Role of Substance P-Dependent Chemotactic Signaling in Postoperative Adhesion Formation.

BACKGROUND: Postoperative adhesions are a potentially life-threatening complication of abdominal surgery. We previously showed that substance P (SP), acting through the neurokinin-1 receptor (NK-1R), is an important early mediator of adhesiogenesis through its regulation of the tissue plasminogen activator/plasminogen activator inhibitor-1 (PAI-1) fibrinolytic system. SP also mediates neurogenic inflammation by recruiting inflammatory leukocytes, such as neutrophils and macrophages. Our objective was to determine the role of SP-dependent chemotactic recruitment of these inflammatory cells through the CXCR2 in postsurgical adhesion formation. MATERIALS AND METHODS: A mouse cecal cauterization model was used to generate intra-abdominal adhesions. Protein and mRNA levels of the chemokines CXCL1 and CXCL2 and their receptor CXCR2 were measured at 3 h and 6 h after surgery in peritoneal tissue and in peritoneal lavages in response to antagonists for the SP receptor and CXCR2, and in IFN-γ knockout mice. RESULTS: Postsurgical adhesion formation was inhibited by both an antagonist to NK-1R and an antagonist to CXCR2. Expression levels of neutrophil chemokines and CXCR2 in peritoneal tissue peaked 3-6 h after surgery and partially depended on SP and IFN-γ, one of its downstream mediators. An NK-1R antagonist inhibited SP-mediated increases in the expression of the PAI-1 inhibitory component of the fibrinolytic system, but the CXCR2 antagonist had no effect. CONCLUSIONS: Postsurgical adhesiogenesis involves upregulation of chemokine signaling that is partially SP- and IFN-γ-dependent. However, the adhesiogenic properties of chemokine signaling are not mediated through the inhibition of fibrinolysis with PAI-1, as was previously shown for SP.

Neurokinin-1 Receptor Deficiency Improves Survival in Murine Polymicrobial Sepsis Through Multiple Mechanisms in Aged Mice.

OBJECTIVE: Substance P (SP) is a neuropeptide that contributes to a proinflammatory state by binding to the neurokinin 1 receptor (NK-1R). Limiting this interaction has been shown to attenuate the acute inflammation. Our hypothesis was that NK-1R activation would contribute to the morbidity and mortality of sepsis in a model using mice genetically deficient in the NK-1R. METHODS: To investigate the role of the SP/NK-1R axis in a murine model of sepsis, cecal ligation and puncture (CLP) in NK-1R deficient and wild type (WT) aged mice was performed. Acute inflammation was assessed by measuring circulating cytokines and clinical parameters. RESULTS: Deletion of the NK-1R results in improved survival following CLP (NK-1R knockout mice survival = 100% vs. WT = 14%). A reduction in the inflammatory cytokines interleukin (IL) 6, macrophage inflammatory peptide 2, and IL-1 receptor antagonist, improved hemodynamic parameters, and increased neutrophilia were present in the NK-1R-deficient mice after CLP compared with WT mice. CONCLUSIONS: These data confirm the hypothesis that eliminating the SP/NK-1R interaction in a highly lethal murine model of sepsis leads to decreased morbidity and mortality through multiple mechanisms.

Combined intraoperative administration of a histone deacetylase inhibitor and a neurokinin-1 receptor antagonist synergistically reduces intra-abdominal adhesion formation in a rat model.

