Hypercapnia and surgical site infection: a randomized trial.

BACKGROUND: Tissue oxygenation is a strong predictor of surgical site infection (SSI). Mild intraoperative hypercapnia increases peripheral, gastrointestinal, and splanchnic tissue oxygenation and perfusion. Hypercapnia also has anti-inflammatory effects. However, it is unknown whether hypercapnia reduces SSI risk. We tested the hypothesis that mild intraoperative hypercapnia reduces the risk of SSI in patients having colon resection surgery. METHODS: With institutional review board approval and subject consent, patients having elective colon resection (e.g. hemicolectomy and low-anterior resection) expected to last >2 h were randomly assigned to intraoperative normocapnia (PE'CO2 ≈ 35 mm Hg; n=623) or hypercapnia ( PE'CO2 ≈ 50 mm Hg; n=592). Investigators blinded to group assignment evaluated perioperative SSI (Center for Disease Control criteria) for 30 postoperative days. SSI rates were compared. RESULTS: Patient and surgical characteristics were comparable among the groups. The SSI rate for normocapnia was 13.3%, and for hypercapnia, it was 11.2% (P=0.29). The Executive Committee stopped the trial after the first a priori determined statistical assessment point because of much smaller actual effect compared with the projected. However, because the actual difference found in the SSI rates (15-16%) were within the 95% confidence intervals (CIs) of the projected relative difference of 33% (95% CI -43 to +24%), our results cannot be considered as 'no difference', and cannot exclude a Type II error. Time to first bowel movement was half-a-day shorter in the hypercapnia group. CONCLUSIONS: Mild hypercapnia appears to have little or-possibly-no ability to prevent SSI after colon resection. Other strategies for reducing SSI risk should thus take priority.

SMAD2 and the relationship of colorectal cancer to inflammatory bowel disease.

Inflammatory bowel diseases (IBDs) affecting the colon [Crohn's disease (CD) and ulcerative colitis (UC)] are associated with an increased risk of colorectal cancer (CRC). Our previous work using oligonucleotide array data indicated that SMAD2 was significantly underexpressed in UC dysplastic tissue compared to benign UC. The aim of this current study was to determine whether single nucleotide polymorphisms (SNPs) within the SMAD2 gene are associated with IBD dysplasia/cancer. We performed an SNP haplotype-based case-control association study. Leukocyte DNA was obtained from 489 unrelated Caucasians (158 UC, 175 CD, 71 CRC, 85 controls). Eleven SNPs were genotyped. All 11 SNPs were in Hardy-Weinberg equilibrium in the control population. Strong linkage disequilibrium was observed among nearly all SMAD2 SNPs. There were no significant associations between SMAD2 allele or haplotype frequencies. Power calculations indicated good power for single-marker analysis (>0.8) and reasonably good power against effects of 0.1-0.15 for haplotype analysis. SMAD2 SNPs were not associated with the development of IBD dysplasia/cancer. This incongruity between our previous microarray data and the findings from this genotype study may be attributed to mechanisms such as alternative splicing of pre-mRNA SMAD2 and/or cross talk with other cellular pathways.

Assessment of publication bias for the surgeon scientist.

BACKGROUND: Publication bias occurs when statistically non-significant (negative) findings are not published. It can profoundly affect the results of systematic reviews and meta-analyses. METHODS: Qualitative and quantitative methods of detecting publication bias are described, including their advantages and disadvantages. RESULTS AND CONCLUSION: Accepted quality standards for the reporting of meta-analyses recommend assessment of publication bias, but currently there is no uniform standard for reporting. Quantitative methods are being used with increasing frequency. Authors should take steps to minimize publication bias, and use both qualitative and quantitative assessment methods to determine whether it is present.

Meta-analysis: antibiotic prophylaxis to prevent peristomal infection following percutaneous endoscopic gastrostomy.

