Elucidation of the Role of TRPV1, VEGF-A, TXA2, Redox Homeostasis, and Inflammatory Cascades in Protection against Cold Injuries by Herbosomal-Loaded PEG-Poloxamer Topical Formulation.

High-altitude regions, cold deserts, permafrost regions, and the polar region have some of the severest cold conditions on earth and pose immense perils of cold injuries to exposed individuals. Accidental and unintended exposures to severe cold, either unintentionally or due to occupational risks, can greatly increase the risk of serious conditions including hypothermia, trench foot, and cold injuries like frostbite. Cold-induced vasoconstriction and intracellular/intravascular ice crystal formation lead to hypoxic conditions at the cellular level. The condition is exacerbated in individuals having inadequate and proper covering and layering, particularly when large area of the body are exposed to extremely cold environments. There is a paucity of preventive and therapeutic pharmacological modalities that have been explored for managing and treating cold injuries. Given this, an efficient modality that can potentiate the healing of frostbite was investigated by studying various complex pathophysiological changes that occur during severe cold injuries. In the current research, we report the effectiveness and healing properties of a standardized formulation, i.e., a herbosomal-loaded PEG-poloxamer topical formulation (n-HPTF), on frostbite. The intricate mechanistic pathways modulated by the novel formulation have been elucidated by studying the pathophysiological sequelae that occur following severe cold exposures leading to frostbite. The results indicate that n-HPTF ameliorates the outcome of frostbite, as it activates positive sensory nerves widely distributed in the epidermis transient receptor potential vanilloid 1 (TRPV1), significantly (p < 0.05) upregulates cytokeratin-14, promotes angiogenesis (VEGF-A), prominently represses the expression of thromboxane formation (TXA2), and significantly (p < 0.05) restores levels of enzymatic (glutathione reductase, superoxide dismutase, and catalase) and nonenzymatic antioxidants (glutathione). Additionally, n-HPTF attenuates oxidative stress and the expression of inflammatory proteins PGF-2α, NFκB-p65, TNF-α, IL-6, IL-1ß, malondialdehyde (MDA), advanced oxidative protein products (AOPP), and protein carbonylation (PCO). Masson's Trichrome staining showed that n-HPTF stimulates cellular proliferation, and increases collagen fiber deposition, which significantly (p < 0.05) promotes the healing of frostbitten tissue, as compared to control. We conclude that protection against severe cold injuries by n-HPTF is mediated via modulation of pathways involving TRPV1, VEGF-A, TXA2, redox homeostasis, and inflammatory cascades. The study is likely to have widespread implications for the prophylaxis and management of moderate-to-severe frostbite conditions.

Dermorphin [D-Arg2, Lys4] (1-4) Amide Alleviates Frostbite-Induced Pain by Regulating TRP Channel-Mediated Microglial Activation and Neuroinflammation.

Cold injury or frostbite is a common medical condition that causes serious clinical complications including sensory abnormalities and chronic pain ultimately affecting overall well-being. Opioids are the first-choice drug for the treatment of frostbite-induced chronic pain; however, their notable side effects, including sedation, motor incoordination, respiratory depression, and drug addiction, present substantial obstacle to their clinical utility. To address this challenge, we have exploited peripheral mu-opioid receptors as potential target for the treatment of frostbite-induced chronic pain. In this study, we investigated the effect of dermorphin [D-Arg2, Lys4] (1-4) amide (DALDA), a peripheral mu-opioid receptor agonist, on frostbite injury and hypersensitivity induced by deep freeze magnet exposure in rats. Animals with frostbite injury displayed significant hypersensitivity to mechanical, thermal, and cold stimuli which was significant ameliorated on treatment with different doses of DALDA (1, 3, and 10 mg/kg) and ibuprofen (100 mg/kg). Further, molecular biology investigations unveiled heightened oxido-nitrosative stress, coupled with a notable upregulation in the expression of TRP channels (TRPA1, TRPV1, and TRPM8), glial cell activation, and neuroinflammation (TNF-α, IL-1ß) in the sciatic nerve, dorsal root ganglion (DRG), and spinal cord of frostbite-injured rats. Treatment with DALDA leads to substantial reduction in TRP channels, microglial activation, and suppression of the inflammatory cascade in the ipsilateral L4-L5 DRG and spinal cord of rats. Overall, findings from the present study suggest that activation of peripheral mu-opioid receptors mitigates chronic pain in rats by modulating the expression of TRP channels and suppressing glial cell activation and neuroinflammation.

