Community Social Paediatrics Approach, an Innovative Healthcare Intervention: Implementation Fidelity in Atlantic Canada.

The Community Social Paediatrics approach (CSPA) is a comprehensive and personalized approach to care that is becoming more widely used throughout Canada. However, data on its implementation fidelity remain scarce. The purpose of this research was to assess the implementation fidelity of a CSPA established in 2017 in Canada. Data were collected through focus group interviews with the CSPA team using an implementation fidelity grid based on the Dr. Julien Foundation standard accreditation criteria. Results showed that on one hand, administrative and financial management and governance were among those domains with lower ratings. On the other hand, assessment/orientation and follow-up/support had high levels of fidelity of implementation. This research helps to better understand which factors are contributing to varying levels of fidelity of implementation. To reach an increased level of fidelity of implementation, it is recommended that adequate resources be in place.

Transforming child and youth mental health care: ACCESS Open Minds New Brunswick in the rural Francophone region of the Acadian Peninsula.

AIM: This paper describes how the transformation of youth mental health services in the rural Francophone region of the Acadian Peninsula in New Brunswick, Canada, is meeting the five objectives of ACCESS Open Minds. METHODS: Implementation of the ACCESS Open Minds framework of care in the Acadian Peninsula of New Brunswick began in 2016 at a well-established volunteer centre and community-based mental health organization. Through focus groups with youth aged 14 to 22 (n = 13), community mapping was used to describe the youth-related mental health service transformation, followed by thematic analysis, validation by member checking and triangulation. RESULTS: Preliminary results show a generally successful implementation of the ACCESS Open Minds model, as evidenced by the transformation of mental health service provision, the enhancement of capacity in human resources and the participation of youth. Transformation was evidenced across the five objectives of mental healthcare of ACCESS Open Minds, albeit to variable extents. Several facilitating factors and challenges are identified based on youths' accounts. CONCLUSIONS: It is possible to successfully implement the ACCESS Open Minds model among francophones living in a minority setting and despite the constraints of a rural area. Most key components of the framework were implemented with high program fidelity. The rural context presents unique challenges that require creative and effective use of resources, while offering opportunities that arise from a culture of resourcefulness and collaboration.

A physician-led initiative to improve clinical documentation results in improved health care documentation, case mix index, and increased contribution margin.

INTRODUCTION: Clinical documentation is the key determinant of inpatient acuity of illness and payer reimbursement. Every inpatient hospitalization is placed into a diagnosis related group with a relative value based on documented procedures, conditions, comorbidities and complications. The Case Mix Index (CMI) is an average of these diagnosis related groups and directly impacts physician profiling, medical center profiling, reimbursement, and quality reporting. We hypothesize that a focused, physician-led initiative to improve clinical documentation of vascular surgery inpatients results in increased CMI and contribution margin. METHODS: A physician-led coding initiative to educate physicians on the documentation of comorbidities and conditions was initiated with concurrent chart review sessions with coding specialists for 3 months, and then as needed, after the creation of a vascular surgery documentation guide. Clinical documentation and billing for all carotid endarterectomy (CEA) and open infrainguinal procedures (OIPs) performed between January 2013 and July 2016 were stratified into precoding and postcoding initiative groups. Age, duration of stay, direct costs, actual reimbursements, contribution margin (CM), CMI, rate of complication or comorbidity, major complication or comorbidity, severity of illness, and risk of mortality assigned to each discharge were abstracted. Data were compared over time by standardizing Centers for Medicare and Medicaid Services (CMS) values for each diagnosis related group and using a CMS base rate reimbursement. RESULTS: Among 458 CEA admissions, postcoding initiative CEA patients (n = 253) had a significantly higher CMI (1.36 vs 1.25; P = .03), CM ($7859 vs $6650; P = .048), and CMS base rate reimbursement ($8955 vs $8258; P = .03) than precoding initiative CEA patients (n = 205). The proportion of admissions with a documented major complication or comorbidity and complication or comorbidity was significantly higher after the coding initiative (43% vs 27%; P < .01). Among 504 OIPs, postcoding initiative patients (n = 227) had a significantly higher CMI (2.23 vs 2.05; P < .01), actual reimbursement ($23,203 vs $19,909; P < .01), CM ($12,165 vs $8840; P < .01), and CMS base rate reimbursement ($14,649 vs $13,496; P < .01) than precoding initiative patients (n = 277). The proportion of admissions with a documented major complication or comorbidity and complication or comorbidity was significantly higher after the coding initiative (61% vs 43%; P < .01). For both CEA and OIPs, there were no differences in age, duration of stay, total direct costs, or primary insurance status between the precoding and postcoding patient groups. CONCLUSIONS: Accurate and detailed clinical documentation is required for key stakeholders to characterize the acuity of inpatient admissions and ensure appropriate reimbursement; it is also a key component of risk-adjustment methods for assessing quality of care. A physician-led documentation initiative significantly increased CMI and CM.

