biomArker-guided Duration of Antibiotic treatment in hospitalised Patients with suspecTed Sepsis (ADAPT-Sepsis): A protocol for a multicentre randomised controlled trial.

Aim: To describe the protocol for a multi-centre randomised controlled trial to determine whether treatment protocols monitoring daily CRP (C-reactive protein) or PCT (procalcitonin) safely allow a reduction in duration of antibiotic therapy in hospitalised adult patients with sepsis. Design: Multicentre three-arm randomised controlled trial. Setting: UK NHS hospitals. Target population: Hospitalised critically ill adults who have been commenced on intravenous antibiotics for sepsis. Health technology: Three protocols for guiding antibiotic discontinuation will be compared: (a) standard care; (b) standard care + daily CRP monitoring; (c) standard care + daily PCT monitoring. Standard care will be based on routine sepsis management and antibiotic stewardship. Measurement of outcomes and costs. Outcomes will be assessed to 28 days. The primary outcomes are total duration of antibiotics and safety outcome of all-cause mortality. Secondary outcomes include: escalation of care/re-admission; infection re-lapse/recurrence; antibiotic dose; length and level of critical care stay and length of hospital stay. Ninety-day all-cause mortality rates will also be collected. An assessment of cost effectiveness will be performed. Conclusion: In the setting of routine NHS care, if this trial finds that a treatment protocol based on monitoring CRP or PCT safely allows a reduction in duration of antibiotic therapy, and is cost effective, then this has the potential to change clinical practice for critically ill patients with sepsis. Moreover, if a biomarker-guided protocol is not found to be effective, then it will be important to avoid its use in sepsis and prevent ineffective technology becoming widely adopted in clinical practice.

Impact of negative pressure wound therapy on enteroatmospheric fistulation in the septic open abdomen.

AIM: The effect of negative pressure wound therapy (NPWT) on the pathogenesis and outcome of enteroatmospheric fistulation (EAF) in the septic open abdomen (OA) is unclear. This study compares the development and outcome of EAF following NPWT with that occurring in the absence of NPWT. METHODS: Consecutive patients admitted with EAF following abdominal sepsis at a National Reference Centre for intestinal failure between 01 January 2005 and 31 December 2015 were included in this study. Patients were divided into two groups based on those that had been treated with NPWT and those that had not (non-NPWT) and characteristics of their fistulas compared. Clinical outcomes concerning nutritional autonomy at 4 years and time to fistula development, size of abdominal wall defect and complete fistula closure were compared between groups. RESULTS: A total of 160 patients were admitted with EAF following a septic abdomen (31-NPWT and 129-non-NPWT). Median (range) time taken to fistulation after OA was longer with NPWT (18 [5-113] vs. 8 [2-60] days, p = 0.004); these patients developed a greater number of fistulas (3 [2-21] vs. 2 [1-10], p = 0.01), involving a greater length of small bowel (42.5 [15-100] cm vs. 30 [3.5-170] cm, p = 0.04) than those who did not receive NPWT. Following reconstructive surgery, nutritional autonomy was similar in both groups (77% vs. 72%) and a comparable number of patients were also fistula-free (100% vs. 97%). CONCLUSIONS: Negative pressure wound therapy appears to be associated with more complex and delayed intestinal fistulation, involving a greater length of small intestine in the septic OA. This did not, however, appear to adversely affect the overall outcome of intestinal and abdominal wall reconstruction in this study.

A comparison between thoracic epidural analgesia and rectus sheath catheter analgesia after open midline major abdominal surgery: randomized clinical trial.

