The Deep Freeze: A Review of Frostbite Management

Introduction

Frostbite is a frequent presenting complaint to emergency departments (EDs) in cold climates. It is more common among those without housing, those with mental health disorders as well as those who work or engage in outdoor activities.⁽¹⁾ These injuries can be debilitating requiring surgical intervention, debridement or amputation in the most severe cases. Complications can include local swelling, necrosis, gangrene, compartment syndrome, contracture and other physical deformities.⁽¹⁾ The high level of morbidity associated to frostbite injuries highlights the importance of initial management in the emergency department which we will review in this post.

Pathophysiology

Frostbite is a freezing cold thermal injury that occurs when tissues are exposed to temperatures below their freezing point (approximately -0.53C).^(1,2) Cold exposure then causes peripheral vasoconstriction with intermittent cycles of vasodilation. Direct cellular injury occurs due to ice crystal formation, cell dehydration and shrinkage as well as electrolyte and pH imbalances.^(1–3) Once rewarming occurs, reperfusion injury cascade triggers the production of free radicals and inflammatory mediators, which then contribute to progressive dermal ischemia.^(1–3)

Initial Patient Evaluation

Early recognition is essential to improving prognosis where paresthesia is often the first symptom of frostbite injury.^(1,2) It is important to also ensure to evaluate the patient for any concurrent pathologies such as hypothermia, trauma or underlying cause of frostbite. Generally, the patient may describe feeling numb, cold and clumsy.^(1,2) Overall, the appearance of affected tissue can be variable including yellow, pale or even mottled blue. Following rewarming, the tissues may appear red, edematous as well as have blister formation.^(1,2)

The purpose of this early assessment can help identify poor or good prognostic signs related to frostbite injury.

Table 1: Prognostic factors in frostbite injuries adapted from Gonzaga et al (4).

Classification

There have been several classification systems proposed for the grading of frostbite. Historically, frostbite was divided into “degrees” including frostnip and first-, second- and third-degree frostbite depending on the depth of the injury.^(1,2) Frostnip is defined as the superficial non-freezing cold injury where there is no formation of ice crystals nor long-term tissue damage.⁽⁵⁾

However, the introduction of a newer classification by Cauchy and colleagues has been adopted by many centers as it gives an early prognostic factor of bone and tissue loss as well as a likely anatomic amputation level.^(2,3,6) This classification further goes on to identify initial management (Table 2).

Figure 1: Supplemental image outlining the classification of frostbite adopted from Cauchy et al. 

Table 2: Management of frostbite injuries at Day 0 per Cauchy and colleagues. Grading scheme following 1h rewarming in 38C bath, IV infusion of chlorohydrate buflomedil and 250mg aspirin (6).

Management in the Field

Initial assessment in the field should consist of traditional ABCDE (airway, breathing, circulation, disability, exposure) approach where primary first-aid and resuscitation takes precedence. Once this has been addressed and frostbite injury has been established, any wet and tight clothing should be removed.⁽¹⁾ Rubbing, massaging, applying dry heat as well as freeze-thaw-cycles must be avoided as this can cause further tissue damage.^(1,2) As such, rewarming should be initiated in the field if it is likely that no further cold exposure will occur during transport. The affected area can also be wrapped in gauze and immobilized for comfort.^(1,2) Once the patient has been stabilized, they should then be transported to the nearest medical facility for ongoing care.

Pre-Hospital Rewarming

If proper resources are available, and definitive care is more than 2 hours away, field rewarming should be done by warm water immersion.^(2,5) This can be done by placing the affected extremity into warm water that is between 37-39°C. Ideally a thermometer should be used as the affected limb will have impaired temperature sensation. If this is not possible, then the unaffected limb or a caregiver’s / healthcare provider’s hand can be used to confirm that the water temperature is appropriate.^(2,5) As an endpoint, rewarming is complete when the affected skin is red/purple and the tissues are pliable.^(1,2) This same procedure can also be performed following arrival to an appropriate medical facility.

In the recently published 2023 American Burn association guidelines,⁽⁷⁾ they pose the question regarding rewarming:

“Among adults with severe limb frostbite, does rapid rewarming in a 38°C to 42°C water bath compared to not using rapid rewarming in a 38°C to 42°C water bath result in a) fewer amputations and or b) more distal level of amputation.”

