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Gynecology SURGICAL TECHNOLOGY INTERNATIONAL Volume 38 Peritoneal Adhesions and their Prevention - Current Trends

BERNHARD KRÄMER , P HD STEFAN KOMMOSS , P HD DEPUTY MEDICAL DIRECTOR & S ENIOR CONSULTANT OF CONSULTANT OF OPERATIVE GYNECOLOGY OPERATIVE GYNECOLOGY

FELIX NEIS , MD JÜRGEN ANDRESS , MD CONSULTANT OF OPERATIVE GYNECOLOGY CONSULTANT OF OPERATIVE GYNECOLOGY

SARA Y B RUCKER , P HD MEDICAL DIRECTOR SASCHA HOFFMANN , MD PROFESSOR OF WOMEN ’S HEALTH AND GYNECOLOGY CONSULTANT OF OPERATIVE GYNECOLOGY

DEPARTMENT FOR WOMEN ’S HEALTH , U NIVERSITY HOSPITAL TÜBINGEN , T ÜBINGEN , G ERMANY

ABSTRACT he development of adhesions after gynecologic surgery is a severe problem with ramifications that go Tbeyond the medical complications patients suffer (which most often include pain, obstruction and infer - tility), since they also impose a huge financial burden on the health care system and increase the workload of surgeons and all personnel involved in surgical follow-up care. Surgical techniques to avoid adhesion forma - tion have not proven to be sufficient and pharmaceutical approaches for their prevention are even less effec - tive, which means that the use of adhesion prevention devices is essential for achieving decent prophylaxis. This review explores the wide range of adhesion prevention products currently available on the market. Par - ticular emphasis is put on prospective randomized controlled clinical trials that include second-look inter - ventions, as these offer the most solid evidence of efficacy. We focused on adhesion scores, which are the most common way to quantify adhesion formation. This enables a direct comparison of the efficacies of dif - ferent devices. While the greatest amount of data are available for oxidized regenerated cellulose, the out - comes with this adhesion barrier are mediocre and several studies have shown little efficacy. The best results have been achieved using adhesion barriers based on either modified starch, i.e., 4DryField ® PH (PlantTec Medical GmbH, Lüneburg, Germany), or expanded polytetrafluoroethylene, i.e., GoreTex (W.L. Gore & Asso - ciates, Inc., Medical Products Division, Flagstaff, AZ), albeit the latter, as a non-resorbable barrier, has a huge disadvantage of having to be surgically removed again. Therefore, 4DryField ® PH currently appears to be a promising approach and further studies are recommended.

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Peritoneal Adhesions and their Prevention - Current Trends KRÄMER/NEIS/BRUCKER/KOMMOSS/ANDRESS/HOFFMANN

BACKGROUND a decline in fibrinolytic capacity. 13 Inhibi - tinuous pain when they retract the vis - tion of tPA can be triggered by plasmino - cera without obstructing them. 37 The Peritoneal healing and adhesion gen-activator-inhibitor (PAI). actual effect of adhesions on pain is diffi - formation Inflammatory reactions lead to an cult to estimate since the pathophysiolo - Following surgical trauma, the time increased release of PAI and, thus, can gy of chronic abdominal pain is still required for regeneration of the peri - also lead to an inhibition of the fibri - poorly understood. 38 Seventy-four to toneum and its mesothelial layer is 5-6 nolytic system. 15 Once fibrin bridges 86% of all cases of small bowel obstruc - days. 1-3 The cellular sequence of this have formed between neighboring tissues tion can be ascribed to post-surgical repair starts with polymorphonuclear or organs that are not normally connect - adhesions, 39,40 which are also the only leukocytes (PMN) attaching to fibrin ed to one another , these mature into factor causing female infertility in 15% strands , followed by infiltration of adhesions. 16 A multitude of growth fac - of cases. 41 Infertility can be caused by macrophages , which form a single-cell tors, cytokines and signaling molecules either peri-tubal adhesions affecting tubal layer to cover the wound surface by day are involved in this process. 16,17 The mat - motility and ovum transport or adhe - 2. During the following days, primitive uration of adhesions includes vasculariza - sions around the ovaries inhibiting follic - mesenchymal cells and first mesothelial tion , which is highly dependent on ular growth. 24 Although adhesiolysis cells, followed by proliferating fibrob - VEGF expression. 17 As in fibrosis, con - surgery may increase the fertility of pre - lasts , can be observed until a single layer nective tissue formation is mediated by viously infertile women, the surgery of mesothelial cells , interconnected by connective tissue growth factors , as well itself imposes a risk of (re-)formation of desmosomes and tight junctions , is pre - as TGF-betas. 18,19 adhesion and, thereby, persistence or sent on the wound surface on day 5 . By The main intra-operative factor pro - even aggravation of the problems caused then, PMNs have vanished and the moting adhesion formation is injury to by the adhesions. Adhesions or adhesion- amount of fibrin has decreased signifi - the peritoneum. 20,21 Other factors related complications are also some of cantly. The amount of macrophages also include the complexity of the the main reasons for readmission. It was begins to decrease from day 5 onwards ; a procedure, 22 tissue necrosis through found that 33% to 44% of patients with continuous basement membrane forms heavy coagulation 23 and bacterial inflam - extensive open surgery were readmitted beneath the mesothelial coverage and mation. 24 For laparoscopic procedures , either directly or likely due to adhesion- blood vessels begin to develop. 4,5 The desiccation through dry insufflation gas , related complications within 10 most probable origin of the new as well as high insufflation pressure (also years. 35,42,43 With 48% and 41% of mesothelial cells is mesenchymal stem leading to the compression of capillary women being readmitted, respectively, cells within the connective tissue. 6 The flow) 25-27 and mesothelial hypoxia surgical procedures on the ovary and fal - 28 mesothelial cells are attracted to the through CO 2 have to be considered as lopian tube have been shown to have the injury site chemotactically , where they possible contributors to adhesion forma - highest risk of adhesion-related readmis - initially form islands and then proliferate tion. For laparotomies, these possible sion. 35 Furthermore, adhesions are one to complete the re-epithelialization. 5,7 contributors include desiccation as a of the main reasons for conversion dur - Healing of the visceral peritoneum does result of heat and/or light 23 and ing subsequent surgeries. 44,45 Adhesioly - not seem to differ significantly from that mesothelial desiccation/abrasion from sis prolongs surgery and post-surgical of the parietal peritoneum , apart from dry swabs. 20,21 recovery and increases the risk of intra- different time intervals of some healing Foreign bodies can also provoke adhe - operative accidental damage of neighbor - stages. 5,8,9 sions; possible sources include suture ing tissues and organs and post-surgical The pathophysiology of adhesiogene - materials ,2,10,29 surgical glove dusting complications. 46-48 A meta-analysis found sis after surgical injury generally depends powders, 30 material extruded from the that the overall incidence of adhesiolysis- on exudation, 10 inflammation and fibrin digestive tract , and hernia mesh - related enterotomy in gynecologic surg - deposition. Inflammatory responses are es. 24,29,31,32 . The likelihood of adhesion eries was 4.8% (95%CI: 0.6-9.1 %). 49 triggered by ischemia in the damaged tis - formation is also influenced by the pro - Another meta study found that the inci - sue through the release of inflammatory cedure performed, and ovarian cystecto - dence rate correlates with the number of mediators from mesothelial cells , as well my, endometriosis, myomectomy, previous laparotomies and the presence as pro-coagulatory and anti-fibrinolytic adhesiolysis, tubal surgery including of bowel fistula. 50 While the incidence reactions. 11 An imbalance between fibri - ectopic pregnancies , and surgical treat - rate of ureteral injuries was considerably nolytic and pro -coagulatory factors leads ment of pelvic inflammatory disease are lower , and regularly below 1%, adhe - to the persistence of the formed polyfib - associated with relatively high adhesio - sions were considered to be a predispos - rin, which under normal physiological genicity. 33 ing factor .51,52 conditions would be degraded by the fib - rinolytic activity of the mesothelium. 12-14 THE AFTETHREM AAFTEHRMATH Economic impact The fibrinolytic system is activated While the possible medical impact of through tPA (tissue-type plasminogen Medical complications adhesions is well known among surgeons , activator), which cleaves plasminogen to Adhesions are the main cause of the extent of the economic ramifications yield active plasmin. The protease plas - chronic abdominal pain, 34 small bowel of adhesions is often neglected . Several min then cleaves fibrin and , therefore , obstructions, 34-36 and secondary female studies have examined the economic can dissolve polyfibrin strands. 12 Howev - infertility. 34-36 Chronic abdominal pain impact of adhesions and adhesion-related er, reduced tPA activity has been found can be divided into continuous and col - complications . The costs associated with in peritoneal tissue as a local response to icky pain. While adhesions more often hos pital stays due to adhesive small surgical trauma , causing (at least in part) cause the latter , they can also cause con - bowel obstructions were examined by