Increasing the number of integrated vascular surgery residency positions is important to address the impending shortage of vascular surgeons in the United States.

OBJECTIVE: The demand for vascular surgeons is expected to far exceed the current supply. In an attempt to decrease the training duration and to address the impending shortage, integrated vascular surgery residencies were approved and have expanded nationally. Meanwhile, vascular fellowships have continued to matriculate approximately 120 trainees annually. We sought to evaluate the supply and demand for integrated vascular residency positions as well as changes in the quality of applicants. METHODS: We conducted a retrospective review of national data compiled by the Association of American Medical Colleges and the National Resident Matching Program regarding integrated vascular surgery residency programs (2008-2015) and fellowships (2007-2016). Variables reviewed included the total number of applicants, sex, U.S. vs international medical school enrollment, applications per program, and applicants per position. In addition, we conducted a retrospective review of applicants to the University of Massachusetts Medical School integrated vascular surgery residency program from 2008 to 2015 to examine these variables and United States Medical Licensing Examination Step 1 and Step 2 CK scores over time. RESULTS: The number of vascular surgery integrated residency positions increased from 4 in 2008 to 56 in 2015. Concurrently, the number of integrated residency applicants grew from 112 in 2008 to 434 in 2015. This increase has been predominantly driven by a 575% increase in U.S. graduate applicants and a 170% increase in women applicants. The percentage of international medical graduates has decreased by 17% during the study period. The total number of applicants per residency position increased from 5.9 to 7.8. Meanwhile, the number of vascular surgery fellowship positions remained stable with an applicant to position ratio near 1:1. At the University of Massachusetts Medical School, the mean United States Medical Licensing Examination Step 1 (226 to 235) and Step 2 CK (237 to 243) scores among integrated residency applicants have improved annually and typically exceed the national average among U.S. applicants who have matched in their preferred specialty. CONCLUSIONS: Since the approval of a primary certificate in vascular surgery and the subsequent rollout of integrated vascular residency programs, the number of residency programs and the quality of residency applicants have continued to increase. Demand from medical school applicants vastly outweighs the current supply of training positions by eightfold. In contrast, demand from fellowship applicants matches the supply of fellowship positions. The matriculation of additional trainees must be met with continued expansion of the integrated vascular surgery residency pathway to manage future public health needs.

Surgeon leadership in the coding, billing, and contractual negotiations for fenestrated endovascular aortic aneurysm repair increases medical center contribution margin and physician reimbursement.

BACKGROUND: Fenestrated endovascular aneurysm repair (FEVAR) allows endovascular treatment of thoracoabdominal and juxtarenal aneurysms previously outside the indications of use for standard devices. However, because of considerable device costs and increased procedure time, FEVAR is thought to result in financial losses for medical centers and physicians. We hypothesized that surgeon leadership in the coding, billing, and contractual negotiations for FEVAR procedures will increase medical center contribution margin (CM) and physician reimbursement. METHODS: At the UMass Memorial Center for Complex Aortic Disease, a vascular surgeon with experience in medical finances is supported to manage the billing and coding of FEVAR procedures for medical center and physician reimbursement. A comprehensive financial analysis was performed for all FEVAR procedures (2011-2015), independent of insurance status, patient presentation, or type of device used. Medical center CM (actual reimbursement minus direct costs) was determined for each index FEVAR procedure and for all related subsequent procedures, inpatient or outpatient, 3 months before and 1 year subsequent to the index FEVAR procedure. Medical center CM for outpatient clinic visits, radiology examinations, vascular laboratory studies, and cardiology and pulmonary evaluations related to FEVAR were also determined. Surgeon reimbursement for index FEVAR procedure, related adjunct procedures, and assistant surgeon reimbursement were also calculated. All financial analyses were performed and adjudicated by the UMass Department of Finance. RESULTS: The index hospitalization for 63 FEVAR procedures incurred $2,776,726 of direct costs and generated $3,027,887 in reimbursement, resulting in a positive CM of $251,160. Subsequent related hospital procedures (n = 26) generated a CM of $144,473. Outpatient clinic visits, radiologic examinations, and vascular laboratory studies generated an additional CM of $96,888. Direct cost analysis revealed that grafts accounted for the largest proportion of costs (55%), followed by supplies (12%), bed (12%), and operating room (10%). Total medical center CM for all FEVAR services was $492,521. Average surgeon reimbursements per FEVAR from 2011 to 2015 increased from $1601 to $2480 while the surgeon payment denial rate declined from 50% to 0%. Surgeon-led negotiations with the Centers for Medicare & Medicaid Services during 2015 resulted in a 27% increase in physician reimbursement for the remainder of 2015 ($2480 vs $3068/case) and a 91% increase in reimbursement from 2011 ($1601 vs $3068). Assistant surgeon reimbursement also increased ($266 vs $764). Concomitant FEVAR-related procedures generated an additional $27,347 in surgeon reimbursement. CONCLUSIONS: Physician leadership in the coding, billing, and contractual negotiations for FEVAR results in a positive medical center CM and increased physician reimbursement.