BACKGROUND: Intra-abdominal adhesions are the most frequent postoperative complication after abdominopelvic surgery. Our laboratory has previously shown that an intraoperative peritoneal lavage containing either the histone deacetylase inhibitor valproic acid (VPA) or a neurokinin-1 receptor antagonist (NK-1RA) reduced adhesions by approximately 50% in a rat model. The objective of this study was to determine whether the combination of these 2 drugs was more effective in reducing adhesions than either alone. METHODS: Rats underwent laparotomy with creation of peritoneal ischemic buttons to induce adhesions. A single dose of VPA (25 mg/kg), NK-1RA (50 mg/kg), a combination of both, or 0.9% saline was lavaged intraperitoneally just before wound closure. On postoperative day 7, adhesions were quantified. To investigate early mechanisms of adhesiogenesis, adhesions were created as described and adhesive button tissue was harvested at 30 minutes and 3 hours postoperatively and fibrinogen and vascular endothelial growth factor (VEGF) protein levels, both indices of peritoneal extravasations, were determined by Western blot analysis. Peritoneal fluid was collected in similar experiments at 30 minutes, and 3 and 6 hours to measure fibrinolytic activity, an index of the ability of the peritoneum to degrade fibrinous adhesions. RESULTS: The coadministration of VPA plus NK-1RA reduces adhesions by 72.6% relative to saline (P < .001); this reduction was greater than either compound alone (P < .001). Peritoneal fibrinolytic activity was significantly increased at 3 and 6 hours postoperatively in animals administered the combination therapy versus saline (P = .01). VPA plus NK-1RA significantly decreased fibrinogen and VEGF protein levels at 3 and 6 hours compared with saline controls. CONCLUSION: These results suggest that a combined pharmacologic approach targeting multiple adhesiogenic pathways provides optimal adhesion prevention.

The neurokinin 1 receptor regulates peritoneal fibrinolytic activity and postoperative adhesion formation.

BACKGROUND: Intra-abdominal adhesions are a common source of postoperative morbidity. Previous studies in our laboratory have shown that a neurokinin 1 receptor antagonist (NK-1RA) reduces abdominal adhesion formation and increases peritoneal fibrinolytic activity. However, the cellular pathway by which the antagonist exerts its effects is unclear, as cultured peritoneal mesothelial cells exposed to the NK-1RA show increases in fibrinolytic activity despite having very low expression of neurokinin 1 receptor (NK-1R) messenger RNA and protein. Our aim was to determine whether the NK-1R plays an essential role in the adhesion-reducing effects of the NK-1RA, or if the NK-1RA is acting independently of the receptor. METHODS: Homozygous NK-1R knockout mice and age matched wild-type mice underwent laparotomy with cecal cautery to induce adhesions. At the time of surgery, mice received a single intraperitoneal dose of either NK-1RA (25 mg/kg) or saline alone. Adhesion severity at the site of cecal cautery was assessed on postoperative day 7. In a separate experiment, peritoneal fluid was collected from wild type and NK-1R knockout mice 24 h after laparotomy with cecal cautery and administration of either NK-1RA or saline. Tissue plasminogen activator levels, representative of total fibrinolytic activity, were then measured in peritoneal fluid. RESULTS: In wild-type mice, NK-1RA administration significantly decreased adhesion formation compared with saline controls. Among the NK-1R knockout mice, there was no significant reduction in adhesion formation by the NK-1RA. Fibrinolytic activity increased 244% in wild-type mice administered NK-1RA compared with saline controls; however, the NK-1RA did not raise fibrinolytic activity above saline controls in NK-1R knockout mice. CONCLUSIONS: These data indicate that the NK-1R mediates the adhesion-reducing effects of the NK-1RA, in part, by the upregulation of peritoneal fibrinolysis, and suggest that the NK-1R is a promising therapeutic target for adhesion prevention.

Histone deacetylase inhibitors decrease intra-abdominal adhesions with one intraoperative dose by reducing peritoneal fibrin deposition pathways.

