Intra-abdominal infections survival guide: a position statement by the Global Alliance For Infections In Surgery.

Intra-abdominal infections (IAIs) are an important cause of morbidity and mortality in hospital settings worldwide. The cornerstones of IAI management include rapid, accurate diagnostics; timely, adequate source control; appropriate, short-duration antimicrobial therapy administered according to the principles of pharmacokinetics/pharmacodynamics and antimicrobial stewardship; and hemodynamic and organ functional support with intravenous fluid and adjunctive vasopressor agents for critical illness (sepsis/organ dysfunction or septic shock after correction of hypovolemia). In patients with IAIs, a personalized approach is crucial to optimize outcomes and should be based on multiple aspects that require careful clinical assessment. The anatomic extent of infection, the presumed pathogens involved and risk factors for antimicrobial resistance, the origin and extent of the infection, the patient's clinical condition, and the host's immune status should be assessed continuously to optimize the management of patients with complicated IAIs.

A Review of "Options in Management of Trauma to the Esophagus" (1982) "Submitted for the Literary Festschrift in Honor of J. David Richardson, MD".

This article is an update of a paper which Dave Richardson and I published in 1982, and serves as both an update of management of esophageal injuries and as a lasting tribute to my mentor and hero J. David Richardson.

Pathogen- and Danger-Associated Molecular Patterns and the Cytokine Response in Sepsis.

The sepsis syndrome is a systemic host inflammatory response accompanied by organ dysfunction in response to invading microbial pathogens. The host recognizes both danger and pathogens through its pattern recognition receptors on immune cells. These receptors bind to pathogen- (PAMP) and danger- (DAMP) associated molecular patterns derived from microbes and host tissues, respectively. These processes set in motion a cascade of events in host cells and tissue, which activate multiple cytokines that serve as activators of the host inflammatory response as well as eventually lead to resolution of the response if the host recovers. The following article describes some of these DAMPs and PAMPs, and how they activate pathways that activate the host cytokine immune response to injury and infection.

Women in surgery: A longer term follow-up.

BACKGROUND: There are an increasing number of women in surgery. Previously, many questions focused upon their ability to complete surgical training and contribute fully to the surgical workforce. More meaningful information lies in identifying the long-term follow-up of where, and in what specialty, women residents eventually practice. METHODS: All residents entering general surgery training at the University of Louisville between 1996 and 2009 were studied. Comparison between men and women was performed for program completion, length of residency training, and eventual specialty practice. RESULTS: One hundred and eight residents entered general surgery residency. Twenty-three (21%) did not complete training. There was no difference in attrition rates between men or women (22% vs. 19%, p = 0.77). Women completing residency were just as likely to practice general surgery (either private or academic practice) as their male counterparts (67% vs. 67% p = 0.96). CONCLUSIONS: Women are a valuable resource in surgery and are able to complete a vigorous residency. Long-term follow-up is crucial and permits us to evaluate this important group of trainees practicing surgery today.

Cost-effectiveness Analysis of Contralateral Prophylactic Mastectomy Compared to Unilateral Mastectomy with Routine Surveillance for Unilateral, Sporadic Breast Cancer.

BACKGROUND: Contralateral prophylactic mastectomy (CPM) rates in younger women with unilateral breast cancer have more than doubled. Studies of cost and quality of life of the procedure remain inconclusive. METHODS: A cost-effectiveness analysis using a decision-tree model in TreeAge Pro 2015 was used to compare long-term costs and quality of life following unilateral mastectomy (UM) with routine surveillance versus CPM for sporadic breast cancer in women aged 45 years. A 10-year risk period for contralateral breast cancer (CBC), reconstruction, wound complications, cost of routine surveillance, and treatment for CBC were used to estimate accrued costs. In addition, a societal perspective was used to estimate quality-adjusted life years (QALYs) following either treatment for a period of 30 years. Medical costs were obtained from the 2014 Medicare physician fee schedule and event probabilities were taken from recent literature. RESULTS: The mean cost of UM with surveillance was $14,141 and CPM was $20,319. Treatment with CPM resulted in $6178 more in costs but equivalent QALYs (17.93) compared with UM over 30 years of follow-up. Even with worst-case scenario and varying assumptions, CPM is dominated by UM in terms of cost and quality. CONCLUSIONS: From this refined model, UM with routine surveillance costs less and provides an equivalent quality of life. Patients undergoing CPM may eliminate the anxiety of routine surveillance, but they face the burden of higher lifetime medical costs.