Acupuncture and herbal medicine in preventing amputation and promoting tissue regeneration in severe frostbite: A case series.

BACKGROUND: Frostbite is a medically significant form of tissue injury that can lead to the potential need for amputation or necessitate tissue regeneration. It occurs most frequently at cryogenic temperatures in extreme altitude climbing, winter sports, and military activities. While acupuncture and herbal medicine have been reported to possess tissue regeneration effectiveness, there is currently no clinical evidence supporting their use in treating grade 3 frostbite cases at risk of amputation. CASE PRESENTATION: Three patients were diagnosed with grade 3 frostbite based on the extent and severity of tissue damage after alpine climbing in the Himalayas. After an urgent treatment, partial body amputation was advised. In order to seek any complementary treatment options and avoid amputation, they were referred to a frostbite expert in traditional Korean medicine. They received a comprehensive treatment consisting of acupuncture, bloodletting, direct moxibustion, and herbal medicine. All the patients showed notable healing of the damaged tissue, which prevented the need for amputation. No adverse effects or other sequelae were observed. CONCLUSION: This case series suggests that complementary medicine, primarily acupuncture and herbal medicine, could be effective for severe frostbite. Further studies with larger sample sizes and control groups are needed to determine the efficacy and safety of this treatment modality for frostbite management.

[Research progress on Huangqi Guizhi Wuwu Decoction and predictive analysis of quality markers].

Huangqi Guizhi Wuwu Decoction is a classic prescription in traditional Chinese medicine(TCM) and is known for its effects of tonifying Qi, warming the meridians, and promoting blood circulation to alleviate obstruction. It is primarily used to treat conditions characterized by Qi stagnation, Yang deficiency, and obstruction, and it exhibits pharmacological effects such as immune regulation, anti-inflammation, analgesia, protection of the cardiovascular and cerebrovascular systems, itch relief, reduction of frostbite symptoms, antioxidative stress, promotion of cell apoptosis, and kidney protection. In modern clinical practice, it is commonly used to treat acute myocardial infarction, sequelae of cerebral infarction, cervical spondylosis, frozen shoulder, lower limb arteriosclerosis, lower limb vascular disorders, peripheral neuropathy in diabetes, and lupus nephritis. Recent research has focused on the chemical components, pharmacological effects, and clinical applications of Huangqi Guizhi Wuwu Decoction. Based on the "five principles" of quality markers(Q-markers) in TCM, this study predicted and analyzed the Q-markers of Huangqi Guizhi Wuwu Decoction. It suggested that astragaloside Ⅳ, formononetin, kaempferol, quercetin, cinnamic acid, cinnamaldehyde, 6-gingerol, paeoniflorin, albiflorin, and gallic acid could serve as Q-markers for Huangqi Guizhi Wuwu Decoction. The findings of this study can provide references for quality control of Huangqi Guizhi Wuwu Decoction and the development of new Chinese medicinal formulations.

Can iloprost be used for treatment of cold weather injury at the point of wounding in a forward operating environment? A literature review.

INTRODUCTION: Cold Weather Injury (CWI) represents a spectrum of pathology, the two main divisions being Freezing Cold Injury (FCI) and Non-Freezing Cold Injury (NFCI). Both are disabling conditions associated with microvascular and nerve injury often treated hours after initial insult when presenting to a healthcarestablishment. Given that iloprost is used for the treatment of FCI, could it be used in a forward operating environment to mitigate treatment delay? Is there a role for its use in the forward treatment of NFCI? This review sought to evaluate the strength of evidence for the potential use of iloprost in a forward operating environment. METHODS: Literature searches were undertaken using the following question for both FCI and NFCI: in [patients with FCI/NFCI] does [the use of iloprost] compared to [standard care] reduce the incidence of [long-term complications]. Medline, CINAHL and EMBASE databases were searched using the above question and relevant alternative terminology. Abstracts were reviewed before full articles were requested. RESULTS: The FCI search yielded 17 articles that were found to refer to the use of iloprost and FCI. Of the 17, one referred to pre-hospital treatment of frostbite at K2 base camp; however, this was utilising tPA. No articles referred to pre-hospital use in either FCI or NFCI. DISCUSSION: Although evidence exists to support the use of iloprost in the treatment of FCI, its use to date has been in hospital. A common theme is delayed treatment due to the challenges of evacuating casualties from a remote location. There may be a role for iloprost in the treatment of FCI; however, further study is required to better understand the risk of its use.

