Thrombolytic Therapy for Limb Salvage in Thrombolytic Therapy for Limb Salvage in Severe FrostbiteSevere Frostbite

Or Cold Feet

Re-warmed Heart

George R. Edmonson MD

Interventional Radiologist

St. Paul Radiology

Regions Hospital, St. Paul, Minnesota

Lake Mille Lacs

FrostbiteFrostbite

• Thermal injury resulting from prolonged exposure to subzero temperatures “Freeze Burns”

• Commonly affects the nose, ears, cheeks, hands and feet

• May be only superficial or Deep/Severe

Traditional Therapy for FrostbiteTraditional Therapy for Frostbite

Who gets FrostbiteWho gets Frostbite

• Military• Mountain climbers• Outdoor sportsmen• Stranded travelers• Mentally ill• Drug and/or alcohol

intoxicated• The very young or very

old

Who gets Frostbite In MinnesotaWho gets Frostbite In Minnesota

• 36 yr man found outside by police stating “I’m a chicken”• 31 yr man Hunting with friend. Drinking several beers and using

crank. Awoke the next morning outside without his gloves.• 90 yr man apparently trying to take out the garbage, found down in

the snow • 14 yr boy snuck out of parents house with bottle of liquor and fell

asleep outside. Found trying to break in at 5AM• 19 yr man smoking marijuana laced with PCP became paranoid

and ran away from his friends• 77 yr man got stuck plowing snow. Lost boot in snow drift

Physiologic Response to ColdPhysiologic Response to Cold

• Initial: Small arteries constrict with skin blanching, stinging or burning

• Subsequent: shunting occurs bypassing the surface vessels to maintain circulation. Numbness and clumsiness with loss of cold sensation

• Final: With further drop in core temp vascular shunting stops and the extremity is allowed to freeze. Cold, grey, bloodless skin

Frostbite: Clinical Findings Frostbite: Clinical Findings

• Superficial frostbite: limited to skin • Edema after thawing with blisters and pain• Deep frostbite: involves muscles, tendons and

bone. Ischemic discoloration. Hemorrhagic blisters common

• Recurrent frostbite: blisters often absent• Ultimately nonviable tissue demarcates and

sloughs or is amputated

Mechanism of Vascular InjuryMechanism of Vascular Injury

• Animal Research: Flash frozen rabbit ears• Ice crystals form: primarily in the fluid around the

cells• Arteries are initially open after thawing then clot

develops due to damage to the cells lining the blood vessels.

• Chemical mediators are released which cause intense spasm and inflammation

• A Freeze, thaw, then refreeze injury causes ice crystals to form inside the cells destroying them

Deep Frostbite Fingers: Deep Frostbite Fingers: Outcome without Reopening of ArteriesOutcome without Reopening of Arteries

Outcome with Restored Blood Flow Outcome with Restored Blood Flow

Rationale for Treatment with TNKase:Rationale for Treatment with TNKase:Plasma Stability and Higher Fibrin SpecificityPlasma Stability and Higher Fibrin Specificity

• Primarily small peripheral vessels are occluded• Drugs are infused through catheters in the upper

arms or legs• Tenecteplase is degraded more slowly in the

bloodstream and binds more firmly to clot when it arrives at the target

• Tenecteplase affects the normal clotting proteins less than similar agents therefore bleeding risk may be lower

Our Patient Care Process: FrostbiteOur Patient Care Process: Frostbite

• Admit to Burn unit via ER. Rapid rewarming of cold extremities. Burn Surgeons assess for severity of injury and blood flow.

• May refer for angiography (x-ray dye study) of affected limbs

• Diagnostic Arteriography: assess for small vessel occlusion and loss of “distal tuft blush” at the tips of digits

• Catheters positioned for simultaneous infusions of treatment drugs into each affected limb.

