Collagen membrane/fleece composite film reduces adhesions in the presence of bleeding in a rabbit uterine horn model.

OBJECTIVE: Determination of efficacy in presence of bleeding of CDS, a collagen/membrane fleece composite, in a rabbit uterine horn simple abrasion model. DESIGN: Randomized, controlled, and blinded study involving standard abrasion of the uterine horns with induction of moderate mesouterine bleeding. SETTING: Research laboratory. PATIENT(S): New Zealand White rabbits. INTERVENTION(S): No treatment (surgical control), CDS film, or INTERCEED barrier (negative reference control). MAIN OUTCOME MEASURE(S) AND RESULT(S): The extent (percent length uterine horn) with adhesions was assessed after 29 or 30 days. Adhesions formed in surgical controls to an extent (85.6% +/- 4.6%) consistent with historic data for this model. INTERCEED failed to reduce adhesions (78.1% +/- 7.7%) indicating that the test conditions of inadequate hemostasis were validated. CDS film, despite this inadequate hemostasis, reduced the extent of adhesions (31% +/- 7.4%; P<.01). Both the tenacity (P=.0008) and degree of uterine convolution (P=.000003) was reduced by CDS film but not by INTERCEED. CONCLUSION(S): Under conditions of inadequate hemostasis CDS effected a reduction in adhesion development. CDS may be useful adjuvant for procedures where hemostasis is difficult to achieve.

Effect of different barriers of oxidized regenerated cellulose (ORC) on cecal and sidewall adhesions in the presence and absence of bleeding.

Adhesion formation after bowel surgery is a significant problem. The objective of this study was to evaluate two adhesion barriers composed of oxidized regenerated cellulose (ORC) in a model of bowel surgery, with and without bleeding. Ceca of female New Zealand White rabbits were abraded with gauze and a 3 x 5 cm patch of peritoneum and underlying muscle was excised from the right sidewall. Animals were randomized to receive no treatment, INTERCEED Barrier (Ethicon, Inc.), or neutralized INTERCEED (nTC7). ORC fabrics were applied to the excision site. Seven days later the percentage of the site and length of cecum with adhesions were estimated. The study was replicated in the presence of blood by nicking small vessels near the site sufficient to saturate the fabrics with blood. With hemostasis, the percentage of the sidewall with adhesions was reduced (p < .01) from 63.2 +/- 14.7% in controls (n = 6) to 4 +/- 2.7% with INTERCEED Barrier (n = 6) and 3 +/- 1.2% (n = 5) with nTC7. With bleeding, however, control (n = 5) levels of adhesions (67 +/- 17.5%) were reduced significantly with nTC7 (5.5 +/- 4%, n = 4; p < .01), but not INTERCEED Barrier (34.2 +/- 18.4%, n = 4). Similar trends were observed when the extent of adherent cecum was examined, since the cecum was the main site of adherence to the sidewall. However in the presence of blood, there was no effect of INTERCEED Barrier on cecal adhesions. We conclude that with hemostasis, both absorbable fabrics of ORC reduced adhesion formation between the injured cecum and abdominal sidewall. The effectiveness of INTERCEED Barrier, but not nTC7, was reduced but not eliminated in the presence of bleeding. This confirms similar observations in models of gynecologic surgery.

Metaanalysis of the safety and efficacy of an adhesion barrier (Interceed TC7) in laparotomy.

