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.

Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Treatment of Frostbite: 2024 Update.

The Wilderness Medical Society convened an expert panel to develop a set of evidence-based guidelines for the prevention and treatment of frostbite. We present a review of pertinent pathophysiology. We then discuss primary and secondary prevention measures and therapeutic management. Recommendations are made regarding each treatment and its role in management. These recommendations are graded on the basis of the quality of supporting evidence and balance between the benefits and risks or burdens for each modality according to methodology stipulated by the American College of Chest Physicians. This is an updated version of the guidelines published in 2019.

Update on Cold-Induced Injuries.

Cold-induced injuries are a major challenge for burn surgeons, leading to significant sequelae for the patients including amputations, long-term disability, and death. Rapid assessment and diagnosis are essential for optimal outcomes. Various therapies have emerged to improve outcomes. Topical, oral, and intravenous agents have shown to minimize the impact of cold-induced injuries. Thrombolytics have shown the greatest promise in improving tissue perfusion outcomes in cold-induced injuries. This article provides an update on the evidence-based assessment and management of cold-induced injuries, as well as reviews outcomes and future directions of this challenging pathology.

Oropharyngeal Swelling and Airway Obstruction from Environmental Cold Exposure: A Case Report.

A 19-year-old male presented with facial frostbite and severe oropharyngeal edema after prolonged riding of a snowmobile without any facial covering. The diffuse swelling eventually progressed to airway obstruction, requiring a surgical airway. No alternative explanation was found for his presentation, making this the first case found in the literature of airway obstruction secondary to environmental cold exposure.

Prolonged critical avalanche burial for nearly 23 h with severe hypothermia and severe frostbite with good recovery: a case report.

BACKGROUND: Accidental hypothermia with severe frostbite is a rare combination of injuries with a high risk for long-term sequelae. There are widely accepted recommendations for the management of avalanche victims and for frostbite treatment, but no recommendation exists for the treatment of frostbite in severe hypothermic patients, specifically for the management of hypothermic avalanche victims presenting with frostbite. CASE PRESENTATION: We present a case of a previously healthy, 53-year-old male skier who was critically buried by an avalanche at 2300 m of altitude at an ambient temperature of - 8 °C for nearly 23 h. The victim was found with the right hand out of the snow and an air connection to outside. He was somnolent with Glasgow Coma Scale 11 (Eye 4, Verbal 2, Motor 5) and spontaneously breathing, in a severely hypothermic state with an initial core temperature of 23.1 °C and signs of cold injuries in all four extremities. After rescue and active external forced air rewarming in the intensive care unit, the clinical signs of first-degree frostbite on both feet and the left hand vanished, while third- to fourth-degree frostbite injuries became apparent on all fingers of the right hand. After reaching a core body temperature of approximately 36 °C, aggressive frostbite treatment was started with peripheral arterial catheter-directed thrombolysis with alteplase, intravenous iloprost, ibuprofen, dexamethasone and regional sympathicolysis with a right-sided continuous axillary block. After ten months, the patient had no tissue loss but needed neuropathic pain treatment with pregabalin. CONCLUSION: The combination of severe accidental hypothermia and severe frostbite is rare and challenging, as drug metabolism is unpredictable in a hypothermic patient and no recommendations for combined treatment exist. There is general agreement to give hypothermia treatment the priority and to begin frostbite treatment as early as possible after full rewarming of the patient. More evidence is needed to identify the optimal dosage and time point to initiate treatment of frostbite in severely hypothermic patients. This should be taken into consideration by future treatment recommendations.

Development and validation of clinically Mimicable model of frostbite injury-induced chronic pain.

