Materiały źródłowe

• #1

  https://journals.lww.com/jtrauma/Fulltext/2000/01000/Frostbite__Pathogenesis_and_Treatment.36.aspx?generateEpub=Article%7Cjtrauma:2000:01000:00036%7C%7C

  Frostbite, once almost exclusively a military problem, is becoming more prevalent among the general population and should now be considered to be within the scope of the civilian physicians practice. […] Research into the pathophysiology has revealed marked similarities in inflammatory processes to those seen in thermal burns and ischemia/reperfusion injury. […] Evidence of the role of thromboxanes and prostaglandins has resulted in more active approaches to the medical treatment of frostbite wounds.

• #1 Frostbite Pathophysiology

  https://frostbitecare.ca/health-professionals/frostbite-pathophysiology

  Frostbite is a condition caused by freezing of the skin and ultimately, if it progresses, freezing of deeper tissues. Frostbite injuries due to exposure are a result of an initial extracellular freezing injury followed by a reperfusion injury due to vasoconstriction and microthrombosis in affected tissues. […] Two main mechanisms lead to tissue damage in the acute phase of frostbite injuries: immediate cellular death during cold exposure and progressive dermal ischemia leading to deterioration and necrosis. […] Upon rewarming of the affected tissue, reperfusion injury can lead to the generation of radical oxygen species and an inflammatory reaction, further damaging tissues. […] During freezing extra and intracellular ice crystal formation may lead to cell damage and circulatory stasis. A cascade of events occur at this point leading to further cell damage, thrombosis and vasoconstriction.

• #1 Frostbite: pathophysiology and treatment options

  https://www.oatext.com/frostbite-pathophysiology-and-treatment-options.php

  Frostbite injury is caused by two separate processes: (1) freezing of the tissue that leads to cellular death and (2) the reperfusion injury that occurs during rewarming. […] The formation of ice crystals begins when tissue temperature falls below 28o F (-2.2 oC) and occurs in both intra- and extracellular spaces causing direct mechanical damage to cell walls. Ice crystals in the intravascular spaces result in the second mechanism of injury that damages the endothelium and causes inflammation resulting in vascular stasis, thrombosis, and tissue ischemia. […] The rewarming and reperfusion cause endothelial injury which results in progressive edema and intravascular thrombosis. […] The direct injury leading to cellular destruction appears irreversible. Tissue can often appear viable initially on rewarming, however, the necrosis that follows is due to microcirculatory collapse leading to the indirect or secondary injury that occurs with reperfusion.

• #1 Frostbite: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/926249-overview

  Frostbite may occur when skin is exposed to extreme cold, at times combined with high winds, resulting in vasoconstriction. […] The effect of skin temperature on cutaneous blood flow involves the following: Normal cutaneous flow is 200-250 mL/min. […] Mechanisms of frostbite injury include the following: Direct cold damage to cells. […] Direct cell damage from ice crystals, which includes protein and lipid disruption and electrolyte shifts. […] Indirect cell damage from intracellular dehydration caused by the presence of extracellular ice crystals. […] Microvascular stasis, thrombus formation, embolic events in the microvasculature, and ischemia. […] Reperfusion inflammatory injury with ultimate tissue necrosis. […] Initial injury is mediated by extracellular-tissue ice crystal formation.

• #1 Frostbite: A Conundrum in High Altitudes | IntechOpen

  https://www.intechopen.com/chapters/75697

  Frostbite is defined as injury to body tissues caused by exposure to extreme cold, typically affecting the extremities and often involving only the skin, which initially becomes white and hard, but in severe cases resulting in gangrene of deeper tissues and loss of the affected parts. […] Two mechanisms that are apparently responsible for cold injury include direct cellular injury and progressive dermal ischemia. […] Due to freezing of tissue there is extracellular ice crystal formation, leading to electrolyte disturbances, intracellular dehydration and shrinkage leading to cell injury and death. […] As temperature further falls, there is intracellular ice crystal formation, which expands leading to mechanical destruction of cells. […] The body responds initially to it by alternating cycles of vasoconstriction and vasodilatation, known as the hunting reaction.

• #1 Frostbite Injuries to the Hand | Indiana Hand to Shoulder Center

  https://www.indianahandtoshoulder.com/blog/frostbite-injuries-to-the-hand

  Frostbite will result when tissue temperatures reach -2°C (28°F) or less. […] Two theories exist on the mechanism of injury in frostbite. A direct injury to the cells is produced by the formation of extracellular ice crystals. This appears to be an early event in the pathophysiology of the injury. Formation of ice crystals in the intercellular space increases its hypertonicity drawing water from the cells. Experimentally it appears that the duration of extracellular hypertonicity is the primary determinant of tissue injury. […] As a consequence of this primary event, a secondary phenomenon of endothelial injury with thrombosis, hemo-concentration and increased viscosity then results. This secondary phenomenon further compromises the biochemical environment of the injured cells, impairs tissue perfusion, enhances local hypoxia and contributes to tissue edema on rewarming.

• #1 Frostbite | Musculoskeletal Key

  https://musculoskeletalkey.com/frostbite-2/

  Frostbite occurs when tissues are subjected to temperatures low enough to form intracellular ice crystals, typically 2C and below. […] More recently, it was recognized that tissue injury occurs not only during freezing, but also during (and often as a result of) rewarming. […] Tissue damage from frostbite can be described as direct cellular injury and progressive tissue ischemia. […] Direct cellular injury formation of both intracellular and extracellular ice crystals, leading to osmotic imbalances and resulting cellular dehydration, electrolyte imbalances, enzyme denaturation, and ultimate cell death. […] Ice crystal formation in the intracellular space can directly damage cell membranes leading to cell lysis. […] Progressive tissue ischemia occurs secondary to vasoconstriction, shunting of blood away from the extremities, blood flow stasis, and thrombosis.

