Interceed (TC7) Adhesion Barrier Study Group, 1989]. Other site-specific barriers soon followed, including Preclude®(Gore-Tex, Flagstaff, AZ, USA) (Surgical Membrane Study Group, 1992) and Seprafilm® bioabsorbable membrane (Genzyme, Cambridge, MA, USA) (Diamond and the Seprafilm Study Group, 1996
). In 1996, an experts' conference was held as part of the International Federation of Fertility and Sterility to evaluate the data supporting the use of barriers and to make recommendations for their application (Holmdahl et al., 1997
). In general, the guidelines supported prophylactic use of adhesion barriers following adnexal surgery or myomectomyprocedures well known to create adhesions with clinical significance. A recognized limitation of these site-specific barriers was the requirement on the part of the surgeon to predict where adhesions would most likely form which would cause clinical problems. This limitation was overcome with the availability of IntergelTM adhesion prevention solution (Gynecare) (Thornton et al., 1998
). In a laparotomy study followed by second-look laparoscopy, instillation of 300 ml of this viscoelastic product into the peritoneal cavity at the end of surgery was shown to improve adhesions at both surgical and non-surgical sites, including those anatomical locations where gravity alone would be likely to reduce the chance of distribution (Johns and diZerega, 1999
; Johns and the INTERGEL International Adhesion Study Group, 1999
). Many of the conservative procedures performed today are performed via a laparoscopic route. Thus, general prophylactic use of adhesion prevention adjuvants requires clinical data from laparoscopic studies followed by second-look laparoscopy to assess efficacy.
The most popular device used for adhesion prevention is the instillation of salt-containing solutions into the peritoneal cavity at the end of surgery in sufficient volume (300500 ml) to allow for `flotation' of the adnexal structures (diZerega, 1994;diZerega and Campeau, 1994
). However, hydroflotation with crystalloids has been shown not to reduce the formation of post-surgical adhesions in a meta-analysis of clinical trials (Wiseman et al., 1998
). These solutions are absorbed from the peritoneal cavity at the rate of 3060 ml per hour, so that by 1012 h post-operation little, if any, crystalloid solution would be left in the pelvis (Shear et al., 1965
; Hart and Magos, 1996
). Peritoneal healing may take as long as 57 days, thereby allowing for an extended period of time for fibrin outpouring from the damaged surfaces to interconnect with adjacent structures in the peritoneal cavity, leading to adhesion formation (diZerega, 1997a
). Therefore, post-surgical instillates with prolonged peritoneal residence times should theoretically be more successful at preventing adhesions at both surgical and remote, non-surgical sites.
Icodextrin is an -1,4 glucose polymer of high molecular weight (Mw average 12 00020 000 daltons) which is rapidly metabolized to glucose by the
-amylase present in the systemic circulation, but is absorbed only slowly from the peritoneal cavity. The colourless, non-viscous, iso-osmolar 4% solution of icodextrin, having an intraperitoneal residence time of at least 4 days (Hosie et al., 2001
), has the potential to reduce post-surgical adhesion formation by means of hydroflotation. In this pilot study, post-surgical instillation of 1 l of 4% icodextrin was investigated in a controlled, prospective, assessor-blinded study in female patients undergoing laparoscopic adnexal surgery with a planned second look to assess efficacy. Preclinical studies with 4% icodextrin in the rabbit double uterine horn model demonstrated that in addition to the significant benefits of post-operative instillation, de-novo formation of adhesions was significantly reduced by frequent intra-operative irrigation (Verco et al., 2000
). Furthermore, it was also shown (Diamond et al., 1998
) that de-novo adhesion formation could be reduced by planned scheduled frequent use of an adhesion prevention adjuvant during surgery. Therefore, in the current study 4% icodextrin or the control (Ringer's lactated saline; RLS) was also used as an intraperitoneal irrigating solution at least every 30 min during the surgical procedure.
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Materials and methods |
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Over a period of 616 weeks, patients made four visits incorporating first- and second-look laparoscopy.
At visit 1 (04 weeks before the scheduled operation), patients were screened for eligibility, including physical examination, pregnancy testing and baseline measurements of blood chemistry, haematology, prothrombin time and urinalysis. Eligible patients were then randomized to one of the two treatment groups, each patient being assigned the next available study number which was pre-allocated to treatment according to a randomization list held on site in a sealed envelope.
