Eric J. Ley

Postoperative infection risk after splenectomy: A prospective cohort study

INTRODUCTIONnSplenectomy is associated with a life-long risk for overwhelming infections. The risk for early post-operative infectious complications following traumatic and elective splenectomy is, however, understudied. This investigation aimed to determine if splenectomy increases the risk for post-operative infections.nnnMETHODSnThis was a retrospective review of prospectively collected data on patients admitted to the surgical intensive care unit (SICU) between 1/2011 and 7/2013 investigating the risk for infectious complications in patients undergoing a splenectomy compared with those undergoing any other abdominal surgery.nnnRESULTSnDuring the 30-month study period, a total of 1884 patients were admitted to the SICU. Of those, 33 (2%) had a splenectomy and 493 (26%) had an abdominal surgery. The two groups were well balanced for age, APACHE IV score >20, and past medical history, including diabetes mellitus, cardiac history, renal failure or immunosuppression. Patients undergoing splenectomy were more likely to have sustained a traumatic injury (30% vs. 7%, pxa0<xa00.01). After adjustment, splenectomy was associated with increased risk for infectious complications (49% vs. 29%, Adjusted Odds Ratio (AOR) [95% CI]: 2.7 [1.3, 5.6], pxa0=xa00.01), including intra-abdominal abscess (9% vs. 3%, AOR [95% CI]: 4.3 [1.1, 16.2], pxa0=xa00.03). On a subgroup analysis, there were no differences between traumatic and elective splenectomy with regards to overall infectious complications (50% vs. 46%, pxa0=xa00.84), although, abdominal abscess developed only in those who had an elective splenectomy (0% vs. 12%, pxa0=xa00.55).nnnCONCLUSIONnSplenectomy increases the risk for post-operative infectious complications. Further studies identifying strategies to decrease the associated morbidity are necessary.

Association Between Enoxaparin Dosage Adjusted by Anti-Factor Xa Trough Level and Clinically Evident Venous Thromboembolism After Trauma.

ImportancenTrauma patients are at high risk for developing venous thromboembolism (VTE). The VTE rate when enoxaparin sodium is dosed by anti-factor Xa (anti-Xa) trough level is not well described.nnnObjectivenTo determine whether targeting a prophylactic anti-Xa trough level by adjusting the enoxaparin dose would reduce the VTE rate in trauma patients.nnnDesign, Setting, and ParticipantsnSingle-institution, historic vs prospective cohort comparison study at an urban, academic, level I trauma center. The prospective cohort was enrolled from August 2014 to May 2015 and compared with a historic cohort admitted from August 2013 to May 2014. Trauma patients who received enoxaparin adjusted by anti-Xa trough level (adjustment group) were compared with those who received enoxaparin sodium at a dosage of 30 mg twice daily (control group). Patients were excluded if they were younger than 18 years, had a length of hospital stay less than 2 days, or had preexisting deep vein thrombosis. Patients were excluded from the adjustment group for changes in the choice of thromboprophylaxis (heparin, enoxaparin once-daily dosing, early ambulation), hospital discharge before initial trough levels could be drawn, or incorrect timing of trough levels.nnnExposuresnAnti-Xa trough levels were monitored in patients in the adjustment group receiving 3 or more consecutive doses of enoxaparin sodium, 30 mg twice daily. Patients with a trough level of 0.1 IU/mL or lower received enoxaparin sodium increased by 10-mg increments. After providing 3 adjusted doses of enoxaparin, the trough level was redrawn and the dosage was adjusted as necessary. Patients in the control group received enoxaparin sodium at a dosage of 30 mg twice daily without adjustments.nnnMain Outcomes and MeasuresnRates of symptomatic VTE (deep vein thrombosis and pulmonary embolism, confirmed by duplex ultrasonography and chest computed tomographic angiography, respectively) and bleeding risk.nnnResultsnA total of 205 patients (mean [SD] age, 41.3 [18.2] years; 75.1% male) were studied, 87 in the adjustment group and 118 in the control group, with similar baseline characteristics and injury profiles. Subprophylactic anti-Xa troughs were noted in 73 of 87 patients (83.9%) in the adjustment group, and the majority of patients (57 of 87 patients [65.5%]) required dosage adjustment of enoxaparin sodium to 40 mg twice daily. Incidence of VTE was significantly lower in the adjustment group than in the control group (1.1% vs 7.6%, respectively; Pu2009=u2009.046). When the adjustment group was compared with the control group, no significant difference was noted in the rate of packed red blood cell transfusion (6.9% vs 12.7%, respectively; Pu2009=u2009.18) or mean (SD) hematocrit at discharge (34.5% [6.3%] vs 33.4% [6.8%], respectively [to convert to proportion of 1.0, multiply by 0.01]; Pu2009=u2009.19).nnnConclusions and RelevancenIn this study, subprophylactic anti-Xa trough levels were common in trauma patients. Enoxaparin dosage adjustment may lead to a reduced rate of VTE without an increased risk of bleeding.

