When should intravenous alteplase be used for frostbite injury?

What data is available for using alteplase in management of frost bite?

Comment by InpharmD Researcher

Consensus guidelines recommend thrombolytic therapy with tissue plasminogen activator (tPA) within 24 hours of thawing for severe frostbite injuries extending to the proximal interphalangeal joints or beyond. Early administration, preferably within 12 hours, is associated with improved tissue salvage and reduced amputation risk. Current treatment protocols emphasize concurrent heparin use and imaging to guide therapy, with careful monitoring in appropriate medical facilities. Clinical evidence, primarily derived from case series and retrospective reviews, suggests that intravenous tPA dosing typically involves a 0.15 mg/kg bolus followed by infusion over six hours, while intra-arterial dosing ranges from 0.25 to 1 mg/h for 48 hours, achieving limb salvage rates exceeding 75% with minimal complications.

Background

Per the Wilderness Medical Society clinical practice guidelines for the prevention and treatment of frostbite, thrombolytic therapy with tissue plasminogen activator (tPA) should be administered either intravenously (IV) or intra-arterially, within 24 hours of tissue thawing. Therapy with tPA has demonstrated potential to salvage tissue, with retrospective studies showing significant reductions in amputation rates. Emerging evidence suggests the importance of early intervention, ideally within 12 hours, as delays may substantially decrease tissue salvage efficacy. Due to the potential risks associated with tPA (systemic and catheter site bleeding, compartment syndrome, and failure to salvage tissue), a risk-benefit analysis is essential before initiating thrombolytic therapy, which is recommended only for deep frostbite injuries extending to the proximal interphalangeal joints of digits or more proximally. Additionally, current protocols advocate a tPA bolus followed by continuous infusion with concurrent heparin, with angiographic or imaging modalities guiding treatment. In general, IV or intra-arterial tPA within 24 hours remains a reasonable choice under suitable conditions (Recommendation Grade 1C). [1]

A 2019 systematic review evaluated thrombolysis for treating frostbitten extremities using tissue plasminogen activator (tPA), primarily assessing limb salvage rate. When comparing intra-arterial and intravenous (IV) tPA administration both routes were found to have equivalent efficacy and complication rates, with IV tPA achieving a limb salvage rate of 77.3% while intra-arterial had a rate of 76.4%. Associated complication rates were 2.7% for IV and 3.7% for intra-arterial. Amongst the included studies, the most common IV dose was a 0.15 mg/kg bolus followed by 0.15 mg/kg infusion over 6 hours, up to a maximum of 100 mg tPA. For intra-arterial use, the typical dose was 0.25-1 mg/h tPA continuously for 48 hours. Triple-phase Tc-99m bone scans and angiograms helped determine candidacy for thrombolysis in severe frostbite cases; IV therapy predominantly relied on bone scans, while intra-arterial favored angiography. Most IV protocols involved a 6-hour tPA infusion transitioning to therapeutic heparin. Intra-arterial thrombolysis lasted 24-48 hours, up to 72 hours maximum. Complications necessitating stopping IV tPA included hematuria, infection/cellulitis, and bleeding. Notably, it was mentioned that bone scans cannot accurately predict amputation level until post-injury day 7, after which thrombolytics lose effectiveness. However, there is no consistent dosing of thrombolytics or duration of tPA infusions used among the included papers. Evidence quality was low, at Level III on average. [2]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What data is available for using alteplase in management of frost bite?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-3 for your response.

