Sean F. Monaghan

Hormonally active women tolerate shock-trauma better than do men: a prospective study of over 4000 trauma patients.

Objective:To test the hypothesis that comparably injured women, especially those in the hormonally active age groups, would manifest a better preserved hemodynamic response and tissue perfusion after major trauma than do men. Summary Background Data:The notion that premenopausal women are more resistant than men to shock and trauma has been shown in numerous preclinical models. However, human studies on the effects of gender on outcome after shock-trauma are less clear, and none has examined the effect of gender on the immediate postinjury response to major trauma. Methods:Prospective series of all patients at a Level I trauma center from January 2000 to December 2005. Study patients were all patients arriving to the trauma area of the emergency department and having a serum lactate drawn within 30 minutes of arrival. Demographic data, injury severity indices, blood utilization, and lactate levels were recorded. Lactate was used as a marker of the hemodynamic response to injury, because it has been shown to be an excellent and accurate indicator of inadequate tissue perfusion. Results:A total of 5192 patients were eligible for the study of which 4106 fulfilled the study requirements and were enrolled. Initial serum lactate levels were significantly lower in premenopausal (age 14–44) and perimenopausal (age 45–54) women than in men of the same age groups (P < 0.001), even though the Injury Severity Score of the women was significantly higher than that of the men (24 vs. 18; P < 0.1). When patients were stratified into major injury groups as well as groups receiving blood transfusions, the premenopausal women were also found to have lower initial serum lactate levels and receive less blood, while having a greater magnitude of injury as reflected in their Injury Severity Score. Conclusion:The data firmly establishes a proof of principle that hormonally active human women have a better physiologic response to similar degrees of shock and trauma than do their male counterparts. These gender-based differences should be taken into account in designing studies evaluating the response to shock-trauma.

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.

BTLA expression contributes to septic morbidity and mortality by inducing innate inflammatory cell dysfunction

A proper innate inflammatory response is essential for prevention of the systemic inflammation associated with sepsis. BTLA is an immune‐regulatory receptor demonstrated to be expressed not only on adaptive immune populations and have potent inhibitory effects on CD4+ T cells but is also expressed on innate cell populations (CD11c+ and CD11b+ cells) and has been shown to diminish pathogen clearance following bacterial and parasite infection. The role of BTLA in sepsis and the mechanisms by which BTLA alters pathogen clearance, however, have not been addressed clearly. Here, we show that following acute experimental sepsis induction in mice (CLP), the number of infiltrating BTLA‐ and HVEM (the ligand for BTLA)‐expressing macrophages, inflammatory monocytes, mature and immature DCs, and neutrophils increased in the peritoneum compared with sham surgery, suggesting that a high level of HVEM:BTLA interactions occurs between these cells at the site of septic insult. Given this, we evaluated BTLA−/− mice, 24 h post‐CLP, and observed a marked increase in the degree of activation on these cell populations, as well as a reduction in peritoneal bacterial burden and IL‐10 induction, and most importantly, BTLA−/− mice exhibited a higher rate of survival and protection from organ injury when compared with WT mice. Such changes were not restricted to experimental mice, as circulating BTLA+ and HVEM+ monocytes and HVEM+ granulocytes were increased in septic ICU patients, supporting a role for BTLA and/or HVEM as potential, novel diagnostic markers of innate immune response/status and as therapeutic targets of sepsis.

Anti-Inflammatory Mechanisms of Sepsis

Over the past two decades, it has become well accepted that sepsis exhibits two, oftentimes concomitant, inflammatory stages; a pro-inflammatory phase, referred to as the systemic inflammatory response syndrome (SIRS), and an anti-inflammatory phase, called the compensatory anti-inflammatory response syndrome (CARS). Considering that therapeutic interventions designed to attenuate the pro-inflammatory septic response have generally failed, much recent research has gone into understanding how and why septic patients display immunosuppressive characteristics, what the significance of septic immunosuppression may be and if there exists any therapeutic targets within the CARS. Herein, we describe the potential mechanisms of the immunosuppressive/CARS phase of sepsis by discussing what anti-inflammatory agents, receptors and cell populations are currently believed to contribute to CARS.