Transcranial Near-Infrared Laser Transmission (NILT) Profiles (800 nm): Systematic Comparison in Four Common Research Species.

Background and Purpose Transcranial near-infrared laser therapy (TLT) is a promising and novel method to promote neuroprotection and clinical improvement in both acute and chronic neurodegenerative diseases such as acute ischemic stroke (AIS), traumatic brain injury (TBI), and Alzheimer’s disease (AD) patients based upon efficacy in translational animal models. However, there is limited information in the peer-reviewed literature pertaining to transcranial near-infrared laser transmission (NILT) profiles in various species. Thus, in the present study we systematically evaluated NILT characteristics through the skull of 4 different species: mouse, rat, rabbit and human. Results Using dehydrated skulls from 3 animal species, using a wavelength of 800nm and a surface power density of 700 mW/cm2, NILT decreased from 40.10% (mouse) to 21.24% (rat) to 11.36% (rabbit) as skull thickness measured at bregma increased from 0.44 mm in mouse to 0.83 mm in rat and then 2.11 mm in rabbit. NILT also significantly increased (p<0.05) when animal skulls were hydrated (i.e. compared to dehydrated); but there was no measurable change in thickness due to hydration. In human calvaria, where mean thickness ranged from 7.19 mm at bregma to 5.91 mm in the parietal skull, only 4.18% and 4.24% of applied near-infrared light was transmitted through the skull. There was a slight (9.2-13.4%), but insignificant effect of hydration state on NILT transmission of human skulls, but there was a significant positive correlation between NILT and thickness at bregma and parietal skull, in both hydrated and dehydrated states. Conclusion This is the first systematic study to demonstrate differential NILT through the skulls of 4 different species; with an inverse relationship between NILT and skull thickness. With animal skulls, transmission profiles are dependent upon the hydration state of the skull, with significantly greater penetration through hydrated skulls compared to dehydrated skulls. Using human skulls, we demonstrate a significant correlation between thickness and penetration, but there was no correlation with skull density. The results suggest that TLT should be optimized in animals using novel approaches incorporating human skull characteristics, because of significant variance of NILT profiles directly related to skull thickness.

In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs.

Microbubble-enhanced, ultrasound-mediated BMP-6 gene delivery to endogenous progenitor cells induces rapid and efficient repair of critical-sized, nonunion bone fractures in mini-pigs. Bubbles and BMP-6 for bone repair Treatments for bone nonunions (fractures that fail to heal) include surgery and bone grafting. As an alternative to viral gene delivery, Bez et al. developed a two-step therapy. First, endogenous mesenchymal stem/progenitor cells were recruited to the bone nonunion by implanting a collagen sponge in the defect site. Two weeks later, bone morphogenetic protein-6 (BMP-6) plasmid DNA and microbubbles were injected into nonunions, and ultrasound was applied to oscillate the microbubbles, which helped the recruited progenitors take up the BMP-6. This therapy led to transient BMP-6 secretion, bone regeneration, and fracture healing over 6 weeks in critical-sized tibial nonunions in mini-pigs. More than 2 million bone-grafting procedures are performed each year using autografts or allografts. However, both options carry disadvantages, and there remains a clear medical need for the development of new therapies for massive bone loss and fracture nonunions. We hypothesized that localized ultrasound-mediated, microbubble-enhanced therapeutic gene delivery to endogenous stem cells would induce efficient bone regeneration and fracture repair. To test this hypothesis, we surgically created a critical-sized bone fracture in the tibiae of Yucatán mini-pigs, a clinically relevant large animal model. A collagen scaffold was implanted in the fracture to facilitate recruitment of endogenous mesenchymal stem/progenitor cells (MSCs) into the fracture site. Two weeks later, transcutaneous ultrasound-mediated reporter gene delivery successfully transfected 40% of cells at the fracture site, and flow cytometry showed that 80% of the transfected cells expressed MSC markers. Human bone morphogenetic protein-6 (BMP-6) plasmid DNA was delivered using ultrasound in the same animal model, leading to transient expression and secretion of BMP-6 localized to the fracture area. Micro–computed tomography and biomechanical analyses showed that ultrasound-mediated BMP-6 gene delivery led to complete radiographic and functional fracture healing in all animals 6 weeks after treatment, whereas nonunion was evident in control animals. Collectively, these findings demonstrate that ultrasound-mediated gene delivery to endogenous mesenchymal progenitor cells can effectively treat nonhealing bone fractures in large animals, thereby addressing a major orthopedic unmet need and offering new possibilities for clinical translation.

