- Public
- Health Professionals
- Resources
- About CFCN
- Contact
Frostbite is an extremity threatening injury while hypothermia is a life threatening injury. As such, frostbite care should not supersede hypothermia care. Care specific to frostbite in a medical facility should begin with ensuring that the tissue is rewarmed. Ideally in warm water with or without a mild antiseptic at 36-42 degrees Celsius. Usually this takes 30 minutes or until the tissue is soft and pliable. Once rewarmed the injury can be given a grade on the Cauchy scale. Immediately after rewarming the tissue may temporarily flush dramatically. In the authors’ experience within an hour of rewarming a clinical impression of severity is possible. Occasionally the grade will progress over the first 24 hours. Due to this, many are aggressive with a grade 2 injury (low amputation risk) in case it truly is a grade 3 (higher amputation risk) the next day. As soon as a severe frostbite injury is recognized, anitthromboxane treatment using ibuprofen and ASA can begin, and iloprost and or thrombolysis can be initiated as soon as possible. In centres where advanced imaging (angiography, bone scan, SPECT-CT) is readily available it may be used to grade the severity and identify digits at risk. However, with variable access in tertiary centres and less access in peripheral community hospital settings, it is best to initiate treatment based on clinical assessment and consider the use of imaging to evaluate response and aid in prognosis.
While all evidence related to frostbite treatments is thin, consensus is slowly building with regards to the treatment of severe frostbite. Based mostly on case series evidence beginning in the 1980s to 2023 the principles to minimize permanent injury and amputation are based on rapid rewarming, antithromboxane treatment, vasodilation/prostacyclin and thrombolytics. More recently evidence is suggesting that hyperbaric oxygen is a possible adjunct. Ideally all of these will be further validated through rigorous investigations. Recent evidence suggests that amputation rate increases with each hour that passes between rewarming and pharmacologic intervention (58). This post-rewarming period when reperfusion injury is leading to progressive ischemia is referred to as warm ischemia time.
Wound care may be performed concurrently with pharmacologic treatment. Care is taken to minimize secondary injury to the delicate frostbitten tissues. Weight bearing should be avoided on injured feet and limbs may be gently dressed and elevated. Aloe vera ointment may be used as a specific antithromboxane treatment. Clear blisters which may harbour antithromboxanes may be gently aspirated or debrided if beginning to fall apart. Hemorrhagic blisters are a sign of a deeper injury and are best left alone unless inhibiting joint movement.
Rapid rewarming was initially demonstrated in a case study by Mills in Alaska identifying that rapid rewarming was preferable to slow rewarming (59). While it is generally recommended to have a tolerable temperature between 36 and 40 degrees celsius for 30 min, the actual water temperature and whether a disinfectant should be added to the water is not clear. While any tub will do, features that comfortably can fit feet or hands, minimize the risk of secondary burns from an exposed heating element and circulating fluid are desirable.
The role of thromboxanes in frostbite was identified by Heggers and al, who aspirated blisters of frostbite patients and found high concentrations of thromboxanes (15). As known vasoconstricting agents an antithromboxane protocol was thought to be of value and was validated in a case control study in the 1980s demonstrating a decreased amputation rate relative to historic controls (19).
Where thromboxanes are understood to be detrimental to frostbite by promoting vasoconstriction and clot formation, prostacyclin is believed to be beneficial to frostbite by promoting vasodilation and inhibiting clot formation. Iloprost, as a synthetic prostaglandin analogue, may mitigate this loss.
Thrombolytics or recombinant tissue plasminogen activators (rtPA) are also used for local fibrinolysis and prevents enlargement of blood clots in frostbitten extremities. Because fibrinolysis can have a procoagulant effect (clot extension and reformation), anticoagulants such as unfractionated heparin (UFH) and low-molecular weight heparins (LMWH), have been used as adjunctive therapy in thrombolytics protocols.
Acetylsalicylic acid (ASA) and ibuprofen are Non-steroidal anti-inflammatory drugs (NSAIDs). They block the arachidonic acid pathway and prevent the formation of thromboxane and prostaglandins causing vasoconstriction, platelet aggregation activation and edema after frostbite.
Acetylsalicylic acid (ASA) and ibuprofen can be used in all grades of frostbite.
Contraindications to Non-steroidal anti-inflammatory drugs (NSAIDs) include, cerebrovascular bleeding or other bleeding disorders, active gastric/duodenal/peptic ulcer, active GI bleeding, inflammatory bowel disease, uncontrolled heart failure, severe renal impairment, severe hepatic impairment, hyperkalemia, third trimester of pregnancy, breast-feeding and systemic lupus erythematosus.
Acetylsalicylic acid (ASA) can be dosed at 325 mg orally every 6 hours and ibuprofen can be dosed at 600 mg orally every 6 hours.
Use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of serious GI adverse events, including gastrointestinal inflammation, gastrointestinal hemorrhage, gastrointestinal ulcer, and gastrointestinal perforation, prolonged bleeding time and an increased risk for hemorrhage, acute kidney injury and an increased risk of serious adverse cardiovascular events.
Acetylsalicylic acid and ibuprofen have been used to treat frostbite since the 1980’s (17,19,60). Acetylsalicylic acid improved frostbitten tissue survival in an animal study (19) and prevented significant tissue loss in one observational study conducted in patients in Chicago (18). In a case-controlled study in Detroit, patients treated with ibuprofen as part of a protocol had less amputation and reduced hospital length of stay compared to control-patients treated with various other methods of treatment (19).