Frostbite, a debilitating condition, significantly affects the well-being of military veterans and high-altitude residents, causing severe clinical complications such as chronic pain that markedly impacts overall quality of life. There has been a notable increase in the development of pre-clinical models for studying frostbite injury, but their suitability for pain evaluation remains limited. The major hurdle in the development of novel therapeutics for the treatment of frostbite-induced chronic pain is the unavailability of well-established preclinical models. In this study, we employed deep-frozen magnets to induce frostbite injury and conducted validation for chronic pain through assessments of face, predictive, and mechanistic validity. Behavioral assays demonstrated that frostbite injury exhibited significant mechanical, thermal & cold hypersensitivity in rats. Further, molecular analysis indicated that frostbite injury triggered the activation of TRP channels (TRPA1, TRPV1 and TRPM8), microgliosis, and neuroinflammation in the dorsal root ganglion (DRG) and spinal cord of rats. Notably, NR2B protein expressions were significantly upregulated in the DRG of injured rats, while no changes were observed in spinal NR2B expressions. Furthermore, the administration of ibuprofen (25, 50, and 100 mg/kg, i.p.) resulted in a significant improvement in behavioral, biochemical, and molecular alterations in frostbite-injured rats. Overall, results suggested that established frostbite model effectively recapitulates face, pharmacological, and mechanistic validity, highlighting its potential for screening future treatment modalities and exploring the intricate mechanisms associated with frostbite-induced chronic pain.

Designing suitable shoes to prevent foot frostbite through optimization of the geometric dimensions of the shoe and sock model.

To prevent frostbite in cold environments, proper dimensions and materials for different parts of shoes along with the optimal design of shoe geometry were investigated. Furthermore, the optimal geometry of shoes was computed using an optimization algorithm to provide maximum thermal protection for the foot while having the lowest weight. The results showed that the length of the shoe sole and the thickness of the sock are the most effective parameters in foot protection against frostbite. Using thicker socks, which only increased the weight by roughly 11%, enhanced the minimum foot temperature by more than 2.3 times. HIGHLIGHTSOptimal design of shoe geometry is used to prevent frostbite in cold environments.A model of a biothermal nonlinear model is developed for the barefoot.Length of the shoe sole and the thickness of the sock are the most effective parameters in protecting the foot against frostbite.For the selected weather conditions, the toes are most likely to have frostbite.The best shoe for the selected weather conditions is the shoe that has the highest amount of thermal insulation in the toe area.

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.

Cold Weather Injuries Among the Active and Reserve Components of the U.S. Armed Forces, July 2018-June 2023.

Cold injuries are a predictable and preventable threat. Continuous surveillance is essential to prevent cold weather injuries and mitigate their adverse impacts on military operations. Military training and combat operations require continued emphasis on effective cold weather injury prevention strategies and adherence to relevant policies and procedures to protect service members against such injuries. For all active component service members (ACSM), the rate of cold weather injuries in 2022-2023 decreased by 15.2% compared to the preceding cold season. The decrease was most pronounced in the Marine Corps, with a 22.0% reduction in the incidence rate of cold injuries. This year's report includes cold injury rates for the Coast Guard. From July 2022 through June 2023, a total of 423 members of the active (n=376) and reserve (n=47) components of the U.S. Armed Forces had at least 1 cold weather injury. The crude overall incidence rate of cold injury among all ACSM during the 2022-2023 cold season was 28.5 per 100,000 person-years (p-yrs), 15.2% lower than the rate observed during the 2021-2022 cold season (33.6 per 100,000 p-yrs). The rates of cold injuries varied among the Armed Forces, with the highest rates per 100,000 p-yrs observed in the Army, at 50.9, followed by the Marine Corps, at 32.2, the Air Force, at 18.9, the Navy, at 8.1, and the Coast Guard, at 5.1. Consistent with previous cold seasons, frostbite (54.0%) remained the most common type of cold injury among ACSM during the 2022-2023 cold season, while the proportions of hypothermia and immersion injuries were 16.5% and 30.3%, respectively. Cold injury rates among ACSM during the 2018 to 2023 cold seasons were generally highest for males, non-Hispanic Blacks, those under 20 years of age, and enlisted members. The number of cold injuries identified in service members deployed outside the U.S during the 2022-2023 cold season (n=10) was comparable to the 2 preceding cold seasons (11 in 2020-2021 and 12 in 2021-2022), with frostbite accounting for half (n=5) of the 2022-2023 cases.

[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.

Optimum design of the geometry of boots and socks with the aim of minimum weight and preventing frostbite.

