Gallstone Pancreatitis and Choledocholithiasis: Using Imaging and Laboratory Trends to Predict the Likelihood of Persistent Stones at Cholangiography.

BACKGROUND: Patients with gallstone pancreatitis (GP) or choledocholithiasis (CDL) may have common bile duct (CBD) stones that persist until cholangiography. The aim of this study is to evaluate pre-cholangiogram factors that predict persistent CBD stones. METHODS: Multiple logistic regression analyses were performed to identify demographic, laboratory, and radiologic predictors of persistent CBD stones and non-therapeutic cholangiography among adults with GP or CDL. RESULTS: In 152 patients from 2010 to 2015, preoperative diagnosis, presence of a CBD stone on US, and age ≥ 60 years were associated with persistent CBD stones. Two risk factors alone had a PPV of 88% and the absence of all risk factors had a NPV of 94%. Age < 60 years and the absence of a CBD stone on US were most predictive of non-therapeutic cholangiography. CONCLUSION: Age, LFTs, and US help predict persistent CBD stones in patients initially presenting with GP or CDL and help minimize non-therapeutic preoperative cholangiography.

Polytrauma patients in the Netherlands and the USA: A bi-institutional comparison of processes and outcomes of care.

BACKGROUND: Modern trauma systems differ worldwide, possibly leading to disparities in outcomes. We aim to compare characteristics and outcomes of blunt polytrauma patients admitted to two Level 1 Trauma Centers in the US (USTC) and the Netherlands (NTC). METHODS: For this retrospective study the records of 1367 adult blunt trauma patients with an Injury Severity Score (ISS) ≥ 16 admitted between July 1, 2011 and December 31, 2013 (640 from NTC, 727 from USTC) were analysed. RESULTS: The USTC group had a higher Charlson Comorbidity Index (mean [standard deviation] 1.15 [2.2] vs. 1.73 [2.8], p<0.0001) and Injury Severity Score (median [interquartile range, IQR] 25 [17-29] vs. 21 [17-26], p<0.0001). The in-hospital mortality was similar in both centers (11% in USTC vs. 10% NTC), also after correction for baseline differences in patient population in a multivariable analysis (adjusted odds ratio 0.95, 95% confidence interval 0.61-1.48, p=0.83). USTC patients had a longer Intensive Care Unit stay (median [IQR] 4 [2-11] vs. 2 [2-7] days, p=0.006) but had a shorter hospital stay (median [IQR] 6 [3-13] vs. 8 [4-16] days, p<0.0001). USTC patients were discharged more often to a rehabilitation center (47% vs 10%) and less often to home (46% vs. 66%, p<0.0001), and had a higher readmission rate (8% vs. 4%, p=0.01). CONCLUSION: Although several outcome parameters differ in two urban area trauma centers in the USA and the Netherlands, the quality of care for trauma patients, measured as survival, is equal. Other outcomes varied between both trauma centers, suggesting that differences in local policies and processes do influence the care system, but not so much the quality of care as reflected by survival.

Using simulation for disaster preparedness.

BACKGROUND: As it addresses both technical and nontechnical skills, simulation-based training is playing an increasingly important role in surgery. In addition to the focus on skill acquisition, it is also important to ensure that surgeons are able to perform a variety of tasks in unique and challenging situations. These situations include responding to mass casualties, dealing with disease outbreaks, and preparing for wartime missions. Simulation-based training can be a valuable training modality in these situations, as it allows opportunities to practice and prepare for high-risk and often low-frequency events. METHODS: During the 8th Annual Meeting of the Consortium of the American College of Surgeons-Accredited Education Institutes in March 2015, a multidisciplinary panel was assembled to discuss how simulation can be used to prepare the surgical community for such high-risk events. CONCLUSION: An overview of how simulation has been used to address needs in each of these situations is presented.

Admissions for isolated nonoperative mild head injuries: Sharing the burden among trauma surgery, neurosurgery, and neurology.

