Charles M. Robertson

A randomized study comparing laparoscopic versus open repair of perforated peptic ulcer using suture or sutureless technique.

OBJECTIVE This study compares laparoscopic versus open repair and suture versus sutureless repair of perforated duodenal and juxtapyloric ulcers. BACKGROUND DATA The place of laparoscopic repair of perforated peptic ulcer followed by peritoneal toilet of the peritoneal cavity has been established. Whether repair of the perforated peptic ulcer by the laparoscopic approach is better than conventional open repair and whether sutured repair is better than sutureless repair are both undetermined. METHODS One hundred three patients were randomly allocated to laparoscopic suture repair, laparoscopic sutureless repair, open suture repair, and open sutureless repair. RESULTS Laparoscopic repair of perforated peptic ulcer (groups 1 and 2) took significantly longer than open repair (groups 3 and 4; 94.3 +/ 40.3 vs. 53.7 +/ 42.6 minutes: Students test, p < 0.001), but the amount of analgesic required after laparoscopic repair was significantly less than in open surgery (median 1 dose vs. 3 doses) (Mann-Whitney U test, p = 0.03). There was no significant difference in the four groups of patients in terms of duration of nasogastric aspiration, duration of intravenous drip, total hospital stay, time to resume normal diet, visual analogue scale score for pain in the first 24 hours after surgery, morbidity, reoperation, and mortality rates. CONCLUSIONS Laparoscopic repair of perforated peptic ulcer is a viable option. Sutureless repair is as safe as suture repair and it takes less time to perform.

A study of proactive ethics consultation for critically and terminally ill patients with extended lengths of stay.

OBJECTIVE To assess the effect of proactive ethics consultation on documented patient care communications and on decisions regarding high-risk intensive care unit (ICU) patients. DESIGN Prospective, controlled study. PATIENTS Ninety-nine ICU patients treated with >96 hrs of continuous mechanical ventilation. INTERVENTIONS Three groups were compared: a) a baseline group enrolled in the study prior to the establishment of the hospitals ethics consultation service; b) a control group where ethics consultation was at the option of the care team; and c) a treatment group where the ethics service intervened proactively after patients received >96 hrs of continuous mechanical ventilation. Patient care planning, for subjects in the proactive group, was reviewed with physicians and with the care team using a standardized set of prompting questions designed to focus discussion of key decision-making and communication issues for critically and terminally ill patients. Issues and concerns were identified and action strategies were suggested to those in charge of the patients care. Formal ethics consultation, using a patient care conference model, was made available upon request. MEASUREMENTS AND MAIN RESULTS Post discharge chart reviews of the three groups indicated no statistically significant differences on important demographic variables including age, gender, and acuity. Comparisons of survivors and nonsurvivors for the three groups indicated, at statistically significant levels, more frequent and documented communications, more frequent decisions to forego life-sustaining treatment, and reduced length of stay in the ICU for the proactive consultation group. CONCLUSION Proactive ethics consultation for high-risk patient populations offers a promising approach to improving decision-making and communication and reducing length of ICU stay for dying patients.

Neutrophil-mediated oxidative burst and host defense are controlled by a Vav-PLCγ2 signaling axis in mice

Oxidative burst, a critical antimicrobial mechanism of neutrophils, involves the rapid generation and release of reactive oxygen intermediates (ROIs) by the NADPH oxidase complex. Genetic mutations in an NADPH oxidase subunit, gp91 (also referred to as NOX2), are associated with chronic granulomatous disease (CGD), which is characterized by recurrent and life-threatening microbial infections. To combat such infections, ROIs are produced by neutrophils after stimulation by integrin-dependent adhesion to the ECM in conjunction with stimulation from inflammatory mediators, or microbial components containing pathogen-associated molecular patterns. In this report, we provide genetic evidence that both the Vav family of Rho GTPase guanine nucleotide exchange factors (GEFs) and phospholipase C-gamma2 (PLC-gamma2) are critical mediators of adhesion-dependent ROI production by neutrophils in mice. We also demonstrated that Vav was critically required for neutrophil-dependent host defense against systemic infection by Staphylococcus aureus and Pseudomonas aeruginosa, 2 common pathogens associated with fatal cases of hospital-acquired pneumonia. We identified a molecular pathway in which Vav GEFs linked integrin-mediated signaling with PLC-gamma2 activation, release of intracellular Ca2+ cations, and generation of diacylglycerol to control assembly of the NADPH oxidase complex and ROI production by neutrophils. Taken together, our data indicate that integrin-dependent signals generated during neutrophil adhesion contribute to the activation of NADPH oxidase by a variety of distinct effector pathways, all of which require Vav.

