Lighting the Way for Necrosis Excision Through Indocyanine Green Fluorescence-Guided Surgery.

BACKGROUND: No objective technique exists to distinguish necrotic from viable tissue, risking over-excision in burns and loss of wound healing potential. Second window indocyanine green (SWIG) is a novel fluorescence-imaging modality being studied to identify residual solid tumors during oncological surgery. SWIG has also been shown to have avidity for necrosis in animal models, but translation of these findings to humans is lacking. The objective of this study was to evaluate SWIG in the identification of burn wound necrosis and compare it with previously published indocyanine green angiography (ICGA) techniques. STUDY DESIGN: This study used mouse, human skin xenograft and human patient burn models. Brightfield and SWIG near-infrared imaging were performed on macroscopic tissue samples, which were then cryopreserved, sectioned, and analyzed for microscopic fluorescence. SWIG fluorescence findings were correlated to visual assessment of the burn wound as well as histological markers of necrosis using hematoxylin and eosin and lactate dehydrogenase stains. RESULTS: We found that SWIG identified burn necrosis in a manner dependent on the dose and timing of indocyanine green (ICG) administration and had an inverse fluorescence signal compared with ICGA. Furthermore, SWIG fluorescence identified the interface of viable and nonviable tissue. CONCLUSION: Our study confirmed that ICGA is an inconsistent and nonstandardized modality to evaluate burn injuries. In contrast, SWIG imaging is a potential imaging modality to objectively prognosticate burn wound healing potential and guide intraoperative burn excision. Further studies are needed to define ratios of fluorescence intensity values to guide surgical decision-making in burn excision and to better define how ICG is retained in necrotic tissue to enhance utility of SWIG in other disease processes.

Pooled safety analysis of STRATA2011 and STRATA2016 clinical trials evaluating the use of StrataGraft® in patients with deep partial-thickness thermal burns.

OBJECTIVE: This analysis includes pooled safety data from 2 clinical trials (NCT01437852; NCT03005106) that evaluated the safety and efficacy of StrataGraft in patients with deep partial-thickness (DPT) burns. METHODS: The study enrolled 101 adult patients with thermal burns covering 3-49% of total body surface area. Patients were followed for up to 1 year. The pooled safety events included: adverse events (AEs), adverse reactions (ARs), serious AEs (SAEs), discontinuation, and deaths; immunological responses (reactivity to panel reactive antibodies [PRA] and human leukocyte antigen [HLA] class 1 alleles); and persistence of allogeneic DNA from StrataGraft. RESULTS: Eighty-seven (86.1%) patients experienced 397 AEs. Thirty patients (29.7%) experienced ARs; 16 patients (15.8%) experienced SAEs. The most frequent AEs were pruritus (n = 31; 30.7%), and blister, hypertension, and hypertrophic scar (n = 11 each; 10.9%); the most common AR was pruritus (n = 13; 12.9%). One patient discontinued the study; 2 patients experienced SAEs (unrelated to StrataGraft) leading to death. PRA and HLA allele reactivity was ≤ 25% at Month 3, with no persistent allogeneic DNA from StrataGraft. CONCLUSIONS: StrataGraft was well tolerated by patients, with a safety profile similar to autograft. StrataGraft may offer a safe alternative to autograft for DPT burns.

An open-label, prospective, randomized, controlled, multicenter, phase 1b study of StrataGraft skin tissue versus autografting in patients with deep partial-thickness thermal burns.

OBJECTIVE: This open-label, controlled, randomized study assessed the safety, tolerability, and efficacy of StrataGraft tissue compared to autograft in the treatment of deep partial-thickness (DPT) burns. METHODS: Thirty subjects with DPT thermal burns (3%-43% total body surface area) were treated with StrataGraft tissue as follows: cohort 1, ≤220 cm2 refrigerated tissue; cohort 2, ≤440 cm2 refrigerated tissue; and cohort 3, ≤440 cm2 cryopreserved tissue. On each subject, two comparable areas of DPT burn were randomized to receive StrataGraft tissue or autograft. Coprimary end points were the percent area of the StrataGraft tissue treatment site undergoing salvage autografting by Day 28 and wound closure of treatment sites by 3 months. RESULTS: By Day 28, no StrataGraft tissue treatment sites underwent autografting. By 3 months, 93% and 100% of the StrataGraft tissue and autograft treatment sites achieved complete wound closure, respectively. No significant differences in observer total and overall opinion POSAS scores between StrataGraft tissue and autograft treatment sites were observed at any timepoint. The most common adverse event was pruritus (17%). CONCLUSIONS: StrataGraft tissue treatment of DPT thermal burns reduced the need for autograft, resulted in wound closure and treatment-site cosmesis comparable to that of autograft, and was well tolerated.

