Lucas P. Neff

Vascular smooth muscle enhances functionality of tissue-engineered blood vessels in vivo

OBJECTIVES There is significant room for improvement in the development of tissue-engineered blood vessels (TEBVs) for vascular reconstruction. Most commonly, TEBVs are seeded with endothelial cells (ECs) only. This provides an antithrombogenic surface but suboptimal physiologic characteristics compared with native arteries, due to lack of smooth muscle cells (SMCs) in the vessel media. Although SMCs are critical in vessel architecture and function throughout the vascular tree, few studies have incorporated SMCs in TEBVs implanted in vivo. As such, the goal of the present study was to evaluate the effect of SMC coseeding with ECs on TEBV maturation, structure, and function after prolonged in vivo maturation. METHODS Dual-seeded TEBVs (dsTEBVs) were created by coseeding autologous ECs derived from circulating progenitor cells and SMCs from artery explants onto the lumen and outer surface of extracellular matrix scaffolds, respectively. Control vessels were seeded with ECs alone (ecTEBV). All vessels were preconditioned to pulsatile flow for 10 to 14 days in a bioreactor, implanted as arterial interposition grafts in sheep, and allowed to heal and adapt in vivo for 4 months before ex vivo physiologic testing and histologic analysis. RESULTS All implants were patent at 4 months. There were no structural failures, aneurysms, or infectious complications. The dsTEBVs exhibited a greater degree of wall maturation, characterized by higher medial cellularity (P = .01) and greater percentage of α-actin (P = .005) and SMC-specific muscle myosin heavy chain (P = .005) staining compared with ecTEBVs. Contractile responses to phenylephrine and serotonin were significantly greater in isolated rings of dsTEBVs than those observed in ecTEBVs (P = .01). CONCLUSIONS To our knowledge, this is the first study that demonstrates enhanced in vivo wall maturation and contractile function of TEBVs coseeded with autologous SMCs and ECs compared with EC seeding alone. These data suggest a coseeding strategy can be accomplished in a clinically relevant timeframe (typically 6 weeks) and may provide advantages for arterial reconstruction compared with vessels engineered only with endothelium.

Bioengineered vascular access maintains structural integrity in response to arteriovenous flow and repeated needle puncture

OBJECTIVE Tissue-engineered blood vessels (TEBV) have been proposed as an alternative to prosthetic grafts for dialysis access. However, arteriovenous (AV) grafts must withstand extreme flow rates and frequent needle trauma. In a proof-of-concept study, we sought to determine whether scaffold-based TEBV could withstand the hemodynamic and mechanical challenges of chronic dialysis access. METHODS TEBV were constructed using decellularized arterial scaffolds seeded with autologous ovine endothelial cells (EC) derived from circulating endothelial progenitor cells (EPC) using a novel high-affinity capture approach. Seeded scaffolds were preconditioned to arterial pressure and flow in a bioreactor for 2 weeks prior to implantation to create carotid artery to jugular vein AV grafts in each animal. TEBV were healed for 1 month before initiating percutaneous needle puncture 3 days/week. TEBV wall geometry and patency were monitored using duplex imaging and were either explanted for histologic analysis at 2 months (n = 5) or followed for up to 6 months until venous outflow stenosis threatened AV graft patency (n = 6). RESULTS Despite high flow, TEBV maintained stable geometry with only modest wall dilation (under 6%) by 4 months after implantation. Needle access was well tolerated with a single puncture site complication, a small pseudoaneurysm, occurring in the late group. Time-to-hemostasis at puncture sites averaged 4 ± 2 minutes. Histologic analysis at 2 months demonstrated repopulation of the outer TEBV wall by host cells and healing of needle punctures by cellular ingrowth and new matrix deposition along the tract. TEBV followed beyond 2 months showed stable wall geometry but, consistent with the primary mode of clinical AV graft failure, all TEBV eventually developed venous anastomotic stenosis (mean, 4.4 ± 0.9 months; range, 3.3-5.6 months postimplantation; n = 6). CONCLUSIONS This pilot study supports the concept of creating dialysis access from scaffold-based autologous TEBV. Engineered AV grafts were created within a clinically relevant time frame and demonstrated stable wall geometry despite high flow and repeated puncture. Cellular ingrowth and puncture site healing may improve wall durability, but venous outflow stenosis remains the primary mode of TEBV graft failure in the ovine model.

Extending the golden hour: Partial resuscitative endovascular balloon occlusion of the aorta in a highly lethal swine liver injury model.