Outcomes of fenestrated and branched endovascular repair of complex abdominal and thoracoabdominal aortic aneurysms.

BACKGROUND: More than 80% of infrarenal aortic aneurysms are treated by endovascular repair. However, adoption of fenestrated and branched endovascular repair for complex aortic aneurysms has been limited, despite high morbidity and mortality associated with open repair. There are few published reports of consecutive outcomes, inclusive of all fenestrated and branched endovascular repairs, starting from the inception of a complex aortic aneurysm program. Therefore, we examined a single center's consecutive experience of fenestrated and branched endovascular repair of complex aortic aneurysms. METHODS: This is a single-center, prospective, observational cohort study evaluating 30-day and 1-year outcomes in all consecutive patients who underwent fenestrated and branched endovascular repair of complex aortic aneurysms (definition: requiring one or more fenestrations or branches). Data were collected prospectively through an Institutional Review Board-approved registry and a physician-sponsored investigational device exemption clinical trial (G130210). RESULTS: We performed 100 consecutive complex endovascular aortic aneurysm repairs (November 2010 to March 2016) using 58 (58%) commercially manufactured custom-made devices and 42 (42%) physician-modified devices to treat 4 (4%) common iliac, 42 (42%) juxtarenal, 18 (18%) pararenal, and 36 (36%) thoracoabdominal aneurysms (type I, n = 1; type II, n = 4; type III, n = 12; type IV, n = 18; arch, n = 1). The repairs included 309 fenestrations, branches, and scallops (average of 3.1 branch arteries/case). All patients had 30-day follow-up for 30-day event rates: three (3%) deaths; six (6%) target artery occlusions; five (5%) progressions to dialysis; eight (8%) access complications; one (1%) paraparesis; one (1%) bowel ischemia; and no instances of myocardial infarction, paralysis, or stroke. Of 10 type I or type III endoleaks, 8 resolved (7 with secondary intervention, 1 without intervention). Mean follow-up time was 563 days (interquartile range, 156-862), with three (3%) patients lost to follow-up. On 1-year Kaplan-Meier analysis, survival was 87%, freedom from type I or type III endoleak was 97%, target vessel patency was 92%, and freedom from aortic rupture was 100%. Average lengths of intensive care unit stay and inpatient stay were 1.4 days (standard deviation, 3.3) and 3.6 days (standard deviation, 3.6), respectively. CONCLUSIONS: These results show that complex aortic aneurysms can now be treated with minimally invasive fenestrated and branched endovascular repair. Endovascular technologies will likely continue to play an increasingly important role in the management of patients with complex aortic aneurysm disease.

An intensive vascular surgical skills and simulation course for vascular trainees improves procedural knowledge and self-rated procedural competence.

BACKGROUND: Surgical skills and simulation courses are emerging to meet the demand for vascular simulation training for vascular surgical skills, but their educational effect has not yet been described. We sought to determine the effect of an intensive vascular surgical skills and simulation course on the procedural knowledge and self-rated procedural competence of vascular trainees and to assess participant feedback regarding the course. METHODS: Participants underwent a 1.5-day course covering open and endovascular procedures on high-fidelity simulators and cadavers. Before and after the course, participants completed a written test that assessed procedural knowledge concerning index open vascular and endovascular procedures. Participants also assessed their own procedural competence in open and endovascular procedures on a 5-point Likert scale (1: no ability to perform, 5: performs independently). Scores before and after the course were compared among postgraduate year (PGY) 1-2 and PGY 3-7 trainees. Participants completed a survey to rate the relevance and realism of open and endovascular simulations. RESULTS: Fifty-eight vascular integrated residents and vascular fellows (PGY 1-7) completed the course and all assessments. After course participation, procedural knowledge scores were significantly improved among PGY 1-2 residents (50% correct before vs 59% after; P < .0001) and PGY 3-7 residents (52% correct before vs 63% after; P = .003). Self-rated procedural competence was significantly improved among PGY 1-2 (2.2 ± 0.1 before vs 3.1 ± 0.1 after; P < .0001) and PGY 3-7 (3.0 ± 0.1 before vs 3.7 ± 0.1 after; P ≤ .0001). Self-rated procedural competence significantly improved for both endovascular (2.4 ± 0.1 before vs 3.3 ± 0.1 after; P < .0001) and open procedures (2.7 ± 0.1 before vs 3.5 ± 0.1 after; P < .0001). More than 93% of participants reported they were "satisfied" or "very satisfied" with the relevance and realism of the open and endovascular simulations. All participants reported they would recommend the course to other trainees. CONCLUSIONS: This intensive vascular surgical skills and simulation course improved procedural knowledge concerning index open vascular and endovascular procedures among PGY 1-2 and PGY 3-7 trainees. The course also improved self-rated procedural competence across all levels of training for open and endovascular procedures. Trainees rated the value of a surgical skills and simulation course highly. These results support strong consideration for the implementation of similar intensive simulation and surgical skills courses with ongoing objective assessment of their educational effect.

