Rajan K. Thakkar

Failure to normalize lymphopenia following trauma is associated with increased mortality, independent of the leukocytosis pattern.

IntroductionFollowing trauma and systemic inflammatory response syndrome (SIRS), the typical response is an elevation of the total complete blood count (CBC) and a reduction of the lymphocyte count. This leukocytosis typically returns to normal within 48 hours. The persistence of a leukocytosis following trauma is associated with adverse outcomes. Although lymphocyte anergy and dysfunction following trauma is associated with increased risk for infection and sepsis, there is a paucity of data regarding the impact of a persistence of a low lymphocyte count in trauma patients.MethodsThis is a retrospective review of prospectively collected data from trauma patients collected over the 5 years of September 2003 to September 2008. Patients were included if the injury severity score (ISS) was >/=15, and they survived at least 3 days. Demographic data, mechanism and injury severity score, mortality, and length of stay were collected from the medical record. Laboratory values for the first 4 hospital days were collected. Leukocyte, neutrophil and lymphocyte counts were extracted from the daily complete blood count (CBC). Patients were then grouped based on response (elevation/depression) of each component of the CBC, and their return, or failure thereof, to normal. Proportional hazards regression with time-varying covariates as well as Kaplan-Meier curves were used to predict risk of death, time to death and time to healthy discharge based on fluctuations of the individual components of the CBC.ResultsThere were 2448 patients admitted over the 5 years included in the analysis. When adjusting for age, gender and ISS the relative risk of death was elevated with a persistent leukocytosis (2.501 (95% CI = 1.477-4.235)) or failure to normalize lymphopenia (1.639 (95% CI = 10.17-2.643)) within the first 4 days following admission. Similar results were seen when Kaplan-Meier curves were created. Persistent lymphopenia was associated with shortest time to death. Paradoxically in survivors persistent lymphopenia was associated with the shortest time to discharge.ConclusionsPersistently abnormal CBC responses are associated with a higher mortality following trauma. This is the first report noting that a failure to normalize lymphopenia in severely injured patients is associated with significantly higher mortality.

Impact of Socioethnic Factors on Outcomes Following Traumatic Brain Injury

BACKGROUND Ethnic minorities and low income families tend to be in poorer health and have worse outcomes for a spectrum of diseases. Health care provider bias has been reported to potentially affect the distribution of care away from poorer communities, minorities, and patients with a history of substance abuse. Trauma is perceived as a disease of the poor and medically underserved. Minorities are overrepresented in low income populations and are also less likely to possess health insurance leading to a potential overlapping effect. Traumatic brain injury (TBI) is a predominant cause of mortality and long-term morbidity, which imposes a considerable social and financial burden. We therefore sought to determine the independent effect on outcome after TBI from race, insurance status, intoxication on presentation, and median income. METHODS A 5-year retrospective chart review of admitted trauma patients aged 18 years and older to a Level I trauma center. Zip code of residency was a surrogate marker for socioeconomic status, because median income for each zip code is available from the US Census. Charts review included race, insurance status, mechanisms of trauma, and injuries sustained. Outcomes were placement of tracheostomy, hospital length of stay (HLOS), leaving Against Medical Advice (AMA), and discharge to home versus rehabilitation and mortality. RESULTS A total of 3,101 TBI patients were included in the analyses. Multivariable logistic and proportional hazard regression analyses were undertaken adjusting for age, gender, Injury Severity Score, and mechanism. Rates of tracheostomy placement were unaffected by race, median income, or insurance status. Race and median income did not affect HLOS, but private insurance was associated with shorter HLOS and intoxication was associated with longer HLOS. Neither race nor intoxication affected rates of AMA, but higher income and private insurance was associated with lower rates of AMA. Non-Caucasian race and lack of insurance had significantly lower likelihood of placement in a rehabilitation center. Mortality was unaffected by race, increased in intoxicated patients, was variably affected by median income, and was lowest in patients with private insurance. CONCLUSIONS An extremely complex interplay exists between socioethnic factors and outcomes after TBI. Few physicians would claim overt discrimination. Tracheostomy, the factor most directed by the surgeon, was unbiased by race, income, or insurance status. The likelihood of placement in a rehabilitation center was significantly impacted by both race and insurance status. Future prospective studies are needed to better address causation.

Programmed death 1 expression as a marker for immune and physiological dysfunction in the critically ill surgical patient.