Neutrophil depletion causes a fatal defect in murine pulmonary Staphylococcus aureus clearance

BACKGROUND Staphylococcus aureus is the most common cause of healthcare-associated pneumonia. Despite the significant morbidity and mortality associated with the disease, animal models of S. aureus pneumonia are rare. MATERIALS AND METHODS We examined the pathogenicity of four different strains of S. aureus (both methicillin-sensitive and -resistant as well as Panton-Valentine leukocidin-positive and -negative) in four strains of immunocompetent inbred and outbred mice (FVB/N, C57Bl/6, BALB/c, ND4; n = 148). The immunological basis for the development of murine S. aureus pneumonia was then determined by selectively depleting neutrophils, lymphocytes, or pulmonary macrophages prior to the onset of infection. An additional cohort of animals was rendered immunosuppressed by induction of abdominal sepsis via cecal ligation and puncture 2, 4, or 7 d prior to the onset of pneumonia. RESULTS Nearly all immunocompetent mice survived, regardless of which strain of S. aureus was used or which strain of mouse was infected. Among animals with immune depletion or prior immunosuppression, survival was decreased only following neutrophil depletion (26% versus 90% alive at 7 d, P < 0.0001). Compared to immunocompetent animals, neutrophil-depleted mice with S. aureus pneumonia had delayed pulmonary bacterial clearance at 16 and 40 h but had no difference in levels of bacteremia. Neutrophil-depleted mice also had elevated levels of pulmonary monocyte chemotactic protein-1 (822 pg/mL versus 150 pg/mL, P < 0.05). In contrast, pulmonary histological appearance was similar in both groups as was dry/wet lung weight. CONCLUSIONS These results suggest that neutrophils play a critical role in the host response to S. aureus pneumonia, and the survival differences observed in neutrophil-depleted mice are associated with alterations in bacterial clearance and pulmonary cytokine response.

Long-term Outcomes of Performing a Postdoctoral Research Fellowship During General Surgery Residency

Objective:To determine whether dedicated research time during surgical residency leads to funding following postgraduate training. Summary Background Data:Unlike other medical specialties, a significant number of general surgery residents spend 1 to 3 years in dedicated laboratory research during their training. The impact this has on obtaining peer reviewed research funding after residency is unknown. Methods:Survey of all graduates of an academic general surgery resident program from 1990 to 2005 (n = 105). Results:Seventy-five (71%) of survey recipients responded, of which 66 performed protected research during residency. Fifty-one currently perform research (mean effort, 26%; range, 2%–75%). Twenty-three respondents who performed research during residency (35%) subsequently received independent faculty funding. Thirteen respondents (20%) obtained NIH grants following residency training. The number of papers authored during resident research was associated with obtaining subsequent faculty grant support (9.3 vs. 5.2, P = 0.02). Faculty funding was associated with obtaining independent research support during residency (42% vs. 17%, P = 0.04). NIH-funded respondents spent more combined years in research before and during residency (3.7 vs. 2.8, P = 0.02). Academic surgeons rated research fellowships more relevant to their current job than private practitioners (4.3 vs. 3.4 by Likert scale, P < 0.05). Both groups considered research a worthwhile use of their time during residency (4.5 vs. 4.1, P = not significant). Conclusions:A large number of surgical trainees who perform a research fellowship in the middle of residency subsequently become funded investigators in this single-center survey. The likelihood of obtaining funding after residency is related to productivity and obtaining grant support during residency as well as cumulative years of research prior to obtaining a faculty position.

Prevalence and Cost of Full-Time Research Fellowships During General Surgery Residency - A National Survey

Objective:To quantify the prevalence, outcomes, and cost of surgical resident research. Summary Background Data:General surgery is unique among graduate medical education programs because a large percentage of residents interrupt their clinical training to spend 1 to 3 years performing full-time research. No comprehensive data exists on the scope of this practice. Methods:Survey sent to all 239 program directors of general surgery residencies participating in the National Resident Matching Program. Results:Response rate was 200 of 239 (84%). A total of 381 of 1052 trainees (36%) interrupt residency to pursue full-time research. The mean research fellowship length is 1.7 years, with 72% of trainees performing basic science research. A significant association was found between fellowship length and postresidency activity, with a 14.7% increase in clinical fellowship training and a 15.2% decrease in private practice positions for each year of full-time research (P < 0.0001). Program directors at 31% of programs reported increased clinical duties for research fellows as a result of Accreditation Council for Graduate Medical Education work hour regulations for clinical residents, whereas a further 10% of programs are currently considering such changes. It costs