A Survey of Mechanical Ventilator Practices Across Burn Centers in North America.

Burn injury introduces unique clinical challenges that make it difficult to extrapolate mechanical ventilator (MV) practices designed for the management of general critical care patients to the burn population. We hypothesize that no consensus exists among North American burn centers with regard to optimal ventilator practices. The purpose of this study is to examine various MV practice patterns in the burn population and to identify potential opportunities for future research. A researcher designed, 24-item survey was sent electronically to 129 burn centers. The χ, Fisher's exact, and Cochran-Mantel-Haenszel tests were used to determine if there were significant differences in practice patterns. We analyzed 46 questionnaires for a 36% response rate. More than 95% of the burn centers reported greater than 100 annual admissions. Pressure support and volume assist control were the most common initial MV modes used with or without inhalation injury. In the setting of Berlin defined mild acute respiratory distress syndrome (ARDS), ARDSNet protocol and optimal positive end-expiratory pressure were the top ventilator choices, along with fluid restriction/diuresis as a nonventilator adjunct. For severe ARDS, airway pressure release ventilation and neuromuscular blockade were the most popular. The most frequently reported time frame for mechanical ventilation before tracheostomy was 2 weeks (25 of 45, 55%); however, all respondents reported in the affirmative that there are certain clinical situations where early tracheostomy is warranted. Wide variations in clinical practice exist among North American burn centers. No single ventilator mode or adjunct prevails in the management of burn patients regardless of pulmonary insult. Movement toward American Burn Association-supported, multicenter studies to determine best practices and guidelines for ventilator management in burn patients is prudent in light of these findings.

Local delivery of allogeneic bone marrow and adipose tissue-derived mesenchymal stromal cells for cutaneous wound healing in a porcine model.

Wound healing remains a major challenge in modern medicine. Bone marrow- (BM) and adipose tissue- (AT) derived mesenchymal stromal/stem cells (MSCs) are of great interest for tissue reconstruction due to their unique immunological properties and regenerative potential. The purpose of this study was to characterize BM and AT-MSCs and evaluate their effect when administered in a porcine wound model. MSCs were derived from male Göttingen Minipigs and characterized according to established criteria. Allogeneic BM- or AT-MSCs were administered intradermally (1 x 10(6) cells) into partial-thickness wounds created on female animals, and covered with Vaseline® gauze or fibrin in a randomized pattern. Animals were euthanized at 7, 10, 14 and 21 days. Tissues were analyzed visually for healing and by microscopic examination for epidermal development and remodelling. Polymerase chain reaction (PCR) was used to detect the presence of male DNA in the specimens. All wounds were healed by 14 days. MSC-injected wounds were associated with improved appearance and faster re-epithelialization compared to saline controls. Evaluation of rete ridge depth and architecture showed that MSC treatment promoted a faster rate of epidermal maturation. Male DNA was detected in all samples at days 7 and 10, suggesting the presence of MSCs. We showed the safety, feasibility and potential efficacy of local injection of allogeneic BM- and AT-MSCs for treatment of wounds in a preclinical model. Our data in this large animal model support the potential use of BM- and AT-MSC for treatment of cutaneous wounds through modulation of healing and epithelialization.

What's in a Name? Recent Key Projects of the Committee on Organization and Delivery of Burn Care.

The Committee for the Organization and Delivery of Burn Care (ODBC) was charged by President Palmieri and the American Burn Association (ABA) Board of Directors with presenting a plenary session at the 45th Meeting of the ABA in Palm Springs, CA, in 2013. The objective of the plenary session was to inform the membership about the wide range of the activities performed by the ODBC committee. The hope was that this session would encourage active involvement within the ABA as a means to improve the delivery of future burn care. Selected current activities were summarized by key leaders of each project and highlighted in the plenary session. The history of the committee, current projects in disaster management, regionalization, best practice guidelines, federal partnerships, product development, new technologies, electronic medical records, and manpower issues in the burn workforce were summarized. The ODBC committee is a keystone committee of the ABA. It is tasked by the ABA leadership with addressing and leading progress in many areas that constitute current challenges in the delivery of burn care.