BACKGROUND: Rectus sheath catheter analgesia (RSCA) and thoracic epidural analgesia (TEA) are both used for analgesia following laparotomy. The aim was to compare the analgesic effectiveness of RSCA with TEA after laparotomy for elective colorectal and urological surgery. METHODS: Patients undergoing elective midline laparotomy were randomized in a non-blinded fashion to receive RSCA or TEA for postoperative analgesia at a single UK teaching hospital. The primary quantitative outcome measure was dynamic pain score at 24 h after surgery. A nested qualitative study (reported elsewhere) explored the dual primary outcome of patient experience and acceptability. Secondary outcome measures included rest and movement pain scores over 72 h, functional analgesia, analgesia satisfaction, opiate consumption, functional recovery, morbidity, safety, and cost-effectiveness. RESULTS: A total of 131 patients were randomized: 66 in the RSCA group and 65 in the TEA group. The median (interquartile range; i.q.r.) dynamic pain score at 24 h was significantly lower after TEA than RSCA (33 (11-60) versus 50.5 (24.50-77.25); P = 0.018). Resting pain score at 72 h was significantly lower after RSCA (4.5 (0.25-13.75) versus 12.5 (2-13); P = 0.019). Opiate consumption on postoperative day 3 (median (i.q.r.) morphine equivalent 17 (10-30) mg versus 40 (13.25-88.50) mg; P = 0.038), hypotension, or vasopressor dependency (29.7 versus 49.2 per cent; P = 0.023) and weight gain to day 3 (median (i.q.r.) 0 (-1-2) kg versus 1 (0-3) kg; P = 0.046) were all significantly greater after TEA, compared with RSCA. There were no significant differences between groups in other secondary outcomes, although more participants experienced serious adverse events after TEA compared with RSCA, which was also the more cost-effective. CONCLUSIONS: TEA provided superior initial postoperative analgesia but only for the first 24 h. By 72 hours RSCA provides superior analgesia, is associated with a lower incidence of unwanted effects, and may be more cost-effective.

Regulation of Peritoneal Inflammatory Response to Implant Material Using an Ex Vivo Model System.

BACKGROUND: Implants used in abdominal wall reconstruction are associated with intra-abdominal inflammation that can cause complications such as adhesions, fistulae, or failure of the implant. This study analyzed the inflammatory response of human peritoneum explants when exposed to different implant materials including synthetic and biological (cross-linked and non-cross-linked). MATERIALS AND METHODS: Human peritoneum explants (parietal and visceral) were incubated in culture with implants used for abdominal wall reconstruction. Implants included Permacol (biological implant with chemical cross-linking); Biodesign and Strattice (biological implants without chemical cross-linking); Prolene (synthetic nonabsorbable); and Vicryl (synthetic absorbable). Control peritoneum samples were incubated without implant. Cytokine concentrations and corresponding gene expression were measured by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively. Further evaluation included assessment of tissue viability and implant-cytokine adsorption. RESULTS: Incubation of human peritoneal explants with Biodesign or Strattice was associated with a significant reduction in interleukin-6, interleukin-1ß, and tumour necrosis factor alpha protein and gene expression compared with control. These could not be explained by reduced cell viability or implant-cytokine adsorption. Incubation of explants in Biodesign-conditioned media displayed a similar effect to incubation of explants with Biodesign itself. CONCLUSIONS: Human peritoneal explants cultured with different mesh implant materials show an altered inflammatory cytokine response suggesting a tissue-specific response. Downregulation of key inflammatory cytokines by the peritoneum exposed to non-cross-linked biological implants may be mediated by the release of soluble factors from these implants inhibiting cytokine gene expression. This ex vivo human peritoneal system provides a novel preclinical model to investigate peritoneum-implant interactions.

Cholelithiasis and Related Morbidity in Chronic Intestinal Failure: a Longitudinal Cohort Study from a National Specialized Centre.

