Elizabeth L. Cureton

Glucagon-like peptide-1 protects mesenteric endothelium from injury during inflammation

Glucagon-like peptide-1 (GLP-1) is a proglucagon-derived hormone with cellular protective actions. We hypothesized that GLP-1 would protect the endothelium from injury during inflammation. Our aims were to determine the: (1) effect of GLP-1 on basal microvascular permeability, (2) effect of GLP-1 on increased microvascular permeability induced by lipopolysaccaride (LPS), (3) involvement of the GLP-1 receptor in GLP-1 activity, and (4) involvement of the cAMP/PKA pathway in GLP-1 activity. Microvascular permeability (L(p)) of rat mesenteric post-capillary venules was measured in vivo. First, the effect of GLP-1 on basal L(p) was measured. Second, after systemic LPS injection, L(p) was measured after subsequent perfusion with GLP-1. Thirdly, L(p) was measured after LPS injection and perfusion with GLP-1+GLP-1 receptor antagonist. Lastly, L(p) was measured after LPS injection and perfusion with GLP-1+inhibitors of the cAMP/PKA pathway. Results are presented as mean area under the curve (AUC)+/-SEM. GLP-1 had no effect on L(p) (AUC: baseline=27+/-1.4, GLP-1=1+/-0.4, p=0.08). LPS increased L(p) two-fold (AUC: LPS=54+/-1.7, p<0.0001). GLP-1 reduced the LPS increase in L(p) by 75% (AUC: LPS+GLP-1=34+/-1.5, p<0.0001). GLP-1 antagonism reduced the effects of GLP-1 by 60% (AUC: LPS+GLP-1+antagonist=46+/-2.0, p<0.001). The cAMP synthesis inhibitor reduced the effects of GLP-1 by 60% (AUC: LPS+GLP-1+cAMP inhibitor=46+/-1.5, p<0.0001). The PKA inhibitor reduced the effects of GLP-1 by 100% (AUC: LPS+GLP-1+PKA inhibitor=56+/-1.5, p<0.0001). GLP-1 attenuates the increase in microvascular permeability induced by LPS. GLP-1 may protect the endothelium during inflammation, thus decreasing third-space fluid loss.

The heart of the matter: utility of ultrasound of cardiac activity during traumatic arrest.

BACKGROUND The clinical utility of determining cardiac motion on ultrasound has been reported for patients presenting in pulseless medical cardiac arrest. However, the relationship between ultrasound-documented cardiac activity and the probability of surviving pulseless electrical activity has not been examined in populations with trauma. We hypothesized that cardiac activity on ultrasound predicts survival for patients presenting in pulseless traumatic arrest. METHODS We conducted a retrospective analysis at our university-based urban trauma center of adult patients with trauma, who were pulseless on hospital arrival. Results of cardiac ultrasound performed during trauma resuscitations were compared with the electrocardiogram (EKG) rhythm and survival. RESULTS Among 318 pulseless patients with trauma, 162 had both EKG tracings and a cardiac ultrasound, and 4.3% of these 162 patients survived to hospital admission. Survival was higher for those with cardiac motion than for those without it (23.5% vs. 1.9% for patients with EKG electrical activity, p = 0.002, and 66.7% vs. 0% for patients without EKG electrical activity, p < 0.001). The sensitivity of ultrasound cardiac motion to predict survival to hospital admission was 86% (specificity, 91%; positive predictive value, 30%; negative predictive value, 99%). When examined by mechanism, sensitivity was 100% for the 111 patients with penetrating trauma and 75% for the 50 patients with blunt trauma. CONCLUSION Survival in pulseless traumatic arrest is very low, but survival for patients with no cardiac motion on ultrasound is also exceedingly rare. Cardiac ultrasound had a negative predictive value approaching 100% for survival to hospital admission. For patients with prolonged prehospital cardiopulmonary resuscitation, ultrasound evaluation of cardiac motion in pulseless patients with trauma may be a rapid way to help determine which patients have no chance of survival in the setting of lethal injuries, so that futile resuscitations can be stopped. (J Trauma Acute Care Surg. 2012;73: 102–110. Copyright

