A clinical study of the local injection of a freshly manufactured 35 kDa hyaluronan fragment for treating chronic wounds.

This study manufactured a 35 kDa hyaluronan fragment (HA35) by enzymatically degrading high-molecular-weight HA using hyaluronidase PH20 derived from bovine testis. The research then examined the therapeutic efficacy of locally administered, tissue-permeable HA35 in alleviating chronic wounds and their associated neuropathic pain. For 20 patients with nonhealing wounds and associated pain lasting over three months, 100 mg of HA35 was injected daily into the healthy skin surrounding the chronic wound for 10 days. Self-assessments before and after treatment indicated that HA35 significantly enhanced wound healing. This was evidenced by the formation of fresh granulation tissue on the wounds (p < 0.0001); reduced darkness, redness, dryness, and damage in the skin surrounding the wounds (p < 0.0001), and a decrease in wound size (p < 0.001). Remarkably, HA35 injections alleviated pain associated with chronic wounds within 24 hours (p < 0.0001). It can be concluded that the low-molecular-weight hyaluronan fragment HA35 potentially enhances the immune response and angiogenesis during wound healing.

Examining the Association between Immunosuppressants and Wound Healing: A Narrative Review.

OBJECTIVE: To review how different classes of immunosuppressants affect wound healing. DATA SOURCES: A literature search was conducted in PubMed, Google Scholar, and the University of Calgary Health Sciences Library. STUDY SELECTION: The researchers initially screened article titles using key words such as "immunosuppressive medication," "wound healing," and "immunosuppression." Articles in which the title and/or abstract contained these key words, that addressed wound healing related to immunosuppressant medications, and were published after 2000 were included in the review. When human data were not available for an immunosuppressant (class), animal studies were included. DATA EXTRACTION: The 61 included articles underwent full text review and summarization. DATA SYNTHESIS: All included studies were summarized descriptively including immunosuppressive mechanism of action, study participants or subjects, and evidence of effects on wound healing. CONCLUSIONS: Corticosteroids and mechanistic target of rapamycin inhibitors most consistently demonstrate detrimental effects on wound healing. For other classes of immunosuppressants, evidence is limited with varying effects on wound healing described. Larger, high-quality studies are required to better understand the effects of immunosuppressants, including those with new mechanisms of action, to identify those with the most impact on wound healing.

INHIBITORS OF INORGANIC POLYPHOSPHATE AND NUCLEIC ACIDS ATTENUATE IN VITRO THROMBIN GENERATION IN PLASMA FROM TRAUMA PATIENTS.

ABSTRACT: Background: Inorganic polyphosphate (polyP) is a procoagulant polyanion. We assessed the impact of polyP inhibition on thrombin generation after trauma using the novel polyP antagonists, macromolecular polyanion inhibitor 8 (MPI 8), and universal heparin reversal agent 8 (UHRA-8). Methods: Plasma thrombin generation (calibrated automated thrombogram, CAT), in 56 trauma patients and 39 controls +/- MPI 8 and UHRA-8 (50 µg/mL), was expressed as lag time (LT, minutes), peak height (PH, nM), and time to peak (ttPeak, minutes), with change in LT (ΔLT) and change in ttPeak (ΔttPeak) quantified. Results expressed in median and quartiles [Q1, Q3], Wilcoxon matched-pairs testing, P < 0.05 significant. Results: Trauma patients had greater baseline PH than controls (182.9 [121.0, 255.2]; 120.5 [62.1, 174.8], P < 0.001). MPI 8 treatment prolonged LT and ttPeak in trauma (7.20 [5.88, 8.75]; 6.46 [5.45, 8.93], P = 0.020; 11.28 [8.96, 13.14]; 11.00 [8.95, 12.94], P = 0.029) and controls (7.67 [6.67, 10.50]; 6.33 [5.33, 8.00], P < 0.001; 13.33 [11.67, 15.33]; 11.67 [10.33, 13.33], P < 0.001). UHRA-8 treatment prolonged LT and ttPeak and decreased PH in trauma (9.09 [7.45, 11.33]; 6.46 [5.45, 8.93]; 14.02 [11.78, 17.08]; 11.00 [8.95, 12.94]; 117.4 [74.5, 178.6]; 182.9 [121.0, 255.2]) and controls (9.83 [8.00, 12.33]; 6.33 [5.33, 8.00]; 16.67 [14.33, 20.00]; 11.67 [10.33, 13.33]; 55.3 [30.2, 95.9]; 120.5 [62.1, 174.8]), all P < 0.001. Inhibitor effects were greater for controls (greater ΔLT and ΔttPeak for both inhibitors, P < 0.001). Conclusion: PolyP inhibition attenuates thrombin generation, though to a lesser degree in trauma than in controls, suggesting that polyP contributes to accelerated thrombin generation after trauma.

