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News: rtPA for Frostbite Promising, but Obstacles Remain

Sorelle, Ruth MPH

doi: 10.1097/01.EEM.0000503368.85326.01


A 42-year-old man, who bivouacked at 7,400 meters on his way down from the summit of the mountain K2, realized in the middle of the night that he was missing a glove. He descended to the base camp with glove replaced and hand thawing, arriving about 14 hours after the start of his bivouac experience. He had a grade 3 frostbite with purplish discoloration of the fingers on the left hand between the metacarpophalangeal and proximal phalangeal joints.

His moderately swollen fingers had no sensation or evidence of capillary refill. Physicians warmed the hand in water at 39°C for three hours. Between 30 to 60 minutes of warming, the physician administered 5 mg morphine sulfate and 5 mg diazepam IV, and gave 800 mg of ibuprofen orally. After 90 minutes of warming, he gave intravenous rtPA, 1.4 mg/kg over 15 minutes, followed by intravenous heparin 1,000 units per hour for four hours. Later, during follow-up in Europe, the man had only sloughing of superficial skin.

A second patient — a 40-year-old male climber — had frostbite of his feet after reaching the summit of K2. Two and a half days later, he was at base camp, about 60 hours after his feet had thawed. He had grade 4 frostbite with discoloration and swelling of all toes at the mid-metatarsals. His feet were numb, with no evidence of capillary refill. He received the same treatment as the first patient. After he returned to Europe several days later, all toes had to be amputated.

The researchers who described the two cases noted that the first patient was treated within the therapeutic window and the second arrived outside that window, probably accounting for the difference in outcome. (Wilderness Environ Med 2016;27[1]:92.) “The case examples should help encourage the use of thrombolytics therapy in the field, when the risk of amputation is high, no contraindications are present, and the physician is familiar with the therapy,” they wrote.

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Pervasive Problem

The two cases also illustrate the dilemma faced by physicians who treat frostbite in a variety of conditions. From the top of Mount Everest, the world's highest mountain, to the street grates of New York City, where the homeless seek heat in the urban freeze, frostbite is a ubiquitous problem, threatening digits and limbs by exposure to relentless cold.

Drugs such as tissue plasminogen activator and iloprost, used with care, may provide new ways of treating this ancient injury, but experts warn that not all frostbite or cold injury will respond. “The best first aid is rapid rewarming,” said David Ahrenholz, MD, a director of the Burn Center at Regions Hospital in St. Paul, MN, and a long-time expert in treating frostbite. He said rewarming requires putting the patient in water between 100°F and 104°F, speeding the metabolism as blood flow is restored. He advised rapid rewarming but noted that 40-50 percent of patients come to the hospital already thawed.



Even rewarming can present problems, Dr. Ahrenholz said. Rewarming the extremities can result in cold blood returning to heart. “When we rewarm a patient, we must know the core temperature before we start rewarming. We put them in a tub [of warm water] and elevate all extremities and rewarm the core.”

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Evolving Therapies

Peter H. Hackett, MD, a clinical professor of emergency medicine at the University of Colorado at Denver and a founding director of the Institute for Altitude Medicine. ( said rtPA is the first thing to come along that shows promise for treating frostbite. Dr. Hackett and his colleagues noted in a proposal for managing severe frostbite in austere environments that the best emerging therapies are thrombolytics and iloprost, a synthetic form of prostacyclin used to treat disorders in which blood vessels are constricted. The drug is not available in IV form in the United States.

Dr. Hackett and colleagues noted that recombinant tissue plasminogen activator must be started within 24 hours and iloprost within 48 hours after rewarming. “Evacuating individuals experiencing frostbite from remote environments within 24 to 48 hours is often impossible,” he said. (Wilderness Environ Med 2016;27[1]:92;

The nature of frostbite itself governs the value of these drugs in treatment and determines which patients to treat and with which drug. One problem is that what is usually called frostbite can have varying presentations: frost nip, chilblains, flash freeze, and cold contact injuries as well as frostbite. As Dr. Ahrenholz described it, frost nip and chilblains do not blister or kill tissue while flash freeze and cold contact injuries usually cause such rapid cooling that large ice crystals form in the cells. These crystals rupture and kill the cells. None of these problems is appropriate for thrombolytic therapy.

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24-Hour Window

Frostbite, however, occurs with lower cooling rates with small ice crystals clogging the extravascular cavity. The damage that cold exposure can do varies with length of exposure, the time that the ice crystals remain in the tissues, and how quickly the patient is rewarmed. “After thaw, the main problem is microclotting in the microcirculation,” Dr. Hatchett said. “If you can reperfuse those areas by busting the clot, it might be helpful.”

Dr. Ahrenholz agreed. Endothelial cells lining blood vessels can be damaged by a slow freeze injury. If the digits or limbs turn bright pink during a thaw, it means that there is flow into the capillaries. If there are blisters, “it's a bad prognostic sign,” he said. “Those patients need thrombolytics.”

To use the clot buster, in particular tissue plasminogen activator, “you have a 24-hour window,” said Dr. Hackett. “You can give the drug intravenously, which doesn't require facilities, or intra-arterially, which does require selective angiography. The sooner you can get to them, the more likely they are to retain the limb or digit.”

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By the Numbers

Frostbite is graded by the numbers. Grade 1 is shows the absence of cyanosis, and results in no bone amputation. Grade 2 shows no cyanosis on the tips of fingers or toes with a moderate risk of amputation. Grade 3 shows cyanosis to the middle joints of fingers or toes, and results in a high risk of amputation. Grade 4 frostbite means that lack of blood flow or cyanosis extends beyond the metacarpophalangeal joint and almost always results in amputation.

Dr. Hatchett, who is a climber himself, said he hopes it will be possible to use intravenous prostacyclin in the United States. “It is probably superior to tPA,” he said. Such research, however, has to be restricted to places where frostbite occurs. “It is difficult to do research on frostbite. It needs to be done in places like Alaska and Minnesota.”

Dr. Ahrenholz described the use of intra-arterial thrombolytic therapy in the treatment of 62 patients in a 14-year review. (J Burn Care Res 2016;37[4]:e323.) A total of 114 patients were admitted to the hospital with frostbite injury, and 64 received rtPA intra-arterially. Complete information was available on 62. Angiography identified 472 digits with frostbite injury and impaired arterial circulation. A complete angiogram was performed after the thrombolytic infusion. They found:

  • Partial or complete amputations of only four of the 198 digits with a distal vascular blush and in 71 of 75 digits with no improvement after infusion.
  • Amputations in 73 of 199 digits with partially restored flow.
  • Overall, the complete digit salvage rate was 68.6 percent.

Dr. Ahrenholz said the protocols varied over the course of the long study. “We were never able to get a large enough group of patients to determine if one thrombolytic was better than another.” He emphasized that the angiogram is the best way to determine if a patient will need an amputation.

Dr. Hatchett said, however, that he worries about people who cannot get to the hospital within that 24-hour interval that makes use of thrombolytics possible. “On Mount Everest, you won't get to a hospital in 24 hours,” he said. He and his colleagues recommend that the time be measured from thawing rather than freezing duration to make a decision on whether to use aggressive therapy.

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