Tyler J. Loftus

Microbial recognition and danger signals in sepsis and trauma

Early host recognition of microbial invasion or damaged host tissues provides an effective warning system by which protective immune and inflammatory processes are initiated. Host tissues responsible for continuous sampling of their local environment employ cell surface and cytosolic pattern recognition receptors (PRRs) that provide redundant and overlapping identification of both microbial and host alarmins. Microbial products containing pathogen-associated molecular patterns (PAMPs), as well as damage-associated molecular patterns (DAMPs) serve as principle ligands for recognition by these PRRs. It is this interaction which plays both an essential survival role in response to infection and injury, as well as the pathologic role in tissue and organ injury associated with severe sepsis and trauma. Elucidating the interaction between ligands and their respective PRRs can provide both a better understanding of the host response, as well as a rational basis for therapeutic intervention. This article is part of a Special Issue entitled: Immune and Metabolic Alterations in Trauma and Sepsis edited by Dr. Raghavan Raju.

A protocol for the management of adhesive small bowel obstruction

BACKGROUND Differentiating between partial adhesive small bowel obstruction (aSBO) likely to resolve with medical management and complete obstruction requiring operative intervention remains elusive. We implemented a standardized protocol for the management of aSBO and reviewed our experience retrospectively. METHODS Patients with symptoms of aSBO were admitted for intravenous fluid resuscitation, bowel rest, nasogastric tube decompression, and abdominal examinations every 4 hours. Laboratory values and a computed tomography scan of the abdomen and pelvis with intravenous contrast were obtained. Patients with peritonitis or computed tomography scan findings suggesting bowel compromise were taken to the operating room for exploration following resuscitation. All other patients received 80 mL of Gastroview (GV) and 40 mL of sterile water via nasogastric tube. Abdominal plain films were obtained at 4, 8, 12, and 24 hours. If contrast did not reach the colon within 24 hours, then operative intervention was performed. RESULTS Over 1 year, 91 patients were admitted with aSBO. Sixty-three patients received GV, of whom 51% underwent surgery. Twenty-four patients went directly to the operating room because of clinical or imaging findings suggesting bowel ischemia. Average time to surgery was within 1 day for the no-GV group and 2 days for the GV group. Patients passing GV to the colon within 5 hours of administration had a 90% rate of resolution of obstruction. There was a direct relationship between the duration of time before passing GV to the colon and hospital length of stay (HLOS) (r2 = 0.459). Patients who received GV and did not require surgery had lower HLOS (3 days vs. 11 days, p < 0.0001). CONCLUSION The GV protocol facilitated early recognition of complete obstruction. Administration of GV had diagnostic and therapeutic value and did not increase HLOS, morbidity, or mortality. LEVEL OF EVIDENCE Therapeutic study, level V. Epidemiologic study, level V.

β-Blockade use for Traumatic Injuries and Immunomodulation: A Review of Proposed Mechanisms and Clinical Evidence.

ABSTRACT Sympathetic nervous system activation and catecholamine release are important events following injury and infection. The nature and timing of different pathophysiologic insults have significant effects on adrenergic pathways, inflammatory mediators, and the host response. Beta adrenergic receptor blockers (&bgr;-blockers) are commonly used for treatment of cardiovascular disease, and recent data suggests that the metabolic and immunomodulatory effects of &bgr;-blockers can expand their use. &bgr;-blocker therapy can reduce sympathetic activation and hypermetabolism as well as modify glucose homeostasis and cytokine expression. It is the purpose of this review to examine either the biologic basis for proposed mechanisms or to describe current available clinical evidence for the use of &bgr;-blockers in traumatic brain injury, spinal cord injury, hemorrhagic shock, acute traumatic coagulopathy, erythropoietic dysfunction, metabolic dysfunction, pulmonary dysfunction, burns, immunomodulation, and sepsis.

Temporary abdominal closure for trauma and intra-abdominal sepsis: different patients, different outcomes.

BACKGROUND Temporary abdominal closure (TAC) after damage control surgery (DCS) for injured patients has been generalized to septic patients. However, direct comparisons between these populations are lacking. We hypothesized that patients with intra-abdominal sepsis would have different resuscitation requirements and lower primary fascial closure rates than trauma patients. STUDY DESIGN We performed a 3-year retrospective cohort analysis of patients managed with TAC for trauma (n = 77) or intra-abdominal sepsis (n = 147). All patients received negative pressure wound therapy (NPWT) TAC with intention for planned relaparotomy and sequential abdominal closure attempts at 24- to 48-hour intervals. RESULTS At presentation, trauma patients had higher rates of hypothermia (31% vs. 18%), severe acidosis (27% vs. 14%), and coagulopathy (68% vs. 48%), and septic patients had higher vasopressor infusion rates (46% vs. 27%). Forty-eight hours after presentation, septic patients had persistently higher vasopressor infusion rates (37% vs. 17%), and trauma patients had received more red blood cell transfusions (6.0 U vs. 0.0 U), fresh frozen plasma (5.0 U vs. 0.0 U), and crystalloid (8,290 vs. 7,159 ml). Among patients surviving to discharge, trauma patients had higher primary fascial closure (PFC) rates (90% vs. 76%). For trauma patients, independent predictors of failure to achieve PCF were ≥2.5 L NPWT output at 48 hours, ≥10 L crystalloid administration at 48 hours, and ≥10 U PRBC + FFP at 48 hours. For septic patients, relaparotomy within 48 hours predicted successful PFC; requirement for ≥3 diagnostic/therapeutic laparotomies predicted failure to achieve PFC. CONCLUSIONS Traumatic injury and intra-abdominal sepsis are associated with distinct pathophysiologic insults, resuscitation requirements, and outcomes. Failure to achieve primary fascial closure in trauma patients was attributable to the triad of hypothermia, acidosis, and coagulopathy; failure to achieve fascial closure in septic patients was dependent upon operative course. Indications and optimal techniques for TAC may differ between these populations. LEVEL OF EVIDENCE Therapeutic study, level IV; prognostic study, level III.

