Darwin N. Ang

Persistent inflammation and immunosuppression: A common syndrome and new horizon for surgical intensive care

ABSTRACT Surgical intensive care unit (ICU) stay of longer than 10 days is often described by the experienced intensivist as a “complicated clinical course” and is frequently attributed to persistent immune dysfunction. “Systemic inflammatory response syndrome” (SIRS) followed by “compensatory anti-inflammatory response syndrome” (CARS) is a conceptual framework to explain the immunologic trajectory that ICU patients with severe sepsis, trauma, or emergency surgery for abdominal infection often traverse, but the causes, mechanisms, and reasons for persistent immune dysfunction remain unexplained. Often involving multiple-organ failure (MOF) and death, improvements in surgical intensive care have altered its incidence, phenotype, and frequency and have increased the number of patients who survive initial sepsis or surgical events and progress to a persistent inflammation, immunosuppression, and catabolism syndrome (PICS). Often observed, but rarely reversible, these patients may survive to transfer to a long-term care facility only to return to the ICU, but rarely to self-sufficiency. We propose that PICS is the dominant pathophysiology and phenotype that has replaced late MOF and prolongs surgical ICU stay, usually with poor outcome. This review details the evolving epidemiology of MOF, the clinical presentation of PICS, and our understanding of how persistent inflammation and immunosuppression define the pathobiology of prolonged intensive care. Therapy for PICS will involve innovative interventions for immune system rebalance and nutritional support to regain physical function and well-being.

Esophageal cancer—the five year survivors

Esophageal cancer in the United States carries a poor prognosis with overall 5 year survival rate of approximately 10%. Due to this dismal outcome, data analyzing factors predictive of survival for greater than 5 years are not available.

Pulmonary embolism prophylaxis with inferior vena cava filters in trauma patients: a systematic review using the meta-analysis of observational studies in epidemiology (MOOSE) guidelines

Prophylactic inferior vena cava filters (pIVCFs) for the prevention of pulmonary embolism (PE) are controversial. Current practice guidelines (EAST and ACCP) are based on the critical appraisal of observational studies. As a result, their recommendations are conflicting and may account for practice pattern variation. The purpose of this study is to critically review the available literature and ascertain the level of evidence both for and against the use of pIVCFs for PE prophylaxis in trauma patients. We searched PubMed and Web of Science for publications from 1950 until July 2010 that assessed the efficacy of PE prevention with pIVCFs in the trauma population. We followed the MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines for design, implementation, and reporting. The Newcastle-Ottawa Score was used for quality and comparability assessment. Seven observational studies met inclusion criteria for this meta-analysis, representing 1,900 patients. Only one study was published in this decade. The rate of PE was statistically lower in the IVCF group compared to a matched control group without IVCFs (OR 0.21, 95% CI 0.09–0.49). There was no significant difference in DVT. Using the MOOSE criteria these results show a decreased likelihood of PE among trauma patients who receive pIVCFs. Although these results could favor the placement of pIVCFs, the lack of contemporary use of pharmacologic prophylaxis across studies does not allow us to make firm conclusions either for or against the routine use of pIVCFs. Prospective randomized trials are needed to determine the role of pIVCFs in high-risk trauma patients.

Utilization of minimally invasive breast biopsy for the evaluation of suspicious breast lesions

BACKGROUND Percutaneous needle biopsy, also known as minimally invasive breast biopsy (MIBB), has become the gold standard for the initial assessment of suspicious breast lesions. The purpose of this study is to determine modern rates of MIBB and open breast biopsy. METHODS The Florida Agency for Health Care Administration outpatient surgery and procedure database was queried for patients undergoing open surgical biopsy and MIBB between 2003 and 2008. RESULTS Although there was an increase in the use of MIBB, the overall rate of open surgical biopsy remained high (∼30%). A reduction in the open biopsy rate from 30% to 10% could be associated with a charge reduction of >

Development of a genomic metric that can be rapidly used to predict clinical outcome in severely injured trauma patients.

37.2 million per year. CONCLUSIONS The current rate of open surgical breast biopsy remains high. Interventions and quality initiatives are warranted, which could lead to a reduction in unnecessary operations for women, improved patient care, and a reduction in breast health care costs.