BACKGROUND Combat-injured patients may require rapid and sustained support during transport; however, the prolonged aortic occlusion produced by conventional resuscitative endovascular balloon occlusion of the aorta (REBOA) may lead to substantial morbidity. Partial REBOA (P-REBOA) may permit longer periods of occlusion by allowing some degree of distal perfusion. However, the ability of this procedure to limit exsanguination is unclear. We evaluated the impact of P-REBOA on immediate survival and ongoing hemorrhage in a highly lethal swine liver injury model. METHODS Fifteen Yorkshire-cross swine were anesthetized, instrumented, splenectomized, and subjected to rapid 10% total blood loss followed by 30% liver amputation. Coagulopathy was created through colloid hemodilution. Randomized swine received no intervention (control), P-REBOA, or complete REBOA (C-REBOA). Central mean arterial pressure (cMAP), carotid blood flow, and blood loss were recorded. Balloons remained inflated in the P-REBOA and C-REBOA groups for 90 minutes followed by graded deflation. The study ended at 180 minutes from onset of hemorrhage or death of the animal. Survival analysis was performed, and data were analyzed using repeated-measures analysis of variance with post hoc pairwise comparisons. RESULTS Mean survival times in the control, P-REBOA, and C-REBOA groups were, 25 ± 21, 86 ± 40, and 163 ± 20 minutes, respectively (p < 0.001). Blood loss was greater in the P-REBOA group than the C-REBOA or control groups, but this difference was not significant (4,722 ± 224, 3,834 ± 319, 3,818 ± 37 mL, respectively, p = 0.10). P-REBOA resulted in maintenance of near-baseline carotid blood flow and cMAP, while C-REBOA generated extreme cMAP and prolonged supraphysiologic carotid blood flow. Both experimental groups experienced profound decreases in cMAP following balloon deflation. CONCLUSION In the setting of severe ongoing hemorrhage, P-REBOA increased survival time beyond the golden hour while maintaining cMAP and carotid flow at physiologic levels.

Adherence to burn center referral criteria: are patients appropriately being referred?

The American Burn Association (ABA) has an established set of criteria for burn center referral to guide healthcare providers and improve patient outcomes. As U.S. healthcare becomes increasingly focused on improving quality of care (ie, pay-for-performance initiatives), assessing and monitoring the referral patterns to burn centers is critical in providing optimal burn care. Few studies have compared admission, treatment, and discharge patterns at burn centers and nonburn centers. Our goal was to compare practice and referral guidelines for patients with burn injuries by reviewing every discharge record in our state over a 2-year period. The study was conducted in a retrospective fashion using our states hospital association patient database of International Classification of Diseases, 9th revision (ICD-9) discharge codes, querying 940.00 to 948.99, over the period of October 1, 2005, to September 30, 2007. Additional variables abstracted included the discharging hospital, outcome, race, gender, payor status, length of stay, procedures, and age. Adherence to referral criteria was established by comparing the discharge ICD-9 codes with the burn center referral criteria established by the ABA and American College of Surgeons Committee on Trauma in Guidelines for the Operation of Burn Centers. Injury patterns were analyzed using the 2 burn centers in our state and the remaining 107 nonburn centers providing care to burn patients. A total of 2036 adult patients aged 18 to 106 years sustained burn injuries requiring hospital admission, and 1416 (70%) met ABA referral criteria based on ICD-9 codes. Of the 1084 patients treated at burn centers, 88% met referral criteria. Of the 952 burns treated entirely at nonburn centers, 48% met referral criteria but were not transferred. The most common burns treated at nonburn centers included injuries to the hand, wrist, face, neck, and lower extremity. The mean number of criteria met by patients treated at nonburn centers was 1.5, and all deaths occurring at nonburn centers met referral criteria. A significantly higher percentage of patients with Medicare were not transferred from nonburn centers (P ≤ .00001), and a significantly higher percentage of patients were discharged to nursing homes as opposed to home (P = .01) from nonburn centers. Forty-seven percent of the patients sustaining burn injuries in our state receive all of their acute inpatient care at nonburn centers, and almost half of these met ABA burn center referral criteria. Given the disparity in discharge placement and immediate availability of burn specialists in our state, all patients meeting ABA referral criteria should be referred to burn centers. More focused outreach and education for initial providers may help improve access and referral to burn centers.

Clearly defining pediatric massive transfusion: cutting through the fog and friction with combat data.