Large-bowel disease presenting as small-bowel obstruction is associated with a poor prognosis.

INTRODUCTION: Small-bowel obstruction (SBO) is a common cause of admission to the surgical service. On rare occasions, a diagnosed SBO is actually due to large-bowel pathology combined with an incompetent ileocecal valve. The purpose of this study was to investigate this phenomenon. METHODS: We performed a retrospective medical record review of patients that were admitted with a diagnosis of SBO at University of Louisville hospital and the Veterans Affairs hospitals in Louisville, KY, from 2006 until 2014. RESULTS: A total of 498 patients were admitted with SBO during this time period. Forty-one patients were found to have an underlying large-bowel disease. The most common large-bowel pathologies included malignancy (51%), inflammation (15%), and infection (15%). Fifteen (43%) of these patients died during admission; 93% of these were due to either their bowel obstruction or the underlying disease state. This was significantly higher than the general population (9.4% mortality, 6% due to underlying disease). CONCLUSIONS: Patients that present with SBO due to a large-bowel source have a much higher mortality rate than those that present with other causes. Rapid identification of these patients will allow for more timely and appropriate treatment.

Anti-inflammatory effects of miR-21 in the macrophage response to peritonitis.

We investigated the role of microRNA-21 in the macrophage response to peritonitis; microRNA-21 expression increases in peritoneal macrophages after lipopolysaccharide stimulation but is delayed until 48 hours after cecal ligation and puncture. MicroRNA-21-null mice and bone marrow-derived cell lines were exposed to cecal ligation and puncture or lipopolysaccharide, and survival, microRNA-21 levels, target messenger RNAs and proteins, and cytokines were assayed. Macrophages were also transfected with microRNA-21 mimics and antagomirs, and similar endpoints were measured. Survival in microRNA-21-null mice was significantly decreased after lipopolysaccharide-induced peritonitis but unchanged after cecal ligation and puncture compared with similarly treated wild-type mice. MicroRNA-21 expression, tumor necrosis factor-α, interleukin 6, and programmed cell death protein 4 levels were increased after lipopolysaccharide addition in peritoneal cells. Pelino1 and sprouty (SPRY) messenger RNAs were similarly increased early, whereas programmed cell death protein 4 messenger RNA was decreased after lipopolysaccharide, and all microR-21 target messenger RNAs were subsequently decreased by 24 hours after lipopolysaccharide. Transfection with mimics and antagomirs led to appropriate responses in microRNA-21 and tumor necrosis factor-α. Knockdown of microRNA-21 in bone marrow-derived cells showed increased tumor necrosis factor-α and decreased interleukin 10 in response to lipopolysaccharide. Target proteins were unaffected by knockdown as was extracellular signal-regulated kinase; however, the nuclear factor κB p65 subunit was increased after lipopolysaccharide in the microRNA-21 knockout cells. In contrast, there was little change in these parameters after cecal ligation and puncture induction between null and wild-type mice. MicroRNA-21 is beneficial to survival in mice following lipopolysaccharide peritonitis. Overexpression of microRNA-21 decreased tumor necrosis factor-α secretion, whereas suppression of microRNA-21 expression increased tumor necrosis factor-α and interleukin 6, and decreased interleukin 10 levels after lipopolysaccharide. Protein targets of microRNA-21 were not different following suppression of microRNA-21. Nuclear factor κB was increased by suppression of microRNA-21. These findings demonstrate microRNA-21 is beneficial in modulating the macrophage response to lipopolysaccharide peritonitis and an improved understanding of the anti-inflammatory effects of microRNA-21 may result in novel, targeted therapy against peritonitis and sepsis.

Trial of short-course antimicrobial therapy for intraabdominal infection.