OBJECTIVE: To evaluate the safety and efficacy of an oxidized, regenerated, cellulose adhesion barrier (Interceed TC7) in the reduction of pelvic adhesions. STUDY DESIGN: Clinical studies published or completed by December 31, 1994, evaluating the barrier used at laparotomy were considered for a metaanalysis. RESULTS: Of 10 studies (n = 560) identified, data from 7 (n = 389) met the inclusion criteria for determining the reduction in the incidence of adhesions and 5 (n = 311) for determining the reduction in adhesion extent (raw surface area after adhesiolysis). There was a 24.2 +/- 3.3% difference in the incidence of adhesions (P < .001) between barrier-treated and untreated sites. Adhesion-free outcomes were 1.5-2.5 times more likely at barrier-treated sites than at sites with good surgical technique alone (odds ratio = 2.89; 95% confidence interval = 2.15-3.90). Barrier treatment resulted in a greater reduction (1.1 +/- 0.4 cm2) in adhesion extent (raw surface area) than good surgical technique alone (P < .001). Four adverse events were recorded; they were typical of those seen after surgery. No event was considered to be definitely related to the use of the barrier. CONCLUSION: The barrier significantly reduced the incidence and extent of adhesions as compared with no treatment, confirming the conclusion from individual studies that it is safe and effective in pelvic laparotomy surgery.

The rates of adhesion development and the effects of crystalloid solutions on adhesion development in pelvic surgery.

OBJECTIVE: To document rates of adhesion development after abdomino-pelvic surgery, stratified by adhesion type, access method, and use of crystalloid solution instillates. DESIGN: Reports from a MEDLINE search (1/1/1966-12/18/1996) detailing rates of adhesion development and meeting the inclusion criteria were subjected to meta-analysis. SETTING: Meta-analysis. PATIENT(S): Patients undergoing abdomino-pelvic surgery. INTERVENTION(S): Intraperitoneal crystalloid solution instillates. MAIN OUTCOME MEASURE(S): Percentage adhesion-free outcome in patients ("patients") or surgical sites ("sites"). RESULT(S): Adhesion-free outcome (sites) was lowest for reformed (26.3% laparotomy; 14.3% laparoscopy), higher for de novo 1b (direct trauma) (45.2% laparotomy, 37.2% laparoscopy), and highest for de novo 1a (indirect trauma) adhesions (82.4% laparoscopy). Crystalloid solution instillates reduced adhesion-free outcome at sites (45.2% versus 20% de novo 1b adhesions in laparotomy) and in patients (43.5% versus 19.9% reformed, laparotomy; 71.7% versus 25% de novo 1b, laparoscopy). CONCLUSION(S): Adhesion-free outcome was lowest for reformed, higher for de novo 1b, and highest for de novo 1a adhesions. Surprisingly, it was lower in laparoscopy than in laparotomy for de novo 1b and reformed adhesions. Crystalloid instillates did not increase adhesion-free outcome. Although limited by the retrospective and heterogeneous nature of the data, these conclusions nonetheless provide a basis on which to formulate future hypotheses.

A randomized clinical trial of oxidized regenerated cellulose adhesion barrier (Interceed, TC7) alone or in combination with heparin.

OBJECTIVE: To compare the efficacy of heparin-saturated oxidized regenerated cellulose absorbable adhesion barrier, Interceed (TC7; Johnson and Johnson Medical Inc., New Brunswick, NJ) to oxidized regenerated cellulose alone for the prevention of postoperative adhesions. DESIGN: Clinical trial. By random assignment, one ovary was wrapped in oxidized regenerated cellulose, and the contralateral ovary was wrapped in oxidized regenerated cellulose saturated with a heparin solution (1,000 U/mL). PATIENT(S): Forty women with defects on both ovaries due to adhesiolysis and/or ovarian cystectomy. MAIN OUTCOME MEASURE: Adhesion formation and raw ovarian surface area were assessed at second-look laparoscopy 10 days to 16 weeks later. RESULT(S): At the second-look laparascopy-adhesions were present on 52.5% (21/40) of the ovaries treated with oxidized regenerated cellulose plus heparin and in 65% (26/40) of the contralateral ovaries treated with oxidized regenerated cellulose alone. For ovaries treated with oxidized regenerated cellulose plus heparin, the raw surface area was reduced from 9.41 +/- 1.27 cm2 (mean +/- SE) at laparotomy to 1.33 +/- 0.52 cm2 at second-look laparoscopy. The corresponding figures for ovaries treated with oxidized regenerated cellulose alone were from 10.24 +/- 1.08 to 1.92 +/- 0.54 cm2, respectively. The mean difference between the reductions in raw surface area (85.9% for oxidized regenerated cellulose plus heparin; 81.3% for oxidized regenerated cellulose alone) was not significantly different from zero (difference = - 0.24 cm2; 95% confidence interval = -2.56 to 3.04). CONCLUSION(S): Adding heparin did not enhance significantly the adhesion-reducing capacity of oxidized regenerated cellulose adhesion barrier when applied to ovarian surfaces after cystectomy and/or ovariolysis at laparotomy. This conclusion is subject to the possibility of a type II error.