• #1 A drug to treat frostbite is finally available

  https://theconversation.com/a-drug-to-treat-frostbite-is-finally-available-223948

  Frostbite is evolutions response to prolonged or extreme cold, causing blood vessels to constrict and blood flow to slow in the extremities. This keeps blood flowing in the vital organs warm, increasing the chance of surviving in the extreme cold. […] Iloprost works by expanding the blood vessels (called a vasodilator) of patients and stopping blood clots from forming. As frostbite causes constriction of blood vessels, this suggests one mechanism through which iloprost helps heal frostbitten tissue is by reversing this constriction. […] Interestingly, iloprost is not only a vasodilator but also reduces oxidative stress, suggesting this dual mechanism of action could help explain its impressive potential as a frostbite treatment.

• #1 Frostbite: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/926249-overview

  Damage also is caused by a cycle of vascular changes referred to as the hunting reaction, which involves alternating cycles of vasoconstriction and vasodilation. […] When the hunting reaction stops at colder temperatures, vasoconstriction persists uninterrupted. […] Prostaglandin F2 and thromboxane A2, which are released during the course of freezing and thawing, potentiate vasoconstriction, platelet aggregation, and thrombosis. […] Various authors have compared the effects of quick freezing and slow freezing at the microscopic level. […] As tissue is rewarmed, reperfusion injury becomes prominent. […] To date, however, agents that block these mediators have had only marginal clinical success. […] The true effect of chemical mediators remains controversial. […] Frostbite injury can be divided into the following 3 zones. […] When external warmth is applied, ischemic insult may occur because perfusion from deep blood vessels tends to return slowly relative to the accelerated tissue oxygen demand.

• #1 Frostbite: A Conundrum in High Altitudes | IntechOpen

  https://www.intechopen.com/chapters/75697

  When vasodilatation occurs, there is reestablishment of blood flow, which is called thawing. […] The repeated freeze/thaw cycle causes most damage, and further leads to progressive thrombotic phase. […] Progressive dermal ischemia is more severe than the direct cellular damage. […] Various studies have shown similarities in the progressive dermal ischemia due to frostbite and thermal burns. […] Platelet and erythrocyte aggregates leads to thrombosis of the vessels in viable tissue. […] Local inflammatory response and associated injuries may cause increased compartment pressures. […] Thrombosis, endothelial damage, intravascular sludging, inflammatory mediators, free radicals, neutrophil adhesion, platelet aggregation, reperfusion injury, and oedema all play a role in contributing to progressive dermal ischemia and leads to cell death.

• #1 Frostbite and Immersion Foot Care

  https://books.allogy.com/v1/tenant/8/books/dc6e09f7-2a93-4629-bd34-59f9d2b73a1f

  Historically, cold Injury, hypothermia and frostbite have been a severe problems for military units on the battlefield. Cold injury requires two things: a low absolute temperature and an exposure duration. […] The ultimate mechanism of injury involves a combination of direct cold injury to the cells, direct intracellular and intercellular ice formation, ischemia from thrombosis of the vasculature, and reperfusion injury. […] Increased rates of frostbite occur at extreme high altitude secondary to ambient temperature decreases and microcirculatory changes that occur at altitudes greater than 17,000 ft. […] Cold injury is not a single diagnosis but rather a spectrum with all categories possibly present on a single extremity, the most distal portion usually being the most severely affected.

• #1 Frostbite: pathophysiology and treatment options

  https://www.oatext.com/frostbite-pathophysiology-and-treatment-options.php

  The mechanism(s) of indirect injury tend(s) to be the focus of frostbite research and the reason for the development of potential adjunctive therapies. […] Other studies indicate that during this second phase of frostbite injury, progressive ischemia leading to tissue necrosis, results from a cellular inflammatory-mediated process is similar-to the seen following ischemic/reperfusion injury. […] The ischemic/reperfusion injury has been described by as the cessation of blood flow followed by vascular reflow and subsequent microvascular damage. […] During the vascular reflow, an inflammatory reaction occurs with neutrophilic aggregation and adherence to endothelial cells leading to the production of free radicals. […] The successful use of superoxide dismutase and deferoxamine in a rabbit ear model of frostbite confirmed that a mechanism of tissue injury in frostbite is mediated by free radicals generated during reperfusion.

• #1 Cold injury – Wikipedia

  https://en.wikipedia.org/wiki/Cold_injury

  This inflammation involves specific molecules (prostaglandins, thromboxanes, bradykinin, histamine) that cause edema and damage to blood vessels, leading to potential blood clot formation and interruption of blood flow. […] The underlying mechanism of nonfreezing cold injury isn’t fully understood, but has been characterized by poor blood flow into tissue exposed to cold, wet conditions. […] This may result in destruction of small blood vessels, which leads to swelling, nerve damage, and tissue breakdown due to pressure injury.

• #1 Frostbite Pathophysiology

  https://frostbitecare.ca/health-professionals/frostbite-pathophysiology

  The degree of frostbite injury and outcomes are related to the degree of microvascular damage and thawing-refreezing cycles during the original tissue insult. Thrombosis and vasoconstriction are mediated by metabolites of the arachidonic acid pathway including thromboxane A2 (TxA2), prostaglandin F2 and thromboxane B2, and are a prominent feature of the reperfusion injury that occurs in rewarmed cyanotic tissue. This leads to intravascular coagulation, sustaining reperfusion injury and potentially causing microthrombi showers that damage the microvasculature, along with thrombus formation in larger vessels.