BACKGROUND: Isolated nonoperative mild head injuries (INOMHI) occur with increasing frequency in an aging population. These patients often have multiple social, discharge, and rehabilitation issues, which far exceed the acute component of their care. This study was aimed to compare the outcomes of patients with INOMHI admitted to three services: trauma surgery, neurosurgery, and neurology. METHODS: Retrospective case series (January 1, 2009 to August 31, 2013) at an academic Level I trauma center. According to an institutional protocol, INOMHI patients with Glasgow Coma Scale (GCS) of 13 to 15 were admitted on a weekly rotational basis to trauma surgery, neurosurgery, and neurology. The three populations were compared, and the primary outcomes were survival rate to discharge, neurological status at hospital discharge as measured by the Glasgow Outcome Score (GOS), and discharge disposition. RESULTS: Four hundred eighty-eight INOMHI patients were admitted (trauma surgery, 172; neurosurgery, 131; neurology, 185). The mean age of the study population was 65.3 years, and 58.8% of patients were male. Seventy-seven percent of patients has a GCS score of 15. Age, sex, mechanism of injury, Charlson Comorbidity Index, Injury Severity Score, Abbreviated Injury Scale in head and neck, and GCS were similar among the three groups. Patients who were admitted to trauma surgery, neurosurgery and neurology services had similar proportions of survivors (98.8% vs 95.7% vs 94.7%), and discharge disposition (home, 57.0% vs 61.6% vs 55.7%). The proportion of patients with GOS of 4 or 5 on discharge was slightly higher among patients admitted to trauma (97.7% vs 93.0% vs 92.4%). In a logistic regression model adjusting for Charlson Comorbidity Index CCI and Abbreviated Injury Scale head and neck scores, patients who were admitted to neurology or neurosurgery had significantly lower odds being discharged with GOS 4 or 5. While the trauma group had the lowest proportion of repeats of brain computed tomography (61.6%), the neurosurgery group had the highest proportion of intensive care unit admission (29.8%), and the neurology group had the longest emergency department stay (7.5 hours), there were no significant differences in duration of hospital stay, in-hospital complications, and readmission within 30 days. CONCLUSIONS: Although there were differences in use of health care resources, and the proportion of patients with GOS of 4 or 5 on discharge was slightly higher among patients admitted to trauma, most clinical outcomes were similar in INOMHI patients admitted to trauma surgery, neurosurgery, or neurology in our institution. A rotational policy of admitting INOMHI patients is feasible among services with expertise in and commitment to the care of these patients. LEVEL OF EVIDENCE: Therapeutic/care management study, level IV.

A hierarchical task analysis of cricothyroidotomy procedure for a virtual airway skills trainer simulator.

BACKGROUND: Despite the critical importance of cricothyroidotomy (CCT) for patient in extremis, clinical experience with CCT is infrequent, and current training tools are inadequate. The long-term goal is to develop a virtual airway skills trainer that requires a thorough task analysis to determine the critical procedural steps, learning metrics, and parameters for assessment. METHODS: Hierarchical task analysis is performed to describe major tasks and subtasks for CCT. A rubric for performance scoring for each task was derived, and possible operative errors were identified. RESULTS: Time series analyses for 7 CCT videos were performed with 3 different observers. According to Pearson's correlation tests, 3 of the 7 major tasks had a strong correlation between their task times and performance scores. CONCLUSIONS: The task analysis forms the core of a proposed virtual CCT simulator, and highlights links between performance time and accuracy when teaching individual surgical steps of the procedure.

Self-expanding foam for prehospital treatment of intra-abdominal hemorrhage: 28-day survival and safety.

BACKGROUND: Intracavitary noncompressible hemorrhage remains a significant cause of preventable death on the battlefield and in the homeland. We previously demonstrated the hemostatic efficacy of an in situ self-expanding poly(urea)urethane foam in a severe, closed-cavity, hepatoportal exsanguination model in swine. We hypothesized that treatment with, and subsequent explantation of, foam would not adversely impact 28-day survival in swine. METHODS: Following a closed-cavity splenic transection, animals received either fluid resuscitation alone (control group, n = 6) or resuscitation plus foam treatment at doses of 100 mL (n = 6), 120 mL (n = 6), and 150 mL (n = 2). Foam was allowed to polymerize in situ and was explanted after 3 hours. The animals were recovered and monitored for 28 days. RESULTS: All 18 animals in the 100-mL, 120-mL, and control groups survived to the 28-day endpoint without complications. The 150-mL group was terminated after the acute phase (n = 2). En bloc explantation of the foam took less than 2 minutes and was associated with millimeter-sized remnant particles. All foam animals required some level of enteric repair (imbrication or resection). Excluding the aborted 150-mL group, all animals survived, with no differences in renal or hepatic function, serum chemistries, or semiquantitative abdominal adhesion scores. Histologic analysis demonstrated that remnant particles were associated with a fibrotic capsule and mild inflammation, similar to that of standard suture reaction. In addition, safety testing (including genotoxicity, pyrogenicity, and cytotoxicity) was performed consistent with the ISO-10993 standard, and the materials passed all tests. CONCLUSION: For a distinct dose range, 28-day recovery after foam treatment and explantation for noncompressible, intra-abdominal hemorrhage is not associated with significant physiologic or biochemical evidence of end-organ dysfunction. A foam volume exceeding the maximum tolerable dose was identified. Bowel repair is required to ensure survival.

