Gordon L Carlson

Randomized clinical trial of the effects of immediate enteral nutrition on metabolic responses to major colorectal surgery in an enhanced recovery protocol

The effects of immediate postoperative enteral nutrition on postoperative nitrogen balance and insulin resistance were studied in patients subjected to an enhanced‐recovery protocol.

Systematic review of preoperative, intraoperative and postoperative risk factors for colorectal anastomotic leaks

Anastomotic leak (AL) represents a dreaded complication following colorectal surgery, with a prevalence of 1–19 per cent. There remains a lack of consensus regarding factors that may predispose to AL and the relative risks associated with them. The objective was to perform a systematic review of the literature, focusing on the role of preoperative, intraoperative and postoperative factors in the development of colorectal ALs.

Interferon-{gamma} selectively increases epithelial permeability to large molecules by activating different populations of paracellular pores.

Impairment of the gut epithelial barrier by agents such as IFNγ may play a key role in the pathogenesis of inflammatory disorders by increasing the paracellular penetration of luminal macromolecules, potentially including bacterial antigens. Owing to limitations of current paracellular probes, little is known about the precise functional changes induced by IFNγ and how these relate to the development of increased macromolecular permeability. Here we investigate how IFNγ modulates this pathway in T84 monolayers using a novel profiling technique that resolves different populations of paracellular pores by simultaneous analysis of 24 permeability probes of defined molecular size. Two types of functional pore present in control monolayers, an abundant restrictive pore with a radius of ∼4.5 Å and a much larger but infrequent, non-restrictive pore, were differentially regulated by IFNγ. Incubation with IFNγ dose-dependently and reversibly increased the frequency of the non-restrictive pores while having no significant effect on the restrictive component. Cytokine-induced increases in β, the descriptor of the non-restrictive pore, correlated closely with increased permeability to large molecules (10 kDa) including E. coli-derived lipopolysaccharide, but not small (0.182 kDa) molecules. This effect was associated with changes in expression of the tight junction proteins occludin and claudin-1. These data suggest that IFNγ selectively increases the transepithelial flux of large molecules by activating specific pathways within the junctional pore. One hypothesis is that this process may be activated in the early stages of the inflammatory response, facilitating the passage of large and potentially antigenic molecules across the gut without gross disruption of the barrier to small molecules.

Glutamine deprivation facilitates tumour necrosis factor induced bacterial translocation in Caco-2 cells by depletion of enterocyte fuel substrate

Background and aims: Factors that induce luminal bacteria to cross the intestinal epithelium following injury remain poorly defined. The aim of this study was to investigate the interaction between glutamine metabolism, energy supply, and inflammatory mediators in determining the translocation of non-pathogenic bacteria across cultured enterocytes. Methods: The effect of tumour necrosis factor α (TNF-α) on translocation of Escherichia coli C25 across Caco-2 epithelial monolayers was studied in the presence of products and inhibitors of glutamine metabolism. Simultaneous measurements of transepithelial electrical resistance (TEER) and flux of lucifer yellow were used to assess effects on the paracellular pathway. Lactate dehydrogenase release was used to monitor enterocyte integrity. Imaging of monolayers in these experimental conditions was undertaken with transmission electron microscopy. Results: Exposure to basolateral TNF-α (20 ng/ml) for six hours induced translocation of E coli across Caco-2 but only if accompanied by simultaneous glutamine depletion (p<0.01). Translocation was inhibited by addition of glutamine for two hours (p<0.01) but not by an isonitrogenous mixture of non-glutamine containing amino acids. Inhibition of glutamine conversion to α-ketoglutarate, but not blockade of glutathione or polyamine synthesis, also induced translocation in the presence of TNF-α. Manipulations that induced bacterial translocation were associated with a marked reduction in enterocyte ATP levels. No effect of these treatments on paracellular permeability or lactate dehydrogenase release was observed. Conditions in which translocation occurred were associated with the presence of bacteria within enterocyte vacuoles but not the paracellular space. Conclusions: In inflammatory conditions, the availability of glutamine as an enterocyte fuel substrate is essential for the preservation of a functional barrier to microorganisms. In conditions of acute glutamine depletion, cytokine mediated bacterial translocation appears to be primarily a transcellular process.

