A Pilot and Feasibility Study to Evaluate Small and Large Bite Fascial Closure Techniques.

INTRODUCTION: Few randomized controlled studies have been conducted comparing a small to large fascial bite technique, yet recommendations have been made to standardize small bite closures. However, large scale randomized controlled trials require considerable effort and may benefit from a pilot study. METHODS: This multi-center randomized controlled pilot study of adult patients undergoing median laparotomy incision investigated the feasibility of studying the outcomes between small and large surgical closure techniques. RESULTS: Fifty of 100 planned patients consented, 32 patients completed surgery, and 19 patients completed the one-year ultrasound. Enrollment was 2.7 versus 8 patients per month pre/post addition of a study coordinator. Clinical results are summarized for feasibility demonstration purposes, but not analyzed for hypothesis testing. The total cost of the pilot study was $19,152.50 and took 22 months from first surgery to final one-year ultrasound. CONCLUSIONS: This feasibility assessment demonstrated the complexity of planning a large-scale randomized trial evaluating small and large bite surgical closure technique. To expand this pilot study to a full scaled sample size study would require dedicated personnel and large grant funding.

The presence of S-sulfonated transthyretin in commercial human serum albumin solutions: Potential contribution to neuropathy.

BACKGROUND: Commercial solutions of human serum albumin (HSA) are administered to critically ill patients for the treatment of shock, restoration of blood volume, and the acute management of burns. Previously, conflicting results on the effects of HSA administration have been reported varying from a favorable increase in total plasma antioxidant capacity to a higher mortality rate in traumatic brain injury (TBI) patients. These results could be partially explained due to the known heterogeneity of HSA solutions. We report the discovery of S-sulfonated human transthyretin (hTTR) in HSA solutions. METHODS: Proteomics was performed on commercially available solutions of 5% HSA by LC-MS analysis. The MS charge envelope for hTTR was deconvolved to the uncharged native hTTR parent mass (13,762 Da). The parent mass was then integrated, and relative proportions of the 2 major species of hTTR, native and S-sulfonated hTTR (13,842 Da), were calculated. RESULTS: The majority of hTTR found in 5% commercial HSA solutions is in the S-sulfonated form regardless of the age of the HSA solution. S-sulfonation of hTTR at the free cysteine residue in position 10 appears to be the result of a mixed disulfide exchange possibly with S-cysteinylated hTTR or S-cysteinylated HSA. hTTR is a tetramer composed of four identical monomers each containing a reduced cysteine residue in position 10. S-sulfonation of hTTR at this cysteine residue can destabilize the hTTR tetramer, an important step in the formation of TTR-related amyloid fibrils. CONCLUSIONS: Administration of a commercial HSA solution that already contains S-sulfonated hTTR could potentially contribute to the development of amyloid-related/polyneuropathy in the critically ill.

Stress Hyperglycemia in Critically Ill Patients: Insight Into Possible Molecular Pathways.

Severe sepsis, systemic inflammatory response syndrome (SIRS), and traumatic brain injury are frequently associated with hyperglycemia in non-diabetic patients. In patients suffering from any of these conditions, hyperglycemia at admission to an intensive care unit (ICU) is directly correlated with increased mortality or morbidity. Although there was initial enthusiasm for insulin treatment to blood glucose levels below 110 mg/dL in these patients, recent understanding suggests that the potential for hypoglycemic complications make this approach potentially dangerous. More moderate glucose control seems to be more beneficial than the aggressive glucose lowering initially suggested. An important publication has shown that hyperlactatemia accompanying hyperglycemia could be the real culprit in bad outcomes. This suggests that coupling moderate glucose lowering with therapeutic agents which might treat the underlying metabolic disturbances in these conditions may be a better strategy. The key metabolic disturbance in these three conditions seems to be persistent glycolysis as an energy source even in the presence of adequate tissue oxygenation (the Warburg Effect). We look at recent advances in understanding aerobic glycolysis and possibly the action of DPP4 on incretins resulting in insulin dysregulation and suggest key metabolic pathways involved in hyperglycemia regulation.

