The 2024 update of the Wilderness Medical Society Clinical Practice Guidelines for the prevention and treatment of frostbite presents a comprehensive review of the pathophysiology, prevention, and therapeutic management of frostbite injuries, with recommendations graded according to the methodology established by the American College of Chest Physicians. [1]
Iloprost has become a first-line therapy for severe (Grade 3-4) frostbite. Evidence from a key randomized trial and multiple case series demonstrates that intravenous iloprost, ideally administered within 48 hours of thawing (but potentially up to 72 hours), significantly reduces amputation rates compared to other treatments like buflomedil or alteplase alone. While the overall evidence is considered low quality due to the lack of large-scale trials, iloprost has consistently shown favorable outcomes and a good safety profile with minimal major side effects. It is particularly advantageous in remote settings as it potentially eliminates the bleeding risks associated with alteplase. The optimal treatment duration is 5 to 8 days, guided by evidence of reperfusion. It is strongly recommended for deep frostbite extending to the distal interphalangeal joint or more proximal, despite the low-quality evidence. [1]
Several other pharmacologic options exist alongside iloprost for frostbite treatment. Thrombolytic therapy (tPA) is a strong recommendation for severe frostbite within 24 hours of injury, offering tissue salvage potential but carrying a substantial risk of bleeding complications. Ibuprofen is a weakly recommended adjunct therapy to be continued for several weeks. Heparin is not suggested as a monotherapy but is used as an adjunct in specific tPA or iloprost protocols. Other vasodilators, such as pentoxifylline, have minimal supporting evidence and are not routinely recommended. Finally, systemic antibiotics are strongly advised only for treating confirmed infections and not for prophylaxis. [1]
A 2024 publication by the American Burn Association (ABA) Clinical Practice Guidelines articulates recommendations on the treatment of severe frostbite, as defined by atmospheric cooling that results in a perfusion deficit to the extremities. Based on a limited body of evidence, intravenous iloprost appears to reduce amputation rates in adults with severe limb frostbite. The primary supporting study, a randomized trial, reported a zero percent amputation rate in patients treated with iloprost alone, compared to a 39.6% rate in the control group. Patients presenting with grade 4 frostbite also received alteplase, but there were no attempts to compare the two agents. These findings are supported by a subsequent cohort study in which no amputations occurred in patients with grade 2 or 3 frostbite who were treated with iloprost. However, the overall quality of the evidence is low due to the weaknesses of the primary and a reliance on other non-randomized case series. Thrombolytics are conditionally recommended for early administration (12 hours or less from rewarming) compared to later administration to reduce amputation complications. [2]
A 2020 guideline from the American Burn Association provides a comprehensive overview of thrombolytic therapy for the treatment of frostbite. The guideline emphasizes targeted treatment for patients presenting with Grade 3 or 4 frostbite injuries, characterized by cyanosis persisting proximal to the distal phalanx and loss of perfusion following rewarming. Recommendations advocate for thrombolytic therapy consideration when there is a clinical indication of soft tissue loss risk and the treatment can be initiated within 48 hours of the initial cold exposure. Patients exhibiting distal blood flow loss confirmed by Doppler signals and without thrombolytic therapy contraindications should engage in urgent discussions with frostbite-specialized burn centers. The guideline further advises that rapid rewarming is critical, but efforts should be made to minimize warm ischemia time for isolated frostbite areas. It suggests the potential delay of rapid rewarming or initiation of thrombolytic therapy before imaging in coordination with specialized centers. Documentation through photographs and doppler signal recordings is essential at rewarming, thrombolytic initiation, and subsequent intervals. Thrombolytic therapy administration should follow local hospital protocols, with preference given to routes allowing the quickest diagnosis-to-treatment time. Additionally, the guideline recommends assessing tissue salvage through photographs and estimated frostbite grades at admission and within a week post-admission, utilizing universal scoring systems like the Hennepin score to facilitate comparative analysis of results. [3]