BACKGROUND: Despite numerous guidelines recommending prophylactic antibiotics prior to percutaneous endoscopic gastrostomy, their use remains controversial. AIM: To conduct a systematic literature review and performed meta-analyses to determine the benefit of antibiotic prophylaxis for percutaneous endoscopic gastrostomy placement. METHODS: We performed a systematic literature review by searching healthcare databases and grey literature for randomized-controlled trials of antibiotic prophylaxis against wound infection after percutaneous endoscopic gastrostomy. Relative risks were calculated for individual trials and data pooled using fixed-effects model. Relative risk reduction, absolute risk reduction and number needed to treat were calculated and are reported with 95% confidence intervals. RESULTS: Ten randomized-controlled trials met the inclusion criteria and 1059 cases were pooled. Overall findings indicated that antibiotic prophylaxis resulted in a relative risk reduction of 64% and an absolute risk reduction of 15%. Number needed to treat to prevent one wound infection was 8. Cephalosporin prophylaxis was associated with a relative risk reduction of 64%, absolute risk reduction of 10% and number needed to treat of 10, whereas penicillin-based prophylaxis was associated with a relative risk reduction of 62%, absolute risk reduction of 13% and number needed to treat of 8. CONCLUSIONS: Antibiotic prophylaxis prior to percutaneous endoscopic gastrostomy is effective in reducing the incidence of percutaneous endoscopic gastrostomy site wound infection. Based on sensitivity analyses, penicillin-based prophylaxis should be the prophylaxis of choice.

Systematic reviews and meta-analysis for the surgeon scientist.

BACKGROUND: Understanding of data-reporting methods is imperative for correct interpretation of the medical literature as well as for proper performance of future clinical research. Recent developments in biostatistics have greatly changed the types of statistical analyses used and the minimum quality standards that must be maintained. METHOD: Different types of review are described, including systematic review with and without meta-analysis. Minimum reporting standards, sources of bias, both quantitative and qualitative, and references are discussed. RESULTS AND CONCLUSION: Meta-analysis has become a clearly defined technique, with reporting standards for both randomized controlled trials and observational studies. It is assuming a wider role in the surgical literature. Although many sources of bias exist, there are clear reporting standards and readers should be aware of these when studying the literature.

Effect of intra-operative end-tidal carbon dioxide partial pressure on tissue oxygenation.

Postsurgical infection risk is correlated with subcutaneous tissue oxygenation. Mild hypercapnia augments cutaneous perfusion. We tested the hypothesis that peripheral tissue oxygenation increases as a function of arterial PCO2 in surgical patients. Twenty patients were randomly assigned to intra-operative end tidal PCO2 of 3.99 (control) or 5.99 kPa (hypercapnia). All other anaesthetic management was per protocol. Tissue oxygen partial pressure, transcutaneous oxygen tension, cerebral oxygen saturation, and cardiac output were measured. Mean (SD) subcutaneous tissue oxygen tension was 8.39 (1.86) kPa in control and 11.84 (2.53) kPa hypercapnia patients (p = 0.014). Cerebral oxygen saturation was 55 (4)% for control vs. 68 (9)% for hypercapnia (p = 0.004). Neither cardiac index nor transcutaneous tissue oxygen tension differed significantly between the groups. Mild intra-operative hypercapnia increased subcutaneous and cerebral oxygenation. Increases in subcutaneous tissue oxygen partial pressure similar to those observed in patients assigned to hypercapnia are associated with substantial reductions in wound infection risk.

Identification of candidate genes in ulcerative colitis and Crohn's disease using cDNA array technology.

Inflammatory bowel disease (IBD) follows a multigenic mode of inheritance, encompassing the clinically discrete phenotypes of ulcerative colitis (UC) and Crohn's disease (CD). The risk of malignant transformation of the colon increases with the duration and extent of IBD and is particularly high for patients with a longstanding history of UC. We wished to identify candidate genes that might be involved in disease pathogenesis based on functional plausibility and their putative role in IBD carcinogenesis. Polyadenylated mRNA (PolyA+ mRNA) preparation from inflamed intestinal mucosa of patients with a longstanding history of UC and CD was performed with subsequent hybridization of alpha phosphorus [alpha-32P]-deoxyadenotriphosphate-labeled complementary deoxyribonucleic acid (DNA) populations to nucleic acid arrays. Of 588 different human gene transcripts arrayed, secreted apoptosis-related protein 1 (Sarp1), frizzled (fz) homologues, and disheveled (dvl) were differentially expressed, being elevated in UC as compared to CD. These genes encode proteins involved in the Wingless-type (Wnt)/beta-catenin signaling pathway. The autonomous expression of Sarp1 and Sarp1-compatible fz receptor genes suggests that the Wnt pathway may be involved in UC carcinogenesis.

Wingless-type frizzled protein receptor signaling and its putative role in human colon cancer.