Insurance Coverage Is Associated with Mortality after Gunshot Trauma

BACKGROUND Poor access to adequate health care coverage is associated with poor outcomes for many chronic medical conditions. We hypothesized that insurance coverage is also associated with mortality after gunshot trauma. STUDY DESIGN The trauma records for gunshot victims and their insurance status were reviewed at our center from January 1998 to December 2007. Patient demographics (age, gender, race, and insurance coverage), injury severity, hospital care (operations and radiographic studies), and in-hospital mortality were analyzed. RESULTS There were 2,164 gunshot trauma activations reviewed during the study period. One-quarter (n = 544) of these patients had insurance and three-quarters (n = 1,620) were uninsured. The in-hospital mortality rate was significantly higher for uninsured patients than for insured patients (9% vs 6%, p = 0.02). After controlling for age, gender, race, and injury severity by logistic regression analysis, the odds ratio for death of uninsured patients was 2.2 (95% CI 1.1 to 4.5). Insured patients did not differ from uninsured patients with respect to mean Injury Severity Score ([ISS] 12.2 +/- 10.7 vs 12.6 +/- 12.4, p = 0.56); similar percentages of patients were severely injured (ISS 16 to 24, 17% vs 15%, p = 0.19) and most severely injured (ISS > 24, 15% vs 16%, p = 0.68). Insured patients did not differ from uninsured patients with respect to use of radiographic imaging (53% vs 50%, p = 0.15) or operative intervention (37% vs 35%, p = 0.35). CONCLUSIONS Despite similar injury severity, uninsured trauma patients were more likely to die after gunshot injury than insured patients. This difference could not be attributed to demographics or hospital resource use. Insurance coverage may reflect the many social determinants of health. Improving the social determinants of health in patients affected by violent trauma may be a step toward improving outcomes after trauma.

A different view of lactate in trauma patients: protecting the injured brain.

BACKGROUND The relationship between lactate and head injury is controversial. We sought to determine the relationship between initial serum lactate, severity of head injury, and outcome. We hypothesized that lactate is elevated in head injured patients, and that initial serum lactate increases as the severity of head injury increases. Furthermore, lactate may be neuroprotective and improve neurologic outcomes. MATERIALS AND METHODS We identified normotensive adult patients over a 6-y period at our university-based urban trauma center with isolated blunt head injury. We performed univariate and multivariate analysis to examine the relationship between lactate and Glasgow coma scale (GCS). The correlation of admission lactate with survival and neurologic function was also examined. RESULTS There were 555 patients who met study criteria. While controlling for injury severity score and age, increased lactate was associated with more severe head injury (P<0.0001). The admission lactate was 2.2+/-0.07, 3.7+/-0.7, and 4.7+/-0.8 mmol/L in patients with mild, moderate, and severe head injury respectively (P<0.01). Patients with moderate or severe head injury and an admission lactate>5 were more likely to have a normal mental status on discharge (P<0.0001). CONCLUSIONS In normotensive isolated head injured patients, there was an increase in serum lactate as head injuries became more severe. Since lactate is a readily available fuel source of the injured brain, this may be a mechanism by which brain function is preserved in trauma patients. Elevations in lactate due to anaerobic metabolism in trauma patients may have beneficial effects by protecting the brain during injury.