Some authors in the early 1980’s have theorized that ibuprofen may be more active against the harmful thromboxanes and that acetylsalicylic acid may impair the production of beneficial prostaglandins in frostbite wound healing (19). To this date, there are no studies comparing acetylsalicylic acid with ibuprofen in frostbite.
Aloe vera extract is a thromboxane inhibitor. It also has antimicrobial and anesthetic properties and can enhance wound healing.
Aloe vera can be used in all grades of frostbite.
Contraindications include a known hypersensitivity to aloe vera.
Apply a cream or a gel containing a minimum of 70% aqueous extract of aloe vera every 6 hours.
Aloe vera’s possible adverse effects include burning, erythema, and itching. It can cause contact dermatitis in sensitive individuals.
Aloe vera improved frostbitten tissue survival in an animal model (19). In two studies where aloe vera was incorporated to a protocol that included nonsteroidal anti-inflammatory drugs (NSAIDs), it improved outcomes compared to traditional treatment (18,19). There is still a paucity of evidence on the topical management of frostbite.
Iloprost is a stable synthetic analog of prostaglandin I2 (prostacyclin or epoprostenol). It is an inhibitor of platelet aggregation and a vasodilator and has been used to address post-rewarming reperfusion injury in frostbite. Iloprost was developed in Germany in the 1980s and is used in Europe intravenously for treatment of Raynaud’s disease, peripheral arterial disease, Buerger’s Disease, critical leg ischaemia and systemic sclerosis.
Iloprost can be considered in presentations of grade 2-4 frostbite within 48-72h of rewarming.
According to the iloprost manufacturer, contraindications to iloprost include pregnancy, lactation, severe coronary heart disease, unstable angina, myocardial infaction within the last six months, acute or chronic congestive heart failure, severe arrhythmias and suspected pulmonary congestion. The product monograph also lists as contraindications conditions where the effects of iloprost on platelets might increase the risk of hemorrhage (e.g. active peptic ulcers, trauma, intracranial hemorrhage)(62).
The most common iloprost dose used for frostbite is 0.5 to 2 ng/kg/min infused for 6 hours daily, for 5 days (16).
In the published studies to date, relatively minor side effects (headache, nausea, flushing) were common with iloprost, which is consistent with the non-frostbite literature. Occasionally more rare but serious side effects (symptomatic hypotension, bleeding) resulted in iloprost discontinuation (16). There is limited information on the safety and tolerability of combining iloprost and alteplase/heparin.
Gauthier et al. conducted a scoping review to identify the extent of the literature describing the use of iloprost in the treatment of frostbite (16). Twenty studies published from 1994 to 2022 examined the use of iloprost for the treatment of frostbite in humans. The majority of publications were case reports (11), followed by case series (7), one prospective single-arm study and one randomised controlled trial. The population in which iloprost has been studied to date is fairly homogeneous. Most patients in published studies were males in their 40s., with sports as the leading cause of frostbite. Despite the studies’ design limitations and population homogeneity, there exists a base of scientific knowledge, with 254 treated patients identified in published studies, including over 1000 frostbitten digits.
There is evidence to suggest that treatment of frostbite with iloprost is associated with reduced amputation rates. Some of the strongest evidence comes from Cauchy et al. (2011) (63). Percentage of amputation of affected digits across treatment arms and for all stages of frostbite were 39.6% in the buflomedil group, 3.1% in the iloprost and alteplase group, and 0% in the iloprost alone group. Poole and Gauthier (33,47), showed a combined digit amputation rate of 0% for Grade 2 and Grade 3, and 50% for Grade 4 frostbite. Crooks et al. (2022) (64) also showed reduced amputations among patients treated with iloprost. They included 90 patients, where 26 were treated with iloprost and 64 received standard care. Significantly lower digital amputation rates were seen among patients treated with iloprost compared to controls for Grade 3 (18% vs 44%, p < 0.001) and Grade 4 (46% vs 95%, p < 0.001) severities.
While there is still no direct comparison of iloprost versus alteplase, in a study from Lindford et al. (2017) (65), iloprost was used if there was a contraindication to thrombolysis, angiographic findings suggesting vasospasm or nonresponse to thrombolysis. One patient had a minimal response to alteplase but had complete reperfusion after iloprost infusion, suggesting iloprost may have benefits when thrombolytics failed.
Iloprost is believed to maintain its efficacy even if initiated later post-rewarming compared to thrombolytics. In Cauchy et al.’s studies (2011 & 2016) (63,66), treatment benefit with iloprost was evident with treatment started more than 12 h after injury and up to 48 h. Pandey et al. (2018) (67) attempted to evaluate if delayed iloprost use up to 72 h would help reduce tissue loss in Grades 3 and 4 frostbite. In their case series of patients evacuated from Himalayan peaks, four received treatment between 48 and 72 h from injury. Two of the patients treated with iloprost had excellent results with minimal tissue loss and two had good results with tissue loss less than expected. One patient with a poor outcome likely experienced a freeze-thaw-refreeze injury. Other authors observed iloprost benefit despite delayed initiation of iloprost 70-h post injury and five-day post-rewarming (68,69).
Most studies show some association between iloprost and reduced amputation rates. Given the paucity of randomised trials and relatively limited study populations to date, adequately powered randomised controlled trials are needed to demonstrate the efficacy and safety of iloprost to treat frostbite.