Association between tranexamic acid administration and mortality based on the trauma phenotype: a retrospective analysis of a nationwide trauma registry in Japan.

BACKGROUND: In trauma systems, criteria for individualised and optimised administration of tranexamic acid (TXA), an antifibrinolytic, are yet to be established. This study used nationwide cohort data from Japan to evaluate the association between TXA and in-hospital mortality among all patients with blunt trauma based on clinical phenotypes (trauma phenotypes). METHODS: A retrospective analysis was conducted using data from the Japan Trauma Data Bank (JTDB) spanning 2019 to 2021. RESULTS: Of 80,463 patients with trauma registered in the JTDB, 53,703 met the inclusion criteria, and 8046 (15.0%) received TXA treatment. The patients were categorised into eight trauma phenotypes. After adjusting with inverse probability treatment weighting, in-hospital mortality of the following trauma phenotypes significantly reduced with TXA administration: trauma phenotype 1 (odds ratio [OR] 0.68 [95% confidence interval [CI] 0.57-0.81]), trauma phenotype 2 (OR 0.73 [0.66-0.81]), trauma phenotype 6 (OR 0.52 [0.39-0.70]), and trauma phenotype 8 (OR 0.67 [0.60-0.75]). Conversely, trauma phenotypes 3 (OR 2.62 [1.98-3.47]) and 4 (OR 1.39 [1.11-1.74]) exhibited a significant increase in in-hospital mortality. CONCLUSIONS: This is the first study to evaluate the association between TXA administration and survival outcomes based on clinical phenotypes. We found an association between trauma phenotypes and in-hospital mortality, indicating that treatment with TXA could potentially influence this relationship. Further studies are needed to assess the usefulness of these phenotypes.

Tranexamic acid in trauma: After 3 hours from injury, when is it safe and effective to use again?

Tranexamic acid (TXA) has proven mortality benefit if used early after traumatic injury, likely related to a combination of bleeding reduction and other non-bleeding effects. If TXA is given more than 3 h after traumatic injury, there is a significant and paradoxical increased risk of death due to bleeding. TXA has level 1 evidence for use as a bleeding reduction agent in isolated orthopedic operations, but in polytrauma patients undergoing orthopedic operations, it is not clear if and when TXA is safe or effective once outside the 3-h window of proven trauma efficacy.

Topical delivery of insulin using novel organogel formulations: An approach for the management of diabetic wounds.

Diabetes mellitus is a growing chronic form of diabetes, with lengthy health implications. It is predicted as poor diabetic wound recovery affects roughly 25% of all diabetes mellitus patients, frequently resulting in lower traumatic injury and severe external factors and emotional expenses. The insulin-resistant condition increases biofilm development, making diabetic wounds harder to treat. Nowadays, medical treatment and management of diabetic wounds, which have a significant amputation rate, a high-frequency rate, and a high death rate, have become a global concern. Topical formulations have played a significant part in diabetic wound management and have been developed to achieve a number of features. Because of its significant biocompatibility, moisture retention, and therapeutic qualities, topical insulin has emerged as an appealing and feasible wound healing process effector. With a greater comprehension of the etiology of diabetic wounds, numerous functionalized topical insulins have been described and shown good outcomes in recent years, which has improved some diabetic injuries. The healing of wounds is a physiological phenomenon that restores skin integrity and heals damaged tissues. Insulin, a powerful wound-healing factor, is also used in several experimental and clinical studies accelerate healing of diverse injuries.