Bilateral versus unilateral bronchoalveolar lavage for the diagnosis of ventilator-associated pneumonia.

BACKGROUND: Ventilator-associated pneumonia (VAP) complicates the clinical course of critically injured intubated patients. Bronchoscopic bronchoalveolar lavage (BAL) represents an invasive and accurate means of VAP diagnosis. Unilateral and blinded techniques offer less invasive alternatives to bronchoscopic BAL. This study evaluated clinical criteria as well as unilateral directed versus bilateral BAL for VAP diagnosis. METHODS: A retrospective chart review of 113 consecutive intubated trauma patients with clinically suspected VAP undergoing unilateral versus bilateral BAL was performed with comparison of positive culture results (>10(4) colony-forming units [CFU]/mL). Culture results were compared with chest radiograph (CXR) infiltrates and white blood cell (WBC) count elevation. RESULTS: Bilateral BAL was more likely to be positive than unilateral BAL (50.4% vs. 25.5%). In 37.1% of bilateral BALs, there was discordance between the sides of positivity or the bacteria isolated. A CXR infiltrate and WBC count elevation did not predict positive BAL. CONCLUSIONS: Clinical indicators of VAP are inaccurate, and bilateral bronchoscopic BAL is more likely than unilateral BAL to provide a positive sample in intubated trauma patients. Techniques that do not sample both lungs reliably should be avoided for diagnosis in this patient population.

Clinical Evaluation of NIKS-Based Bioengineered Skin Substitute Tissue in Complex Skin Defects: Phase I/IIa Clinical Trial Results.

BACKGROUND: Complex skin defects, such as burns and acute cutaneous trauma, are life-threatening injuries, often requiring temporary allograft placement to maintain fluid homeostasis and prevent infection until permanent wound closure is possible. THE PROBLEM: The current standard of care for the management of full-thickness wounds that are unable to be closed in a single surgical stage is temporary coverage with cadaver allograft until an acceptable wound bed has been established. This approach has limitations including limited availability of human cadaver skin, the risk of disease transmission from cadaveric grafts, and inconsistent cadaver allograft quality. BASIC/CLINICAL SCIENCE: Near-diploid neonatal human keratinocyte cell line (NIKS)-based human skin tissue is a full-thickness, living human skin substitute composed of a dermal analog containing normal human dermal fibroblasts and a fully-stratified, biologically and metabolically active epidermis generated from NIKS keratinocytes, a consistent and unlimited source of pathogen-free human epidermal progenitor cells. CLINICAL CARE RELEVANCE: NIKS-based human skin tissue is a living bioengineered skin substitute (BSS) intended to provide immediate wound coverage and promote wound healing through sustained expression by living cells of wound healing factors. CONCLUSION: A phase I/IIa clinical trial found that NIKS-based BSS was well tolerated and comparable to cadaver allograft in the ability to prepare full-thickness complex skin defects prior to autografting. There were no deaths and no adverse events (AE) associated with this BSS. Exposure of the study subjects to the skin substitute tissue did not elicit detectable immune responses. Notably, this tissue remained viable and adherent in the wound bed for at least 7 days.

StrataGraft skin substitute is well-tolerated and is not acutely immunogenic in patients with traumatic wounds: results from a prospective, randomized, controlled dose escalation trial.

