Merril T. Dayton

Alvimopan, a novel, peripherally acting μ opioid antagonist: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus

Objective:To demonstrate that alvimopan (6 or 12 mg) accelerates recovery of gastrointestinal (GI) function in patients undergoing laparotomy for bowel resection or radical hysterectomy. Summary Background Data:Postoperative ileus (POI) following laparotomy may increase morbidity and extend hospitalization. Opioids can contribute to the duration of POI. Alvimopan is a novel opioid receptor antagonist in development for the management of POI. Methods:A total of 510 patients scheduled for bowel resection or radical hysterectomy were randomized (1:1:1) to receive alvimopan 6 mg, alvimopan 12 mg, or placebo orally ≥2 hours before surgery, then twice a day (b.i.d.) until hospital discharge or for up to 7 days. The primary efficacy end point was a composite of time to recovery of upper and lower GI function. An associated secondary end point was time to hospital discharge order written. Results:The modified intent-to-treat population included 469 patients (451 bowel resection and 18 radical hysterectomy patients). Time to recovery of GI function was accelerated for the alvimopan 6 mg (hazard ratio [HR] = 1.28; P < 0.05) and 12 mg (HR = 1.54; P < 0.001) groups with a mean difference of 15 and 22 hours, respectively, compared with placebo. The time to hospital discharge order written was also accelerated in the alvimopan 12 mg group (HR = 1.42; P = 0.003) with a mean difference of 20 hours compared with placebo. The incidence of adverse events was similar among treatment groups. Conclusions:Alvimopan accelerated GI recovery and time to hospital discharge order written compared with placebo in patients undergoing laparotomy and was well tolerated.

Prevention of postoperative abdominal adhesions by a novel, glycerol/sodium hyaluronate/carboxymethylcellulose-based bioresorbable membrane: A prospective, randomized, evaluator-blinded multicenter study

INTRODUCTIONPostoperative abdominal adhesions are associated with significant morbidity and mortality, placing a substantial burden on healthcare systems worldwide. Development of a bioresorbable membrane containing up to 23 percent glycerol and chemically modified sodium hyaluronate/carboxymethylcellulose offers ease of handling and has been shown to provide significant postoperative adhesion prevention in animals. This study was designed to assess the safety of glycerol hyaluronate/carboxymethylcellulose and to evaluate its efficacy in reducing the incidence, extent, and severity of postoperative adhesion development in surgical patients.METHODSTwelve centers enrolled 120 patients with ulcerative colitis or familial polyposis who were scheduled for a restorative proctocolectomy and ileal pouch-anal anastomosis with diverting loop ileostomy. Before surgical closure, patients were randomized to no antiadhesion treatment (control) or treatment with glycerol hyaluronate/carboxymethylcellulose membrane under the midline incision. At ileostomy closure, laparoscopy was used to evaluate the incidence, extent, and severity of adhesion formation to the midline incision.RESULTSData were analyzed using the intent-to-treat population. Treatment with glycerol hyaluronate/carboxymethylcellulose resulted in 19 of 58 patients (33 percent) with no adhesions compared with 6 of 60 adhesion-free patients (10 percent) in the no treatment control group (P = 0.002). The mean extent of postoperative adhesions to the midline incision was significantly lower among patients treated with glycerol hyaluronate/carboxymethylcellulose compared with patients in the control group (P < 0.001). The severity of postoperative adhesions to the midline incision was significantly less with glycerol hyaluronate/carboxymethylcellulose than with control (P < 0.001). Adverse events were similar between treatment and no treatment control groups with the exception of abscess and incisional wound complications were more frequently observed with glycerol hyaluronate/carboxymethylcellulose.CONCLUSIONSGlycerol hyaluronate/carboxymethylcellulose was shown to effectively reduce adhesions to the midline incision and adhesions between the omentum and small bowel after abdominal surgery. Safety profiles for the treatment and no treatment control groups were similar with the exception of more infection complications associated with glycerol hyaluronate/carboxymethylcellulose use. Animal models did not predict these complications.

Should total number of lymph nodes be used as a quality of care measure for stage III colon cancer

Objective:To assess whether TNODS is an independent prognostic factor after adjusting for the lymph node ratio (LNR). Summary Background Data:The medical literature has suggested that the TNODS is associated with better survival in stage II and III colon cancer. Thus TNODS was endorsed as a quality measure for patient care by American College of Surgeons, National Quality Forum. There is, however, little biologic rationale to support this linkage. Methods:A total of 24,477 stage III colon cancer patients were identified from Surveillance, Epidemiology, and End Results cancer registry and categorized into 4 groups, LNR1 to LNR4, according to LNR interval: <0.07, 0.07 to 0.25, 0.25 to 0.50, and >0.50. Patients were also stratified according to TNODS into high TNODS (≥12) and low TNODS (<12) groups. The method of Kaplan-Meier was used to estimate the 5-year survival and the log-rank test was used to test the survival difference among the different groups. Results:Patients with high TNODS have better survival compared with those with low TNODS (5-year survival 51.0% vs. 45.0%, P < 0.0001). However, after stratifying by LNR status, there was no significant survival difference between patients with high TNODS and those with low TNODS within strata LNR2 (5-year survival 56.3% vs. 56.0%, P = 0.26). Ironically, patients with high TNODS had significantly worse survival than those with low TNODS within strata LNR3 (5-year survival 41.2% vs. 47.4%, P = 0.0009) and LNR 4 (5-year survival 22.0% vs. 32.1%, P < 0.0001). Conclusions:The previously reported prognostic effect of TNODS on node-positive colon cancer was confounded by LNR. This observation calls into question the use of TNODS as a quality measure for colon cancer patients’ care.