ABSTRACT Programmed death 1 (PD-1) is an inhibitor protein receptor for the immune system and has been shown to be upregulated in animal models of critical illness as well as after trauma and in burn victims in humans. It is believed that PD-1 may play a role in the immune dysfunction seen in surgical critical illness. However, although prior studies have associated changes in PD-1 expression with altered immune cell function, it is not known if a correlation with clinical status exists. We therefore aimed to describe a potential role for PD-1 in the immune dysfunction seen in critically ill trauma and surgical patients. This is an observational cohort study. Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were calculated on critically ill and injured trauma and surgical intensive care unit patients from a tertiary care/level I trauma center. Blood was drawn within 24 h of establishment of diagnosis and admission to the intensive care unit to measure circulating cytokine levels, as well as PD-1 expression on circulating cells. Main outcome measures included PD-1 expression on leukocytes and the relationship to physiological dysfunction (APACHE II) as well as the correlation of PD-1 expression and interleukin 10 levels among patients with severe physiological dysfunction. Samples were collected from 90 critically ill surgical patients. Among patients with severe physiological dysfunction (APACHE II >20), there were increased numbers of granulocytes (median, 144 vs. 90 cells/&mgr;L; P = 0.037) and monocytes (median, 12 vs. 6 cells/&mgr;L; P = 0.022) with PD-1 expression. In addition, among patients with an APACHE II score of greater than 20, there was a larger percentage of CD3+ cells (44% vs. 29%; P = 0.015) expressing PD-1. When only patients with an APACHE II score greater than 20 were assessed, PD-1 expression on monocytes correlated positively with interleukin levels in the serum (r = 0.525, P = 0.05). Variability in the expression of PD-1 on leukocytes in critical surgical illness correlates with physiological dysfunction and suggests that PD-1 may be a valuable tool in the assessment of immune dysfunction following trauma or severe surgical insult.

Mechanisms of indirect acute lung injury: a novel role for the coinhibitory receptor, programmed death-1.

Objective:To determine the contribution of programmed death receptor (PD)-1 in the morbidity and mortality associated with the development of indirect-acute lung injury. Background:The immune cell interaction(s) leading to indirect-acute lung injury are not completely understood. In this respect, we have recently shown that the murine cell surface coinhibitory receptor, PD-1, has a role in septic morbidity/mortality that is mediated in part through the effects on the innate immune arm. However, it is not know if PD-1 has a role in the development of indirect-acute lung injury and how this may be mediated at a cellular level. Methods:PD-1 -/- mice were used in a murine model of indirect-acute lung injury (hemorrhagic shock followed 24 hours after with cecal ligation and puncture-septic challenge) and compared to wild type controls. Groups were initially compared for survival and subsequently for markers of pulmonary inflammation, influx of lymphocytes and neutrophils, and expression of PD-1 and its ligand—PD-L1. In addition, peripheral blood leukocytes of patients with indirect-acute lung injury were examined to assess changes in cellular PD-1 expression relative to mortality. Results:PD-1 -/- mice showed improved survival compared to wild type controls. In the mouse lung, CD4+, CD11c+, and Gr-1+ cells showed increased PD-1 expression in response to indirect-acute lung injury. However, although the rise in bronchial alveolar lavage fluid protein concentrations, lung IL-6, and lung MCP-1 were similar between PD-1 -/- and wild type animals subjected to indirect acute lung injury, the PD-1 -/- animals that were subjected to shock/septic challenge had reduced CD4:CD8 ratios, TNF-&agr; levels, MPO activity, and Caspase 3 levels in the lung. Comparatively, we observed that humans, who survived their acute lung injury, had significantly lower expression of PD-1 on T cells. Conclusions:PD-1 expression contributes to mortality after the induction of indirect-acute lung injury and this seems to be associated with modifications in the cellular and cytokine profiles in the lung.