Effect of valproic acid and injury on lesion size and endothelial glycocalyx shedding in a rodent model of isolated traumatic brain injury.

BACKGROUND: In isolated traumatic brain injury (TBI), little is known about the endothelial response and the effects of endothelial glycocalyx shedding. We have previously shown that treatment with valproic acid (VPA) improves outcomes following TBI and hemorrhagic shock.In this model, we hypothesized that severe isolated TBI would cause shedding of the endothelial glycocalyx, as measured by serum syndecan-1 (sSDC-1) levels. We further hypothesized that VPA treatment would reduce this response and reduce lesion size volume. METHODS: Forty Sprague-Dawley rats were allocated to TBI + VPA (n = 8), TBI + saline vehicle control infusion (n = 8), sham + saline vehicle control infusion (n = 6), or sham + VPA (n = 8). TBI animals were subjected to severe controlled cortical impact and killed 6 hours after injury. VPA 300 mg/kg was given as an intravenous bolus 30 minutes after injury. Serum samples were analyzed for sSDC-1, and lesion size was determined on Nissl-stained cryosections. RESULTS: sSDC-1 was significantly elevated in injured compared with uninjured animals at 3 hours (p = 0.0009) and 6 hours (p = 0.0007) after injury. This effect was significantly more pronounced in the animals treated with VPA (p = 0.019) 3 hours after injury, in which sSDC-1 levels were also significantly inversely correlated with lesion size (ρ = -0.55, p = 0.038).Lesion size was significantly smaller in TBI + VPA (40.45 mm ± 13.83 mm) as compared with vehicle control (59.57 mm ± 16.83 mm) (p = 0.023). CONCLUSION: Severe isolated TBI caused shedding of the endothelial glycocalyx. Treatment with VPA was associated with increased glycocalyx shedding and reduced lesion size volume in injured animal.

Mandatory health care insurance is associated with shorter hospital length of stay among critically injured trauma patients.

BACKGROUND: The implementation of the Affordable Care Act stimulated interest in outcomes of patients in Massachusetts, a state mandating health insurance as of 2006. We sought to determine the impact of an insurance mandate on hospital use and outcomes among trauma intensive care unit (ICU) patients. METHODS: This is a retrospective cohort study of trauma patients admitted to the ICU conducted at an academic, trauma center. Patients before (2004-2006) and after (2008-2012) the implementation of mandatory health insurance were compared using propensity matching to control for confounders. Outcomes were hospital length of stay (LOS), ICU LOS, in-hospital mortality, and discharge disposition. RESULTS: Overall, 1,668 trauma patients were included, with 530 matched on the propensity score in each group. Hospital LOS decreased by a median of 2.0 days, from 9.0 days (interquartile range, 4-15 days; p < 0.01) before to 7.0 days (interquartile range, 4-14) after implementation of the legislation. There were no differences in ICU LOS (3.0 days to 3.0 days, p = 0.44) and mortality (odds ratio [OR], 1.16; 95% confidence interval [CI], 0.83-1.63). Compared with discharges to home, the patients were more likely to be discharged home with home health services after the legislation (OR, 1.70; 95% CI, 1.08-2.68), but there was no significant change in the likelihoods of the patients being discharged to skilled nursing and rehabilitation facilities (OR, 0.97; 95% CI, 0.72-1.31). CONCLUSION: Implementation of health care reform was associated with a decrease in hospital LOS, with an increase in use of home health services and no change in ICU LOS and mortality among trauma ICU patients at our institution. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III.

Self-expanding foam for prehospital treatment of severe intra-abdominal hemorrhage: dose finding study.