Iloprost is currently not commercialized in Canada. It can be obtained through Health Canada Special Access Program by completing a “Future use request”.
www.canada.ca/en/health-canada/services/drugs-health-products/special-access/drugs.html
Some hospitals across Canada carry iloprost for future use in frostbite. Contact them for more information on how to access iloprost:
Dr. Alex Poole, General Surgeon/Josianne Gauthier, Clinical Pharmacist, Whitehorse General Hospital, Yukon Territory (contact info: [email protected])
Several thrombolytics, mainly alteplase, have been used in the treatment of frostbite. Alteplase is a recombinant tissue plasminogen activator (rtPA). It works by binding to fibrin in a thrombus and activating plasminogen, which causes local fibrinolysis and prevents enlargement of blood clots in frostbitten extremities. (51). Alteplase is used in other conditions such as acute ischemic stroke and pulmonary embolism.
Alteplase can be used for severe frostbite (Grade 3- 4), within 12-24 hours of rewarming.
Contraindications to alteplase vary according to the indication for which it is given. The alteplase product monograph (for acute myocardial infarction) include the following contraindications: active internal bleeding, history of stroke, recent (within two months) intracranial, or intraspinal surgery or trauma, intracranial neoplasm, arteriovenous malformation, or aneurysm, known bleeding diathesis, severe uncontrolled hypertension (systolic BP > 180 mm Hg and/or diastolic BP > 110 mm Hg), recent traumatic cardiopulmonary resuscitation and recent severe trauma. (Activase Product Monograph Hoffmann-La Roche).
Thrombolytics can be administered intra-arterial or intravenous. However, the intra-arterial route of administration requires contrast administration and angiography to perform catheter-directed intra-arterial thrombolysis.
A common intravenous dosing regimen of alteplase for frostbite is 0.15 mg/kg bolus over 15 minutes then 0.15 mg/kg/hour for 6 hours. After weight-based calculations, this results in a dose greater than the dose used in stroke but less than pulmonary embolism or ST elevation myocardial infarction (STEMI).
Because fibrinolysis can have a procoagulant effect, anticoagulants, unfractionated heparin (UFH) and low-molecular weight heparins (LMWH), may be used as adjunctive therapy in thrombolytic protocols (4).
Thrombolytics carry a risk of bleeding and haemorrhage. In a recent study detailing bleeding complications in severe frostbite patients treated with intravenous alteplase, 8.4% of patients had bleeding resulting in change of management or intervention (51).
In the early 1990s, the Hennepin County Medical Center in Minneapolis piloted the use of thrombolytics in the treatment of frostbite (61). Several thrombolytics, mainly alteplase, have been used in the treatment of frostbite with over 15 published studies, totalling over 300 patients (54,56).
In two systematic reviews on the use of thrombolytics in the treatment of frostbite published in 2019, the limb salvage rates ranged from 0% to 100%, with similar salvage rates seen between intraarterial and intravenous administration (54,56). The American Burn Association published in 2023 a systematic review of the evidence (51). Amongst the eight studies that met inclusion criteria, including the presence of a comparator (e.g. no thrombolytics) and at least one of the predefined outcomes measured and reported, thrombolytics therapy demonstrated a trend towards improved salvage, both in terms of fewer amputations and a more distal level of amputations (34).
Studies have demonstrated a rapid loss of efficacy with delay of administration of thrombolytics. Nygaard et al. showed that the time from rewarming to alteplase significantly impacted amputation rate, with each hour of delayed treatment leading to an additional 27% loss of tissue (58). As per this study, alteplase should ideally be initiated within 4 h of rewarming, with some benefits observed up to 12 h post-rewarming (58).
Frostbite is not an infection-prone injury. Antibiotics are generally not required and antibiotic prophylaxis is not currently recommended (20). Tetanus prophylaxis should be used as per usual guidelines (20).
Hyperbaric oxygen (HBOT) works through inhalation of high concentrations of oxygen in a pressurized chamber. HBOT increases levels of dissolved oxygen in plasma, facilitating tissue hyperoxygenation and promoting angiogenesis, preserving the viability of ischemic tissues, preventing ischemic/reperfusion syndromes, and even modulating the immune system response (21).
Hyperbaric oxygen therapy should be started as soon as possible post injury for maximum efficacy in preventing the ischemia-reperfusion injury complex, however, benefit has been reported initiating HBOT up to four weeks after the initial injury (22).
The only absolute contraindication to HBOT is an untreated pneumothorax. There are many relative contraindications and evaluation by a hyperbaric physician is necessary prior to initiation of treatment. Relative contraindications include history of spontaneous pneumothorax or thoracic surgery, COPD, asthma, pregnancy, presence of a cardiac defibrillator, history of epilepsy, high fever, history of ear or sinus disease and/or active infection, history of optic neuritis, insulin dependent diabetes, congenital spherocytosis, latent tuberculosis, active use of caffeine, nicotine, cocaine or amphetamines, active untreated cancer, some chemotherapies (23).
Hyperbaric oxygen treatments are usually administered for 90 minutes duration at a pressure of 2.0–2.5 atmospheres absolute for acute injuries. Common frequency of HBOT is twice daily for up to a week, followed by once daily for a total duration ranging from 14 days to several weeks, as determined by local clinical expertise.
Potential side effects of HBOT include oxygen toxicity, barotrauma, ocular side effects and claustrophobia while in the chamber. These, however, are rare with no side effects reported in the treatment of frostbite.
HBOT has been used with success in limited case series and trials. It has been demonstrated to improve amputation levels when compared to early bone scans, and improves outcomes when used as an adjuvant therapy with iloprost (24,25).