Ulcerative colitis and cancer.

Patients with ulcerative colitis (UC) are at an increased risk for the development of colorectal cancer (CRC). Unlike sporadic CRC, the cancer in UC patients arises from a focal or multifocal dysplastic mucosa in areas of inflammation. The clinical features of UC‐associated cancer are similar to those found in patients with hereditary non‐polyposis colorectal cancer. As with other varieties of CRC, UC‐associated cancer exhibits a variety of genetic and molecular changes/abnormalities. These abnormalities are however clustered in areas of mucosae with histological abnormalities. The magnitude and timing of these changes are however significantly different. Surveillance and identification of patients at risk for cancer are a challenging problem. J. Surg. Oncol. 2010; 101:706‐712.

The Prognostic Superiority of Log Odds of Positive Lymph Nodes in Stage III Colon Cancer

BackgroundLiterature showed that lymph node ratio (LNR) and total number of lymph nodes (TNODS) are independent prognostic factors in node-positive colon cancer. Our study assesses the prognostic superiority of the log odds of positive lymph nodes (LODDS) in the same patient population.Material and MethodsA total of 24,477 stage III colon cancer cases from the SEER registry were reviewed. Patients were categorized based on LNR into LNR1 to LNR4, according to cutoff points 0.07, 0.25, and 0.50, and based on LODDS into LODDS1 to LODDS5, according to cutoff points −2.2, −1.1, 0, and 1.1. The relative risk (RR), and 95% confidence interval (CI) were evaluated using the method of Kaplan–Meier and Cox model.ResultsPatients with LNR4 could be classified into LODDS4 (61.4%) and LODDS5 (38.4%). The survival in these two groups was significantly different (5-year survival, 33.5% vs. 23.3%, p < 0.0001). Univariate analysis showed that the higher LNR (RR = 3.45, 95% CI = 3.26–3.66) or low TNODS (RR = 0.99, 95% CI = 0.986–0.99) was significantly associated with poor survival. However, after adjusting for LODDS status, the association did not appear to be significant (LNR, RR = 0.90, 95% CI = 0.65–1.24, p = 0.52; TNODS, RR = 1.001, 95% CI = 0.997–1.005, p = 0.54).ConclusionColon cancer patients with LNR4 disease represent a heterogeneous group. The previously reported prognostic association of TNODS and LNR and outcome of stage III disease were confounded by LODDS.

What Is New in Cytokine Research Related to Trauma/Critical Care

Cytokines are low molecular weight proteins whose production can be modified by various insults. They have the potential to modify cellular responses to these insults. Recent years have seen a plethora of research in cytokine biology in trauma and critical care.

Regulated expression of the IL-31 receptor in bronchial and alveolar epithelial cells, pulmonary fibroblasts, and pulmonary macrophages.

Interleukin-31 (IL-31), an IL-6 cytokine family member, is proposed to play a role in animal models of airway hyperreactivity. It is produced by activated T cells and signals via a heterodimeric receptor complex composed of IL-31Ralpha and OSMRbeta. Only low levels of IL-31Ralpha expression have been demonstrated in pulmonary epithelial cell lines, however, and little is known about the ability to regulate its expression and signaling. Therefore, primary cultures of human bronchial and alveolar epithelial cells, pulmonary fibroblasts, pulmonary macrophages, and established lines of immortalized bronchial epithelial cells (HBE) and alveolar carcinoma cells (A549) were analyzed by RT-PCR, immunoblotting, and thymidine incorporation. Distinct, cell type-specific regulation of IL-31Ralpha expression was detected. Transforming growth factor-beta (TGF-beta) enhanced IL-31Ralpha mRNA expression in primary cultures and established lines of epithelial cells, but not in macrophages. In contrast, interferon-gamma (IFN-gamma) induced IL-31Ralpha mRNA expression in macrophages. IL-31Ralpha protein expression was below detection threshold in primary epithelial cell cultures but was detectable in A549 cells and increased with TGF-beta treatment. In HBE and A549 cells, TGF-beta pretreatment increased IL-31-mediated Stat3 and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. In A549 cells, TGF-beta magnified IL-31-dependent suppression of proliferation. The data suggest that increased IL-31Ralpha expression correlates with an enhanced response to IL-31.