B and T lymphocyte attenuator expression on CD4+ T-cells associates with sepsis and subsequent infections in ICU patients

IntroductionSepsis is a deadly inflammatory condition that often leads to an immune suppressed state; however, the events leading to this state remain poorly understood. B and T lymphocyte attenuator (BTLA) is an immune-regulatory receptor shown to effectively inhibit CD4+ T-cell function. Therefore, our objectives were to determine: 1) if lymphocyte BTLA expression was altered in critically ill patients and experimentally induced septic mice, 2) whether augmented CD4+ T-cell BTLA expression was associated with poor septic patient outcomes, and 3) if BTLA expression affected the CD4+ T-cell apoptotic cell loss observed in the lymphoid organs of septic mice.MethodsChanges in CD4+ lymphocyte BTLA expression were compared with morbid event development in critically ill ICU patients (11 septic and 28 systemic inflammatory response syndrome subjects). Wild type and BTLA gene deficient mice were utilized to evaluate the expression and role of BTLA in septic lymphocyte apoptotic cell loss.ResultsThe observed septic ICU patients had a significantly higher percentage of peripheral blood BTLA+ CD4+ lymphocytes compared with critically ill non-septic individuals. Moreover, the non-septic patients with CD4+ T-cells that were greater than 80% BTLA+ were more susceptible to developing nosocomial infections. Additionally, in general, critically ill patients with CD4+ T-cells that were greater than 80% BTLA+ had longer hospital stays. Comparatively, circulating CD4+ T-cell and B-cell BTLA expression increased in septic mice, which associated with the increased septic loss of these cells. Finally, the loss of these cells and cellular apoptosis induction in primary and secondary lymphoid organs were reversed in BTLA deficient mice.ConclusionsAn increased BTLA+ CD4+ lymphocyte frequency in the observed critically ill non-septic patients was associated with a subsequent infection; therefore, BTLA may act as a biomarker to help determine nosocomial infection development. Additionally, BTLA expression contributed to primary and secondary lymphoid organ apoptotic cell loss in experimentally septic mice; thus, BTLA-induced apoptotic lymphocyte loss may be a mechanism for increased nosocomial infection risk in critically ill patients. This study had a relatively small human subject cohort; therefore, we feel these findings warrant future studies evaluating the use of BTLA as a critically ill patient nosocomial infection biomarker.

Identification of B7-H1 as a Novel Mediator of the Innate Immune/Proinflammatory Response as well as a Possible Myeloid Cell Prognostic Biomarker in Sepsis

Identifying relevant mediators responsible for the pathogenesis during sepsis may lead to finding novel diagnostic and therapeutic targets. Recent studies indicate programmed cell death receptor (PD)-1 plays a significant role in the development of immune suppression associated with sepsis. In this study, we determine whether B7-H1, the primary ligand of PD-1, contributes to the pathogenesis of sepsis. We report that B7-H1 is upregulated extensively on various immune cells during sepsis and B7-H1 gene deficiency protects mice from the lethality of sepsis. In terms of the histological development of multiple organ damage and inflammatory cytokine levels in circulation or at infectious site, B7-H1–deficient mice showed a remarkable reduction in these indices when compared with wild-type mice. However, B7-H1 gene-deficient mice did not exhibit a lower bacterial burden when compared with wild-type mice, although they recruited more macrophages and neutrophils into infectious site. In addition, we found that, during sepsis, whereas there were no marked differences affecting ex vivo macrophage cytokine productive capacity between PD-1 and B7-H1 gene-deficient mice, preservation of ex vivo macrophage phagocytic function was only seen in septic PD-1 knockout mouse cells. Finally, higher percentage B7-H1+ neutrophils in peripheral blood correlated not only with higher levels of pro- and anti-inflammatory cytokines/chemokines (CCL2, IL-6, CXCL2, KC, TNF-α, and IL-10), but with lethal outcome as well. Together, these results indicate B7-H1 contributes to septic morbidity in fashion distinct from PD-1 and suggest B7-H1 expression on neutrophils could be used as a biomarker of septic severity.

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.

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.