BACKGROUND: Noncompressible abdominal bleeding is a significant cause of preventable death on the battlefield and in the civilian trauma environment, with no effective therapies available at point of injury. We previously described the development of a percutaneously administered, self-expanding, poly(urea)urethane foam that improved survival in a lethal Grade V hepatic and portal vein injury model in swine. In this study, we hypothesized that survival with foam treatment is dose dependent. METHODS: A high-grade hepatoportal injury was created in a closed abdominal cavity, resulting in massive noncompressible hemorrhage. After injury, the animals were divided into five groups. The control group (n = 12) was treated only with fluid resuscitation, and four polymer groups received different dose volumes (Group 1, n = 6, 64 mL; Group 2, n = 6, 85 mL; Group 3, n = 18, 100 mL; and Group 4, n = 10, 120 mL) in addition to fluids. Ten minutes after injury, the foam was percutaneously administered, and animals were monitored for 3 hours. RESULTS: Survival with hepatoportal injury was highest in Group 4 (90%) and decreased in a dose-dependent fashion (Group 3, 72%; Group 2, 33%; Group 1, 17%). All polymer groups survived significantly longer than the controls (8.3%). Hemorrhage rate was reduced in all groups but lowest in Group 4 versus the control group (0.34 [0.052] vs. 3.0 [1.3] mL/kg/min, p < 0.001). Increasing foam dose volume was associated with increased peak intra-abdominal pressure (88.2 [38.9] in Group 4 vs. 9.5 [3.2] in the controls, p < 0.0001) and increased incidence of focal bowel injuries. CONCLUSION: The self-expanding foam significantly improves survival in a dose-dependent fashion in an otherwise lethal injury. Higher doses are associated with better survival but resulted in the need for bowel resection.

Sternal fracture--an analysis of the National Trauma Data Bank.

BACKGROUND: The clinical significance of sternal fractures (SFs) after blunt trauma is heavily debated. We aimed to test the hypothesis that isolated SF is not associated with significant morbidity or mortality. MATERIALS AND METHODS: The National Trauma Data Bank (NTDB) sets for 2007-2010 were retrospectively examined. Adult subjects with SF were identified by International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes. Data collected included demographics, mechanisms of injury, clinical variables, and in-hospital mortality. The primary outcome measure was in-hospital mortality. Secondary outcome measures included hospital length of stay, intensive care unit days, and ventilator days. RESULTS: A total of 32,746 subjects with SF were included. Motor vehicle crash (MVC) was the most common mechanism (84%) in this group and SF was present in 3.7% of all patients admitted after MVC. The mean age was 51 y, 66% were males, and most were white (74%). Overall in-hospital mortality was 8.8% and mortality with isolated SF was 3.5%. Increasing thoracic fracture burden (rib fracture, clavicular fracture, and scapular fracture) was associated with increasing hospital length of stay, intensive care unit days, ventilator days, and mortality. On multivariate regression analysis, other significant predictors of mortality were cardiac arrest, acute respiratory distress syndrome, pulmonary embolism, blunt cardiac injury, pulmonary contusion, increasing age, and lack of insurance. CONCLUSIONS: SFs occur in 3.7% of victims after MVC. With isolated SF, the mortality rate is low (3.5%); the tendency for poorer outcomes is most heavily influenced by associated injuries (pulmonary contusions, other thoracic fractures), complications (cardiac arrest, pulmonary embolism, acute respiratory distress syndrome), comorbidities (currently on or requiring dialysis, residual neurologic deficit from stroke), and lack of insurance.

Differential effects of fresh frozen plasma and normal saline on secondary brain damage in a large animal model of polytrauma, hemorrhage and traumatic brain injury.

BACKGROUND: We have previously shown that the extent of traumatic brain injury (TBI) in large animal models can be reduced with early infusion of fresh frozen plasma (FFP), but the precise mechanisms remain unclear. In this study, we investigated whether resuscitation with FFP or normal saline differed in their effects on cerebral metabolism and excitotoxic secondary brain injury in a model of polytrauma, TBI, and hemorrhagic shock. METHODS: Yorkshire swine (n = 10) underwent Grade III liver injury, rib fracture, standardized TBI, and volume-controlled hemorrhage, (40% ± 5%) and were randomly resuscitated with either FFP or normal saline. Hemodynamic parameters and brain oxygenation were continuously monitored, while microdialysis was used to measure the brain concentrations of pyruvate, lactate, glutamate, and glycerol at baseline; 1 hour and 2 hours after shock; immediate postresuscitation (PR); as well as 2, 4, and 6 hours PR. Cells from the injured hemisphere were separated into mitochondrial and cytosolic fractions and analyzed for activity of the pyruvate dehydrogenase complex (PDH). RESULTS: There were no baseline differences in cerebral perfusion pressure, brain oxygenation, as well as concentrations of pyruvate, lactate, glutamate, and glycerol between the groups. At 2 hours and 4 hours PR, the FFP group had significantly higher cerebral perfusion pressures (52 [5] mm Hg vs. 43 [2] mm Hg, p = 0.016; and 50 [7] mm Hg vs. 37 [1] mm Hg, p = 0.008, respectively). There was a sustained and significant (p < 0.05) drop in the glutamate and glycerol levels in the FFP group, implying a decrease in excitotoxicity and brain damage, respectively. Mitochondrial PDH activity was significantly higher (2,666.2 [638.2] adjusted volume INT × mm vs. 1,293.4 [88.8] adjusted volume INT × mm, p = 0.008), and cytosolic PDH activity was correspondingly lower (671.4 [209.2] adjusted volume INT × mm vs. 3070.7 [484.3] adjusted volume INT × mm, p < 0.001) in the FFP group, suggesting an attenuation of mitochondrial dysfunction and permeability. CONCLUSION: In this model of TBI, polytrauma, and hemorrhage, FFP resuscitation confers neuroprotection by improving cerebral perfusion, diminishing glutamate-mediated excitotoxic secondary brain injury and reducing mitochondrial dysfunction.