• Blisters and wounds managed in burn unit with debridement or amputation as appropriate

Our Historical ApproachOur Historical Approach

• We have been treating frostbite of the extremities with various drugs to dissolve clots and relieve arterial spasm for approx 15 years.

• Patients who decline the drugs receive standard supportive care only

• Initially: IA Urokinase (UK) with vasodilator papaverine and therapeutic doses of heparin (a “blood thinner”).

Generally successful for reopening the arteries over 2-3 days UK was taken off the market.

• TPA was being given for acute heart attacks and Reteplase for blood clots in the lungs

• TPA: We tried a relatively high dose with heparin. Bleeding complications limited use.

• Reteplase: lower dose with low dose heparin used for the next few winters

Frostbite Study DesignFrostbite Study Design

• FDA and Institutional review board approval obtained. Off label experimental use of drugs.

• Open label: Prospective enrollment effort• Up to 10 hospitalized patients ages 18-65 yrs• Drug infusions directly into arteries of the

affected limbs• 1-3 limbs treated per patient

Study EndpointsStudy Endpoints

• Angiographic: Flow re-established through occluded vessels to the tips of fingers/toes

• Failure to change on 24 hour angiogram i.e. no response to treatment efforts

• Clinical: reappearance of distal perfusion • 45 Days: Assess for amputations• Outcome analysis by patient and by limb after

drug infusion and at 45 days follow up

Clinical Results: TNKClinical Results: TNK

• 6 patients enrolled, all at risk of amputation• 3 patients (4 limbs) responded well with no amputations• 3 patients (6 limbs) had incomplete angiographic

response. – 2 improved noticeably then developed infections

requiring partial amputation.– 1 patient failed to respond and lost 8 fingers. Thumbs

saved• There were no major periprocedural complications

Complete response: TenecteplaseComplete response: Tenecteplase

• 20 YO male lost 1 shoe while running through woods from police. Presented with blue right foot with 3 black toes. Initial loss of motor function.

• Initial Angiogram: severe vasospasm with no flow to 2nd + 3rd toes.

• Right leg Treated overnight: 17 hrs with TNK

• Exuberant flow reestablished with distal blush to toes

• No amputations on 5 wk follow up. (incarcerated)

Partial Restoration of Bloodflow: 18 yrs male Partial Restoration of Bloodflow: 18 yrs male Loss of 1st toe vs. Midfoot amputationLoss of 1st toe vs. Midfoot amputation

Incomplete response: 18 yrs MaleIncomplete response: 18 yrs MaleRight foot Recovery Limited by bone infectionRight foot Recovery Limited by bone infection

24 Month Reteplase Review (12 pts)24 Month Reteplase Review (12 pts)

• IRB allowed us to look back only 24 months• 10 patients age 14 -77 years (16 limbs) survived

to follow up• All treated with various doses of Reteplase and

Papaverine• 6 patients recovered with no amputations• 4 patients lost 31 digits at 45 days. 2 had more

distal amputation that anticipated• 2 patients excluded from comparison:

died 2 weeks after treatment of other causes

ConclusionsConclusions

• Intra-arterial Tenecteplase appears to be safe and effective for reperfusion of limbs devitalized by frostbite

• 50% of trial patients avoided amputations which were considered likely without the drug infusions. TNK required less time to reopen arteries than earlier drugs

• 5 of 6 patients improved during therapy.• Update: winter 2007-08.

– We treated 6 more frostbite patients. – 5 of 6 had complete response. 1 non response– To date: 8 of 12 TNKase Rx patients (68%) saved

from amputation– TNK offers a modest improvement over reteplase – Both are much better than traditional treatment

Future ConsiderationsFuture Considerations

More work is need to understand the causes of failures and optimize the treatment protocol

• Increase heparin dose to reduce rethrombosis. We have had no bleeding problems thus far

• Add antiplatelet drugs to reduce clot formation• Consider a randomized trial between

intravenous and intra-arterial administration of drugs. Two sites have reported some success with high dose IV drug administration.