The presentation of frostbite is challenging to prognosticate in the acute stages and remains difficult until many weeks after injury. Imaging modalities at the time of initial presentation may be used to predict tissue reperfusion, microvascular damage, and late sequelae of frostbite injury.
The role of x-ray in acute frostbite management is limited. Initial radiographs may show soft tissue swelling and underlying traumatic injuries, which provides limited prognostic information.
Distal subtraction angiography (DSA), has diagnostic potential in investigating acute frostbite with vascular compromise. DSA is useful to identify perfusion, target sites for thrombolysis, and for monitoring reperfusion following treatment. It can identify poorly perfused sites that are otherwise not clinically obvious (26-28). It has limited evidence in its utility for evaluating frostbite in the sub-acute and chronic phases of the condition.
Bone scintigraphy (bone scan) has been shown to support diagnosis and prognosis for frostbite. Bone scans evaluate microvascular injury and bone perfusion, and can demarcate level of amputation in cases of severe frostbite (Grade 3-4) (26,29). One study suggests that a bone scan at 7-10 days post injury is able to predict amputation accurately in 84% of cases, weeks before the tissue can be evaluated clinically for viability (30). The utility of bone scan at dates beyond these time points has not been investigated.
CT combined with nuclear medicine (SPECT/CT) combines the functional information derived from bone scintigraphy with the anatomical data provided from CT. SPECT/CT may have great utility in guiding surgical planning or providing functional information towards perfusion of frostbite affected regions, at earlier stages than is apparent clinically. Compared to bone scintigraphy, SPECT/CT allows for greater spatial resolution and evaluation of small digits such as distal phalanges (26). While availability of this technology remains a challenge, SPECT/CT appears to have strong utility in prognosticating frostbite injuries. SPECT/CT has not been evaluated outside the acute phases of the condition.
Fluorescent microangiography is a modality with evidence to suggest its utility in evaluating frostbite. Lacey et al in 2019 demonstrated a strong positive correlation between microangiography studies and amputation level (31). The major advantage of microangiography is that it can be performed at bedside, minimizing imaging and thus time to treatment (32,33).
|
Medication |
Dose |
|
ASA |
325 mg q6h PO |
|
Ibuprofen |
400mg q6h PO |
|
tPA (Alteplase) |
0.15mg/kg IV bolus over 15 minutes, followed by a continuous infusion of 0.15mg/kg/hr IV for 6 hours
|
|
Enoxaparin |
1mg/kg SC BID for 12 days If LMWH is contraindicated, use IV heparin
|
|
Iloprost |
0.5ng/kg/min IV 6h/day for 5 days at maximum tolerable rate
|
Commissioner O of the. FDA. FDA; 2024 [cited 2024 Jun 27]. FDA Approves First Medication to Treat Severe Frostbite. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-medication-treat-severe-frostbite.
Lorentzen AK, Penninga L. Frostbite-A Case Series From Arctic Greenland. Wilderness Environ Med. 2018 Sep;29(3):392–400.
Commissioner O of the. FDA. FDA; 2024 [cited 2024 Jun 27]. FDA Approves First Medication to Treat Severe Frostbite. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-medication-treat-severe-frostbite.
Lorentzen AK, Penninga L. Frostbite-A Case Series From Arctic Greenland. Wilderness Environ Med. 2018 Sep;29(3):392–400.
Zhang Y, Song J, Huang G. Comprehensive Treatment of Single Finger Frostbite: A Case Study. J Burn Care Res Off Publ Am Burn Assoc. 2021 May 7;42(3):555–9.
McIntosh SE, Freer L, Grissom CK, Auerbach PS, Rodway GW, Cochran A, et al. Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Treatment of Frostbite: 2019 Update. Wilderness Environ Med. 2019 Dec 1;30(4):S19–32.
Lorentzen AK, Penninga L. Frostbite-A Case Series From Arctic Greenland. Wilderness Environ Med. 2018 Sep;29(3):392–400.
Zhang Y, Song J, Huang G. Comprehensive Treatment of Single Finger Frostbite: A Case Study. J Burn Care Res Off Publ Am Burn Assoc. 2021 May 7;42(3):555–9.
McIntosh SE, Freer L, Grissom CK, Auerbach PS, Rodway GW, Cochran A, et al. Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Treatment of Frostbite: 2019 Update. Wilderness Environ Med. 2019 Dec 1;30(4):S19–32.
Regli IB, Strapazzon G, Falla M, Oberhammer R, Brugger H. Long-Term Sequelae of Frostbite-A Scoping Review. Int J Environ Res Public Health. 2021 Sep 14;18(18):9655.
Higdon B, Youngman L, Regehr M, Chiou A. Deep Frostbite Treated With Hyperbaric Oxygen and Thrombolytic Therapies. Wounds Compend Clin Res Pract. 2015 Aug;27(8):215–23.
Davis A, Sinopoli B, Mann N, Stenbit AE. A Photographic Case of Frostbite Treated with Delayed Hyperbaric Oxygen Therapy. High Alt Med Biol. 2022 Jun;23(2):194–7.
Coward A, Endorf FW, Nygaard RM. Revision Surgery Following Severe Frostbite Injury Compared to Similar Hand and Foot Burns. J Burn Care Res Off Publ Am Burn Assoc. 2022 Sep 1;43(5):1015–8.
Endorf FW, Nygaard RM. Social Determinants of Poor Outcomes Following Frostbite Injury: A Study of the National Inpatient Sample. J Burn Care Res Off Publ Am Burn Assoc. 2021 Nov 24;42(6):1261–5.