25% HUMAN SERUM ALBUMIN IMPROVES HEMODYNAMICS AND PREVENTS THE NEED FOR NEARLY ALL PREHOSPITAL RESUSCITATION IN A RAT ( RATTUS NORVEGICUS ) MODEL OF TRAUMA AND HEMORRHAGE.

ABSTRACT: Combat casualty care can be complicated by transport times exceeding the "golden hour," with intervention and resuscitation limited to what the medic can carry. Pharmaceutical albumin comes highly saturated with nonesterified fatty acids (NEFAs). We recently showed that treatment with 25% bovine serum albumin (BSA) loaded with oleic acid, but not NEFA-free BSA, improved survival for hours after severe hemorrhage and often eliminated the need for resuscitation in rats. However, it was unknown whether pharmaceutical albumin, derived from human sources and loaded with caprylic acid (CA), would have the same benefits. We compared adjunct treatment with oleic acid-saturated BSA, CA-saturated BSA, pharmaceutical human serum albumin, or a no-albumin control in a similar rat hemorrhagic shock model to determine whether the three NEFA-albumin groups provided the same benefits relative to control. We found almost no significant differences among the NEFA-albumin groups in any measure. Mortality in controls was too low to allow for detection of improvement in survival, but NEFA-albumin groups had significantly improved hemodynamics, lactate clearance, and greatly reduced fluid requirements compared with controls. Contrary to expectations of "dehydration," 25% albumins shifted little additional fluid into the vasculature. Rather, they restored protein to the autotransfusion fluid. Nonesterified fatty acids-albumin did not worsen lung permeability, but we observed a loss of circulating protein suggesting it may have increased overall vascular permeability. Our findings suggest that, though imperfect, 25% human serum albumin could be a solution for resuscitation in austere conditions requiring prolonged field care.

Thrombosis prophylaxis following trauma.

PURPOSE OF REVIEW: This review explores the persistent occurrence of venous thromboembolic events (VTE) in major trauma patients despite standard thrombosis prophylaxis with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH). It investigates the inadequacies of standard pharmacologic prophylaxis and proposes alternative approaches not covered in current trauma guidelines. RECENT FINDINGS: Recent studies highlight the effectiveness of monitoring and adjusting subcutaneous LMWH doses based on anti-Xa levels for the purpose of reducing VTE in trauma patients. The need for dose adaptation arises due to factors like fluctuating organ function, varying antithrombin levels, interaction with plasma proteins, and altered bioavailability influenced by oedema or vasopressor use. Additionally, promising alternatives such as intravenous LMWH, UFH, and argatroban have shown success in intensive care settings. SUMMARY: The standard dosing of subcutaneous LMWH is often insufficient for effective thrombosis prophylaxis in trauma patients. A more personalised approach, adjusting doses based on specific effect levels like anti-Xa or choosing an alternative mode of anticoagulation, could reduce the risk of insufficient prophylaxis and subsequent VTE.

Antidote vs. unspecific hemostatic agents for the management of direct oral anticoagulant-related bleeding in trauma.