In order to design shoes suitable for cold environments, knowledge of the thermal conditions inside the shoes and the variables affecting those conditions is necessary. A two-dimensional model of a boot and sock was developed to investigate the effect of the materials and dimensions of various parts of shoes and to design geometry for them to prevent foot frostbite. The optimization algorithm was used to optimize the dimensions of the boots to maximize the minimum foot temperature with the lowest boot weight. Two types of shoe soles and two kinds of shoe uppers were used to design suitable shoes. The results show the following: (1) In the design boots, the thermal insulation of the toe area plays an essential role in preventing frostbite. Two variables of the thickness of the toe cap and the length of the shoe sole had the greatest impact on the design of shoes with the least weight and the most protection against frostbite. So that to increase minimum foot temperature from 7°C to 15°C, 16°C, or 17°C, only the amounts of these variables should increase. (2) In designing the suitable boot, choosing the proper shoe sole had a significant effect on increasing the thermal insulation in the shoe and reducing its weight. So, for the boot with a minimum foot temperature of 20°C, by changing the shoe sole from EVA08 to EVA12, the weight is reduced by 42%. (3) To maximize the minimum foot temperature, it is necessary to use thick socks.

A multifunctional sensor for real-time monitoring and pro-healing of frostbite wounds.

Flexible epidermal sensors based on conductive hydrogels hold great promise for various applications, such as wearable electronics and personal healthcare monitoring. However, the integration of conductive hydrogel epidermal sensors into multiple applications remains challenging. In this study, a multifunctional PAAm/PEG/hydrolyzed keratin (Hereinafter referred to as HK)/MXene conductive hydrogel (PPHM hydrogel) was designed as a high-performance therapeutic all-in-one epidermal sensor. This sensor not only accelerates wound healing but also provides wearable human-computer interaction. The developed sensor possesses highly sensitive sensing properties (Gauge Factor = 4.82 at high strain), strong mechanical tensile properties (capable of achieving a maximum elongation at break of 600 %), rapid self-healing capability, stable self-adhesive capability, biocompatibility, freeze resistance at -20 °C, and adjustable photo-thermal conversion capability. This therapeutic all-in-one sensor can sensitively monitor human movements, enabling the detection of small electrophysiological signals for diagnosing relevant activities and diseases. Furthermore, using a rat frostbite model, we demonstrated that the composite hydrogel sensor can serve as an effective wound dressing to accelerate the healing process. This study serves as a valuable reference for the development of multifunctional flexible epidermal sensors for personal smart health monitoring. STATEMENT OF SIGNIFICANCE: Accelerated wound healing reduces the risk of wound infection, and conductive hydrogel-based sensors can monitor physiological signals. The multifunctional application of conductive hydrogel sensors combined with wound diagnostic and therapeutic capabilities can meet personalized medical requirements for wound healing and sensor monitoring. The aim of this study is to develop a multifunctional hydrogel patch. The multifunctional hydrogel can be assembled into a flexible wearable high-performance diagnostic and therapeutic integrated sensor that can effectively accelerate the healing of frostbite wounds and satisfy the real-time monitoring of multi-application scenarios. We expect that this study will inform efforts to integrate wound therapy and sensor monitoring.

Frostbite and Mortality in Mountaineering Women: A Scoping Review-UIAA Medical Commission Recommendations.

Kriemler, Susi, Kaste Mateikaite-Pipiriene, Alison Rosier, Linda E. Keyes, Peter Paal, Marija Andjelkovic, Beth A. Beidleman, Mia Derstine, Jacqueline Pichler Hefti, David Hillebrandt, Lenka Horakova, and Dominique Jean; for the UIAA MedCom Writing Group on Women's Health in the Mountains. Frostbite and mortality in mountaineering women: a scoping review-UIAA Medical Commission recommendations. High Alt Med Biol. 24:247-258, 2023. Background: The harsh environment of high altitudes (HA) poses many serious health risks for mountaineers, including cold injuries and death. The aim of this work was to review whether female mountaineers are at special risk for frostbite or death at HA compared with their male counterparts. Methods: The UIAA Medical Commission convened an international author team to review women's health issues at HA and to publish updated recommendations. Pertinent literature from PubMed and Cochrane was identified with additional publications found by hand search. The primary search focus was for articles assessing cold injuries and death in women mountaineers at HA. Results: We reviewed the literature and identified 20 relevant studies: 2 studies on frostbite at HA, plus 7 studies and 1 report for death at HA. An additional 10 studies about frostbite at low altitude were included. We found that female mountaineers at HA were at lower risk of death than their male counterparts, but sex differences in frostbite were inconclusive. Conclusions: The frequency of cold injuries and mortality in female mountaineers is not yet well studied, and the studies that have been published tend to lack precise exposure data. More studies and registries with sex-differentiated data are needed.

