Intraoperative Radiation Therapy: A Large Integrated Health Care System's Approach and Outcomes.

Introduction Intraoperative radiation therapy (IORT) may not be as effective in the community compared with clinical trials. Methods The authors reviewed data from the electronic health records of patients who received IORT between February 2014 and February 2020 at a single center within a large integrated health care system. The primary outcome was ipsilateral breast tumor recurrence. Results Of 5731 potentially eligible patients, 245 (4.3%) underwent IORT (mean age: 65.4 ± 0.4 years; median follow-up time: 3.5 years ± 2.2 months). According to the American Society for Radiation Oncology's accelerated partial breast irradiation guidelines based on final pathology, 51% of patients were suitable candidates for IORT, 38.4% were cautionary, and 10.6% were unsuitable. For adjuvant therapy, 6.5% had consolidative whole breast irradiation, and 66.4% received endocrine treatment. At the median follow-up time of 3.5 years, overall ipsilateral breast tumor recurrence was 3.7%. Recurrences tended to be more frequent in patients who refused or did not complete endocrine treatment than in those who received it (7.4% vs 1.9%, p = 0.07). The complication rate was 14.7%, with seroma being the most common (8.2%). Discussion The IORT ipsilateral breast tumor recurrence rate of 3.7% confirms a higher-than-expected rate compared to randomized clinical trials, possibly due to less compliance with endocrine therapy. Conclusion The authors subsequently revised their IORT protocol to require endocrine treatment as a part of the IORT treatment plan and to strongly recommend adjuvant whole breast irradiation for all patients deemed cautionary or unsuitable for IORT according to the American Society for Radiation Oncology's accelerated partial breast irradiation guidelines.

Patients Older 65 Years With Early Breast Cancer Prefer Intraoperative Radiation as a Locoregional Treatment Choice.

BACKGROUND: Patients 65 years old or older with early endocrine-responsive breast cancer have many treatment options, including no radiation. This study aimed to evaluate treatment preference when intraoperative radiation therapy (IORT) is offered in this population. METHODS: The study reviewed patients 65 years old or older with a diagnosis of early-stage endocrine-responsive breast cancer in 2016-2019 at a single hospital in a large integrated health care system. Electronic medical records of multidisciplinary breast tumor board discussion, treatment options documented by the treatment team, and final treatment offered were reviewed. Variables including age at biopsy, language, endocrine treatment, and comorbidities were collected. Regression analysis was used to evaluate for variables associated with patients' choice regarding radiation treatment. RESULTS: The institutional IORT guidelines were met by 63 patients in the described age group who had a documented offer of all radiation treatment options. The median age of the patients was 70 years (interquartile range 63-77 years). Overall, 74.6% of the patients chose IORT, and 14.3% opted for whole-breast irradiation. Only 4.8% chose to omit radiation after breast-conserving surgery, and 6.3% chose mastectomy. The patients who chose IORT were more likely to receive endocrine treatment (odds ratio 3.70; p = 0.03). Age, race, language, and comorbidities were not associated with preference for IORT (p < 0.05). CONCLUSIONS: Patients 65 years old or older with early-stage endocrine-responsive breast cancer preferred to have IORT despite counsel about the lack of survival benefit. This study suggests that local cancer control with the convenient radiation delivery method is important to the described patient population.

Rapid Implementation of Intraoperative Ultrasonography to Reduce Wire Localization in The Permanente Medical Group.

CONTEXT: Preoperative wire localization (WL), the most common localization technique for nonpalpable breast lesions, has drawbacks including scheduling constraints, cost, and patient discomfort. OBJECTIVE: To reduce WL use in our health care system, we investigated using hydrogel clips to facilitate intraoperative ultrasonography-guided lumpectomies. DESIGN: We retrospectively reviewed electronic medical records of patients with nonpalpable, ultrasound-visible breast lesions who underwent lumpectomy by 7 surgeons at 4 pilot sites in Kaiser Permanente Northern California between January 2015 and October 2015. Hydrogel clips, used for several years before the study period, were placed routinely during core-needle biopsy in all patients with nonpalpable, ultrasound-visible breast lesions. MAIN OUTCOME MEASURES: Localization method, lesion size, margin positivity, and receipt of neoadjuvant therapy. RESULTS: One hundred forty-three patients underwent hydrogel clip placement and lumpectomy by pilot-site surgeons. Localization consisted of intraoperative ultrasonography alone, preoperative skin marking, or WL. Of the 143 patients, 71.3% did not need WL (60.8% ultrasonography alone and 10.5% skin marking). The non-WL and WL groups had similarly sized lesions, and the positive margin rate was 7.2% overall, with no significant difference between the non-WL and WL groups (5.9% vs 11.5%, p = 0.33). Of the 12 patients who underwent neoadjuvant chemotherapy, 8 (67%) did not require WL. CONCLUSION: A multifacility protocol using intraoperative ultrasonography to visualize hydrogel clips was implemented, which decreased WL procedures and produced no significant difference in margin positivity between the WL and non-WL groups. This technique can be a cost-effective alternative to WL in patients who are candidates for hydrogel clip placement.

