Jason W. Smith

Immunologic Responses to Critical Injury and Sepsis

Almost 2 million patients are admitted to hospitals in the United States each year for treatment of traumatic injuries, and these patients are at increased risk of late infections and complications of systemic inflammation as a result of injury. Host response to injury involves a general activation of multiple systems in defending the organism from hemorrhagic or infectious death. Clinicians have the capability to support the critically injured through their traumatic insult with surgery and improved critical care, but the inflammatory response generated by such injuries creates new challenges in the management of these patients. It has long been known that local tissue injury induces systemic changes in the traumatized patient that are often maladaptive. This article reviews the effects of injury on the function of immune system cells and highlights some of the clinical sequelae of this deranged inflammatory-immune interaction.

Necrotizing peripheral vasculitis/vasculopathy following the use of cocaine laced with levamisole.

The objective of this study was to describe a novel presentation of peripheral vasculitis associated with levamisole-adulterated cocaine. Cocaine abuse is widespread in the United States with 5.3 million people using cocaine in 2008. Over the past decade, drug enforcement officials have noticed the presence of levamisole in confiscated cocaine samples as an adulterant. Known side effects of cocaine-related levamisole ingestion have included agranulocytosis and a cutaneous acral purpura that is histopathologically characterized by a mixture of inflammation (vasculitis) and occlusion (vasculopathy). A 54-year-old man who nasally ingested cocaine laced with levamisole developed widespread necrotic/purpuric skin lesions on approximately 20% of his body with an acral accentuation. These lesions were complicated by multiple areas of sloughing and necrosis. He was initially treated with topical silver sulfadiazine dressing changes but progressed to require debridement and split-thickness skin grafting. Peripheral vasculitis/vasculopathy with severe necrosis resembling Coumadin necrosis is a relatively recently recognized sequelae from levamisole-adulterated cocaine use.

The prevalence and impact of prescription controlled substance use among injured patients at a Level I trauma center

BACKGROUND There has been increasing attention focused on the epidemic of prescription drug use in the United States, but little is known about its effects in trauma. The purpose of this study was to define the prevalence of prescription controlled substance use among trauma patients and determine its effects on outcome. METHODS A retrospective review of all patients admitted to a Level 1 trauma center from January 1, 2011, to December 31, 2011, was performed. Patients dying within 24 hours or without home medication reconciliations were excluded. Data review included preexisting benzodiazepine or narcotic use, sex, age, mechanism of injury, Injury Severity Scores (ISSs), intensive care unit (ICU) and overall length of stay, ventilator days, and overall cost. SAS version 9.3 was used for the analysis, and p ⩽ 0.05 was considered significant. RESULTS A total of 1,700 patients met inclusion criteria. Of these, 340 (20.0%) were on prescription narcotics and/or benzodiazepines at the time of admission. Patients in the narcotic/benzodiazepine group were significantly older (48 years vs. 43 years) and more likely to be women (43.7% vs. 28.9%). There was no difference in mechanism, ISS, or the presence of head injury between groups. Both ICU length of stay (3.3 days vs. 2.1 days) and total length of stay (7.8 days vs. 6.1 days) were significantly longer in patients on outpatient narcotics and/or benzodiazepines. Excluding severely injured patients, the need for mechanical ventilation was also increased among outpatient controlled substance users (15.8% vs. 11.0%). CONCLUSION There is a substantial prevalence of preexisting controlled substance use (20%) among patients at our Level 1 trauma center. Preexisting controlled substance use is associated with longer total hospital and ICU stays. Among mildly to moderately injured patients, preinjury controlled substance is also associated with the need for mechanical ventilation. LEVEL OF EVIDENCE Prognostic study, level III.

New perspectives for a new century: implications of pathogen responses for the future of antimicrobial therapy.