Fistuloclysis can successfully replace parenteral feeding in the nutritional support of patients with enterocutaneous fistula

Use of total parenteral nutrition (TPN) in patients with acute intestinal failure due to enteric fistulation might be avoided if a simpler means of nutritional support was available. The aim of this study was to determine whether feeding via an intestinal fistula (fistuloclysis) would obviate the need for TPN.

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.

Systematic review of genetic influences on the prognosis of colorectal cancer.

In terms of genetics, colorectal cancer is one of the best understood of all malignant diseases. Genetic influences on prognosis may have far‐reaching implications, especially for the design of surgical and chemoradiotherapeutic regimens. However, their significance in determining prognosis remains unclear. This study aimed to review the literature on the specific role of key genes in determining the survival of patients with colorectal cancer.

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.

Intestinal rehabilitation and bowel reconstructive surgery: improved outcomes in children with short bowel syndrome.

Background and Aim: Short bowel syndrome poses a great challenge to pediatric teams. Several innovative techniques in the management of total parenteral nutrition (TPN) and bowel reconstructive surgery have improved the outcomes of these children. The authors present their experience during the last decade as a specialist unit using improved techniques and multidisciplinary approaches in the management of this condition. Methods: All of the children presenting with short bowel syndrome between 2000 and 2009 were identified. Diagnosis, length of residual gut, age at definitive surgery, length of gut prelengthening, length of gut postlengthening, TPN status, and survival were recorded. Median values were calculated. Results: Twenty-seven children were identified (14 boys, 13 girls). Overall survival was 92%. Two children died. Nineteen children required bowel lengthening and 8 children had simple bowel reconstruction while on our protocol. Overall median age at definitive surgery was 12 months. Overall median residual gut length for these was 35.5 cm, whereas the median residual gut length for patients undergoing bowel lengthening was 25 cm. Postbowel lengthening, the median gut length was 90 cm. TPN data were unavailable for 2 patients. Overall, excluding the 2 patients who died and the 2 we have no TPN data on, of 23 patients, 21 (91%) are now off TPN. Conclusions: Our series shows improved results not only with survival but also in the number of patients that are off TPN. Multidisciplinary approach consisting of both medical and surgical expertise is necessary in the management of these patients. The authors advocate centralisation of short gut services to experienced centers with multidisciplinary expertise.

Serum leptin concentrations and their relation to metabolic abnormalities in human sepsis

Circulating leptin concentrations are raised in animal models of inflammation and sepsis. The purpose of this study was to determine the effect of sepsis on serum leptin concentration in humans and to examine the relationship between leptin and the metabolic consequences of sepsis. Resting energy expenditure, insulin sensitivity, and fasting serum leptin, plasma insulin, and cortisol concentrations were measured in 20 subjects with intra-abdominal sepsis and 20 healthy control subjects, before and during a 2-h period of euglycemic hyperinsulinemia. Fasting serum leptin concentrations were similar in septic and control subjects. In simple regression analysis, serum leptin concentrations correlated significantly with percent body fat in both septic patients ( r = 0.64, P < 0.005) and healthy subjects ( r = 0.75, P < 0.0001). Multiple regression analyses additionally indicated that percent body fat, fasting plasma insulin, and plasma cortisol, but not sepsis, were significant and independent determinants of serum leptin concentration. No relationship between leptin and resting energy expenditure or insulin sensitivity was identifiable. A major metabolic role for leptin in human sepsis therefore appears unlikely.Circulating leptin concentrations are raised in animal models of inflammation and sepsis. The purpose of this study was to determine the effect of sepsis on serum leptin concentration in humans and to examine the relationship between leptin and the metabolic consequences of sepsis. Resting energy expenditure, insulin sensitivity, and fasting serum leptin, plasma insulin, and cortisol concentrations were measured in 20 subjects with intra-abdominal sepsis and 20 healthy control subjects, before and during a 2-h period of euglycemic hyperinsulinemia. Fasting serum leptin concentrations were similar in septic and control subjects. In simple regression analysis, serum leptin concentrations correlated significantly with percent body fat in both septic patients (r = 0. 64, P < 0.005) and healthy subjects (r = 0.75, P < 0.0001). Multiple regression analyses additionally indicated that percent body fat, fasting plasma insulin, and plasma cortisol, but not sepsis, were significant and independent determinants of serum leptin concentration. No relationship between leptin and resting energy expenditure or insulin sensitivity was identifiable. A major metabolic role for leptin in human sepsis therefore appears unlikely.