BACKGROUND: We previously demonstrated that postoperative peritoneal injury and inflammation contribute to adhesiogenesis. Recent evidence suggests that in addition to their role of interfering with the acetylation status of nuclear histone proteins, histone deacetylase inhibitors (HDACIs) including valproic acid (VPA) can target nonhistone proteins to resolve inflammation and modulate immune cells. We hypothesized that HDACIs could reduce adhesions. METHODS: Seventy-two rats underwent laparotomy with creation of 6 peritoneal ischemic buttons to induce adhesions. A single intraperitoneal (IP) dose of 50 mg/kg VPA was administered intraoperatively, whereas controls received vehicle. To evaluate the timing, 25 rats underwent ischemic button creation with either an intraoperative or a delayed IP dose of VPA at 1, 3, or 6 hours postoperatively. On postoperative day 7, adhesions were quantified. To investigate mechanisms, ischemic buttons were created in 24 rats and either VPA or saline was administered in 1 intraoperative dose. At 3 or 24 hours later, peritoneal fluid was collected and fibrinolytic activity measured. Alternatively, button tissue was collected 30 minutes postoperatively to measure tissue factor, fibrinogen, and vascular endothelial growth factor (VEGF) by real-time polymerase chain reaction or Western blot. RESULTS: A single intraoperative dose of VPA reduced adhesions by 50% relative to controls (P < .001). Delayed dosing did not reduce adhesions. In operated animals, peritoneal fibrinolytic activity was not different between groups. Tissue factor mRNA was downregulated by 50% (P = .02) and protein by 34% (P < .01) in animals administered VPA versus saline. VPA decreased fibrinogen protein by 56% and VEGF protein by 25% compared with saline (P = .03). CONCLUSION: These findings suggest that VPA rapidly reduces the extravasation of key adhesiogenic substrates into the peritoneum. A single, intraoperative intervention provides an ideal dosing strategy and indicates an exciting new role for HDACIs in adhesion prevention.

Is pyloric gland metaplasia in ileal pouch biopsies a marker for Crohn's disease?

BACKGROUND: Approximately 5-10 % of ulcerative colitis (UC) patients who undergo ileal pouch-anal anastomosis (IPAA) will develop postoperative complications such as refractory pouchitis or a change in diagnosis to Crohn's disease (CD). Serological markers and histologic aspects of the pouch such as pyloric gland metaplasia (PGM) have been associated with a risk for these complications. METHODS: Twenty-eight IPAA patients with either CD of the pouch or chronic pouchitis (cases) and 36 IPAA controls who experienced a normal postoperative course were originally consented. Of these 64 subjects, 22 cases and 17 controls had histopathologic and serologic data available and were subsequently enrolled. Demographic and clinical data were entered into a database, blood analyzed for serological markers (Prometheus Labs, San Diego, CA) and biopsies of the pouch and the afferent limb reviewed by two GI pathologists. RESULTS: Of the cases, 55 % (12/22) had evidence of PGM in their pouch and/or small bowel biopsies, as compared to 12 % (2/17) of the controls (p = 0.006). Of 13 subjects with CD, 77 % (10/13) were found to have PGM versus subjects with chronic pouchitis in which 22 % (2/9) were found to have PGM (p = 0.03). There was a trend of ASCA positivity (both IgG and IgA, p = 0.20) and of higher ASCA titer levels (p = 0.07) with postoperative complications. CONCLUSION: This study suggests that the presence of ileal pouch PGM is associated with postoperative complications and favors a diagnosis of CD over UC with chronic pouchitis.

Early versus late adhesiolysis for adhesive-related intestinal obstruction: a nationwide analysis of inpatient outcomes.

BACKGROUND: Classical teaching advocates watchful waiting for 2 days before operating on adhesive-related intestinal obstructions (AIOs). Our aim was to compare the clinical and cost outcomes of early versus late adhesiolysis for AIOs. DESIGN: Patients undergoing adhesiolysis for AIOs from the 2007 Nationwide Inpatient Sample were stratified to early (≤2 days from admission) vs. late (>2 days) adhesiolysis. The primary outcome was in-hospital mortality and secondary outcomes were post-operative complications (POCs), post-operative length of stay (PLOS), and in-hospital cost. RESULTS: From 5,443 patients who underwent adhesiolysis for AIOs, 53 and 47 % underwent early and late adhesiolysis, respectively. Late adhesiolysis patients were older (65.0 vs. 60.1 years) and more co-morbid compared to the early group (p < 0.05). After adjustment with propensity score methods, late adhesiolysis patients had no difference in mortality (odds ratio [OR] 0.95, 95%-confidence intervals [CI] 0.67-1.36, p = 0.79) or POCs (OR 1.01, 95%CI 0.89-1.14, p = 0.91) compared to the early group, but had 9.8 % increased PLOS and 41.9 % increased in-hospital cost (p < 0.001). CONCLUSIONS: The 2-day limit of watchful waiting is not associated with increased mortality or POCs for those patients undergoing adhesiolysis for an AIO. Late adhesiolysis, however, was associated with significantly increased PLOS and in-hospital cost compared to early adhesiolysis.