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Gynecology SURGICAL TECHNOLOGY INTERNATIONAL Volume 38

Menzies et al .53 In an analysis of over 100 episode. With annual costs in Sweden € and an efficacy of 25% for one year in cases , they found that the costs for refer - between 40 and 60 million €, the costs of the UK could save over 40 million € over ral, follow-up, hospital ward/ICU stay, inpatient readmission are almost as high the following 10 years. theater time, investigations and drugs as those for gastric cancer . The inpatient added up to over 4,600 GBP per patient burden of abdominal and gynecological AADDHEESISOINO PNRE VENTPIORNE WVITEHNOUTTI ON when surgical treatment was necessary adhesiolysis in the United States was ana - WITHOUT BABRARRRIIERRSS (37% of cases) , while conservative treat - lyzed by Sikirica et al. 58 They found that , ment still required a total cost of over in 2005 , there were over 350,000 adhe - Adapted surgical techniques 1,600 GBP per patient. A prospective siolysis-related hospitalizations , of which The most obvious and effective strate - study by Ivarsson et al. 54 to assess the 23% were for primary and 77% were for gy for adhesion prevention is to avoid direct costs of bowel obstruction result - secondary adhesiolysis. Almost 1 million surgery. 60 If this is not an option , surgical ing from adhesions found that 60% of days of care were attributed to adhesioly - techniques that minimize trauma and bowel obstructions were caused by adhe - sis-related procedures and inpatient post-operative contact of injured sites sions , and 60% of patients who required expenditures totaled $2.3 billion ( $1.4 should be chosen. 60 For this purpose , operative treatment experienced major billion for primary and $926 million for careful tissue handling and minimization complications including death. The secondary adhesiolysis). Of the sec - of electrocoagulation should be imple - authors extrapolated the expenses to the ondary adhesiolysis procedures, 46% mented and manipulation of the peri - national level of Sweden , and estimated involved the female reproductive tract , toneum should be avoided as much as that adhesive small bowel obstructions for a total of 57,000 additional days of possible. Furthermore, the level of desic - lead to over 2,300 hospital admissions care and attributable costs of $220 mil - cation and abrasion and the subsequent annually , which is equivalent to 26 per lion . In summary, multiple factors con - damage to peritoneal cells can be mini - 100,000 people , and total costs of about tribute to the financial burden of mized through frequent moistening of $13 million . Ray et al. 55 examined inpa - adhesions, including additional surgeries, the surgical area as well as of the gas tient care and expenditures related to further and longer hospitalizations, sup - used, the avoidance of dry swabs and abdominal adhesiolysis in the United plementary investigations and drugs, towels and the reduction of heat and States in 1994. They found that adhesiol - prolonged and more severe re-interven - light. Care should be taken to avoid ysis was responsible for over 300,000 or tions, as well as longer recovery times chronic inflammatory reactions that may 1% of hospitalizations, which is equiva - and more frequent follow-up care visits . be caused by foreign bodies and favor lent to 117 adhesion-related hospitaliza - An additional factor that is often over - adhesion formation. 61 Since laparoscopic tions per 100,000 people. This sums up looked is the loss of productivity : sur - approaches produce less peritoneal trau - to almost 850,000 days of inpatient care geons, hospital personal and aftercare ma than open surgery , adhesion forma - and direct costs of about $1.3 billion for physicians have to invest time in the tion can indeed be reduced , but not hospitalization and surgeon expendi - treatment of adhesion-related complica - prevented. 62 Even laparoscopy intro - tures. The addition of adhesiolysis to tions , and hospital beds and operating duces new problems like hypoxia of peri - other surgical procedures added ≈1-2 rooms are unnecessarily occupied. Con - toneal cells , which can be induced by days of inpatient care. A population- sidering the huge economic impact of increased intra-abdominal pressure com - based study by Kössi et al. 56 of the surgi - adhesions and adhesion-related conse - pressing supporting blood vessels 28 or cal workload and economic impact of quences, the routine use of effective through laparoscopic graspers that apply bowel obstruction caused by postopera - adh esion prevention measures would far more pressure on tissues than what is tive adhesions found that 29% of hospi - appear to be mandatory. Wilson 59 actually be needed to hold them, thereby talized patients needed surgery with a developed an economic model to assess causing significant tissue damage. 63,64 An mean hospital stay of 11 -19 days , for a how effective adhesion barriers needed epidemiological study found that the total of 1 ,118 inpatient days. Extrapola - to be if they were to be economically overall risk of adhesion-related readmis - tion to the national level of Finland yield - viable due to a reduction in readmissions sion following laparoscopic and open ed total costs of inpatient episodes of based on the Surgical and Clinical Adhe - surgeries is comparable. 65 Although over 2 million £ and an extra 124 days in sions Research Group (SCAR) database. instillation of crystalloid solutions is a the operating theater . Tingstedt et al. 57 It calculates the percentage reduction in widespread approach to reduce adhesion conducted a long-term follow-up and readmissions (efficacy) that an adhesion- formation, a meta-analysis of clinical cost analysis following surgery for small reduction product must achieve to studies using Ringer’s lactate (RL) or bowel obstruction caused by intra- return the cost of investment. For this saline solution conclusively showed no abdominal adhesions for 102 patients purpose , he compared the cumulative reduction in adhesion formation. 66 As with surgery for adhesion-caused small costs of adhesion-related readmissions polyfibrin strands are the basic building bowel obstruction. During the follow-up since surgery per patient without treat - blocks during adhesion formation and period (median = 14 years) , 102 patients ment (control) and with an adhesion bar - blood is the primary source of fibrin, 67,68 experienced 273 episodes (2.7 per rier priced at 130 € per treatment. The effective hemostatic measures are the patient) of intestinal obstruction (after model was designed to yield the required foundation of adhesion reduction. 69 the index operation). Of these , 87% efficacy to return the cost of treatment resulted in inpatient readmission and after 1 or 3 years. For 1 year, amortiza - Pharmaceutical approaches 47% resulted in further surgery. The tion of the costs requires an efficacy of Pharmaceutical approaches for adhe - cost of adhesion-related problems in this 53%, and for 3 years, this falls to 26%. sion prevention target the underlying study was almost 1.6 million € , which is The author concluded that the use of an mechanisms of adhesion formation. equivalent to 6,702 € per inpatient anti-adhesion product with a cost of 130 Steroids have been used due their anti-

