Traumatic Parafalcine Subdural Hematoma: A Clinically Benign Finding.

BACKGROUND: Guidelines for management of intracranial hemorrhage do not account for bleed location. We hypothesize that parafalcine subdural hematoma (SDH), as compared to convexity SDH, is a distinct clinical entity and these patients do not benefit from critical care monitoring or repeat imaging. METHODS: We identified patients presenting to a single level I trauma center with isolated head injuries from February 2016 to August 2017. We identified 88 patients with isolated blunt traumatic parafalcine SDH and 228 with convexity SDH. RESULTS: Demographics, comorbidities, and use of antiplatelet and anticoagulant agents were similar between the groups. As compared to patients with convexity SDH, patients with parafalcine SDH had a significantly lower incidence of radiographic progression, and had no cases of neurologic deterioration, neurosurgical intervention, or mortality (all P < 0.005). Compared to patients admitted to the intensive care unit, patients with parafalcine SDH admitted to the floor had a shorter length of stay (2.0 ± 1.6 versus 3.8 ± 2.9 d, P < 0.005) with no difference in outcomes. CONCLUSIONS: Patients presenting with a parafalcine SDH are a distinct and relatively benign clinical entity as compared to convexity SDH and do not benefit from repeat imaging or intensive care unit admission.

Initial safety and feasibility of cold-stored uncrossmatched whole blood transfusion in civilian trauma patients.

BACKGROUND: The transfusion of cold-stored uncrossmatched whole blood (WB) has not been extensively used in civilian trauma resuscitation. This report details the initial experience with the safety and feasibility of using WB in this setting after a change of practice at a Level 1 trauma center was instituted. METHODS: Up to two units of uncrossmatched group O positive WB that was leukoreduced using a platelet-sparing filter from male donors were transfused to male trauma patients with hypotension secondary to bleeding. Hemolytic marker haptoglobin and reports of transfusion reactions in these patients were followed. Additionally, transfusion volumes and outcomes were compared to a historical cohort of male trauma patients who received at least one red blood cell (RBC) unit, but not WB, during the first 24 hours of admission. RESULTS: There were 47 WB patients who were transfused with a mean (SD) of 1.74 (0.61) WB units. The median haptoglobin concentration on post-WB transfusion Day 1 was 25.1 (9.3) mg/dL in 7 of 30 non-group O recipients. No adverse reactions in temporal relation to the WB transfusions were reported. There were 145 male historical control patients identified who were resuscitated with component therapy; the median volume of incompatible plasma transfused to the WB versus component therapy group was not significantly different (1,000 vs. 800 mL, respectively; p = 0.38); the mean plasma:RBC (0.99 [0.47] vs. 0.77 [ 0.73], respectively; p = 0.006) and platelet:RBC (0.72 [0.40] vs. 0.51 [0.734], respectively; p < 0.0001) ratios were significantly higher in the WB group. CONCLUSION: Transfusion of two units of cold-stored uncrossmatched WB is feasible and seems to be safe in civilian trauma resuscitation. Determining the efficacy of WB with regard to reducing the number of blood products transfused in the first 24 hours or improving recipient survival will require a larger randomized trial. LEVEL OF EVIDENCE: Therapeutic study, level IV.

Whole blood: the future of traumatic hemorrhagic shock resuscitation.

Toward the end of World War I and during World War II, whole-blood transfusions were the primary agent in the treatment of military traumatic hemorrhage. However, after World War II, the fractionation of whole blood into its components became widely accepted and replaced whole-blood transfusion to better accommodate specific blood deficiencies, logistics, and financial reasons. This transition occurred with very few clinical trials to determine which patient populations or scenarios would or would not benefit from the change. A smaller population of patients with trauma hemorrhage will require massive transfusion (>10 U packed red blood cells in 24 h) occurring in 3% to 5% of civilian and 10% of military traumas. Advocates for hemostatic resuscitation have turned toward a ratio-balanced component therapy using packed red blood cells-fresh frozen plasma-platelet concentration in a 1:1:1 ratio due to whole-blood limited availability. However, this "reconstituted" whole blood is associated with a significantly anemic, thrombocytopenic, and coagulopathic product compared with whole blood. In addition, several recent military studies suggest a survival advantage of early use of whole blood, but the safety concerns have limited is widespread civilian use. Based on extensive military experience as well as recent published literature, low-titer leukocyte reduced cold-store type O whole blood carries low adverse risks and maintains its hemostatic properties for up to 21 days. A prospective randomized trial comparing whole blood versus ratio balanced component therapy is proposed with rationale provided.