Substance P is an early mediator of peritoneal fibrinolytic pathway genes and promotes intra-abdominal adhesion formation.

BACKGROUND: The substance P (SP) or neurokinin-1 receptor pathway has been implicated in intra-abdominal adhesion formation, in large part through its effects on peritoneal fibrinolysis. This study investigates the role of SP as an early mediator of the messenger RNA (mRNA) expression of key components of the peritoneal fibrinolytic system and other fundamental adhesiogenic pathways. MATERIALS AND METHODS: Intra-abdominal adhesions were surgically induced in 28 rats using the ischemic button model. mRNA levels of tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), hypoxia-inducible factors (HIFs) 1α and 2α, and vascular endothelial growth factor A (VEGF-A) were measured in adhesive button tissue taken at time 0 and 1, 3, 6, 12, and 24h after surgery in rats receiving an intraoperative peritoneal bolus (25mg/kg) of a neurokinin-1 receptor antagonist (NK-1RA) or saline. Peritoneal fluid fibrinolytic activity was measured in peritoneal lavages taken at the same time points. RESULTS: SP levels increased (P≤0.05) within 1h postoperatively followed by an increase (P≤0.05) in tPA mRNA expression from 3 to 6h after surgery along with a striking increase (P≤0.05) in PAI-1 mRNA expression from 3 to 12h. NK-1RA administration further increased (P≤0.05) tPA mRNA expression and significantly blunted the increase in PAI-1 mRNA levels. The NK-1RA increased (P≤0.05) fitbrinolytic activity in peritoneal fluid at 3, 12, and 24h after surgery. HIF-1α and VEGF-A mRNA expressions increased from 3 to 12h (P≤0.05) and from 1 to 3h (P≤0.05) after surgery, respectively, whereas HIF-2α mRNA expression steadily decreased. NK-1RA delayed the rise in HIF-1α mRNA and ablated the changes in HIF-2α and VEGF-A mRNAs. CONCLUSIONS: SP is a pleiotropic early regulator of mRNA levels of key adhesiogenic mediators after surgery, suggesting that it may be a viable therapeutic target.

Plasminogen activator inhibitor-1 is increased in colonic epithelial cells from patients with colitis-associated cancer.

BACKGROUND: Patients with long-term ulcerative colitis are at risk for developing colorectal cancer. METHODS: Archival formalin-fixed paraffin-embedded tissue from ulcerative colitis patients who underwent a colectomy for high-grade dysplasia or carcinoma was examined for changes in expression of plasminogen activator inhibitor-1 (PAI-1) as well as other mediators of inflammation-associated cancer. Epithelia from areas of colons that showed histologic evidence of carcinoma, high-grade dysplasia, and epithelia that were not dysplastic or malignant but did contain evidence of prior inflammation (quiescent colitis) was microdissected using laser capture microscopy. mRNA was extracted from the microdissected tissue and PCR array analysis was performed. To extend our findings, PAI-1 protein levels were determined using immunohistochemistry. RESULTS: The mRNA expression of PAI-1 is increased 6-fold (p=0.02) when comparing the carcinoma group to the quiescent colitis group; increases were also observed in NFKB2, REL, SRC, and VEGFA. The protein levels of PAI-1 are increased by 50% (p<0.001) in high-grade dysplasia and by 60% (p<0.001) in carcinoma when compared to the quiescent colitis group. CONCLUSIONS: The increase in PAI-1 in high-grade dysplasia and carcinoma suggests a functional role for PAI-1 in malignant transformation in colitis-associated cancer. PAI-1 could also prove a useful diagnostic marker to identify patients at risk for neoplasia and it may be a useful therapeutic target to treat colitis-associated cancer.