Thrombolytic Use in Management of Frostbite Injuries: Eight Year Retrospective Review at a Single Institution
Design	Single center, retrospective review N= 102
Objective	To review frostbite injury treatment practices at an American Burn Association-verified burn center to evaluate if thrombolytics improved outcomes
Study Groups	tPA (n= 12) No tPA (n= 28)
Inclusion Criteria	Presentation within 24 hours from injury, physical assessment by indicating vascular compromise, significant injury (second degree frostbite, injury involving 2+ fingers, the thumb, forefoot, other injuries per clinician discretion)
Exclusion Criteria	Recent surgery with a significant risk of bleeding (< 3 months), recent trauma (except mild trauma), unable to lie still for an arteriogram, small children with small vessels, pregnant woman, recent cerebrovascular accident or brain metastasis, recent gastrointestinal bleed, severe hypertension, bleeding diathesis, irreversible ischemia
Methods	Patient data were compiled via retrospective chart review. Route of tPA administration, intravenous (IV) or intra-arterial (IA), was determined per clinician's discretion. tPA infusion was initiated at a rate of 10.5 mg/h, to be coadministered with heparin. Duration of infusion was determined by angiography, but did not exceed 48 hours. A case-control analysis was conducted to compare tPA patients to those with similar injury who did not receive tPA.
Duration	Patients admitted between January 2010 to April 2018
Outcome Measures	Affected number of fingers and/or toes, length of hospital stay, number of operations, amputations, skin grafts, or bleeding complications
Baseline Characteristics		tPA (n= 12)	No tPA (n= 28)	p-Value
	Age, years	40.3 ± 16.6	44.8 ± 18	0.511
	Male	10 (83.3%)	20 (74.4%)	0.426
	Race White Black Other	9 (75%) 3 (25%) 0	21 (75%) 5 (17.9%) 2 (7.1%)	0.784
	Homeless	1 (8.3%)	6 (21.4%)	0.652
	Tobacco use	8 (66.7%)	19 (67.9%)	0.810
	Alcohol-related	7 (58.3%)	10 (35.7%)	0.296
	Drug-related	2 (16.7%)	8 (28.6%)	0.244
	Delayed > 24 hours	0	10 (35.7%)	0.019
	Worst Degree Second Third	7 (58.3%) 5 (41.7%)	18 (64.3%) 10 (35.7%)	0.722
	Worst Grade Grade 2 Grade 3	6 (50%) 6 (50%)	16 (57.1%) 12 (42.9%)	0.677
Results	Endpoint	tPA	No tPA	p-Value
	Number of fingers affected	5.7 ± 5	3.9 ± 4.7	0.310
	Number of toes affected	4.7 ± 4	6.2 ± 4.4	0.301
	Length of stay, day	5.3 ± 4.5	9.9 ± 9.6	0.046
	Number of operations	0.25 (0 to 2)	0.95 (0 to 6)	0.037
	Any operation	2 (16.7%)	15 (53.6%)	0.030
	Any amputation	2 (16.7%)	10 (35.7%)	0.285
	Any skin graft	1 (8.3%)	10 (35.7%)	0.124
	Bleeding complications	2 (16.7%)	0	0.085
Adverse Events	Common Adverse Events: N/A
	Serious Adverse Events: Hemarthrosis, scalp wound bleeding, eye ecchymosis, thigh hematoma
	Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions	Our study shows that patients treated with thrombolytics were less likely to require an operation and had shorter hospital stays. Furthermore, based on angiography, 84.7% of digits with vascular compromise were salvaged with thrombolytics. While there are no large, randomized, and controlled studies supporting the use of thrombolytics in the management of severe frostbite, a large body of literature supports its use, and it has become the standard of care at many institutions. However, prospective, well-designed, and multi-institutional studies are warranted to establish evidence-based treatment guidelines for the management of frostbite injuries.
InpharmD Researcher Critique	Despite compilation of data over the course of 8 years, overall sample size was limited. Additionally, the study is limited by its retrospective design, with lack of a side-by-side comparator group, instead relying on a case-control design.