Early treatment with lyophilized plasma protects the brain in a large animal model of combined traumatic brain injury and hemorrhagic shock.

BACKGROUND: Combination of traumatic brain injury (TBI) and hemorrhagic shock (HS) can result in significant morbidity and mortality. We have previously shown that early administration of fresh frozen plasma (FFP) in a large animal model of TBI and HS reduces the size of the brain lesion as well as the associated edema. However, FFP is a perishable product that is not well suited for use in the austere prehospital settings. In this study, we tested whether a shelf-stable, low-volume, lyophilized plasma (LSP) product was as effective as FFP. METHODS: Yorkshire swine (42-50 kg) were instrumented to measure hemodynamic parameters, intracranial pressure, and brain tissue oxygenation. A prototype, computerized, cortical impact device was used to create TBI through a 20-mm craniotomy: 15-mm cylindrical tip impactor at 4 m/s velocity, 100-millisecond dwell time, and 12-mm penetration depth. Volume-controlled hemorrhage was induced (40-45% total blood volume) concurrent with the TBI. After 2 hours of shock, animals were treated with (1) normal saline (NS, n = 5), (2) FFP (n = 5), and (3) LSP (n = 5). The volume of FFP and LSP matched the shed blood volume, whereas NS was 3 times the volume. Six hours after resuscitation, brains were sectioned and stained with TTC (2, 3, 5-Triphenyltetrazolium chloride), and lesion size (mm) and swelling (percent change in volume compared with the contralateral, uninjured side) were measured. RESULTS: This protocol resulted in a highly reproducible brain injury, with clinically relevant changes in blood pressure, cardiac output, tissue hypoperfusion, intracranial pressure, and brain tissue oxygenation. Compared with NS, treatment with LSP significantly (p < 0.05) decreased brain lesion size and swelling (51% and 54%, respectively). CONCLUSION: In a clinically realistic combined TBI + HS model, early administration of plasma products decreases brain lesion size and edema. LSP is as effective as FFP, while offering many logistic advantages.

Mechanical ventilation weaning and extubation after spinal cord injury: a Western Trauma Association multicenter study.

BACKGROUND: Respiratory failure after acute spinal cord injury (SCI) is well recognized, but data defining which patients need long-term ventilator support and criteria for weaning and extubation are lacking. We hypothesized that many patients with SCI, even those with cervical SCI, can be successfully managed without long-term mechanical ventilation and its associated morbidity. METHODS: Under the auspices of the Western Trauma Association Multi-Center Trials Group, a retrospective study of patients with SCI at 14 major trauma centers was conducted. Comprehensive injury, demographic, and outcome data on patients with acute SCI were compiled. The primary outcome variable was the need for mechanical ventilation at discharge. Secondary outcomes included the use of tracheostomy and development of acute lung injury and ventilator-associated pneumonia. RESULTS: A total of 360 patients had SCI requiring mechanical ventilation. Sixteen patients were excluded for death within the first 2 days of hospitalization. Of the 344 patients included, 222 (64.5%) had cervical SCI. Notably, 62.6% of the patients with cervical SCI were ventilator free by discharge. One hundred forty-nine patients (43.3%) underwent tracheostomy, and 53.7% of them were successfully weaned from the ventilator, compared with an 85.6% success rate among those with no tracheostomy (p < 0.05). Patients who underwent tracheostomy had significantly higher rates of ventilator-associated pneumonia (61.1% vs. 20.5%, p < 0.05) and acute lung injury (12.8% vs. 3.6%, p < 0.05) and fewer ventilator-free days (1 vs. 24 p < 0.05). When controlled for injury severity, thoracic injury, and respiratory comorbidities, tracheostomy after cervical SCI was an independent predictor of ventilator dependence with an associated 14-fold higher likelihood of prolonged mechanical ventilation (odds ratio, 14.1; 95% confidence interval, 2.78-71.67; p < 0.05). CONCLUSION: While many patients with SCI require short-term mechanical ventilation, the majority can be successfully weaned before discharge. In patients with SCI, tracheostomy is associated with major morbidity, and its use, especially among patients with cervical SCI, deserves further study. LEVEL OF EVIDENCE: Prognostic study, level III.