We wish to identify new candidate genes involved in the pathogenesis of human colon cancer to better understand the diversity of phenotype presentation that varies from individual to individual. Our working hypothesis is that genetic polymorphism of genes in the Wingless-type (Wnt) frizzled protein receptor pathway is associated with the susceptibility to develop colon cancer. The putative role of the Wnt pathway in sporadic human malignancy of the colon suggests involvement in inherited cancer as well. beta-catenin is the crucial messenger in frizzled receptor signaling, transmitting Wnt-ligand signals such as signals from secreted apoptosis-related proteins to the nucleus. It functions as a genome denunciator by initiating amplification of oncogenes. The net effect of beta-catenin depends on the magnitude of its accumulation in the cytoplasm and, therefore, upon expression profiles of genes in the Wnt pathway. We propose that variations in allelic frequencies of genes involved in the beta-catenin cascade may either promote or impede malignant transformation of the colon. If certain polymorphisms in Wnt signaling through beta-catenin predispose to colon cancer, this might manifest as decreased binding affinity of proteins such as axin or the adenomatous polyposis coli protein to beta-catenin. Association studies are proposed to test the hypothesis, which could serve as an initial step toward understanding the complexity of tumor biology. The clinical rationale in unraveling the genetic susceptibility to cancer lies in identification of a subgroup of individuals who may benefit from beta-catenin targeting agents, which could potentially overcome this genetic instability.

Association of susceptibility locus for inflammatory bowel disease on chromosome 16 with both ulcerative colitis and Crohn's disease.

A susceptibility locus for inflammatory bowel disease (IBD) on chromosome 16 (IBD1) has been linked to Crohn's disease in genome-wide linkage studies. We performed a case-control study with two markers for this locus using leukocyte DNA from 127 Crohn's patients, 83 ulcerative colitis patients, and 74 control patients. Allele, genotype, and haplotype frequencies of the polymerase chain reaction products were determined using autoradiography. Haplotype frequencies differed for ulcerative colitis and Crohn's disease, particularly for haplotype CC (22% ulcerative colitis vs 10% Crohn's disease, P = 0.002 Chi2 = 10.0) and haplotype CD (18% Crohn's disease vs 9% ulcerative colitis, P = 0.025 Chi2 = 5.02). These data demonstrate the association of the IBD1 locus with both ulcerative colitis and Crohn's disease in a group of unrelated IBD patients. The use of such microsatellite markers when combined with others, might help distinguish ulcerative colitis from Crohn's disease in patients with ambiguous clinical and histological features.

Dynamic rectus abdominis muscle sphincter for stoma continence: an acute functional study in a dog model.

Fecal stomal incontinence is a problem that continues to defy surgical treatment. Previous attempts to create continent stomas using dynamic myoplasty have had limited success due to denervation atrophy of the muscle flap used in the creation of the sphincter and because of muscle fatigue resulting from continuous electrical stimulation. To address the problem of denervation atrophy, a stomal sphincter was designed using the most caudal segment of the rectus abdominis muscle, preserving its intercostal innervation as well as its vascular supply. The purpose of the present study was to determine whether this rectus abdominis muscle island flap sphincter design could maintain stomal continence acutely. In this experiment, six dogs were used to create eight rectus abdominis island flap stoma sphincters around a segment of distal ileum. Initially, the intraluminal stomal pressures generated by the sphincter using different stimulation frequencies were determined. The ability of this stomal sphincter to generate continence at different intraluminal bowel pressures was then assessed. In all cases, the rectus abdominis muscle sphincter generated peak pressures well above those needed to maintain stomal continence (60 mmHg). In addition, each sphincter was able to maintain stomal continence at all intraluminal bowel pressures tested.

Omental transposition for low pelvic anastomoses.

Surgeons' opinions differ regarding the role of the omentum in low pelvic intestinal anastomoses. This study was undertaken to define the anatomy and surgical technique of omental transposition to the pelvis. We studied 45 cadavers to elucidate surgical aspects of omental mobilization, lengthening, and transposition into the pelvic cavity. In addition, intraoperative studies of omental transposition to the pelvis were performed in 20 patients with chronic ulcerative colitis, familial adenomatous polyposis, and rectal cancer who were undergoing ileal J-pouch anal anastomosis or low anterior resection. The most important anatomic variables for omental transposition are three variants of arterial blood supply: (1) In 56% of patients, there is one right, one (or two) middle, and one left omental artery. (2) In 26% of patients, the middle omental artery is absent. (3) In the remaining 18% of patients, the gastroepiploic artery is continued as a left omental artery but with various smaller connections to the right or middle omental artery. The first stage of omental lengthening is detachment of the omentum from the transverse colon mesentery. This must be performed carefully, as the omentum is closely adherent to the right transverse mesocolon. The second stage is the actual lengthening of the omentum. The third stage is placement of the omental flap into the pelvis. Creation of an omental pedicle is a simple surgical procedure. This procedure can be performed quickly, does not involve significant blood loss, and may reduce the frequency of complications after low pelvic anastomoses.