A multidisciplinary approach to vascular surgery procedure coding improves coding accuracy, work relative value unit assignment, and reimbursement.

BACKGROUND: Vascular surgery procedural reimbursement depends on accurate procedural coding and documentation. Despite the critical importance of correct coding, there has been a paucity of research focused on the effect of direct physician involvement. We hypothesize that direct physician involvement in procedural coding will lead to improved coding accuracy, increased work relative value unit (wRVU) assignment, and increased physician reimbursement. METHODS: This prospective observational cohort study evaluated procedural coding accuracy of fistulograms at an academic medical institution (January-June 2014). All fistulograms were coded by institutional coders (traditional coding) and by a single vascular surgeon whose codes were verified by two institution coders (multidisciplinary coding). The coding methods were compared, and differences were translated into revenue and wRVUs using the Medicare Physician Fee Schedule. Comparison between traditional and multidisciplinary coding was performed for three discrete study periods: baseline (period 1), after a coding education session for physicians and coders (period 2), and after a coding education session with implementation of an operative dictation template (period 3). The accuracy of surgeon operative dictations during each study period was also assessed. An external validation at a second academic institution was performed during period 1 to assess and compare coding accuracy. RESULTS: During period 1, traditional coding resulted in a 4.4% (P = .004) loss in reimbursement and a 5.4% (P = .01) loss in wRVUs compared with multidisciplinary coding. During period 2, no significant difference was found between traditional and multidisciplinary coding in reimbursement (1.3% loss; P = .24) or wRVUs (1.8% loss; P = .20). During period 3, traditional coding yielded a higher overall reimbursement (1.3% gain; P = .26) than multidisciplinary coding. This increase, however, was due to errors by institution coders, with six inappropriately used codes resulting in a higher overall reimbursement that was subsequently corrected. Assessment of physician documentation showed improvement, with decreased documentation errors at each period (11% vs 3.1% vs 0.6%; P = .02). Overall, between period 1 and period 3, multidisciplinary coding resulted in a significant increase in additional reimbursement ($17.63 per procedure; P = .004) and wRVUs (0.50 per procedure; P = .01). External validation at a second academic institution was performed to assess coding accuracy during period 1. Similar to institution 1, traditional coding revealed an 11% loss in reimbursement ($13,178 vs $14,630; P = .007) and a 12% loss in wRVU (293 vs 329; P = .01) compared with multidisciplinary coding. CONCLUSIONS: Physician involvement in the coding of endovascular procedures leads to improved procedural coding accuracy, increased wRVU assignments, and increased physician reimbursement.

Endovascular repair of ruptured abdominal aortic aneurysms does not reduce later mortality compared with open repair.

OBJECTIVE: Endovascular aneurysm repair (EVAR) of ruptured abdominal aortic aneurysms (RAAAs) reduces in-hospital mortality compared with open repair (OR), but it is unknown whether EVAR reduces long-term mortality. We hypothesized that EVAR of RAAA would independently reduce long-term mortality compared with OR. METHODS: The Vascular Quality Initiative database (2003-2013) was used to determine Kaplan-Meier 1-year and 5-year mortality after EVAR and OR of RAAA. Multivariate analysis was performed to identify patient and operative characteristics associated with mortality at 1 year and 5 years after RAAA repair. RESULTS: Among 590 patients who underwent EVAR and 692 patients who underwent OR of RAAA, the lower mortality seen in the hospital after EVAR (EVAR 23% vs OR 35%; P < .001) persisted at 1 year (EVAR 34% vs OR 42%; P = .001) and 5 years (EVAR 50% vs OR 58%; P = .003) after repair. After adjusting for patient and operative characteristics, EVAR did not independently reduce mortality at 1 year (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.7-1.1) or 5 years (HR, 0.95; 95% CI, 0.77-1.2) compared with OR. Dialysis dependence (HR, 3.9; 95% CI, 1.8-8.6), home oxygen use (HR, 1.9; 95% CI, 1.3-2.7), cardiac ejection fraction <50% (HR, 1.5; 95% CI, 1.03-2.1), female gender (HR, 1.3; 95% CI, 1.04-1.6), and age (HR, 1.06; 95% CI, 1.05-1.08 per 5 years) as well as cardiac arrest (HR, 3.4; 95% CI, 2.5-4.5), loss of consciousness (HR, 1.7; 95% CI, 1.3-2.2), and preoperative systolic blood pressure <90 mm Hg (HR, 1.4; 95% CI, 1.1-1.8) on admission predicted mortality at 1 year and 5 years after RAAA repair. Type I endoleak (HR, 2.2; 95% CI, 1.2-3.8) also predicted mortality at 1 year. CONCLUSIONS: EVAR does not independently reduce long-term mortality compared with OR. Patient comorbidities and indices of shock on admission are the primary independent determinants of long-term mortality. However, the lower early mortality observed in the Vascular Quality Initiative for patients selected to undergo EVAR of RAAA compared with patients selected for OR is sustained over time, suggesting that EVAR for RAAA is beneficial in appropriate candidates. Better elucidation of the key selection factors, including aneurysm anatomy, is needed to best select patients for EVAR and OR to reduce long-term mortality.