Botulinum Toxin A in the treatment of frostbite sequelae - results from a blinded, early-phase, comparative trial.

INTRODUCTION: Freezing Cold Injuries (FCI) have been associated with long-term sequelae including vasospasm. The aims of the pilot study are to explore the research methodology and investigate the tolerability and safety of treatment with Botulinum Toxin-A (BTX-A) in FCI Sequelae. METHODOLOGY: This pilot study tests the logistics, the treatment setting and the follow-up procedure in an early-phase, double-blinded, randomized, controlled trial study-design. The variables in the study were subjective symptoms, peripheral micro-vascularization/rewarming, somatosensory responsiveness, and generic measure of health status. RESULTS: No major challenges or difficulties were noticed according to the protocol or the study methodology. The monitoring of tolerability and safety of treatment with BTX-A did not reveal any major unwanted and/or adverse reactions among the patients in the pilot study and no challenges occurred during data collection of endpoints. The study revealed an inaccuracy of the 2nd degree FCI diagnosis and uncover a need for relevant and sufficient clinical information for FCI classification. CONCLUSIONS: This pilot study showed the study methodology with minor adjustments is feasible in a future full-scale clinical trial. The recruitment process needs to be more refined to ensure that the eligible study participants are a homogenous group of FCI patients.

Iloprost for the treatment of frostbite: a scoping review.

We performed a scoping review to identify the extent of the literature describing the use of iloprost in the treatment of frostbite. Iloprost is a stable synthetic analog of prostaglandin I2. As a potent inhibitor of platelet aggregation and vasodilator, it has been used to address the post-rewarming reperfusion injury in frostbite. The search using iloprost and frostbite as key words and MeSH terms yielded 200 articles. We included in our review the literature examining iloprost for the treatment of frostbite in humans in the form of primary research, conference proceedings and abstracts. Twenty studies published from 1994 to 2022 were selected for analysis. The majority were retrospective case series consisting of a homogeneous population of mountain sport enthusiasts. A total of 254 patients and over 1000 frostbitten digits were included among the 20 studies. The larger case series demonstrated a decrease in amputation rates relative to untreated patients. Primary gaps in the literature include a paucity of randomised trials and relatively limited study populations to date. While the case evidence is promising, a multi-centre collaboration would be crucial to adequately power prospective randomised studies to definitively determine if iloprost has a role in the treatment of frostbite.

The Effects of Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor Gel on Third-Degree Frostbite Wounds in Northeastern China: A Randomized Controlled Trial.

The aim of the study was to investigate the effects of the rhGM-CSF gel on third-degree frostbite wounds. Sixty-two patients who had suffered third-degree frostbite on their hand or foot (91 wounds in total) were selected using a convenience sampling method and randomly allocated to two groups: the rhGM-CSF group(31patients,45 frostbite wounds) received the rhGM-CSF gel when wound dressing change daily; however, the control group (31patients, 46 frostbite wounds) received aloe glue. The wound healing time, the score of inflammation about the wound and the positive bacterial culture of wound secretions were used to measure outcomes, respectively. Data were analyzed using SPSS (25.0), Student's t test or Mann-Whitney U test and chi-square test or Fisher exact test were selected, as appropriate. The healing time of the rhGM-CSF group was (12.2 ± 5.0) days, which was significantly shorter than that of the control group (15.5 ± 4.7) days (P < .0001). The rhGM-CSF group's wound inflammation scores on the 7th and 14th day of treatment were (0.96 ± 0.21) and (1.88 ± 0.29), respectively, which were better than those of the control group (1.12 ± 0.24) and (1.38 ± 0.15) (both P < .0001). The positive bacterial culture of wound secretions in the rhGM-CSF group was also better than that in the control group on the 3rd, 7th, and 14th day after treatment (P = .027, .004, .030, respectively). According to the results, using rhGM-CSF gel considerably increases the speed of frostbite wounds healing, and have an effect on protecting third-degree frostbite wounds regarding the positive effects. Trial Registration: This trial was registered in the Chinese Clinical Trial Register, ChiCTR1900021299.