Excessively long hospital stays after trauma are not related to the severity of illness: let's aim to the right target!

IMPORTANCE: Reduction in length of hospital stay is a veritable target in reducing the overall costs of health care. However, many existing approaches are flawed because the assumptions of what cause excessive length of stay are incorrect; we methodically identified the right targets in this study. OBJECTIVE: To identify the causes of excessively prolonged hospitalization (ExProH) in trauma patients. DESIGN: The trauma registry, billing databases, and medical records of trauma admissions were reviewed. Excessively prolonged hospitalization was defined by the standard method used by insurers, which is a hospital stay that exceeds the Diagnosis Related Group-based trim point. The causes of ExProH were explored in a unique potentially avoidable days database, used by our hospital's case managers to track discharge delays. SETTING: Level I academic trauma center. PARTICIPANTS: Adult trauma patients admitted between January 1, 2006, and December 31, 2010. MAIN OUTCOMES AND MEASURES: Excessively prolonged hospitalization and hospital cost. RESULTS: Of 3237 patients, 155 (5%) had ExProH. The patients with ExProH compared with non-ExProH patients were older (mean [SD] age, 53 [21] vs 47 [22] years, respectively; P = .001), were more likely to have blunt trauma (92% vs 84%, respectively; P = .03), were more likely to be self-payers (16% vs 11%, respectively; P = .02) or covered by Medicare/Medicaid (41% vs 30%, respectively; P = .002), were more likely to be discharged to post-acute care facilities than home (65% vs 35%, respectively; P < .001), and had higher hospitalization cost (mean, $54 646 vs $18 444, respectively; P < .001). Both groups had similar Injury Severity Scores, Revised Trauma Scores, baseline comorbidities, and in-hospital complication rates. Independent predictors of mortality were discharge to a rehabilitation facility (odds ratio = 4.66; 95% CI, 2.71-8.00; P < .001) or other post-acute care facility (odds ratio = 5.04; 95% CI, 2.52-10.05; P < .001) as well as insurance type that was Medicare/Medicaid (odds ratio = 1.70; 95% CI, 1.06-2.72; P = .03) or self-pay (odds ratio = 2.43; 95% CI, 1.35-4.37; P = .003). The reasons for discharge delays were clinical in only 20% of the cases. The remaining discharges were excessively delayed because of difficulties in rehabilitation facility placement (47%), in-hospital operational delays (26%), or payer-related issues (7%). CONCLUSIONS AND RELEVANCE: System-related issues, not severity of illness, prolong hospital stay excessively. Cost-reduction efforts should target operational bottlenecks between acute and postacute care.

Pharmacologic modulation of cerebral metabolic derangement and excitotoxicity in a porcine model of traumatic brain injury and hemorrhagic shock.

BACKGROUND: Cerebral metabolic derangement and excitotoxicity play critical roles in the evolution of traumatic brain injury (TBI). We have shown previously that treatment with large doses of valproic acid (VPA) decreases the size of brain lesion. The goal of this experiment was to determine whether this effect was owing to metabolic modulation. METHODS: Yorkshire swine (n = 9) underwent a protocol of computer-controlled TBI and 40% hemorrhage and were resuscitated randomly with either fresh frozen plasma equal to the volume of shed blood (FFP; n = 4) or VPA (300 mg/kg) and FFP (FFP+VPA; n = 5). Hemodynamics, brain oxygenation, and blood glucose were monitored continuously for 6 hours after resuscitation. Cerebral microdialysis was used to measure glucose, lactate, pyruvate, glutamate, and glycerol levels at baseline, 1 and 2 hours post-shock, post-resuscitation (PR), and at 2, 4, and 6 hours PR. Brain samples from the injured side were then separated into mitochondrial and cytosolic fractions, and activity of pyruvate dehydrogenase complex (PDH) was measured using a dipstick assay kit. RESULTS: At baseline, there was no difference in brain lactate, pyruvate, glycerol, and glutamate concentrations between the groups. At all time points, there were no differences between the groups in brain oxygenation, cerebral perfusion pressure, or blood and brain glucose concentrations. After VPA infusion (PR time point), however, there was sustained decrease in lactate (0.91 ± 0.47 vs 2.54 ± 0.59 mmol/L; P < .01) and pyruvate (12.80 ± 4.89 vs 46.25 ± 9.22; P < .001) concentrations compared with the FFP alone group, implying superior glucose utilization for ATP production. There was also a decrease in concentrations of glutamate (6.64 ± 3.68 vs 42.25 ± 27.07 mmol/L; P = .02) and glycerol (19.20 ± 6.76 vs 69.75 ± 30.07 mmol/L; P = .01), in the FFP+VPA group, signifying lesser degree of excitotoxicity and brain damage, respectively. Brain PDH activity was greater in the mitochondrial fractions (5,984 ± 504 adjusted volume intensity [INT] × mm(2) vs 4,332 ± 1,055 INT × mm(2); P = .04) and lower in cytosolic fractions in the FFP+VPA group (1,597 ± 1,395 vs 4,026 ± 1,067 INT × mm(2); P = .03), indicating better mitochondrial membrane function and enhanced mitochondrial PDH retention. CONCLUSION: VPA treatment attenuates perturbation of post-traumatic cerebral metabolism by mitigating mitochondrial dysfunction, and decreases glutamate-mediated excitotoxic damage. These properties could explain its effectiveness in decreasing lesion size and post-traumatic cerebral edema.