Although the discovery of new classes of antibiotics has lagged behind in the last three decades, the incidence of life-threatening nosocomial infections that are resistant to multiple antibacterial agents has increased steadily. Recent advances in bacterial pathogenicity through the identification of a number of virulence factors and the bacterial genetics behind it have opened the way to a clearer understanding of the pathogen–host relationship. Bacteria communicate with each other through specific signaling chemicals to act as a community rather than individual cells to achieve a critical density or a “quorum.” Establishment of quorum is the initiating signal for turning on a variety of virulence factors essential for the pathogenicity and dissemination of pathogens through the host. Pathogenic bacteria use a variety of biochemical mediators, collectively called “virulence factors,” to invade and attack host tissues and to avoid detection and elimination by the host immune system. Delineating the specific responses the host immune system elicits in response to specific virulence factors and quorum-sensing molecules is essential to the development of new diagnostic methods for early detection of an infection and the prognosis to a given antibacterial therapy. Identification of inhibitors of virulence factors will represent new antimicrobial therapeutic modalities, and this can be used synergistically with current antibiotic therapy because they act through independent prokaryotic pathways to inhibit bacterial growth and survival.

Insulin inhibits hepatocyte iNOS expression induced by cytokines by an Akt-dependent mechanism

Hepatocyte inducible nitric oxide synthese (iNOS) expression is a tightly controlled pathway that mediates hepatic inflammation and hepatocyte injury in a variety of disease states. We have shown that cyclic adenosine monophosphate (cAMP) regulates cytokine-induced hepatocyte iNOS expression through mechanisms that involve protein kinase B/Akt. We hypothesized that insulin, which activates Akt signaling in hepatocytes, as well as signaling through p38 and MAPK p42/p44, would regulate iNOS expression during inflammation. In primary rat hepatocytes, insulin inhibited cytokine-stimulated nitrite accumulation and iNOS expression in a dose-dependent manner. Inhibition of MAPK p42/p44 with PD98059 had no effect on iNOS activation, whereas SB203580 to block p38 reversed insulins inhibitory effect. However, insulin did not increase p38 activation and inhibition of p38 signaling with a dominant negative p38 plasmid had no effect on cytokine- or insulin-mediated effects on iNOS. We found that SB203580 blocked insulin-induced Akt activation. Inhibition of Akt signaling with LY294002 or a dominant negative Akt plasmid increased cytokine-stimulated nitrite production and iNOS protein expression and blocked the inhibitory effects of insulin. NF-κB induces iNOS expression and can be regulated by Akt, but insulin had no effect on cytokine-mediated IκBα levels or NF-κB p65 translocation. Our data demonstrate that insulin inhibits cytokine-stimulated hepatocyte iNOS expression and does so through effects on Akt-mediated signaling.

Does chest tube location matter? An analysis of chest tube position and the need for secondary interventions.

BACKGROUND Tube thoracostomy is a common procedure used in the management of thoracic trauma. Traditional teaching suggests that chest tubes should be directed in specific locations to improve function. Common examples include anterior and superior placement for pneumothorax, inferior and posterior placement for hemothorax, and avoidance of the pulmonary fissure. The purpose of this study was to examine the effect of specific chest tube position on subsequent chest tube function. METHODS A retrospective review of all patients undergoing tube thoracostomy for trauma from January 1, 2010, to September 30, 2012, was performed. Only patients undergoing computed tomography scans following chest tube insertion were included so that positioning could be accurately determined. Rib space insertion level and positioning of the tube relative to the lung parenchyma were recorded. The duration of chest tube drainage and the need for secondary interventions were determined and compared for tubes in different rib spaces and locations. For purposes of comparison, tubes placed above the sixth rib space were considered “high,” and those at or below it were considered “low.” RESULTS A total of 291 patients met criteria for inclusion. Forty-eight patients (16.5%) required secondary intervention. Neither high chest tube placement nor chest tube location relative to lung parenchyma was associated with an increased need for secondary interventions. On multivariate analysis, only chest Abbreviated Injury Scale (AIS) scores, mechanism, and volume of hemothorax were found to be significant risk factors for the need for secondary interventions. CONCLUSION Chest tube location does not influence the need for secondary interventions as long as the tube resides in the pleural space. The severity of chest injury is the most important factor influencing outcome in patients undergoing tube thoracostomy for trauma. Tube thoracostomy technique should focus on safe insertion within the pleural space and not on achieving a specific tube location. LEVEL OF EVIDENCE Therapeutic study, level IV.

17β-Estradiol attenuates cytokine-induced nitric oxide production in rat hepatocyte.