Cancer causes increased mortality and is associated with altered apoptosis in murine sepsis

41.5 million to pay the 634 trainees who perform research fellowships each year, the majority of which is paid for by departmental funds (40%) and institutional training grants (24%). Conclusions:Interrupting residency to perform a research fellowship is a common and costly practice among general surgery residents. Although performing a research fellowship is associated with clinical fellowship training after residency, it is unclear to what extent this practice leads to the development of surgical investigators after postgraduate training.

MITOCHONDRIAL RESUSCITATION WITH EXOGENOUS CYTOCHROME C IN THE SEPTIC HEART

Objective:Whereas most septic patients have an underlying comorbidity, most animal models of sepsis use mice that were healthy before the onset of infection. Malignancy is the most common comorbidity associated with sepsis. The purpose of this study was to determine whether mice with cancer have a different response to sepsis than healthy animals. Design:Prospective, randomized controlled study. Setting:Animal laboratory in a university medical center. Subjects:C57Bl/6 mice. Interventions:Animals received a subcutaneous injection of either 250,000 cells of the transplantable pancreatic adenocarcinoma cell line Pan02 (cancer) or phosphate-buffered saline (healthy). Three weeks later, mice given Pan02 cells had reproducible, nonmetastatic tumors. Both groups of mice then underwent intratracheal injection of either Pseudomonas aeruginosa (septic) or 0.9% NaCl (sham). Animals were killed 24 hrs postoperatively or followed-up 7 days for survival. Measurements and Main Results:Mice with cancer and healthy mice appeared similar when subjected to sham operation, although cancer animals had lower levels of T- and B-lymphocyte apoptosis. Septic mice with cancer had increased mortality compared to previously healthy septic mice subjected to the identical injury (52% vs. 28%; p = .04). This was associated with increased bacteremia but no difference in local pulmonary infection. Septic mice with cancer also had increased intestinal epithelial apoptosis. Although sepsis induced an increase in T- and B-lymphocyte apoptosis in all animals, septic mice with cancer had decreased T- and B-lymphocyte apoptosis compared to previously healthy septic mice. Serum and pulmonary cytokines, lung histology, complete blood counts, and intestinal proliferation were similar between septic mice with cancer and previously healthy septic mice. Conclusions:When subjected to the same septic insult, mice with cancer have increased mortality compared to previously healthy animals. Decreased systemic bacterial clearance and alterations in intestinal epithelial and lymphocyte apoptosis may help explain this differential response.

The systemic inflammatory response syndrome.

OBJECTIVE Mitochondrial dysfunction may play a role in the pathogenesis of sepsis-induced organ dysfunction. Respiratory-chain deficiencies that occur in sepsis, however, have never been shown to cause organ failure or to be reversible. Cytochrome oxidase uses electrons donated by its substrate, cytochrome c, to reduce oxygen to H2O. In the septic heart, cytochrome oxidase is competitively inhibited. We hypothesized that cytochrome oxidase inhibition coupled with reduced substrate availability is a reversible cause of sepsis-associated myocardial depression. DESIGN Prospective observational study aimed to overcome myocardial cytochrome oxidase inhibition with excess cytochrome c and improve cardiac function. SETTING University hospital-based laboratory. SUBJECTS Seventy-five C57Bl6 male mice. INTERVENTIONS Mice underwent cecal ligation and double puncture, sham operation, or no operation. Exogenous cytochrome c or an equal volume of saline was intravenously injected at the 24-hr time point. All animals were evaluated 30 mins after injection. MEASUREMENTS AND MAIN RESULTS Exogenous cytochrome c readily repleted cardiac mitochondria with supranormal levels of substrate (>1.6 times baseline), restored heme c content, and increased cytochrome oxidase kinetic activity. This increased left ventricular pressure and increased pressure development during isovolumic contraction (dP/dtmax) and relaxation (dP/dtmin) by >45% compared with saline injection. CONCLUSION Impaired oxidative phosphorylation is a cause of sepsis-associated myocardial depression, and mitochondrial resuscitation with exogenous cytochrome c overcomes cytochrome oxidase inhibition and improves cardiac function.