Early propranolol after traumatic brain injury is associated with lower mortality.

BACKGROUND &bgr;-Adrenergic receptor blockers (BBs) administered after trauma blunt the cascade of immune and inflammatory changes associated with injury. BBs are associated with improved outcomes after traumatic brain injury (TBI). Propranolol may be an ideal BB because of its nonselective inhibition and ability to cross the blood-brain barrier. We determined if early administration of propranolol after TBI is associated with lower mortality. METHODS All adults (age ≥ 18 years) with moderate-to-severe TBI (head Abbreviated Injury Scale [AIS] score, 3–5) requiring intensive care unit (ICU) admission at a Level I trauma center from January 1, 2013, to May 31, 2015, were prospectively entered into a database. Administration of early propranolol was dosed within 24 hours of admission at 1 mg intravenous every 6 hours. Patients who received early propranolol after TBI (EPAT) were compared with those who did not (non-EPAT). Data including demographics, hospital length of stay (LOS), ICU LOS, and mortality were collected. RESULTS Over 29 months, 440 patients with moderate-to-severe TBI met inclusion criteria. Early propranolol was administered to 25% (109 of 440) of the patients. The EPAT cohort was younger (49.6 years vs. 60.4 years, p < 0.001), had lower Glasgow Coma Scale (GCS) score (11.7 vs. 12.4, p = 0.003), had lower head AIS score (3.6 vs. 3.9, p = 0.001), had higher admission heart rate (95.8 beats/min vs. 88.4 beats/min, p = 0.002), and required more days on the ventilator (5.9 days vs. 2.6 days, p < 0.001). Similarities were noted in sex, Injury Severity Score (ISS), admission systolic blood pressure, hospital LOS, ICU LOS, and mortality rate. Multivariate regression showed that EPAT was independently associated with lower mortality (adjusted odds ratio, 0.25; p = 0.012). CONCLUSION After adjusting for predictors of mortality, early administration of propranolol after TBI was associated with improved survival. Future studies are needed to identify additional benefits and optimal dosing regimens. LEVEL OF EVIDENCE Therapeutic study, level IV.

Body mass index strongly impacts the diagnosis and incidence of heparin-induced thrombocytopenia in the surgical intensive care unit.

BACKGROUND The obese state has been linked to several immune-mediated conditions. Our objective was to examine the association of body mass index (BMI) with the diagnosis of heparin-induced thrombocytopenia (HIT). METHODS Prospectively collected data on patients in the surgical and cardiac intensive care unit suspected of having HIT between January 2007 and August 2014 were analyzed. Patients were categorized into five discrete BMI (kg/m2) groups and compared. Data collected included Warkentin 4-T scores, antiplatelet factor 4 (anti-PF4OD) values, serotonin release assay values, and thromboembolic diseases. HIT positivity was defined as serotonin release assay value greater than 20%. RESULTS Of 304 patients meeting inclusion criteria, mean (SD) age was 62.1 (16.5) years, 59% were male, and mean (SD) BMI was 27 (6) kg/m2. Thirty-six (12%) were positive for HIT. Incidence of HIT increased progressively with BMI (0%, 8%, 11%, 19%, 36%; p < 0.001). Compared with patients with normal BMI, patients with a BMI of 30 kg/m2 to 39.9 kg/m2 had a 200% increase in the odds for HIT (odds ratio [OR], 2.94; 95% confidence interval [CI], 1.20–7.54; p = 0.019), while patients with a BMI of 40 kg/m2 or greater had a 600% increase (OR, 6.98; 95% CI, 1.59–28.2; p = 0.012). After regression analysis, BMI remained an independent predictor of the development of HIT (adjusted OR per kg/m2, 1.08; 95% CI, 1.02–1.14; p = 0.010). Anti-PF4OD values greater than or equal to 2.0 also increased with BMI (p < 0.001). In-hospital mortality increased significantly with BMI above normal (p = 0.026). Warkentin 4-T scores, deep venous thrombosis, pulmonary embolism, and stroke incidence did not correlate with changes in BMI. CONCLUSION Increasing BMI seems to be strongly associated with increased rates of HIT in intensive care unit patients. Obesity is an important new clinical variable for estimating the pretest probability of HIT, and patient “thickness” could be considered a fifth “T” of the 4-T scoring system. Additional biochemical work is indicated to decipher the role of obesity in this immune-mediated condition. LEVEL OF EVIDENCE Prognostic/epidemiologic study, level III.