PURPOSE OF REVIEW: The advent of direct oral anticoagulants (DOACs) marks a significant milestone in anticoagulant treatment. However, DOACs can exacerbate bleeding, which is challenging for the treating clinician, especially when combined with traumatic injury. RECENT FINDINGS: In major bleeding associated with DOACs, rapid reversal of the anticoagulant effects is crucial. Recent observational and nonrandomized interventional trials have demonstrated the effectiveness of the specific antidotes andexanet alfa and idarucizumab as well as the unspecific prothrombin complex concentrates (PCCs) to counteract the anticoagulant effects of DOACs. The European Society of Anaesthesiology and Intensive Care guideline for severe perioperative bleeding and the European trauma guideline propose divergent recommendations for the use of andexanet alfa and PCC to obtain hemostasis in Factor Xa inhibitor-related bleeding. The conflicting recommendations are due to limited evidence from clinical studies and the potential increased risk of thromboembolic complications after the administration of andexanet. Regarding dabigatran-associated major bleeding, both guidelines recommend the specific reversal agent idarucizumab as first-line therapy. SUMMARY: Current guidelines recommend specific antidots and PCCs in DOAC-related major bleeding. Prospective randomized trials comparing specific vs. nonspecific hemostatic agents in the perioperative setting are needed to evaluate the effectiveness and safety of the hemostatic agents.

Direct oral anticoagulants in trauma patients.

PURPOSE OF REVIEW: Direct oral anticoagulants (DOACs) are increasingly prescribed for prevention of thromboembolic events. Thus, trauma care providers are facing a steadily raising number of injured patients on DOACs. RECENT FINDINGS: Despite a predictable pharmacokinetic profile, the resulting plasma levels of trauma patients upon admission and bleeding risks remain uncertain. Therefore, recent guidelines recommend the measurement of DOAC plasma concentrations in injured patients. Alternatively, DOAC specific visco-elastic tests assays can be applied to identify DOAC patients at bleeding risk.Bleeding complications in trauma patients on DOACs are generally higher compared to nonanticoagulated subjects, but comparable to vitamin K antagonists (VKAs). In particular, a traumatic brain injury does not carry an increased risk of intracranial bleeding due to a DOAK intake compared to VKAs. Current studies demonstrated that up to 14% of patients with a hip fracture are on DOACs prior to surgery. However, the majority can be operated safely within a 24h time window without an increased bleeding rate.Specific antagonists facilitate rapid reversal of patients on DOACs. Idarucizumab for dabigatran, and andexanet alfa for apixaban and rivaroxaban have been approved for life threatening bleeding. Alternatively, prothrombin complex concentrate can be used. Dialysis is a potential treatment option for dabigatran and haemoabsorption with special filters can be applied in patients on FXa-inhibitors. SUMMARY: Current guidelines recommend the measurement of DOAC plasma levels in trauma patients. Compared to VKAs, DOACs do not carry a higher bleeding risk. DOAC specific antagonists facilitate the individual bleeding management.

Pre-hospital tranexamic acid administration in patients with a severe hemorrhage: an evaluation after the implementation of tranexamic acid administration in the Dutch pre-hospital protocol.

PURPOSE: To evaluate the pre-hospital administration of tranexamic acid in ambulance-treated trauma patients with a severe hemorrhage after the implementation of tranexamic acid administration in the Dutch pre-hospital protocol. METHODS: All patients with a severe hemorrhage who were treated and conveyed by EMS professionals between January 2015, and December 2017, to any trauma-receiving emergency department in the eight participating trauma regions in the Netherlands, were included. A severe hemorrhage was defined as extracranial injury with > 20% body volume blood loss, an extremity amputation above the wrist or ankle, or a grade ≥ 4 visceral organ injury. The main outcome was to determine the proportion of patients with a severe hemorrhage who received pre-hospital treatment with tranexamic acid. A Generalized Linear Model (GLM) was performed to investigate the relationship between pre-hospital tranexamic acid treatment and 24 h mortality. RESULTS: A total of 477 patients had a severe hemorrhage, of whom 124 patients (26.0%) received tranexamic acid before arriving at the hospital. More than half (58.4%) of the untreated patients were suspected of a severe hemorrhage by EMS professionals. Patients treated with tranexamic acid had a significantly lower risk on 24 h mortality than untreated patients (OR 0.43 [95% CI 0.19-0.97]). CONCLUSION: Approximately a quarter of the patients with a severe hemorrhage received tranexamic acid before arriving at the hospital, while a severe hemorrhage was suspected in more than half of the non-treated patients. Severely hemorrhaging patients treated with tranexamic acid before arrival at the hospital had a lower risk to die within 24 h after injury.

