Role of matrix metalloproteinase-8 as a mediator of injury in intestinal ischemia and reperfusion.

Acute mesenteric ischemia is associated with high morbidity and mortality. In recent studies, we found that the intestine is an important source of matrix metalloproteinase (MMP)8 during intestinal injury. We hypothesized that genetic ablation or pharmacological inhibition of MMP8 would reduce intestinal injury in mice subjected to intestinal ischemia-reperfusion (I/R) injury. Male mice aged 8-12 wk were subjected to intestinal I/R injury by transient occlusion of the superior mesenteric artery for 30 min. MMP8 was inhibited by genetic and pharmacological approaches. In vivo study endpoints included several functional, histological, and biochemical assays. Intestinal sections were assessed for barrier function and expression of tight junction proteins. I/R injury led to increased intestinal and systemic expression of MMP8. This increase was associated with increased intestinal neutrophil infiltration, epithelial injury, and permeability. I/R injury was associated with increased systemic inflammation and weight loss. These parameters were ameliorated by inhibiting MMP8. I/R injury caused a loss of the tight junction protein claudin-3, which was ameliorated by genetic ablation of MMP8. MMP8 plays an important role in intestinal I/R injury through mechanisms involving increased inflammation and loss of claudin-3. Inhibition of MMP8 is a potential therapeutic strategy in this setting.-Daly, M. C., Atkinson, S. J., Varisco, B. M., Klingbeil L., Hake, P., Lahni, P., Piraino, G., Wu, D., Hogan, S. P., Zingarelli, B., Wong, H. R. Role of matrix metalloproteinase-8 as a mediator of injury in intestinal ischemia and reperfusion.

Matrix Metalloproteinase-8 Augments Bacterial Clearance in a Juvenile Sepsis Model.

Genetic ablation or pharmacologic inhibition of matrix metalloproteinase-8 (MMP8) improves survival in an adult murine sepsis model. Because developmental age influences the host inflammatory response, we hypothesized that developmental age influences the role of MMP8 in sepsis. First, we compared sepsis survival between wild type (WT, C57BL/6) and MMP8 null juvenile-aged mice (12-14 days) after intraperitoneal injection of a standardized cecal slurry. Second, peritoneal lavages collected at 6 and 18 hours after cecal slurry injection were analyzed for bacterial burden, leukocyte subsets, and inflammatory cytokines. Third, juvenile WT mice were pretreated with an MMP8 inhibitor prior to cecal slurry injection; analysis of their bacterial burden was compared to vehicle-injected animals. Fourth, the phagocytic capacity of WT and MMP8 null peritoneal macrophages was compared. Finally, peritoneal neutrophil extracellular traps (NETs) were compared using immunofluorescent imaging and quantitative image analysis. We found that juvenile MMP8 null mice had greater mortality and higher bacterial burden than WT mice. Leukocyte counts and cytokine concentrations in the peritoneal fluid were increased in the MMP8 null mice, relative to the wild type mice. Peritoneal macrophages from MMP8 null mice had reduced phagocytic capacity compared to WT macrophages. There was no quantitative difference in NET formation, but fewer bacteria were adherent to NETs from MMP8 null animals. In conclusion, in contrast to septic adult mice, genetic ablation of MMP8 increased mortality following bacterial peritonitis in juvenile mice. The increase in mortality in MMP8 null juvenile mice was associated with reduced bacterial clearance and reduced NET efficiency. We conclude that developmental age influences the role of MMP8 in sepsis.

Intestine-Derived Matrix Metalloproteinase-8 Is a Critical Mediator of Polymicrobial Peritonitis.