BACKGROUND: Short-term studies have shown that patients with type III intestinal failure often develop gallstones and have recommended prophylactic cholecystectomy. In this retrospective cohort study, we aimed to define the incidence and clinical consequences of cholelithiasis over an extended time period, in order to refine the role of prophylactic cholecystectomy in type III intestinal failure. METHODS: Data were retrospectively collected from a prospectively maintained audit. Patients with intestinal failure for 5 years or more were included. Kaplan-Meier analysis was used to estimate cumulative incidence over time. Predictors of cholelithiasis were evaluated by Cox regression. RESULTS: Between 1 January 1983 and 1 December 2008, 81 patients were commenced on parenteral support lasting 5 years or more. Of 63 patients with no pre-existing gallstones on imaging, 17 (27%) developed gallstones during a median observation period of 133 months. On Kaplan-Meier analysis, the incidence at 10 years was 21%; at 20 years, 38%; and at 30 years, 47%. Thirteen of the 17 had symptoms and ten required surgical and/or endoscopic intervention. Increased weekly calorific content (P 0.003) and the provision of parenteral lipids (P 0.003) were predictors of cholelithiasis on univariable Cox regression. CONCLUSION: Many patients with long-term intestinal failure develop gallstones over time, with a 20-year incidence of 38%. The majority of those have symptoms or complications and require intervention. Therefore, prophylactic en-passant cholecystectomy is justified when gallstones are present in type III intestinal failure, supporting routine pre-operative imaging of the gallbladder prior to abdominal surgery.

Use of Anal Acoustic Reflectometry in the Evaluation of Men With Passive Fecal Leakage.

BACKGROUND: Men with passive fecal leakage represent a distinct clinical entity in which the pathophysiology remains unclear. Standard anorectal investigations fail to demonstrate consistent abnormalities in this group. Anal acoustic reflectometry is a new test of anal sphincter function with greater sensitivity and discriminatory ability than conventional anal manometry. OBJECTIVE: The aim of this study was to determine whether men with fecal leakage have an abnormality in anal sphincter function that is detectable by anal acoustic reflectometry. DESIGN: This was an age-matched study of continent and incontinent men. SETTINGS: The study was conducted at a university teaching hospital. PATIENTS: Male patients with isolated symptoms of fecal leakage were recruited. Anal acoustic reflectometry, followed by conventional anal manometry, was performed. Results were then compared with those from an age-matched group of men with no symptoms of anal incontinence or anorectal pathology. MAIN OUTCOME MEASURES: Variables measured with anal acoustic reflectometry and anal manometry in the incontinent and continent men were compared. RESULTS: Thirty subjects were recruited, of whom 15 were men with fecal leakage and 15 were continent men. There was a significantly higher incidence of previous anorectal surgery in the men with leakage. The anal acoustic reflectometry variables of opening and closing pressure were significantly lower in leakers compared with continent subjects (p = 0.003 and p = 0.001). Hysteresis was significantly greater in the male leaker group (p = 0.026). No difference was seen in anal manometry. LIMITATIONS: With a larger sample size, the effect of previous anorectal surgery and the presence of an anal sphincter defect could be clarified. CONCLUSIONS: Anal acoustic reflectometry is a sensitive test of anal sphincter function and, unlike anal manometry, can discriminate male leakers from continent subjects. An identifiable abnormality has been detected using anal acoustic reflectometry, which may further our understanding of the pathogenesis in this group.

Central Venous Catheter Salvage in Home Parenteral Nutrition Catheter-Related Bloodstream Infections: Long-Term Safety and Efficacy Data.

BACKGROUND: Catheter-related bloodstream infections (CRBSIs) are a serious complication in the provision of home parenteral nutrition (HPN). Antibiotic salvage of central venous catheters (CVCs) in CRBSI is recommended; however, this is based on limited reports. We assessed the efficacy of antibiotic salvage of CRBSIs in HPN patients. MATERIALS AND METHODS: All confirmed CRBSIs occurring in patients receiving HPN in a national intestinal failure unit (IFU), between 1993 and 2011, were analyzed. A standardized protocol involving antibiotic and urokinase CVC locks and systemic antibiotics was used. RESULTS: In total, 588 patients were identified with a total of 2134 HPN years, and 297 CRBSIs occurred in 137 patients (65 single and 72 multiple CRBSIs). The overall rate of CRBSI in all patients was 0.38 per 1000 catheter days. Most (87.9%) infections were attributable to a single microorganism. In total, 72.5% (180/248) of CRBSIs were salvaged when attempted (coagulase-negative staphylococcus, 79.8% [103/129], Staphylococcus aureus, 56.7% [17/30]; polymicrobial infections, 67.7% [21/30]; and miscellaneous, 66.1% [39/59]). CVC salvage was not attempted in 49 episodes because of life-threatening sepsis (n = 18), fungal infection (n = 7), catheter problems (n = 20), and CVC tunnel infection (n = 4). Overall, the CVC was removed in 33.7% (100/297) of cases. There were 5 deaths in patients admitted to the IFU for management of the CRBSI (2 severe sepsis at presentation, 3 metastatic infection). CONCLUSIONS: This is the largest reported series of catheter salvage in CRBSIs and demonstrates successful catheter salvage in most cases when using a standardized protocol.