Synergistic effects of fresh frozen plasma and valproic acid treatment in a combined model of traumatic brain injury and hemorrhagic shock.

INTRODUCTION: Traumatic brain injury (TBI) and hemorrhagic shock (HS) are major causes of trauma-related deaths and are especially lethal as a combined insult. Previously, we showed that early administration of fresh frozen plasma (FFP) decreased the size of the brain lesion and associated swelling in a swine model of combined TBI+HS. We have also shown separately that addition of valproic acid (VPA) to the resuscitation protocol attenuates inflammatory markers in the brain as well as the degree of TBI. The current study was performed to determine whether a combined FFP+VPA treatment strategy would exert a synergistic effect. METHODS: Yorkshire swine (42-50 kg) were instrumented to measure hemodynamic parameters, intracranial pressure, and brain tissue oxygenation. TBI was created through a 20-mm craniotomy using a computer-controlled cortical impactor: 15-mm cylindrical tip impactor at 4 m/s velocity, 100 ms dwell time, and 12-mm penetration depth. The TBI was synchronized with the initiation of volume-controlled hemorrhage (40 ± 5% of total blood volume). After a 2-hour period of shock, animals were randomized to 1 of 3 resuscitation groups (n = 5 per group): (1) 0.9% saline (NS); (2) FFP; and (3) FFP and VPA 300 mg/kg (FFP+VPA). The resuscitative volume for FFP was equivalent to the shed blood, whereas NS was 3 times this volume. VPA treatment was started 1 hour after hemorrhage. Animals were monitored for 6 hours post-resuscitation. At this time the brains were harvested, sectioned into 5-mm slices, and stained with 2,3,5-triphenyltetrazolium chloride to quantify the lesion size (mm(3)) and brain swelling (percent change compared with the uninjured side). RESULTS: The combined TBI+HS model resulted in a highly reproducible brain injury. Lesion size and brain swelling (mean value ± standard error of the mean) in the FFP+VPA group (1,459 ± 218 mm(3) and 13 ± 1%, respectively) were less than the NS group (3,285 ± 131 mm(3) [P < .001] and 37 ± 2% [P < .001], respectively), and the FFP alone group (2,160 ± 203 mm(3) [P < .05] and 22 ± 1% [P < .001], respectively). CONCLUSION: In a large animal model of TBI+HS, early treatment with a combination of FFP and VPA decreases the size of brain lesion and the associated swelling.

Development of a lethal, closed-abdomen grade V hepato-portal injury model in non-coagulopathic swine.

BACKGROUND: Hemorrhage within an intact abdominal cavity remains a leading cause of preventable death on the battlefield. Despite this need, there is no existing closed-cavity animal model to assess new hemostatic agents for the preoperative control of intra-abdominal hemorrhage. METHODS: We developed a novel, lethal liver injury model in non-coagulopathic swine by strategic placement of two wire loops in the medial liver lobes including the hepatic and portal veins. Distraction resulted in grade V liver laceration with hepato-portal injury, massive bleeding, and severe hypotension. Crystalloid resuscitation was started once mean arterial pressure (MAP) fell below 65 mm Hg. Monitoring continued for up to 180 min. RESULTS: We demonstrated 90% lethality (9/10) in swine receiving injury and fluid resuscitation, with a mean survival time of 43 min. Previous efforts in our laboratory to develop a consistently lethal swine model of abdominal solid organs, including preemptive anticoagulation, a two-hit injury with controlled hemorrhage prior to liver trauma, and the injury described above without resuscitation, consistently failed to result in lethal injury. CONCLUSION: This model can be used to screen other interventions for pre hospital control of noncompressible.