The Potential Influence of Common Viral Infections Diagnosed during Hospitalization among Critically Ill Patients in the United States

Objective:Many patients have complicated recoveries following severe trauma due to the development of organ injury. Physiological and anatomical prognosticators have had limited success in predicting clinical trajectories. We report on the development and retrospective validation of a simple genomic composite score that can be rapidly used to predict clinical outcomes. Design:Retrospective cohort study. Setting:Multi-institutional level 1 trauma centers. Patients:Data were collected from 167 severely traumatized (injury severity score >15) adult (18–55 yr) patients. Methods:Microarray-derived genomic data obtained from 167 severely traumatized patients over 28 days were assessed for differences in messenger RNA abundance among individuals with different clinical trajectories. Once a set of genes was identified based on differences in expression over the entire study period, messenger RNA abundance from these subjects obtained in the first 24 hours was analyzed in a blinded fashion using a rapid multiplex platform, and genomic data reduced to a single metric. Results:From the existing genomic dataset, we identified 63 genes whose leukocyte expression differed between an uncomplicated and complicated clinical outcome over 28 days. Using a multiplex approach that can quantitate messenger RNA abundance in less than 12 hours, we reassessed total messenger RNA abundance from the first 24 hours after trauma and reduced the genomic data to a single composite score using the difference from reference. This composite score showed good discriminatory capacity to distinguish patients with a complicated outcome (area under a receiver–operator curve, 0.811; p <0.001). This was significantly better than the predictive power of either Acute Physiology and Chronic Health Evaluation II or new injury severity score scoring systems. Conclusions:A rapid genomic composite score obtained in the first 24 hours after trauma can retrospectively identify trauma patients who are likely to develop complicated clinical trajectories. A novel platform is described in which this genomic score can be obtained within 12 hours of blood collection, making it available for clinical decision making.

Identification and description of a novel murine model for polytrauma and shock.

Viruses are the most common source of infection among immunocompetent individuals, yet they are not considered a clinically meaningful risk factor among the critically ill. This work examines the association of viral infections diagnosed during the hospital stay or not documented as present on admission to the outcomes of ICU patients with no evidence of immunosuppression on admission. This is a population-based retrospective cohort study of University HealthSystem Consortium (UHC) academic centers in the U.S. from the years 2006 to 2009. The UHC is an alliance of over 90% of the non-profit academic medical centers in the U.S. A total of 209,695 critically ill patients were used in this analysis. Eight hospital complications were examined. Patients were grouped into four cohorts: absence of infection, bacterial infection only, viral infection only, and bacterial and viral infection during same hospital admission. Viral infections diagnosed during hospitalization significantly increased the risk of all complications. There was also a seasonal pattern for viral infections. Specific viruses associated with poor outcomes included influenza, RSV, CMV, and HSV. Patients who had both viral and bacterial infections during the same hospitalization had the greatest risk of mortality RR 6.58, 95% CI (5.47, 7.91); multi-organ failure RR 8.25, 95% CI (7.50, 9.07); and septic shock RR 271.2, 95% CI (188.0, 391.3). Viral infections may play a significant yet unrecognized role in the outcomes of ICU patients. They may serve as biological markers or play an active role in the development of certain adverse complications by interacting with coincident bacterial infection.

Acute kidney injury is associated with early cytokine changes after trauma.

Objective:To develop a novel polytrauma model that better recapitulates the immunologic response of the severely injured patient by combining long-bone fracture, muscle tissue damage, and cecectomy with hemorrhagic shock, resulting in an equivalent Injury Severity Score of greater than 15. We compared this new polytrauma/shock model to historically used murine trauma-hemorrhage models. Design:Pre-clinical controlled in vivo laboratory study. Setting:Laboratory of Inflammation Biology and Surgical Science. Subjects:Six- to 10-week-old C57BL/6 (B6) mice. Interventions:Mice underwent 90 minutes of shock (mean arterial pressure 30 mm Hg) and resuscitation via femoral artery cannulation followed by laparotomy (trauma-hemorrhage), hemorrhage with laparotomy and femur fracture, or laparotomy with cecetomy and femur fracture with muscle tissue damage (polytrauma). Mice were euthanized at 2 hours, 1 day, and 3 days postinjury. Measurements and Main Results:The spleen, bone marrow, blood, and serum were collected from mice for analysis at the above time points. None of the models were lethal. Mice undergoing polytrauma exhibited a more robust inflammatory response with significant elevations in cytokine/chemokine concentrations when compared with traditional models. Polytrauma was the only model to induce neutrophilia (Ly6G+CD11b+ cells) on days 1 and 3 (p < 0.05). Polytrauma, as compared to trauma-hemorrhage and hemorrhage with laparotomy and femur fracture, induced a loss of circulating CD4+ T cell with simultaneous increased cell activation (CD69+ and CD25+), similar to human trauma. There was a prolonged loss of major histocompatibility complex class II expression on monocytes in the polytrauma model (p < 0.05). Results were confirmed by genome-wide expression analysis that revealed a greater magnitude and duration of blood leukocyte gene expression changes in the polytrauma model than the trauma-hemorrhage and sham models. Conclusions:This novel polytrauma model better replicates the human leukocyte, cytokine, and overall inflammatory response following injury and hemorrhagic shock.