OBJECTIVE: Inhibition of matrix metalloproteinase-8 improves survival following cecal ligation and puncture in mice, making it a potential therapeutic target. In the current study, we expand our understanding of the role of matrix metalloproteinase-8 in sepsis by using an adoptive transfer approach and alternative sepsis models. DESIGN: We used three different sepsis models: cecal ligation and puncture, cecal slurry, and intestinal implantation. In our first model, adoptive transfer experiments were followed by cecal ligation and puncture to test the hypothesis that matrix metalloproteinase-8-containing myeloid cells are a critical factor in sepsis following cecal ligation and puncture. Our second model, cecal slurry, used intraperitoneal injections of cecal contents to induce polymicrobial peritonitis without tissue compromise in the recipient. Our third model, intestinal implantation, involved ligating and puncturing a cecum from a donor, and then removing the cecum and placing it into the recipient's peritoneal cavity. Clinically, blood samples were drawn from pediatric patients within 24 hours of meeting criteria for septic shock. SETTING: Basic science laboratory. SUBJECTS: Wild type and genetically modified mice. INTERVENTIONS: Experimental models of sepsis. MEASUREMENTS AND MAIN RESULTS: In our adoptive transfer experiments, matrix metalloproteinase-8 null mice receiving wild-type marrow had a survival advantage when compared with wild-type mice receiving matrix metalloproteinase-8 null marrow, suggesting that matrix metalloproteinase-8-containing myeloid cells are not a critical factor in sepsis following cecal ligation and puncture. In our cecal slurry model, no survival advantage was seen among matrix metalloproteinase-8 null mice. Our third model, intestinal implantation, found that mice receiving matrix metalloproteinase-8 null intestine had a survival advantage when compared with mice receiving wild-type intestine, regardless of recipient genotype. Clinically, median matrix metalloproteinase-8 serum concentrations were higher in patients with sepsis and primary intestinal pathology than in septic patients without primary intestinal pathology. CONCLUSIONS: Intestine-derived matrix metalloproteinase-8 is a critical component of septic peritonitis secondary to intestinal compromise.

Combining Prognostic and Predictive Enrichment Strategies to Identify Children With Septic Shock Responsive to Corticosteroids.

OBJECTIVES: Prognostic and predictive enrichment strategies are fundamental tools of precision medicine. Identifying children with septic shock who may benefit from corticosteroids remains a challenge. We combined prognostic and predictive strategies to identify a pediatric septic shock subgroup responsive to corticosteroids. DESIGN: We conducted a secondary analysis of 288 previously published pediatric subjects with septic shock. For prognostic enrichment, each study subject was assigned a baseline mortality probability using the pediatric sepsis biomarker risk model. For predictive enrichment, each study subject was allocated to one of two septic shock endotypes, based on a 100-gene signature reflecting adaptive immunity and glucocorticoid receptor signaling. The primary study endpoint was complicated course, defined as the persistence of two or more organ failures at day 7 of septic shock or 28-day mortality. We used logistic regression to test for an association between corticosteroids and complicated course within endotype. MEASUREMENTS AND MAIN RESULTS: Among endotype B subjects at intermediate to high pediatric sepsis biomarker risk model-based risk of mortality, corticosteroids were independently associated with more than a 10-fold reduction in the risk of a complicated course (relative risk, 0.09; 95% CI, 0.01-0.54; p = 0.007). CONCLUSIONS: A combination of prognostic and predictive strategies based on serum protein and messenger RNA biomarkers can identify a subgroup of children with septic shock who may be more likely to benefit from corticosteroids. Prospective validation of these strategies and the existence of this subgroup are warranted.

The effect of hospital volume on resection margins in rectal cancer surgery.

BACKGROUND: We hypothesized that after controlling for case-mix differences, the rates of positive resection margin after rectal cancer surgery vary substantially in the United States and that high-volume hospitals have lower margin positivity rates. MATERIALS AND METHODS: Patients treated with oncologic resection for stage I-III rectal cancer were selected from the 1998-2010 National Cancer Data Base. Hierarchical regression models were used to calculate risk- and reliability-adjusted positive margin rates and hospital level variability in positive margin rates using Empirical Bayes techniques. RESULTS: A total of 113,113 patients were treated at 1446 hospitals. The mean overall risk- and reliability-adjusted positive margin rate was 7.3%. High-volume hospitals did not have a lower rate of adjusted margin positivity (7.4%, P = 0.75). When both case mix and hospital volume differences were factored into the model, variability in margin positivity rates increased by 9.8%, implying that referral to high-volume hospitals alone would not improve margin positivity rates. CONCLUSIONS: Rectal cancer margin positivity rates vary substantially in the United States, despite adjusting for differences in case mix. These results support standardization of surgical technique and pathologic assessment as part of a broader initiative that identifies and refers patients to higher performing hospitals rather than simply to higher volume hospitals.