Interestingly, there is no compelling evidence of human studies; however, they do describe that in animal studies where extremities were exposed to extreme cold temperatures, rapid rewarming showed an advantage with less tissue loss when compared to spontaneous rewarming. Following these animal studies rapid rewarming was performed in humans and continues to be recommended based on expert consensus.

In-Hospital Management

Upon arrival to a medical facility, patients should be assessed in a systematic approach, with initial assessment of their ABCs. Given likely prolonged cold exposure in patients presenting with frostbite injuries, they should also be assessed for hypothermia. Recommendations from the Wilderness Medical Society (WMS) suggest that patients with mild hypothermia (35-32°C) should have concurrent treatment for hypothermia and frostbite.^(5,8) Conversely, those with moderate (32-28°C) or severe (<28°C) hypothermia should be treated effectively for hypothermia prior to treatment of frostbite injury.^(5,8) Warming of the affected extremity can be performed as described above in the pre-hospital warming section.

Management of frostbite injuries can be broken down as follows:

Advanced In-Hospital Therapies

Thrombolytic Therapy

In treating frostbite injury, rapid rewarming addresses the ice crystal phase of cellular damage, but does not treat damage or thrombosis that may have already occurred in affected vessels.⁽¹²⁾

To investigate this, Twomey and colleagues performed an open label study in 2005 to investigate the safety and efficacy of tissue plasminogen activator (tPA) in the treatment of severe frostbite.⁽¹²⁾ They administered tPA to all patients with severe frostbite that did not improve with rapid rewarming, had absent Doppler pulses in the distal limb or digits, without perfusion by technetium 99-m three-phase bone scan and no contraindication to tPA use. In this study, 19 patients with a total of 174 digits at risk of amputation were given intraarterial or intravenous tPA. Two patients had to have therapy stopped due to increased bleeding. In all, 16 of 19 patients responded to tPA treatment and this was one of the first studies demonstrating effective treatment with tPA and heparin for frostbite to prevent amputation.⁽¹²⁾ They found this treatment was most effective in patients who had less than 24 hours of cold exposure, warm ischemia times less than 6 hours and no freeze-thaw cycles.⁽¹²⁾

Subsequently, in their retrospective review of clinical outcomes in 2007, Bruen and colleagues demonstrated that administration of tPA decreased the rate of digital amputation from 41% to 10% when administered within 24 hours of injury.⁽¹³⁾ This was one of the first advances in the treatment of frostbite in over more than 25 years.

The American Burn Association just released Clinical Practice guidelines in April of this year and in their guidelines they have a conditional recommendation for thrombolytics.⁽⁷⁾ From the studies they reviewed, there is a trend towards improved salvage with thrombolytic therapy both in terms of fewer amputations and a more distal level of amputations. In these guidelines they do not make a recommendation for intravenous vs intra-arterial TPA given insufficient evidence.

In discussion with one of local Ottawa plastic surgeons, Dr Brent Trull, he recommends having a low threshold to call plastic surgery to discuss possible thrombolysis for a patient who is presenting to the ED within 24 hours of rewarming. 

Iloprost

Iloprost has been an emerging therapy for severe frostbite, first published in 1994.⁽¹⁸⁾ Iloprost is a synthetic prostaglandin analogue that has been historically used for the treatment of pulmonary hypertension and acts by dilating systemic and pulmonary arteries and impairing platelet aggregation. It can also reduce capillary permeability, suppress platelet aggregation and activates fibrinolysis.⁽²⁾

These findings were subsequently followed by a randomized control trial performed by Cauchy and colleagues in 2011.⁽¹⁹⁾ In this study, patients were randomized to one of three treatment regimens after receiving usual care of rewarming of affected part, 250mg Aspirin and 400mg intravenous buflomedil. One group received 250mg Aspirin and buflomedil (400mg for 1 hour per day), the second group received 250mg Aspirin plus prostacyclin (0.5-2 ng of iloprost per kg of body weight per minute for 6 hours per day) and the last group received 250mg of Aspirin, iloprost and fibrinolysis (100mg of recombinant tissue plasminogen activator for the first day only). Risk of amputation in the buflomedil group was 60% compared to 0% in the group receiving prostacyclin alone and 19% in the group receiving prostacyclin plus rt-TPA.⁽¹⁹⁾ This is the only trial found in a 2020 systematic review investigating this question and it was deemed low quality evidence given small sample size, unclear risk of bias and use of buflomedil which has now been discontinued.⁽²⁰⁾ Buflomedil is an alpha-adrenolytic agent that was previously widely in Europe but is not currently approved in the United States or Canada.⁽⁵⁾

