Thrombolytic Therapy Saves Frostbitten Limbs

WASHINGTON — Thrombolytic therapy has resulted in limb salvage among 18 patients with severe frostbite treated at one Minnesota hospital in the last few years.

Thrombolytic therapy has been available for management of frostbite for 10 years and has the potential to reduce the need for some of the amputations. However, use of this protocol has not extended to the rural northern areas where most cases of frostbite are treated.

Severe frostbite results in ischemia and blistering with subsequent demarcation and loss of tissue. Prostaglandins and other chemical mediators are released locally, resulting in intense spasm and blistering. Arterial thrombosis results from injury to endothelial cells that retract to expose subintimal collagen, subsequently triggering acute thrombosis after rewarming.

The worse scenario is a freeze-thaw-refreeze injury in which, upon refreeze, ice crystals form intracellularly and kill the cells, rather than extracellularly as occurs in the initial freeze injury, according to Dr. George R. Edmonson of St. Paul (Minn.) Radiology.

Traditional treatment for frostbite has simply been to rewarm the affected extremity, wait to see how much tissue recovers, then amputate the rest. But over the last couple of decades, investigators have been experimenting with intra-arterial infusion of various thrombolytic and vasodilating agents to dissolve clots and relieve arterial spasm, in attempts to preserve more tissue and salvage more limbs.

At the annual meeting of the Society of Interventional Radiology, Dr. Edmonson described the patient care process used at Regions Hospital, also in St. Paul. Patients are admitted from the emergency department to the burn unit, where surgeons assess the affected limb for severity of injury and blood flow. Diagnostic arteriography is done to assess small vessel occlusion and loss of “distal tuft blush” at the tips of digits. Catheters are positioned for simultaneous infusion of treatment drugs into each affected limb. Blisters and wounds are managed in the burn unit with debridement or amputation as appropriate.

Since the mid-1990s, Dr. Edmonson and his associates have been treating frostbite of the extremities with a variety of combined antithrombotic, antiplatelet, and vasodilating agents. Initially, they used urokinase along with heparin and papaverine, then switched to reteplase, and now have moved to using tenecteplase (TNK) because of its superior plasma stability and higher fibrin specificity compared with reteplase. Tenecteplase is degraded more slowly in the bloodstream during infusion, and binds more firmly to the clot at the target than do similar agents. Because it also affects the normal clotting proteins to a lesser degree, it may therefore reduce the risk of bleeding, he explained.

During three unusually mild Minnesota winters, six patients aged 18–65 years with severe frostbite who were at risk for amputation were treated for up to 72 hours with intra-arterial TNK infusions at 0.25 mg/hour per limb with coaxial papaverine at 30 mg/hour per limb and intravenous heparin at 500 mcg/hour. They were managed in the burn unit with arteriography during the infusion.

Of the six patients, three who had 16 involved digits responded well and required no amputations. The other three (six limbs, 30 digits) had incomplete angiographic responses. Of those, two (four limbs, 20 involved digits) improved noticeably following TNK infusion, but then developed infections and required partial amputations. One patient—who needed intubation for alcohol withdrawal—failed to respond and lost eight fingers, but his thumbs were saved. There were no major bleeds or other periprocedural complications.

Those results were compared with data from 10 surviving patients (aged 14–77 years) of 12 who were treated with the same protocol using various doses of reteplase and papaverine over a 2-year period. Six of the patients recovered with no amputations, four had lost 31 digits at 45 days, and two had amputations but more distally than would have been anticipated without treatment.

More recently, six more frostbite patients were treated with TNK. Five of these patients had complete response and one had no response. To date, 8 out of 12 TNK-treated patients have been saved from amputation.

Response to TNK is more rapid than is response to reteplase, with arteries reopening within an average of 24 hours, compared with 36 for reteplase and 72 for urokinase. However, all of these agents are far better than the traditional wait-and-amputate treatment of the past, Dr. Edmonson said.

In an interview after the meeting, Dr. Edmonson explained that the difference between frostbite and typical peripheral vascular occlusion or thrombosis is that in frostbite, all of the small collateral vessels are thrombosed as well as the primary named arteries. The cut-off of flow is abrupt and complete, rather than an interruption with ischemia and some limited collaterals.