THERAPEUTIC ACCESSIBILITY OF CASPASE MEDIATED CELL DEATH AS A KEY PATHOMECHANISM IN INDIRECT ACUTE LUNG INJURY

Objective:Indirect acute lung injury is associated with high morbidity and mortality. However, the underlying pathophysiology is only marginally understood, and so far no pathophysiologic-based remedy exists. We hypothesized that apoptosis of lung epithelial cells is a pathophysiological relevant process in the development of indirect acute lung injury and that it should be accessible to a siRNA-based therapeutic intervention in vivo. Design:Prospective, randomized, controlled animal study. Setting:Basic science laboratory of a university affiliated level one trauma center. Subjects:Male C3H/HeN mice, 8 wks old, n = 121. Interventions:First, siRNA sequences to knock-down caspase-3 expression at a RNA and protein level were evaluated in vitro. Then, C3H/HeN mice were subjected to hemorrhagic shock, after which they received either a caspase-3 siRNA or a control/nonsense siRNA. Subsequently, they were then subjected to polymicrobial sepsis (induced by cecal ligation and puncture). Measurements and Main Results:Twelve and 24 hrs after sepsis, increased lung epithelial apoptosis was observed, as evidenced by active caspase-3 Western blotting, caspase-3, TUNEL-, and M-30 immunohistochemistry. Hallmarks of acute lung injury, such as increased concentrations of pulmonary cytokines/chemokines, lung protein leakage, myeloperoxidase activity, and altered lung histology, were evident in response to these insults. The single intratracheal instillation of caspase-3 siRNA not only attenuated lung apoptosis and inflammation but also ameliorated the development of acute lung injury in treated mice. Most interestingly, this experimental therapeutic approach markedly improved 10-day survival of hemorrhaged septic mice. Conclusions:Apoptosis of lung epithelial cells is a relevant pathomechanism in the development of hemorrhage-induced indirect septic acute lung injury, and caspase-3 appears to be a valuable therapeutic target accessible by siRNA treatment in vivo.

The development of a urinary tract infection is associated with increased mortality in trauma patients.

BACKGROUND In October 2008, Medicare and Medicaid stopped paying for care associated with catheter-related urinary tract infections (UTIs). Although most clinicians agree UTIs are detrimental, there are little data to support this belief. METHODS This is a retrospective review of trauma registry data from a Level I trauma center between 2003 and 2008. Two proportional hazards regressions were used for analyses. The first predicted acquisition of UTI as a function of indwelling urinary catheter use, adjusting for age, diabetes, gender, and injury severity. The second predicted hospital mortality as a function of UTI, covarying for age, gender, chronic obstructive pulmonary disease, congestive heart failure, hypertension, diabetes, pneumonia, and injury severity. RESULTS After excluding patients who stayed in the hospital <3 days and those with a UTI on arrival, 5,736 patients were included in the study. Of these patients, 680 (11.9%) met criteria for a UTI, with 487 (71.6%) indwelling urinary catheter-related infections. Predictors of UTI included the interaction between age and gender (p = 0.0018), Injury Severity Score (p = 0.0021), and indwelling urinary catheter use (p < 0.001). The development of a UTI predicted the risk of in-hospital death as a patients age increased (p = 0.002). Similar results were seen when only catheter-associated UTIs are included in the analysis. CONCLUSIONS Indwelling urinary catheter use is connected to the development of UTIs, and these infections are associated with a greater mortality as the age of a trauma patients increases.

Neutrophil-endothelial interactions mediate angiopoietin-2-associated pulmonary endothelial cell dysfunction in indirect acute lung injury in mice.

Unresolved inflammation in the lung is thought to elicit loss of endothelial cell (EC) barrier integrity and impaired lung function. We have shown, in a mouse model of shock/sepsis, that neutrophil interactions with resident pulmonary cells appear central to the pathogenesis of indirect acute lung injury (iALI). Normally, EC growth factors angiopoietin (Ang)-1 and Ang-2 maintain vascular homeostasis through tightly regulated interaction with the kinase receptor Tie2 expressed on ECs. Although Ang-1/Tie2 has been shown to promote vessel integrity, stimulating downstream prosurvival/antiinflammatory signaling, Ang-2, released from activated ECs, is reported to promote vessel destabilization. This mechanism of regulation, together with recent clinical findings that plasma Ang-2 levels are significantly elevated in patients who develop acute respiratory distress syndrome, has focused our investigation on the contribution of Ang-2 to the development of iALI. A murine model of hemorrhagic shock-induced priming for the development of iALI after subsequent septic challenge was used in this study. Our findings show that 1) Ang-2 is elevated in our experimental model for iALI, 2) direct EC/neutrophil interactions contribute significantly to EC Ang-2 release, and 3) suppression of Ang-2 significantly decreases inflammatory lung injury, neutrophil influx, and lung and plasma IL-6 and TNF-α. These findings support our hypothesis and suggest that Ang-2 plays a role in the loss of pulmonary EC barrier function in the development of iALI in mice resultant from the sequential insults of hemorrhagic shock and sepsis and that this is mediated by EC interaction with activated neutrophils.