Local Secretion of Urocortin 1 Promotes Microvascular Permeability during Lipopolysaccharide-Induced Inflammation

Urocortin 1 (Ucn1) is a neuropeptide that regulates vascular tone and is implicated in both the vascular and immune cell-mediated responses to inflammation. The role of Ucn1 in regulating microvascular permeability has not been determined. We hypothesized that local Ucn1 release promotes microvascular permeability and that this effect augments the local gastrointestinal vascular response to lipopolysaccharide (LPS)-induced systemic inflammation. We measured hydraulic (L(p)) and macromolecule permeability in mesenteric venules. We show that a continuous infusion of 10(-7) m Ucn1 in a postcapillary venule increased L(p) 2-fold over baseline, as did LPS-induced inflammation. However, simultaneous infusion of Ucn1 and LPS markedly increased L(p) by 7-fold. After local knockdown of Ucn1 using RNA interference, infusion of Ucn1 with LPS resulted in return to 2-fold increase, confirming that Ucn1 synergistically augments hydraulic permeability during inflammation. LPS and Ucn1 treatment also resulted in increased numbers of interstitial microspheres, which colocalized with CD31(+) immune cells. Ucn1 activity is mediated through two receptor subtypes, CRH-R(1) and CRH-R(2). CRH-R(1) receptor blockade exacerbated, whereas CRH-R(2) receptor blockade decreased the LPS-induced increase in L(p). Finally, treatment with the c-JUN N-terminal kinase (JNK) antagonist SP600125 during infusion of LPS, but not Ucn1, decreased L(p). These findings suggest that Ucn1 increases microvascular permeability and acts synergistically with LPS to increase fluid and macromolecule losses during inflammation. Knockdown of endogenous Ucn1 during inflammation attenuates synergistic increases in L(p). Ucn1s effect on L(p) is partially mediated by the CRH-R(2) receptor and acts independently of the c-JUN N-terminal kinase signal transduction pathway.

Expedited Treatment of Lower Extremity Gunshot Wounds

BACKGROUND Patients with isolated lower extremity gunshot wounds are currently admitted for observation and often undergo angiography. We hypothesized that if such patients have a normal ankle-brachial index (ABI), they can be discharged safely from the emergency department without invasive imaging or admission. STUDY DESIGN We retrospectively reviewed the records of hemodynamically stable patients with isolated lower extremity gunshot wounds seen at our urban, university-based trauma center and who were discharged from the emergency department. Evaluation consisted of determining which patients were hemodynamically normal, had no fractures, and had an ABI > or =0.9. Patients with an ABI <0.9 underwent CT angiography. We then applied this practice algorithm prospectively, adding evaluation of high probability proximity wounds by ultrasonography or CT angiography to rule out missed injuries. RESULTS The retrospective review identified 182 patients who met our criteria. None had bleeding, limb ischemia, or limb loss. The specificity of the evaluation in the retrospective study to predict safe discharge was 100%, with a negative predictive value of 98%. There were 90 patients in the prospective study. Bleeding, limb ischemia, or limb loss did not develop in any patient. The prospective algorithm for predicting safe discharge home had a 100% positive predictive value and 98% negative predictive value. Using this algorithm, costs were 992 dollars per patient. If every patient received ultrasonography or CT angiography, it would have been 1,135 dollars or 4,632 dollars, respectively, per patient. CONCLUSIONS Hemodynamically normal patients with lower extremity gunshot wounds without fracture and an initial ABI > or =0.9 can be discharged safely from the emergency department without additional diagnostic imaging, potentially saving health care costs.

Gender differences among recidivist trauma patients.