Bleeding Complications in Patients With Severe Frostbite Injury.

Frostbite is caused by exposure to cold temperatures and can lead to severe injury resulting in amputations. Tissue plasminogen activator (tPA) is a thrombolytic agent that has demonstrated efficacy preventing amputation in frostbite patients. The goal of frostbite management with tPA is to salvage tissue without causing clinically significant bleeding complication. The purpose of this study was to characterize bleeding complications in severe frostbite patients managed with and without tPA. Retrospective chart review of severe frostbite patients admitted to a single ABA verified burn center. Bleeding events were grouped: category 0: no bleed; category 1: bleed not resulting in change or intervention; category 2: bleed resulting in change of management; and category 3: bleed resulting in change of management and intervention. Over a 7-year period, 188 patients were included in the study. Most patients had no documentation suggesting a bleeding complication: 69.7% category 0, 19.1% category 1, 4.8% category 2, and 6.4% category 3. There was no significant difference in category 2 or 3 bleeding complications between patients treated with or without tPA. Overall, 9 of the 143 patients (6.3%) treated with tPA had a category 2 or 3 bleeding complication within 12 hours of tPA completion and 12 of 143 (8.4%) within 24 hours of tPA completion. Based on the low risk of severe bleeding and significant benefit relative to limb or digit salvage demonstrated in this study, we conclude that tPA is safe and effective for the treatment of frostbite in appropriately selected patients.

Research progress on Huangqi Guizhi Wuwu Decoction and predictive analysis of quality markers / 中国中药杂志

Huangqi Guizhi Wuwu Decoction is a classic prescription in traditional Chinese medicine(TCM) and is known for its effects of tonifying Qi, warming the meridians, and promoting blood circulation to alleviate obstruction. It is primarily used to treat conditions characterized by Qi stagnation, Yang deficiency, and obstruction, and it exhibits pharmacological effects such as immune regulation, anti-inflammation, analgesia, protection of the cardiovascular and cerebrovascular systems, itch relief, reduction of frostbite symptoms, antioxidative stress, promotion of cell apoptosis, and kidney protection. In modern clinical practice, it is commonly used to treat acute myocardial infarction, sequelae of cerebral infarction, cervical spondylosis, frozen shoulder, lower limb arteriosclerosis, lower limb vascular disorders, peripheral neuropathy in diabetes, and lupus nephritis. Recent research has focused on the chemical components, pharmacological effects, and clinical applications of Huangqi Guizhi Wuwu Decoction. Based on the "five principles" of quality markers(Q-markers) in TCM, this study predicted and analyzed the Q-markers of Huangqi Guizhi Wuwu Decoction. It suggested that astragaloside Ⅳ, formononetin, kaempferol, quercetin, cinnamic acid, cinnamaldehyde, 6-gingerol, paeoniflorin, albiflorin, and gallic acid could serve as Q-markers for Huangqi Guizhi Wuwu Decoction. The findings of this study can provide references for quality control of Huangqi Guizhi Wuwu Decoction and the development of new Chinese medicinal formulations.

Bedside Fluorescence Microangiography for Frostbite Diagnosis in the Emergency Department.

INTRODUCTION: Frostbite leads to progressive ischemia eventually causing tissue necrosis if not quickly reversed. Patients with frostbite tend to present to the emergency department (ED) for assessment and treatment. Acute management includes rewarming, pain management, and (when indicated) thrombolytic therapy. Thrombolytic therapy in severe frostbite injury may decrease rates of amputation and improve patient outcomes. Fluorescence microangiography (FMA) has been used to distinguish between perfused and non-perfused tissue. The purpose of this study was to evaluate the potential role of FMA in the acute care of patients with frostbite, specifically its role as a tool to identify perfusion deficit following severe frostbite injury, and to explore its role in time to tissue plasminogen activator (tPA). METHODS: This retrospective analysis included all patients from December 2020-March 2021 who received FMA in a single ED as part of their initial frostbite evaluation. In total, 42 patients presented to the ED with concern for frostbite and were evaluated using FMA. RESULTS: Mean time from arrival in the ED to FMA was 46.3 minutes. Of the 42 patients, 14 had clinically significant perfusion deficits noted on FMA and received tPA. Mean time to tPA (measured from ED arrival to administration of tPA) for these patients was 117.4 minutes. This is significantly faster than average historical times at our institution of 240-300 minutes. CONCLUSION: Bedside FMA provides objective information regarding perfusion deficits and allows for faster decision-making and improved times to tPA. Fluorescence microangiography shows promise for quick and efficient evaluation of perfusion deficits in frostbite-injured patients. This could lead to faster tPA administration and potentially greater rates of tissue salvage after severe frostbite injury.