A pilot study on the randomization of inferior vena cava filter placement for venous thromboembolism prophylaxis in high-risk trauma patients.

BACKGROUND Acute kidney injury (AKI) occurs in 26% of trauma patients and is associated with increased mortality and risk for nosocomial infections (NCIs). We compared serial plasma cytokine levels in patients with posttraumatic AKI to determine whether the early cytokine changes are associated with the occurrence of AKI and NCI. METHODS We performed a secondary analysis of the Inflammation and the Host Response to Injury database to include adult blunt trauma patients who had available plasma proteomic analyses. AKI was defined by the RIFLE (Risk, Injury, Failure, Loss, and End-stage Kidney) classification, which requires a 50% increase in serum creatinine. The association among AKI, NCI, and plasma cytokines was analyzed using a mixed model analyses and logistic regression. RESULTS Among 147 patients in the cohort, prevalence of NCI was 73% and 52% for patients with and without AKI, respectively. In mixed model analyses adjusted for clinical factors, AKI patients developed significant early increase in IL-1ra, IL-8, MCP1, and IL-6; early decrease in sTNFR2; and late decrease in IL-1ra, IL-4, and IL-6 concentrations, compared with patients without AKI and regardless of NCI. The change in cytokine pattern differed for sIL1R2, CXCL1, and MIP1&bgr;, depending on the occurrence of NCI. Patients with AKI and NCI had lower early and late sIL1R2 and higher early and late CXCL1 and MIP1&bgr; levels. Within the first 24 hours of injury, adding plasma levels of IL-1ra, IL-8, MCP1, IL-6, and sTNFR2 to clinical parameters of injury severity provided a predictive model for AKI superior to clinical model only (p < 0.001). CONCLUSION AKI trauma patients exhibit simultaneous changes in proinflammatory and anti-inflammatory serial plasma cytokine levels. The predictive model for AKI that combines plasma cytokine levels with clinical data within 24 hours of injury requires further prospective validation in larger studies. LEVEL OF EVIDENCE Prognostic study, level III.

Complication Rates among Trauma Centers

BACKGROUND Placement of prophylactic inferior vena cava filters (pIVCFs) for the prevention of pulmonary embolism (PE) in high-risk trauma patients (HRTPs) are widely practiced despite the lack of Level I data supporting this use. We report the 2-year interim analysis of the Filters in Trauma pilot study. METHODS This is a single institution, prospective randomized controlled pilot feasibility study in a Level I trauma center. HRTPs were identified for pIVCF placement by the Eastern Association for the Surgery of Trauma guidelines. From November 2008 to November 2010, HRTPs were enrolled and randomized to either pIVCF or no pIVCF. All patients received pharmacologic prophylaxis when safe. Primary outcomes included feasibility objectives and secondary outcomes were incidence of PE, deep vein thrombosis (DVT), and death. RESULTS Thirty-four of 38 enrolled patients were eligible for analysis. The baseline sociodemographic characteristics were balanced between the both groups. Results of the feasibility objectives included: time from admission to enrollment (mean, 47.4 hours ± 22.0 hours), time from enrollment to randomization (mean, 4.8 hours ± 9.1 hours), time from randomization to IVCF placement (mean, 16.9 hours ± 9.2 hours), adherence to weekly compression ultrasound within first month (IVCF group = 44.4%; non-IVCF group = 62.5%), and 1-month clinical follow-up (IVCF group = 83.3%; non-IVCF group = 100%). At 6-month follow-up, one PE in the nonfilter group and one DVT in the filter group had occurred. One non-PE-related death occurred in the filter group. Barriers to enrollment included inability to obtain informed consent due to patient refusal or no next of kin identified and delayed notification of eligibility status. CONCLUSION Our pilot study demonstrates for the first time that a randomized controlled trial evaluating the efficacy of pIVCFs in trauma patients is feasible. This pilot data will be used to inform the design of a multicenter randomized controlled trial to determine the incidence of PE and DVT in HRTPs receiving pIVCFs versus no pIVCF.