• #1 Long-Term Sequelae of Frostbite—A Scoping Review

  https://www.mdpi.com/1660-4601/18/18/9655

  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. […] 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. […] Upon rewarming of frozen tissue, reperfusion injury with the generation of radical oxygen species (ROS) leads to an inflammatory response. […] The presence of prostaglandin F2α and thromboxane B2, molecules that are known to be involved in vasoconstriction, platelet aggregation, and thrombosis, in both frostbite and burn injury blister fluid has been reported, indicating similar mechanisms of injury.

• #1 Frostbite – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK536914/

  Frostbite causes injury in the following ways: Direct damage of the cold to the tissues, Indirect damage caused by dehydration, Formation of ice crystals that leads to alteration in electrolytes and lipid layers, Stasis of the microvessels leading to thrombus formation and ischemia, Reperfusion injury. […] Initially, extracellular ice crystals form in exposed tissue. […] Continued cold exposure can cause intracellular ice crystals to form. […] Should tissue thawing occur, a reperfusion-associated inflammatory response through proinflammatory cytokines may cause additional tissue damage. […] Frostbite injury is classified into three zones which include: Zone of coagulation which is the most distal and often the most severely injured. Here the injury is irreversible, Zone of stasis is the middle zone where the injury can be moderate to severe. but it reversible, Zone of hyperemia is the proximal zone, which is the least injured.

• #1 Frostbite – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK536914/

  Frostbite, also known as freezing cold injury is tissue damage that occurs due to cold exposure, occurring at temperatures below zero degrees celsius. […] Prolonged duration and lower temperatures increase the risk of frostbite and the extent of the injury. […] Certain pre-existing conditions, including peripheral vascular disease, malnutrition, Raynaud’s disease, diabetes mellitus, and tobacco use may worsen frostbite-related tissue damage. […] Frostbite, also known as freezing cold injury (FCI) is tissue damage as a result to cold exposure, occurring at temperatures below 0 degrees C. […] Patients are at high risk for ischemic tissue injury and necrosis. […] The goal of treatment is to salvage as much tissue as possible so that maximal function remains. […] Frostbite has a prejudice for distal extremities, digits, and those portions of exposed skin with decreased perfusion (nose, ears) and less insulation. […] The constellation of microvascular injury, venous stasis, and microthrombi all contribute to the development of ischemia attributed to frostbite. […] Depending on the extent of the exposure and subsequent cellular damage, injuries may be reversible or irreversible.

• #1 42. Frostbite | Plastic Surgery Key

  https://plasticsurgerykey.com/42-frostbite/

  The disruption of normal vascular flow due to microvascular thrombosis leads to cellular anaerobic metabolism and subsequent tissue hypoxia. […] It has been postulated that an increase in the ratio of TXA2/PGI2 could lead to increased platelet aggregation and thrombosis and thus the balance between physiologic levels of prostacyclin (prostaglandin I2) and thromboxane A2 is crucial for reducing further tissue necrosis in frostbite injury. […] The main goal of treatment is to prevent further tissue damage and to limit limb morbidity. […] Rapid rewarming ideally occurs through total immersion of the affected area in a warm whirlpool water bath between 37 and 44 C. […] It has been shown that blisters filled with clear or milky fluid contain elevated levels of inflammatory mediators prostaglandin F2 (PGF2) and thromboxane B2, an inactive metabolite/product of thromboxane A2 (TXA2), which both propagate platelet aggregation, thrombosis, and vasoconstriction.

• #1 Frostbite: Signs, stages, symptoms, management and prevention

  https://www.webmd.com/first-aid/frostbite

  Frostbite occurs when your skin and tissues freeze. This condition happens when you’re exposed to temperatures below the freezing point of the skin. […] As your extremities become colder and colder, ice crystals form in the fluid in your tissue. This ice can lead to the death of the tissue in the affected area or areas, as reduced blood flow causes lower oxygen supply to your tissues. […] The doctor will also classify the condition as superficial or deep and whether the outcome of your frostbite will be favorable or poor. Normal skin color, blisters with clear fluid, the ability to deform the skin with pressure, and the skin becoming pink when thawed are signs that the skin damage may be temporary. Blisters with dark fluid, skin turning dark blue when thawed, and being unable to indent the skin with pressure are signs of permanent skin damage.

• #1 Frostbite – Wikipedia

  https://en.wikipedia.org/wiki/Frostbite

  Frostbite is a skin injury that occurs when someone is exposed to extremely low temperatures, causing the freezing of the skin or other tissues, commonly affecting the fingers, toes, nose, ears, cheeks and chin areas. […] The underlying mechanism involves injury from ice crystals and blood clots in small blood vessels following thawing. […] In frostbite, cooling of the body causes narrowing of the blood vessels (vasoconstriction). Prolonged exposure to temperatures below 2 C (28 F) may cause ice crystals to form in the tissues, and prolonged exposure to temperatures below 4 C (25 F) may cause ice crystals to form in the blood. Ice crystals can damage small blood vessels at the site of injury. […] Rewarming causes tissue damage through reperfusion injury, which involves vasodilation, swelling (edema), and poor blood flow (stasis). Platelet aggregation is another possible mechanism of injury. […] The pathological mechanism by which frostbite causes body tissue injury can be characterized by four stages: Prefreeze, freeze-thaw, vascular stasis, and the late ischemic stage.

• #1 Long-Term Sequelae of Frostbite—A Scoping Review

  https://www.mdpi.com/1660-4601/18/18/9655

  Following acute pathology, frostbite long-term sequelae are associated with vasomotor dysfunction—in particular, vasospasm leading to circulatory disturbances, resulting in chronic pain and cold hypersensitivity. Also, cold-induced nerve damage is linked to neuropathic pain and ischemic neuritis. […] The underlying bone and cartilage damage are thought to be mostly a consequence of circulatory insufficiency during frostbite injury, although direct cold damage may also be involved. […] The exact role of the TPR family in thermal hyperalgesia secondary to frostbite is still under debate and needs further investigation.

