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.

Enhanced Recovery After Surgery (ERAS®) Society Consensus Guidelines for Emergency Laparotomy Part 3: Organizational Aspects and General Considerations for Management of the Emergency Laparotomy Patient.

BACKGROUND: This is Part 3 of the first consensus guidelines for optimal care of patients undergoing emergency laparotomy using an enhanced recovery after surgery (ERAS) approach. This paper addresses organizational aspects of care. METHODS: Experts in management of the high-risk and emergency general surgical patient were invited to contribute by the International ERAS® Society. PubMed, Cochrane, Embase, and MEDLINE database searches were performed for ERAS elements and relevant specific topics. Studies were selected with particular attention to randomized clinical trials, systematic reviews, meta-analyses and large cohort studies, and reviewed and graded using the Grading of Recommendations, Assessment, Development and Evaluation system. Recommendations were made on the best level of evidence, or extrapolation from studies on elective patients when appropriate. A modified Delphi method was used to validate final recommendations. RESULTS: Components of organizational aspects of care were considered. Consensus was reached after three rounds of a modified Delphi process. CONCLUSIONS: These guidelines are based on best current available evidence for organizational aspects of an ERAS® approach to patients undergoing emergency laparotomy and include discussion of less common aspects of care for the surgical patient, including end-of-life issues. These guidelines are not exhaustive but pull together evidence on important components of care for this high-risk patient population. As much of the evidence is extrapolated from elective surgery or emergency general surgery (not specifically laparotomy), many of the components need further evaluation in future studies.

Consensus Guidelines for Perioperative Care for Emergency Laparotomy Enhanced Recovery After Surgery (ERAS®) Society Recommendations Part 2-Emergency Laparotomy: Intra- and Postoperative Care.

BACKGROUND: This is Part 2 of the first consensus guidelines for optimal care of patients undergoing emergency laparotomy (EL) using an Enhanced Recovery After Surgery (ERAS) approach. This paper addresses intra- and postoperative aspects of care. METHODS: Experts in aspects of management of high-risk and emergency general surgical patients were invited to contribute by the International ERAS® Society. PubMed, Cochrane, Embase, and Medline database searches were performed for ERAS elements and relevant specific topics. Studies on each item were selected with particular attention to randomized clinical trials, systematic reviews, meta-analyses, and large cohort studies and reviewed and graded using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. Recommendations were made on the best level of evidence, or extrapolation from studies on elective patients when appropriate. A modified Delphi method was used to validate final recommendations. Some ERAS® components covered in other guideline papers are outlined only briefly, with the bulk of the text focusing on key areas pertaining specifically to EL. RESULTS: Twenty-three components of intraoperative and postoperative care were defined. Consensus was reached after three rounds of a modified Delphi Process. CONCLUSIONS: These guidelines are based on best available evidence for an ERAS® approach to patients undergoing EL. These guidelines are not exhaustive but pull together evidence on important components of care for this high-risk patient population. As much of the evidence is extrapolated from elective surgery or emergency general surgery (not specifically laparotomy), many of the components need further evaluation in future studies.

Guidelines for Perioperative Care for Emergency Laparotomy Enhanced Recovery After Surgery (ERAS) Society Recommendations: Part 1-Preoperative: Diagnosis, Rapid Assessment and Optimization.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) protocols reduce length of stay, complications and costs for a large number of elective surgical procedures. A similar, structured approach appears to improve outcomes, including mortality, for patients undergoing high-risk emergency general surgery, and specifically emergency laparotomy. These are the first consensus guidelines for optimal care of these patients using an ERAS approach. METHODS: Experts in aspects of management of the high-risk and emergency general surgical patient were invited to contribute by the International ERAS® Society. Pubmed, Cochrane, Embase, and MEDLINE database searches on English language publications were performed for ERAS elements and relevant specific topics. Studies on each item were selected with particular attention to randomized controlled trials, systematic reviews, meta-analyses and large cohort studies, and reviewed and graded using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. Recommendations were made on the best level of evidence, or extrapolation from studies on non-emergency patients when appropriate. The Delphi method was used to validate final recommendations. The guideline has been divided into two parts: Part 1-Preoperative Care and Part 2-Intraoperative and Postoperative management. This paper provides guidelines for Part 1. RESULTS: Twelve components of preoperative care were considered. Consensus was reached after three rounds. CONCLUSIONS: These guidelines are based on the best available evidence for an ERAS approach to patients undergoing emergency laparotomy. Initial management is particularly important for patients with sepsis and physiological derangement. These guidelines should be used to improve outcomes for these high-risk patients.

Frailty in the perioperative setting.