BACKGROUND Massive transfusion (MT) in pediatric patients remains poorly defined. Using the largest existing registry of transfused pediatric trauma patients, we sought a data-driven MT threshold. METHODS The Department of Defense Trauma Registry was queried from 2001 to 2013 for pediatric trauma patients (<18 years). Burns, drowning, isolated head injury, and missing Injury Severity Score (ISS) were excluded. MT was evaluated as a weight-based volume of all blood products transfused in the first 24 hours. Mortality at 24 hours and in the hospital was calculated for increasing transfusion volumes. Sensitivity and specificity curves for predicting mortality were used to identify an optimal MT threshold. Patients above and below this threshold (MT+ and MT−, respectively) were compared. RESULTS The Department of Defense Trauma Registry yielded 4,990 combat-injured pediatric trauma patients, of whom 1,113 were transfused and constituted the study cohort. Sensitivity and specificity for 24-hour and in-hospital mortality were optimal at 40.1-mL/kg and 38.6-mL/kg total blood products in the first 24 hours, respectively. With the use of a pragmatic threshold of 40 mL/kg, patients were divided into MT+ (n = 443) and MT− (n = 670). MT+ patients were more often in shock (68.1% vs. 47.0%, p < 0.001), hypothermic (13.0% vs. 3.4%, p < 0.001), coagulopathic (45.0% vs. 29.6%, p < 0.001), and thrombocytopenic (10.6% vs. 5.0%, p = 0.002) on presentation. MT+ patients had a higher ISS, more mechanical ventilator days, and longer intensive care unit and hospital stay. MT+ was independently associated with an increased 24-hour mortality (odds ratio, 2.50; 95% confidence interval, 1.28–4.88; p = 0.007) and in-hospital mortality (odds ratio, 2.58; 95% confidence interval, 1.70–3.92; p < 0.001). CONCLUSION Based on this large cohort of transfused combat-injured pediatric patients, a threshold of 40 mL/kg of all blood products given at any time in the first 24 hours reliably identifies critically injured children at high risk for early and in-hospital death. This evidence-based definition will provide a consistent framework for future research and protocol development in pediatric resuscitation. LEVEL OF EVIDENCE Diagnostic study, level II. Prognostic/epidemiologic study, level III.

Partial resuscitative balloon occlusion of the aorta (P-REBOA): Clinical technique and rationale

Resuscitative endovascular balloon occlusion of the aorta (REBOA) has continued to evolve as a viable tool of modern trauma resuscitation. Developed from the convergence of trauma and endovascular surgery, REBOA has increasingly been used at select centers as a resuscitative adjunct for trauma patients with life-threatening noncompressible truncal hemorrhage. Even as prospective registry data seek to capture and analyze outcomes of early use of REBOA, ongoing device innovation and technique refinement seek to mitigate potential risks associated with aortic occlusion. It is hypothesized that early use of REBOA preserves cerebral perfusion and coronary filling in the setting of lifethreatening hypotension and hypovolemia secondary to hemorrhage. Laboratory data have demonstrated that the use of REBOA in the setting of hemorrhagic shock results in increased central aortic pressure, carotid flow, and brain oxygenation, and early reports suggest REBOA may improve outcomes in select patient populations. These benefits of REBOAmust be weighed against the consequence of sustained complete aortic occlusion, primarily profound distal ischemia and associated reperfusion

Emerging Endovascular Therapies for Non-Compressible Torso Hemorrhage

ABSTRACT Management of non-compressible torso hemorrhage (NCTH) remains a challenge despite continued advancements in trauma resuscitation. Resuscitative thoracotomy with aortic cross-clamping and recent advances in endovascular aortic occlusion, including resuscitative endovascular occlusion of the aorta, have finite durations of therapy due to the inherent physiologic stressors that accompany complete occlusion. Here, we attempt to illuminate the current state of aortic occlusion for trauma resuscitation including explanation of the deleterious consequences of complete occlusion, potential methods and limitations of existing technology to overcome these consequences, and a description of innovative methods to improve the resuscitation of NCTH. By explaining the complexity and potential deleterious effects of resuscitation augmented with aortic occlusion, our goal is to provide practitioners with a real-world perspective on current endovascular technology and to encourage the continued innovation required to overcome existing obstacles.

Extending resuscitative endovascular balloon occlusion of the aorta: Endovascular variable aortic control in a lethal model of hemorrhagic shock