OBJECTIVE: The goal of this study was to assess the immunogenicity and antigenicity of StrataGraft skin tissue in a randomized phase I/II clinical trial for the temporary management of full-thickness skin loss. BACKGROUND: StrataGraft skin tissue consists of a dermal equivalent containing human dermal fibroblasts and a fully stratified, biologically active epidermis derived from Near-diploid Immortalized Keratinocyte S (NIKS) cells, a pathogen-free, long-lived, consistent, human keratinocyte progenitor. METHODS: Traumatic skin wounds often require temporary allograft coverage to stabilize the wound bed until autografting is possible. StrataGraft and cadaveric allograft were placed side by side on 15 patients with full-thickness skin defects for 1 week before autografting. Allografts were removed from the wound bed and examined for allogeneic immune responses. Immunohistochemistry and indirect immunofluorescence were used to assess tissue structure and cellular composition of allografts. In vitro lymphocyte proliferation assays, chromium-release assays, and development of antibodies were used to examine allogeneic responses. RESULTS: One week after patient exposure to allografts, there were no differences in the numbers of T or B lymphocytes or Langerhans cells present in StrataGraft skin substitute compared to cadaver allograft, the standard of care. Importantly, exposure to StrataGraft skin substitute did not induce the proliferation of patient peripheral blood mononuclear cells to NIKS keratinocytes or enhance cell-mediated lysis of NIKS keratinocytes in vitro. Similarly, no evidence of antibody generation targeted to the NIKS keratinocytes was seen. CONCLUSIONS: These findings indicate that StrataGraft tissue is well-tolerated and not acutely immunogenic in patients with traumatic skin wounds. Notably, exposure to StrataGraft did not increase patient sensitivity toward or elicit immune responses against the NIKS keratinocytes. We envision that this novel skin tissue technology will be widely used to facilitate the healing of traumatic cutaneous wounds.This study was registered at www.clinicaltrials.gov (NCT00618839).

Functional implications of long-term pain following outpatient inguinal herniorrhaphy--a prospective evaluation.

BACKGROUND: The purpose of the present study is to assess pain and functional outcomes at 1 y following inguinal herniorrhaphy in which patients were randomized to receive a continuous wound infusion of bupivacaine to receiving a saline infusion. METHODS: Patients received saline or bupivacaine prior to incision and then for 60 h postoperatively. The incidence, severity, and functional interference of pain were assessed for five postoperative days, and at 1 y. RESULTS: Seventy patients completed a survey 1 y following herniorrhaphy. Four percent (3/72) of patients were in moderate to severe pain "almost always" or "often". Twenty-one percent (15/72) of patients experienced pain with ambulation. There was no difference between groups at 1 y. CONCLUSIONS: The incidence of moderate or severe pain is concerning 1 y following surgery. Functional aberrations associated with pain should be assessed in all studies evaluating long-term pain after herniorrhaphy.

Biomaterials modulate interleukin-8 and other inflammatory proteins during reepithelialization in cutaneous partial-thickness wounds in pigs.

Acute and chronic cutaneous wounds remain a clinical challenge that require a mechanistic understanding to advance treatment options. For example, the role of inflammatory mediators during wound healing is not completely understood. Biomimetic materials, such as an in situ photopolymerizable semi-interpenetrating network (sIPN) derived from extracellular matrix components, show great potential in improving healing through the delivery of therapeutic agents and the function as a temporary tissue scaffold. In this study, we characterized the temporal profile of porcine cutaneous partial-thickness wound healing in response to Xeroform and sIPN treatment via histological and inflammatory protein analyses in epidermal, remodeling dermal, and dermal regions. Generally, interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-10, IL-12p70, interferon-γ, and tumor necrosis factor-α, but not IL-8, were expressed in the epidermis and remodeling dermis in a time course that followed the progression of epidermal maturation in response to both treatments. Differences in cellularity and protein expression were observed between treatments in a time- and region-dependent manner. In particular, the healing response to sIPN exemplified a potentially key relationship between IL-8 expression and reepithelialization. These results provide insights into the expression of inflammatory mediators and the time course of cutaneous healing and the capacity for biomaterials to further modulate this relationship.

Multifunctional photopolymerized semiinterpenetrating network (sIPN) system containing bupivacaine and silver sulfadiazine is an effective donor site treatment in a swine model.