In patients stratified by preoperative risk, endovascular repair of ruptured abdominal aortic aneurysms has a lower in-hospital mortality and morbidity than open repair.

OBJECTIVE: Previous studies have reported that endovascular repair (EVAR) of ruptured abdominal aortic aneurysms (RAAAs) has lower postoperative mortality than open repair (OR). However, comparisons involved heterogeneous populations that lacked adjustment for preoperative risk. We hypothesize that for RAAA patients stratified by a validated measure of preoperative mortality risk, EVAR has a lower in-hospital mortality and morbidity than does OR. METHODS: In-hospital mortality and morbidity after EVAR and OR of RAAA were compared in patients from the Vascular Quality Initiative (2003-2013) stratified by the validated Vascular Study Group of New England RAAA risk score into low-risk (score 0-1), medium-risk (score 2-3), and high-risk (score 4-6) groups. RESULTS: Among 514 patients who underwent EVAR and 651 patients who underwent OR of RAAA, EVAR had lower in-hospital mortality (25% vs 33%, P = .001). In risk-stratified patients, EVAR trended toward a lower mortality in the low-risk group (n = 626; EVAR, 10% vs OR, 15%; P = .07), had a significantly lower mortality in the medium-risk group (n = 457; EVAR, 37% vs OR, 48%; P = .02), and no advantage in the high-risk group (n = 82; EVAR, 95% vs OR, 79%; P = .17). Across all risk groups, cardiac complications (EVAR, 29% vs OR, 38%; P = .001), respiratory complications (EVAR, 28% vs OR, 46%; P < .0001), renal insufficiency (EVAR, 24% vs OR, 38%; P < .0001), lower extremity ischemia (EVAR, 2.7% vs OR, 8.1%; P < .0001), and bowel ischemia (EVAR, 3.9% vs OR, 10%; P < .0001) were significantly lower after EVAR than after OR. Across all risk groups, median (interquartile range) intensive care unit length of stay (EVAR, 2 [1-5] days vs OR, 6 [3-13] days; P < .0001) and hospital length of stay (EVAR, 6 [4-12] days vs OR, 13 [8-22] days; P < .0001) were lower after EVAR. CONCLUSIONS: This novel risk-stratified comparison using a national clinical database showed that EVAR of RAAA has a lower mortality and morbidity compared with OR in low-risk and medium-risk patients and that EVAR should be used to treat these patients when anatomically feasible. For RAAA patients at the highest preoperative risk, there is no benefit to using EVAR compared with OR.

Systemic inflammatory response does not correlate with acute lung injury associated with mechanical ventilation strategies in normal lungs.

BACKGROUND: Mechanical ventilation (MV) can lead to ventilator-induced lung injury secondary to trauma and associated increases in pulmonary inflammatory cytokines. There is controversy regarding the associated systemic inflammatory response. In this report, we demonstrate the effects of MV on systemic inflammation. METHODS: This report is part of a previously published study (Hong et al. Anesth Analg 2010;110:1652-60). Female pigs were randomized into 3 groups. Group H-Vt/3 was ventilated with a tidal volume (Vt) of 15 mL/kg predicted body weight (PBW)/positive end-expiratory pressure (PEEP) of 3 cm H(2)O; group L-Vt/3 with a Vt of 6 mL/kg PBW/PEEP of 3 cm H2O; and group L-Vt/10 with a Vt of 6 mL/kg PBW/PEEP of 10 cm H(2)O, for 8 hours. Each group had 6 subjects (n = 6). Prelung and postlung sera were analyzed for inflammatory markers. Hemodynamics, airway mechanics, and arterial blood gases were monitored. RESULTS: There were no significant differences in systemic cytokines among groups. There were similar trends of serum inflammatory markers in all subjects. This is in contrast to findings previously published demonstrating increases in inflammatory mediators in bronchoalveolar lavage. CONCLUSION: Systemic inflammatory markers did not correlate with lung injury associated with MV.

Trauma hemorrhagic shock-induced lung injury involves a gut-lymph-induced TLR4 pathway in mice.