ASCA IgG and CBir antibodies are associated with the development of Crohn's disease and fistulae following ileal pouch-anal anastomosis.

BACKGROUND: For ulcerative colitis (UC) patients undergoing ileal pouch-anal anastomosis (IPAA), postoperative complications include chronic pouchitis and development of Crohn's disease (CD) of the pouch. AIMS: The aim of this study was to determine if serologic markers obtained postoperatively are associated with the development of complications in UC patients after IPAA. METHODS: A retrospective chart review was conducted of UC patients with IPAA were tested for expression of serologic markers. Complications abstracted from medical records included postoperative fistula, CD of the pouch, chronic pouchitis, and diversion or excision of the pouch. RESULTS: 142 patients were enrolled, 44 of whom developed complications. Positive serologic profiles for ASCA IgG and anti-CBir1 markers were found to be associated with the development of any complication, (P = 0.017 and P = 0.002, respectively). A positive anti-CBir1 test was also found to be associated with CD of the pouch and/or fistula formation (P < 0.001). Similarly, both ASCA IgG and anti-CBir1 titers were significantly associated with postoperative IPAA complications (P = 0.034 and P = 0.001, respectively), and anti-CBir1 titers were associated with CD of the pouch and/or fistula formation (P < 0.001). Complications developed after a median follow-up of 216 months (range 1-264). CONCLUSIONS: ASCA IgG and anti-CBir1 markers were associated with the development of complications after IPAA, specifically fistulae and/or CD of the pouch. The ability to identify patients at high risk for adverse outcomes may allow for early aggressive therapy, which may decrease the rate of pouch failure. A prospective study of patients with preoperative serology is ongoing.

A sprayable hyaluronate/carboxymethylcellulose adhesion barrier exhibits regional adhesion reduction efficacy and does not impair intestinal healing.

BACKGROUND: While bioresorbable solid barriers such as Seprafilm® prevent adhesions, their efficacy is limited to sites of application. The aim of this study was to assess the effectiveness of the sprayable adhesion barrier Sepraspray® in preventing adhesions to sites of direct application and to remote sites. METHODS: Intraabdominal adhesions were induced in 30 rats by creating three ischemic buttons on each side of a midline incision. To assess efficacy, Sepraspray (5 mg/button) or Seprafilm (1 cm(2)/button) was applied over three buttons on one side of the peritoneum. Operated control animals received no treatment. On day 7, adhesions were scored as percent of buttons with adhesions. To assess safety, 81 rats underwent a colonic transection repaired with an end-to-end anastomosis. Both barriers were applied circumferentially to anastomoses. Controls received no product. The integrity of healing anastomosed colonic wounds was assessed by burst pressure and tensile strength at days 3, 5, and 7 postoperatively. RESULTS: The direct application of both Sepraspray and Seprafilm significantly (p < 0.001) reduced adhesion formation compared to controls. While Seprafilm had no remote effect on adhesion formation, Sepraspray significantly (p < 0.001) reduced adhesion formation to contralateral ischemic buttons. Neither barrier affected anastomotic integrity at any time point. CONCLUSIONS: Sepraspray has widespread efficacy throughout the peritoneum in reducing adhesions without compromising intestinal healing. Furthermore, this sprayable alternative offers the potential for easier intraabdominal application.

LITAF mediation of increased TNF-α secretion from inflamed colonic lamina propria macrophages.