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Peritoneal Adhesions and their Prevention - Current Trends KRÄMER/NEIS/BRUCKER/KOMMOSS/ANDRESS/HOFFMANN inflammatory effects ,70,71 heparin adhesion formation, most commonly of the number of sites lyzed”. This suc - because of its anti-coagulatory effect, 72-74 using adhesion scores for quantification . cess rate in the Adept ® group (49%) was tissue-plasminogen activator (t-PA) Alternatively, results are expressed as significantly greater than that in the con - because it catalyzes plasmin activation, rates of adhesion-free outcome and adhe - trol group (38%). The ratio of patients which in turn cleaves fibrin, 75 and sion incidence. These approaches do not with significantly reduced pelvic pain promethazine because it is an antagonist consider the impact of the barriers on was the same in both groups. of the inflammation-mediating histamine adhesion reduction when adhesions form Trew et al .87 examined the outcomes in combination with the steroid dexam - nonetheless. Adhesion score results also with Adept ® in 330 women undergoing ethasone. 76 Despite this reasoned consider adhesion-free outcomes (with a laparoscopic removal of myomas or approach, no success has been achieved value of zero), and thus provide the high - endometriotic cysts. The mean total with the use of pharmaceuticals for adhe - est explanatory power. Accordingly, mAFS score was 8.4 in the control and sion reduction. 77 A possible explanation these are the outcomes focused on in the 8.1 in the Adept ® group (not statistically for this poor result might be their rapid present review and given whenever pos - significant) and the mean number of de clearance from the serosal cavity. 78,79 sible. Additionally, as the title suggests, novo adhesions was 2.6 in both groups. Additionally, it has been suggested that this review deals with peritoneal adhe - The authors stated that there was no evi - the use of only one extracellular media - sion formation. Therefore , RCTs dealing dence of a clinical effect. tor might be insufficient to have an out - with other approaches (e.g. , intrauterine Additionally, several studies on the come, while the combination of several adhesion prevention) are discussed only use of Adept ® in animal models showed might show a synergetic effect. 80,81 briefly . no significant adhesion reduction 88-91 Although slight progress has been made Table I provides an overview of the and , in an animal peritonitis model , with the additional use of drug-releasing gynecologic RCTs that have examined Adept ® even increased adhesion forma - barrier systems in an animal model, 82 no adhesion-barrier efficacy using either tion, as well as abscess formation .92 comprehensive data are available . For saline solution, RL or no adhesion pre - Further drawbacks of Adept ® arise pharmaceutical approaches , their perma - vention treatment for the control. Adhe - from its incompatibility with the place - nency and side effects during the healing sion scores are presented whenever ment of drainages. 60 Furthermore, process are an additional issue to be con - available . Adept ® is contraindicated in the pres - sidered. 83 For example, corticosteroids ence of frank infections (e.g. , peritonitis) are associated with immunosuppression Icodextrin in the abdomino-pelvic cavity, in proce - and poor wound healing, the latter of Aqueous solutions of icodextrin were dures with laparotomy incisions (where which is also a problem with the use of originally used for peritoneal dialysis . it could lead to serious post-operative anti-fibrinolytics. 33 The colloid osmotic agent icodextrin wound complications), and in proce - In conclusion, adapted surgical tech - increases the osmotic pressure , initiating dures involving bowel resection or repair niques and pharmaceutical approaches transudation of serum, which compen - or appendectomy (where anastomotic alone are not able to sufficiently prevent sates for absorption of fluid into the lym - failure, ileus and peritonitis could adhesion formation . Therefore, addition - phatic system to prolong the occur ), according to the product’s al measures are required, which is where prevalence. 77,84 For adhesion prevention, instructions for use. adhesion barriers come into play. the effect is based on the principle of hydroflotation. After application , the Expanded polytetrafluorethylene Adhesion barriers organs float in the solution , thereby pre - (ePTFE) A multitude of barriers are available venting their direct contact , which is In contrast to most other materials for adhesion prevention. These can be necessary for the formation of that are used as a basis for adhesion bar - categorized based on the state of matter adhesions. 85 In addition to this effect, fac - riers, PTFE is synthetic. It is a hydropho - (liquid, semi-solid, solid), which is in a tors mediating adhesion formation are bic polymer that is commonly known certain form (gauze, membrane, sheet, diluted . The only icodextrin preparation under the brand name Teflon ™. For powder, gel and so forth ). Efficacy , that is currently available for adhesion medical applications, expanded PTFE retention time and side effects primarily prevention is Adept ® from Baxter (Deer - grafts are made by extrusion of PTFE depend on the material used, rather than field, IL, USA) , which, according to the resin mixed with a lubricant. Manufac - on the form in which it is delivered . product’s instructions for use, is only tured into thin sheets of 0.1 mm gauge , Considering the disadvantages of these indicated for gynecologic laparoscopic it is used as a non-resorbable adhesion possible classifications , in this review, adhesiolysis surgery . There are two pub - barrier under the trade name Gore-Tex adhesion barriers are sorted by material, lished second -look RCTs on the use of Surgical Membrane ® (W.L. Gore & taking into account an adequate degree Adept ® for adhesion prevention in gyne - Associates, Inc., Medical Products Divi - of detail, as well as efficacy, retention cology. Both used RL for the control sion, Flagstaff, AZ, USA ). Unlike other time and side effects . Most barriers are group. Brown et al. 86 included 402 solid barriers , it has to be fixed by based on organic polymers , with poly - women undergoing laparoscopic gyneco - suture. 93 saccharides being the most common logical adhesiolysis . Although AFS scores The efficacy of the Gore-Tex Surgical superordinate category. were apparently used , the net scores Membrane ® was examined after Strong emphasis is placed on prospec - were not given. The main result is myomectomies in 27 patients .94 Only tive, randomized controlled clinical trials expressed as “clinical success ”, which is patients with two separate incisions were with second-look intervention. These defined as “the percentage of patients in included ; one was treated with the enable the best possible evidence of effi - whom the number of sites with adhe - ePTFE membrane while the other was cacy based on the direct assessment of sions decreased by at least three or 30% left untreated. Using an adhesion score

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Table I Overview of randomized controlled trials on the prevention of peritoneal adhesion in gynecology with second-looks and a control group receiving saline solution, Ringer’s lactate (RL) solution or no treatment No. of Outcome Outcome Material Product name Indication Main outcome b Improvement c Significant Ref. patients a Control Intervention Removal of myomas or Icodextrin Adept ® 330 Score (mAFS) 8.4 8.1 4% No 87 endometriotic cysts

Icodextrin Adept ® Adhesiolysis 402 “Clinical success” 38% 49% 11% Yes 86

Gore-Tex Surgi - ePTFE Myomectomy 27 Score 7.6 1.0 87% Yes 94 cal membrane ORC Interceed ® Endometriosis resection 32 Adhesion- free patients 75% 13% 62% Yes 100

ORC Interceed ® Myomectomy 50 Adhesion- free patients 60% 12% 48% Yes 101

ORC Interceed ® Ovarian cystectomy 17d Adhesion- free outcome 76% 35% 39% Yes 102 23% 16% 7% (laparoscopy) (laparoscopy) (laparoscopy) ORC Not specified Intracapsular myomectomy 694 Rate of adhesions No 62 28% 22% 22% (laparotomy) (laparotomy) (laparotomy) ORC Interceed ® Endometriosis resection 40 Score 1.1 0.4 64% No 103

ORC Interceed ® Polycystic ovarian syndrome 21 d Adhesion incidence 33% 43% -10% No 106

ORC Interceed ® Polycystic ovarian syndrome 8d Score 6.7 9.9 -48% No 107 Adhesiolysis (with ORC Interceed ® 28 d Score 0.9 0.7 22% No 104 hydrocortisone instillation) Adhesiolysis on ovaries, ORC Interceed ® 66 d Severity score 4.9 6.8 -39% Yes 108 fallopian tubes, and fimbriae ORC Interceed ® Adhesiolysis 63 d Adhesion incidence 76% 41% 35% Yes 97