At visit 2, urine pregnancy testing was repeated as necessary and the patients underwent laparoscopic surgery and received their assigned study treatment. Before the planned surgical procedure, adhesions were assessed and adnexal adhesions lysed. The procedure was videotaped via the laparoscope for third-party blinded assessment of adhesions present before surgery. Adverse events were recorded and prothrombin time measured from blood samples taken before discharge from hospital. Current medications could be continued and their use was also recorded.
At visit 3 (follow-up) 14 weeks after surgery, blood samples were collected for laboratory tests, and adverse events and concomitant medications assessed.
At visit 4, 612 weeks after the first surgery, second-look laparoscopy was performed to evaluate adhesions, and was again videotaped for third-party blinded assessment of adhesions. Before the surgical procedure, adverse events and use of concomitant medications were assessed, and blood and urine samples collected for laboratory tests including pregnancy testing.
The study was carried out in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice. The protocol was reviewed and approved by the Institutional Review Board associated with each study centre, and all patients provided their written informed consent at the first study visit.
Patients
Adult female patients (aged 18 years) who were scheduled for laparoscopic peritoneal cavity surgery for pelvic pain and/or infertility problems which might require tubal and ovarian surgery were entered into the study. The patients were in good general health and had to be using clinically approved birth control precautions for the duration of the study. They were excluded on pre-operative or intra-operative evidence of pregnancy, including ectopic pregnancy. Other pre-operative exclusion criteria were a history of malignancy in the past 5 years (excluding carcinoma in situ), active pelvic or abdominal infection, known allergy to starch-based polymers, concurrent use of systemic corticosteroids, antineoplastics or radiation, blood/urine values above the upper range of normal [serum glutamate-oxaloacetate transaminase (SGOT), serum glutamate-pyruvate transaminase (SGPT) and/or bilirubin >20%; blood urea nitrogen and creatinine >30%] considered clinically significant, and anticipation of the need for post-operative hydrotubation. Patients were also excluded if the primary purpose of the operation was tubal ligation for sterilization or if any additional surgical procedure (other than adhesiolysis) was planned concurrently. Further exclusions were made if the following criteria were met intra-operatively: clinical evidence of cancer; more than half of the available anatomical study sites contained adhesions; changes to the intended surgical procedure other than adhesiolysis; and use of any product (other than the test treatment) for the purpose of preventing adhesion formation.
Patients were free to withdraw from the study at any time, and could also be withdrawn by the investigator if considered to be in the patient's best interest, whether or not related to an adverse event. After withdrawal or completion of the study all patients were monitored by follow-up as clinically indicated.
Study treatments
Patients who met the entry criteria at visit 1 were assigned randomly to receive either the investigational or control study treatment. Randomization was in blocks of four, with equal randomization to each of the study groups. Sealed treatment codes for 20 consecutively numbered patients were provided to each centre by the supplier of the investigational product, 4% icodextrin solution (Adept®; ML Laboratories PLC, Leicester, UK). This is a sterile, clear, colourless, non-viscous fluid containing icodextrin at a concentration of 4% (w/v) in an electrolyte solution of approximate ionic composition (mmol/l): sodium (133), calcium (1.75), magnesium (0.25), chloride (96) and lactate (40). In appearance and handling this solution is indistinguishable from the control product RLS which was supplied by each study centre, this being the routine solution used during laparoscopic gynaecological surgery. The solutions were warmed to approximately body temperature before use in the peritoneal cavity.
Intra-operative lavage (at least 100 ml every 30 min) was carried out using the allocated study solution, with aspiration of this fluid during the surgical procedure. At the end of the procedure, Trendelenburg's position was reversed to lower the pelvis and the remaining intra-operative solution was aspirated from the abdominal cavity. A volume of the same study solution was then instilled into the peritoneal cavity via the trocars, and all ports 10 mm were sutured to minimize leakage. Patients in the icodextrin group each received a final instillation of 1000 ml of the 4% icodextrin solution. Patients in the RLS control group received the final instillation volume considered to be the normal practice at that study centre (4001000 ml RLS).
Assessment criteria
Safety evaluation of the study treatment was carried out by monitoring (at study visits and follow-up) of adverse events (including severity and relationship to study device), changes in laboratory blood/urine values and post-operative recovery (assessed by changes in concomitant medication). As a secondary safety variable, if an increase in the incidence, extent and severity of adhesions occurred in the icodextrin group only at an interim stage, the study would be terminated at that point.