Time-dependent effect of tolmetin sodium in a rabbit uterine adhesion model.

Tolmetin is a nonsteroidal anti-inflammatory drug (NSAID) that reduces adhesion formation in several animal models after a single intraperitoneal (i.p.) dose delivered at the time of surgery. We set out to determine the period during which tolmetin could prevent adhesions. Adhesions were induced in New Zealand White rabbits (2-3 kg) by abrading the uterine horns and removing their mesouterine vasculature. Tolmetin sodium (1 mg/5 ml saline) was given at various times relative to the start of surgery as a single dose i.p. One week later adhesions were assessed using a standard scoring system (0 = no adhesions; 1 = light adhesions involving both uterine horns; 2 = more tenacious adhesions to bowel or bladder; 3 = tenacious adhesions to bowel and bladder partly immobilizing the uterus; 4 = completely fixed horns adherent to bowel and bladder). Scores were arranged in ascending rank order. Mean rank positions were calculated for each group and compared against controls (Dunnett's multiple comparison). Tolmetin sodium was most effective when administered within 1 hour of surgery. Mild effects could still be observed after 4 hours and the effect diminished after 24 hours. When these effects are compared to the temporal biochemical and cellular effects of tolmetin obtained in related studies, the data support the hypothesis that tolmetin reduces adhesions at least in part by modulating fibrinolytic activity of resident macrophages and macrophages present in the early postsurgical period.

Fibrinolytic drugs prevent pericardial adhesions in the rabbit.

Epicardial adhesions are believed to form secondarily to impaired pericardial fibrinolytic activity. This activity was reconstituted in a rabbit pericardial adhesion model with single doses of the fibrinolytic agents tissue plasminogen activator (t-PA), t-PA analog (Fb-Fb-CF), and streptokinase (SK), resulting in reductions in the extent and tenacity of adhesion formation. Adhesions of the median strip of the anterior cardiac surface were reduced in area from 89% (n = 22) in controls, to 28% (n = 5) by treatment with Fb-Fb-CF (0.94 mg), and to 49% (n = 7) by treatment with SK (93,750 IU). A modified fabric of oxidized regenerated cellulose (mTC7) used to deliver the agent to the cardiac surface did not interfere with the activity of these agents (Fb-Fb-CF 19%, n = 14; SK 33%, n = 7). t-PA (0.94 mg) was also found to reduce adhesion formation in combination with mTC7 (4%, n = 4), although the appearance of significant postoperative bruising and bleeding resulted in a decision to terminate the treatment of further animals with t-PA with and without mTC7. Postoperative bruising, bleeding, and swelling, to a lesser extent, were associated with SK and Fb-Fb-CF. Despite the efficacy of the these fibrinolytic drugs further work is required to assess their safety before they are used clinically.

Effect of thrombin-induced hemostasis on the efficacy of an absorbable adhesion barrier.