ORC Interceed ® Endometriosis resection 28 d Adhesion incidence 82% 50% 32% Yes 97

ORC Interceed ® Ovarian diseases 55 d Severity score 1.1 0.8 27% No 105 Removal of adhesions, HA HyaRegen ® myomas, ovarian cysts or 215 Score (mAFS) 0.9 0.3 67% Yes 125 endometriotic cysts HA Hyalobarrier Myomectomy 52 Score 2.1 2.1 0% No 126

HA Intergel ® Peritoneal cavity surgery 23 Score (AFS) Not specified Not specified Not specified Yes 122

HA Intergel ® Peritoneal cavity surgery 147 Score (mAFS) 1.3 0.5 54% Yes 123

HA Intergel ® Peritoneal cavity surgery 265 Score (mAFS) 2.3 1.3 43% Yes 124 Change of score HA/CMC Sepraspray ® Myomectomy 41 1.6 0.7 53% No 138 (mAFS) 2.4 (severity) 1.9 (severity) 21% (severity) HA/CMC Seprafilm ® Myomectomy 127 Score Yes 140 1.7 (extent) 1.2 (extent) 1.2 (extent) manuscript manuscript manuscript manuscript manuscript Modified 4DryField ® Endometriosis resection in Score in in in in 146 starch preparation preparation preparation preparation preparation PEG SprayGel ™ Myomectomy 66 Severity score 1.9 1.0 47% Yes 154

PEG SprayGel ™ Myomectomy 58 Score (mAFS) 2.6 1.1 58% Yes 155 Adhesiolysis, salpingotomy PEG SprayGel ™ 15 Score 2.4 1.2 50% No 156 and/or cystectomy 1.6 (severity) 0.8 (severity) 50% (severity) PEG SprayShield ™ Myomectomy 15 Score No 157 0.9 (extent) 0.6 (extent) 33% (extent) OxiPlex/AP Gel PEG Adnexal surgeries 49 Score (AFS) 15.8 9.1 42% Yes 158 or Intercoat Oxiplex/AP Gel PEG Resection of endometriosis 37 Score (AFS) 14.0 6.2 56% Yes 159 or Intercoat Oxiplex/AP Gel PEG Adnexal surgery 28 Score (AFS) 11.6 8.1 30% No 153 or Intercoat a: number of patients in the primary outcome evaluation; b: if an adhesion score was given, this was always used as the main outcome; c: calculated as (Con - trol-Intervention)/Control*100 for outcomes not measured in %,u and by direct subtraction for outcomes measured in %; bold values are adhesion score results; d: study used intra-patient controls (one side treated with the respective product and the other side served as an untreated control); thus, all patients belong to both groups. mAFS, modified American Fertility Society; ePTFE, expanded polytetrafluorethylene ; ORC, oxidized regenerated cellulose; HA, hyaluronic acid; HA/CMC, hyaluronate + carboxymethylcellulose; PEG, polyethylene glycol

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Peritoneal Adhesions and their Prevention - Current Trends KRÄMER/NEIS/BRUCKER/KOMMOSS/ANDRESS/HOFFMANN ranging from 0 to 11 , a statistically sig - which the highest number of RCTs patients without a barrier. They used a nificant reduction from 7.6 to 1.0 could (n=12) concerning gynecologic applica - four-point adhesion score from 0 to 3, be achieved. Haney et al . compared the tions have been published . However, only which was reduced from 1.1 to 0.4. Li impact of ePTFE (Gore-Tex Surgical four of them reported statistically signifi - and Cooke observed the effect of Inter - Membrane ®) and oxidized regenerated cant efficacy in comparison to untreated ceed ® after gynecologic adhesiolysis cellulose (ORC) (Interceed ®; Ethicon, controls; of the remaining eight, six did when hydrocortisone acetate solution Inc., Somerville, NJ, USA) after gyneco - not find any significant differences (750 mg/30 ml) was instilled into the logic adhesiolysis. 95 They used both between ORC and untreated controls peritoneal cavity before closure. 104 They products in 32 patients covering the left and two even found that the control was included 28 women, who had one side of and right pelvic sidewalls , respectively. significantly superior (one of them was the pelvic cavity covered with The same scoring system as in the afore - versus an active control). Two of the four Interceed ®, while the other was left mentioned study was used. While ePTFE trials describing significant efficacy were untreated. They scored adhesion severity again gave a score of 1.0, ORC gave a published in 1995 by Mais et al. , who on a scale from 0 to 3 , resulting in mean significantly higher score of 4.8. applied ORC in 16 women undergoing values of 0.9 for the controls and 0.7 for PTFE is among the most inert bioma - laparoscopic endometriosis surgery 100 the intervention group. In addition, the terials known, resisting biologic degrada - and in 25 women undergoing laparo - extent of adhesion was measured; the tion even after several years in vivo. scopic myomectomy, 101 respectively. mean was 38 mm 2 in the control and 16 However, the long-term implications of Both treatment groups were compared mm 2 in the intervention group. The leaving PTFE in the abdominal cavity to equally -sized untreated control authors noted that the combined use of remain unknown. 94 The need for groups . In the endometriosis study, Mais any intraperitoneal irrigants or instillants removal considerably limits its usage 96 et al. evaluated the adhesion incidence, might possibly lead to the displacement and could promote further adhesion for - which was reduced by 63%. In the of Interceed ®. mation after the required re-intervention myomectomy study , the number of adhe - In the fourth study with insignificant for product removal . Therefore, the pos - sion-free patients was evaluated, which improvement, in 55 patients with bilat - itive anti-adhesive effect of ePTFE is lim - was reduced by 48% . These reports did eral ovarian disease , one ovary was ited to the time between the initial not provide more detailed results regard - wrapped with Interceed ® while the other surgery and the re-intervention for prod - ing adhesion extent or severity. Sekiba was left uncovered. 105 Adhesion severity uct removal. examined the use of Interceed ® for infer - was scored from 0 to 3. Adhesion severi - tility , as well as endometriosis surgery. 97 ty was slightly reduced from 1.1 to 0.8 Oxidized regenerated cellulose This study included 63 infertility through Interceed ® treatment and the (ORC) patients, who underwent adhesiolysis adhesion area was reduced from 2.8 to Regenerated cellulose is manufac - surgery , and 28 women with severe 1.7 cm². The percentage of ovaries that tured from natural cellulose sources like endometriosis. In both populations, developed adhesions was significantly wood in a process that basically modifies Interceed ® was only used on one side of reduced from 75% to 53% . and rearranges its structure. Controlled the pelvic cavity , while the other served In the remaining four RCTs , ORC oxidation of the product leads to ORC, as a control. The incidence of adhesion led to a worse outcome than the respec - which can be manufactured into fabrics was reduced from 76% to 41% in the tive control groups, and in two of these for medical applications. The most com - infertility surgery group and from 82% (one against ePTFE and one against an monly known and used preparation of to 50% in the endometriosis surgery untreated control) this deterioration was ORC is Interceed ®, an absorbable off- group. The fourth positive examination statistically significant. Saravelos and Li white knitted fabric from Ethicon was performed in laparoscopic ovarian examined the application of Interceed ® (Somerville, NJ, USA) . Interceed ® cystectomy patients .102 In 17 patients, after standardized surgery for polycystic adheres to deperitonealized areas with - one ovary was treated with Interceed ®, ovarian syndrome. 106 In 21 women with out suturing and forms a soft , gelatinous while the other served as an untreated bilateral ovarian treatment , one ovary mass , which protects the tissue during control . Ovaries were free of adhesions was covered with Interceed ®, while the re-epithelialization. 97 According to its in 13 of 17 patients in the Interceed ® other was left untreated. The authors instructions for use, Interceed ® is group vs. six of 17 patients in the control found that the incidence of adhesions absorbed over 4 weeks. Apart from act - group . with Interceed ® treatment (43%) was ing as a physical barrier to isolate wound Four publications described RCT out - 10% higher (not significant) than that in sites , additional effects have been comes where the ORC -treated group the control group (33%). Greenblatt and ascribed to ORC. For example, in cell tended to achieve better results than the Casper 107 used the same approach in 8 culture experiments , it increased the tis - controls , but these differences were not women. They used the AFS score and sue plasminogen activator (tPA)/plas - statistically significant. obtained a mean score of 9.9 for the minogen activator inhibitor (PAI) 1 ratio Tinelli et al. examined a not explicitly Interceed ® side and 6.7 for the control in fibroblasts isolated from adhesion tis - specified ORC barrier after intracapsular side. Although the difference was not sues. 98 Furthermore, it reduced the myomectomy in 694 women. 62 The rate significant, it confirmed the negative secretion of inflammatory mediators by of adhesions was decreased from 23% to findings by Saravelos and Li. In a study acting on macrophages ’ ability to interact 16% in laparoscopic surgery and from on prevention of the reformation of with scavenger receptor ligands, another 28% to 22% in laparotomy. Wallwiener bilateral adhesions on ovaries, fallopian potential mechanism to decrease adhe - et al .103 studied the effect of Interceed ® tubes, and fimbriae in microsurgical sion formation. 99 in 20 women after endometriosis resec - operations for fertility, 108 66 women ORC is the adhesion barrier for tion and compared them to 20 control were treated with Interceed ® on one