Risk factors and consequences of anastomotic leak after colectomy: a national analysis.

BACKGROUND: Previous research has identified a number of patient and operative factors associated with anastomotic leak after colectomy; however, a study that examines these factors on a national level with direct coding for anastomotic leak is lacking. OBJECTIVE: The purpose of this work was to identify risk factors associated with anastomotic leak on a national level and quantify the additional morbidity and mortality experienced by these patients. DESIGN: We performed a retrospective analysis of patients who underwent segmental colectomy with anastomosis from the 2012 American College of Surgeons National Surgical Quality Improvement Program colectomy procedure-targeted database. Anastomotic leak was defined as minor leak requiring percutaneous intervention or major leak requiring laparotomy. Multivariate logistic regression was used to determine predictors of anastomotic leak and its impact on postoperative outcomes. SETTINGS: This study was conducted at a tertiary university department. PATIENTS: This study includes 13,684 patients who underwent segmental colectomy with anastomosis at American College of Surgeons National Surgical Quality Improvement Program-affiliated hospitals in 2012. MAIN OUTCOME MEASURES: The primary outcome studied was anastomotic leak. RESULTS: The overall leak rate was 3.8%. Male sex, steroid use, smoking, open approach, operative time, and preoperative chemotherapy were associated with increased anastomotic leaks and diverting ileostomy with decreased incidence of leaks on multivariate analysis. Increased length of stay (13 vs 5 days; p < 0.001) and increased 30-day mortality (6.8% vs 1.6%; p < 0.001) were also seen in patients who experienced leaks. These patients also experienced increased readmission rates (43.5% vs 8.3%; p < 0.001) and were 37 times more likely to require reoperation as a complication of their primary procedure (p < 0.001). LIMITATIONS: The main limitations of this study include its retrospective nature and the limited 30-day outcomes recorded in the American College of Surgeons National Surgical Quality Improvement Program database. CONCLUSIONS: This study identified patient and operative risk factors for anastomotic leak on a national scale. It also demonstrates that these patients have increased morbidity and 30-day mortality rates, experience multiple readmissions to the hospital, and have a higher likelihood of requiring further operative intervention.

Enhanced Recovery after Colorectal Surgery: Can We Afford Not to Use It?

BACKGROUND: Enhanced recovery pathways (ERPs) aim to reduce length of stay without adversely affecting short-term outcomes. High pharmaceutical costs associated with ERP regimens, however, remain a significant barrier to widespread implementation. We hypothesized that ERP would reduce hospital costs after elective colorectal resections, despite the use of more expensive pharmaceutical agents. STUDY DESIGN: An ERP was implemented in January 2016 at our institution. We collected data on consecutive colorectal resections for 1 year before adoption of ERP (traditional, n = 160) and compared them with consecutive resections after universal adoption of ERP (n = 146). Short-term surgical outcomes, total direct costs, and direct hospital pharmacy costs were compared between patients who received the ERP and those who did not. RESULTS: After implementation of the ERP, median length of stay decreased from 5.0 to 3.0 days (p < 0.01). There were no differences in 30-day complications (8.1% vs 8.9%) or hospital readmission (11.9% vs 11.0%). The ERP patients required significantly less narcotics during their index hospitalization (211.7 vs 720.2 morphine equivalence units; p < 0.01) and tolerated a regular diet 1 day sooner (p < 0.01). Despite a higher daily pharmacy cost ($477 per day vs $318 per day in the traditional cohort), the total direct pharmacy cost for the hospitalization was reduced in ERP patients ($1,534 vs $1,859; p = 0.016). Total direct cost was also lower in ERP patients ($9,791 vs $11,508; p = 0.004). CONCLUSIONS: Implementation of an ERP for patients undergoing elective colorectal resection substantially reduced length of stay, total hospital cost, and direct pharmacy cost without increasing complications or readmission rates. Enhanced recovery pathway after colorectal resection has both clinical and financial benefits. Widespread implementation has the potential for a dramatic impact on healthcare costs.

In the Absence of a Mechanical Bowel Prep, Does the Addition of Pre-Operative Oral Antibiotics to Parental Antibiotics Decrease the Incidence of Surgical Site Infection after Elective Segmental Colectomy?