Rossis CG, Yiacoumettis AM, Elemenoglou J. Squamous cell carcinoma of the heel developing at site of previous frostbite. J R Soc Med. 1982 Sep;75(9):715–8.
Mohr WJ, Jenabzadeh K, Ahrenholz DH. Cold injury. Hand Clin. 2009 Nov;25(4):481–96.
Weatherley-White RCA, Sjostrom B, Paton BC. Experimental studies in cold injury: II. The pathogenesis of frostbite. J Surg Res. 1964 Jan 1;4(1):17–22.
Quintanilla R, Krusen FH, Essex HE. Studies on frost-bite with special reference to treatment and the effect on minute blood vessels. Am J Physiol. 1947 Apr;149(1):149–61.
Manson PN, Jesudass R, Marzella L, Bulkley GB, Im MJ, Narayan KK. Evidence for an early free radical-mediated reperfusion injury in frostbite. Free Radic Biol Med. 1991;10(1):7–11.
Robson MC, Heggers JP. Evaluation of hand frostbite blister fluid as a clue to pathogenesis. J Hand Surg. 1981 Jan;6(1):43–7.
McIntosh SE, Freer L, Grissom CK, Rodway GW, Giesbrecht GG, McDevitt M, et al. Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Treatment of Frostbite: 2024 Update. Wilderness Environ Med. 2024 Jun;35(2):183–97.
Wibbenmeyer L, Lacey AM, Endorf FW, Logsetty S, Wagner ALL, Gibson ALF, et al. American Burn Association Clinical Practice Guidelines on the Treatment of Severe Frostbite. J Burn Care Res Off Publ Am Burn Assoc. 2023 Apr 13;irad022.
Higdon B, Youngman L, Regehr M, Chiou A. Deep Frostbite Treated With Hyperbaric Oxygen and Thrombolytic Therapies. Wounds Compend Clin Res Pract. 2015 Aug;27(8):215–23.
Davis A, Sinopoli B, Mann N, Stenbit AE. A Photographic Case of Frostbite Treated with Delayed Hyperbaric Oxygen Therapy. High Alt Med Biol. 2022 Jun;23(2):194–7.
Coward A, Endorf FW, Nygaard RM. Revision Surgery Following Severe Frostbite Injury Compared to Similar Hand and Foot Burns. J Burn Care Res Off Publ Am Burn Assoc. 2022 Sep 1;43(5):1015–8.
Endorf FW, Nygaard RM. Social Determinants of Poor Outcomes Following Frostbite Injury: A Study of the National Inpatient Sample. J Burn Care Res Off Publ Am Burn Assoc. 2021 Nov 24;42(6):1261–5.
Rossis CG, Yiacoumettis AM, Elemenoglou J. Squamous cell carcinoma of the heel developing at site of previous frostbite. J R Soc Med. 1982 Sep;75(9):715–8.
Mohr WJ, Jenabzadeh K, Ahrenholz DH. Cold injury. Hand Clin. 2009 Nov;25(4):481–96.
Weatherley-White RCA, Sjostrom B, Paton BC. Experimental studies in cold injury: II. The pathogenesis of frostbite. J Surg Res. 1964 Jan 1;4(1):17–22.
Quintanilla R, Krusen FH, Essex HE. Studies on frost-bite with special reference to treatment and the effect on minute blood vessels. Am J Physiol. 1947 Apr;149(1):149–61.
Zhang Y, Song J, Huang G. Comprehensive Treatment of Single Finger Frostbite: A Case Study. J Burn Care Res Off Publ Am Burn Assoc. 2021 May 7;42(3):555–9.
Quintanilla R, Krusen FH, Essex HE. Studies on frost-bite with special reference to treatment and the effect on minute blood vessels. Am J Physiol. 1947 Apr;149(1):149–61.
Gauthier J, Morris-Janzen D, Poole A. Iloprost for the treatment of frostbite: a scoping review. Int J Circumpolar Health. 2023 Dec;82(1):2189552.
Quintanilla R, Krusen FH, Essex HE. Studies on frost-bite with special reference to treatment and the effect on minute blood vessels. Am J Physiol. 1947 Apr;149(1):149–61.
McCauley RL, Heggers JP, Robson MC. Frostbite. Methods to minimize tissue loss. Postgrad Med. 1990 Dec;88(8):67–8, 73–7.
McCauley RL, Hing DN, Robson MC, Heggers JP. Frostbite injuries: a rational approach based on the pathophysiology. J Trauma. 1983 Feb;23(2):143–7.
Heggers JP, Robson MC, Manavalen K, Weingarten MD, Carethers JM, Boertman JA, et al. Experimental and clinical observations on frostbite. Ann Emerg Med. 1987 Sep;16(9):1056–62.
McIntosh SE, Freer L, Grissom CK, Rodway GW, Giesbrecht GG, McDevitt M, et al. Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Treatment of Frostbite: 2024 Update. Wilderness Environ Med. 2024 Jun;35(2):183–97.
Heggers JP, Robson MC, Manavalen K, Weingarten MD, Carethers JM, Boertman JA, et al. Experimental and clinical observations on frostbite. Ann Emerg Med. 1987 Sep;16(9):1056–62.
Manson PN, Jesudass R, Marzella L, Bulkley GB, Im MJ, Narayan KK. Evidence for an early free radical-mediated reperfusion injury in frostbite. Free Radic Biol Med. 1991;10(1):7–11.
McCauley RL, Heggers JP, Robson MC. Frostbite. Methods to minimize tissue loss. Postgrad Med. 1990 Dec;88(8):67–8, 73–7.