BACKGROUND: The successful treatment of intraabdominal infection requires a combination of anatomical source control and antibiotics. The appropriate duration of antimicrobial therapy remains unclear. METHODS: We randomly assigned 518 patients with complicated intraabdominal infection and adequate source control to receive antibiotics until 2 days after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 days of therapy (control group), or to receive a fixed course of antibiotics (experimental group) for 4±1 calendar days. The primary outcome was a composite of surgical-site infection, recurrent intraabdominal infection, or death within 30 days after the index source-control procedure, according to treatment group. Secondary outcomes included the duration of therapy and rates of subsequent infections. RESULTS: Surgical-site infection, recurrent intraabdominal infection, or death occurred in 56 of 257 patients in the experimental group (21.8%), as compared with 58 of 260 patients in the control group (22.3%) (absolute difference, -0.5 percentage point; 95% confidence interval [CI], -7.0 to 8.0; P=0.92). The median duration of antibiotic therapy was 4.0 days (interquartile range, 4.0 to 5.0) in the experimental group, as compared with 8.0 days (interquartile range, 5.0 to 10.0) in the control group (absolute difference, -4.0 days; 95% CI, -4.7 to -3.3; P<0.001). No significant between-group differences were found in the individual rates of the components of the primary outcome or in other secondary outcomes. CONCLUSIONS: In patients with intraabdominal infections who had undergone an adequate source-control procedure, the outcomes after fixed-duration antibiotic therapy (approximately 4 days) were similar to those after a longer course of antibiotics (approximately 8 days) that extended until after the resolution of physiological abnormalities. (Funded by the National Institutes of Health; STOP-IT ClinicalTrials.gov number, NCT00657566.).

Predicting academic performance in surgical training.

INTRODUCTION: During surgical residency, trainees are expected to master all the 6 competencies specified by the ACGME. Surgical training programs are also evaluated, in part, by the residency review committee based on the percentage of graduates of the program who successfully complete the qualifying examination and the certification examination of the American Board of Surgery in the first attempt. Many program directors (PDs) use the American Board of Surgery In-Training Examination (ABSITE) as an indicator of future performance on the qualifying examination. Failure to meet an individual program's standard may result in remediation or a delay in promotion to the next level of training. Remediation is expensive in terms of not only dollars but also resources, faculty time, and potential program disruptions. We embarked on an exploratory study to determine if residents who might be at risk for substandard performance on the ABSITE could be identified based on the individual resident's behavior and motivational characteristics. If such were possible, then PDs would have the opportunity to be proactive in developing a curriculum tailored to an individual resident, providing a greater opportunity for success in meeting the program's standards. METHODS: Overall, 7 surgical training programs agreed to participate in this initial study and residents were recruited to voluntarily participate. Each participant completed an online assessment that characterizes an individual's behavioral style, motivators, and Acumen Index. Residents completed the assessment using a code name assigned by each individual PD or their designee. Assessments and the residents' 2013 ABSITE scores were forwarded for analysis using only the code name, thus insuring anonymity. Residents were grouped into those who took the junior examination, senior examination, and pass/fail categories. A passing score of ≥70% correct was chosen a priori. Correlations were performed using logistic regression and data were also entered into a neural network (NN) to develop a model that would explain performance based on data obtained from the TriMetrix assessments. RESULTS: A total of 117 residents' TriMetrix and ABSITE scores were available for analysis. They were divided into 2 groups of 64 senior residents and 53 junior residents. For each group, the pass/fail criteria for the ABSITE were set at 70 and greater as passing and 69 and lower as failing. Multiple logistic regression analysis was complete for pass/fail vs the TriMetrix assessments. For the senior data group, it was found that the parameter Theoretical correlates with pass rate (p < 0.043, B = -0.513, exp(B) = 0.599), which means increasing theoretical scores yields a decreasing likelihood of passing in the examination. For the junior data, the parameter Internal Role Awareness correlated with pass/fail rate (p < 0.004, B = 0.66, exp(B) = 1.935), which means that an increasing Internal Role Awareness score increases the likelihood of a passing score. The NN was able to be trained to predict ABSITE performance with surprising accuracy for both junior and senior residents. CONCLUSION: Behavioral, motivational, and acumen characteristics can be useful to identify residents "at risk" for substandard performance on the ABSITE. Armed with this information, PDs have the opportunity to intervene proactively to offer these residents a greater chance for success. The NN was capable of developing a model that explained performance on the examination for both the junior and the senior examinations. Subsequent testing is needed to determine if the NN is a good predictive tool for performance on this examination.

Poor outcome in bacterial peritonitis is associated with dysregulated microRNAs and an increased inflammatory response.