• #1 Frostbite – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK536914/

  Frostbite is a clinical diagnosis. […] Technetium-99 (Tc-99) triple phase scanning and magnetic resonance angiography (MRA) may help to determine extent of amputation in the first few days after injury. […] Patients with full-thickness injuries and evidence of ischemia and no restoration of tissue perfusion after rewarming may be candidates for thrombolytic (tPA) therapy. […] tPA may reduce the need for digital amputation. […] Frostbite survivors may have an intolerance to cold in previously frostbitten areas, which may be a consequence of vasospasm and abnormal autonomic tone following cold injury.

• #1 Frostbite: Review and Current Concepts | American Board of Family Medicine

  https://www.jabfm.org/content/11/1/34

  Research done during the past 15 years has clarified the pathogenesis of frostbite injury and led to a better understanding of how to limit tissue loss. […] The pathogenesis is linked to tissue freezing, hypoxia, and the release of inflammatory mediators. […] Optimum therapy is based on the rapid reversal of tissue freezing by rewarming in 1 04-108F water and the institution of oral and topical antiprostaglandin therapy to limit the release of inflammatory mediators.

• #1 Frostbite and Immersion Foot Care

  https://tccc.org.ua/en/guide/frostbite-and-immersion-foot-care-cpg

  Cold injury has occurred when upon re-warming there is pain and swelling or gross signs of ischemia or skin injury. […] The mainstay of treatment of the cold injury is re-warming. Rapid active re-warming is done in 104-108F (40-42C) water for 15- 30 minutes as long as care can occur in an environment where there is no risk of refreezing. […] The goal is complete thawing and maximum perfusion as evidenced by hyperemia, swelling, and pain. […] It is also very important that when rapid re-warming is done, it is to be completed, as refreezing after partial thawing will result in more severe injury. […] Rapid re-warming can be conducted at point of initial care, but early evacuation to definitive care should be considered at the earliest available time. […] If perfusion is compromised, papaverine, a vasodilator, may be introduced intraarterially at a rate of 30 mg/hr to decrease local vasospasm. […] For cases of full thickness injury (third and fourth degree) with infection, debridement and possible amputation are to be conducted expediently.

• #1 Emergency Management of Frostbite – CanadiEM

  https://canadiem.org/emergency-management-of-frostbite/

  Frostbite occurs when tissues are exposed below their freezing point of -0.53oC for a period of time. […] In frostbite, some cells are killed while many others are only injured and have the potential to be salvaged with optimal care. […] NSAIDs block the production of prostaglandins and thromboxane, which are responsible for the vascular stasis and late ischemic phases of injury. […] Iloprost is a synthetic prostaglandin analogue that inhibits platelet aggregation, contains vasodilatory properties, and may contribute to fibrinolysis. […] Edema is thought to worsen progressive dermal ischemia and puts the tissue at higher risk for infection. […] Hemorrhagic blisters suggest deeper injury to the dermal vascular plexus. […] The mainstay is rapid moist rewarming which should be done as soon as possible. […] The addition of an anti platelet agent (NSAID) is relatively low risk with significant potential benefit, especially when used for a short course (3-5 days).

• #1 Frostbite treatment: a systematic review with meta-analyses | Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine | Full Text

  https://sjtrem.biomedcentral.com/articles/10.1186/s13049-023-01160-3

  Iloprost is a synthetic prostaglandin I2 that has been used to treat frostbite. Like other prostacyclins, it inhibits platelet aggregation and promotes vasodilation. Iloprost may stimulate the release of endogenous tissue plasminogen activator or counteract its inhibitory effects. Iloprost reduces vasoconstriction induced by thromboxane A2, and may reduce oxidative stress from free radicals, moderating reperfusion injury. […] Thrombolytics work by binding to fibrin within a thrombus and activating plasminogen, causing local fibrinolysis and inhibiting blood clot formation. A systematic review found comparable limb salvage rates for frostbite patients treated with intra-arterial and intravenous thrombolysis, (76% vs. 77%). Use of thrombolytics is associated with a risk of hemorrhage. […] Recommendations to treat frostbite with low molecular weight dextran, ibuprofen, or topical aloe vera are based on mechanistic reasoning or animal studies, rather than clinical data.

• #1 Frostbite: pathophysiology and treatment options

  https://www.oatext.com/frostbite-pathophysiology-and-treatment-options.php

  Hyperbaric oxygen therapy (HBO2) initially, seems counterintuitive for use with an injury such as frostbite where tissue damage results from ischemia, because high levels of oxygen are linked to vasoconstriction and reduced blood flow. […] However, HBO2 reverses vasoconstriction in ischemic tissue and the resulting hyperoxia, from oxygen dissolved in plasma, surpasses any potential reduction in blood flow. […] In addition to the hyperoxygenation, another mechanism of HBO2 therapy is an increased diffusion distance thus improving oxygenation in hypoxic tissue. […] This allows marginal tissue to be maintained until revascularization has been established. […] Angiogenesis is also a process stimulated by HBO2. […] The mechanism(s) involved in the delayed tissue damage following cold injury represent a complex cascade of factors. […] The similarities of frostbite to thermal burns and ischemia reperfusion injury suggest that including the use of HBO2 as part of the treatment regimen is an area of investigation that should be pursued.

• #1 Hyperbaric Oxygen Therapy with Iloprost Improves Digit Salvage in Severe Frostbite Compared to Iloprost Alone

  https://www.mdpi.com/1648-9144/57/11/1284

  HBO promotes the formation of the healing sulcus between necrotic and healthy tissues. […] The SOS-Frostbite program is the first controlled prospective study that evaluates the effect of early HBO additive to iloprost on severe frostbite. Results show more favorable outcome in terms of the functionality and quality of life in patients treated by HBO: HBO added to the standard care with iloprost might improve frostbite injury outcomes by doubling the chance to preserve the number of injured segments from amputation.