Clinically relevant redifferentiation of fibroblast-like chondrocytes into functional chondrocytes by the low molecular weight fraction of human serum albumin.

OBJECTIVES: Traumatic joint injury induces chondrocyte dysfunction and progressive breakdown of articular cartilage, leading to post-traumatic osteoarthritis (PTOA). In this condition, dysfunctional fibroblast-like chondrocytes (FLCs) no longer express proteins required for cartilage maintenance, such as SOX9 and collagen-type II (COL2). Interleukin-6 (IL-6) has been demonstrated to downregulate expression of these two critical proteins in chondrocytes, and increased IL-6 levels have been measured in patients with PTOA. The <5kDa fraction of human serum albumin (LMWF5A) has been suggested to modulate this pathway, as decreased levels of IL-6 are secreted by immunostimulated LMWF5A-treated macrophages. Our objective was to determine whether LMWF5A induces an in vitro model of FLCs to redifferentiate into functional chondrocytes. METHODS: SOX9 and COL2 were monitored via western blot, and COL2 was detected with immunofluorescence. Aggrecan and IL-6 were quantified by ELISA. Glycosaminoglycan (GAG) levels were quantified with alcian blue. RESULTS: We found that LMWF5A significantly increases the principal cartilage transcription factor SOX9 and the SOX9 target protein COL2 in monolayer-cultured FLCs. Multiple LMWF5A treatments of 3-D pellet FLC cultures over 2wks resulted in a significant decrease in IL-6 and significant increases in the major players of articular cartilage mechanics, aggrecan and highly-sulfated GAGs. CONCLUSIONS: These data support the hypothesis and clinical outcomes of two phase III clinical trials that LMWF5A-treatment induces chondrogenesis and supports functional cartilage. We propose that LMWF5A could maintain articular cartilage integrity in all joints following traumatic injury.

The anti-inflammatory effect of LMWF5A and N-acetyl kynurenine on macrophages: Involvement of aryl hydrocarbon receptor in mechanism of action.

After a traumatic insult, macrophages can become activated leading to general inflammation at the site of injury. Activated macrophages are partially regulated by the aryl hydrocarbon receptor (AhR) which when activated suppresses inflammation by limiting the secretion of pro-inflammatory cytokines and promoting the over expression of immuno-modulatory mediators. This study aims to determine whether the low molecular weight fraction of 5% human serum albumin (LMWF5A) and N-acetyl kynurenine (NAK), an N-acetyl tryptophan (NAT) breakdown product in LMWF5A, can regulate inflammation by inhibiting macrophage activation through the AhR since kynurenine is a known AhR agonist. Using LCMS, we demonstrate that NAT is non-enzymatically degraded during accelerated aging of LMWF5A with high heat accelerating degradation. More importantly, NAK is a major degradation product found in LMWF5A. THP-1 monocytes were differentiated into macrophages using phorbol 12-myristate 13-acetate (PMA) and pre-treated with 2-fold dilutions of LMWF5A or synthetic NAK with or without an AhR antagonist (CH223191) prior to overnight stimulation with lipopolysaccharide (LPS). Treatment with LMWF5A caused a 50-70% decrease in IL-6 release throughout the dilution series. A dose-response inhibition of IL-6 release was observed for NAK with maximal inhibition (50%) seen at the highest NAK concentration. Finally, an AhR antagonist partially blocked the anti-inflammatory effect of LMWF5A while completely blocking the effect of NAK. A similar inhibitory effect was observed for CXCL-10, but the AhR antagonist was not effective suggesting additional mechanisms for CXCL-10 release. These preliminary findings suggest that LMWF5A and NAK partially promote the suppression of activated macrophages via the AhR receptor. Therefore, LMWF5A, which contains NAK, is potentially a useful therapeutic in medical conditions where inflammation is prevalent such as trauma, sepsis, and wound healing.