Effectiveness of intravenous prostaglandin to reduce digital amputations from frostbite: an observational study.

PURPOSE: We assessed the effectiveness and safety of a 5-day intravenous prostaglandin (iloprost) protocol at reducing digital amputation for patients with severe frostbite injuries at urban emergency departments. METHODS: This retrospective study examines consecutive patients who presented to Calgary emergency departments from April 2017 to April 2020 with Grade 2-4 frostbite injuries. Patients from February 2019 onward were managed using a 5-day iloprost infusion protocol, whereas patients prior to this time were managed with standard care (local best practice without iloprost as a therapeutic option). The primary effectiveness outcome was rate of affected digits amputated, stratified by frostbite severity. The secondary safety outcome was the incidence of serious adverse events associated with iloprost (allergic reactions or symptomatic hypotension requiring treatment or discontinuation of the infusion). RESULTS: 90 patients were included, 26 were treated with iloprost, compared to 64 patients who received usual care. Both the treatment and usual care groups experienced substantial rates of homelessness and substance use. No digital amputations were required for patients with Grade 2 injuries in either group, but significantly lower digital amputation rates were observed for patients with more severe frostbite injuries treated with iloprost versus usual care: Grade 3 (18% vs 44%, p < 0.001), Grade 4 (46% vs 95%, p < 0.001). No serious adverse events were associated with iloprost. CONCLUSION: In this unselected socially complex urban population, administration of iloprost for patients with frostbite was shown to be safe and was associated with lower digital amputation rates, particularly for those with more severe injuries.

RéSUMé: OBJECTIF: Nous avons évalué l'efficacité et la sécurité d'un protocole de 5 jours de prostaglandine intraveineuse (iloprost) pour réduire l'amputation digitale chez les patients souffrant d'engelures graves dans les services d'urgence urbains. MéTHODES: Cette étude rétrospective examine des patients consécutifs qui se sont présentés aux services d'urgence de Calgary d'avril 2017 à avril 2020 avec des engelures de niveau 2 à 4. À compter de février 2019, les patients ont été traités au moyen d'un protocole de perfusion d'iloprost de 5 jours, tandis que les patients avant cette période ont été pris en charge avec des soins standard (meilleures pratiques locales sans iloprost comme option thérapeutique). Le principal résultat d'efficacité était le taux de doigts affectés amputés, stratifié selon la gravité des gelures. Le critère secondaire de sécurité était l'incidence des événements indésirables graves associés à l'iloprost (réactions allergiques ou hypotension symptomatique nécessitant un traitement ou l'arrêt de la perfusion). RéSULTATS: 90 patients ont été inclus, 26 ont été traités avec de l'iloprost, contre 64 patients qui ont reçu les soins habituels. Les groupes de traitement et de soins habituels ont tous deux connu des taux importants de sans-abrisme et de consommation de substances. Aucune amputation digitale n'a été nécessaire pour les patients présentant des lésions de grade 2 dans l'un ou l'autre groupe, mais des taux d'amputation digitale significativement plus faibles ont été observés pour les patients présentant des lésions de gelures plus sévères traités par iloprost par rapport aux soins habituels : Grade 3 (18 % contre 44 %, p < 0,001), Grade 4 (46 % contre 95 %, p < 0,001). Aucun événement indésirable grave n'a été associé à l'iloprost. CONCLUSION: Dans cette population urbaine non sélectionnée et socialement complexe, l'administration d'iloprost pour les patients souffrant d'engelures s'est avérée sûre et a été associée à des taux d'amputation digitale plus faibles, en particulier pour ceux présentant des blessures plus graves.

Early Use of Iloprost in Nonfreezing Cold Injury.