Malodour from oral malignant fungating wound: sprayed metronidazole - case report.

Metronidazole gel or ointment is recommended for the treatment of malodour from malignant fungating wounds. However, this medication may not settle adequately in oral lesions because its texture causes discomfort and it tends to be washed out by saliva. We report a case of malodour due to an oral lesion that was well controlled with sprayed metronidazole.

Associations with Prehospital Antibiotic Receipt among Combat Casualties with Open Wounds: A Department of Defense Trauma Registry Study.

INTRODUCTION: Current Tactical Combat Casualty Care (TCCC) guidelines recommend antibiotic administration for all open wounds to prevent infection. We identified associations between demographics, procedures, and medicines with the receipt of prehospital antibiotics among combat casualties. MATERIALS AND METHODS: We used a series of emergency department procedure codes to identify adult subjects within the Department of Defense Trauma Registry from January 2007 to August 2016 who sustained open wounds. We compared demographics, procedures, and medicines administered among casualties receiving prehospital wound prophylaxis versus casualties not receiving antibiotic prophylaxis. We controlled for confounders with multivariable logistical regression. RESULTS: We identified 18,366 encounters meeting inclusion criteria. Antibiotic recipients (n = 2384) were comparable to nonrecipients (n = 15,982) with regard to age and sex. Antibiotic recipients were more likely to sustain injuries from firearms and undergo all procedures examined related to hemorrhage control, airway management, pneumothorax treatment, and volume replacement except for intraosseous access. Antibiotic recipients were less likely to sustain injuries from explosives. Antibiotic recipients had a modestly higher survival than nonrecipients (97.4% versus 96.0%). Associations with prehospital antibiotic receipt in multivariable logistic regression included non-North Atlantic Treaty Organization military force affiliation (odds ratio (OR) 4.65, 95% CI, 1.0-20.8), tachycardia (OR 3.4, 95% CI, 1.1-10.5), intubation (OR 2.0, 95% CI, 1.1-3.8), and administration of tranexamic acid (OR 5.6, 95% CI, 1.2-26.5). CONCLUSIONS: The proportion of combat casualties with open wounds receiving prehospital antibiotics was low despite published recommendations for early antibiotics in patients with open wounds. These findings highlight the ongoing need for additional educational and quality assurance initiatives to continue improving adherence to TCCC guidelines with regard to prehospital antibiotic administration. Future studies are necessary to determine reasons for suboptimal TCCC guideline compliance.

Propriedades Químicas e Farmacológicas do Gênero Copaifera no Tratamento de Lesões/feridas: Revisão Integrativa / Chemical and Pharmacological Properties of the Genus Copaifera in the Treatment of Injuries/wounds: Integrative Review / Propiedades Químicas y Farmacológicas del Género Copaifera en el Tratamiento de Lesiones/heridas: Revisión Integradora