Rapid detection of health-care-associated bloodstream infection in critical care using multipathogen real-time polymerase chain reaction technology: a diagnostic accuracy study and systematic review.

BACKGROUND: There is growing interest in the potential utility of real-time polymerase chain reaction (PCR) in diagnosing bloodstream infection by detecting pathogen deoxyribonucleic acid (DNA) in blood samples within a few hours. SeptiFast (Roche Diagnostics GmBH, Mannheim, Germany) is a multipathogen probe-based system targeting ribosomal DNA sequences of bacteria and fungi. It detects and identifies the commonest pathogens causing bloodstream infection. As background to this study, we report a systematic review of Phase III diagnostic accuracy studies of SeptiFast, which reveals uncertainty about its likely clinical utility based on widespread evidence of deficiencies in study design and reporting with a high risk of bias. OBJECTIVE: Determine the accuracy of SeptiFast real-time PCR for the detection of health-care-associated bloodstream infection, against standard microbiological culture. DESIGN: Prospective multicentre Phase III clinical diagnostic accuracy study using the standards for the reporting of diagnostic accuracy studies criteria. SETTING: Critical care departments within NHS hospitals in the north-west of England. PARTICIPANTS: Adult patients requiring blood culture (BC) when developing new signs of systemic inflammation. MAIN OUTCOME MEASURES: SeptiFast real-time PCR results at species/genus level compared with microbiological culture in association with independent adjudication of infection. Metrics of diagnostic accuracy were derived including sensitivity, specificity, likelihood ratios and predictive values, with their 95% confidence intervals (CIs). Latent class analysis was used to explore the diagnostic performance of culture as a reference standard. RESULTS: Of 1006 new patient episodes of systemic inflammation in 853 patients, 922 (92%) met the inclusion criteria and provided sufficient information for analysis. Index test assay failure occurred on 69 (7%) occasions. Adult patients had been exposed to a median of 8 days (interquartile range 4-16 days) of hospital care, had high levels of organ support activities and recent antibiotic exposure. SeptiFast real-time PCR, when compared with culture-proven bloodstream infection at species/genus level, had better specificity (85.8%, 95% CI 83.3% to 88.1%) than sensitivity (50%, 95% CI 39.1% to 60.8%). When compared with pooled diagnostic metrics derived from our systematic review, our clinical study revealed lower test accuracy of SeptiFast real-time PCR, mainly as a result of low diagnostic sensitivity. There was a low prevalence of BC-proven pathogens in these patients (9.2%, 95% CI 7.4% to 11.2%) such that the post-test probabilities of both a positive (26.3%, 95% CI 19.8% to 33.7%) and a negative SeptiFast test (5.6%, 95% CI 4.1% to 7.4%) indicate the potential limitations of this technology in the diagnosis of bloodstream infection. However, latent class analysis indicates that BC has a low sensitivity, questioning its relevance as a reference test in this setting. Using this analysis approach, the sensitivity of the SeptiFast test was low but also appeared significantly better than BC. Blood samples identified as positive by either culture or SeptiFast real-time PCR were associated with a high probability (> 95%) of infection, indicating higher diagnostic rule-in utility than was apparent using conventional analyses of diagnostic accuracy. CONCLUSION: SeptiFast real-time PCR on blood samples may have rapid rule-in utility for the diagnosis of health-care-associated bloodstream infection but the lack of sensitivity is a significant limiting factor. Innovations aimed at improved diagnostic sensitivity of real-time PCR in this setting are urgently required. Future work recommendations include technology developments to improve the efficiency of pathogen DNA extraction and the capacity to detect a much broader range of pathogens and drug resistance genes and the application of new statistical approaches able to more reliably assess test performance in situation where the reference standard (e.g. blood culture in the setting of high antimicrobial use) is prone to error. STUDY REGISTRATION: The systematic review is registered as PROSPERO CRD42011001289. FUNDING: The National Institute for Health Research Health Technology Assessment programme. Professor Daniel McAuley and Professor Gavin D Perkins contributed to the systematic review through their funded roles as codirectors of the Intensive Care Foundation (UK).

