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Most data were available for the rabbit uterine simple abrasion model, which was generally predictive of clinical outcome for most gynecologic clinical models. Important technical differences between models - even in the same species - might determine the behaviors and interpretation of the model. Cecal/sidewall models in rats or rabbits were found...
Contexts in source publication
Context 1
... uterine horn models A number of adhesion models involving various injuries to the uterine horns of rabbits have been described (Table 1). Many of these bear little in common with each other except a name. ...Context 2
... responses were censured at 100%. Variants of the UH model (letters A -F) are as described in Table 1. When more than one reference is shown, averages have been taken. ...Context 3
... responses were censured at 100%. Variants of the UH model (letters A -F) are as described in Table 1. When more than one reference is shown, averages have been taken. ...Similar publications
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Citations
... Another reason why investment in adhesion barriers may have waned is because a number of product failures have only been evident at the clinical trial phase. Companies have failed to take advantage of the correlations we have observed between data generated in animals and data generated in humans and the selection of appropriate decision-making models [153]. Notable failures for which correlations were available before the conduct of the clinical trial include ...
1 SUMMARY
The purpose of this paper is to review the progress being made to tackle adhesions, both in terms of advances and “retreats” and to list some of the challenges for the future.
1.1 Are adhesions still an extensive and costly problem?
Advances: Several pharmacoeconomic analyses highlight the cost and burden of adhesions. While certain adhesion barriers reduce adhesion formation, there is evidence that adhesion barriers may improve other surgical outcomes only in some reports.
Retreats: The cost of in-patient procedures for adhesions in the USA outpaced that of other inpatient hospital services by 27% from 1997 to 2013.
Challenges: There were over 350,000 in-patient procedures related to abdominopelvic adhesions in 2013 (USA) with aggregate direct costs between $6.2 and $12 billion, equivalent to 20%-40% of the entire budget of the US National Institutes of Health (NIH). These costs do not include outpatient care, work losses, family disruptions, pain management or adhesion-related infertility. While we have achieved some success, the adhesions “community” must emulate the success that groups advocating for other medical conditions have achieved by educating the public that adhesion related complications can happen to anyone undergoing surgery. We still lack reliable data that address whether adhesion barriers improve surgical outcomes. Much of the data on the cost and burden of adhesions comes from the USA and also Europe. More data are needed to assess the extent of the problem around the world.
1.2 Is adhesion-related bowel obstruction still a problem?
Advances: Recently issued professional guidelines for the management of obstruction may reflect an increased awareness about adhesions and willingness and ability to tackle them. Mortality associated with adhesion-related bowel obstruction has declined in the USA from a high of 2421 in 2000 to 1545 in 2013. There is some evidence that adhesion barriers may influence SBO-related measures, but more data are required.
Retreats: Although adhesions research in general has declined, research related to adhesive bowel obstruction is scant.
Challenges: Adhesion related bowel obstruction remains a significant and costly problem with 97,945 (all) and 76,805 (principal) discharges in the US in 2013. These accounted for 95% of the costs of all abdominopelvic adhesions discharges. We must develop better prevention strategies for patients most at risk of obstruction and for those who have already obstructed.
1.3 Is adhesion-related infertility still a problem?
Advances: We are beginning to understand the economic impact of treating adhesion-related infertility secondary to other procedures.
Retreats: Because of advances in assisted reproductive technologies, little progress has been made in improving adhesion-dependent fertility outcomes after surgery.
Challenges: Due to cost and ethical issues of assisted reproductive technologies, adnexal adhesiolysis may be making a resurgence in popularity.
1.4 Is adhesion-related pain still a problem?
Advances: We are now clarifying the relationship between adhesions and pain. There is enough of an association between adhesions and pain to justify their prevention initially, but due to central sensitization, neural cross-talk and the development of CAPPS (Complex Abdomino-Pelvic and Pain Syndrome), adhesiolysis may not be as successful as would be expected if the only reason for pain was a direct, local irritant effect of adhesions. Wearable therapeutic ultrasound appears helpful for pain in adhesions patients.
Retreats: Lack of good quality data and misinterpretation of some existing data has added to the confusion about the use of adhesiolysis for pain.
Challenges: We must understand better the complex relationship between adhesions and pain. Non-surgical approaches should certainly be used before resorting to surgery but since the therapeutic effect of laparoscopy combined with adhesiolysis may be great enough to justify its performance, adhesiolysis should nonetheless remain an option for ARD patients. We must address the fibrosis that occurs at the “base” of the adhesion to address nerve entrapment which may account for adhesion pain.
1.5 Have adhesion barriers achieved their potential?
Advances: Creation of ICD9-CM code 99.77 has allowed tracking of adhesion barrier usage, but shows a slow rate of their adoption, reaching only about 12% for some procedures in the USA.