Therapeutic treatment of frostbite may be initiated following on-field medical care and additional medical care (i.e., passive and/or active rewarming). Due to severe thrombus formation originating from endothelial damage, therapeutic treatment of frostbite may be initiated with thrombolytic therapy consisting of intra-arterial thrombolysis using tissue plasminogen activator within 24 hours of injury. Some anecdotal evidence from case reports suggests aggressive thrombolytic therapy within this timeframe can significantly reduce tissue damage and prevent morbidity, allowing for salvage of tissue and reduced amputation rate from 41% to 15%. Importantly, rTPA is most effective when administered within 6 to 24 hours of rewarming. Iloprost may be considered with thrombolytics are contraindicated or ineffective. Although based mostly on case reports as well as one small controlled trial (Table 4). Iloprost is considered to be an emerging and effective treatment for frostbite, resulting in dilation of systemic and pulmonary arterial vascular beds to decrease incidence of frostbite related amputations. Additionally, anticoagulant therapy, when administered within 24 hours, is advantageous in preventing potential amputation, as demonstrated in anecdotal evidence for streptokinase and heparin. Heparin may be given at a dose of 500 mg/hour along with rTPA, to be continued for 72 to 96 hours. Considerations for heparin therapy are noted, however; no freeze thaw cycles may have occurred within the past 24 hours, and no contraindications (e.g., trauma, surgery, bleeding, neurological impairment) may be present. Additionally adjuvant therapy for frostbite includes pentoxifylline, administered as one 400 mg tablet three times daily for 2 to 6 weeks, to accommodate maximized blood flow into the small damaged vessels, reducing tissue damage and increasing tissue survival. Finally, wound care and infective prophylaxis may be indicated if blister rupture is observed to prevent infection and sepsis, while anti-inflammatory drugs, like NSAIDs, may be utilized until wounds have healed. While not a pharmacological treatment, hyperbaric oxygen therapy may be utilized at onset of injury and up to 21 days after to increase particle pressure of oxygen within the tissue, reducing hypoxemia and decreasing incidence of amputation. [4, 5]
A 2020 Cochrane meta-analysis, which sought to assess the benefits and harms of various frostbite management options, identified only a single eligible randomized trial for inclusion. This open-label study of 47 participants with severe frostbite was judged to be at a high risk of bias. All participants received a baseline treatment of rapid rewarming, aspirin, and the since-withdrawn drug buflomedil before being randomized into one of three groups: additional buflomedil, iloprost alone, or iloprost plus recombinant tissue plasminogen activator (rtPA). The results suggest that both iloprost and iloprost plus rtPA may significantly reduce amputation rates compared to buflomedil alone, risk ratio (RR) 0.05 (95% CI 0.00 to 0.78; p= 0.03; very low-quality evidence), with no statistically significant difference in efficacy between the two iloprost regimens. While adverse events like flushing and nausea were common, there were no deaths or withdrawals. The Cochrane reviewers concluded that the evidence supporting these findings is of very low quality, as it stems from a single, potentially biased trial that used a withdrawn comparator drug. They emphasized a critical paucity of reliable evidence and a pressing need for high-quality randomized trials to establish effective frostbite treatments. [6]
A 2023 systematic review and meta-analysis evaluated the effectiveness of various treatments for frostbite. The review, which included data from 71 articles comprising 978 frostbite cases, aimed to assess the outcomes associated with pharmacologic and non-pharmacologic interventions used for Grade 2 to 4 frostbite injuries. The treatment modalities assessed included thrombolytics such as recombinant tPA, vasodilators like iloprost, regional anesthesia techniques, and adjunctive therapies such as hyperbaric oxygen therapy (HBOT) and nonsteroidal anti-inflammatory drugs (NSAIDs). [7]
Notably, a 2011 randomized controlled trial (RCT) demonstrated that IV iloprost, when administered within 48 hours, significantly improved outcomes in patients with severe frostbite, achieving near-total digit salvage rates. Analysis of tissue salvage rates using the Hennepin Score indicated that patients treated with thrombolytics within 24 hours had a 25% higher tissue salvage rate than those receiving conservative treatment. Similarly, digit salvage meta-analyses showed a fivefold reduction in amputation risk with thrombolytic use. Based on these findings, iloprost and thrombolytic therapy may offer the most benefit in reversing early-stage frostbite progression, while the effectiveness of other commonly used treatments, such as NSAIDs and HBOT, remains unsubstantiated due to a lack of robust clinical data. [8]