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Three Part Question

In [patients presenting to hospital with severe frostbite] does [intravenous thrombolytic therapy] reduce [the rate of amputation]?

Clinical Scenario

A 40 year old male patient is brought to the hospital after being lost while snowmobiling for 3 days where the average temperature was -32 Celsius. After ensuring he is stable, you noticed he has frostbite on his feet. Despite appropriate rewarming, his toes and portions of his feet look very dark and you're worried about possible amputation. You wonder whether thrombolytic therapy could salvage his toes and feet.

Search Strategy

Ovid MEDLINE(R) and Epub Ahead of Print, In-Process, In-Data-Review & Other Non-Indexed Citations and Daily 1946 to February 10, 2023

[exp Frostbite OR exp Cold Injury] AND [exp Fibrinolytic Agents OR exp Thrombolytic Therapy OR rt-PA.mp. OR exp Tissue Plasminogen Activator OR tPA.mp. OR exp Plasminogen Activators OR reteplase.mp. OR alteplase.mp. OR exp Tenecteplase OR exp Streptokinase OR urokinase.mp. OR exp Urokinase-Type Plasminogen Activator OR thrombolytics.mp.] LIMIT to human and English language

Search Outcome

69 articles were identified. 3 of which were systematic reviews and 1 meta-analysis. The original articles in those reviews were captured with the search strategy. Case series with >10 patients, case control, cohort, and randomized controlled trials were included. Additional inclusion criteria were intravenous thrombolytics and amputation as an outcome. All other methods of thrombolytic delivery were excluded. 5 papers met the inclusion criteria and are summarized below.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Johnson AR, et al. 2011 United States of America	11 patients between the age of 19-64 at a single burn unit. Each patient was imaged with triple-phase bone scintiscan to identify digits at risk. They each received a 0.15 mg/kg bolus and a 0.15 mg/kg/hour infusion for 6 hours of IV tPA.	Retrospective Case Series	Amputation Rate	43/73 digits at risk were amputated (59%)	No comparison group. No baseline characteristics collected on patients that could contribute likelihood to require amputation. Small sample size.
Nygaard RM et al. 2017 United States of America	73 patients ages 11-83 years old from a single centre burn centre that were admitted with frostbite and evidence of perfusion defects on triple phase bone scan. 45 received tPA and 28 did not. They each received a 0.15 mg/kg bolus and a 0.15 mg/kg/hour infusion for 6 hours of IV tPA.	Retrospective Cohort	Amputation Rate	There was no statistical (p=0.092) difference between those that received tPA (16/45, 36%) and those that did not (14/28, 50%)	Relatively small sample size. Unclear why the patients in the no tPA group did not receive tPA. Limited information on the nature (temperature and duration) of the cold exposure.
			Frostbite severity	Frostbite severity scores did not differ between those that received tPA and those that did not
Cauchy E, et al 2011 France	47 adults (44 men, 3 women) following mountain rescue with at least one digit demonstrating grade 3 or 4 frostbite. They all initially received 250mg of ASA and 400mg of buflomedil. 15 were randomized to receive that same treatment for 8 days. 16 were randomized to receive 250mg of ASA and 0.5-2 ng/kg of Iloprost for 8 days. 16 received 250mg of ASA and 2 ng/kg of Iloprost for 8 days with the addition of 100mg of rt-PA on day one.	Open Label Randomized Controlled Trial	Amputation Rate Patient Level	Both Iloprost alone (0%, 0/16) and Iloprost with rt-PA (19%, 3/16) had statistically significant lower amputations than buflomedil alone (60%, 9/15). There was no statistically significant difference between Iloprost and Iloprost plus rt-PA.	No baseline characteristics presented, large potential for confounding. A very specific population of people requiring mountain rescue, not generalizable. No blinding or concealment of allocation. Very small sample size.
Carmichael H, et al. 2022 United States of America	199 patients between the ages of 29-52 that were admitted to a single burn centre with grade 3 or 4 frostbite. 40 received IV tPA prior to transfer to the hospital, 32 received IV tPA on arrival, and 127 did not receive IV tPA.	Case Control	Amputation	Pre-transfer tPA had an odds ratio of 0.14 (0.05-0.40) compared to no tPA. However, tPA on arrival compared to no tPA had similar odds of amputation OR 0.74 (0.28-1.93)	The group that did not receive tPA had statistically significant less severe frostbite and were older. Relatively small sample size.
Rogers C, et al. 2022 United States of America	A convenience sample of 131 patients admitted to a single burn centre with a frozen limb or digit. 104 received intravenous thrombolytic therapy.	Case Control	Limb Salvage	The use of thrombolytics had an adjusted odds ratio of 11.9 (1.57,89.4)	Small sample size - a post hoc power calculation was completed indicating a required sample size of 364 to detect differences with a power of 80%. It is unclear how the two cohorts were selected - potential for selection bias.

Comment(s)

Intravenous thrombolytic therapy has been used in the treatment of frostbite for many years. However, the evidence for its use overall is low quality.

Clinical Bottom Line

In a patient that is otherwise going to require and amputation, it is reasonable to try thrombolytic therapy.

References

1. Johnson AR, Jensen HL, Peltier G, DelaCruz E. Efficacy of intravenous tissue plasminogen activator in frostbite patients and presentation of a treatment protocol for frostbite patients Foot Ankle Spec 2011;4(6):344-8
2. Nygaard RM, Lacey AM, Lemere A, Dole M, Gayken JR, Lambert Wagner AL, Fey RM Time Matters in Severe Frostbite: Assessment of Limb/Digit Salvage on the Individual Patient Level J Burn Care Res 2017;38(1):53-59
3. Cauchy E, Cheguillaume B, Chetaille E A controlled trial of a prostacyclin and rt-PA in the treatment of severe frostbite N Engl J Med 2011 ;364(2):189-90
4. Carmichael H, Michel S, Smith TM, Duffy PS, Wiktor AJ, Lambert Wagner A Remote Delivery of Thrombolytics Prior to Transfer to a Regional Burn Center for Tissue Salvage in Frostbite: A Single-center Experience of 199 Patients J Burn Care Res 2022; 43(1):54-60
5. Rogers C, Lacey AM, Endorf FW, Punjabi G, Whitley A, Gayken J, Fey R, Schmitz K, Nygaard RM The Effects of Rapid Rewarming on Tissue Salvage in Severe Frostbite Injury J Burn Care Res 2022;43(4):906-911
6. Murphy J, Endorf FW, Winters MK, Rogers C, Walter E, Neumann N, Weber L, Lacey AM, Punjabi G, Nygaard RM Bleeding Complications in Patients with Severe Frostbite Injury J Burn Care Res 2022; Epub ahead of print