McCauley RL, Hing DN, Robson MC, Heggers JP. Frostbite injuries: a rational approach based on the pathophysiology. J Trauma. 1983 Feb;23(2):143–7.
Heggers JP, Robson MC, Manavalen K, Weingarten MD, Carethers JM, Boertman JA, et al. Experimental and clinical observations on frostbite. Ann Emerg Med. 1987 Sep;16(9):1056–62.
McCauley RL, Hing DN, Robson MC, Heggers JP. Frostbite injuries: a rational approach based on the pathophysiology. J Trauma. 1983 Feb;23(2):143–7.
Heggers JP, Robson MC, Manavalen K, Weingarten MD, Carethers JM, Boertman JA, et al. Experimental and clinical observations on frostbite. Ann Emerg Med. 1987 Sep;16(9):1056–62.
Kahle AC, Cooper JS. Hyperbaric Physiological And Pharmacological Effects of Gases. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Dec 29]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK470481/
Gawdi R, Cooper JS. Hyperbaric Contraindications. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2024 Jun 27]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK557661/
Ghumman A, St Denis-Katz H, Ashton R, Wherrett C, Malic C. Treatment of Frostbite With Hyperbaric Oxygen Therapy: A Single Center’s Experience of 22 Cases. Wounds Compend Clin Res Pract. 2019 Dec;31(12):322–5.
Magnan MA, Gayet-Ageron A, Louge P, Champly F, Joffre T, Lovis C, et al. Hyperbaric Oxygen Therapy with Iloprost Improves Digit Salvage in Severe Frostbite Compared to Iloprost Alone. Med Kaunas Lith. 2021 Nov 22;57(11):1284.
Frostbite: Spectrum of Imaging Findings and Guidelines for Management | RadioGraphics [Internet]. [cited 2020 Oct 19]. Available from: https://pubs.rsna.org/doi/10.1148/rg.2016160045
Bruen KJ, Ballard JR, Morris SE, Cochran A, Edelman LS, Saffle JR. Reduction of the incidence of amputation in frostbite injury with thrombolytic therapy. Arch Surg Chic Ill 1960. 2007 Jun;142(6):546–51; discussion 551-553.
Ibrahim AE, Goverman J, Sarhane KA, Donofrio J, Walker TG, Fagan SP. The emerging role of tissue plasminogen activator in the management of severe frostbite. J Burn Care Res Off Publ Am Burn Assoc. 2015;36(2):e62-66.
Frostbite: Spectrum of Imaging Findings and Guidelines for Management | RadioGraphics [Internet]. [cited 2020 Oct 19]. Available from: https://pubs.rsna.org/doi/10.1148/rg.2016160045
Santapau A, Razola P, Tardin L, Andrés A, Prats E, Banzo J. The role of bone scanning in severe frostbite of the feet in a mountaineer. Rev Espanola Med Nucl E Imagen Mol. 2013 Mar;32(2):113–4.
Cauchy E, Chetaille E, Lefevre M, Kerelou E, Marsigny B. The role of bone scanning in severe frostbite of the extremities: a retrospective study of 88 cases. Eur J Nucl Med. 2000 May;27(5):497–502.
Frostbite: Spectrum of Imaging Findings and Guidelines for Management | RadioGraphics [Internet]. [cited 2020 Oct 19]. Available from: https://pubs.rsna.org/doi/10.1148/rg.2016160045
Lacey AM, Fey RM, Gayken JR, Endorf FW, Schmitz KR, Punjabi GV, et al. Microangiography: An Alternative Tool for Assessing Severe Frostbite Injury. J Burn Care Res Off Publ Am Burn Assoc. 2019 Aug 14;40(5):566–9.
Raleigh SM, Samson M, Nygaard R, Endorf F, Walter J, Masters T. Bedside Fluorescence Microangiography for Frostbite Diagnosis in the Emergency Department. West J Emerg Med. 2022 Oct 23;23(6):872–7.
Poole A, Gauthier J, MacLennan M. Management of severe frostbite with iloprost, alteplase and heparin: a Yukon case series. CMAJ Open. 2021 Jun;9(2):E585–91.
Early Mobilization in Lower Extremity Frostbite Injury: Preliminary Experience at a Single Burn Center - PubMed [Internet]. [cited 2024 Jun 27]. Available from: https://pubmed-ncbi-nlm-nih-gov.proxy.lib.nosm.ca/28570307/
Environmental Cold-Induced Injury - ClinicalKey [Internet]. [cited 2024 Jun 27]. Available from: https://www-clinicalkey-com.proxy.lib.nosm.ca/#!/content/playContent/1-s2.0-S0039610906001575?returnurl=https:%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0039610906001575%3Fshowall%3Dtrue&referrer=https:%2F%2Fpubmed.ncbi.nlm.nih.gov%2F
Frostbite: Spectrum of Imaging Findings and Guidelines for Management | RadioGraphics [Internet]. [cited 2020 Oct 19]. Available from: https://pubs.rsna.org/doi/10.1148/rg.2016160045
Cauchy E, Chetaille E, Lefevre M, Kerelou E, Marsigny B. The role of bone scanning in severe frostbite of the extremities: a retrospective study of 88 cases. Eur J Nucl Med. 2000 May;27(5):497–502.
Greenwald D, Cooper B, Gottlieb L. An algorithm for early aggressive treatment of frostbite with limb salvage directed by triple-phase scanning. Plast Reconstr Surg. 1998 Sep;102(4):1069–74.