Experience with a Nonopioid Protocol in Ambulatory Breast Surgery: Opioids are Rarely Necessary and Use is Surgeon-Dependent.

CONTEXT: Surgeons write 1.8% of all prescriptions and 9.8% of all opioid prescriptions. Even small doses prescribed for short-term use can lead to abuse; thus, surgeons are uniquely able to combat the opioid epidemic by changing prescribing practices. As part of a department wide quality improvement project, we initiated a nonopioid protocol for all patients undergoing ambulatory breast surgery. OBJECTIVE: To determine the feasibility of a nonopioid protocol for patients undergoing ambulatory breast surgery and to determine if patient-related factors contribute to surgeon adherence to a nonopioid protocol in ambulatory breast surgery. DESIGN: Retrospective chart review of a prospectively collected database, with χ2 analysis and a multiple logistic regression model with the surgeon as the random effect. MAIN OUTCOME MEASURE: Protocol adherence. RESULTS: A total of 180 patients, with a median age of 63 years (range = 18-95 years), were included. Of these, 127 (70.6%) did not receive opioids; in this group there were 2 hematomas (1.6%), and 3 patients required an opioid prescription (2.4%). Fifty-three (29.4%) were prescribed opioids against protocol; in this group, there was 1 hematoma (1.9%). The operating surgeon was the only variable independently correlated with protocol adherence (p < 0.0001). Age, race/ethnicity, surgery type, and history of long-term opioid use were not. CONCLUSION: Ambulatory breast surgery patients tolerated a nonopioid pain regimen well. Surgeons' decisions, rather than patient characteristics, primarily drove the choice of pain management in our study. We believe our protocol can be improved with stricter implementation and education, which must be balanced with practitioner independence.

Utility of Human Epidermal Growth Factor Receptor 2 (HER2) Retesting of Histologic Grade 3 Invasive Breast Carcinomas.

BACKGROUND: American Society of Clinical Oncology and College of American Pathologists guidelines recommend repeated evaluation of human epidermal growth factor receptor 2 (HER2) status on surgical specimens from patients with a diagnosis by core-needle biopsy of Grade 3, HER2-negative invasive tumors of the breast. However, there are limited data to support reflexive testing. OBJECTIVE: To evaluate the utility of HER2 retesting of histologic Grade 3, HER2-negative invasive breast carcinomas. METHODS: We evaluated 78 patients from Kaiser Permanente East Bay in whom Grade 3, HER2-negative invasive breast carcinoma was diagnosed between 2015 and 2017 by core biopsy, to compare HER2 status on core biopsy vs excisional biopsy specimen. The HER2 status was determined by immunohistochemistry, fluorescent in situ hybridization, or both. All patients were retested for HER2 status on surgical specimen according to the aforementioned guidelines. Recipients of neoadjuvant chemotherapy were excluded. RESULTS: One of the 78 patients demonstrated negative-to-positive status discordance between core biopsy and surgical specimens and was treated with trastuzumab. One patient was HER2 negative by core biopsy and was HER2 equivocal by immunohistochemical and fluorescent in situ hybridization evaluation of the surgical specimen. Seventy-six patients demonstrated concordant HER2 status between core biopsy and surgical specimens. CONCLUSION: The rate of clinically significant HER2 status discordance between core biopsy and surgical specimens in patients with Grade 3 breast carcinoma is low. However, given the dramatically improved survival conferred by trastuzumab therapy, our findings support reflex HER2 testing of surgical specimens for patients with core biopsy-diagnosed HER2-negative breast carcinoma.