BACKGROUND: Pre-operative oral antibiotics administered the day prior to elective colectomy have been shown to decrease the incidence of surgical site infections (SSI) if a mechanical bowel prep (MBP) is used. Recently, the role for mechanical bowel prep has been challenged as being unnecessary and potentially harmful. We hypothesize that if MBP is omitted, oral antibiotics do not alter the incidence of SSI following colectomy. METHODS: We selected patients who underwent an elective segmental colectomy from the 2012 and 2013 National Surgical Quality Improvement Program colectomy procedure targeted database. Indications for surgery included colon cancer, diverticulitis, inflammatory bowel disease, or benign polyp. Patients who received mechanical bowel prep were excluded. The primary outcome measured was surgical site infection, defined as the presence of superficial, deep or, organ space infection within 30 d from surgery. RESULTS: A total of 6,399 patients underwent elective segmental colectomy without MBP. The incidence of SSI differed substantially between patients who received oral antibiotics, versus those who did not (9.7% vs. 13.7%, p=0.01). Multivariate analysis indicated that age, smoking status, operative time, perioperative transfusions, oral antibiotics, and surgical approach were associated with post-operative SSI. When controlling for confounding factors, the use of pre-operative oral antibiotics decreased the incidence of surgical site infection (odds ratio=0.66, 95% confidence interval=0.48-0.90, p=0.01). CONCLUSION: Even in the absence of mechanical bowel prep, pre-operative oral antibiotics appear to reduce the incidence of surgical site infection following elective colectomy.

Corticosteroids and pediatric septic shock outcomes: a risk stratified analysis.

BACKGROUND: The potential benefits of corticosteroids for septic shock may depend on initial mortality risk. OBJECTIVE: We determined associations between corticosteroids and outcomes in children with septic shock who were stratified by initial mortality risk. METHODS: We conducted a retrospective analysis of an ongoing, multi-center pediatric septic shock clinical and biological database. Using a validated biomarker-based stratification tool (PERSEVERE), 496 subjects were stratified into three initial mortality risk strata (low, intermediate, and high). Subjects receiving corticosteroids during the initial 7 days of admission (n = 252) were compared to subjects who did not receive corticosteroids (n = 244). Logistic regression was used to model the effects of corticosteroids on 28-day mortality and complicated course, defined as death within 28 days or persistence of two or more organ failures at 7 days. RESULTS: Subjects who received corticosteroids had greater organ failure burden, higher illness severity, higher mortality, and a greater requirement for vasoactive medications, compared to subjects who did not receive corticosteroids. PERSEVERE-based mortality risk did not differ between the two groups. For the entire cohort, corticosteroids were associated with increased risk of mortality (OR 2.3, 95% CI 1.3-4.0, p = 0.004) and a complicated course (OR 1.7, 95% CI 1.1-2.5, p = 0.012). Within each PERSEVERE-based stratum, corticosteroid administration was not associated with improved outcomes. Similarly, corticosteroid administration was not associated with improved outcomes among patients with no comorbidities, nor in groups of patients stratified by PRISM. CONCLUSIONS: Risk stratified analysis failed to demonstrate any benefit from corticosteroids in this pediatric septic shock cohort.

Anthropology in research on the quality of health services

A presente crise no setor saúde causou uma expansao da pesquisa ligada à qualidade dos serviços de saúde. Pesquisas na área de saúde pública ligadas à qualidade dos serviços geralmente avaliavam o uso ou nao de critérios predefinidos para edificaçoes, equipamentos e procedimentos técnicos. Enfoca a contribuiçao que a antropologia pode dar para a pesquisa em qualidade de serviços e inclui critérios populares na avaliaçao da qualidade. Métodos de avaliaçao rápida de critérios populares indicam que os conflitos entre os provedores e os usuários dos serviços de saúde sao decorrentes apenas de divergências quanto a modelos explanatórios e, sendo assim, podem ser resolvidos através de treinamento e educaçao. A abordagem holística em antropologia demonstra que a questao da qualidade de serviços deve ser vista dentro do contexto da estrutura dos serviços de saúde, das circunstâncias sócio-econômicas da vida dos usuários e das diferenças entre os modelos médicos e populares de saúde