References:

Heard J, Shamrock A, Galet C, Pape KO, Laroia S, Wibbenmeyer L. Thrombolytic Use in Management of Frostbite Injuries: Eight Year Retrospective Review at a Single Institution. J Burn Care Res. 2020;41(3):722-726. doi:10.1093/jbcr/iraa028

The Use of Thrombolytic Therapy in the Treatment of Frostbite Injury
Design	Case series
Case 1	A 24-year-old male, weighing 79.4 kg with no significant medical history, was found sleeping on a dry-docked boat that had caught fire, causing full thickness third degree burns to the dorsum of both feet and cold injuries affecting all 10 digits. The patient's urine drug screen was positive for cannabinoids. Time to rewarming and time of cold exposure were unknown as the patient was transferred from an outside hospital. His injuries upon admission were classified as grade three due to the involvement of the bilateral feet. On arrival, the patient received a tissue plasminogen activator (tPA) bolus of 10.8 mg and infusion of 60 mg during 6 hours, followed by a continuous infusion of heparin. He was then discharged on warfarin therapy for 4 weeks. The patient’s digits could not be salvaged, and all 10 affected digits were amputated. He was lost to follow-up during incarceration.
Case 2	A 91-year-old male weighing 61.2 kg had fallen and lost consciousness for an unknown amount of time outdoors. He has a medical history of essential hypertension, coronary atherosclerosis, acute myocardial infarction, renal failure, atrial fibrillation, and angina. He was found to be hypothermic with spots of frostbite on his face, knees, hands, and feet. Injuries to the knees and face were grade one, and the right foot was classified as grade three frostbite. The duration of cold exposure was unknown, however rewarming did occur within 6 hours. There were a total of 20 digits affected. He received a tPA bolus of 9 mg followed by an infusion of 60mg during 6 hours. He was not continued on therapeutic anticoagulation, heparin or warfarin, following tPA administration due to oozing that was noted from the patient's wounds. The patient’s digits were successfully treated and none required amputation.
Case 3	A 45-year-old male weighing 80.4 kg with a medical history of alcoholism was transferred from an outside hospital with grade three frostbite to the right foot. He woke up with his toes on his right foot frozen together, with all five digits affected. He reported that he was wearing socks and shoes at the time of injury. Blood alcohol level was positive on arrival. The duration of cold exposure was unknown, and the patient was rewarmed within 6 hours. The patient received a tPA bolus of 8mg and an infusion of 85mg during 6 hours, followed by a continuous infusion of heparin. The patient was discharged on aspirin 325mg daily for 30 days and required a below the knee amputation, which included all five affected digits.
Case 4	A 20-year-old male weighing 69kg with no significant medical history had been walking outdoors in the cold for 1 to 2 hours. He initially presented intoxicated and disoriented to an outside hospital, where he was rewarmed before transfer. A total of 10 digits on the bilateral feet were affected by grade two frostbite injury. On arrival, he was given a 10.4 mg bolus of tPA followed by an infusion of 62.1mg during 6 hours. He was then started on a continuous infusion heparin drip and discharged on 30 days of therapy with aspirin 325 mg. No digits were amputated during admission.
Case 5	A 53-year-old male weighing 67.8kg with a medical history of diabetes and hepatitis C had collapsed while walking in woods near his house the night before admission. The patient reported being in the snow for about an hour. He was initially seen at an outside hospital where cyanosis of distal digits was noted, but with pulses in all the affected 10 digits on his bilateral hands. On arrival, he was positive for cocaine and opiate intoxication. Frostbite injuries were classified as grade three to the bilateral hands. Intravenous tPA was started with a bolus of 10.7 mg, followed by a 6-hour infusion of 64.26mg. He was transitioned to a heparin drip and discharged with 30 days of aspirin 325 mg. None of the affected digits were amputated during admission.
Case 6	A 61-year-old male weighing 84.1 kg with medical history of hypertension had been driving a Bobcat machine in an attempt to remove snow when he noted the injury 1 day before admission. All 10 digits on the patient’s hands were affected, which indicates grade three frostbite injury. The amount of cold exposure was less than 24 hours and patients hands rewarmed without medical attention due to delayed presentation. He received a tPA bolus of 13.4 mg followed by an infusion of 80.46mg during 6 hours. He was then transitioned to a heparin drip and discharged on warfarin for 28 days. One of the patient’s digits was partially amputated on follow-up.
Study Author Conclusions	The administration of tPA was not associated with any serious adverse events in these 6 patients and was associated with improved outcomes. One minor adverse effect was identified in the second patient, which led to the avoidance of further anticoagulation but did not affect outcomes. In patients with frostbite injury, infusion of tPA is safe in patients without contraindications and may partially or completely restore perfusion to at risk digits. Restoring perfusion can ultimately lead to a reduced number of digits requiring amputation. The use of a guideline with clear criteria to assist in selecting patients that can be safely treated with tPA for frostbite injury is recommended.