Nonfreezing cold injury (NFCI) is caused by prolonged exposure to cold, usually wet conditions and represents a separate pathological entity from frostbite. The pathophysiology of NFCI is characterized by vasoconstriction and microcirculatory disturbance. Iloprost, a synthetic prostaglandin analogue with vasodilatory properties is a recognized adjuvant treatment in frostbite; however, its role in NFCI is unclear. We present a case of a 29-y-old man with severe NFCI to both forefeet after prolonged immersion in cold seawater. Initial treatment with passive rewarming, analgesia and aspirin was initiated. Infusion of iloprost was used within 24 h from presentation and was well tolerated. This resulted in reduced tissue loss compared to the apparent tissue damage documented during the initial assessment. Delayed surgical intervention allowed minor debridement and minor toe amputations, maintaining the patient's ability to ambulate. This case demonstrates the safe use of iloprost in acute NFCI and highlights the importance of delayed surgical intervention in patients presenting with severe NFCI.

Remote Delivery of Thrombolytics Prior to Transfer to a Regional Burn Center for Tissue Salvage in Frostbite: A Single-center Experience of 199 Patients.

While much has been published on the efficacy and safety of systemic thrombolytics in the treatment of acute frostbite, there has been limited investigation into administration outside a tertiary care setting. Here, we present a single-center experience with remote initiation of intravenous tissue plasminogen activator (tPA) at referring hospitals prior to transfer to a regional burn center. A modified Hennepin Quantification Score based on tissue involvement was used to determine eligibility for tPA and to quantify the severity of amputation. This is a retrospective review of patients with acute frostbite of the digits admitted to a single verified burn center over a 5-yr period. Of 199 patient admissions, 40 received tPA remotely pre-transfer, 32 received tPA on admission to our institution, and 127 patients did not qualify for tPA therapy according to the protocol. Comparing patients who required any amputation (n = 99, 49.7%) to those who did not, patients who received remote tPA had lower odds of any amputation compared to both those receiving tPA at our institution (OR 0.19, 95% CI 0.05-0.65, P = 0.01) and the group receiving no tPA (OR 0.14, 95% CI 0.05-0.40, P < 0.001) after controlling for confounders. Only one patient receiving pre-transfer tPA according to the protocol (2.3%) had a significant bleeding event requiring transfusion. These results support the protocolized use of thrombolytic therapy for frostbite prior to transfer to a tertiary center.

The Effects of Rapid Rewarming on Tissue Salvage in Severe Frostbite Injury.

Frostbite is a high morbidity injury caused by soft tissue freezing, which can lead to digit necrosis requiring amputation. Rapid rewarming is a first-line treatment method that involves placing affected digits into a warm water bath. This study aims to assess the clinical practices for frostbite at facilities outside of dedicated burn centers, and any impact these practices have on tissue salvage. Retrospective chart review at a single burn center identified frostbite patients admitted directly or as transfers over a 7-year period. Records were reviewed to identify initial treatment strategies. If given, time to thrombolytics from admit was noted. Tissue salvage rates were calculated from radiologically derived tissue at-risk scores and final amputation scores. One-hundred patients were transferred from outside facilities, and 108 were direct admissions (N = 208). There was no significant difference in group demographics. Rapid rewarming was the initial treatment modality more commonly in direct admit patients (P = .016). The use of rapid rewarming did not correlate with tissue salvage (P = .112). Early use of thrombolytics had a positive impact on tissue salvage (P = .003). Thrombolytics were given 1.2 hours earlier in direct admit patients (P = .029), however there was no difference in tissue salvage rates between the groups (P = .127). Efforts should focus on larger scale study to further assess the effectiveness of rapid rewarming. Although rapid rewarming did not significantly impact tissue salvage in this study, we continue to recommend its use over less studied treatment methods, and continue to view it as an important bridge to burn center transfer and administration of thrombolytic therapy.

Hyperbaric Oxygen Therapy with Iloprost Improves Digit Salvage in Severe Frostbite Compared to Iloprost Alone.