Destruction of Phalangeal Epiphyses by Frostbite | Radiology [Internet]. [cited 2024 Jun 27]. Available from: https://pubs-rsna-org.proxy.lib.nosm.ca/doi/10.1148/93.4.859?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
Vinson HA, Schatzki R. Roentgenologic Bone Changes Encountered in Frostbite, Korea 1950–51. Radiology. 1954 Nov;63(5):685–95.
Ellis R, Short JG, Simonds BD. Unilateral Osteoarthritis of the Distal Interphalangeal Joints Following Frostbite. Radiology. 1969 Oct;93(4):857–8.
Norheim A, Rannestad B, Howes R, Rein E, Jorum E, Friedl K, et al. Abstracts from The Cold Weather Operations Conference 2021. Int J CIRCUMPOLAR Health. 2022 Dec 31;81(1).
Fabian JC, Taljaard M, Perry JJ. A retrospective cohort study examining treatments and operative interventions for frostbite in a tertiary care hospital. CJEM. 2017 Mar;19(2):88–95.
Richard L, Golding H, Saskin R, Jenkinson JIR, Francombe Pridham K, Gogosis E, et al. Cold-related injuries among patients experiencing homelessness in Toronto: a descriptive analysis of emergency department visits. CJEM. 2023 Aug;25(8):695–703.
Endorf FW, Nygaard RM. Social Determinants of Poor Outcomes Following Frostbite Injury: A Study of the National Inpatient Sample. J Burn Care Res Off Publ Am Burn Assoc. 2021 Nov 24;42(6):1261–5.
Endorf FW, Alapati D, Xiong Y, DiGiandomenico C, Rasimas CS, Rasimas JJ, et al. Biopsychosocial factors associated with complications in patients with frostbite. Medicine (Baltimore). 2022 Aug 26;101(34):e30211.
Richard L, Golding H, Saskin R, Jenkinson JIR, Francombe Pridham K, Gogosis E, et al. Cold-related injuries among patients experiencing homelessness in Toronto: a descriptive analysis of emergency department visits. CJEM. 2023 Aug;25(8):695–703.
McIntosh SE, Freer L, Grissom CK, Rodway GW, Giesbrecht GG, McDevitt M, et al. Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Treatment of Frostbite: 2024 Update. Wilderness Environ Med. 2024 Jun;35(2):183–97.
Poole A, Ahmed Y, Davidson M. The Occasional frostbite. Can J Rural Med Off J Soc Rural Physicians Can J Can Med Rurale J Off Soc Med Rurale Can. 2024 Jan 1;29(1):30–6.
Murphy J, Endorf FW, Winters MK, Rogers C, Walter E, Neumann N, et al. Bleeding Complications in Patients With Severe Frostbite Injury. J Burn Care Res Off Publ Am Burn Assoc. 2023 Jul 5;44(4):745–50.
C R, Am L, Fw E, G P, A W, J G, et al. The Effects of Rapid Rewarming on Tissue Salvage in Severe Frostbite Injury. J Burn Care Res Off Publ Am Burn Assoc [Internet]. 2022 Jul 1 [cited 2024 Oct 8];43(4). Available from: https://pubmed.ncbi.nlm.nih.gov/34791315/
Lacey AM, Rogers C, Endorf FW, Fey RM, Gayken JR, Schmitz KR, et al. An Institutional Protocol for the Treatment of Severe Frostbite Injury-A 6-Year Retrospective Analysis. J Burn Care Res Off Publ Am Burn Assoc. 2021 Aug 4;42(4):817–20.
Hutchison RL, Miller HM, Michalke SK. The Use of tPA in the Treatment of Frostbite: A Systematic Review. Hand N Y N. 2019 Jan;14(1):13–8.
Heard J, Shamrock A, Galet C, Pape KO, Laroia S, Wibbenmeyer L. Thrombolytic Use in Management of Frostbite Injuries: Eight Year Retrospective Review at a Single Institution. J Burn Care Res Off Publ Am Burn Assoc. 2020 May 2;41(3):722–6.
Drinane J, Kotamarti VS, O’Connor C, Nair L, Divanyan A, Roth MZ, et al. Thrombolytic Salvage of Threatened Frostbitten Extremities and Digits: A Systematic Review. J Burn Care Res Off Publ Am Burn Assoc. 2019 Aug 14;40(5):541–9.
Drinane J, Heiman AJ, Ricci JA, Patel A. Thrombolytic Salvage of the Frostbitten Upper Extremity: A Systematic Review. Hand N Y N. 2022 May;17(3):397–404.
Nygaard RM, Lacey AM, Lemere A, Dole M, Gayken JR, Lambert Wagner AL, et al. Time Matters in Severe Frostbite: Assessment of Limb/Digit Salvage on the Individual Patient Level. J Burn Care Res Off Publ Am Burn Assoc. 2017 Feb;38(1):53–9.
C R, Am L, Fw E, G P, A W, J G, et al. The Effects of Rapid Rewarming on Tissue Salvage in Severe Frostbite Injury. J Burn Care Res Off Publ Am Burn Assoc [Internet]. 2022 Jul 1 [cited 2024 Oct 8];43(4). Available from: https://pubmed.ncbi.nlm.nih.gov/34791315/
Lacey AM, Rogers C, Endorf FW, Fey RM, Gayken JR, Schmitz KR, et al. An Institutional Protocol for the Treatment of Severe Frostbite Injury-A 6-Year Retrospective Analysis. J Burn Care Res Off Publ Am Burn Assoc. 2021 Aug 4;42(4):817–20.