Diagnostic accuracy of SeptiFast multi-pathogen real-time PCR in the setting of suspected healthcare-associated bloodstream infection.

PURPOSE: SeptiFast is a real-time PCR assay which targets ribosomal DNA sequences of bacteria and fungi, enabling detection and identification of the commonest pathogens in blood within a few hours, including those acquired in healthcare settings. We report here the first detailed assessment of SeptiFast that focuses on healthcare-associated bloodstream infections which develop during routine critical care. METHODS: This was a prospective multicentre study designed to compare the clinical diagnostic accuracy of SeptiFast versus microbiological culture and independent clinical adjudication. This Phase III diagnostic study was performed in an adequately sized cohort of adult patients who developed new signs of suspected bloodstream infection while receiving routine critical care. RESULTS: Of 1,006 new episodes of suspected bloodstream infection in 853 patients, 922 (92 %) of these episodes in 795 patients met the inclusion criteria of the study. Patients had been exposed to a median of 8 days (interquartile range 4-16) of hospital care and had received high levels of organ support and recent antibiotic exposure. The SeptiFast test, when compared with bloodstream infection at the species/genus level, had a greater specificity [0.86, 95 % confidence interval (CI) 0.83-0.88] than sensitivity (0.50, 95 % CI 0.39-0.61). There was a low prevalence of blood culture-proven pathogens (9.2 %, 95 % CI 7.4-11.2 %), and the post-test probabilities of both a positive (26.3 %, 95 % CI 19.8-33.7 %) and a negative SeptiFast test (5.6 %, 95 % CI 4.1-7.4 %) indicated potential limitations of this technology in diagnosing bloodstream infection. CONCLUSION: When compared with blood culture, SeptiFast is likely to have limited utility for the diagnosis of healthcare-associated bloodstream infection in critical care patients despite its potential to deliver results more rapidly.

Thoracic Epidural analgesia versus Rectus Sheath Catheters for open midline incisions in major abdominal surgery within an enhanced recovery programme (TERSC): study protocol for a randomised controlled trial.

BACKGROUND: Thoracic epidural analgesia (TEA) is recommended for post-operative pain relief in patients undergoing major abdominal surgery via a midline incision. However, the effectiveness of TEA is variable with high failure rates reported post-operatively. Common side effects such as low blood pressure and motor block can reduce mobility and hinder recovery, and a number of rare but serious complications can also occur following their use.Rectus sheath catheters (RSC) may provide a novel alternative approach to somatic analgesia without the associated adverse effects of TEA. The aim of this study is to compare the efficacy of both techniques in terms of pain relief, patient experience, post-operative functional recovery, safety and cost-effectiveness. METHODS/DESIGN: This is a single-centre randomised controlled non-blinded trial, which also includes a nested qualitative study. Over a two-year period, 132 patients undergoing major abdominal surgery via a midline incision will be randomised to receive either TEA or RSC for post-operative analgesia. The primary outcome measures pain scores on moving from a supine to a sitting position at 24 hours post wound closure, and the patient experience between groups evaluated through in-depth interviews. Secondary outcomes include pain scores at rest and on movement at other time points, opiate consumption, functional recovery, morbidity and cost-effectiveness. DISCUSSION: This will be the first randomised controlled trial comparing thoracic epidurals to ultrasound-guided rectus sheath catheters in adults undergoing elective midline laparotomy. The standardised care provided by an Enhanced Recovery Programme makes this a comparison between two complex pain packages and not simply two analgesic techniques, in order to ascertain if RSC is a viable alternative to TEA. TRIAL REGISTRATION: Current Controlled Trials ISRCTN81223298 (16 January 2014).