Background and Objectives: Frostbite is a freezing injury that can lead to amputation. Current treatments include tissue rewarming followed by thrombolytic or vasodilators. Hyperbaric oxygen (HBO) therapy might decrease the rate of amputation by increasing cellular oxygen availability to the damaged tissues. The SOS-Frostbite study was implemented in a cross-border program among the hyperbaric centers of Geneva, Lyon, and the Mont-Blanc hospitals. The objective was to assess the efficacy of HBO + iloprost among patients with severe frostbite. Materials and Methods: We conducted a multicenter prospective single-arm study from 2013 to 2019. All patients received early HBO in addition to standard care with iloprost. Outcomes were compared to a historical cohort in which all patients received iloprost alone between 2000 and 2012. Inclusion criteria were stage 3 or 4 frostbite and initiation of medical care <72 h from frostbite injury. Outcomes were the number of preserved segments and the rate of amputated segments. Results: Thirty patients from the historical cohort were eligible and satisfied the inclusion criteria, and 28 patients were prospectively included. The number of preserved segments per patient was significantly higher in the prospective cohort (mean 13 ± SD, 10) compared to the historical group (6 ± 5, p = 0.006); the odds ratio was significantly higher by 45-fold (95%CI: 6-335, p < 0.001) in the prospective cohort compared to the historical cohort after adjustment for age and delay between signs of freezing and treatment start. Conclusions: This study demonstrates that the combination of HBO and iloprost was associated with higher benefit in patients with severe frostbite. The number of preserved segments was two-fold higher in the prospective cohort compared to the historical group (mean of 13 preserved segments vs. 6), and the reduction of amputation was greater in patients treated by HBO + iloprost compared with the iloprost only.

Exploring the frostbite healing potential of hyaluronic acid based hydrogel of Manuka honey through in-silico antithrombotic and anti-platelet studies of major phytoconstituents and in-vivo evaluation in Wistar rat model.

OBJECTIVE: Development of Frostbite healing hydrogel of Manuka honey and hyaluronic acid. SIGNIFICANCE: Frostbite is a cold-induced ischemic vascular injury non-responsive to most of the wound healing products. Thrombus-induced ischemia is the main cause of frostbite-related necrosis. Hyaluronic acid is known to possess significant antithrombotic and wound healing activity. Moreover, Manuka Honey is also rich in flavonoids and polyphenols with potential antithrombotic activity. These two agents were together utilized to develop a frostbite healing formulation. METHODS: In-silico antithrombotic efficacy of major phytoconstituents of Manuka honey was evaluated using in-silico-docking studies against Tissue plasminogen activator and Cyclooxygenase-1 protein. Further in-vivo frostbite healing evaluation was carried out in Wistar rats, by inducing frostbite with a supercooled rod. RESULTS: The results indicate that major leptosin and other major phytoconstituent of Manuka honey has significant antithrombotic property. The hydrogel formulation of HA and MH possess significant antimicrobial efficacy. The wound contraction studies and histopathological evaluation reveals that the hydrogel also has a good frostbite healing activity showing complete wound healing within an 18-day period. The findings of the western blotting studies suggest that the hydrogel acts by VEGF- NRF-2 pathway. CONCLUSION: This result implies that the prepared hydrogel can serve as an effective frostbite healing formulation.

Long-Term Sequelae of Frostbite-A Scoping Review.

Frostbite is tissue damage caused by freezing temperatures and constitutes an important cause of morbidity in cold climate zones and high altitude. The direct effects of sub-zero temperatures lead to tissue freezing, electrolyte shifts and pH alterations, microvascular damage, and eventually to cell death. Upon rewarming, inflammatory reperfusion injury and thrombosis may lead to further tissue damage. Several studies and various case reports show that many patients suffer from long-term sequelae such as vasomotor disturbances (associated with susceptibility to refreezing), and neuropathic and nociceptive pain, as well as damage to skeletal structures. There are still many uncertainties regarding the pathophysiology of these sequelae. It has been shown that the transient receptor potential channel (TRP) family plays a role in cold allodynia. Botulinum Toxin type A (BTX-A) injections have been reported to be beneficial in vasomotor and neuropathic disturbances secondary to frostbite. Epidural sympathetic block has been used for short-term treatment of frostbite induced chronic pain. Furthermore, amitriptyline, gabapentinoids, and duloxetine may have some benefits. Frostbite arthritis clinically resembles regular osteoarthritis. In children there is a risk of epiphyseal cartilage damage leading to bone deformities. Despite some promising therapeutic concepts, the scarcity of data on frostbite long-term sequelae in the literature indicates the need of more in-depth studies of this pathology in all its aspects.