Efficacy was measured by assessing the incidence, extent (less than one-third, one-third to two-thirds, or more than two-thirds of the site covered) and severity of adhesions in 23 anatomical study sites, scored using a modified version of the American Fertility Society (mAFS) system (American Fertility Society, 1988; Table I
). Video recordings were made of the adhesions present at first and second laparoscopy, which were first assessed by the investigator in the light of the intra-operative score sheet. They were then scored by an independent observer under blinded conditions. Any queries were subsequently raised with the investigator by the blinded reviewer in order to establish a final reconciled score in each case.
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Efficacy and safety were assessed from changes in the number, extent, severity and mAFS scores of adhesions. Numbers of patients showing reduced scores were tested using 2-tests to compare treatment effects. More exhaustive tests were considered inappropriate for the pilot study owing to small groups with unequal baseline adhesions. Significance was set at P < 0.05.
The per protocol population met all inclusion criteria, excluding patients with adhesions affecting >50% of available anatomical sites at first surgery but including patients with no adhesions at first surgery. An adhesion shift analysis was carried out to compare the numbers of per protocol patients in the two treatment groups who showed a reduction in adhesion incidence between first- and second-look laparoscopy. For this purpose, adhesions were ranked into four incidence-based categories (number of adhesions): none (0); mild (14); moderate (59); and severe (10), so that a shift to a lesser category indicated a definite reduction in adhesions.
The reformation efficacy analysis further excluded patients with no adhesions at first surgery (e.g. endometriosis only). As baseline adhesion data showed a skewed distribution, median values were presented in addition to geometric means.
Results
Patient disposition
Among 89 patients who were screened, 62 were considered eligible for entry into the study and underwent first surgery and treatment with either 4% icodextrin (n = 34) or RLS (n = 28). Four patients (three icodextrin, one RLS) were withdrawn after first surgery due to major protocol violation (prior partial or total hysterectomy/non-gynaecological or adnexal surgery). One evaluable patient (icodextrin) did not return within the period allowed for second look and was withdrawn for protocol violation. The remaining patients completed both first- and second-look surgical procedures and were fully evaluated by video review. Four further protocol violators were subsequently withdrawn; one (icodextrin) because the study device was not used correctly, and three (two icodextrin, one RLS) having adhesions at >50% of available sites. Fifty-three fully evaluable patients (27 icodextrin, 26 RLS) were thus included in the per protocol analysis, and 42 (23 icodextrin, 19 RLS) met the criteria for the reformation efficacy analysis. Demographic data are summarized in Table II, and primary diagnoses in Table III
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No clinically significant changes occurred in blood/urine laboratory values or prothrombin time between baseline samples and those taken during the course of the study in either treatment group; these values (not shown) were also similar between treatments. Changes in concomitant medications indicated no overall difference in post-operative recovery between the treatment groups. The study solution, 4% icodextrin, therefore showed a safety profile similar to that of the routinely used standard.
Any increase in adhesions between first and second laparoscopy would have been further cause for concern. However, in the per protocol patients, an overall reduction in the number of adhesions and adhesion scores was demonstrated between first and second surgery in the 4% icodextrin treatment group (n = 27), with less improvement occurring in the RLS control group (n = 26). No safety concerns were raised by using 4% icodextrin in place of RLS in laparoscopic surgery for gynaecological procedures.
Efficacy
Although both study groups demonstrated a reduction in adhesions between first- and second-look laparoscopy, the shift analysis in per protocol patients (n = 53) showed a non-significant trend (P = 0.07) favouring 4% icodextrin over RLS (Figure 1). At second look, a similar proportion of each group (52% icodextrin, 54% RLS) showed no change from their baseline adhesion ranking. A greater proportion of icodextrin-treated patients (37%; 10/27) than RLS-treated patients (15%; 4/26) had shifted to a milder category, whereas more RLS patients than icodextrin patients had moved to a worse category [31 (8/26) versus 11% (3/27)].
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Discussion |
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Compared with the RLS control, 4% icodextrin appeared to be more effective in reducing post-operative formation and reformation of adhesions, and it is the first device to demonstrate an absolute reduction in adhesions at second-look laparoscopy. However, statistical significance was not achieved in this pilot study owing to small groups of varied baseline severity. The predominance of patients with a more severe baseline condition in the icodextrin group had the potential to weaken demonstration of a positive effect, as these individuals could be inherently more prone to adhesion reformation.
