Transcript Slide - Society Of Interventional Radiology

Thrombolytic Therapy for Limb Salvage in
Severe Frostbite
Or
Cold Feet
Re-warmed Heart
George R. Edmonson MD
Interventional Radiologist
St. Paul Radiology
Regions Hospital, St. Paul, Minnesota
Lake Mille Lacs
Frostbite
• 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 Frostbite
Who 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 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 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
• 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 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:
Outcome without Reopening of Arteries
Outcome with Restored Blood Flow
Rationale for Treatment with TNKase:
Plasma 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: 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 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 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 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: 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: 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
Loss of 1st toe vs. Midfoot amputation
Incomplete response: 18 yrs Male
Right foot Recovery Limited by bone infection
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
Conclusions
•
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 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.