BACKGROUND Gender differences among trauma recidivist patients are not well-understood. We hypothesized that males are more likely to be repeatedly involved in the trauma system and have a shorter time to recurrence between repeat episodes of injury compared with females. MATERIALS AND METHODS A retrospective analysis of trauma patients treated at an urban university-based trauma center was performed. Variables including gender, race, insurance status, age, mechanism of injury, outcomes, and injury secondary to domestic violence were compared. Differences were compared using χ(2) tests and log-rank (Mantel-Cox) Kaplan-Meier cumulative event curves. RESULTS We identified 689 trauma recidivist patients (4.0% of all trauma visits) over a 10-y period. Compared to single-visit patients, recidivist patients were more likely to be male (87% versus 73%), uninsured (78% versus 66%), and have injuries secondary to assaults (54% versus 37%) (P < 0.05). Time from the first to second trauma visit was shorter for females compared with males (23 ± 2.5 versus 30 ± 1.2 mo, P < 0.02). Additionally, female recidivists were more likely to be involved in blunt trauma than were male recidivists (69% versus 43%, P < 0.001). Furthermore, domestic violence was identified in a higher proportion of female recidivist patients than female single-visit patients (3.5% versus 1.6%, P < 0.0003). CONCLUSIONS Contrary to our hypothesis, female recidivist trauma patients have a much shorter time to recurrence for a second traumatic injury than do males. Female recidivists have a high likelihood of assault-associated injuries and domestic violence. Trauma centers should screen for domestic violence among trauma patients to aid in preventing further repeat episodes of injury.

Lipoxin A4 Attenuates Microvascular Fluid Leak During Inflammation

BACKGROUND The release of proinflammatory cytokines during inflammation disturbs the endothelial barrier and can initiate significant intravascular volume loss. Proinflammatory cytokines also induce the expression of anti-inflammatory mediators, such as lipoxin, which promote the resolution of inflammation. Our hypothesis is that lipoxin A(4) (LXA(4)) reverses the increased microvascular fluid leak observed during inflammatory conditions. MATERIALS AND METHODS Microvascular fluid leak (L(p)) was measured in rat mesenteric venules using a micro-cannulation technique. L(p) was measured under the following conditions: (1) LXA(4) (100 nM) alone (n = 5), (2) LXA(4) (100 nM) administered after endothelial hyperpermeability induced by a continuous perfusion of 10 nM platelet activating factor (PAF) (n = 5), (3) LXA(4) (100 nM) perfused after inflammation induced by a systemic bolus of 10 mg/kg lipopolysaccharide (LPS) (n = 5), and (4) LXA(4) (100 nM) perfused after LPS-induced inflammation during inhibition of c-Jun N-terminal kinase (n = 4). RESULTS LXA(4) alone slightly increased L(p) from baseline (L(p)-baseline = 1.05 +/- 0.03, L(p)-LXA(4) = 1.55 +/- 0.04; P < 0.0001). PAF increased L(p) 4-fold (L(p)-baseline = 1.20 +/- 0.10, L(p)-PAF = 4.49 +/- 0.95; P < 0.0001). LXA(4) administration after PAF decreased L(p) 66% versus PAF alone (from 4.49 +/- 0.95 to 1.54 +/- 0.13; P = 0.0004). LPS-induced inflammation increased L(p) over 2-fold (L(p)-baseline = 1.05 +/- 0.03, L(p)-LPS = 2.27 +/- 0.13; P < 0.0001). LXA(4) administration after LPS decreased L(p) 42% versus LPS alone (from 2.27 +/- 0.13 to 1.31 +/- 0.05; P < 0.0001). The effect of c-Jun N-terminal kinase inhibition during LPS-induced inflammation attenuated the decrease in leak cause by LXA(4) by 51% (P = 0.0002). CONCLUSION After either LPS or PAF, LXA(4) attenuated the intravascular volume loss caused by these inflammatory mediators. The activity of LXA(4) may be partly mediated by the c-Jun N-terminal kinase signaling pathway. These data support an anti-inflammatory role for LXA(4) and suggests a potential pharmacologic role for LXA(4) during inflammation.

Ghrelin decreases microvascular leak during inflammation.