American College of Surgeons trauma center verification versus state designation: are Level II centers slipping through the cracks?

BACKGROUND: Single-center experience has shown that American College of Surgeons (ACS) trauma verification can improve outcomes. The current objective was to compare mortality between ACS-verified and state-designated centers in a national sample. METHODS: Subjects 16 years or older from ACS-verified or state-designated Level I and II centers were identified in the National Trauma Databank 2007 to 2008. A predictive mortality model was constructed using Trauma Quality Improvement Project methodology. Imputation was used for missing data. Probability of mortality in the model determined expected deaths. Observed-to-expected (O/E) mortality ratios with 90% confidence interval (CI) and outliers (90% CI more than or less than 1.0) were compared across ACS and state Level I and II centers. The mortality model was repeated with ACS versus state included. RESULTS: There were 900,274 subjects. The model had an area under the curve of 0.92 to predict death. Level I ACS centers had a lower median O/E ratio compared with state centers (0.95 [interquartile range, 0.82-1.05] vs. 1.02 [interquartile range, 0.87-1.15]; p < 0.01), with no difference in Level II centers. Level II state centers had more high O/E outliers. ACS verification was an independent predictor of survival in Level II centers (odds ratio, 1.26; 95% CI, 1.20-1.32; p < 0.01) but not in Level I centers (p = 0.84). CONCLUSION: Level II centers have a disproportionate number of high mortality outliers, and ACS verification is a predictor of survival. Level I ACS centers have lower O/E ratios overall, but no difference in outliers. ACS verification seems beneficial. These data suggest that Level II centers benefit most, and promoting Level II ACS verification may be an opportunity for improved outcomes. LEVEL OF EVIDENCE: Prognostic study, level III.

Development of a standard swine hemorrhage model for efficacy assessment of topical hemostatic agents.

BACKGROUND: The diverse information of efficacy of hemostatic products, obtained from different military laboratories using different models, has made it difficult to ascertain the true benefit of new hemostatic agents in military medicine. The aim of this study was to recommend a standard hemorrhage model for efficacy testing acceptable by most investigators in the field and avoid contradictory and duplicative efforts by different laboratories. METHODS: The swine femoral artery injury model (6-mm arteriotomy) with some modifications was tested to standardize the model. The suggested modifications included no splenectomy, one-time treatment, 30 seconds free bleeding, and 5 L limit for fluid resuscitation. The model was tested with all or some of these modifications in four experimental conditions (n = 5-6 pigs per condition) using Combat Gauze (CG) as control agent. RESULTS: The primary end points including blood pressure, blood loss, and survival rates were modestly changed in the four conditions. The second experimental condition in which bleeding was treated with a single CG with 3-minute compression produced the most suitable results. The average blood loss was 99 mL/kg, and hemostasis was achieved in one-third of the pigs, which led to matching survival rate. CONCLUSION: A rigorous hemorrhage model was developed for future evaluation of new hemostatic agents and comparison with CG, the current standard of care. This model may not be suitable for testing every agent and some modifications may be necessary for specific applications. Furthermore, laboratory studies using this or similar models must be accompanied by operational testing in the field to confirm the efficacy and practical utility of selected agents when used on the battlefield.

CTLA4-Ig-based conditioning regimen to induce tolerance to cardiac allografts.