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Gynecology SURGICAL TECHNOLOGY INTERNATIONAL Volume 38 side , while the other was left as an Hyaluronic acid Lundorff et al .123 used the mAFS score to untreated control. Adhesion severity Hyaluronic acid (HA) is a natural quantify adhesion development at 24 scores (0 to 4) were ascribed to each component of the extracellular matrix sites in 147 women . The score was sig - ovary, fallopian tube and fimbria , respec - that is also present in the peritoneal nificantly reduced from 1.3 to 0.5. Sepa - tively , during both interventions and fluid .118 Peritoneal mesothelial cells syn - rate evaluations for the different kinds of mean aggregates were calculated to thesize HA in vitro and it is thought to be procedures examined showed that the determine the difference between the involved in the regulation of fluid reten - reduction was significant for adhesiolysis first and second interventions; this was tion and the maintenance of structural (from 1.7 to 0.6) and ovarian procedures 4.9 in the control and 6.8 in the inter - integrity. 119 Hyaluronic acid has high (from 2.4 to 0.5) , but not for myomec - vention group , which reflects a statisti - water-binding capacities and forms a vis - tomies (0.8 vs. 0.3) or tubal procedures cally significant worsening under cous gel after water absorption. Unmod - (1.5 vs . 0.6). Johns et al . followed the treatment with Interceed ®. The authors ified HA is subject to rapid degradation same approach in 265 women .124 The also noted that meticulous hemostasis and is cleared from the site of adminis - median mAFS score was 2.3 in the con - should always be achieved before applica - tration within hours. 120 trols and 1.3 in the intervention group tion. If Interceed ® turns black after The most commonly known product (statistically significant). In addition to application, it has to be removed and that used unmodified HA is the discon - ionic cross -linking , there is also a possi - hemostasis must be re-established. Only tinued Sepracoat ® by Genzyme (Cam - bility for covalent cross -linking of HA . thereafter can a new piece of Interceed ® bridge, MA, USA). It was supposed to be This can be achieved without foreign be applied. As mentioned earlier , ORC applied , not after , but rather before and molecules through condensation to form gave statistically significant inferior during surgery as a temporary protective inter- and intra-molecular esters of HA , results after gynecologic adhesiolysis coating to reduce tissue damage and the in some of the carboxyl groups are ester - compared to ePTFE. 95 resulting adhesion formation . However, ified with hydroxyl groups of the same The aforementioned incompatibility no gynecologic second -look RCTs using and/or different HA molecules. This of Interceed ® with the presence of blood unmodified HA barriers have been pub - highly viscous product is called auto- has also been described in more detail : lished. cross -linked polysaccharide (ACP) gel. It clinical observations indicate that small The rapid clearance rate that makes also has a higher adhesivity and more bleedings are sufficient to allow blood to unmodified HA unsuitable for use as an prolonged residence time on the injured permeate the material , resulting in adhesion barrier that prevents postsurgi - surface than unmodified HA 120 and is fibroblasts growing along the strands of cal contact between injured areas can be resorbed by the body after approximately the clotted blood, followed by collagen improved through crosslinking. Addition seven days. Products based on auto- deposition , vascular proliferation , and of ferric ions (Fe 3+ ) leads to ionic bond cross -linked hyaluronic acid include finally adhesion formation through the cross -linking with the carboxylate groups Hyalobarrier by Anika Therapeutics Inc. barrier. 22,109 Related to this issue, it has of the hyaluronate. This leads to (Bedford, MA, USA) and HyaRegen ® by been noted that use after myomectomy increased viscosity and prolonged BioRegen Biomedical Co. Ltd. may be precluded as hemostasis at the intraperitoneal residence time . (Changzhou, China) . Liu et al . examined myomectomy site is rarely complete. 110 Direct comparison of the ionically the latter in 215 women undergoing In addition, in several animal studies , cross-linked approach with unlinked laparoscopic surgery for primary Interceed ® failed to prevent adhesion for - hyaluronic acid in animal studies showed removal of adhesions, myomas, ovarian mation. 91,111-116 In animal studies with that ferric hyaluronate gel was more effi - cysts, or endometriotic cysts. 125 Patients intact peritoneum, application of ORC cient than hyaluronic acid even when the were evaluated using the mAFS score at was shown to result in a sloughing of the concentration of hyaluronic acid was 24 sites, which yielded a median of 0.9 mesothelial layer of the peritoneum, increased to match that of the ferric in the saline solution-treated control which is an obligatory injury to all con - hyaluronate gel. 121 Products based on group and a significantly lower value of tacting peritoneal surfaces and subse - ionically cross -linked hyaluronic acid 0.3 in the intervention group. Mais et quent de novo adhesion formation. include Intergel by Lifecore Biomedical al .126 examined the effect of Hyalobarrier Possible explanations for this result (Chaska, MN, USA), a gel made of sodi - in 52 women undergoing laparoscopic include the acidity of the material , as well um hyaluronate, ionically cross -linked myomectomy. A non-significant number as activated leukocytes responsible for with ferric ion (0.5%), and adjusted to of treated women were free of adhesions degradation, which may function as a cel - isotonicity with sodium chloride solu - and the total adhesion score (Operative lular bridge leading to a common healing tion. To date , three gynecologic second- Laparoscopy Study Group Adhesion site and coalescing adhesions. Additional - look RCTs using ionically cross -linked Score) was 2.1 in both groups. Several ly , ORC elicits a peritoneal fluid inflam - HA gel have been published. In all cases, studies on intrauterine application of matory exudate characterized by large Intergel was used in patients undergoing ACP found contradictory results con - numbers of activated macrophages. 117 peritoneal cavity surgery ; they received cerning its efficacy at preventing adhe - The authors assumed that these issues either 300 mL of Intergel or RL as a sion, including positive 127-129 and might be responsible for the inferiority of peritoneal instillate at the end of surgery. negative 130,131 outcomes. ACP gel did ORC compared to ePTFE. Histological Thornton et al .122 used an adapted AFS not reduce adhesion formation in an ani - analyses of adhesions formed despite the score at 18 different sites in 23 women . mal peritonitis model, 132 an animal adhe - presence of ORC showed substantial Although the score was significantly sion induction model, 133 or an animal amounts of Interceed ® remnants in agglu - reduced in the intervention group, the ischemic button model .134 tination sites associated with a local results were not given as numerical val - The blended HA-based product inflammatory response. 91 ues, which complicates comparisons . Medicurtain (Shin Poong Pharmaceutical