Dysregulation of TNF-α in lamina propria macrophages (LPM) is a feature of inflammatory bowel diseases (IBD). LPS-Induced-TNF-Alpha-Factor (LITAF) is a transcription factor that mediates TNF-α expression. To determine whether LITAF participates in the mediation of TNF-α expression in acutely inflamed colonic tissues, we first established the TNBS-induced colonic inflammation model in C57BL/6 mice. LPM were harvested from non-inflamed and inflamed colonic tissue and inflammatory parameters TNF-α and LITAF mRNA and protein levels were measured ex-vivo. LPM from TNBS-treated mice secreted significantly more TNF-α at basal state and in response to LPS than LPM from untreated mice (p<0.05). LITAF mRNA and protein levels were elevated in LPM from TNBS compared with untreated animals and LPS further increased LITAF protein levels in LPM from inflamed tissue (P<0.05). To further confirm the role of LITAF in acutely inflamed colonic tissues, TNBS-induced colonic inflammation was produced in LITAF macrophage specific knockout mice (LITAF mac -/- mice) and compared to wild type (WT) C57BL/6. Twenty four hours following TNBS administration, colonic tissue from LITAF mac -/- mice had less MPO activity and reduced colonic TNF-α mRNA then WT C57BL/6 mice (p<0.05). LPM harvested from LITAF mac -/- secreted significantly less TNF-α in response to LPS than wild type (WT) C57BL/6 (p<0.05). This study provides evidence that LITAF contributes to the regulation of TNF-α in LPM harvested following acute inflammation or LPS treatment paving the way for future work focusing on LITAF inhibitors in the treatment of TNF-α-mediated inflammatory conditions.

Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer.

Patients with chronic ulcerative colitis (UC) are at high risk for developing colorectal cancer. In this study, archival formalin-fixed paraffin-embedded colonic tissue from patients with UC who developed carcinoma (CA) or high-grade dysplasia (HGD) was examined for changes in expression of the proinflammatory and mitogenic neurokinin-1 receptor (NK-1R). Laser capture microscopy was used to microdissect epithelia from areas of colons that showed histologic evidence of CA, HGD, and epithelia that were not dysplastic or cancerous but did contain evidence of prior inflammation (quiescent colitis). mRNA was extracted from the dissected tissue, and PCR array analysis was performed on extracted mRNA. Two antibodies were necessary to separately estimate the protein levels of the truncated (tr-NK-1R) and full-length (fl-NK-1R) receptors by immunohistochemistry. mRNA expression of tr-NK-1R increased 14-fold (P = 0.02) when comparing the HGD and CA groups. In contrast, the fl-NK-1R transcript showed no significant differences among groups. The protein levels of the total NK-1R increased by 40% (P = 0.02) in HGD and 80% (P = 0.0007) in CA compared with quiescent colitis. There were no significant changes in protein levels of the fl-NK-1R. We conclude that the increase in total NK-1R protein in HGD and CA is attributable to an increase in tr-NK-1R, suggesting there may be a functional role for tr-NK-1R in malignant transformation in colitis-associated cancer. The tr-NK-1R could prove useful as a diagnostic marker to identify patients at risk for neoplasia and may serve as a useful therapeutic target in the treatment of colitis-associated cancer.

N-acetyl-l-cysteine decreases intra-abdominal adhesion formation through the upregulation of peritoneal fibrinolytic activity and antioxidant defenses.