Previously, we have shown in a cross-comparison study that multifunctional photopolymerized semiinterpenetrating network (sIPN) system is an effective donor site treatment in a swine model. The advantages of sIPN include spray-on application, in situ photopolymerization, and ability to cover large contoured areas. sIPN has also been shown to be an effective delivery vehicle for keratinocyte growth factor, dexamethasone, bupivacaine, and silver sulfadiazine in vitro. Our aim for this study was to show that these products delivered to the wound bed with sIPN would not change the wound healing characteristics compared with the control site through qualitative clinical evaluation and to compare the rate and quality of donor site healing through histologic evaluation. Eight Yucatan swine of 40 lbs each were randomly divided into four groups of two pigs before surgery. Each animal had 5.6% TBSA of skin harvested from two different dorsal regions, with one at 22/1000th-inch and the other at 30/1000th-inch setting on the dermatome. Each test site on each animal was then sequentially dressed with 50 cm(2) of Xeroform gauze, sIPN, sIPN loaded with 0.5% bupivacaine, or sIPN loaded with 1% silver sulfadiazine. sIPN with or without soluble drugs were applied as liquid, then photopolymerized in situ to form an elastic covering. Each of the test areas was separated by 50 cm(2) of autograft, which was used to divide the test areas. Wound assessment and killing occurred at days 7, 9, 14, and 21. A full-thickness biopsy was taken from each of the study areas for histological analysis. By 14 days, all areas showed complete epidermal coverage histologically. The 30/1000th-inch site revealed a thicker, more irregular dermis compared with the 22/1000th-site. Evaluation of the day-21 sites revealed equal thinning and flattening of the new epidermis. No site showed full restoration of the rete ridges. No signs of infection were seen in clinical or histological evaluations of any treatment. The addition of bupivacaine and silver sulfadiazine to sIPN does not show any alterations in wound healing of a donor site in a swine model when compared with sIPN without loaded drugs and a standard control dressing. This efficacy may be coupled with established localized sIPN drug delivery profiles and allow further studies to evaluate the efficacy of these drugs to promote healing, eradicate and prevent infection, and manage pain.

Motorcycle helmets and rider safety: a legislative crisis.

Over the past four decades, motorcycle helmet laws within the United States have been in a state of flux and have been shaped by the conflicting influences of the federal government's initiatives to shape state policies and motorcycle advocates' persistent lobbying efforts. Examination of individual state experiences with motorcycle helmet legislation demonstrates that universal motorcycle helmet laws effectively promote helmet use compliance, reduce morbidity and mortality in motorcycle crashes, and lower the health care costs and associated societal burdens of these crash victims. Motorcycle advocates have challenged the implementation of these laws and directly influenced the weakening or frank repeal of these laws to negative consequence. We offer this review as an educational resource to encourage and facilitate health care worker participation in legislative efforts to support implementation and maintenance of universal motorcycle helmet laws.

Phase I/II clinical evaluation of StrataGraft: a consistent, pathogen-free human skin substitute.

BACKGROUND: Large wounds often require temporary allograft placement to optimize the wound bed and prevent infection until permanent closure is feasible. We developed and clinically tested a second-generation living human skin substitute (StrataGraft). StrataGraft provides both a dermis and a fully-stratified, biologically-functional epidermis generated from a pathogen-free, long-lived human keratinocyte progenitor cell line, Neonatal Immortalized KeratinocyteS (NIKS). METHODS: Histology, electron microscopy, quantitative polymerase chain reaction, and bacterial growth in vitro were used to analyze human skin substitutes generated from primary human keratinocytes or NIKS cells. A phase I/II, National Institute of Health-funded, randomized, safety, and dose escalation trial was performed to assess autograft take in 15 patients 2 weeks after coverage with StrataGraft skin substitute or cryopreserved cadaver allograft. RESULTS: StrataGraft skin substitute exhibited a fully stratified epidermis with multilamellar lipid sheets and barrier function as well as robust human beta defensin-3 mRNA levels. Analysis of the primary endpoint in the clinical study revealed no differences in autograft take between wound sites pretreated with StrataGraft skin substitute or cadaver allograft. No StrataGraft-related adverse events or serious adverse events were observed. CONCLUSIONS: The major finding of this phase I/II clinical study is that performance of StrataGraft skin substitute was comparable to cadaver allograft for the temporary management of complex skin defects. StrataGraft skin substitute may also eliminate the risk for disease transmission associated with allograft tissue and offer additional protection to the wound bed through inherent antimicrobial properties. StrataGraft is a pathogen-free human skin substitute that is ideal for the management of severe skin wounds before autografting.

Phenotyping Clostridium septicum infection: a surgeon's infectious disease.