Poole and colleagues implemented the Yukon Frostbite Protocol in 2015 and subsequently reviewed charts of all patients who were treated as per the protocol between 2015 and 2020.⁽²¹⁾ Using the grading system introduced by Cauchy and colleagues, grade 1-4 frostbite were managed with: daily hydrotherapy; debridement and aspiration of clear blisters; topical administration of aloe vera; regular ibuprofen; and pantoprazole. Patients with grade 2-4 frostbite received iloprost. Patients with grade 4 frostbite within 24 hours of rewarming also received alteplase. There were 22 patients enrolled in the study with 142 affected digits. All digits with grade 2 or 3 frostbite were salvaged, as were 50% of those with grade 4 frostbite. Four patients required amputation. All 29 digits amputated had grade 4 frostbite, the majority of digits (19) were from one patient. This study thus demonstrated a salvage rate of 100% for grade 2 or 3 frosbite and 50% for grade 4 frostbite. This is an improvement compared to other studies reporting the risk of amputation without iloprost or thrombolysis to be 31% for grade 2 frostbite, 67% for grade 3 frostbite and 98-100% for grade 4 frostbite.⁽⁶⁾

Figure 2: Management algorithm proposed with Iloprost based on degree of frostbite.

Interestingly, a recent 2022 study published by Crooks and colleagues from Calgary, assessed the effectiveness of a 5-day course of IV iloprost at reducing digital amputation for patients with severe frostbite injuries in an urban setting.⁽²²⁾ In this retrospective study, 90 patients were included where 26 were treated with iloprost and 64 patients received usual care. Frostbite grading was performed as per the classification system described by Cauchy and colleagues.⁽⁶⁾ There were no digital amputations in patients with grade 2 frostbite. Lower digital amputation rates were observed for patients with more severe frostbite injuries treated with iloprost compared to usual care: Grade 3 (18% vs 44%, p < 0.001); grade 4 (46% vs 95%, p <0.001). This study did not show as significant benefit when compared to previous literature and perhaps this was related to the comorbidities of the patients included. Patients included in this study were from an urban cohort with significant medical and social comorbidities (52.4% unhoused in the standard care arm), while previous studies had looked at healthy mountaineers.^(19,21)

Figure 3: ED management of frostbite with Iloprost based on grade of injury curtesy of Dr. Crooks.

Hyperbaric Oxygen

Hyperbaric oxygen (HBO) has been used to aid in wound healing. It is thought that HBO may improve frostbite outcome by increasing the cellular oxygen availability to the damaged tissues. This can then help to mitigate the inflammatory cascade.^(2,23)

From 2013 to 2019, Magnan and colleagues performed a multi-center prospective single-arm study where they compared patients in their prospective cohort who received early HBO in addition to standard care with iloprost.⁽²³⁾ They compared this to a historical cohort where patients received iloprost alone between 2000 and 2012. In this study they included patients with: grades 3 or 4 frostbite according to the Cauchy classification; initiation of medical care within 72 hours from frostbite injury; and, no contraindications to aspirin, iloprost or HBO. Standard treatment consisted of rewarming of frostbitten extremities for 60 min and 250mg ASA. Those with grade 3 or 4 frostbite then received the first iloprost infusion immediately and were hospitalized for 7 days. Those in the HBO group also received HBO daily in addition to the iloprost infusions. Technecium 99 bone scan was performed at day 3 and day 7. Patients were also follow up at 6 months and 1 year post treatment. The primary outcome of the study was the number of preserved segments at 12 months. Each phalanx and each metacarpal or metatarsal is defined as a segment. Their results demonstrated a higher number of preserved segments per patient in the prospective group with HBO treatment compared to the historical control (13 SD +/- 10 vs (6SD +/- 5). In the prospective cohort 57% of patients had three to four preserved segments compared to 13% in the control group (p<0.001).

Take Home Messages

1. Assess extent of injury after 60 minutes of rewarming the extremity.
2. For frostbite management:
   1. Follow routine tetanus guidelines;
   2. There is no evidence for prophylactic antibiotics;
   3. There is weak evidence for application of aloe vera;
   4. Consider debriding and / or aspirating clear blisters.
3. In patients presenting up to 72 hours of injury with grade 2-4 frostbite consider calling your local plastic surgeon early. These patients may be eligible for limb salvage therapy with TPA / iloprost.