Local recurrence rates are low in high-risk neoadjuvant breast cancer in the I-SPY 1 Trial (CALGB 150007/150012; ACRIN 6657).

BACKGROUND: Increasingly, women with stage 2 and 3 breast cancers receive neoadjuvant therapy, after which many are eligible for breast-conserving surgery (BCS). The question often arises as to whether BCS, if achievable, provides adequate local control. We report the results of local recurrence (LR) from the I-SPY 1 Trial in the setting of maximal multidisciplinary treatment where approximately 50 % of patients were treated with BCS. METHODS: We analyzed data from the I-SPY 1 Trial. Women with tumors ≥3 cm from nine clinical breast centers received neoadjuvant doxorubicin, cyclophosphamide and paclitaxel followed by definitive surgical therapy, and radiation at physician discretion. LR following mastectomy and BCS were analyzed in relation to clinical characteristics and response to therapy as measured by residual cancer burden. RESULTS: Of the 237 patients enrolled in the I-SPY 1 Trial, 206 were available for analysis. Median tumor size was 6.0 cm, and median follow-up was 3.9 years. Fourteen patients (7 %) had LR and 45 (22 %) had distant recurrence (DR). Of the 14 patients with LR, nine had synchronous DR; one had DR > 2 years later. Only four (2 % of evaluable patients) had LR alone. The rate of LR was low after mastectomy and after BCS, even in the setting of significant residual disease. CONCLUSIONS: Overall, these patients at high risk for early recurrence, treated with maximal multidisciplinary treatment, had low LR. Recurrence was associated with aggressive biological features such as more advanced stage at presentation, where LR occurs most frequently in the setting of DR.

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.

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.

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.

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.

Women rule.

Female animals tolerate trauma and hemorrhage better than male animals AND Estrogen has rapid nongenomic effects that protect organs from damage and attenuate insult-induced inflammation MOREOVER The survival deficit from trauma and hemorrhage produced in ovariectomized female animals is repaired with administration of exogenous estrogen AND Women survive injury, sepsis, and trauma-hemorrhage-induced hypoxemia/reperfusion better than men THEREFORE Women rule ... in survival after trauma, thus, men would benefit from being more like women.

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.

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 microM 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.

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.

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). Ucn1's 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.

Single-contrast computed tomography for the triage of patients with penetrating torso trauma.

BACKGROUND: We have used single-contrast (intravenous contrast only) computed tomography (SCCT) for triaging hemodynamically stable patients with penetrating torso trauma. We hypothesized that SCCT safely determines the need for operative exploration. Furthermore, trauma surgeons without specialized training in body imaging can accurately apply this modality. METHODS: We retrospectively reviewed the records of patients with penetrating torso injuries at a university-based urban trauma center to establish the accuracy of SCCT in determining the need for exploratory laparotomy. The scan was considered positive or negative with respect to the need for exploratory laparotomy as documented by the attending surgeon, who may have considered the read of the on call radiologist if available. In a separate study, four trauma surgeons independently reviewed 42 SCCT scans to establish whether the scans alone could be used to determine whether operative exploration was necessary. RESULTS: Between 1997 and 2008, 306 hemodynamically stable patients with penetrating torso trauma were triaged by SCCT. Overall, SCCT predicted the need for laparotomy with 98% sensitivity and 90% specificity. The positive predictive value was 84% and the negative predictive value (NPV) was 99%. In the 222 patients with gunshot wounds, SCCT had 100% sensitivity and 100% NPV. In the 84 patients with stab wounds, SCCT had 92% sensitivity and 97% NPV. Trauma surgeon agreement in the retrospective review of 42 computed tomography scans was "nearly perfect": positive predictive value was 93% and NPV was 92% for determining the need for exploratory laparotomy surgery. CONCLUSIONS: SCCT is safe and effective for triaging hemodynamically stable patients with penetrating torso trauma. It successfully determined the need for operative intervention with appropriate clinical accuracy without the additional costs, morbidity, and delay of oral and rectal contrast. Trauma surgeons can reproducibly interpret SCCT with high-predictive accuracy as to whether patients with penetrating torso trauma require operative exploration.

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 Fisher's 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.

Lipoxin a(4) 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.

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.