Management of multiple frostbite casualties at a burn center: San Antonio, Texas, 12-20 February 2021.

BACKGROUND: Frostbite is an insidious disease that normally affects people of cold climates. Winter Storm Uri, which occurred from February 12-20, 2021, created unique metrological conditions for Texas. It caused prolonged sub-freezing temperatures and led to rolling blackouts, affecting 2.8 million Texans including 300,000 people in San Antonio. We report 13 frostbite patients admitted to one burn center during this event. OBJECTIVE: We aimed to determine the at-risk population for frostbite, to categorize their injury severity, and to describe their treatment. A secondary aim was to describe the rehabilitation management of these patients. METHODS: This is a single-center retrospective study. Each patient's injuries were assessed by a topographical grading system. Comparisons were made among those who were admitted to the intensive care unit (ICU), admitted to the progressive care unit (PCU), and treated as outpatients. RESULTS: Thirteen patients were identified. Ten (76.9 %) considered themselves homeless, and 9 (69.2 %) were directly exposed to the elements. The median delay between time of injury and presentation to a medical facility was 3 days (IQR 1-6). Only 3 patients presented to a medical facility within 24 h. Six (46 %) sustained grade 2 injuries, 2 (15 %) sustained grade 3 injuries, and 5 (38%) sustained grade 4 injuries. Only one patient met criteria to receive tissue plasminogen activator (tPA), which was discontinued due to hematochezia. Patients admitted to the ICU, when compared to patients admitted to the ward, had a longer length of stay (median 73 days v. 12 days, p = 0.0215), and required more amputations at below-the-knee or higher levels (3 v. 0, p-value 0.0442). CONCLUSION: In a region unaccustomed and perhaps unprepared to deal with winter storms, the population is particularly vulnerable to frostbite. Lack of awareness of frostbite injuries likely led to the delay in the presentation of patients, which prevented the timely use of tPA. Increasing public awareness may increase readiness.

Experiences of frostbite injury from recreational use of nitrous oxide canisters in a UK burns center: Not a laughing matter.

Nitrous oxide is used as a recreational drug. Contact frostbite injury from compressed gas canisters has previously been described in the literature, but an increased number of such cases has been noted in our busy regional burns center in the UK. A single-center prospective case series of all patients referred and treated for frostbite injury secondary to misuse of nitrous oxide compressed gas canisters between January and December 2022 is presented. Data collection was performed through a referral database and patient case notes. Sixteen patients, of which 7 were male and 9 were female, satisfied the inclusion criteria. Mean patient age was 22.5 years. The median TBSA was 1%. In total, 50% of patients in the cohort had a delayed initial presentation to A&E of greater than 5 days. Eleven patients were reviewed at our burns center for further assessment and management. In total, 11 patients had bilateral inner thigh frostbite injuries, of which 8 had necrotic full-thickness injury, including subcutaneous fat. Seven patients were reviewed at our burns center and offered excision and split-thickness skin graft. Four patients presented with contact frostbite injury to the hand and one patient to the lower lip. This subgroup was managed successfully with conservative management alone. The reproducible pattern of frostbite injury secondary to the abuse of nitrous oxide compressed gas canisters is demonstrated in our case series. The distinct pattern of injury, patient cohort, and anatomical area affected presents an opportunity for targeted public health intervention in this group.

Prevention and Treatment of Nonfreezing Cold Injuries and Warm Water Immersion Tissue Injuries: Supplement to Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Treatment of Frostbite.

We convened an expert panel to develop evidence-based guidelines for the evaluation, treatment, and prevention of nonfreezing cold injuries (NFCIs; trench foot and immersion foot) and warm water immersion injuries (warm water immersion foot and tropical immersion foot) in prehospital and hospital settings. The panel graded the recommendations based on the quality of supporting evidence and the balance between benefits and risks/burdens according to the criteria published by the American College of Chest Physicians. Treatment is more difficult with NFCIs than with warm water immersion injuries. In contrast to warm water immersion injuries that usually resolve without sequelae, NFCIs may cause prolonged debilitating symptoms, including neuropathic pain and cold sensitivity.