Duodenal gangliocytic paraganglioma: A case report and literature review

Highlights • Differentiation between GP and GIST alters treatment algorithms.• Primary management of duodenal GP consists of resection with negative margins.• Surveillance alone is safe and effective following resection with negative margins.• For regionally advanced disease, consider adjuvant radiotherapy.

Dysregulated myelopoiesis and hematopoietic function following acute physiologic insult

Purpose of review The purpose of this review is to describe recent findings in the context of previous work regarding dysregulated myelopoiesis and hematopoietic function following an acute physiologic insult, focusing on the expansion and persistence of myeloid-deriver suppressor cells, the deterioration of lymphocyte number and function, and the inadequacy of stress erythropoiesis. Recent findings Persistent myeloid-derived suppressor cell (MDSC) expansion among critically ill septic patients is associated with T-cell suppression, vulnerability to nosocomial infection, chronic critical illness, and poor long-term functional status. Multiple approaches targeting MDSC expansion and suppressor cell activity may serve as a primary or adjunctive therapeutic intervention. Traumatic injury and the neuroendocrine stress response suppress bone marrow erythropoietin receptor expression in a process that may be reversed by nonselective beta-adrenergic receptor blockade. Hepcidin-mediated iron-restricted anemia of critical illness requires further investigation of novel approaches involving erythropoiesis-stimulating agents, iron administration, and hepcidin modulation. Summary Emergency myelopoiesis is a dynamic process with unique phenotypes for different physiologic insults and host factors. Following an acute physiologic insult, critically ill patients are subject to persistent MDSC expansion, deterioration of lymphocyte number and function, and inadequate stress erythropoiesis. Better strategies are required to identify patients who are most likely to benefit from targeted therapies.

Sepsis and Critical Illness Research Center investigators: protocols and standard operating procedures for a prospective cohort study of sepsis in critically ill surgical patients

Introduction Sepsis is a common, costly and morbid cause of critical illness in trauma and surgical patients. Ongoing advances in sepsis resuscitation and critical care support strategies have led to improved in-hospital mortality. However, these patients now survive to enter state of chronic critical illness (CCI), persistent low-grade organ dysfunction and poor long-term outcomes driven by the persistent inflammation, immunosuppression and catabolism syndrome (PICS). The Sepsis and Critical Illness Research Center (SCIRC) was created to provide a platform by which the prevalence and pathogenesis of CCI and PICS may be understood at a mechanistic level across multiple medical disciplines, leading to the development of novel management strategies and targeted therapies. Methods Here, we describe the design, study cohort and standard operating procedures used in the prospective study of human sepsis at a level 1 trauma centre and tertiary care hospital providing care for over 2600 critically ill patients annually. These procedures include implementation of an automated sepsis surveillance initiative, augmentation of clinical decisions with a computerised sepsis protocol, strategies for direct exportation of quality-filtered data from the electronic medical record to a research database and robust long-term follow-up. Ethics and dissemination This study has been registered at ClinicalTrials.gov, approved by the University of Florida Institutional Review Board and is actively enrolling subjects. Dissemination of results is forthcoming.

Daily propranolol administration reduces persistent injury-associated anemia following severe trauma and chronic stress.