BACKGROUND: Peritonitis is a common cause of surgical sepsis. The failure of the host to mount an appropriate immune response contributes to persistence of the infection. We investigated the role microRNAs may play in this failed immune response. METHODS: Klebsiella pneumoniae was injected intraperitoneally in mice. Weight loss was used to predict clinical outcome. Peritoneal exudate cells (PECs) and supernatant were collected. RNA from PECs was run on screening microRNA array cards to determine gene expression, and validated by single assay analysis. Cytokine levels in supernatant were assayed by enzyme-linked immunosorbent assay. RESULTS: Despite similar bacterial levels, PEC counts were higher in the predicted death group. The predicted deaths had higher levels of proinflammatory tumor necrosis factor-α/IL-6 and significantly lower levels of interleukin-10. MiR-221 was up-regulated in both the predicted death and predicted survivor groups. Five miRNAs were up-regulated in the predicted survivor group compared with normal controls. CONCLUSION: Higher PEC counts and proinflammatory cytokines in the predicted death group indicates an exaggerated inflammatory response, with lower IL-10 levels despite similar bacterial counts. There were two dysregulated miRNAs with transcriptional targets that may explain our results. A more balanced immune response with an appropriate counter inflammatory response may be important for improving survival.

Accuracy of computed tomography in small bowel obstruction.

Small bowel obstruction is a common clinical occurrence, primarily caused by adhesions. The diagnosis is usually made on the clinical findings and the presence of dilated bowel loops on plain abdominal radiograph. Computed tomography (CT) is increasingly used to diagnose the cause and location of the obstruction to aid in the timing of surgical intervention. We used a retrospective chart review to identify patients with a diagnosis of small bowel obstruction between 2009 and 2012. We compared the findings on CT with the findings at operative intervention. Sixty patients had abdominal CT and subsequent surgical intervention. Eighty-three per cent of CTs were correct for small intestine involvement and 80 per cent for colon involvement. The presence of adhesions or perforation was correctly identified in 21 and 50 per cent, respectively. Sixty-four per cent correctly identified a transition point. The presence of a mass was correctly identified in 69 per cent. Twenty per cent of the patients who had ischemic small bowel at surgery were identified on CT. CT has a role in the clinical assessment of patients with small bowel obstruction, identifying with reasonable accuracy the extent of bowel involvement and the presence of masses and transition points. It is less reliable at identifying adhesions, perforations, or ischemic bowel.

A natural immune modulator attenuates stress hormone and catecholamine concentrations in polymicrobial peritonitis.

BACKGROUND: Activated hexose correlated compound (AHCC), derived from shiitake mushrooms, increases resistance to infection in immunocompromised hosts with positive effects on dendritic cells, natural killer cell function and interleukin 12 production. It may also be attenuating the systemic inflammatory response by regulating the secretion of cortisol and norepinephrine (NE). METHODS: Female Swiss-Weber mice were pretreated with AHCC (Amino Up Chemical Co., Sapporo, Japan) or water by gavage for 10 days before undergoing cecal ligation and puncture (CLP). Peritoneal exudate cells and blood samples were harvested at 4 hours and 24 hours following CLP. Plasma and peritoneal concentrations of cortisol and NE were obtained using enzyme-linked immunosorbent assay. Peritoneal bacteria were quantified by colony counts after 4 hours and 24 hours. Significance was denoted by a p < 0.05. RESULTS: Plasma and peritoneal cortisol concentrations were increased 4 hours after CLP compared with normal controls, with no difference between the pretreated groups. Concentrations of cortisol decreased from 4 hours to 24 hours after CLP with AHCC (plasma, p = 0.009; peritoneal, p < 0.001), and peritoneal cortisol at 24 hours was lower with AHCC as compared with water (p = 0.028). There was no change in plasma or peritoneal NE concentrations at 4 hours. At 24 hours, higher concentrations of NE were detected in both plasma and peritoneal fluid, with lower plasma concentrations in those gavaged with AHCC (p = 0.015). There was no significant difference in peritoneal bacteria counts. CONCLUSION: Enhanced immune function observed with AHCC could be caused by attenuated concentrations of stress hormones and catecholamines.

Differential microRNA (miRNA) expression could explain microbial tolerance in a novel chronic peritonitis model.

