What treatments work best for frostbite injuries?

What is frostbite?

Frostbite is an injury to skin and the tissues beneath that is caused by exposure of the skin to freezing temperatures. Freezing temperatures cause ice crystals to form in the tissue, this reduces the blood supply to the tissue and damages it. The parts of the body most commonly affected are the fingers, toes, nose, ears and cheeks. Symptoms include a loss of feeling in the affected areas, combined with a pale waxy discolouration of the skin, followed eventually by blisters and swelling. If the affected areas are not warmed up, and the exposure to the cold continues, deeper layers of tissue may become affected, which may ultimately result in loss of the tissue, that is, removal of fingers or toes (amputations).

Warming up (rewarming) of frostbitten areas may cause severe pain. At present, treatment involves:

- rapid rewarming of the affected area in a 37 °C to 39 °C whirlpool bath;

- giving the patient pain-killing medication in the form of aspirin and ibuprofen; and

- if the affected area does not return to normal after rewarming, transferring the patient to hospital for further treatment.

Several different specialised treatments can be given in hospitals, including a medication called 'iloprost', which may increase blood flow to frostbitten areas. It is hoped that iloprost may reverse the damage to frostbitten tissue.

How current is the evidence?

The evidence in this review includes research published up to 25 February 2020.

What did we do?

We searched for studies that compared medicines that affect the whole body, or treatments applied to the skin (topical therapies), or rewarming techniques used to treat frostbite injuries to another treatment for frostbite, or a 'dummy' treatment (placebo), or no treatment. We looked for randomised controlled studies, in which the treatments received were decided at random, because these studies usually give the most reliable evidence about the effects of treatments.

We were interested in:

- the risk of amputation;

- serious and non-serious unwanted effects of treatment (adverse events);

- intense pain, especially upon rewarming;

- long-lasting pain;

- how well people who had frostbite could perform activities of daily living;

- the quality of life experienced by people who had frostbite;

- the number of people who withdrew from treatment because of problems caused by the therapy;

- the length of time people did not attend their work because of frostbite;

- the length of time to full return to work; and

- the number of deaths.

What did we find?

We found one randomised controlled trial (RCT) involving 47 people who were rescued by mountain rescue teams in the French Alps. Everybody was treated with a dose of two medicines, aspirin and buflomedil, then allocated to one of three groups for further treatment.

Group 1 received additional buflomedil (since this RCT took place, buflomedil was withdrawn from use because of reports of severe adverse events associated with its use);

Group 2 received another medicine called iloprost;

Group 3 received iloprost and a substance involved naturally in the breakdown of blood clots (recombinant tissue plasminogen activator (rtPA)).

What are the results of our review?

People who received iloprost or iloprost combined with rtPA had fewer amputations than those who received buflomedil. There was little or no difference between the number of amputations in people who received iloprost compared to those who received iloprost combined with rtPA.

The trial reported adverse effects, but did not attribute them to the different treatments. Adverse effects included hot flushes, feeling sick (nausea), heart palpitations and vomiting. There were no withdrawals from the trial because of unwanted effects of treatment, and there were no deaths.

This RCT did not report on intense pain, long-lasting pain, activities of daily living, quality of life, time off work, or time until a full return to work.

High quality RCTs are needed to confirm the result of this study, and to establish the best way to treat frostbite injuries.

How reliable are these results?

As we included only one, poorly reported RCT with possible problems in its design and a very small number of participants, our confidence in its findings are very low.

Authors' conclusions: 

There is a paucity of evidence regarding interventions for frostbite injuries. Very low-quality evidence from a single small trial indicates that iloprost, and iloprost plus rtPA, in combination with buflomedil may reduce the need for amputation in people with severe frostbite compared to buflomedil alone. However, buflomedil has been withdrawn from use. High quality randomised trials are needed to establish firm evidence for the treatment of frostbite injuries.

Read the full abstract...

Frostbite is a thermal injury caused when tissue is exposed to sub-zero temperatures (in degrees Celsius) long enough for ice crystals to form in the affected tissue. Depending on the degree of tissue damage, thrombosis, ischaemia, necrosis (tissue death), gangrene and ultimately amputation may occur. Several interventions for frostbite injuries have been proposed, such as hyperbaric oxygen therapy, sympathectomy (nerve block), thrombolytic (blood-thinning) therapy and vasodilating agents such as iloprost, reserpine, pentoxifylline and buflomedil, but the benefits and harms of these interventions are unclear.


To assess the benefits and harms of the different management options for frostbite injuries.

Search strategy: 

On 25 February 2020, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase (OvidSP), ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED), Conference Proceedings Citation Index-Science (CPCI-S), as well as trials registers. Shortly before publication, we searched Clinicaltrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform, OpenGrey and GreyLit (9 November 2020) again. We investigated references from relevant articles, and corresponded with a trial author.

Selection criteria: 

We included randomised controlled trials (RCTs) that compared any medical intervention, e.g. pharmacological therapy, topical treatments or rewarming techniques, for frostbite injuries to another treatment, placebo or no treatment.

Data collection and analysis: 

Two authors independently extracted data. We used Review Manager 5 for statistical analysis of dichotomous data with risk ratio (RR) with 95% confidence intervals (CIs). We used the Cochrane 'Risk of bias' tool to assess bias in the included trial. We assessed incidence of amputations, rates of serious and non-serious adverse events, acute pain, chronic pain, ability to perform activities of daily living, quality of life, withdrawal rate from medical therapy due to adverse events, occupational effects and mortality. We used GRADE to assess the quality of the evidence.

Main results: 

We included one, open-label randomised trial involving 47 participants with severe frostbite injuries. We judged this trial to be at high risk of bias for performance bias, and uncertain risk for attrition bias; all other risk of bias domains we judged as low.

All participants underwent rapid rewarming, received 250 mg of aspirin and 400 mg intravascular (IV) buflomedil (since withdrawn from practice), and were then randomised to one of three treatment groups for the following eight days. Group 1 received additional IV buflomedil 400 mg for one hour per day. Group 2 received the prostacyclin, iloprost, 0.5 ng to 2 ng/kg/min IV for six hours per day. Group 3 received IV iloprost 2 ng/kg/min for six hours per day plus fibrinolysis with 100 mg recombinant tissue plasminogen activator (rtPA) for the first day only.

The results suggest that iloprost and iloprost plus rtPA may reduce the rate of amputations in people with severe frostbite compared to buflomedil alone, RR 0.05 (95% CI 0.00 to 0.78; P = 0.03; very low-quality evidence) and RR 0.31 (95% CI 0.10 to 0.94; P = 0.04; very low-quality evidence), respectively. Iloprost may be as effective as iloprost plus rtPA at reducing the amputation rate, RR 0.14 (95% CI 0.01 to 2.56; P = 0.19; very low-quality evidence). There were no reported deaths or withdrawals due to adverse events in any of the groups; we assessed evidence for both outcomes as being of very low quality. Adverse events (including flushing, nausea, palpitations and vomiting) were common, but not reported separately by comparator arm (very low-quality evidence). The included study did not measure the outcomes of acute pain, chronic pain, ability to perform activities of daily living, quality of life or occupational effects.