Pharmacologic resuscitation for hemorrhagic shock combined with traumatic brain injury.

BACKGROUND: We have previously demonstrated that valproic acid (VPA), a histone deacetylase inhibitor, can improve survival after hemorrhagic shock (HS), protect neurons from hypoxia-induced apoptosis, and attenuate the inflammatory response. We have also shown that administration of 6% hetastarch (Hextend [Hex]) after traumatic brain injury (TBI) decreases brain swelling, without affecting size of the lesion. This study was performed to determine whether addition of VPA to Hex would decrease the lesion size in a clinically relevant large animal model of TBI + HS. METHODS: Yorkshire swine (42-50 kg) were instrumented to measure hemodynamic parameters, intracranial pressure, and brain tissue oxygenation. A custom-designed, computer-controlled cortical impact device was used to create a TBI through a 20-mm craniotomy: 15-mm cylindrical tip impactor at 4-m/s velocity, 100-millisecond dwell time, and 12-mm penetration depth. Volume-controlled hemorrhage was started (40% blood volume) concurrent with the TBI. After 2 hours of shock, animals were randomized to one of three resuscitation groups (n = 7 per group) as follows: (1) isotonic sodium chloride solution; (2) 6% hetastarch, Hex; and (3) Hex and VPA 300 mg/kg (Hex + VPA). Volumes of Hex matched the shed blood, whereas that of the isotonic sodium chloride solution was three times the volume. VPA treatment was started after an hour of shock. After 6 hours of postresuscitation monitoring, brains were sectioned into 5-mm slices and stained with 2, 3, 5-Triphenyltetrazolium chloride to quantify the lesion size (mm) and brain swelling (percent change compared with uninjured side). Levels of acetylated histone H3 were determined to quantify acetylation, and myeloperoxidase and interleukine-1ß (IL-1ß) levels were measured as markers of brain inflammation. RESULTS: Combination of 40% blood loss with cortical impact and a period of shock (2 hours) and resuscitation resulted in a highly reproducible brain injury. Lesion size and brain swelling in the Hex + VPA group (1,989 [156.8] mm, and 19% [1.6%], respectively) were significantly smaller than the isotonic sodium chloride solution group (3,335 [287.9] mm and 36% [2.2%], respectively). Hex alone treatment significantly decreased the swelling (27% [1.6%]) without reducing the lesion size. The number of CD11b-positive cells as well as myeloperoxidase and IL-1 levels in the brains were significantly reduced by the VPA treatment. CONCLUSION: In a combined HS and TBI model, treatment with artificial colloid (Hex) improves hemodynamic parameters and reduces swelling, without affecting the actual size of the brain lesion. Addition of VPA effectively reduces both the size of brain lesion and associated swelling by attenuating the inflammatory response.

Histone deacetylase inhibitor suberoylanilide hydroxamic acid attenuates Toll-like receptor 4 signaling in lipopolysaccharide-stimulated mouse macrophages.

OBJECTIVE: We have previously demonstrated that pretreatment and posttreatment of animals with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, can improve survival in a mouse model of lipopolysaccharide (LPS)-induced severe shock. This study was designed to assess whether SAHA affects LPS/Toll-like receptor 4 signaling through acetylation of heat shock protein 90 (HSP90) and degradation of its client protein interleukin-1 receptor-associated kinase 1 (IRAK1). METHODS: RAW264.7 cells were exposed to LPS (1 µg/mL) for 2 h, followed by treatment with SAHA (10 µM) or geldanamycin (3 µM), an inhibitor of HSP90. Sham (no SAHA, no LPS) macrophages served as a control. The cells were harvested at different time points, and time zero served as the reference point. RESULTS: LPS dramatically increased protein expression of myeloid differentiation factor 88 and IRAK1, and stimulated nuclear translocation of nuclear factor κB, leading to an increases of gene expression and protein production of tumor necrosis factor α and interleukin-6. Treatment with SAHA significantly attenuated these LPS-stimulated alterations. LPS or SAHA did not change the levels of HSP90 protein, but immunoprecipitation studies demonstrated that SAHA treatment enhanced acetylation of HSP90, and increased the dissociation of IRAK1, compared to the LPS control. CONCLUSIONS: SAHA suppresses LPS/Toll-like receptor 4 signaling in LPS-stimulated macrophages through multiple potential mechanisms. It inhibits the function of HSP90 through hyperacetylation of the chaperone protein, which results in dissociation and degradation of the client protein IRAK1 and, at least in part, leads to a decrease in nuclear translocation of nuclear factor κB and attenuation of key proinflammatory cytokine expression.