Management of the open abdomen: a national study of clinical outcome and safety of negative pressure wound therapy.

OBJECTIVE: To determine clinical outcome of open abdomen therapy and assess the influence of negative pressure wound therapy on outcome. BACKGROUND: Leaving the abdomen open (laparostomy) is an option following laparotomy for severe abdominal sepsis or trauma. Negative pressure wound therapy (NPWT) has become a popular means of managing laparostomy wounds. It may facilitate nursing care and delayed primary wound closure but the evidence to support its use is poor and concern has arisen about the risk of intestinal fistulation from exposed bowel, leading to an increased risk of death. METHODS: Prospective observational study of 578 patients treated with an open abdomen in 105 hospitals in the United Kingdom between January 1, 2010, and June 30, 2011. Propensity analysis was used to compare adverse outcomes (fistulation, death, intestinal failure, bleeding requiring intervention) and delayed primary closure rates in patients who did and did not receive NPWT. FINDINGS: The most common indication for an open abdomen (n = 398, 68.9%) was abdominal sepsis. Overall hospital mortality was 28.2%. The majority of patients (n = 355, 61.4%) were treated with NPWT. Intestinal fistulation [relative risk (RR) = 0.83, 95% confidence interval (CI): 0.44-1.58], death (RR = 0.87, 95% CI: 0.64-1.20), bleeding (RR = 0.74, 95% CI: 0.45-1.23), and intestinal failure (RR = 1.00, 95% CI: 0.64-1.57) were no more common in patients receiving NPWT, but the rate of delayed primary closure was significantly lower (RR = 0.74, 95% CI: 0.60-0.90, P = 0.002) when NPWT was used. CONCLUSIONS: The indications for an open abdomen in the United Kingdom appear to be significantly different to those described in N. America, where its use in the management of trauma predominates. NPWT in patients with an open abdomen is not associated with an increase in mortality or intestinal fistulation. It is, however, associated with a reduced rate of delayed primary closure. Although this may be related to patient selection, NPWT may leave patients with abdominal wall defects that require further treatment.

Gastric necrosis complicating acute gastric dilatation after Nissen fundoplication.

A woman in her 70s was referred for the management of complex intestinal fistulation, which had developed as a postoperative complication of laparoscopic Nissen fundoplication. Surgical treatment of a jejunocolocutaneous fistula and formation of a double-barrelled ileocolostomy was undertaken uneventfully. Routine postoperative nasogastric intubation was not undertaken. On the seventh postoperative day she had nausea and hiccupping. A chest x-ray demonstrated a massively dilated stomach which was decompressed with a nasogastric tube. The patient sustained a cardiac arrest and was resuscitated. A subsequent CT scan demonstrated acute gastric necrosis but the patient was judged too unwell for surgical intervention and died. Postmortem examination revealed emphysematous gastric necrosis. This case highlights the potentially fatal consequences of acute gastric dilatation following major abdominal surgery in patients who have previously had a Nissen fundoplication and are consequently unable to vomit.

Acute intestinal failure.

PURPOSE OF REVIEW: The review aims to highlight the importance of acute gastrointestinal failure in the postoperative patient, to clarify the clinical circumstances in which acute intestinal failure complicates postoperative management, and to discuss recent advances and controversy in our understanding of the cause and pathogenesis. RECENT FINDINGS: Acute postoperative intestinal failure ranges from a self-limiting condition of disordered intestinal peristaltic activity, through to a complex critical illness state associated with abdominal sepsis and intestinal fistulation. Recent developments have focused on the mechanisms of paralytic ileus and preventive strategies, usually as part of programmes of 'fast-track' or 'enhanced recovery' care, and on the optimum management of patients with severe abdominal sepsis, including planned versus on-demand relaparotomy, open abdominal management of severe sepsis and negative pressure wound therapy. SUMMARY: Many cases of acute intestinal failure are preventable. Improvements in understanding and preventing paralytic ileus through changes in postoperative care may facilitate recovery of gastrointestinal function after abdominal surgery. Further and better-organized studies are needed to define the optimum strategies for treating patients with severe abdominal sepsis, managing the patient with the open abdomen and defining the role of enteral, as opposed to parenteral nutritional support in such patients.