Update on bariatric surgery in adolescence.

Purpose of review Recent evidence highlighting the prevalence of severe obesity in the pediatric population, coupled with disappointing outcomes related to medical weight loss interventions, has led to increased interest in bariatric surgery. This article focuses on recent additions to the literature regarding the current indications and outcomes of adolescent bariatric surgery, emerging guidelines on the development of surgical weight loss programs and the status of access to bariatric surgical care for adolescents in the United States. Recent findings Current data have shown a steady rise in the use of bariatric surgery among adolescents and serve to highlight the prevalence of several important obesity-related comorbidities. In addition to reports showing the safety and efficacy of adolescent bariatric surgery, a number of investigators have demonstrated significant improvement in key physiological and metabolic parameters (i.e., glucose metabolism, elevated blood pressure, dyslipidemia, etc.), offering updated consensus-driven guidelines for the indications for surgical intervention, as well as the development of multidisciplinary adolescent-specific care. Despite favorable outcomes, a disparity exists between the pediatric and adult populations related to access to such care. Summary In contrast to previous small and mostly retrospective series, contemporary studies have shown that adolescent bariatric surgery is well tolerated and effective. Despite these findings and the emergence of a national consensus regarding multidisciplinary care, skepticism among primary care providers, as well as significant challenges related to healthcare access, remain. Longitudinal studies and open dialogue within the medical community are needed.

Inflammatory mechanisms in sepsis: elevated invariant natural killer T-cell numbers in mouse and their modulatory effect on macrophage function.

ABSTRACT Invariant natural killer T cells (iNKT) cells are emerging as key mediators of innate immune cellular and inflammatory responses to sepsis and peritonitis. Invariant natural killer T cells mediate survival following murine septic shock. Macrophages are pivotal to survival following sepsis. Invariant natural killer T cells have been shown to modulate various mediators of the innate immune system, including macrophages. We demonstrate sepsis-inducing iNKT-cell exodus from the liver appearing in the peritoneal cavity, the source of the sepsis. This migration was affected by programmed death receptor 1. Programmed death receptor 1 is an inhibitory immune receptor, reported as ubiquitously expressed at low levels on iNKT cells. Programmed death receptor 1 has been associated with markers of human critical illness. Programmed death receptor 1–deficient iNKT cells failed to demonstrate similar migration. To the extent that iNKT cells affected peritoneal macrophage function, we assessed peritoneal macrophages’ ability to phagocytose bacteria. Invariant natural killer T−/− mice displayed dysfunctional macrophage phagocytosis and altered peritoneal bacterial load. This dysfunction was reversed when peritoneal macrophages from iNKT−/− mice were cocultured with wild-type iNKT cells. Together, our results indicate that sepsis induces liver iNKT-cell exodus into the peritoneal cavity mediated by programmed death receptor 1, and these peritoneal iNKT cells appear critical to regulation of peritoneal macrophage phagocytic function. Invariant natural killer T cells offer therapeutic targets for modulating immune responses and detrimental effects of sepsis.

Local tissue expression of the cell death ligand, fas ligand, plays a central role in the development of extrapulmonary acute lung injury.

Indirect acute lung injury (ALI) is a common manifestation in critically ill patients. Using a model of indirect ALI in mice, our laboratory has shown that local/pulmonary inhibition of extrinsic death receptor protein (Fas) leads to a decrease in lung inflammation and improved survival. However, it is unknown if local, i.e., autocrine/paracrine, inhibition of Fas ligand (FasL) affects Fas-expressing target cells itself or blockade of the actions of a more distal/endocrine source of FasL that accounts for these findings. To examine this, we used a model of indirect ALI in mice (dual insult of hemorrhagic shock followed 24 h later by cecal ligation and puncture, in which animals received FasL small interfering RNA (siRNA) intratracheally (local silencing) or intravenously (systemic/distal delivery) after hemorrhage. After intratracheal delivery of FasL siRNA, there was a significant decrease in inflammatory cytokines, myeloperoxidase activity, and caspase 3 activity in lung tissue along with protein leak as compared with controls. There was no difference found in these various outcome markers between those treated with intravenously administered FasL siRNA versus controls. The observation that local silencing of FasL, as opposed to distal/systemic silencing, ameliorates the effects of indirect ALI suggests not only that FasL produced in an autocrine/paracrine fashion in local tissues has pathological consequences within the lungs, but also that FasL might be a valuable pulmonary therapeutic target.