• #1 Hypothermia and frostbite – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/hypothermia-and-frostbite/

  Frostbite is a tissue injury that can occur after exposure to freezing temperatures and typically affects the face, ears, fingers, and/or toes; frostbite can occur with or without hypothermia. […] Severe localized tissue injury; due to freezing of interstitial and cellular spaces after prolonged exposure to very cold temperatures. […] Frostbite can occur with or without hypothermia. […] The extent of tissue injury from frostbite is challenging to define initially. Accurate prognosis requires careful observation and may only be possible weeks to months after thawing. […] Frostbite is classically staged by degree of injury, similar to burns, but this can be difficult to assess prior to thawing. […] The simplified staging is easier to apply clinically. […] The initial paresthesia is followed by numbness of the affected region.

• #1 Bone scintigraphy outperformed anatomic images in frostbite injuries: a case report | EJNMMI Reports | Full Text

  https://ejhi.springeropen.com/articles/10.1186/s41824-022-00146-1

  Frostbite injuries occur due to the formation of ice crystals intracellularly and extracellularly which provokes microcirculatory dysfunction, osmotic gradient alterations and inflammatory reactions. […] Intracellular ice crystal formation stimulates a cascade of deleterious effects resulting in the production of prostaglandins, cytokines and oxygen free radicals as an intent to remove ice crystals and preserve cells. Notwithstanding, these products impoverish the cell environment and produce detrimental effects, such as hypoxia and microthrombosis, creating a vicious circle where the production of more substances is stimulated, resulting in cell death. […] Multiphase technetium-99m-methylenediphosphonate (99mTc-MDP) bone scintigraphy may hasten clinical management of frostbite injuries as it furnish high and precise clinical-imaging correlation by determining the extent of injury and can accurately predict the level of amputation if required.

• #1 Hypothermia and frostbite – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/hypothermia-and-frostbite/

  The presence or absence of shivering does not accurately reflect the stage of hypothermia. […] Do not debride hemorrhagic vesicles. […] The lethal triad of hypothermia, acidosis, and coagulopathy is associated with poor outcomes in patients with cold exposure and severe trauma. […] Tissue demarcation (e.g., to guide the need for amputation) may only occur 1-3 months after the frostbite injury.

• #2

  https://journals.lww.com/jtrauma/Fulltext/2000/01000/Frostbite__Pathogenesis_and_Treatment.36.aspx?generateEpub=Article%7Cjtrauma:2000:01000:00036%7C%7C

  Frostbite, once almost exclusively a military problem, is becoming more prevalent among the general population and should now be considered to be within the scope of the civilian physicians practice. […] Research into the pathophysiology has revealed marked similarities in inflammatory processes to those seen in thermal burns and ischemia/reperfusion injury. […] Evidence of the role of thromboxanes and prostaglandins has resulted in more active approaches to the medical treatment of frostbite wounds.

• #2 Frostbite: pathophysiology and treatment options

  https://www.oatext.com/frostbite-pathophysiology-and-treatment-options.php

  Frostbite injury is caused by two separate processes: (1) freezing of the tissue that leads to cellular death and (2) the reperfusion injury that occurs during rewarming. […] The formation of ice crystals begins when tissue temperature falls below 28o F (-2.2 oC) and occurs in both intra- and extracellular spaces causing direct mechanical damage to cell walls. Ice crystals in the intravascular spaces result in the second mechanism of injury that damages the endothelium and causes inflammation resulting in vascular stasis, thrombosis, and tissue ischemia. […] The rewarming and reperfusion cause endothelial injury which results in progressive edema and intravascular thrombosis. […] The direct injury leading to cellular destruction appears irreversible. Tissue can often appear viable initially on rewarming, however, the necrosis that follows is due to microcirculatory collapse leading to the indirect or secondary injury that occurs with reperfusion.

• #2 Frostbite: Pathophysiology, Epidemiology, Diagnosis, Treatment, and Prevention – PubMed

  https://pubmed.ncbi.nlm.nih.gov/33320326/

  Frostbite can occur during cold-weather operations when the temperature is 0C (32F). When skin temperature is =-4C (=25F), ice crystals form in the blood, causing mechanical damage, inflammation, thrombosis, and cellular death. […] Lower temperatures, higher wind speeds, and moisture exacerbate the process. […] Thrombolytics show promise in the early treatment of frostbite. […] In hospital settings, bone scintigraphy with single-photon emission computed tomography (SPECT) 2 to 4 days postinjury provides detailed information on the depth of the injury.

• #2 Frostbite Injuries to the Hand | Indiana Hand to Shoulder Center

  https://www.indianahandtoshoulder.com/blog/frostbite-injuries-to-the-hand

  Frostbite will result when tissue temperatures reach -2°C (28°F) or less. […] Two theories exist on the mechanism of injury in frostbite. A direct injury to the cells is produced by the formation of extracellular ice crystals. This appears to be an early event in the pathophysiology of the injury. Formation of ice crystals in the intercellular space increases its hypertonicity drawing water from the cells. Experimentally it appears that the duration of extracellular hypertonicity is the primary determinant of tissue injury. […] As a consequence of this primary event, a secondary phenomenon of endothelial injury with thrombosis, hemo-concentration and increased viscosity then results. This secondary phenomenon further compromises the biochemical environment of the injured cells, impairs tissue perfusion, enhances local hypoxia and contributes to tissue edema on rewarming.