Prospective evaluation of early propranolol after traumatic brain injury

BACKGROUNDnAlthough beta-adrenergic receptor blockade may improve outcomes after traumatic brain injury (TBI), its early use is not routine. We hypothesize that judicious early low-dose propranolol after TBI (EPAT) will improve outcomes without altering bradycardia or hypotensive events.nnnMETHODSnWe conducted a prospective, observational study on all patients who presented with moderate-to-severe TBI from March 2010-August 2013. Ten initial patients did not receive propranolol (control). Subsequent patients received propranolol at 1-mg intravenous every 6xa0h starting within 12xa0h of intensive care unit (ICU) admission (EPAT) for a minimum of 48xa0h. Heart rate and blood pressure were recorded hourly for the first 72xa0h. Bradycardia and hypotensive events, mortality, and length of stay (LOS) were compared between cohorts to determine significant differences.nnnRESULTSnThirty-eight patients were enrolled; 10 control and 28 EPAT. The two cohorts were similar when compared by gender, emergency department (ED) systolic blood pressure, ED heart rate, and mortality. ED Glasgow coma scale was lower (4.2 versus 10.7, Pxa0<xa00.01) and injury severity score higher in control. EPAT patients received a mean of 10xa0±xa014 doses of propranolol. Hypotensive events were similar between cohorts, whereas bradycardia events were higher in control (5.8 versus 1.6, Pxa0=xa00.05). ICU LOS (15.4 versus 30.4xa0d, Pxa0=xa00.02) and hospital LOS (10 versus 19.1xa0d, Pxa0=xa00.05) were lower in EPAT. Mortality rates were similar between groups (10% versus 10.7%, Pxa0=xa00.9). The administration of propranolol led to no recorded complications.nnnCONCLUSIONSnAlthough bradycardia and hypotensive events occur early after TBI, low-dose intravenous propranolol does not increase their number or severity. Early use of propranolol after TBI appears to be safe and may be associated with decreased ICU and hospital LOS.

Novel oral anticoagulants and trauma: The results of a prospective American Association for the Surgery of Trauma Multi-Institutional Trial.

BACKGROUND The number of anticoagulated trauma patients is increasing. Trauma patients on warfarin have been found to have poor outcomes, particularly after intracranial hemorrhage (ICH). However, the effect of novel oral anticoagulants (NOAs) on trauma outcomes is unknown. We hypothesized that patients on NOAs would have higher rates of ICH, ICH progression, and death compared with patients on traditional anticoagulant and antiplatelet agents. METHODS This was a prospective observational trial across 16 trauma centers. Inclusion criteria was any trauma patient admitted on aspirin, clopidogrel, warfarin, dabigatran, rivaroxaban, or apixaban. Demographic data, admission vital signs, mechanism of injury, injury severity scores, laboratory values, and interventions were collected. Outcomes included ICH, progression of ICH, and death. RESULTS A total of 1,847 patients were enrolled between July 2013 and June 2015. Mean age was 74.9 years (SD ± 13.8), 46% were female, 77% were non-Hispanic white. At least one comorbidity was reported in 94% of patients. Blunt trauma accounted for 99% of patients, and the median Injury Severity Score was 9 (interquartile range, 4–14). 50% of patients were on antiplatelet agents, 33% on warfarin, 10% on NOAs, and 7% on combination therapy or subcutaneous agents. Patients taking NOAs were not at higher risk for ICH on univariate (24% vs. 31%) or multivariate analysis (incidence rate ratio, 0.78; confidence interval 0.61–1.01, p = 0.05). Compared with all other agents, patients on aspirin (90%, 81 mg; 10%, 325 mg) had the highest rate (35%) and risk (incidence rate ratio, 1.27; confidence interval, 1.13–1.43; p < 0.001) of ICH. Progression of ICH occurred in 17% of patients and was not different between medication groups. Study mortality was 7% and was not significantly different between groups on univariate or multivariate analysis. CONCLUSION Patients on NOAs were not at higher risk for ICH, ICH progression, or death. LEVEL OF EVIDENCE Prognostic/epidemiologic study, level III.