Are facilities following best practices of pediatric abdominal CT scans

BACKGROUND Established guidelines for pediatric abdominal CT scans include reduced radiation dosage to minimize cancer risk and the use of intravenous (IV) contrast to obtain the highest-quality diagnostic images. We wish to determine if these practices are being used at nonpediatric facilities that transfer children to a pediatric facility. METHODS Children transferred to a tertiary pediatric facility over a 16-mo period with abdominal CT scans performed for evaluation of possible appendicitis were retrospectively reviewed for demographics, diagnosis, radiation dosage, CT contrast use, and scan quality. If CT scans were repeated, the radiation dosage between facilities was compared using Student t-test. RESULTS Ninety-one consecutive children transferred from 29 different facilities had retrievable CT scan images and clinical information. Half of CT scans from transferring institutions used IV contrast. Due to poor quality or inconclusive CT scans, 19 patients required a change in management. Children received significantly less radiation at our institution compared to the referring adult facility for the same body area scanned on the same child (9.7 mSv versus 19.9 mSv, P = 0.0079). CONCLUSION Pediatric facilities may be using less radiation per CT scan due to a heightened awareness of radiation risks and specific pediatric CT scanning protocols. The benefits of IV contrast for the diagnostic yield of pediatric CT scans should be considered to obtain the best possible image and to prevent additional imaging. Every facility performing pediatric CT scans should minimize radiation exposure, and pediatric facilities should provide feedback and education to other facilities scanning children.

Lower extremity endovascular interventions: Can we improve cost-efficiency?

OBJECTIVE Management of lower extremity arterial disease with endovascular intervention is on the rise. Current practice patterns vary widely across and within specialty practices that perform endovascular intervention. This study evaluated reimbursement and costs of different approaches for offering endovascular intervention and identified strategies to improve cost-efficiency. METHODS The medical records of all patients admitted to a university health system during 2005 for an endovascular intervention were retrospectively reviewed. Procedure type, setting, admission status, and financial data were recorded. Groups were compared using analysis of variance, Student t test for independent samples, and chi2. RESULTS A total of 296 endovascular interventions were completed, and 184 (62%) met inclusion criteria. Atherectomy and stenting were significantly more costly when performed in the operating room than in the radiology suite: atherectomy, dollars 6596 vs dollars 4867 (P = .002); stent, dollars 5884 vs dollars 3292, (P < .001); angioplasty, dollars 2251 vs dollars 1881 (P = .46). Reimbursement was significantly higher for inpatient vs ambulatory admissions (P < .001). Costs were lowest when the endovascular intervention was done in the radiology suite on an ambulatory basis and highest when done as an inpatient in the operating room (dollars 5714 vs dollars 12,278; P < .001). Contribution margins were significantly higher for inpatients. Net profit was appreciated only for interventions done as an inpatient in the radiology suite. Reimbursement, contribution margins, and net profit were significantly lower among private pay patients in both the ambulatory and inpatient setting. The 30-day hospital readmission after ambulatory procedures was seven patients (6%). CONCLUSIONS Practice patterns for endovascular interventions differ considerably. Costs vary by procedure and setting, and reimbursement depends on admission status and accurate documentation; these dynamics affect affordability. Organizing vascular services within a hub will ensure that care is delivered in the most cost-efficient manner. Guidelines may include designating the radiology suite as the primary venue for endovascular interventions because it is less costly than the operating room. Selective stenting policies should be considered. Contracts with private insurers must include carve-outs for stent costs and commensurate reimbursement for ambulatory procedures, and Current Procedural Terminology (CPT; American Medical Association, Chicago, Ill) coding must be proficient to make ambulatory endovascular interventions fiscally acceptable.

Dual Kidney Transplants From Very Old or Very Young Donors: Long-Term Outcomes and Complications

The disparity between donors and the demand for organ transplants grows steadily. Annually, 4700 patients die on the kidney transplant waiting list in the United States. To increase utilization of deceased donor organs, we expanded our acceptable criteria to include very old (VO) or very young (VY) donors. We transplanted both such kidneys (dual transplant) into a single recipient and evaluated the long-term outcomes and complications. From July 2001 to December 2005, 16 patients (mean age 68, range 60-78) received dual kidneys from VO (mean age 72, range 60-79) donors and 6 patients (mean age 47, range 27-72) were transplanted from VY (mean age 17 months, range 2-36) donors. Seventy-four percent of these kidneys were imported after rejection by their local center due to low glomerular filtration rate (GFR) and extreme age. One- and 5-year patient survival rates were 100% and 88%, respectively. Death-censored 1- and 5-year graft survival rates for recipient of VO kidneys were 95% and 93%, and 66% and 50% for recipients of VY kidneys, respectively. Five-year graft survival rate for recipients of VO donor kidneys was 93% and was equal to the survival of standard deceased donor (SCD) kidney transplants (87%). The 5-year survival of dual transplants from VO donors was higher than expanded criteria deceased donor (ECD; P=.05). Over a mean follow-up of 66±28 months, rejection rates were 10%, not statistically different than other groups. Of 22 dual transplants, four patients experienced urinary tract infections; three developed incisional subcutaneous seromas, and there were more urinary leaks compared to SCD (13.6% vs 2%, P=.002). The average 1- and 5-year estimated GFR (Cockcroft-Gault) was 57.4 and 54.6 mL/min, respectively. When properly placed in a single patient, such marginal organs are a valuable resource that offer comparable outcomes to SCD transplants and superior outcomes to ECD organs.