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Co. Ltd. , Seoul, South Korea) combines monary embolism; however, fistula and the first 1-3 days . 4DryField ® PH has sodium hyaluronate with hydroxylethyl peritonitis occurred significantly more been examined in a RCT after the resec - starch (HES). The latter is a pharmaco - frequently in the Seprafilm ® group than tion of deep-infiltrating endometriosis in logical anti-coagulant that reduces the in controls. In a subpopulation of a second look design. 146 Adhesions were activity of several proteins in the coagu - patients in whom Seprafilm ® was scored with regard to their severity and lation cascade and increases prothrombin wrapped around fresh bowel anasto - extent , with a score based on the AFS time and partial thromboplastin moses, leak-related events, including score , and the incidence was evaluated as time .135,136 Therefore, Medicurtain can anastomic leak, fistula, peritonitis, well. The mean total adhesion score and only be applied when the application site abscess, and sepsis, occurred significantly the incidence were lower in the inter - is completely hemostatic , according to more frequently. In another controlled vention group. The manuscript that the product’s instructions for use . No clinical study in general surgery, Cohen describes this study is in preparation and gynecologic second -look RTCs on the et al. 142 observed that infection compli - the results will be published soon . A ret - use of HA/HES-based barriers have been cations (abscess and incisional wound rospective controlled study including 40 published . complications) were significantly more women who underwent adhesiolysis and , frequent with glycerol hyaluronate/car - in some cases, resection of endometriosis Hyaluronate + boxymethylcellulose than in an untreated and other pathologies , compared 4Dry - carboxymethylcellulose control group. Klinger et al. 143 reported Field ® with an untreated control group. (HA/CMC) intense peritoneal inflammation at the The results showed that the severity and This approach uses a combination of site of Seprafilm ® placement and a corre - extent of adhesions could be significantly two anionic polysaccharides, car - sponding foreign body granuloma reac - reduced. 147 In gynecological studies boxymethylcellulose and hyaluronate tion. Similar observations were reported without control groups , 4DryField ® (most commonly as sodium by Remzi et al. 144 David et al . reported showed a distinct reduction of adhesion hyaluronate), which have been modified an inflammatory reaction caused by formation by 80% after the resection of chemically. The mixture is available in extensive adhesion formation , as well as endometriosis, 69 and by 85% after the different forms ; as foils and as powder. a giant cell foreign body reaction resection of endometriomas. 148 Animal HA/CMC transforms into a gel after towards Seprafilm ®.137 Furthermore , in studies have also demonstrated that this being placed on the peritoneum , where several animal studies , Seprafilm ® failed product can reduce adhesions , with it is reabsorbed within about 7 days. 137 A to prevent adhesion formation. 91,115,134 reduction rates in comparison to well-known and extensively studied Furthermore, the handling of Seprafilm ® untreated controls of 88-100 %. 149,150 . preparation is Seprafilm ® adhesion barri - has been described as a major limitation , Additionally, a direct comparison to er by Baxter (Deerfield, IL, USA). As its since it is somewhat brittle and difficult Interceed ®, Seprafilm ® and Adept ® foil form significantly hampers laparo - to apply. 142 showed that it is significantly more effi - scopic application , a powder that comes cient than any of these .91 with a special spray applicator was devel - Modified starch oped under the name Sepraspray ®, but it Starch can be modified and cross - Polyethylene glycol (PEG) has apparently been discontinued. Fos - linked to improve its capabilities in med - Polyethylene glycol has been used for sum et al. 138 tested Sepraspray ® after ical applications. Most commonly , this is adhesion prevention in SprayShield ™ laparoscopic myomectomy in compari - done to produce hemostatic devices , but (Covidien plc, Dublin, Ireland), formerly son to an untreated control. They includ - there also is a product that combines this SprayGel ™ (Confluent Surgical Inc., ed 41 women and used the mAFS score. approach with the possibility for adhe - Waltham, MA, USA), a two-component They reported the scores as differences sion prevention, 4DryField ® PH. It system consisting of two different poly - between the first and second interven - comes in the form of a powder and , ethylene glycol-based fluids. 77 Further - tions: 1.6 in the control and 0.7 in the when applied as such , it acts as a hemo - more, composite adhesion barriers have intervention group, which were not sig - stat. It is hygroscopic and absorbs the been introduced: Oxiplex/AP Gel or nificantly different . Although Seprafilm ® watery components of blood , thereby Intercoat ®, a gel composed of polyethyl - has been studied extensively , most trials concentrating enzymes and cells partak - ene glycol and carboxymethyl cellulose, have been done in the field of general ing in blood clotting , resulting in acceler - and REPEL-CV ®, a polymeric film for surgery , and only a very few have ated hemostasis. For adhesion cardiac surgery consisting of polylactic addressed gynecologic indications. 139 The prevention, it has to be transformed into acid and polyethylene glycol. 151,152 The only RCT was performed by Dia - a gel with sodium chloride solution. This retention time of these products varies mond ,140 who examined adhesion reduc - can either be done extracorporeally , and greatly , from about 5 to 14 days for tion after uterine myomectomy in then the gel is applied directly , or the SprayGel ™ and SprayShield ™77 to 29 days comparison to an untreated control in powder is applied and then transformed for REPEL-CV 152 and 6 weeks or more 127 women. Both the mean uterine in situ through dripping with an irriga - for Oxiplex/AP Gel. 153 The results of adhesion severity (1.9 vs. 2.4) and tion system . The amount of saline used three RCTs for SprayGel ™ were promis - extent (1.2 vs. 1.7) scores were slightly can be varied , leading to gels of different ing. Mettler et al. 154,155 and ten Broek et but significantly reduced. Some safety viscosities adaptable to the specific al. 156 found a reduction of adhesion for - concerns have been expressed regarding requirements of the respective surgery. It mation after myomectomy and in the use of Seprafilm ®. In a comprehen - is absorbed after approximately seven patients with different gynecological sive RCT in general surgery including days, 145 which is the most obvious differ - pathologies, respectively. According to a 1791 patients, Beck et al .141 found no ence from starch-based hemostatic meta-analysis of the efficacy of difference in abscess incidence or pul - devices, which are all absorbed within SprayGel ™ by ten Broek et al. 156 based