• #2 Frostbite: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/926249-overview

  Frostbite may occur when skin is exposed to extreme cold, at times combined with high winds, resulting in vasoconstriction. […] The effect of skin temperature on cutaneous blood flow involves the following: Normal cutaneous flow is 200-250 mL/min. […] Mechanisms of frostbite injury include the following: Direct cold damage to cells. […] Direct cell damage from ice crystals, which includes protein and lipid disruption and electrolyte shifts. […] Indirect cell damage from intracellular dehydration caused by the presence of extracellular ice crystals. […] Microvascular stasis, thrombus formation, embolic events in the microvasculature, and ischemia. […] Reperfusion inflammatory injury with ultimate tissue necrosis. […] Initial injury is mediated by extracellular-tissue ice crystal formation.

• #2 Frostbite: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/926249-overview

  Damage also is caused by a cycle of vascular changes referred to as the hunting reaction, which involves alternating cycles of vasoconstriction and vasodilation. […] When the hunting reaction stops at colder temperatures, vasoconstriction persists uninterrupted. […] Prostaglandin F2 and thromboxane A2, which are released during the course of freezing and thawing, potentiate vasoconstriction, platelet aggregation, and thrombosis. […] Various authors have compared the effects of quick freezing and slow freezing at the microscopic level. […] As tissue is rewarmed, reperfusion injury becomes prominent. […] To date, however, agents that block these mediators have had only marginal clinical success. […] The true effect of chemical mediators remains controversial. […] Frostbite injury can be divided into the following 3 zones. […] When external warmth is applied, ischemic insult may occur because perfusion from deep blood vessels tends to return slowly relative to the accelerated tissue oxygen demand.

• #2 Frostbite – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK536914/

  Frostbite, also known as freezing cold injury is tissue damage that occurs due to cold exposure, occurring at temperatures below zero degrees celsius. […] Prolonged duration and lower temperatures increase the risk of frostbite and the extent of the injury. […] Certain pre-existing conditions, including peripheral vascular disease, malnutrition, Raynaud’s disease, diabetes mellitus, and tobacco use may worsen frostbite-related tissue damage. […] Frostbite, also known as freezing cold injury (FCI) is tissue damage as a result to cold exposure, occurring at temperatures below 0 degrees C. […] Patients are at high risk for ischemic tissue injury and necrosis. […] The goal of treatment is to salvage as much tissue as possible so that maximal function remains. […] Frostbite has a prejudice for distal extremities, digits, and those portions of exposed skin with decreased perfusion (nose, ears) and less insulation. […] The constellation of microvascular injury, venous stasis, and microthrombi all contribute to the development of ischemia attributed to frostbite. […] Depending on the extent of the exposure and subsequent cellular damage, injuries may be reversible or irreversible.

• #2 Long-Term Sequelae of Frostbite—A Scoping Review

  https://www.mdpi.com/1660-4601/18/18/9655

  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. […] 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. […] Upon rewarming of frozen tissue, reperfusion injury with the generation of radical oxygen species (ROS) leads to an inflammatory response. […] The presence of prostaglandin F2α and thromboxane B2, molecules that are known to be involved in vasoconstriction, platelet aggregation, and thrombosis, in both frostbite and burn injury blister fluid has been reported, indicating similar mechanisms of injury.

• #2 Frostbite Pathophysiology

  https://frostbitecare.ca/health-professionals/frostbite-pathophysiology

  The degree of frostbite injury and outcomes are related to the degree of microvascular damage and thawing-refreezing cycles during the original tissue insult. Thrombosis and vasoconstriction are mediated by metabolites of the arachidonic acid pathway including thromboxane A2 (TxA2), prostaglandin F2 and thromboxane B2, and are a prominent feature of the reperfusion injury that occurs in rewarmed cyanotic tissue. This leads to intravascular coagulation, sustaining reperfusion injury and potentially causing microthrombi showers that damage the microvasculature, along with thrombus formation in larger vessels.

• #2 A retrospective cohort study examining treatments and operative interventions for frostbite in a tertiary care hospital | Canadian Journal of Emergency Medicine | Cambridge Core

  https://www.cambridge.org/core/journals/canadian-journal-of-emergency-medicine/article/retrospective-cohort-study-examining-treatments-and-operative-interventions-for-frostbite-in-a-tertiary-care-hospital/FC732AF62103B7BFFB8A3B96054167D2

  Adherence to the treatment protocol is presented in Table 2. […] Adherence to each treatment ranged from 0.8% for daily hydrotherapy to 32.8% for analgesia across all patient groups. […] None of the 265 patients received all 12 treatments in the protocol. […] Adherence to other therapies that fell outside of the treatment protocol are also indicated in Table 2, specifically use of wound dressings (24.5%), hyperbaric chamber (3.4%), antibacterial cream (13.6%) and aloe vera (not associated with blister treatment) (8.3%). […] The rate of operative intervention was 7.7% in patients with deep frostbite who did not receive any treatments listed in the protocol and ranged from 0.0% to 100.0% per treatment for those who did receive some treatments in the protocol. […] None of the other therapies were associated with an operative intervention in deep the frostbite group.

• #2 42. Frostbite | Plastic Surgery Key

  https://plasticsurgerykey.com/42-frostbite/

  The general frostbite sequence begins with complete tissue ischemia, followed by reperfusion, and ultimately tissue necrosis. […] Three distinct mechanisms are central in understanding the pathophysiology of frostbite by which tissue damage can occur: direct cold-induced cell damage from cell crystallization, indirect cellular injury from local hypoxia from vasoconstriction and microvascular thrombosis, and release of inflammatory mediators post-thaw from reperfusion injury and cell death. […] As vascular integrity remains grossly intact post-thaw, there is generally full restoration of circulatory reflow with increased vascular permeability due to endothelial damage. […] The combination of stasis and increased viscosity promotes thrombus formation. […] Thrombosis and proximal arterio-venous shunting lead to progressive dermal ischemia and loss of tissue.