BACKGROUND: Clostridium septicum infection is associated with malignancy. Whether disease phenotype is affected by malignant status is not known. Surgical treatment is used frequently but its impact on survival has not been examined in a cohort >30 patients. METHODS: A PubMed search of English language journal articles yielded 320 cases. Full information (infection location, cancer type, operative intervention, and survival) was available for 224 cases + 7 at our institution not previously reported. RESULTS: Seventy-two percent of patients had malignancy or malady of the gastrointestinal (GI) or hematologic (HEME) organ systems. HEME survival was inferior to GI survival (35% versus 55%, P = 0.03). Overall, patients who underwent operation had improved survival (57% versus 26%; P < 0.0001) and this association was maintained within GI and HEME cohorts (P = 0.002 and 0.005, respectively). More GI than HEME patients underwent operation (81% versus 51%, P < 0.001). GI patients were more likely than HEME patients to experience infection of skin and soft tissues (SSTI, P = 0.006). Diabetics were more likely to experience SSTI than nondiabetics (77% versus 45%, P < 0.001). CONCLUSIONS: C. septicum infectious phenotype varies with host milieu. The SSTI phenotype is more common in GI and diabetic patients. This recognition may aid in directing the search for occult malignancy, which must be performed given the >70% incidence of concomitant cancer. This infection is more fatal in HEME versus GI patients, perhaps due in part to less HEME group operative intervention. Primary surgical therapy should be considered in GI or HEME patients as operative intervention benefits both groups.

Retrievable inferior vena cava filters in high-risk trauma and surgical patients: factors influencing successful removal.

BACKGROUND: An Inferior vena cava filter (IVCF) provides prophylaxis against pulmonary embolism in patients that cannot be anticoagulated. A removable IVCF (R-IVCF) provides prophylaxis during a high-risk period while potentially eliminating long-term complications associated with a permanent IVCF. Factors influencing success of R-IVCF removal are ill-defined. METHODS: The study was a retrospective review of a prospectively maintained patient registry comprising patients who received an R-IVCF (Bard Recovery and G2) at an academic level 1 trauma center. The influence of time in vivo, filter design, and filter head position on computed abdominal tomographic (CAT) scan (touching caval wall vs. free) on removal success was examined. RESULTS: Ninety-two patients each received an R-IVCF. Thirty-nine patients underwent removal attempt and 30 R-IVCFs were removed. Time in vivo did not affect removal success (success: 228 +/- 104 days versus unsuccessful: 289 +/- 158 days, p = 0.18). Filter design impacted filter head position (Recovery: 43% touching versus G2: 6% touching, p = 0.023). Position of the filter head influenced removal success (touching: 50% success versus free: 88% success, p = 0.021). CONCLUSIONS: Position of the filter head is the key determinant of removal success. Specific device designs may impact filter head position as was the case with the two designs in this analysis. Time in vivo does not affect removal success.

Practice guidelines for deep venous thrombosis prophylaxis in burns.

Measures to prevent deep venous thrombosis (DVT), including low-dose subcutaneous heparin, low molecular weight heparin, or sequential compression devices, may be considered in high-risk patients, specifically those with a previous history of thromboembolic disease, and in patients with significant burns of the lower extremities. The purpose of this guideline is to review the principles of prophylaxis for DVT in burn patients and to present a reasonable approach for the treatment of patients during burn resuscitation. This guideline is designed to aid those physicians who are responsible for the triage and initial management of burn patients. DVT in the burn patient is a more common event than previously reported, with incidence ranging from 1% to 23% in the few available series. The suspected risk of bleeding using low-dose heparin has deterred most burn surgeons from using heparin routinely in all burn patients. Much remains unknown, however, regarding the real risks and benefits of this complication and its treatment. A Medline search of all English language citations from 1966 through 2006 was undertaken using the key words "deep vein thrombosis" and "deep venous thrombosis" with "burns." This produced 18 references. The addition of the key words "pulmonary embolism" with "burns" produced a total of 82 references, of which 7 were felt to be relevant to this topic based on evidentiary classification of the data. There are no prospective, randomized, controlled studies evaluating the effectiveness of any prophylactic preventive measures against DVT in burn patients. The apparently low incidence of this condition in burn patients would appear to preclude its evaluation in a single-center study, and no multicenter studies have been conducted.