BACKGROUND: Injurious non-microbial factors released from the stressed gut during shocked states contribute to the development of acute lung injury (ALI) and multiple organ dysfunction syndrome (MODS). Since Toll-like receptors (TLR) act as sensors of tissue injury as well as microbial invasion and TLR4 signaling occurs in both sepsis and noninfectious models of ischemia/reperfusion (I/R) injury, we hypothesized that factors in the intestinal mesenteric lymph after trauma hemorrhagic shock (T/HS) mediate gut-induced lung injury via TLR4 activation. METHODS/PRINCIPAL FINDINGS: The concept that factors in T/HS lymph exiting the gut recreates ALI is evidenced by our findings that the infusion of porcine lymph, collected from animals subjected to global T/HS injury, into naïve wildtype (WT) mice induced lung injury. Using C3H/HeJ mice that harbor a TLR4 mutation, we found that TLR4 activation was necessary for the development of T/HS porcine lymph-induced lung injury as determined by Evan's blue dye (EBD) lung permeability and myeloperoxidase (MPO) levels as well as the induction of the injurious pulmonary iNOS response. TRIF and Myd88 deficiency fully and partially attenuated T/HS lymph-induced increases in lung permeability respectively. Additional studies in TLR2 deficient mice showed that TLR2 activation was not involved in the pathology of T/HS lymph-induced lung injury. Lastly, the lymph samples were devoid of bacteria, endotoxin and bacterial DNA and passage of lymph through an endotoxin removal column did not abrogate the ability of T/HS lymph to cause lung injury in naïve mice. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that non-microbial factors in the intestinal mesenteric lymph after T/HS are capable of recreating T/HS-induced lung injury via TLR4 activation.

The anatomic sites of disruption of the mucus layer directly correlate with areas of trauma/hemorrhagic shock-induced gut injury.

BACKGROUND: The intestinal mucus layer is an important but understudied component of the intestinal barrier. Consequently, we tested the hypothesis that the anatomic sites of loss of the mucus layer would directly correlate with sites of intestinal villous injury after trauma-hemorrhagic shock (T/HS) and may, therefore, serve as loci of gut barrier failure. Consequently, to investigate this hypothesis, we used Carnoy's fixative solution to prepare fixed tissue blocks where both the gut morphology and the mucus layer could be assessed on the same tissues slides. METHODS: Male Sprague-Dawley rats were subjected to a laparotomy (trauma) and 90 minutes of sham shock (T/SS) or 35 mm Hg × 90 minutes of actual shock (T/HS). Three hours after resuscitation, the rats were killed, and samples of the terminal ileum were processed by fixation in Carnoy's solution. Gut injury was evaluated by determining the percentage of villi injured. The status of the intestinal mucus layer was quantified by determining the percentage of the villi covered by the mucus and the mucus thickness. RESULTS: Histologic analysis of gut injury showed that the incidence of gut injury was ∼10-fold higher in the T/HS than the T/SS rats (T/SS=2.5% ± 0.5% vs. T/HS=22.4% ± 0.5% of injured villi; p<0.01). The T/SS rats had 98% of their ileal mucosa covered with a mucus layer, and this was decreased after T/HS to 63% ± 3% (T/HS vs. T/SS; p<0.001). Furthermore, loss of the mucus layer was found to directly correlate with villous injury with a regression coefficient of r=0.94 (p<0.001). CONCLUSION: This study shows that T/HS significantly reduces the intestinal mucus layer and causes villous injury and that a correlation exists between specific anatomic sites of T/HS-induced loss of the mucus layer and gut injury.

HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury.

Acute lung injury (ALI) and the development of the multiple organ dysfunction syndrome (MODS) are major causes of death in trauma patients. Gut inflammation and loss of gut barrier function as a consequence of splanchnic ischemia-reperfusion (I/R) have been implicated as the initial triggering events that contribute to the development of the systemic inflammatory response, ALI, and MODS. Since hypoxia-inducible factor (HIF-1) is a key regulator of the physiological and pathophysiological response to hypoxia, we asked whether HIF-1 plays a proximal role in the induction of gut injury and subsequent lung injury. Utilizing partially HIF-1α-deficient mice in a global trauma hemorrhagic shock (T/HS) model, we found that HIF-1 activation was necessary for the development of gut injury and that the prevention of gut injury was associated with an abrogation of lung injury. Specifically, in vivo studies demonstrated that partial HIF-1α deficiency ameliorated T/HS-induced increases in intestinal permeability, bacterial translocation, and caspase-3 activation. Lastly, partial HIF-1α deficiency reduced TNF-α, IL-1ß, cyclooxygenase-2, and inducible nitric oxide synthase levels in the ileal mucosa after T/HS whereas IL-1ß mRNA levels were reduced in the lung after T/HS. This study indicates that prolonged intestinal HIF-1 activation is a proximal regulator of I/R-induced gut mucosal injury and gut-induced lung injury. Consequently, these results provide unique information on the initiating events in trauma-hemorrhagic shock-induced ALI and MODS as well as potential therapeutic insights.

Estrogen receptor hormone agonists limit trauma hemorrhage shock-induced gut and lung injury in rats.

