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. 2020 Dec 20;12(12):CD012980.
doi: 10.1002/14651858.CD012980.pub2.

Interventions for frostbite injuries

Anne Kathrine Lorentzen  1 , Christopher Davis  2 , Luit Penninga  3
Affiliations

Interventions for frostbite injuries

Anne Kathrine Lorentzen et al. Cochrane Database Syst Rev. .

Abstract

Background: 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.

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

Search methods: 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.

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.

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Conflict of interest statement

AKL: none known

LP: none known

CD: none known

Figures

1
1
Study flow diagram
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: Iloprost vs buflomedil, Outcome 1: Incidence of amputations (patients)
1.2
1.2. Analysis
Comparison 1: Iloprost vs buflomedil, Outcome 2: Incidence of amputations (body parts)
1.3
1.3. Analysis
Comparison 1: Iloprost vs buflomedil, Outcome 3: Incidence of amputations (severity)
1.4
1.4. Analysis
Comparison 1: Iloprost vs buflomedil, Outcome 4: Incidents of amputations (time)
1.5
1.5. Analysis
Comparison 1: Iloprost vs buflomedil, Outcome 5: Withdrawal due to study medication
1.6
1.6. Analysis
Comparison 1: Iloprost vs buflomedil, Outcome 6: Mortality
2.1
2.1. Analysis
Comparison 2: Iloprost + rtPA vs buflomedil, Outcome 1: Incidence of amputations (patients)
2.2
2.2. Analysis
Comparison 2: Iloprost + rtPA vs buflomedil, Outcome 2: Incidence of amputations (body parts)
2.3
2.3. Analysis
Comparison 2: Iloprost + rtPA vs buflomedil, Outcome 3: Incidence of amputations (severity)
2.4
2.4. Analysis
Comparison 2: Iloprost + rtPA vs buflomedil, Outcome 4: Incidence of amputations (time)
2.5
2.5. Analysis
Comparison 2: Iloprost + rtPA vs buflomedil, Outcome 5: Withdrawal due to study medication
2.6
2.6. Analysis
Comparison 2: Iloprost + rtPA vs buflomedil, Outcome 6: Mortality
3.1
3.1. Analysis
Comparison 3: Iloprost vs iloprost + rtPA, Outcome 1: Incidence of amputations (patients)
3.2
3.2. Analysis
Comparison 3: Iloprost vs iloprost + rtPA, Outcome 2: Incidence of amputations (body parts)
3.3
3.3. Analysis
Comparison 3: Iloprost vs iloprost + rtPA, Outcome 3: Incidence of amputations (severity)
3.4
3.4. Analysis
Comparison 3: Iloprost vs iloprost + rtPA, Outcome 4: Incidence of amputations (time)
3.5
3.5. Analysis
Comparison 3: Iloprost vs iloprost + rtPA, Outcome 5: Withdrawal due to study medication
3.6
3.6. Analysis
Comparison 3: Iloprost vs iloprost + rtPA, Outcome 6: Mortality
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References

References to studies included in this review

Cauchy 2011 {published data only}
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