BACKGROUND: Transplant rejection and toxicity associated with chronic immunosuppressive therapy remain a major problem. Mixed hematopoietic chimerism has been shown to produce tolerance to solid organ transplants. However, currently available protocols to induce mixed hematopoietic chimerism invariably require toxic pre-conditioning. In this study, we investigated a non-toxic CTLA4-Ig-based protocol to induce donor-specific tolerance to cardiac allografts in rats. METHODS: Fully mismatched, 4 to 6 week old ACI (RT1.A(a)) and Wistar Furth (RT1.A(u)) rats were used as cell/organ donors and recipients, respectively. Recipients were treated with CTLA4-Ig 2 mg/kg/day (on days 0, 2, 4, 6, 8), tacrolimus 1 mg/kg/day (daily, from days 0 to 9), and a single dose of anti-lymphocyte serum (10 mg) on day 10, soon after total body irradiation (300 cGy) and donor bone marrow (100 x 10(6) T-cell depleted cells) transplantation (BMT). Six weeks after BMT, chimeric animals received heterotopic heart transplants. RESULTS: Hematopoietic chimerism was 18.8 +/- 10.6% at day 30, and was stable (24 +/- 10%) at 1 year post-BMT; there was no graft versus host disease. Chimeric recipients (RT1.A(u)) permanently accepted (>360 days) donor-specific (RT1.A(a); n = 6) hearts, yet rapidly rejected (<9 days) third-party hearts (RT1.A(l); n = 5). Graft (heart) tolerant (>100 days) recipients accepted donor-specific secondary skin grafts (>200 days) while rejected the third-party skin grafts (<9 days). Lymphocytes of graft tolerant animals demonstrated hyporesponsiveness in mixed lymphocyte cultures in a donor-specific manner. Tolerant graft histology showed no obliterative arteriopathy or chronic rejection. CONCLUSIONS: The CTLA4-Ig based conditioning regimen with donor BMT produced mixed chimerism and induced donor- specific tolerance to cardiac allografts.

Newborn endothelin receptor type B mutant (piebald) mice have a higher resting anal sphincter pressure than newborn C57BL/6 mice.

Hirschsprung's disease is characterized by aganglionosis of the distal colon and hypertonicity of the anal sphincter. Endothelin receptor type B mutant (piebald) mice phenotypically resemble infants with Hirschsprung's disease in that these mice are susceptible to developing toxic megacolon because of the absence of ganglion cells in their distal colon. Therefore, we hypothesized that newborn piebald mice would have a higher resting anal sphincter pressure than would newborn wild-type mice. To test this hypothesis, we developed a reliable and reproducible technique for measuring the resting anal sphincter pressure in mice. Heterozygote breeding pairs of endothelin receptor type B mutant mice were purchased and bred in our animal facility. Pregnant, time-dated C57BL/6J mice provided control newborn mice. One-day-old newborn mice were evaluated for resting anal sphincter pressure. Under the operating microscope, a 24-gauge open-tip epidural catheter was placed into the anus until a deflection (approximately 3 to 5 mm) was noticed on a polygraph pressure monitor. Three consecutive measurements were obtained for each mouse. Mean values for each group were determined and compared using Student's t test. The resting anal sphincter pressure (mean +/- standard deviation) in newborn C57BL/6J mice was 13.3 +/- 2.6 mmHg, whereas that in piebald mice 22.7 +/- 2.5 mmHg (P < 0.0001). Therefore, because of their increased resting anal sphincter pressure, piebald mice may provide a useful animal model for the study of Hirschsprung's disease.

Hepatocyte nuclear factor 4 response to injury involves a rapid decrease in DNA binding and transactivation via a JAK2 signal transduction pathway.

The injury response is a complex set of events, which represents the reaction of a biological system to a perceived change in its environment in an attempt to maintain system integrity. Isolation of individual events or components of this response cannot describe the overall process, but may reflect general mechanisms that have evolved over time to solve the complex requirements of the injury response. The process, generally termed the acute phase response, is a series of organ-specific responses that begin shortly after a systemic injury. In the liver, this response involves both dramatic inductions and reductions in specific sets of genes, and an overall widespread global change in proteins produced. This can be thought of as a phenotypic change or 'reprogramming' of the liver. These changes in protein production are modulated and regulated at the level of transcription and involve significant manipulations of transcriptional regulatory mechanisms. Hepatocyte nuclear factor 4 (HNF-4) is a liver enriched transcription factor that regulates a large number of liver-specific genes, which play important roles in the critical pathways modulated by the response to injury. HNF-4 also performs an essential role in overall development and is critical for the normal expression of multiple genes in the developed liver, as well as being upstream of HNF-1 in a transcriptional hierarchy that drives hepatocyte differentiation. The role of HNF-4 in regulating liver-specific transcriptional changes directed by injury remains to be defined. In our cell-culture and whole-animal models, we demonstrate that the binding activity of HNF-4 decreases quickly after injury due to post-translational modification by phosphorylation. The mechanisms by which HNF-4 is modified after injury involve the activation of Janus kinase 2 (JAK2) signal transduction pathways, but the direct or indirect interaction of JAK2 with HNF-4 remains to be defined.