BACKGROUND After severe trauma, patients develop a norepinephrine-mediated persistent, injury-associated anemia. This anemia is associated with suppression of bone marrow (BM) erythroid colony growth, along with decreased iron levels, and elevated erythropoietin (EPO) levels, which are insufficient to promote effective erythropoiesis. The impact of norepinephrine on iron regulators, such as ferroportin, transferrin, and transferrin receptor-1 (TFR-1), is unknown. Using a clinically relevant rodent model of lung contusion (LC), hemorrhagic shock (HS), and chronic stress (CS), we hypothesize that daily propranolol (BB), a nonselective &bgr; blocker, restores BM function and improves iron homeostasis. METHODS Male Sprague-Dawley rats were subjected to LCHS ± BB and LCHS/CS ± BB. BB was achieved with propranolol (10 mg/kg) daily until the day of sacrifice. Hemoglobin, plasma EPO, plasma hepcidin, BM cellularity and BM erythroid colony growth were assessed. RNA was isolated to measure transferrin, TFR-1 and ferroportin expression. Data are presented as mean ± SD; *p < 0.05 versus untreated counterpart by t test. RESULTS The addition of CS to LCHS leads to persistent anemia on posttrauma day 7, while the addition of BB improved hemoglobin levels (LCHS/CS: 10.6 ± 0.8 vs. LCHS/CS + BB: 13.9 ± 0.4* g/dL). Daily BB use after LCHS/CS improved BM cellularity, colony-forming units granulocyte, erythrocyte, monocyte megakaryocyte, burst-forming unit erythroid and colony-forming unit erythroid cell colony growth. LCHS/CS + BB significantly reduced plasma EPO levels and increased plasma hepcidin levels on day 7. The addition of CS to LCHS resulted in decreased liver ferroportin expression as well as decreased BM transferrin and TFR-1 expression, thus, blocking iron supply to erythroid cells. However, daily BB after LCHS/CS improved expression of all iron regulators. CONCLUSION Daily propranolol administration after LCHS/CS restored BM function and improved anemia after severe trauma. In addition, iron regulators are significantly reduced after LCHS/CS, which may contribute to iron restriction after injury. However, daily propranolol administration after LCHS/CS improved iron homeostasis.

Acute Kidney Injury Following Exploratory Laparotomy and Temporary Abdominal Closure.

Background: Acute kidney injury (AKI) following exploratory laparotomy and temporary abdominal closure (TAC) is poorly understood but clinically significant. We hypothesized that the prevalence of AKI would be highest 96 h following TAC, early hypoxemia would predict AKI, and that AKI would be an independent predictor of mortality. Methods: We performed a retrospective analysis of 251 acute care surgery patients managed with TAC by negative pressure wound therapy (NPWT). Kidney Disease: Improving Global Outcomes AKI stages were assessed on admission, initial TAC, and following TAC at 48 h, 96 h, and 7 d. Multivariate regression was performed to identify risk factors for AKI and inpatient mortality. Results: Fifty-seven percent of all patients developed AKI within 7 days of laparotomy (stage 1: 14%, 2: 21%, 3: 22%). The prevalence of AKI peaked 48 h following TAC, and stage correlated with inpatient mortality (stage 0: 7%, 1: 13%, 2: 19%, 3: 37%, P < 0.001). Overall mortality was 14%. Factors predictive of stage 2 or 3 AKI at 48 h included age >65 years (OR 2.6 [95% CI 1.4–4.9]), NPWT output >30 mL/h from first TAC to 48 h (2.0 [1.1–3.9]), and three parameters at initial laparotomy: mean arterial pressure <60 mm Hg (2.9 [1.0–8.5]), temperature <36°C (2.1 [1.1–3.8]), and anion gap >21 mEq/L (1.9 [1.0–3.7]). AKI was an independent predictor of inpatient mortality (5.5 [2.5–11.8]). Conclusions: AKI is common following TAC, reaches greatest prevalence 48 h after initial laparotomy, and is associated with increased mortality. NPWT fluid loss is a risk factor for AKI that is unique to TAC patients.

Predicting appendiceal tumors among patients with appendicitis.

BACKGROUND As nonoperative management of appendicitis gains popularity, vigilance for appendiceal tumors becomes increasingly important. We hypothesized that, among patients presenting with acute appendicitis, those with advanced age, multiple comorbidities, atypical presentation, and complicated appendicitis would be more likely to have underlying appendiceal tumors. METHODS We performed a 4-year retrospective cohort analysis of 677 consecutive adult patients who underwent appendectomy for appendicitis at our tertiary care center. Patients with an appendiceal tumor on their final pathology report were compared to patients with no tumor. Conditions present on admission were used to create a multivariate logistic regression model to predict appendiceal tumor. Risk factors were reported as odds ratio (OR) [95% CI]. Model strength was assessed by area under the receiver operating characteristic curve. RESULTS Seventeen patients (2.5%) had an appendiceal tumor. Within this group. 14 underwent immediate appendectomy, two initially had nonoperative management but failed to improve on antibiotics and underwent appendectomy during the initial admission, and one had successful nonoperative management and elective appendectomy 19 days after discharge. Four variables contributed to the multivariate model to predict the presence appendiceal tumor: age ≥ 50 (OR 3.6 [1.1–11.4]), outpatient steroid/immunosuppressant use (OR 12.1 [2.0–72.5]), the absence of migratory right lower quadrant pain (OR 4.7 [1.2–18.1]), and the appearance of a phlegmon on CT scan (OR 7.0 [1.6–30.2]); model area under the receiver operating characteristic curve: 0.860 [0.705–0.969]. CONCLUSION For patients presenting with acute appendicitis, conditions present on admission may predict underlying appendiceal tumor. Patients with advanced age, multiple comorbidities, atypical presentation, and complicated appendicitis should be considered for appendectomy during the index admission or at earliest convenience if nonoperative management is necessary. LEVEL OF EVIDENCE Prognostic study, level III.