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Gynecology SURGICAL TECHNOLOGY INTERNATIONAL Volume 38 on the three aforementioned RCTs, the firmed histologically, indicating capillary ePTFE-based membranes yielded odds ratio was 0.27 (95% CI 0.11 - dilatation and edema. 162 Although the remarkable results, with the highest 0.67) . In contrast, an experimental study authors also found increased mortality in reduction in all of the RCTs included by Rajab et al. 151 found only a minor dif - mice after the application of high doses with a score reduction of 87% , thus sig - ference in adhesion formation compared of Intercoat ®, they assumed that this nificantly outperforming ORC in a direct to an untreated control group. should not be a concern in humans . comparison . Nevertheless , they cannot SprayGel ™ was discontinued and be recommended for adhesion preven - replaced by SprayShield ™, which is simi - DISCUSSIODN ISCUSSION tion: the huge drawback of ePTFE is the lar but slightly modified, including a dif - requirement of a subsequent surgery ferent color and alterations that influence Many different approaches to reduce because it has to be removed .33,164 Not the time of absorption. 77 For post-operative adhesion formation have only would this be an avoidable surgical SprayShield ™, the results of only one been developed. Since there is no stan - intervention, it could again be a source RCT with second-look are available. 157 In dardized validation score , and indeed for adhesion formation , diminishing its this trial, SprayShield ™ did not prevent there are different adhesion classifica - original efficiency. Therefore, ePTFE is adhesion formation, contradicting the tions and distinctions in the interpreta - not commonly used for adhesion preven - promising results for its predecessor. tion of the results, a comparative tion nowadays. Contradictory results have also been assessment of the efficacy of the diverse ORC only yielded mediocre results found in five RCTs on Oxiplex/AP Gel adhesion prevention barriers is diffi - based on a comparison of the number of or Intercoat ®. A slight decrease in adhe - cult. 163 We tried to tackle this problem RCTs that found a statistically significant sion scores between the first and second by focusing on adhesion score results , reduction (four) to the number without adnexal surgeries from 11.9 to 9.1 was but a direct comparison is still limited a significant reduction (eight). In addi - found by Lundorff et al .158 Here, the since these scores are not available in all tion, even in RCTs with significant control group showed an increase in the studies. Even the main indicator, i.e., the results , the ORC groups showed a rather mean adhesion score from 8.8 to 15.8, statistical significance of the results, is large degree of remaining adhesion for - resulting in a significantly better adhesion not necessarily straightforward when mation and only one of them yielded score at second-look in the intervention two studies use different outcomes. Nev - more than 50% improvement. Also , group. Similar results were also obtained ertheless , since most studies do provide ORC is the only material that showed a in a trial on endometriosis surgery by adhesion score results and there are plen - significant worsening when compared to diZerega et al. 159 In that study, the mean ty of them in gynecologic surgery , it is an untreated control in a RCT. It has also adhesion score of adnexa in the interven - still possible to obtain a clear picture of been reported that Interceed ® seems to tion group slightly decreased from 8.4 to the efficacy of the relevant adhesion bar - aggravate rather than prevent adhesion 6.2, whereas it increased from 10.0 to riers. formation if blood is present , and its 14 .0 in the control group. When com - Apart from its efficacy regarding tis - effectiveness and safety have not been paring the adhesion scores from the sec - sue separation , an ideal adhesion barrier demonstrated in laparoscopic surgery. 140 ond-look surgeries between the should persist for about seven days, be Hyaluronate-based barriers that intervention and control groups, this dif - absorbed/metabolized without initiating included HA ionically cross -linked ference was statistically significant. 159 In inflammatory reactions, not be influ - through Fe(III) seem to work better than contrast, the results from an RCT by enced by the presence of blood , and nei - those based on auto -cross -linked HA. Of Young et al. 153 do not indicate a reduc - ther compromise wound healing nor the two ACP trials, only one gave statisti - tion of adhesion formation through the promote bacterial growth. 140 cally significant results and the briefly use of Oxiplex/AP Gel or Intercoat ®. In Although the solution form of icodex - mentioned intrauterine trials showed this study, adhesion scores remained sta - trin comes with the advantage of com - inconclusive outcomes as well. The dif - tistically identical between first (8.0) and plete coverage in every case, convincing ference does not necessarily have to be second (8.1) surgeries. Only a slight, not results are not available , as only one of due to the different cross -linking statistically significant , advantage when the two RCTs yielded statistically signifi - processes , since the low-viscosity gel of comparing the second-looks of both cant results , albeit with only a slight dif - the former formulation is used as a cavity groups was found , since in the control ference between the two groups (11% instillant with volumes of about 300 mL , adnexa , the score somewhat increased improvement) , and a main outcome was while the latter is a gel of higher viscosity from 8.0 to 11.6. Two RCTs on not commonly used. Overall, the princi - that is applied directly (and only) to the intrauterine application of Oxiplex/AP ple of physical wound separation through wound surfaces in small volumes of Gel or Intercoat ® found contradictory (semi-) solid barriers outperforms the around 10 mL. The lower viscosity alone results concerning its adhesion preven - principle of hydroflotation . One of the likely does not explain a better protec - tion efficacy, with positive 160 and nega - main requirements for an adhesion barri - tive effect , indicating that the volume is tive 161 outcomes. The long resorption er is that it should remain in place an important factor that influences effica - time of Oxiplex/AP Gel or Intercoat ® throughout the critical 7-day period of cy . and REPEL-CV raises concerns about peritoneal healing. 140 Accordingly, the Both HA/CMC RCTs describe their possible foreign body reactions. In an quick absorption of icodextrin solution application in myomectomy. Although experimental study with Intercoat ®, from the peritoneal cavity can be one of these did not give statistically sig - marked redness of the peritoneal cavity assumed to be a major issue. When the nificant results, the small number of and increased intraperitoneal fluid were product is gone by day four , the critical patients could have been a factor. In the found one week after application of the 7-day period for peritoneal healing is not other, larger RCT , a significant reduction product. 162 This observation was con - entirely covered . was achieved . As Sepraspray ™ has been