Marked differences in intraperitoneal residence times between icodextrin (which is absorbed slowly over a period of several days) and crystalloid solutions (which remain in the cavity for ~24 h) support the idea that prolonged hydroflotation helps to keep peritoneal surfaces apart during the key stages of wound repair, thus reducing the likelihood of adhesion formation (diZerega and Campeau,1994; Hart and Magos, 1996
; Hosie et al., 2001
). Safety is a major concern for intraperitoneal solutions with prolonged exposure, a case in point being dextran 70. This macromolecular solution, which is an
-1,6-linked dextrose polymer, has a longer dwell time than RLS when instilled into the cavity, but its osmotic and antigenic properties produce unacceptable local and systemic side-effects (Gauwerky et al., 1986
; Sites et al., 1997
). The number of patients entered into the present study (n = 62) was unusually large for a pilot study, but is justified by the extensive safety profile of icodextrin in other indications, namely daily peritoneal dialysis (using a 7.5% solution) in end-stage renal failure patients and intraperitoneal chemotherapy (Davies, 1994
; McArdle et al., 1994
; Mistry et al., 1994
; Topley et al., 1994
; Kerr et al., 1996
; Dawnay and Miller, 1997
; Peers and Gokal, 1997
; Posthuma et al., 1997
). This represents a clinical experience in excess of 10 000 patient-years, and currently some 7000 patients have been receiving 7.5% icodextrin as a peritoneal dialysis solution for periods of months or years.
Icodextrin is an -1,4-linked dextrin polymer of glucose which, unlike dextran 70, is a substrate for
-amylase in the bloodstream and undergoes metabolism, ultimately via maltose, to glucose. The large icodextrin molecule is absorbed only gradually from the peritoneal cavity by way of the lymphatic system which, given the absence of
-amylase in the human peritoneal cavity, accounts for its prolonged residence following instillation. Use of a 4% concentration avoids the fluid build-up which is essential to the function of 7.5% icodextrin as a peritoneal dialysis solution (Peers and Gokal, 1997
). An intraperitoneal volume of 2 l of 4% icodextrin has been shown to remain for 12 days, and then to decline slowly to about half this volume after a 4-day period (Hosie et al., 2001
). These properties of icodextrin suggest a wider potential for use of the 4% solution in general as well as gynaecological surgery, and as a carrier for treatments of infectious and neoplastic diseases (Dobbie and Gilbert, 1999
; Gilbert et al., 1999a
,b
).
The potential benefit of using 4% icodextrin as an intra-operative wash and post-operative instillate in gynaecological surgery was indicated in preclinical studies with the rabbit double uterine horn and sidewall models, in which significant reductions were achieved in both the de-novo formation and reformation of surgically induced adhesions (Verco et al., 2000). In the same preclinical studies, RLS had little effect on post-surgical adhesions, which is consistent with overall clinical findings (Wiseman et al., 1998
). These standard rabbit models have also predicted the clinical effectiveness of Intergel, a viscous solution of hyaluronic acid (HA) with a prolonged intraperitoneal residence time, which reduced adhesions at both surgical and non-surgical sites following laparotomy procedures (Johns and diZerega, 1999
). In contrast, the clinical use of a low-viscosity HA solution both during and at the end of surgery had a more limited effect in protecting the peritoneal surfaces only from indirect surgical trauma. Thus, de-novo adhesions were reduced at non-surgical sites, but no such benefit was seen at surgical sites (Diamond et al., 1998
). Site-specific barriers are effective, but have the obvious limitation of requiring accurate placement at potential sites of adhesion formation (Diamond and the Seprafilm Study Group, 1996
; Holmdahl et al., 1997
). This can be especially difficult during laparoscopic procedures, whereas solutions such as 4% icodextrin are simply instilled into the peritoneal cavity through trocar ports (Verco and Brown, 2000
).
The results of this investigation support preclinical observations (Verco et al., 2000) that the use of 4% icodextrin as an irrigant during adnexal surgery, followed by instillation of a larger volume at the end of surgery, leads to a reduction in the number and severity of adhesions observed at second-look laparoscopy. Given the design limitations of an open-label pilot study intended primarily to establish clinical safety, the efficacy conclusions are strengthened by the elimination of bias by means of third party-blinded evaluation of adhesions. Together with the favourable overall safety profile of icodextrin, these preliminary data encourage the undertaking of more extensive clinical studies of 4% icodextrin as an adjuvant device for adhesion reduction in both gynaecological and general surgery. A double-blind, Phase III pivotal study is currently underway in the USA.
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Acknowledgements |
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Notes |
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References |
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Submitted on March 16, 2001; resubmitted on August 9, 2001; accepted on November 11, 2001.