• #2 Frostbite: Signs, stages, symptoms, management and prevention

  https://www.webmd.com/first-aid/frostbite

  Frostbite occurs when your skin and tissues freeze. This condition happens when you’re exposed to temperatures below the freezing point of the skin. […] As your extremities become colder and colder, ice crystals form in the fluid in your tissue. This ice can lead to the death of the tissue in the affected area or areas, as reduced blood flow causes lower oxygen supply to your tissues. […] The doctor will also classify the condition as superficial or deep and whether the outcome of your frostbite will be favorable or poor. Normal skin color, blisters with clear fluid, the ability to deform the skin with pressure, and the skin becoming pink when thawed are signs that the skin damage may be temporary. Blisters with dark fluid, skin turning dark blue when thawed, and being unable to indent the skin with pressure are signs of permanent skin damage.

• #2 Frostbite Facts for Kids

  https://kids.kiddle.co/Frostbite

  Frostbite is a skin injury that occurs when someone is exposed to extremely low temperatures, causing the freezing of the skin or other tissues, commonly affecting the fingers, toes, nose, ears, cheeks and chin areas. […] The underlying mechanism involves injury from ice crystals and blood clots in small blood vessels following thawing. […] In frostbite, cooling of the body causes narrowing of the blood vessels (vasoconstriction). Prolonged exposure to temperatures below 2 C (28 F) may cause ice crystals to form in the tissues, and prolonged exposure to temperatures below 4 C (25 F) may cause ice crystals to form in the blood. Ice crystals can damage small blood vessels at the site of injury. Typically, prolonged exposure to temperatures below 0.55 C (31.01 F) may cause frostbite. […] Rewarming causes tissue damage through reperfusion injury, which involves vasodilation, swelling (edema), and poor blood flow (stasis). Platelet aggregation is another possible mechanism of injury. Blisters and spasm of blood vessels (vasospasm) can develop after rewarming. […] The pathological mechanism by which frostbite causes body tissue injury can be characterized by four stages: Prefreeze, freeze-thaw, vascular stasis, and the late ischemic stage.

• #2 The Triaging and Treatment of Cold-Induced Injuries (30.10.2015)

  https://di.aerzteblatt.de/int/archive/article/172742/The-triaging-and-treatment-of-cold-induced-injuries

  The tissue damage in frostbite is caused by formation of ice crystals (1). The severity of injury ranges from circumscribed superficial cutaneous lesions to necrosis of all layers of the skin (2). As well as the above-mentioned similarities between frostbite and burns, there are also distinct differences. For example, angiogenesis begins much sooner in frostbite injuries, and inflammation is less accentuated than in burns but persists much longer (3). In contrast to burn injuries, frostbite does not completely destroy the extracellular matrix. Extracellular ice crystals damage the cell membrane, dehydration of the cells ensues, and the result is hyperosmolar cell death (4). Migrating fibroblasts replace the dead cells (3). […] The principal factor in the development of NFCI is thought to be the persisting vasoconstriction (5). If the nerves are cooled to under 10 C, they suffer relevant damage (17). Large myelinated fibers are more susceptible than small and unmyelinated fibers (17, e1e5). The precise pathophysiological foundations of the neural damage have not yet been uncovered (18, 19, e1, e6). Hypothermia of the nerves is held to be responsible for the ensuing damage (Table 4). […] Prostaglandin F 2 (PGF2) and thromboxane A2 (TXA2) lead to thrombocyte aggregation and thus extension of the area of ischemia (2).

• #2 Frostbite – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK536914/

  Frostbite is a clinical diagnosis. […] Technetium-99 (Tc-99) triple phase scanning and magnetic resonance angiography (MRA) may help to determine extent of amputation in the first few days after injury. […] Patients with full-thickness injuries and evidence of ischemia and no restoration of tissue perfusion after rewarming may be candidates for thrombolytic (tPA) therapy. […] tPA may reduce the need for digital amputation. […] Frostbite survivors may have an intolerance to cold in previously frostbitten areas, which may be a consequence of vasospasm and abnormal autonomic tone following cold injury.

• #2 Hypothermia and Cold Weather Injuries | AAFP

  https://www.aafp.org/pubs/afp/issues/2019/1201/p680.html

  Rapid rewarming should be done in a water bath maintained at 98.6 to 102.2F (37 to 39C). The extremity should be actively swirled, avoiding the bath edge, until the tissue appears red or purple and is soft to touch (30 to 60 minutes). […] The frostbitten extremity should not be used unless essential for evacuation, and rewarming should be avoided if refreezing is a risk.

• #2 42. Frostbite | Plastic Surgery Key

  https://plasticsurgerykey.com/42-frostbite/

  As elevated levels of prostaglandin production contribute to the pathogenesis of frostbite, early prevention with anti-thromboxanes such as topical aloe vera gel has suggested as treatment adjuncts. […] The mechanism of thrombolysis is through the activation of plasminogen conversion to plasmin, which is capable of cleaving cross-links between fibrin molecules that form thrombi.

• #2 Frostbite on hands and feet – Medizinonline

  https://medizinonline.com/en/frostbite-on-hands-and-feet/

  A good alternative to systemic thrombolysis is therapy with iloprost (Ilomedin), a synthetic prostacyclin derivative. It causes platelet aggregation inhibition, peripheral vasodilation, increase of capillary density, reduction of capillary permeability and stimulates endogenous fibrinolytic potential. Via this effect, it also reduces progressive tissue ischemia.