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Peritoneal Adhesions and their Prevention - Current Trends KRÄMER/NEIS/BRUCKER/KOMMOSS/ANDRESS/HOFFMANN discontinued , the results with HaemoCer ™ (BioCer Entwicklungs- toneal adhesion formation more tangi - Seprafilm ™ are of greater interest. How - GmbH, Bayreuth, Germany) , for ble. ever, with significant improvements of patients undergoing open and laparo - 167 CONCLUSION AND OUTLOOK 21% and 29 %, respectively, the corre - scopic gynecological surgeries. Like CONCLUSION AND OUTLOOK sponding RCT was only moderately suc - Arista ™, HaemoCer ™ was found to be cessful . Furthermore, a Cochrane ineffective in preventing adhesions. 167 The rationale for the routine use of database systematic review from 2008 The short retention time (only about 1 -3 adhesion prevention devices has been a criticized the statistical analyses used in days ) of starch powder-based hemostats subject of discussion for decades. To the study and suggested that the results like Arista ™ and HaemoCer ™ is likely to date , high efficacy is expected from Gore should be interpreted with caution. 165 In be an important reason for their reduced Tex Surgical Membrane and 4DryField ®. addition, the decent coverage of very efficacy. The former device, however, is non- uneven surfaces with Seprafilm ™ can be Of the seven RCTs that used different absorbable and its removal requires addi - quite difficult, especially for the inexpe - PEG-based barriers, only four achieved tional surgery . The latter device is a rienced surgeon , and it cannot be applied statistically significant results . As all resorbable barrier. Intergel ®, which is laparoscopically, 140 which severely limits three products mentioned here had a also absorbable, achieved an improve - its applicability . trial in which they failed to give a signifi - ment of 43% to 54%. Secondary end - The modified starch-based device cant improvement, the proof of their point results regarding the severity of 4DryField ® gave remarkable results for efficacy is inconclusive . Improvement adhesion -related complications after bar - an absorbable barrier . The possibility of was between 30% and 58% with rier usage are still scarce and should be a using it as a combined product for hemo - SprayGel ™, which represents the best focus of future RCTs. In general , the stasis and adhesion prevention is intrigu - results among the PEG-based devices. routine use of effective adhesion barriers ing and could be one of the factors that While , on one hand , the easy applicabili - in addition to adhesion-minimizing sur - contributes to its promising outcome . ty of PEG-based gels is an advantage, its gical practices is highly recommended , as The basis for adhesion formation is the long resorption time has the disadvan - adhesion prevention is pivotal and development of fibrin strands and grids tage of possible foreign body reactions. A approaches other than barrier application between two surgically injured sites. The further issue of products like SprayGel ™ fall short. A review of the economic main source of the fibrin is blood, which is the rather high cost .33 impact of adhesions and their prevention is why meticulous hemostasis is a corner - In general, adhesion barriers are usu - has shown that the health care system stone for effective adhesion prevention ally tolerated well . No clear evidence of benefits greatly from the use of effective and why minor bleeding after surgery a negative influence on wound healing or adhesion barriers , which is associated may limit the efficacy of anti-adhesion promotion of bacterial growth has been with considerable cost savings . STI agents . This issue might be solved by the found for any of the barriers described AUTHORS’ DISCLOSURES application of a modified starch-based here . The possible , but rare , side effects AUTHORS’ DISCLOSURE powder for hemostasis . Accordingly, the of some of the products seem to be justi - combination of hemostasis and adhesion fiable considering the possible benefits, BK gratefully acknowledges assistance prevention in a single device is intriguing as adhesion formation may have far more with writing and editing this manuscript and of practical value. 166 Several different serious consequences. In addition , the from PlantTec Medical GmbH (Lüneb - modified starch powder-based devices use of an adhesion barrier does not con - urg, Germany . The other authors declare are available on the market , but, except siderably prolong surgery. Except for that there are no conflicts of interest. for 4DryField ®, there are all intended cases with extensive preparation require - only for hemostasis. Considering the ments or, e.g. , foil-like membranes that ReferenceRs EFERENCES apparent similarity of these hemostatic have to be rolled up to be applied 1. Ellis H, Harrison W, Hugh TB. The healing of peri - agents, their use for adhesion prevention through a trocar and then cautiously toneum under normal and pathological conditions. Br J might seem promising. However, a rolled out again, adhesion barriers can Surg 1965;52:471-6. recent study that directly compared normally be placed quickly. Considering 2. Hubbard Jr TB, Khan MZ, Carag Jr VR, Albites VE, 4DryField ® to another starch-based the patient ’s quality of life, more studies Hricko GM. The pathology of peritoneal repair: its ™ relation to the formation of adhesions. Ann Surg 1967; hemostat , Arista AH (Becton Dickin - with secondary endpoint results, such as 165(6):908-16. son, Franklin Lakes, NJ, USA ), showed development of postoperative pain or 3. Shapiro L, Holste J-L, Muench T, diZerega G. ™ Rapid reperitonealization and wound healing in a pre - that adhesion formation in the Arista - fertility rates, would be desirable . How - clinical model of abdominal trauma repair with a com - treated group was not reduced , but ever, the quantification of parameters posite mesh. Int J Surg 2015;22:86-91. rather equal to that in the untreated con - like quality of life and pain remains diffi - 4. Raftery AT. Cellular events in peritoneal repair: a ® review. In: Pelvic Surgery - Adhesion Formation and trol group, whereas 4DryField signifi - cult, as several other factors are relevant Prevention. diZerega GS, DeCherney AH, Diamond cantly reduced adhesion formation and the impact of remaining adhesion MP, et al., eds. New York, NY: Springer; 1997: 3-10. 149 5. diZerega GS. Peritoneum, peritoneal healing, and compared to both other groups . The formation even in a case with significant - adhesion formation. In: Peritoneal Surgery. diZerega authors stated that starch-based hemo - ly effective adhesion reduction remains GS, ed. New York, NY: Springer; 2000:3-37. stats generally do not have the capability 6. Lucas PA, Warejcka DJ, Young HE, Lee BY. For - unclear. Therefore, more emphasis on mation of abdominal adhesions is inhibited by antibod - to function as effective adhesion preven - secondary endpoint results during fol - ies to transforming growth factor-beta1. J Surg Res tion devices and , instead, the effective - low-up, as well as the presentation of 1996;65(2):135-8. ness depends on the specific properties results so that they can be compared 7. diZerega GS, Campeau JD. Peritoneal repair and 149 post-surgical adhesion formation. Hum Reprod Update of the individual product. This notion between studies are desirable . This 2001;7(6):567147-55. is supported by clinical results for anoth - would help make the diverse but diffuse 8. diZerega GS, DeCherney AH, Diamond MP, et al. eds. Pelvic Surgery - Adhesion Formation and Preven - er starch-powder-based hemostat , risks resulting from post-operative peri - tion. New York, NY: Springer; 1997.

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9. Raftery AT. Regeneration of parietal and visceral Obstetrician & Gynaecologist 2004;6(S2):1-16. tion-based study of the surgical workload and econom - peritoneum: an electron microscopical study. J Anat doi.org/10.1576/toag.6.2.1.26993 ic impact of bowel obstruction caused by postoperative 1973;115(Pt 3):375-92. 34. Parker MC, Wilson MS, van Goor H, et al. Adhe - adhesions. Br J Surg 2003;90(11):1441-4. 10. diZerega GS. Biochemical events in peritoneal tis - sions and colorectal surgery - call for action. Colorec - 57. Tingstedt B, Isaksson J, Andersson R. Long-term sue repair. Eur J Surg Suppl 1997;577(1):10-16. tal Dis 2007;9 Suppl 2:66-72. follow-up and cost analysis following surgery for small 11. Hellebrekers BWJ, Kooistra T. Pathogenesis of 35. Ellis H, Moran BJ, Thompson JN, et al. Adhesion- bowel obstruction caused by intra-abdominal adhe - postoperative adhesion formation. Br J Surg 2011; related hospital readmissions after abdominal and sions. 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Gynecology SURGICAL TECHNOLOGY INTERNATIONAL Volume 38 to prevent postsurgical peritoneal adhesions: In vitro J Biomater Appl 2015;30(4):463-71. surgery: Results of a randomized controlled pilot and in vivo characterization. Biomaterials 2016;96:33- 146. Krämer B, Kommoss S, Hoffmann S, et al. Eine study. Gynecol Surg 2012;9(1):29-35. 46. prospektive, randomisierte, kontrollierte klinische 157. Tchartchian G, Hackethal A, Herrmann A, et al. 134. van Steensel S, Liu H, Vercoulen TF, et al. Pre - Studie zur Adhäsionsprophylaxe nach Resektion von Evaluation of SprayShield Adhesion Barrier in a single vention of intra-abdominal adhesions by a hyaluronic Endometriose mit 4DryField PH. Geburtshilfe Frauen - center: randomized controlled study in 15 women acid gel; an experimental study in rats. J Biomater heilkd 2020;80(10):e156. (in German) undergoing reconstructive surgery after laparoscopic Appl 2020:885328220954188. 147. Ziegler N, Torres de la Roche AL, de Wilde RL. myomectomy. Arch Gynecol Obstet 2014;290(4): 135. Strauss RG, Stump DC, Henriksen RA. Hydrox - Adhäsionsprophylaxe nach gynäkologischen Adhäsiol - 697-704. yethyl starch accentuates von Willebrand’s disease. yse-Operationen mit 4DryField PH - eine kontrol - 158. Lundorff P, Donnez J, Korell M, Audebert AJ, Transfusion 1985;25(3):235-7. lierte, retrospektive, monozentrische Studie mit Block K, diZerega GS. Clinical evaluation of a vis - 136. Warren BB, Durieux ME. Hydroxyethyl starch: Second-look-Laparoskopien. Geburtshilfe Frauen - coelastic gel for reduction of adhesions following safe or not. Anesth Analg 1997 Jan;84(1):206-12. heilkd 2020;80(10):e162-e163. gynaecological surgery by laparoscopy in Europe. Hum 137. David M, Sarani B, Moid F, Tabbara S, Orkin BA. 148. Torres-de la Roche LA, Devassy R, de Wilde MS, Reprod 2005;20(2):514-20. Paradoxical inflammatory reaction to Seprafilm: case et al. A new approach to avoid ovarian failure as well 159. diZerega GS, Coad J, Donnez J. 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