The frailty syndrome is defined as a decrease in physiological reserve across multiple organ systems leading to increased vulnerability to external stressors. Studies across surgical subspecialties and in emergency and elective settings have identified frailty as an independent predictor of adverse postoperative clinician-reported, patient-reported and process-related outcomes. Although frailty is not specific to the older population, it is associated with ageing and therefore is increasingly observed in the ageing surgical population. Identifying frailty early in the perioperative pathway affords the opportunity to assess risk, modify the syndrome, inform shared decision making and plan the surgical pathway. Multiple tools to screen and diagnose frailty exist with limited appraisal of clinometric properties. A pragmatic approach to these tools is advocated with a future focus on collaborative approaches to modify the syndrome using multicomponent methodology such as comprehensive geriatric assessment and adapt the pathway to the needs of the frail surgical patient.

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.

Reduced MGMT activity in human colorectal adenomas is associated with K-ras GC->AT transition mutations in a population exposed to methylating agents.

There is increasing evidence to suggest that O(6)-alkyl guanine DNA-alkyltransferase (MGMT) activity provides protection against alkylating agent induced formation of GC-->AT transition mutations in the K-ras oncogene of colorectal tumours. As this mutagenic event occurs during the growth of adenomas, both biomarkers of exposure (N7-methylguanine levels in DNA) and susceptibility (MGMT activity) were measured in biopsy samples obtained from normal and adenomatous tissue from 34 patients with large adenomas (>10 mm in size). There was no correlation between MGMT activity in the adenoma and in matched normal tissue. However, MGMT activity was significantly lower in adenoma tissue than in adjacent normal mucosa (5.18 versus 7.05 fmol/microg DNA, P = 0.01), particularly in men and those whose age was greater than the median. Upon stratification by K-ras mutational status, MGMT activity was lower in adenomas bearing a K-ras GC-->AT transition mutation (mean 4.21 fmol/microg DNA) than in adjacent normal tissue (mean 7.7 fmol/microg DNA; P < 0.004). In contrast, there was no significant difference in MGMT activity in adenomas lacking a K-ras GC-->AT transition mutation and adjacent normal mucosa. N7-methylguanine levels however did not vary with age, gender, K-ras mutational status or MGMT activity. These results are consistent with the acquisition of K-ras GC-->AT transition mutations in adenomas with low MGMT activity as a result of unavoidable exposure to methylating agents.

Heterogeneity of O(6)-alkylguanine-DNA alkyltransferase activity in colorectal cancer: implications for treatment.

OBJECTIVES: MGMT (O(6)-alkylguanine-DNA alkyltransferase) reverses the carcinogenic, mutagenic and cytotoxic effects of alkylating agents. Measurement of MGMT activity in tumours might thus be of use in selecting those patients with colorectal cancer who may be sensitive to adjuvant alkylating agent therapy. The aim of this study was to assess whether measurement of MGMT activity in a single tumour biopsy is representative of the whole tumour. METHODS: Multiple symmetrically spaced biopsies were taken from colorectal cancers obtained from 9 patients. MGMT activity was then measured in cell-free extracts by quantifying the transfer of [(3)H]methyl group from calf thymus DNA methylated in vitro with N-nitroso-N-[(3)H]-methylurea to the MGMT protein. RESULTS: MGMT activity was detected in all tumour samples with the activity ranging between 3.6 and 36.2 fmol/microg DNA and 202-1,986 fmol/mg protein. Heterogeneity in MGMT activity (ratio of maximum/minimum MGMT levels per tumour) varied between 1.3 and 5.4. CONCLUSIONS: Measurement of MGMT activity in a single biopsy is not necessarily indicative of the level throughout the tumour. The response of colorectal cancers to alkylating agent treatment is likely to be non-uniform both within the tumour and between patients.

DNA alkylation and repair in the large bowel: animal and human studies.

O6-methylguanine (O6-MeG), a procarcinogenic DNA adduct that arises from exposure to methylating agents, has been detected in human colorectal DNA at levels comparable to those that cause adverse effects in model systems. O6-MeG levels vary within the colon, being higher in the cancer-prone regions of the large bowel. In rats and mice, O6-MeG persistence in colon DNA is associated with the induction of colon tumors after treatment with methylating agents. These tumors frequently contain K-ras GC-->AT transition mutations, which is consistent with the mutagenic properties of O6-MeG: such mutations are also commonly found in human colorectal cancers. O6-Alkylguanine adducts are removed by the DNA repair protein, O6-alkylguanine DNA-alkyltransferase (MGMT). MGMT overexpression in transgenic mice reduces the formation of K-ras GC-->AT mutations and tumors induced by methylating agents. Interindividual variations in human colon MGMT activity are large and large bowel tumors can occur in regions of low activity. Low MGMT activity in normal mucosa has been associated with the occurrence of K-ras GC-->AT mutations, whereas reduced MGMT expression and an increased frequency of K-ras GC-->AT mutations in colorectal cancers have been linked to MGMT promoter methylation. MGMT activity is also lower in adenomas than in adjacent normal tissue but only in those adenomas with this specific mutation. These results are entirely consistent with the hypothesis that GC-->AT mutations in the K-ras oncogene result from the formation and persistence of O6-alkylguanine lesions in colorectal DNA. Human exposure to endogenous or exogenous alkylating agents may thus be an environmental determinant of colorectal cancer risk.