Retreats: Little progress has been made developing effective adhesion barriers that can eliminate adhesion-related bowel obstruction, infertility and pain, as well as reduce costs. Regulatory, legal, integrity or safety issues with Intergel, Seprafilm and Adcon have added to the hurdles of the regulatory climate that impede investment in development of anti-adhesions products in the USA. This has had global repercussions.
Challenges: Adhesion barriers have not achieved their potential. Government and private investment in adhesions research must be encouraged to ensure the smooth development of these sorely needed products. Regulatory pathways must be redefined to meet the challenges of approving the barrier use in the context of simultaneous measures such as conditioning.
1.6 Progress in developing anti-adhesion products
Advances: Despite the adverse effect of the US business and regulatory climate on the development of anti-adhesion products, companies around the world have taken on the challenge of developing anti-adhesion products. Advances have been made with improved formulations of hyaluronic acid or PEG-based products. Advances have been made in understanding the interaction between hypoxia, inflammation, fibrinolysis, genetic factors, oxidative stress and adhesions. There are some promising clinical data regarding “peritoneal conditioning” which uses a modified insufflation gas, heparin lavage, an adhesion barrier and peri-operative steroids.
Challenges: We must develop anti-adhesion barriers that can be placed around the bowel without fear of ileus, abscess, infection or dehiscence. Barriers must be capable of laparoscopic delivery and function in the presence of bleeding. Barriers must not potentiate tumor growth. Drug-device combinations, or biologically based products will likely break the limit of efficacy seen with the current generation of barriers. We must develop drug-polymer products that can both act as adhesion barriers and provide pharmacological modulation of adhesions or fibrosis. We must look to gene therapy, cell therapy and tissue engineering approaches to preventing adhesions. We must develop a good method of imaging adhesions non-invasively and quantitatively. We must strive to reduce the absolute incidence of adhesions rather than reduce the extent or severity of adhesions based on an abstract scoring system.
1.7 Non-Barrier reduction of adhesions and their consequences
Advances: Whether laparoscopy improves adhesions-related outcomes remains unclear. More widespread use of warm and humid insufflation gases, or modification of gases in other ways may be needed to settle this question. The banning of powdered gloves which provides a source of peritoneal irritation is an advance. We are beginning to understand the role of manual techniques to treat or prevent adhesions.
Retreats: Hysterectomy is still performed for pain in large numbers despite the lack of evidence to support its use. Treating these patients non-surgically would remove a large number of patients from the pool of people at-risk from adhesions and other sequelae. While great efforts are being made to limit the use of opioids for chronic pain, little progress has been made on expediting development and regulatory and reimbursement approval for non-opioid alternatives.
Challenges: We need to understand how lifestyle and medical factors affect conditions related to adhesions. Smoking, overweight status and exercise are associated with gynecological adhesions, although the causal relationship is not known. Pre-operative modification of a patient’s inflammatory state can help to improve surgical outcomes. This would include smoking cessation, dietary modification, use of anti-oxidants and use of anti-inflammatory drugs. Prediction of a patient’s adhesion propensity may permit preventative approaches to be tailored to the patient. We must develop a multidisciplinary approach to treating the wide range of problems experienced by adhesions patients – pain, obstruction, bowel, urinary, genital and musculoskeletal issues.
1.8 Treating and Preventing ARD as a subset of CAPPS
Advances: Perhaps the biggest advance that has been made is in the understanding the holistic nature of the problem of adhesions in terms of Adhesion Related Disorder (ARD) and Complex Abdomino-Pelvic & Pain Syndrome (CAPPS), and how many symptoms experienced by adhesions patients may be a manifestation of central sensitization or functional somatization. This has lead to the development of a wearable therapeutic ultrasound device to treat many painful symptoms which can obviate the need for surgery for pain in the absence of defined pathology. Although adhesiolysis should remain an option for adhesions patients in pain, non-surgical alternatives such as wearable ultrasound and manipulative techniques should be attempted first.
1.9 What do adhesions patients want us to know?
Patients were asked through social media “What is the single most important thing you would like to say to doctors and scientists working on adhesions?” Their answers fell into the following categories:
1. Please understand how this has affected my life.
2. Please understand that I really hurt and that I sometimes feel all alone.
3. Please learn and teach about adhesions and their consequences.
4. My most important symptoms are pain and constipation.
5. Please improve diagnostic methods for adhesions.
6. Learn how to prevent adhesions and treat patients.
1.10 Conclusion
We have come a long way in understanding the etiology and pathogenesis of adhesions. We see signs that adhesion barriers may provide clinical benefit and we have started to understand the nature of pain and related conditions. We have better strategies for dealing with obstruction and for treating adhesion-related pain but we still have much to do.