The importance of diagnostic accuracy in colonic inflammatory bowel disease.

OBJECTIVE: Crohn's disease (CD) and ulcerative colitis (UC) may both affect the colon. However, in approximately 10-20% of these cases, it is impossible to distinguish between these two entities either clinically or histologically, and a diagnosis of indeterminate colitis (IC) is made. Correct diagnosis is important because surgical treatment and long-term prognosis differ for UC and CD. The purpose of this study was to determine the extent of interobserver agreement among board-certified pathologists and a specialist gastrointestinal (GI) pathologist regarding the histological diagnosis of colonic inflammatory bowel disease (IBD). METHODS: A total of 24 university medical center pathologists from eight institutions evaluated 84 colectomy specimens and 35 sets of biopsy specimens from 119 consecutive patients with colonic IBD. A specialist GI pathologist subsequently reviewed all cases without knowledge of clinical data and prior diagnosis. RESULTS: The GI pathologist's diagnoses differed from the initial diagnoses in 45% of surgical specimens and 54% of biopsy specimens. Of 70 cases initially diagnosed as UC, 30 (43%) were changed to CD or IC, whereas 4 of 23 cases (17%) initially diagnosed as CD were changed to UC or IC. The kappa coefficient for the overall agreement of initial diagnoses with the specialist GI pathologist's diagnoses was -0.01 (p = 0.98). CONCLUSIONS: There is significant interobserver variation in the histological diagnosis of colonic IBD. This may have a profound effect on clinical patient care and, especially, on the choice of operation. More accurate diagnostic criteria are needed to facilitate patient care and to optimize treatment outcome.

Safety and efficacy of dynamic graciloplasty for fecal incontinence: report of a prospective, multicenter trial. Dynamic Graciloplasty Therapy Study Group.

PURPOSE: Dynamic graciloplasty has been used for intractable fecal incontinence, and good results have been reported. The aim of this study was to assess prospectively the safety and efficacy of dynamic graciloplasty for intractable fecal incontinence in a prospective, multicenter trial. METHODS: A total of 123 adults were treated with dynamic graciloplasty at 20 institutions. Continence was assessed preoperatively and postoperatively by use of 14-day diaries. RESULTS: There was one treatment-related death. One hundred eighty-nine adverse events occurred in 91 patients (74 percent). Forty-nine patients (40 percent) required one or more operations to treat complications. One hundred seventy (90 percent) events were resolved. Sixty-three percent of patients without pre-existing stomas recorded a 50 percent or greater decrease in incontinent events 12 months after dynamic graciloplasty, and an additional 11 percent experienced lesser degrees of improvement. Twenty-six percent were not improved, worsened, or exited. In patients with pre-existing stomas, 33 percent achieved successful outcomes at 12 months. This number increased to 60 percent at 18 months. Seventy-eight percent of patients had increased enema retention time, and mean anal canal pressures improved significantly at 12 months. Significant changes in quality of life were also observed. CONCLUSIONS: Objective improvement can be demonstrated in the majority of patients with end-stage fecal incontinence treated with dynamic graciloplasty. Reduction in incontinence episodes can be correlated with improved quality of life. Adverse events are frequently encountered, but most resolve with treatment.

What's new with tumor markers for colorectal cancer?

BACKGROUND/AIMS: Many tumor markers have been utilized in the follow-up care of colorectal cancer patients. No marker, however, has proven reliably accurate in detecting recurrent disease. METHODS: The strengths and weaknesses of currently available tumor markers are reviewed, with attention to related cost and efficacy. RESULTS: Tumor antigens, enzymes, and genetic markers have been used as tumor markers. CEA and CA 19.9 are the most widely utilized; however, genetic markers are the most promising for the future. CONCLUSIONS: Currently available markers have significant limitations. Development of genetic markers may greatly enhance our ability to predict prognosis and the need for adjuvant therapy. Marker-guided therapy may play an increasing role in this disease.