Outcome of reconstructive surgery for intestinal fistula in the open abdomen.

OBJECTIVE: To determine factors which influence the outcome of surgical techniques to close enterocutaneous fistulas within the open abdomen. SUMMARY BACKGROUND DATA: Enterocutaneous fistulation within an open abdominal wound is associated with considerable morbidity and mortality. The factors that influence the outcome of reconstructive surgery are unclear. METHODS: Sixty-one patients undergoing 63 operations to close enterocutaneous fistulas associated with open abdominal wounds were referred to a national center for further management. Once sepsis had been eradicated, nutritional status restored and local conditions in the abdomen judged to be suitable, fistulas were resected and the abdominal wall reconstructed by suture repair with and without component separation, or by suture repair in combination with absorbable or nonabsorbable prosthetic mesh. Patients were followed up for 16 to 84 months postoperatively. RESULTS: There were 3 postoperative deaths (4.8%). Major complications, including postoperative respiratory and surgical site infection occurred in 52 of 63 (82.5%) procedures. Refistulation occurred in 7 cases (11.1%) but was more common when the abdominal wall was reconstructed with prosthetic mesh (7 of 29, 24.1%) than with sutures (0 of 34, 0%). Porcine collagen mesh was associated with a particularly high rate of refistulation (5 of 12, 41.7%). CONCLUSIONS: Simultaneous reconstruction of the intestinal tract and abdominal wall remains associated with a high complication rate, justifying the management of such patients in specialized units. Simultaneous reconstruction of the abdominal wall with prosthetic mesh is associated with a particularly high incidence of recurrent postoperative fistulation and should be avoided if possible.

Early molecular and functional changes in colonic epithelium that precede increased gut permeability during colitis development in mdr1a(-/-) mice.

BACKGROUND: The early molecular changes preceding the onset of mucosal inflammation in colitis and their temporal relationship with gut permeability remain poorly defined. This study investigated functional and transcriptomic changes in mdr1a(-/-) mice lacking the intestinal transporter P-glycoprotein, which develop colitis spontaneously when exposed to normal enteric flora. METHODS: Mdr1a(-/-) mice were housed in specific pathogen-free conditions to slow colitis development and compared to congenic controls. Mucosal permeability and cytokine secretion were analyzed in ex vivo colon. Gene expression in colonic mucosal and epithelial preparations was analyzed by microarray and qPCR. Colonocyte responsiveness to bacterial antigens was measured in short-term culture. RESULTS: Colon from 4-5-week-old, disease-free mdr1a(-/-) mice was histologically normal with no evidence of increased permeability compared to controls. However, these tissues display a distinctive pattern of gene expression involving significant changes in a small number of genes. The majority of upregulated genes were associated with bacterial recognition and the ubiquitin-proteasome system and were gamma-interferon (IFN-gamma) responsive. Expression of the antiinflammatory factor pancreatitis-associated protein (PAP) and the related gene RegIIIgamma were markedly reduced. Colonocytes from 4-5-week mdr1a(-/-) exhibit similar transcriptomic changes, accompanied by higher basal chemokine secretion and increased responsiveness to LPS. Significant increases in colonic permeability were associated with older (12-16-week) mdr1a(-/-) mice displaying molecular and functional evidence of active inflammation. CONCLUSIONS: These studies show that early epithelial changes associated with altered responsiveness to bacteria precede increased permeability and mucosal inflammation in this model of colitis, highlighting the importance of P-glycoprotein in regulating interactions with the commensal microflora.