... However, these were preliminary studies and cannot be extrapolated to human beings. In fact, even immunological properties of the animals in the same species are not identical [43]. But small animal models such as the rat are the most frequently used models for screening experiments. ...
Evaluation of treatment attempts in postoperative adhesion formation is pivotal for the prevention of several morbidities including infertility, pelvic pain, bowel obstruction, and subsequent intraoperative complications. The purpose of this systemic review was to assess the literature on the rat uterine horn model for adhesion formation and treatment modalities to prevent adhesion in the most frequently used experimental animal model.
We performed a systemic review of publications from January 1(st) 2000 to December 31(st) 2013 via a PubMed search. A high number of agents were evaluated for the prevention of postoperative adhesion formation in the rat uterine horn model.
According to most of the studies, adjuvants such as antiinflamatuars, antiestrogens, antioxidants were effective to prevent adhesion formation.
Prevention of adhesion formation is pivotal and numerous types of agents were described in the literature were summarized in this review.
... Specifically, the rabbit model has been shown to be useful for adhesion related studies. 31 For this study, we do not attempt to extend our animal data to clinical outcomes in human subjects. One potential method that we could use for future clinical studies would be noninvasive adhesion detection via abdominal ultrasonography. ...
Objective:
Manipulation of cotton operating room towels within the abdominal cavity in open abdominal surgery has been associated with the formation of peritoneal adhesions. In a rabbit model, the use of standard cotton operating room towels is compared to the Lap Pak, a silicone bowel-packing device, to determine the potential for reducing the risk of adhesions.
Methods:
Thirty rabbits were randomly assigned to 3 groups. The rabbits underwent a sham surgery with incision only (n = 10), placement of operating room towels (n = 10), or placement of a Lap Pak (n = 10). After 14 days, the rabbits were sacrificed and the peritoneal cavity explored for adhesions. The number, tenacity, ease of dissection, and density of adhesions were recorded, and the adhesions quantitatively graded using a Modified Hopkins Adhesion scoring system.
Results:
The operating room towel group had an average adhesion score of 2.5, and 8 (80%) rabbits developed adhesions. The sham group had an average adhesion score of 0.3 and one rabbit (10%) developed adhesions. The Lap Pak group had an average adhesion score of 0.2 and 1 rabbit (10%) developed adhesions. The frequency and severity of adhesions in the operating room towel group were significantly greater from that of the baseline sham group. There was no significant difference between the Lap Pak and sham groups.
Conclusions:
In this rabbit laparotomy model, the use of the Lap Pak to retract the bowels resulted in significantly fewer adhesions compared to cotton operating room towels. Lap Pak may be beneficial for bowel packing in general abdominal surgeries.
... The rabbit uterine horn simple abrasion model was performed essentially as described by Wiseman et al. (8) with or without the bleeding modification. This model has been used extensively for the determination of efficacy of putative antiadhesion agents, and good correlations exist between data obtained in animals and that obtained clinically (21). ...
... The efficacy of Adhexil appears superior to that of Seprafilm, Interceed, and Spray-Gel. Given historic correlations in the uterine horn model between animal and clinical data (21), and the additional ability of Adhexil to control bleeding, there is justification to proceed with the further investigation of Adhexil as an adhesion barrier. ...
To compare the efficacy of a fibrin preparation supplemented with tranexamic acid (Adhexil) with that of established devices, and to determine whether its effect is limited to the site of application.
Rabbit uterine horns were abraded in nonbleeding and bleeding variants of an established adhesions model. In a separate study, a sidewall excision with approximation of the abraded cecum was added. Animals randomly received Adhexil at both, neither, or either loci.
Laboratory study.
Seventy-two female New Zealand White rabbits (Oryctolagus cuniculus).
Adhexil, Seprafilm or SprayGel and Interceed.
The extent of adhesions was evaluated 13 to 16 days after surgery.
Adhexil reduced adhesions (15 +/- 7%; 15 +/- 4%) compared with controls (74 +/- 13%; 78 +/- 9%) in the bleeding and nonbleeding models, respectively. The reductions resulting from the use of Seprafilm (39 +/- 17%; 34 +/- 14%) or SprayGel (61 +/- 18%; 43 +/- 14%) (n = 4) were not statistically significant. In the bleeding model, Interceed (48 +/- 15%) reduced adhesions only modestly.
In the combined uterine and sidewall model, Adhexil reduced selectively the extent and incidence of adhesions. The absolute and relative performance of Adhexil in an established adhesions model and in the presence of bleeding justifies its further investigation.