References:

Wexler A, Zavala S. The Use of Thrombolytic Therapy in the Treatment of Frostbite Injury. J Burn Care Res. 2017;38(5):e877-e881. doi:10.1097/BCR.0000000000000512

Thrombolytic Therapy in the Acute Management of Frostbite Injuries
Design	Case Report
Results	A previously healthy 16-year-old male presented for suspected frostbite to both hands. The patient had been found wandering in the middle of the road with ungloved hands in -10.5 to -12.8 degrees Celsius with wind chill factors of -14 to -19 degrees Celsius. Once returned home, the patient's hands were described as "cold and red" and re-warming of the hands by soaking them in warmed water was attempted. After warming, the patient's hands began swelling and his skin began to darken. The patient was then transported to the emergency department for evaluation. At the referring facility, he was given an intravenous dose of cefazolin and divided doses of morphine sulfate and hydromorphone for analgesia. After treatment, the patient was transferred by to tertiary care for plastic surgery evaluation. Upon arrival, his hands and fingers demonstrated dorsal abrasions, discoloration, and hemorrhagic blisters. The right hand demonstrated mottling and discoloration of the ring and small fingers distal to the proximal interphalangeal (PIP) joint and of the long fingertip. The ring finger has small hemorrhagic blisters on the dorsal surface. The left hand had more serious injuries, with all digits affected. Doppler pulses to the left index and long finger were not present distal to the PIP joint. A 1 L bolus of normal saline was infused, and both hands were placed in warm water baths for 20 minutes. Hand and finger arteriography demonstrated several areas of impaired arterial microcirculation. 3000 unites of heparin were infused, followed by intra-arterial infusion of 50 mcg of nitroglycerine bilaterally via catheters placed in the brachial arteries. Continuous infusions of tissue plasminogen activator (tPA) 0.25 mg and 500 units of heparin per hour were provided to each brachial catheter and femoral sheath. The tPA infusion began with 8 hours of the patient being discovered outside. 8 hours following initiation of tPA therapy, a repeat angiography was performed through the existing arterial catheters that revealed improved circulation in the right hand but continued impairment to the distal microcirculation of the left hand. The right-sided brachial catheter was removed, but the left stayed for continued tPA therapy. 12 hours after, a third angiographic exam of the left hand demonstrated improved distal circulation in all digits except the ring finger. Left-sided tPA was discontinued. Wound care was performed daily and physical therapy was initiated once he was discharged. The patient eventually required split thickness skin grafts, in the left ring and small finger. After skin grafts, the patient healed without complication and has retained full function to both hands.
Author Conclusions	Thrombolytic therapy offers victims with ischemic injury from frostbite the potential for limb and digit salvage if provided within 24 hours of injury. The most advantageous screening study, tPA dose, and route of administration have not been produced due to lack of data. More research is needed to further understand the impact of thrombolytic therapy in frostbite patients.

References:

Wagner C, Pannucci CJ. Thrombolytic therapy in the acute management of frostbite injuries. Air Med J. 2011;30(1):39-44. doi:10.1016/j.amj.2010.08.006