Objetivo:Identificar propriedades químicas e farmacológicas do gênero Copaifera no tratamento de lesões e feridas. Método: Revisão integrativa da literatura realizada nas bases de dados LILACS, MEDLINE, PubMed, Taylor & Francis e Scopus, em janeiro de 2022, por meio da estratégia de busca: "Chemical Properties" AND "Copaifera" AND "Wounds and Injuries" e "Pharmacology" AND "Copaifera" AND "Wounds and Injuries". Foram incluídos artigos originais, de texto completo, identificados de acordo nível de evidência, redigidos em português, inglês ou espanhol. Resultados: Na busca primária foram encontrados 261 artigos. Após a seleção sistematizada, 12 estudos foram selecionados para análise qualitativa. Espécies do gênero Copaifera apresentam propriedades farmacológicas favoráveis ao tratamento de feridas: controle da dor inflamatória, diminuição da reação inflamatória, reepitelização e reparo tecidual, angiogênese, retração da ferida e remodelagem de cicatrizes. Dentre as propriedades químicas associadas ao tratamento de lesões, destacam-se presença de compostos bioativos: diterpenos, 3-hidroxi-copálico, sesquiterpenos, éster kolavic-15-metílico. Entre os diterpenos testados, o caurenoico e os ácidos copálicos mostraram atividades hemolíticas significativas. Apenas o ácido copálico e o ácido hardwíckiico inibiram a produção de óxido nítrico em macrófagos ativados por lipopolissacarídeos. Conclusão: As plantas do gênero Copaifera apresentam propriedades químicas e farmacológicas favoráveis ao tratamento de lesões e feridas

Objective:To identify chemical and pharmacological properties of Copaifera in the treatment of injuries and wounds. Method: Integrative literature review conducted in the LILACS, MEDLINE, PubMed, Taylor & Francis and Scopus databases in January 2022, using the search strategy: "Chemical Properties" AND "Copaifera" AND "Wounds and Injuries" and "Pharmacology" AND "Copaifera" AND "Wounds and Injuries." Original articles, full text, identified according to level of evidence, written in Portuguese, English or Spanish, were included. Results: In the primary search 261 articles were found. After systematized selection, 12 studies were selected for qualitative analysis. Species of the genus Copaifera have pharmacological properties favorable for wound treatment: control of inflammatory pain, reduction of inflammatory reaction, tissue reepithelialization and repair, angiogenesis, wound retraction and scar remodeling. Among the chemical properties associated with the treatment of injuries, the presence of bioactive compounds stand out: diterpenes, 3-hydroxy-copalic, sesquiterpenes, kolavic-15-methyl ester. Among the tested diterpenes, kaurenoic and copalic acids showed significant hemolytic activities. Only copalic acid and hardwickiic acid inhibited nitric oxide production in lipopolysaccharide-activated macrophages. Conclusion: Plants of the genus Copaifera have chemical and pharmacological properties favorable for the treatment of injuries and wounds.

Objetivo:Identificar las propiedades químicas y farmacológicas del género Copaifera en el tratamiento de lesiones y heridas. Método: Revisión integradora de la literatura realizada en las bases de datos LILACS, MEDLINE, PubMed, Taylor & Francis y Scopus, en enero de 2022, mediante la estrategia de búsqueda: "Chemical Properties" AND "Copaifera" AND "Wounds and Injuries" e "Pharmacology" AND "Copaifera" AND "Wounds and Injuries". Se incluyeron artículos originales, a texto completo, identificados según el nivel de evidencia, escritos en portugués, inglés o español. Resultados: En la búsqueda primaria se encontraron 261 artículos. Tras una selección sistematizada, se seleccionaron 12 estudios para el análisis cualitativo. Las especies del género Copaifera presentan propiedades farmacológicas favorables para el tratamiento de las enfermedades: control del dolor inflamatorio, disminución de la reacción inflamatoria, reepitelización y reparación tecidual, angiogénesis, retracción de la piel y remodelación de las cicatrices. Entre las propiedades químicas asociadas al tratamiento de las lesiones, destaca la presencia de compuestos bioactivos: diterpenos, 3-hidroxicopálico, sesquiterpenos, éster kolavico-15-metilo. Entre los diterpenos probados, los ácidos kaurenoico y copálico mostraron actividades hemolíticas significativas. Sólo el ácido copálico y el ácido hardwickiico inhibieron la producción de óxido nítrico en macrófagos activados por lipopolisacáridos. Conclusión: Las plantas del género Copaifera presentan propiedades químicas y farmacológicas favorables para el tratamiento de lesiones y heridas.