We observed persistent peritoneal bacteria despite a transient early innate immune response to intraperitoneal (IP) Klebsiella pneumoniae. Pretreatment with LPS prior to peritonitis induced a tolerant pattern of pro-inflammatory cytokine protein production over 72 h, but not at the mRNA level. MicroRNAs (miRNAs) regulate inflammatory cytokines and may explain this paradox. After pretreatment with IP LPS or saline, C57BL/6 mice were given 10(3) CFU of K. pneumoniae IP. Total RNA was isolated from peritoneal exudate cells (4 h, 24 h and 48 h following infection). mRNA and miRNA expression levels were detected and bioinformatics pathway analysis was performed, followed by measuring TNF-α, IL-1ß, IL-6 and High-mobility Group Box 1 (HMBG1) protein levels. Of 88 miRNAs studied, 30 were significantly dysregulated at all time points in the LPS-pretreated group, including MiR-155, -146a, -142-3p, -299, and -200c -132 and -21. TNF-α, regulated by miR-155 and miR-146a, was decreased in the LPS-pretreated group at all time points (P < 0.05), as were HMGB1, a key alarmin regulated by miR-146, -142-3p, -299 and -200c (P < 0.05), and IL-1ß and IL-6, both regulated by miR-132and miR-21 respectively (P < 0.05). Specific dysregulation of miR-155, -146a, -142-3p, -299, and -200c -132 and -21 with their corresponding effects on the TLR and NF-κB signaling pathways during inflammation, suggests a plausible mechanism for tolerance in this novel chronic model with persistent peritoneal infection.

Macrophage genetic reprogramming during chronic peritonitis is augmented by LPS pretreatment.

BACKGROUND: Persistent and tertiary chronic peritonitis is a clinically challenging problem especially in those who are critically ill. This could be attributed to a state of immune-paralysis, known as microbial tolerance. Microbial tolerance is the diminished pro-inflammatory protein response following repeated stimulation by numerous pathogen-associated molecular patterns (PAMPs) of varying origins, which we have shown in this novel model of chronic peritonitis. We aimed in this study to investigate the molecular mechanisms behind microbial tolerance and the early innate immune response resolution in this model. METHODS: C57BL/6 mice were pretreated intra-peritoneally (IP) with saline or endotoxin LPS 10 mg/kg (LPS 10). Following pretreatment, peritonitis was induced 24 h later injecting 10(3)Klebsiella pneumonia CFU IP. Gentamicin was administered 4 h prior to infection and BID thereafter. Peritoneal exudate cells (PEC) were obtained through peritoneal lavage and RNA was isolated (n = 3) at 4, 24, and 48 h following infection. SA Biosciences© RT2-Profiler PCR array mouse Toll-like receptor signaling pathway (PAMM_018A) data were further analyzed by Ingenuity Pathway Inc. analysis (IPA). RESULTS: Of the 89 genes studied, 26 were significantly up-regulated (fold change > 1.2 and P value < 0.05) in the saline pretreated group at 4, 24, and 48 h after infection. There were no down-regulated genes. In the LPS-pretreated group, 35 genes were significantly up-regulated; of these genes, 13 were not increased in the saline pretreated infected mice. This left 22 up-regulated genes in both infected groups. At 4 h, 6 of these 22 genes (CHUK, HMGB1, HSPD1, IRAK2, LY96, and TLR4) were further 2-fold increased in the LPS pretreatment group compared with the saline pretreatment group. Only IRAK2 was 2-fold increased at 24 h. By 48 h, no LPS effect was seen. When applying IPA analysis, six main canonical pathways were constantly dysregulated in the same significance order in both the saline and LPS group at 4, 24, and 48 h. These were: Toll-like receptor and NF-κB signaling, hepatic cholestasis, interleukin-6, and LPS-mediated MAPK signaling pathways, and pattern recognition receptors of bacterial pathway. CONCLUSION: Peritonitis increased PEC gene expression associated with sepsis and a pro-inflammatory response, which was further augmented by LPS pretreatment over 24 h only. Prior exposure to LPS did not induce PEC gene tolerance to subsequent infection with Klebsiella at the mRNA level. Post-transcriptional modification as microRNA down-regulation of inflammatory cytokines could possibly explain such phenomena.