BACKGROUND The duration of use and efficacy of resuscitative endovascular balloon occlusion of the aorta (REBOA) is limited by distal ischemia. We developed a hybrid endovascular-extracorporeal circuit variable aortic control (VAC) device to extend REBOA duration in a lethal model of hemorrhagic shock to serve as an experimental surrogate to further the development of endovascular VAC (EVAC) technologies. METHODS Nine Yorkshire-cross swine were anesthetized, instrumented, splenectomized, and subjected to 30% liver amputation. Following a short period of uncontrolled hemorrhage, REBOA was instituted for 20 minutes. Automated variable occlusion in response to changes in proximal mean arterial pressure was applied for the remaining 70 minutes of the intervention phase using the automated extracorporeal circuit. Damage-control surgery and whole blood resuscitation then occurred, and the animals were monitored for a total of 6 hours. RESULTS Seven animals survived the initial surgical preparation. After 20 minutes of complete REBOA, regulated flow was initiated through the extracorporeal circuit to simulate VAC and provide perfusion to distal tissue beds during the 90-minute intervention phase. Two animals required circuit occlusion for salvage, while five animals tolerated sustained, escalating restoration of distal blood flow before surgical hemorrhage control. Animals tolerating distal flow had preserved renal function, maintained proximal blood pressure, and rapidly weaned from complete REBOA. CONCLUSION We combined a novel automated, extracorporeal circuit with complete REBOA to achieve EVAC in a swine model of uncontrolled hemorrhage. Our approach regulated proximal aortic pressure, alleviated supranormal values above the balloon, and provided controlled distal aortic perfusion that reduced ischemia without inducing intolerable bleeding. This experimental model serves as a temporary surrogate to guide future EVAC catheter designs that may provide transformational approaches to hemorrhagic shock.

The Effectiveness of Regionalized Burn Care: An Analysis of 6,873 Burn Admissions in North Carolina from 2000 to 2007

BACKGROUND The effectiveness and benefits of regionalized trauma care are well substantiated; however, the effectiveness of regionalized burn care and potential benefits of burn center verification have not been fully validated. STUDY DESIGN This was a retrospective study of all acute burn admissions using a statewide discharge database from October 1, 2000, to September 30, 2007. Demographics, referral patterns, care practices, and outcomes were compared between 2 American Burn Association (ABA)-verified burn centers (VBCs) and the remaining 107 nonburn centers (NBCs) in North Carolina. RESULTS Overall, 6,873 adult burn patients required admission, with 79% of them meeting ABA burn center referral criteria. Of the 5,402 patients meeting ABA referral criteria, 43% were admitted to an NBC, and 25% of all NBC patients had burn operations. Burns admitted to NBCs tended to involve the hand/wrist and lower extremities. Older patients with comorbidities/concomitant trauma were more likely to be admitted to NBCs (p < 0.0001); however, larger burns were more likely to be admitted to a VBC (p < 0.0001). More NBC patients were discharged to nursing homes (p < 0.0001). Patients with Medicare were more likely to be admitted to NBCs (p < 0.0001), and uninsured patients or those with Workmans Compensation insurance were more likely to be admitted to VBCs (p < 0.0001), and payer status remained a significant predictor of treatment at a VBC on regression analysis. CONCLUSIONS This is the most comprehensive study of its kind and demonstrates that ABA burn center referral criteria are not always used for effective regionalized burn care or to ensure the best possible outcomes. Even with establishment of the burn center verification process, the mere presence of a VBC is insufficient for effective regionalized care. A greater emphasis is needed on the development of burn care systems.

Multidrug-Resistant Pathogens and Pneumonia: Comparing the Trauma and Surgical Intensive Care Units

BACKGROUND As acute care surgery evolves, more trauma surgeons are caring for critically ill general surgery as well as trauma patients. However, these two populations are unique, and infectious complications may need to be addressed differently, as the causative organisms may not be the same in the two groups. To study this, we evaluated ventilator-associated (VAP) and hospital-acquired (HAP) pneumonia in the trauma (TICU) and general surgical (SICU) intensive care units to investigate differences in the causative pathogens. Our hypothesis was that SICU patients would have a higher incidence of multi-drug-resistant (MDR) organisms causing VAP/HAP, possibly contributing to inadequate empiric antibiotic (IEA) coverage. METHODS Retrospective review of 116 patients admitted with VAP or HAP over a one-year period to the TICU (n = 72) or SICU (n = 44) at a tertiary medical center. Culture was followed by initiation of empiric antibiotics on the basis of an antibiotic algorithm derived from trauma patients. Demographics, illness, and pneumonia characteristics were assessed; MDR organisms were identified. RESULTS Multi-drug-resistant organisms caused 30.6% of first pneumonias in the TICU vs. 65.9% in the SICU (p = 0.0002). Subsequent pneumonias were seen in 31.8% of SICU patients and 16.7% of TICU patients (p = 0.0576). Inadequate empiric antibiotic coverage was documented in 38.6% of SICU pneumonias vs. 26.4% in the TICU (p = 0.12). CONCLUSIONS Multiply-resistant pathogens cause a significantly greater number of VAP/HAPs in the SICU than in the TICU. Associated with this, when using an antibiotic algorithm based on TICU bacterial pathogens, there is a trend toward a greater likelihood of subsequent pneumonias and toward more IEA coverage in the SICU population compared with TICU patients. Our results indicate that these distinct patient populations have different pathogens causing VAP/HAP and affirm the necessity for population-specific algorithms to tailor empiric coverage for presumed VAP/HAP.