BACKGROUND: Intraperitoneal adhesions occur in more than 94% of patients after abdominal surgery. Mechanisms that decrease oxidative stress and upregulate peritoneal fibrinolysis reduce adhesions. N-acetyl-l-cysteine (NAC) is a clinically relevant antioxidant whose effect on peritoneal fibrinolysis and ability to decrease adhesions has not been established. The aims of this study were to determine if NAC reduces adhesions and to characterize its potential mechanism(s) of action. METHODS: Male Wistar rats (n = 92) received 0.9% saline (OP Control), intraperitoneal NAC (150 mg/kg, OP + NAC), or oral NAC (1200 mg/kg) twice daily on preoperative day 1, day of operation, and postoperative day 1. Adhesions were induced on the day of operation using our previously described ischemic button model. Animals were killed on postoperative day 7 for adhesion scoring. Peritoneal tissue and fluid from the intraperitoneal NAC group were measured at 24 hours for fibrinolytic activity, tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), total glutathione, and 8-isoprostane (8-IP). The effect of NAC on tPA and PAI-1 production was tested in vitro in human mesothelial cells. The effect of NAC on intestinal wound healing was measured using colonic anastomotic burst pressures. RESULTS: Intraperitoneal NAC reduced adhesions by 53% (P < .001) compared to OP Controls without affecting anastomotic wound healing. NAC increased the tPA/PAI-1 protein ratio and peritoneal fibrinolytic activity by 69% and 127%, respectively, compared to OP Controls (P < .05). NAC did not restore total glutathione levels in peritoneal adhesion tissue but decreased 8-IP by 46% and 65% (P < .05) in peritoneal tissue and fluid, respectively, compared to OP Controls. Human mesothelial cells incubated with NAC exhibited a concentration-dependent increase in the tPA/PAI-1 ratio, which supported in vivo observations (P < .05). Oral NAC did not decrease adhesions. CONCLUSION: NAC administered intraperitoneally decreased adhesion formation while upregulating peritoneal fibrinolytic activity and antioxidant defenses without affecting normal anastomotic wound healing. These data suggest a potential new therapeutic use for NAC in adhesion prevention.

Preoperative infliximab is not associated with an increased risk of short-term postoperative complications after restorative proctocolectomy and ileal pouch-anal anastomosis.

INTRODUCTION: Considerable controversy exists over whether the preoperative use of infliximab (IFX) for refractory ulcerative colitis (UC) increases the risk for surgical complications after restorative proctocolectomy and ileal pouch-anal anastomosis (IPAA). The aim of this study was to assess the association between preoperative IFX use and short-term surgical complications in a single-surgeon cohort at a tertiary care academic center. METHODS: UC patients who underwent IPAA from September 2005 through May 2009 were retrospectively identified. Twenty-nine patients treated with IFX within 12 weeks of surgery and 52 non-IFX control subjects were identified. Short-term postoperative outcomes were compared between groups occurring within 30 days of loop ileostomy closure. RESULTS: Patients were similar with respect to demographics, co-morbidities, rate of emergency surgery, hand-sewn anastomosis, and preoperative use of cyclosporine, azathioprine, and high-dose steroids. IFX patients were more likely to have received a laparoscopic hand-assisted IPAA, low-, medium-, and any-dose steroids, 6-mercaptopurine (6-MP), methotrexate, and to have failed medical therapy. There was no short-term mortality. Overall postoperative and infectious complications were similar between IFX and non-IFX groups. Multivariate regression models revealed no independent predictors for postoperative complications when including IFX [odds ratio (OR) 0.78, p = 0.67], laparoscopic hand-assisted IPAA, 6-MP, methotrexate, steroids, failure of medical therapy, and body mass index. CONCLUSIONS: Preoperative IFX use was not associated with an increased risk of short-term postoperative complications after IPAA.

The efficacy of a hyaluronate-carboxymethylcellulose bioresorbable membrane that reduces postoperative adhesions is increased by the intra-operative co-administration of a neurokinin 1 receptor antagonist in a rat model.