OBJECTIVE Nitric oxide (NO) regulation during shock and sepsis is complex. NO production by endothelial NO synthase maintains microvascular perfusion and prevents shock-induced organ injury. However, the overproduction of NO by inducible NO synthase (iNOS) contributes to liver dysfunction after shock and is associated with increased tissue damage and mortality. Estrogen improves organ function and outcome after shock and sepsis, but the mechanism is unknown. We hypothesized that 17&bgr;-estradiol would improve organ function by regulating the production of hepatocyte NO. METHODS Isolated rat hepatocytes were stimulated in vitro with pro-inflammatory cytokines to induce NO synthesis with or without estrogen. Nitrite was detected after 24 hours. INOS protein was determined using Western blot analysis. RESULTS Cytokine stimulation increased nitrite and iNOS protein in a dose-dependent manner. The cytokine-induced nitrite increase was significantly decreased by estrogen. iNOS expression was also diminished in cultures with the higher doses of estrogen. CONCLUSION 17&bgr;-Estradiol decreases cytokine-stimulated iNOS expression and NO production. The down-regulation of iNOS expression may account for the beneficial role of estrogens in models of sepsis and shock.

Sweet's syndrome with neurologic manifestations in a patient with esophageal adenocarcinoma: Case report and review of the literature

Background  Sweets syndrome, also known as febrile neutrophilic dermatosis, can occur in patients with an underlying malignancy and can present with extracutaneous manifestations, including neurologic symptoms.

Statewide Experience with Clostridium difficile Colitis in Academic and Non-Academic Medical Centers

BACKGROUND Clostridium difficile colitis is a nosocomial infection that can present as minor, readily treated symptoms or as fulminant colitis leading to death. Risk factors for C. difficile colitis have been defined, and certain populations of hospitalized patients appear to be particularly susceptible. However, most information on C. difficile colitis is from large tertiary-care medical centers. Whether the community hospital experience is similar to that of large referral centers is unknown. METHODS We abstracted all cases of C. difficile colitis (ICD-9-CM 008.45) for 2003-2005 from a state database and divided the hospitals into academic and nonacademic centers. Cases were stratified according to whether the colitis was listed as the primary presenting diagnosis or a secondary diagnosis. Demographic information, associated diagnoses, length of stay, and deaths were analyzed. RESULTS The incidence of C. difficile colitis increased from 2003 to 2005, and the majority of cases occurred at nonacademic centers. Patients in nonacademic centers more frequently had C. difficile colitis as the primary diagnosis, had a shorter length of stay, were older, and were more frequently women. The mortality rate was higher for secondary (8.5%) than for primary (2.6%; p < 0.05) C. difficile colitis, but there was no difference between academic and nonacademic centers. CONCLUSIONS The incidence of C. difficile colitis is increasing in this statewide database. Compared with academic medical centers, nonacademic centers deal with a higher rate of primary C. difficile colitis that is associated with a lower mortality rate and shorter stay than secondary colitis.

Organ donation as an outcome of traumatic cardiopulmonary arrest: A cost evaluation.

BACKGROUND Survival after traumatic cardiopulmonary arrest (TCPA) is rare and requires significant resource expenditure. Organ donation as an outcome of TCPA resuscitation has not yet been included in a cost analysis. The aims of this study were to identify variables associated with survival and organ donation after TCPA, and to estimate the cost of achieving these outcomes. We hypothesized that the inclusion of organ donation as a potential outcome would make TCPA resuscitation more cost-effective. METHODS Adult patients who required resuscitation for TCPA at a level I trauma center were retrospectively reviewed over 36 months. Data were obtained from medical records, hospital accounting records, and the local organ procurement agency. Outcomes included survival to discharge, neurologic function, and organ donor eligibility. An individual-level state-transition cost-effectiveness model was used to evaluate the cost of TCPA resuscitation with and without organ donation included as an outcome. Incremental cost-effectiveness ratio was calculated to determine additional cost per life saved when organ donation is included. RESULTS Over the study period, 8,932 subjects were evaluated. Traumatic cardiopulmonary arrest occurred in 237 patients (3%). The mortality rate was 97%. Variables associated with survival included emergency department disposition to the operating room (p < 0.01) and reactive pupils (p < 0.001). Of seven survivors, four were discharged neurologically intact. Of the patients with TCPA, 5% were eligible for organ donation with a procurement rate of 2%. Organ donor eligibility was associated with arrest after arrival to the emergency department (p < 0.01) and transfusion of fresh frozen plasma (p = 0.01). The cost of TCPA resuscitation per survivor was