• #2 Frostbite: pathophysiology and treatment options

  https://www.oatext.com/frostbite-pathophysiology-and-treatment-options.php

  Hyperbaric oxygen therapy (HBO2) initially, seems counterintuitive for use with an injury such as frostbite where tissue damage results from ischemia, because high levels of oxygen are linked to vasoconstriction and reduced blood flow. […] However, HBO2 reverses vasoconstriction in ischemic tissue and the resulting hyperoxia, from oxygen dissolved in plasma, surpasses any potential reduction in blood flow. […] In addition to the hyperoxygenation, another mechanism of HBO2 therapy is an increased diffusion distance thus improving oxygenation in hypoxic tissue. […] This allows marginal tissue to be maintained until revascularization has been established. […] Angiogenesis is also a process stimulated by HBO2. […] The mechanism(s) involved in the delayed tissue damage following cold injury represent a complex cascade of factors. […] The similarities of frostbite to thermal burns and ischemia reperfusion injury suggest that including the use of HBO2 as part of the treatment regimen is an area of investigation that should be pursued.

• #2 Hyperbaric Oxygen Therapy with Iloprost Improves Digit Salvage in Severe Frostbite Compared to Iloprost Alone

  https://www.mdpi.com/1648-9144/57/11/1284

  The goal of treatment is to limit tissue damage from hypoxia and acidosis, mitigate the subsequent prothrombotic cascade, reduce edema and the inflammatory response, and minimize the impact of the ischemic–reperfusion syndrome. […] Currently, the Wilderness Medical Society guidelines do not recommend HBO treatment for frostbite. However, HBO may improve frostbite outcome by increasing the cellular oxygen availability to the damaged tissues. This may help to mitigate the negative impact of the inflammatory cascade and the ischemia–reperfusion syndrome. […] The physiological mechanism of HBO action is well known, but there are no previous randomized controlled trials conducted to evaluate the added value of HBO on frostbite injury outcomes. Regarding frostbite physiopathology, there are good reasons as to why HBO could improve frostbite injury outcomes. HBO has a direct action on tissue ischemia, increasing dissolved oxygen and improving oxygen transportation in the blood. The HBO decreases blood viscosity and minimizes the inflammatory cascade. There is a hyperoxic vasoconstriction in the micro vascularization of healthy tissues, inducing a redistribution of blood to hypoxic territories.

• #2 Bone scintigraphy outperformed anatomic images in frostbite injuries: a case report | EJNMMI Reports | Full Text

  https://ejhi.springeropen.com/articles/10.1186/s41824-022-00146-1

  Frostbite injuries occur due to the formation of ice crystals intracellularly and extracellularly which provokes microcirculatory dysfunction, osmotic gradient alterations and inflammatory reactions. […] Intracellular ice crystal formation stimulates a cascade of deleterious effects resulting in the production of prostaglandins, cytokines and oxygen free radicals as an intent to remove ice crystals and preserve cells. Notwithstanding, these products impoverish the cell environment and produce detrimental effects, such as hypoxia and microthrombosis, creating a vicious circle where the production of more substances is stimulated, resulting in cell death. […] Multiphase technetium-99m-methylenediphosphonate (99mTc-MDP) bone scintigraphy may hasten clinical management of frostbite injuries as it furnish high and precise clinical-imaging correlation by determining the extent of injury and can accurately predict the level of amputation if required.

• #3 Deep Frostbite: The Question of Treatment

  https://www.gavinpublishers.com/article/view/deep-frostbite-the-question-of-treatment

  Within the spectrum of peripheral cold injuries, frostbite is the most serious lesion in many cases leading to the amputation of fingers or a limb. […] The pathophysiology of frostbite is well characterized; it involves two main pathways: (a) intracellular changes that lead to cell death, (b) tissue ischemia and thrombus formation. […] The pathophysiologic mechanism that underlies frostbite injury has been studied in several model systems throughout the literature. There are two general mechanisms underlying frostbite injury, which occur simultaneously. The first is direct cellular damage, which is formed during the initial freeze process. The second is the delayed process mediated by progressive tissue ischemia which is attributed to thrombus formation and inflammatory response. […] The second mechanism, involving tissue ischemia, is considered to contribute more to the clinical outcome than the direct mechanical injury.

• #3 Frostbite: A Conundrum in High Altitudes | IntechOpen

  https://www.intechopen.com/chapters/75697

  When vasodilatation occurs, there is reestablishment of blood flow, which is called thawing. […] The repeated freeze/thaw cycle causes most damage, and further leads to progressive thrombotic phase. […] Progressive dermal ischemia is more severe than the direct cellular damage. […] Various studies have shown similarities in the progressive dermal ischemia due to frostbite and thermal burns. […] Platelet and erythrocyte aggregates leads to thrombosis of the vessels in viable tissue. […] Local inflammatory response and associated injuries may cause increased compartment pressures. […] Thrombosis, endothelial damage, intravascular sludging, inflammatory mediators, free radicals, neutrophil adhesion, platelet aggregation, reperfusion injury, and oedema all play a role in contributing to progressive dermal ischemia and leads to cell death.

• #3 Frostbite treatment: a systematic review with meta-analyses | Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine | Full Text

  https://sjtrem.biomedcentral.com/articles/10.1186/s13049-023-01160-3

  Iloprost is a synthetic prostaglandin I2 that has been used to treat frostbite. Like other prostacyclins, it inhibits platelet aggregation and promotes vasodilation. Iloprost may stimulate the release of endogenous tissue plasminogen activator or counteract its inhibitory effects. Iloprost reduces vasoconstriction induced by thromboxane A2, and may reduce oxidative stress from free radicals, moderating reperfusion injury. […] Thrombolytics work by binding to fibrin within a thrombus and activating plasminogen, causing local fibrinolysis and inhibiting blood clot formation. A systematic review found comparable limb salvage rates for frostbite patients treated with intra-arterial and intravenous thrombolysis, (76% vs. 77%). Use of thrombolytics is associated with a risk of hemorrhage. […] Recommendations to treat frostbite with low molecular weight dextran, ibuprofen, or topical aloe vera are based on mechanistic reasoning or animal studies, rather than clinical data.

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