Avery B. Nathens

Genomic responses in mouse models poorly mimic human inflammatory diseases

A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.

Diagnosis and Management of Complicated Intra-abdominal Infection in Adults and Children: Guidelines by the Surgical Infection Society and the Infectious Diseases Society of America

Evidence-based guidelines for managing patients with intra-abdominal infection were prepared by an Expert Panel of the Surgical Infection Society and the Infectious Diseases Society of America. These updated guidelines replace those previously published in 2002 and 2003. The guidelines are intended for treating patients who either have these infections or may be at risk for them. New information, based on publications from the period 2003-2008, is incorporated into this guideline document. The panel has also added recommendations for managing intra-abdominal infection in children, particularly where such management differs from that of adults; for appendicitis in patients of all ages; and for necrotizing enterocolitis in neonates.

A genomic storm in critically injured humans

Critical injury in humans induces a genomic storm with simultaneous changes in expression of innate and adaptive immunity genes.

Guidelines for the Selection of Anti-infective Agents for Complicated Intra-abdominal Infections

Joseph S. Solomkin, John E. Mazuski, Ellen J. Baron, Robert G. Sawyer, Avery B. Nathens, Joseph T. DiPiro, Timothy Buchman, E. Patchen Dellinger, John Jernigan, Sherwood Gorbach, Anthony W. Chow, and John Bartlett Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Surgery, Washington University School of Medicine, St. Louis, Missouri; Department of Microbiology, Stanford University School of Medicine, Palo Alto, California; Department of Surgery, University of Virginia, Charlottesville; Department of Surgery, University of Washington, Seattle; University of Georgia College of Pharmacy, Department of Surgery, Medical College of Georgia, Augusta, and Centers for Disease Control and Prevention, Atlanta; Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

Randomized, Prospective Trial of Antioxidant Supplementation in Critically Ill Surgical Patients

ObjectiveTo determine the effectiveness of early, routine antioxidant supplementation using α-tocopherol and ascorbic acid in reducing the rate of pulmonary morbidity and organ dysfunction in critically ill surgical patients.Summary Background DataOxidative stress has been associated with the develo

Management of severe head injury: Institutional variations in care and effect on outcome

ObjectiveThe purpose of this study was three-fold: a) to examine variations in care of patients with severe head injury in academic trauma centers across the United States; b) to determine the proportion of patients who received care according to the Brain Trauma Foundation guidelines; and c) to correlate the outcome from severe traumatic brain injury with the care received. DesignRetrospective data collection for consecutive patients with closed head injury and long bone fracture admitted over an 8-month period. SettingThirty-four academic trauma centers in the United States PatientsAll patients admitted with a presenting Glasgow Coma Scale score ≤8. Measurements and Main ResultsVariations in care were assessed, including prehospital intubation, intracranial pressure monitoring, use of osmotic agents, hyperventilation, and computed tomography scan utilization. Aggressive centers were defined as those placing intracranial pressure monitors in >50% of patients meeting the Brain Trauma Foundation criteria for intracranial pressure monitoring. The primary outcome variables were mortality, functional status at discharge, and length of stay. Kaplan-Meier survival analysis was performed for aggressive vs. nonaggressive centers. A Cox proportional hazard model was used to evaluate the association between type of center and mortality rate. Length of stay was evaluated by using linear regression. ResultsThere was considerable variation in the rates of prehospital intubation, intracranial pressure monitoring, intracranial pressure-directed therapy, and head computed tomography scan utilization across centers. Management at an aggressive center was associated with a significant reduction in the risk of mortality (hazard ratio, 0.43; 95% confidence interval, 0.27–0.66). There was no statistically significant difference in functional status at the time of discharge for survivors. Adjusted length of stay for survivors at aggressive centers was shorter, compared with the length of stay at nonaggressive centers: −6 days (95% confidence interval, −14 to 2 days). ConclusionConsiderable national variation in the care of severely head-injured patients persists. An “aggressive” management strategy is associated with decreased mortality rate for patients with severe head injury, with no significant difference in functional status at discharge among survivors.

Effectiveness of state trauma systems in reducing injury-related mortality: a national evaluation.

BACKGROUND Regional trauma systems were proposed 2 decades ago to reduce injury mortality rates. Because of the difficulties in evaluating their effectiveness and the methodologic limitations of previously published studies, the relative benefits of establishing an organized system of trauma care remains controversial. METHODS Data on trauma systems were obtained from a survey of state emergency medical service directors, review of state statutes and a previously published trauma system inventory. Injury mortality rates were obtained from national vital statistics data, whereas motor vehicle crash (MVC) mortality rates were obtained from the Fatality Analysis Reporting System. Mortality rates were compared between states with and without trauma systems. RESULTS As of 1995, 22 states had regional trauma systems. States with trauma systems had a 9% lower crude injury mortality rate than those without. When MVC-related mortality was evaluated separately, there was a 17% reduction in deaths. After controlling for age, state speed laws, restraint laws, and population distribution, there remained a 9% reduction in MVC-related mortality rate in states with a trauma system. CONCLUSION These data demonstrate that a state trauma system is associated with a reduction in the risk of death caused by injury. The effect is most evident on analysis of MVC deaths.

Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America.

Evidence-based guidelines for managing patients with intra-abdominal infection were prepared by an Expert Panel of the Surgical Infection Society and the Infectious Diseases Society of America. These updated guidelines replace those previously published in 2002 and 2003. The guidelines are intended for treating patients who either have these infections or may be at risk for them. New information, based on publications from the period 2003-2008, is incorporated into this guideline document. The panel has also added recommendations for managing intra-abdominal infection in children, particularly where such management differs from that of adults; for appendicitis in patients of all ages; and for necrotizing enterocolitis in neonates.

Traumatic rupture of the thoracic aorta: Should one always operate immediately?

Although the traditional therapy for blunt traumatic rupture of the thoracic aorta (TRA) is immediate operative repair, there may be a selective role for delayed repair, particularly in patients with head trauma, respiratory failure, or cardiac dysfunction. The present study examines the hypothesis that TRA can be managed by selective delayed operative repair. Clinical data were collected from 59 consecutive patients with TRA at a regional trauma unit. All TRAs were at the aortic isthmus. Patients were retrospectively classified into three groups: group I (n=12) included patients who either arrived in extremis or rapidly became unstable during triage; group II (n=3) included patients who had no contraindications to early repair and underwent repair at the time of diagnosis; and group III (n=44) consisted of patients who because of concomitant injuries or sepsis required initial admission and management in the intensive care unit until their clinical status had improved sufficiently to allow for deliberate delayed operative repair of the TRA. The delay ranged from 1 day to 7 months. Eight patients have yet to undergo repair and remain well at follow-up from 1 to 4 years. Overall survival rates in groups I, II, and III were 17%, 100%, and 82%, respectively. The surgery-related mortality rate in group III was 10% (three patients). Only two (4.5%) patients in group III died as a result of a ruptured aorta within 72 hours of admission. In conclusion, contrary to surgical doctrine, TRA may not require immediate operative repair in all cases, but may instead be managed selectively depending on the patients clinical status.

The effect of age on functional outcome in mild traumatic brain injury: 6-month report of a prospective multicenter trial

OBJECTIVE Elderly patients (aged 60 years and older) have been demonstrated to have an increased mortality after isolated traumatic brain injury (TBI); however, the prognosis of those patients surviving their hospitalization is unknown. We hypothesized that surviving elderly patients would also have decreased functional outcome, and this study examined the functional outcome of patients with isolated TBI at discharge and at 6 months posthospitalization. METHODS This was a multicenter prospective study of all patients with isolated moderate to severe TBI defined as Head Abbreviated Injury Scale score of 3 with an Abbreviated Injury Scale score in any other body area of 1. Patients surviving to discharge gave their consent and were enrolled. Data collected included demographics, Glasgow Coma Scale (GCS) score at admission, and neurosurgical interventions. Outcome data included discharge disposition and Glasgow Outcome Scale score and modified Functional Independence Measure (FIM) score at discharge and at 6 months. RESULTS Two hundred thirty-five patients were enrolled, with 44 (19%) aged greater than or equal to 65 years. Mechanisms of injury were falls (34%), assaults (28%), motor vehicle collisions (14%), pedestrian (11%), and other (12%). Falls were more common in the older patients and assaults in the younger group. The mean admitting GCS score was 12.8 (95% confidence interval [CI], 12.4-13.3), with older patients having a higher mean GCS score, 14.1 (95% CI, 13.6-14.6) versus 12.5 (95% CI, 12.0-13.1; p = 0.03). There were no differences in the percentage of patients admitted to the intensive care unit or requiring neurosurgical intervention between younger and older patients. Because there were few elderly patients with low GCS scores who survived to discharge, outcome measures focused on those patients with GCS scores of 13 to 15. A greater percentage of elderly were discharged to rehabilitation (28% vs. 16%, p =0.08). The mean discharge FIM score was 10.4 (95% CI, 9.8-11.0) for the elderly versus 11.4 (95% CI, 11.1-11.7) for the young (p =0.001), with 68% elderly and 89% young discharged with total independent scores of 11 to 12. At 6 months, the difference narrowed, but the mean FIM score was still greater for the young group, 11.7 (95% CI, 11.6-11.9) versus 11.0 (95% CI, 10.6-11.4; p < 0.001). CONCLUSION Functional outcome after isolated mild TBI as measured by the Glasgow Outcome Scale and modified FIM is generally good to excellent for both elderly and younger patients. Older patients required more inpatient rehabilitation and lagged behind their younger counterparts but continued to recover and improve after discharge. Although there were statistically significant differences in the FIM score at both discharge and 6 months, the clinical importance of these small differences in the mean FIM score to the patients quality of life is less clear. Measurable improvement in functional status during the first 6 months after injury is observed in both groups. Aggressive management and care of older patients with TBI is warranted, and efforts should be made to decrease inpatient mortality. Continued follow-up is ongoing to determine whether these outcomes persist at 12 months.