Hutchison RL, Miller HM, Michalke SK. The Use of tPA in the Treatment of Frostbite: A Systematic Review. Hand N Y N. 2019 Jan;14(1):13–8.
Heard J, Shamrock A, Galet C, Pape KO, Laroia S, Wibbenmeyer L. Thrombolytic Use in Management of Frostbite Injuries: Eight Year Retrospective Review at a Single Institution. J Burn Care Res Off Publ Am Burn Assoc. 2020 May 2;41(3):722–6.
Drinane J, Kotamarti VS, O’Connor C, Nair L, Divanyan A, Roth MZ, et al. Thrombolytic Salvage of Threatened Frostbitten Extremities and Digits: A Systematic Review. J Burn Care Res Off Publ Am Burn Assoc. 2019 Aug 14;40(5):541–9.
Drinane J, Heiman AJ, Ricci JA, Patel A. Thrombolytic Salvage of the Frostbitten Upper Extremity: A Systematic Review. Hand N Y N. 2022 May;17(3):397–404.
Mills WJ, Whaley R, Fish W. Frostbite: experience with rapid rewarming and ultrasonic therapy. Part III. 1961. Alaska Med. 1993;35(1): 19–27. Part III. 1961.
Heggers JP, Phillips LG, McCauley RL, et al. Frostbite: experimental and clinical evaluations of treatment. J Wilderness Med. 1990:27–32.
McCauley RL, Heggers JP, Robson MC. Frostbite. Methods to minimize tissue loss. Postgrad Med. 1990 Dec;88(8):67–8, 73–7.
Heggers JP, Robson MC, Manavalen K, Weingarten MD, Carethers JM, Boertman JA, et al. Experimental and clinical observations on frostbite. Ann Emerg Med. 1987 Sep;16(9):1056–62.
Heggers JP, Phillips LG, McCauley RL, et al. Frostbite: experimental and clinical evaluations of treatment. J Wilderness Med. 1990:27–32.
Skolnick AA. Early data suggest clot-dissolving drug may help save frostbitten limbs from amputation. JAMA. 1992;267(15):2008–2010.
Hutchison RL, Miller HM, Michalke SK. The Use of tPA in the Treatment of Frostbite: A Systematic Review. Hand N Y N. 2019 Jan;14(1):13–8.
Drinane J, Kotamarti VS, O’Connor C, Nair L, Divanyan A, Roth MZ, et al. Thrombolytic Salvage of Threatened Frostbitten Extremities and Digits: A Systematic Review. J Burn Care Res Off Publ Am Burn Assoc. 2019 Aug 14;40(5):541–9.
Ilomedin Package Insert. Bayer HealthCare
Cauchy E, Cheguillaume B, Chetaille E. A controlled trial of a prostacyclin and rt-PA in the treatment of severe frostbite. N Engl J Med. 2011;364(2):189-90.
Poole A, Gauthier J, MacLennan M. Management of severe frostbite with iloprost, alteplase and heparin: a Yukon case series. CMAJ Open. 2021 Jun;9(2):E585–91.
Poole A, Gauthier J. Treatment of severe frostbite with iloprost in northern Canada. CMAJ Can Med Assoc J J Assoc Medicale Can. 2016 Dec 6;188(17–18):1255–8.
Crooks S, Shaw BH, Andruchow JE, Lee CH, Walker I. Effectiveness of intravenous prostaglandin to reduce digital amputations from frostbite: an observational study. CJEM. 2022;24(6):622-629.
Lindford A, Valtonen J, Hult M, Kavola H, Lappalainen K, Lassila R, Aho P, Vuola J. The evolution of the Helsinki frostbite management protocol. Burns. 2017;43(7):1455-1463.
Cauchy E, Chetaille E, Pham E, et al. Iloprost With and Without rt-PA: Treatment of 131 Cases of Severe Frostbite. 7th World Congress of Mountain and Wilderness Medicine. Telluride, Colorado. July 30 - August 4, 2016. (Abstract)
Cauchy E, Cheguillaume B, Chetaille E. A controlled trial of a prostacyclin and rt-PA in the treatment of severe frostbite. N Engl J Med. 2011;364(2):189-90.
Cauchy E, Chetaille E, Pham E, et al. Iloprost With and Without rt-PA: Treatment of 131 Cases of Severe Frostbite. 7th World Congress of Mountain and Wilderness Medicine. Telluride, Colorado. July 30 - August 4, 2016. (Abstract)
Pandey P, Vadlamudi R, Pradhan R, Pandey KR, Kumar A, Hackett P. Case Report: Severe Frostbite in Extreme Altitude Climbers-The Kathmandu Iloprost Experience. Wilderness Environ Med. 2018;29(3):366-374
Magnan DM, Gelsomino M, Louge P, Pignel R. Successful Delayed Hyperbaric Oxygen Therapy and Iloprost Treatment on Severe Frostbite at High Altitude. High Alt Med Biol. 2022;23(3):294-297.
Imray C, Grieve A, Dhillon S; Caudwell Xtreme Everest Research Group. Cold damage to the extremities: frostbite and non-freezing cold injuries. Postgrad Med J. 2009 Sep;85(1007):481-8
Lansdorp CA, Roukema GR, Boonstra O, Dokter J, van der Vlies C. Delayed treatment of frostbite with hyperbaric oxygen: a report of two cases. Undersea Hyperb Med J Undersea Hyperb Med Soc Inc. 2017;44(4):365–9.