Cell death after traumatic brain injury: Detrimental role of anoikis in healing.

Within the first few hours of a traumatic brain injury, the activity of extracellular matrix degradative enzymes increases. As a result, the blood brain barrier becomes disrupted as secondary white matter injury increases. Anoikis, a form of apoptosis, results from cells detaching from the extracellular matrix leading to cell death. This "homelessness" (anoikis) of cells hinders recovery progression, exacerbating brain injury while disrupting synaptic plasticity and other central nervous system functions. Here, we discuss the current knowledge of molecular pathways and proteins involved in both the activation and inhibition of anoikis.

Association of Injury Factors, Not Body Mass Index, With Hospital Resource Usage in Trauma Patients.

BACKGROUND: Allocating resources appropriately requires knowing whether obese patients use more resources during a hospital stay than nonobese patients. OBJECTIVES: To determine if trauma patients with different body mass indexes differed in use of resources measured as a multifaceted outcome variable. METHODS: A trauma registry was used for a retrospective study of adult patients admitted to a midwestern level I trauma center. Patients were stratified into 3 groups: nonobese (normal weight, overweight), obese, and morbidly obese. Three canonical correlation analyses were used to determine the relationship between patient/injury characteristics and hospital resource usage. RESULTS: In a sample of 9771 patients, 71.2% were non-obese, 23.8% obese, and 5.0% morbidly obese. For patient/injury characteristics, Injury Severity Score and physiological complications were significant variables for all 3 groups. Scores on the Glasgow Coma Scale were significant for nonobese patients only. For resource usage, intensive care unit length of stay and procedures were significant variables for all 3 groups. CONCLUSIONS: Associations between body mass index and outcomes have been noted when assessed as independent variables. However, when resource usage was assessed as a multifaceted outcome variable, injury factors (higher Injury Severity Score, lower scores on the Glasgow Coma Scale, more physiological complications) were associated with resource usage (increased length of stay in the intensive care unit and increased number of procedures). These findings provide clinicians a new perspective for evaluating the complex relationship between patient/injury characteristics and hospital resource usage.

Acceptability and implementation of debriefings after trauma resuscitation.

Postresuscitation debriefings allow team members to reflect on performance and discuss areas for improvement. Pre-/postsurveys of trauma team members (physicians, mid-level practitioners, technicians, pharmacists, and nurses) were administered to evaluate the acceptability of debriefings and self-perceptions after multidisciplinary trauma resuscitations. After a 3-month trial period, improvements were observed in perceptions of psychological and patient safety, role on team, team communication, and acceptability of the debriefing initiative. Regrouping for a debriefing requires organizational change, which may be more easily assimilated if team members recognize the potential for process improvement and feel confident about success.

Assessing the use of venous thromboembolism risk assessment profiles in the trauma population: is it necessary?

Deep venous thrombosis (DVT) and the subsequent development of venous thromboembolism (VTE) are a significant cause of mortality, morbidity, and cost of care in trauma patients. This study aims to: 1) validate 5 as a critical threshold for high risk; 2) validate risk factors associated with DVT/VTE development; 3) evaluate exogenous estrogen and smoking as risk factors; and 4) analyze daily risk assessment profile (RAP) score changes. We performed a retrospective chart review of trauma patients admitted from January 2001 through December 2005. Univariate odds ratios were performed to assess potential risk factors for VTE. Of the 110 charts reviewed, 31 patients had confirmed DVT/VTE. Three of 26 patients with an RAP score < 5 suffered a VTE; one resulted in death. Significant risk factors included femoral venous line insertion, operation longer than 2 hours, head abbreviated injury score > 2, and Glasgow Coma Scale score < 8. RAP fluctuations were due to a changing Glasgow Coma Scale score, and whether the patient received more than four transfusions, was in surgery for more than 2 hours, or required a femoral venous catheter or major venous repair. The RAP critical value (5) was not validated. We recommend all trauma patients be treated with prophylactic anticoagulants throughout the hospital stay unless clear contraindications exist.