BACKGROUND: Bioresorbable membranes composed of hyaluronic acid and carboxymethylcellulose (HA/CMC) are the most effective method to prevent intra-abdominal adhesions; however, their efficacy may be limited to the site of application. Previous studies in our laboratory have shown that the intraperitoneal administration of a neurokinin-1 receptor antagonist (NK-1RA) reduces adhesions; however, the co-administration of HA/CMC plus an NK-1RA has not been studied. METHODS: Adhesions were induced in rats by creating ischemic buttons on the peritoneum. Rats received NK-1RA, HA/CMC, HA/CMC+NK-1RA or saline intraperitoneally at surgery. The HA/CMC was applied either bilaterally over all ischemic buttons or unilaterally over half the ischemic buttons. Animals were sacrificed and adhesions quantified at 7 days. Peritoneal fluid was collected at 24 hours to measure peritoneal tissue plasminogen activator (tPA) activity using a bioassay. RESULTS: The bilateral placement of HA/CMC alone reduced adhesions by 62% (P < .05) while the NK-1RA when administered alone reduced adhesions by 45% (P < .05), both groups compared with saline controls. The bilateral placement of HA/CMC+ NK-1RA decreased adhesions by 86% (P < .05) compared with saline controls and by 70% (P < .05) compared with either HA/CMC or NK-1RA alone. Unilateral application of HA/CMC resulted in a 41% decrease (P < .05) in adhesions where placed compared with the distal unprotected buttons in the same animal. However, the unilateral placement of HA/CMC+NK-1RA reduced adhesions by nearly 75% (P < .05) at the site of HA/CMC application compared with HA/CMC + saline, and by 45% (P < .05) at the distal unprotected buttons compared with saline controls. HA/CMC and the NK-1RA alone as well as HA/CMC+NK-1RA increased peritoneal tPA activity by 124%, 432%, and 192%, respectively (P < .05) compared with saline controls. CONCLUSION: The co-administration of HA/CMC plus NK-1RA not only increases the efficacy of the membrane at the site of application, but significantly reduces adhesions formation at distal unprotected sites. This combination may represent an emerging concept in more effective adhesion prevention throughout the peritoneum.

Stasis predisposes ileal pouch inflammation in a rat model of ileal pouch-anal anastomosis.

BACKGROUND: While restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has become the definitive surgical treatment for patients suffering from chronic ulcerative colitis (CUC), pouchitis still remains a major late complication. Fecal stasis has been implicated in the etiology of ileal inflammation; however, the mechanism(s) remain unclear, in part due to the lack of an animal model. Our goal was to surgically mimic the IPAA procedure in a rat to investigate the hypothesis that stasis leads to biochemical changes that predispose the ileal pouch to inflammation. MATERIALS AND METHODS: Thirty-two Sprague-Dawley rats underwent total colectomy with either straight ileorectal (IRA) or IPAA, and 11 nonoperated rats served as controls (Controls). Twenty-one d postoperatively, 48 h serial barium radiographs and 12 h charcoal transit follow-through studies were performed. Following sacrifice, ileal tissue was harvested for the measurement of myeloperoxidase activity (MPO) activity, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) mRNA levels, and histology. RESULTS: Serial barium radiographs showed stasis in the ileal pouch compared with IRA animals, and charcoal transit times that were two times longer (P ≤ 0.05) than that in the straight IRA rats. Ileal pouch MPO levels were significantly elevated in the IPAA rats compared with the straight IRA rats. ICAM-1 and VCAM-1 mRNA levels were not associated with neutrophil infiltration. CONCLUSIONS: These studies showed that ileal pouch stasis predisposes biochemical and histological evidence of ileal pouch mucosal inflammation. Studies such as this may provide the rationale for novel, adjunct therapies for the management of pouchitis in patients having undergone IPAA for CUC.

Completion mucosectomy for retained rectal mucosa following restorative proctocolectomy with double-stapled ileal pouch-anal anastomosis.

INTRODUCTION: Colectomy with ileal pouch-anal anastomosis has become widely accepted and is now considered the procedure of choice for patients with ulcerative colitis (UC) as well as familial adenomatous polyposis (FAP). DISCUSSION: The clear patient advantage of functional continence has pushed this procedure to the forefront in treating both UC and FAP. As a result, the procedure continues to evolve with recent debate centering on the question of whether to perform a double-stapled technique without rectal mucosectomy or a handsewn anastomosis following transanal mucosectomy. Although continence and complication rates continue to be hotly debated, it is understood that performing the stapled procedure does leave a rectal cuff, which carries with it the possibility of disease persistence or recurrence. As such, if the rectal cuff becomes symptomatic or dysplastic, it must be removed. This is accomplished by performing a transanal completion mucosectomy and reconstructing the ileal pouch-anal anastomosis.