Field intubation in civilian patients with hemorrhagic shock is associated with higher mortality.

BACKGROUND Field intubation (FI) by emergency medical service personnel on severely injured trauma patients remains a contentious practice. Clinical studies suggest an association between FI and adverse outcomes in patients with traumatic brain injury. Military tactical emergency casualty care recommends deferring intubation and providing supplemental oxygenation until reaching a more equipped destination. In addition, animal models with penetrating hemorrhagic shock demonstrate increased acidosis with intubation before resuscitation. The purpose of this study was to evaluate the impact of FI on outcomes in trauma patients with hemorrhagic shock requiring massive transfusion. METHODS The Los Angeles County Trauma System Database was retrospectively queried for all trauma patients 16 years or older with hemorrhagic shock requiring massive transfusion (≥6 U packed red blood cells in the first 24 hours) between January 1, 2012, and June 30, 2014. Demographics, clinical and transfusion data, and outcomes were compared between patients who received FI and those who did not (NO-FI). Multivariate regression analysis was used to adjust for confounders. RESULTS Of 552 trauma patients meeting inclusion criteria, 63 (11%) received FI, and the remaining 489 (89%) were NO-FI. Age, sex, and incidence of blunt injury were similar between the FI and the NO-FI group. The FI cohort presented with a lower median Glasgow Coma Scale (GCS) score (3 vs. 14, p < 0.001), a lower median systolic blood pressure (86 mm Hg vs. 104 mm Hg, p < 0.001), and a higher median Injury Severity Score (ISS) (41 vs. 29, p < 0.001). Mortality was significantly higher in FI patients (83% vs. 43%, p < 0.001). Transfusion patterns and total field times were similar in both groups. After adjusting for confounders, FI patients had increased odds of mortality (adjusted odds ratio, 2.89; 95% confidence interval, 1.08–7.78; p = 0.035). In addition, FI was identified as an independent predictor of mortality (adjusted odds ratio, 3.41; 95% confidence interval, 1.35–8.59; p = 0.009). CONCLUSION FI may be associated with higher mortality in trauma patients with hemorrhagic shock requiring massive transfusion. Less invasive airway interventions and rapid transport might improve outcomes for these patients. LEVEL OF EVIDENCE Therapeutic study, level IV; epidemiologic study, level III.

A model of recurrent concussion that leads to long-term motor deficits, CTE-like tauopathy and exacerbation of an ALS phenotype.

BACKGROUND Concussion injury is the most common form of traumatic brain injury (TBI). How recurrent concussions alter long-term outcomes is poorly understood, especially as related to the development of neurodegenerative disease. We evaluated the functional and pathological consequences of repeated TBI over time in wild type (WT) rats as well as rats harboring the human SOD1G93A mutation (“SOD1”), a model of familial amyotrophic lateral sclerosis (ALS). METHODS A total of 42 rats, 26 WT and 16 SOD1, were examined over a study period of 25 weeks (or endpoint). At postnatal day 60, 20 WT and 7 SOD1 rats were exposed to mild, bilateral TBI once per week for either 2 weeks (2×TBI) or 5 weeks (5×TBI) using a controlled cortical impact device. Six WT and nine SOD1 rats underwent sham injury with anesthesia alone. Twenty WT rats were euthanized at 12 weeks after first injury and six WT rats were euthanized at 25 weeks after first injury. SOD1 rats were euthanized when they reached ALS disease endpoint. Weekly body weights and behavioral assessments were performed. Tauopathy in brain tissue was analyzed using immunohistochemistry. RESULTS 2XTBI injured rats initially demonstrated recovery of motor function but failed to recover to baseline within the 12-week study period. Relative to both 2XTBI and sham controls, 5XTBI rats demonstrated significant deficits that persisted over the 12-week period. SOD1 5XTBI rats reached a peak body weight earlier than sham SOD1 rats, indicating earlier onset of the ALS phenotype. Histologic examination of brain tissue revealed that, in contrast with sham controls, SOD1 and WT TBI rats demonstrated cortical and corpus collosum thinning and tauopathy, which increased over time. CONCLUSIONS Unlike previous models of repeat brain injury, which demonstrate only transient deficits in motor function, our concussion model of repeat, mild, bilateral TBI induced long-lasting deficits in motor function, decreased cortical thickness, shrinkage of the corpus callosum, increased brain tauopathy, and earlier onset of ALS symptoms in SOD1 rats. This model may allow for a greater understanding of the complex relationship between TBI and neurodegenerative diseases and provides a potential method for testing novel therapeutic strategies.