BACKGROUND Obesity is a risk factor for poor outcomes after trauma, and circulating levels of ghrelin are decreased in obese patients. We hypothesized that ghrelin modifies microvascular permeability. The purposes of this study were to determine (1) the effect of ghrelin on microvascular permeability, (2) the effect of ghrelin on microvascular permeability during lipopolysaccharide (LPS)-induced inflammation, (3) the involvement of the growth hormone secretagogue receptor (GHS-R1a) cell receptor, and (4) the involvement of nuclear factor kappa B (NF-kappaB). METHODS Hydraulic permeability (Lp), a measure of transendothelial fluid leak, was measured in rat mesenteric postcapillary venules. Lp was measured during continuous administration of (1) ghrelin (3 micromol/L), (2) ghrelin and systemic LPS (10 mg/kg), (3) the GHS-R1a receptor antagonist, (D-Arg1 D-Phe5 D-Trp7,9 Leu11)-substance P (9 micromol/L) plus ghrelin and LPS, and (4) an NF-kappaB inhibitor, parthenolide (10 micromol/L) plus ghrelin and LPS. RESULTS Ghrelin alone had no effect (p > 0.7). Compared with LPS alone, ghrelin plus LPS decreased Lp (Lp: ghrelin + LPS = 1.60 +/- 0.16 vs. LPS = 2.27 +/- 0.14, p < 0.006). The GHS-R1a ghrelin receptor antagonist blunted the effect of ghrelin by 86% during LPS-induced inflammation (Lp: ghrelin + LPS = 1.60 +/- 0.16 vs. ghrelin antagonist + ghrelin + LPS = 2.17 +/- 0.27, p < 0.018). NF-kappaB inhibition did not influence the initial increased microvascular leak effect of ghrelin (p > 0.8). CONCLUSIONS Although ghrelin has no effect on basal microvascular permeability, it has a biphasic effect with an overall decrease in microvascular permeability during LPS-induced inflammation through the GHS-R1a receptor, independent of NF-kappaB. Ghrelin is a key mediator of inflammation and may contribute to the increased morbidity and mortality in obese trauma patients.

Hepatic vascular malformation in a patient with Simpson-Golabi-Behmel syndrome.

Simpson et al. [1975], Behmel et al. [1984], and Golabi and Rosen [1984] described an X-linked syndrome, characterized by preand post-natal overgrowth anddysplastic changes in several tissues. Neri et al. [1988] suggested this condition be named Simpson–Golabi–Behmel syndrome (SGBS). SGBS patients have craniofacial abnormalities, abdominal, skeletal, and urologic malformations, and an increased incidence of embryonic neoplasia such as Wilms tumor, neuroblastoma, hepatoblastoma, and rhabdomyosarcoma [Hughes-Benzie et al., 1992]. We describe a 2-year-old boy with SGBS who presented with a hepatic lesion, which upon resection was found to be a vascular malformation. In addition to developing visceral solid malignancies, SGBS patients may also be at risk for developing vascular malformations. The patient was born at 40 4/7weeks to a 17-yearold primigravid mother who is a known carrier of SGBS and part of the family studied by Chen et al. [1993]. Multiple anomalies identified in utero included polyhydramniosis, fetal macrosomia, truncus arteriosus with ventricular septal defect, and renal pyelectasis. At birth the patient weighed 4.3 kg (93rd centile), was 52 cm long (75th centile) with a head circumference of 36 cm (55th centile). He had a broad, flat nasal bridge, macroglossia, bilateral renal cysts, distal phalangeal hypoplasia, and diastasis recti. He underwent repair of a type II truncus arteriosus, atrial septal aneurysm, and secundum atrial septal defect few days after birth. His karyotype was 46,XY. At age 1 year, magnetic resonance imaging was obtained to evaluate a potential tethered cord. This was not found, but a focal lesion in the right posterior liver was identified incidentally. The patient was followed closely clinically due to the concern for visceral tumors in this population, and follow-up computed tomography confirmed a vascular appearing mass (Fig. 1). Serum b-human chorionic gonadotropin and a-fetoprotein levels were normal. A tagged red blood cell nuclear scan was obtained, but the study did not show focal pooling in the liver consistent with a hemangioma or vascular malformation. Due to uncertainty of diagnosis, the mass was excised without complication. This was a 1.7 1.5 1.3 cm unencapsulated lesion composed of multiple variably sized vessels with