Kristopher C. Dozier

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.

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.

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.

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.

Vascular clamp stabilization of pylorus during laparoscopic pyloromyotomy

We describe a technique of grasping the pylorus during laparoscopic pyloromyotomy using a percutaneously inserted vascular clamp. The use of the vascular clamp results in better visualization and stabilization during laparoscopic pyloromyotomy.

Endothelin 1 and prostacyclin attenuate increases in hydraulic permeability caused by platelet-activating factor in rats.

We have previously documented that endothelin 1 (ET-1) and prostacyclin (PGI2) decrease basal state hydraulic permeability (Lp). The aim of this study was to investigate the ability of ET-1 and PGI2 to modulate transendothelial fluid flux during situations in which Lp was artificially elevated with platelet-activating factor (PAF). We hypothesized that ET-1 and PGI2 administration before PAF exposure would prevent the increase in Lp secondary to PAF. In addition, in a potentially more clinically relevant situation, we also hypothesized that ET-1 and PGI2 administration after PAF exposure would attenuate the increase in Lp secondary to PAF. Microvascular Lp was measured in rat mesenteric postcapillary venules. Exposure to 10 nM PAF increased Lp 4-fold (P < 0.001). If the administration of 80 pM ET-1 or 10 &mgr;M PGI2 was completed before PAF exposure, no PAF-associated increase in Lp was observed (P < 0.001). The administration of ET-1 or PGI2 after PAF exposure attenuated the peak increase in Lp caused by PAF alone by 55% and 57%, respectively (P < 0.001). We conclude that ET-1 and PGI2 administration before PAF exposure prevents PAF-induced elevations in Lp, and in a more clinically relevant situation, ET-1 and PGI2 administered after PAF exposure attenuate the PAF-induced increase in Lp. Endothelin 1 and PGI2 receptors may provide important therapeutic targets for decreasing the microvascular fluid leak-associated morbidity resulting from shock and sepsis.

Despite the Increasing Use of Nonoperative Management of Firearm Trauma, Shotgun Injuries Still Require Aggressive Operative Management

BACKGROUND The energy dissipation between gunshot and shotgun blasts is very different. Injuries from shotgun blasts vary depending on the distance of the victim from the shooter, the choke of the shotgun, the pellet load, and the wad of the ammunition. We postulated that gunshot and shotgun blasts create different injury patterns that dictate different treatment plans. METHODS Medical records of patients with gunshot and shotgun trauma were reviewed from 1998 through 2007 at our university-based trauma center. Statistical comparisons were made via Fishers test or t-test calculations. RESULTS We evaluated 2833 patients injured by firearms; of these 61 had shotgun wounds (2.2%). The remainder sustained gunshot wounds. Mortality between shotgun and gunshot trauma patients was similar (7% versus 9%, respectively, P=0.8). There was no difference in the mean Injury Severity Score (ISS) (13.7+/-1.6 versus 12.9+/-0.2; P=0.6). Overall, 61% of patients underwent operative intervention after shotgun injuries versus 36% of patients with gunshot wounds (P<0.0001). Patients surviving shotgun injuries had a longer length of stay (10.1+/-2.0 d versus 5.9+/-0.21, P<0.05). CONCLUSIONS Although the injury severity was similar, injuries from shotguns required more operations and resource utilization. Shotgun blasts can create impressive superficial injuries as well as significant deep organ damage. An aggressive operative approach to managing shotgun trauma is advantageous.

Endothelin-1 attenuates increases in hydraulic conductivity due to platelet-activating factor via prostacyclin release

We previously showed that endothelin-1 (ET-1) and prostacyclin (PGI(2)) similarly attenuate increases in microvascular permeability induced by platelet-activating factor (PAF). This led us to hypothesize that ET-1 attenuates trans-endothelial fluid flux during PAF through PGI(2) release. We tested this hypothesis in three phases. First, bovine pulmonary artery endothelial cells were exposed to 0.008-8 μM ET-1 and assayed for PGI(2) release. Second, to determine whether increased transmonolayer flux after PAF could be attenuated by ET-1 or PGI(2) and reversed by PGI(2) synthesis inhibition or PGI(2) receptor blockade, we measured endothelial cell transmonolayer flux after cells were exposed to 10 nM PAF plus 10 μM PGI(2) or 80 pM ET-1, with or without 500 μM tranylcypromine (PGI(2) synthase inhibitor) or 20 μM CAY-10441 (PGI(2) receptor blocker). Finally, hydraulic conductivity (L(p)) was measured in rat mesenteric venules in vivo after exposure to 10 nM PAF and 80 pM ET-1 with or without tranylcypromine (100 and 500 μM) or CAY-10441 (2 and 20 μM). We found that in vitro, ET-1 stimulated a dose-dependent increase in PGI(2) production (from 126 to 217 pg/ml, P < 0.01). Compared with PAF alone, PGI(2) plus PAF and ET-1 plus PAF decreased transmonolayer flux similarly by 52 and 46%, respectively (P < 0.01), while tranylcypromine and CAY-10441 reversed these effects by 92 and 47%, respectively (P < 0.05). In vivo, PAF increased L(p) fourfold (P < 0.01) and ET-1 attenuated this effect by 83% (P < 0.01). Tranylcypromine and CAY-10441 reversed the ET-1 attenuation in L(p) during PAF by 55 and 45%, respectively (P < 0.01). We conclude that ET-1 may stimulate endothelial cell PGI(2) release to attenuate the increases in transmonolayer flux and hydraulic conductivity secondary to PAF.