... However, to be useful in evaluating the clinical potential of a new substance or device, any animal model should ideally be shown to respond to established adhesion production methods and antiadhesion interventions in a manner similar to humans, otherwise the applicability of the conclusions regarding the utility of intervention in that model may be spurious. 12 However, none of the mouse models have been validated using a substance with demonstrated adhesion prevention properties in humans. This paper discusses a simple, fast, and reliable technique for abdominal adhesion development in the mouse which we have validated using a hyaluronan/carboxymethylcellulose barrier (HA/CMC) currently in clinical use. ...
Introduction: Most initial trials of antiadhesion technologies are currently carried out in rats or rabbits. This paper describes a simple, reliable technique for producing intraperitoneal adhesions in the mouse. This model has been validated using a hyaluronan/carboxymethylcellulose (HA/CMC) barrier (Seprafilm, Genzyme, Somerville, NJ) currently in clinical use.
Methods: Adult, FVB mice were anesthetized with isoflurane. Celiotomy was performed in each mouse and the cecum and abdominal wall were abraded with sandpaper in a standardized manner. The mice either received no treatment or the cecum was wrapped in the HA/CMC membrane. Treatment groups were assigned, after abrasion, by coin toss. One (1) week later, the mice were euthanized and the adhesions were scored by two trained investigators blinded to the treatment group of each animal and the other investigator's adhesion score.
Results: Maximum adhesion grades were significantly lower (p = 0.009, Wilcoxon rank-sum) for the HA/CMC group (median = 0; s = 1.21; n = 18) than for the control group (mean = 2; s = 0.85; n = 24). The risk of any adhesion formation for the HA/CMC group was only half (relative risk [RR] = 0.51, 95% confidence interval [CI] = 0.30-0.87) as large as the risk of adhesion formation in the control group. Eight (8) mice (16%) died during the experiment. The risk of death was 8 times higher for mice treated with HA/CMC membrane than for the controls (RR = 7.7; 95% CI = 1.0-57), suggesting that treatment with HA/CMC could have increased the risk of mortality.
Conclusions: This simple technique for adhesion formation is reliable and allows fast throughput of animals. The extent of adhesion prevention with HA/CMC membrane suggests that trials of adhesion prevention technologies in this model system may mirror those seen in humans.
The purpose of this article is to review progress in the field of abdominopelvic adhesions and the validity of its two underlying assumptions: (1) The formation of adhesions results in infertility, bowel obstruction, or other complications. Reducing or avoiding adhesions will curb these sequelae. (2) “Adhesions” is a monolithic entity to be tackled without regard to any other condition.
Evidence is discussed to validate the first assumption. We reviewed progress in the field by examining hospital data. We found a growing trend in the number and cost of discharges for just two adhesion-related diagnoses, and the low usage of adhesion barriers appears in at most 5% of appropriate procedures. Data from an Internet-based survey suggested that the problem may be partly due to ignorance among patients and physicians about adhesions and their prevention.
Two other surveys of patients visiting the adhesions.org Web site defined more fully adhesion-related disorder (ARD). The first survey (N = 466) described a patient with chronic pain, gastrointestinal disturbances, an average of nine bowel obstructions, and an inability to work or maintain family or social relationships. The second survey (687 U.S. women) found a high (co-) prevalence of abdominal or pelvic adhesions (85%), chronic abdominal or pelvic pain (69%), irritable bowel syndrome (55%), recurrent bowel obstruction (44%), endometriosis (40%), and interstitial cystitis (29%).
This pattern suggests that although “adhesions” may start out as a monolithic entity, an adhesions patient may develop related conditions (ARD) until they merge into an independent entity where they are practically indistinguishable from patients with multiple symptoms originating from other abdominopelvic conditions such as pelvic or bladder pain. Rather than use terms that constrain the required multidisciplinary, biopsychosocial approach to these patients by the paradigms of the specialty related to the patient's initial symptom set, the term complex abdominopelvic and pain syndrome (CAPPS) is proposed.
It is essential to understand not only the pathogenesis of the “initiating” conditions but also how they progress to CAPPS. In our ARD sample, not only was the frequency of women with hysterectomies (56%) higher than expected (21 to 33%), but also the rates of the “initiating” conditions was 40 to 400% higher in patients with hysterectomies than in those without. This may represent increased surgical trauma or the loss of protection against oxidative stress. Related was the higher frequency of ARD patients reporting hemochromatosis (HC; 5%) than expected (~0.5%) and the higher rates (20 to 700%) of initiating conditions in patients with HC than in those without HC. Together with findings related to the toxicity of Intergel, these findings raise the possibility that heterozygotes for genes regulating oxidative stress are at greater risk of developing surgical complications as well as more severe and progressive conditions such as CAPPS.