BACKGROUND: Acute lung injury (ALI) and the development of the multiple organ dysfunction syndrome (MODS) is a major cause of death in trauma patients. Earlier studies in trauma hemorrhagic shock (T/HS) have documented that splanchnic ischemia leading to gut inflammation and loss of barrier function is an initial triggering event that leads to gut-induced ARDS and MODS. Since sex hormones have been shown to modulate the response to T/HS and proestrous (PE) females are more resistant to T/HS-induced gut and distant organ injury, the goal of our study was to determine the contribution of estrogen receptor (ER)alpha and ERbeta in modulating the protective response of female rats to T/HS-induced gut and lung injury. METHODS/PRINCIPAL FINDINGS: The incidence of gut and lung injury was assessed in PE and ovariectomized (OVX) female rats subjected to T/HS or trauma sham shock (T/SS) as well as OVX rats that were administered estradiol (E2) or agonists for ERalpha or ERbeta immediately prior to resuscitation. Marked gut and lung injury was observed in OVX rats subjected to T/HS as compared to PE rats or E2-treated OVX rats subjected to T/HS. Both ERalpha and ERbeta agonists were equally effective in limiting T/HS-induced morphologic villous injury and bacterial translocation, whereas the ERbeta agonist was more effective than the ERalpha agonist in limiting T/HS-induced lung injury as determined by histology, Evan's blue lung permeability, bronchoalevolar fluid/plasma protein ratio and myeloperoxidase levels. Similarly, treatment with either E2 or the ERbeta agonist attenuated the induction of the intestinal iNOS response in OVX rats subjected to T/HS whereas the ERalpha agonist was only partially protective. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates that estrogen attenuates T/HS-induced gut and lung injury and that its protective effects are mediated by the activation of ERalpha, ERbeta or both receptors.

Estrogenic hormone modulation abrogates changes in red blood cell deformability and neutrophil activation in trauma hemorrhagic shock.

BACKGROUND: Decreased red blood cell (RBC) deformability and activation of neutrophils (polymorphonuclear leukocytes [PMN]) after trauma-hemorrhagic shock (T/HS) have been implicated in the development of multiple organ dysfunction. Experimentally, female animals seemed to be protected from the effects of T/HS, at least in part, because of elevated estrogen levels. Thus, we examined the relative role of estrogen receptor (ER)-alpha and -beta in this protective response. METHODS: To accomplish this goal, RBC deformability and neutrophil respiratory burst activity were measured in several groups of hormonally intact or ovariectomized (OVX) female rats subjected to T/HS (laparotomy plus hemorrhage to an MAP of 30 mm Hg to 35 mm Hg for 90 minutes) or trauma-sham shock (T/SS) and 3 hours of reperfusion. These groups included rats receiving vehicle, estradiol, or either an ER-alpha agonist or an ER-beta agonist administered at the end of the shock period just before volume resuscitation. RESULTS: RBC deformability and neutrophil activation were similar among all the T/SS groups and were not different from that observed in the non-OVX female rats subjected to T/HS. In contrast, RBC deformability was reduced and neutrophil activation was increased in the OVX, T/HS female rats as compared with the T/SS groups or the non-OVX, T/HS rats. The administration of estrogen to the T/HS, OVX rats returned RBC and neutrophil function to normal. Both the ER-alpha and -beta agonist partially, but not completely, protected the OVX rats from T/HS-induced loss of RBC deformability, whereas only the ER-beta agonist prevented the increase in neutrophil activation. CONCLUSIONS: The protective effects of estrogen on T/HS-induced RBC deformability are mediated, at least in part, via activation of both ER-alpha and -beta, whereas ER-beta activation is involved in limiting T/HS-induced neutrophil activation.

Low tidal volume and high positive end-expiratory pressure mechanical ventilation results in increased inflammation and ventilator-associated lung injury in normal lungs.

BACKGROUND: Protective mechanical ventilation with low tidal volume (Vt) and low plateau pressure reduces mortality and decreases the length of mechanical ventilation in patients with acute respiratory distress syndrome. Mechanical ventilation that will protect normal lungs during major surgical procedures of long duration may improve postoperative outcomes. We performed an animal study comparing 3 ventilation strategies used in the operating room in normal lungs. We compared the effects on pulmonary mechanics, inflammatory mediators, and lung tissue injury. METHODS: Female pigs were randomized into 3 groups. Group H-Vt/3 (n = 6) was ventilated with a Vt of 15 mL/kg predicted body weight (PBW)/positive end-expiratory pressure (PEEP) of 3 cm H(2)O, group L-Vt/3 (n = 6) with a Vt of 6 mL/kg PBW/PEEP of 3 cm H(2)O, and group L-Vt/10 (n = 6) with a Vt of 6 mL/kg PBW/PEEP of 10 cm H(2)O, for 8 hours. Hemodynamics, airway mechanics, arterial blood gases, and inflammatory markers were monitored. Bronchoalveolar lavage (BAL) was analyzed for inflammatory markers and protein concentration. The right lower lobe was assayed for mRNA of specific cytokines. The right lower lobe and right upper lobe were evaluated histologically. RESULTS: In contrast to groups H-Vt/3 and L-Vt/3, group L-Vt/10 exhibited a 6-fold increase in inflammatory mediators in BAL (P < 0.001). Cytokines in BAL were similar in groups H-Vt/3 and L-Vt/3. Group H-Vt/3 had a significantly lower lung injury score than groups L-Vt/3 and L-Vt/10. CONCLUSION: Comparing intraoperative strategies, ventilation with high PEEP resulted in increased production of inflammatory markers. Low PEEP resulted in lower levels of inflammatory markers. High Vt/low PEEP resulted in less histologic lung injury.

