Prostacyclin rt-PA for Frostbite

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Cauchy E, Cheguillaume B, Chetaille E.. "A controlled trial of a prostacyclin and rt-PA in the treatment of severe frostbite". NEJM. 2011. 364(6):189-190.
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Clinical Question

In patients with one digit having stage 3 or 4 frostbite, how does therapy of buflomedil compared to iloprost compared to iloprost plus rt-PA for rates of amputation.

Bottom Line

For stages 2-4 frostbite, iloprost appears to be an effective agent to help avoid amputation. The addition of rt-PA to iloprost demonstrated an increase in rate of amputation but cannot be ruled out as an appropriate option for select patients with the addition of heparin to avoid re-thrombosis. Buflomedil, due to lack of efficacy and adverse effect profile should be avoided.

Major Points

Many difference treatment modalities have been suggested for the treatment of severe frostbite. Many of these include: hemodilution, platelet-aggregation inhibitors, low-molecu- lar-weight heparin, unfractionated heparin, alpha-adrenergic vasodilators, calcium-channel blockers, nonsteroidal anti-inflammatories, prostacyclin analogues, fibrinolytic agents, and hyperbaric oxygen. The majority of the available evidence are comprised of small RCT's and case series. Given the rarity of the condition, conducting a large randomized control trial would be significantly challenging. Given this single centre, open label trial lasted for 12 years and included 47 patients and is one of the largest, with 11[1] and 32[2] being some of the runners up. The aspirin used in the trial has been largely replace by ibuprofen by most centres as it is thought that the ASA bocks some of the beneficial prostacyclins necessary for healing. For Stage 2-4 frostbite iloprost may be one of the best treatment options and for Stage 4 the addition of recombinant tissue plasminogen activator (rt-PA) may be considered but the optimal dose of rt-PA requires further study. Since last guidelines were published new recommendations[3] and systematic reviews[4] have been published that may offer further guidance.

Guidelines

Wilderness Medical Society Practice Guidelines for the Prevention and Treatment of Frostbite (2011, adapted)[5] Immediate Medical Therapy—Hospital (or High Level Field Clinic)

  1. Treat hypothermia (Grade 1C Recommendation)
  2. Maintain Hydration (Grade 1C)
  3. Rapid rewarming of frozen tissues (Grade 1B)
  4. Debridement of blisters only if appear infected or affect range of motion (Grade 2C)
  5. Topical aloe vera every 6 hours or dressing change (Grade 2C)
  6. Avoid empiric systemic antibiotics unless significant trauma or sepsis (Grade 1C)
  7. Administer Tetanus prophylaxis (Grade 1C)
  8. Ibuprofen 12mg/kg twice daily until healing (Grade 2C)
  9. Thrombolytic therapy within 24 hours of thawing (Grade 1C)
  10. Imaging may help predicting amputation (Grade 1C)
  11. Heparins or LMWH only as adjutant to thrombolytics (Not recommended as monotherapy, insufficient data)
  12. Vasodilation with prostacyclin/iloprost (Grade 1C)

Design

  • Single Centre, open-label, RCT
  • N=47
    • Buflomedil (n=15)
    • Iloprost (n=16)
    • Iloprost + rt-PA (n=16)
  • Setting: France
  • Enrollment: 1996-2008
  • Mean follow-up: 8 days
  • Primary outcome: Amputation

Population

Inclusion Criteria

  • at least one digit (finger or toe) with

frostbite stage 3 (lesion extending just past the proximal phalanx) or stage 4 (lesion extending proximal to the metacarpal or metatarsal joint

Exclusion Criteria

  • contraindications to study drug
  • severe trauma
  • hypothermia

Baseline Characteristics

  • Male: 44
  • Female: 3
  • Mean Age: 33.1 years
  • Frostbite location:
    • Feet: 33
    • Hands: 29
    • Both: 15

Interventions

Rapid re-warming, ASA 250mg, buflomedil 400mg IV, then randomized for 8 days of ASA 250mg plus:

  • buflomedil 400mg once daily
  • iloprost 0.5-2 ng/kg/minute
  • rt-PA 100mg (Day 1 only) + iloprost 0.5-2 ng/kg/minute

Outcomes

Primary Outcome

Patients with Amputation, all stages
Buflomedil vs. Iloprost: 60% vs. 0% (P<0.001)
Buflomedil vs. Iloprost+rt-PA: 60% vs. 19% (P<0.03)

Adverse Events

All groups, none leading to medication discontinuation:

  • Hot flash: 55%
  • Nausea: 25%
  • Palpitation: 15%
  • Vomiting: 5%

Subgroup Analysis

Presented as Buflomedil(n=106) vs. Iloprost(142) vs. Iloprost+rt-PA(n=159)

Digital Amputations, all stages (47/407)
39.6% vs. 0% vs. 3.1%
Digital Amputations, all stages, ≤12h to treatment (13/271 digits)
33.9% vs. 0% vs. 1.4%
Digital Amputations, all stages, >12h to treatment (34/136)
53.4% vs. 0% vs. 20.0%
Digital Amputations, all stages, Stage 2 (4/155)
6.5% vs. 0% vs. 3.3%
Digital Amputations, all stages, Stage 3 (31/215)
47.0% vs. 0% vs. 0%
Digital Amputations, all stages, Stage 4 (12/37)
100% vs. 0% vs. 12.0%
Finger amputations, all stages (22/183 fingers)
49% vs. 0% vs. 2%
Toe amputations, all stages (25/224 toes)
34% vs. 0% vs. 4%

Criticisms

  • Not following thrombolysis with continuing anticoagulation may have led to the increased rate of amputation
    • the anti-inflammatory affects of heparin may have an additive effect
  • Letter to the editor
  • No true control arm
  • Unclear rates of adverse events per medication

Funding

Not stated

Further Reading

  1. Johnson AR et al. Efficacy of intravenous tissue plasminogen activator in frostbite patients and presentation of a treatment protocol for frostbite patients. Foot Ankle Spec 2011. 4:344-8.
  2. Bruen KJ et al. Reduction of the incidence of amputation in frostbite injury with thrombolytic therapy. Arch Surg 2007. 142:546-51; discussion 551-3.
  3. Cauchy E et al. A New Proposal for Management of Severe Frostbite in the Austere Environment. Wilderness Environ Med 2016. 27:92-9.
  4. Heil K et al. Freezing and non-freezing cold weather injuries: a systematic review. Br. Med. Bull. 2016. 117:79-93.
  5. McIntosh, Scott E. et al. Wilderness Medical Society Practice Guidelines for the Prevention and Treatment of Frostbite. Wilderness & Environmental Medicine 2011;22(2):156-166