Serosal injury, bleeding and fibrin deposition are major factors in the development of surgical adhesions; meticulous hemostasis is desirable but not always achievable. The effects of thrombin on adhesion formation and the performance of Interceed Barrier were tested in separate series using a standard model and two levels of bleeding: an "oozing" model in which rabbit uterine horns were scraped to produce uncontrolled punctate bleeding and a "bleeding" model, in which four small blood vessels nicked on the ligament to each horn produced heavier bleeding. Substantial clots in the bleeding model were not removed. Adhesions, assessed after two weeks, were not worsened by the use of thrombin to control bleeding. While Interceed Barrier alone did not reduce adhesions at sites of bleeding, achieving hemostasis with thrombin and then applying Interceed Barrier significantly reduced adhesions. The effect was not achieved by applying thrombin to previously blood-soaked Interceed Barrier. The efficacy of Interceed Barrier applied after achieving hemostasis was further improved by moistening it with heparin. Achieving hemostasis at a bleeding site with thrombin facilitates the efficacy of Interceed Barrier.

A biomechanical study of tendon adhesion reduction using a biodegradable barrier in a rabbit model.

Adhesion formation associated with tendon surgery is a widespread problem in which a healing tendon becomes adherent via scar tissue to surrounding structures such as bone, muscle, skin, tendon sheath, or other tendons. A model is described in which adhesions were generated reproducibly between the plantaris and Achilles tendons of the rabbit using a partial tenotomy, a Bunnel suture, and immobilization. Using this model, the effect of an absorbable barrier, INTERCEED (TC7), on adhesion formation was investigated. This material, which is a fabric comprised of oxidized regenerated cellulose, was found to diminish significantly the extent and severity of intertendinous adhesions, assessed both mechanically and histologically. No evidence of a foreign body reaction was observed.

Transforming growth factor-beta (TGF beta) is chemotactic for human monocytes and induces their expression of angiogenic activity.

TGF beta stimulates human blood monocyte migration, with peak migratory response occurring consistently at a concentration of 16-100 fg/ml. Checkerboard analysis revealed both chemotactic and chemokinetic components to this response. At higher concentrations (10-100 pg/ml), TGF beta stimulated expression of angiogenic activity by monocytes. While mRNA for TNF alpha was undetectable in resting monocytes, high steady state levels of TNF alpha mRNA were rapidly induced in TGF beta-treated monocytes. TGF beta is secreted by a number of neoplastic cells as well as normal cells such as platelets and lymphocytes. TGF beta may recruit monocytes from the circulation, and subsequently activate them to express angiogenic activities such as TNF alpha, thus playing an important role in wound repair, inflammation and tumor growth.

The Gemini conundrum--a problem of unpairable data: statistical comparison of ratios each derived from two separately estimated parameters.

In biological studies it may be necessary to compare ratios of two separately estimated parameters under test and control conditions. Since it is not always possible technically to obtain paired data for the two parameters, how does one take account of their variances? By extending previously described approximations in a modified t-test we present a BASIC computer program which may be used to solve this problem.

Macrophage-induced angiogenesis is mediated by tumour necrosis factor-alpha.

Macrophages are important in the induction of new blood vessel growth during wound repair, inflammation and tumour growth. We show here that tumour necrosis factor-alpha (TNF-alpha), a secretory product of activated macrophages that is believed to mediate tumour cytotoxicity, is a potent inducer of new blood vessel growth (angiogenesis). In vivo, TNF-alpha induces capillary blood vessel formation in the rat cornea and the developing chick chorioallantoic membrane at very low doses. In vitro, TNF-alpha stimulates chemotaxis of bovine adrenal capillary endothelial cells and induces cultures of these cells grown on type-1 collagen gels to form capillary-tube-like structures. The angiogenic activity produced by activated murine peritoneal macrophages is completely neutralized by a polyclonal antibody to TNF-alpha, suggesting immunological features are common to TNF-alpha and the protein responsible for macrophage-derived angiogenic activity. In inflammation and wound repair, TNF-alpha could augment repair by stimulating new blood vessel growth; in tumours, TNF-alpha might both stimulate tumour development by promoting vessel growth and participate in tumour destruction by direct cytotoxicity.