Ethyl pyruvate prevents inflammatory responses and organ damage during resuscitation in porcine hemorrhage.

Hemorrhage remains a common cause of death despite the recent advances in critical care, in part because conventional resuscitation fluids fail to prevent lethal inflammatory responses. Here, we analyzed whether ethyl pyruvate can provide a therapeutic anti-inflammatory potential to resuscitation fluids and prevent organ damage in porcine hemorrhage. Adult male Yorkshire swine underwent lethal hemorrhage with trauma and received no resuscitation treatment or resuscitation with Hextend alone, or supplemented with ethyl pyruvate. Resuscitation with ethyl pyruvate did not improve early hemodynamics but prevented hyperglycemia, the intrinsic coagulation pathway, serum aspartate aminotransferase, and myeloperoxidase in the major organs. Resuscitation with ethyl pyruvate provided an anti-inflammatory potential to restrain serum TNF and high-mobility group B protein 1 levels. Ethyl pyruvate inhibited nuclear factor [kappa]B in the spleen but not in the other major organs. In contrast, ethyl pyruvate inhibited NO in all the major organs, and it also inhibited TNF production in the major organs but in the lung and heart. The most significant effects were found in the terminal ileum where ethyl pyruvate inhibited cytokine production, restrained myeloperoxidase activity, preserved the intestinal epithelium, and prevented the systemic distribution of bacterial endotoxin. Ethyl pyruvate can provide therapeutic anti-inflammatory benefits to modulate splenic nuclear factor [kappa]B, restrain inflammatory responses, and prevent hyperglycemia, the intrinsic coagulation pathway, and organ injury in porcine hemorrhage without trauma.

Mesenteric lymph duct ligation improves survival in a lethal shock model.

The goal of this study was to test the hypothesis that factors released from the gut and carried in the mesenteric lymph contribute to mortality in a lethal gut I/R model. To test this hypothesis, a lethal splanchnic artery occlusion (SAO) shock model was used in male Sprague-Dawley rats. In the first set of experiments, ligation of the mesenteric lymph duct (LDL), which prevents gut-derived factors carried in the intestinal lymphatics from reaching the systemic circulation, significantly improved 24-h survival after a 20-min SAO insult (0% vs. 60% survival; P < 0.05). This increase in survival in the LDL-treated rats was associated with a blunted hypotensive response. Because increased iNOS-induced NO levels have been implicated in SAO-induced shock, we measured plasma nitrite/nitrate levels and liver iNOS protein levels in a second group of animals. Ligation of the mesenteric lymph duct significantly abrogated the SAO-induced increase in plasma nitrite/nitrate levels and the induction of hepatic iNOS (P < 0.05). In an additional series of studies, we documented that LDL increased not only 24-h but also long-term 7-day survival. During the course of these studies, we made the unexpected finding that Sprague-Dawley rats from different animal vendors had differential resistance to SAO, and that the time of the year that the experiments were carried out also influenced the results. Nonetheless, in conclusion, these studies support the hypothesis that factors carried in the mesenteric lymph significantly contribute to the development of irreversible shock after SAO.

Trauma-shock-induced gut injury and the production of biologically active intestinal lymph is abrogated by castration in a large animal porcine model.

Although small animal rodent studies indicate that there is a sexual dimorphism in the resistance to organ injury after trauma-hemorrhagic shock (T/HS), confirmatory studies are largely lacking in more clinically relevant large animal species. Thus, we tested the hypothesis that castration would reduce the susceptibility of adult minipigs to gut injury and abrogate the production of biologically active intestinal (mesenteric) lymph after T/HS. The hemodynamic response to T/HS was similar between castrated and noncastrated minipigs. Mesenteric lymph collected during the preshock period and in the trauma-sham shock (T/SS) animals did not have increased biological activity. However, T/HS-lymph from the noncastrated males increased the respiratory burst of normal neutrophils, increased endothelial cell monolayer permeability, and was cytotoxic for endothelial cells. Castration abrogated the T/HS-induced neutrophil-activating and endothelial-injurious activities of mesenteric lymph, and the biological activity of the T/HS-lymph from the castrated minipigs was not different from the T/SS animals. As compared with the T/SS minipigs, T/HS increased ileal mucosal injury and intestinal permeability. This increase in gut permeability after T/HS was manifest by in vivo bacterial translocation and by the increased passage of bacteria as well as permeability probes across intestinal segments when tested in the Ussing chamber system. In contrast, neither mucosal injury nor increased intestinal permeability was observed in the castrated minipigs subjected to T/HS. In summary, this large animal porcine study validates the notion that castration limits gut injury and the production of biologically active intestinal lymph after T/HS.