Epoprostenol Plus Conventional Therapy in COld and Frostbite Injury (ECCO)

Phase 4Not Yet RecruitingNCT07424378

University of Colorado, Denver66 enrolled

Overview

Severe frostbite injury can result in significant lifelong disability and amputation. Various medicines, including intravenous vasodilators (prostaglandins/iloprost, pentoxifylline, buflomedil) along with thrombolytics (alteplase), have been described to counter tissue ischemia after rewarming, with poor quality of evidence. An in-class prostacyclin, epoprostenol, has similar pharmacodynamic properties to iloprost including vasodilation and platelet inhibition and has been used in peripheral tissue ischemia such as Raynaud's and scleroderma. In this trial, we will evaluate the effectiveness and safety of epoprostenol treatment for severe frostbite injury in addition to standard of care.

Prospective single center placebo controlled randomized trial comparing epoprostenol versus placebo in patients already receiving the standard of care for frostbite, including alteplase. Hypothesis: treatment effect of epoprostenol will be greater than placebo, independent of prior alteplase administration. Standard of care in both groups includes immediate warm water rewarming, thrombolysis with alteplase if they are a thrombolytic candidate per our usual care, immediate therapeutic anticoagulation if received thrombolysis, and ibuprofen at the attending physician's discretion. Study Aim: To determine the efficacy and safety of treatment with epoprostenol versus placebo in adult patients with severe frostbite injury. Intervention Group: Standard of care plus epoprostenol intravenous infusion titrated based on tolerability for 5 days. Control Group: Standard of care plus placebo (normal saline) infusion dosed and titrated to match epoprostenol infusion for 5 days.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Interventions

Standard of care plus Epoprostenol infusion for 8 hours (hrs) per day up to 5 days maximumDRUG

An in-class prostacyclin, epoprostenol (originally derived prostaglandin), has similar pharmacodynamic properties to Iloprost including vasodilation and platelet inhibition, is widely available and already stocked at most hospitals for already approved indications (pulmonary hypertension). Epoprostenol has advantageous pharmacokinetics including organ independent elimination, a shorter half-life allowing for a faster "off-set" of action, and decades of experience of use for other indications. This randomized controlled trial will assess the efficacy and safety of epoprostenol for frostbite in addition to our standard of care treatment for frostbite: rewarming and qualified early thrombolytic therapy.

Standard of Care + Placebo (Normal Saline)infusion for 8 hours per day up to 5 days maximumDRUG

The placebo or Normal saline will be given exactly the same as the intervention drug - via intravenous infusion for 8 hours a day up to 5 days maximum. Vital signs and monitoring will be the same. The packaging will be labeled "study medication" (epoprostenol or placebo) and neither the participant, treating clinicians, or study personnel will be able to tell the difference as both epoprostenol and normal saline have identical color, general appearance, and viscosity.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Aged ≥ 18 years 2. Admitted to University of Colorado Hospital (UCH) Burn and Frostbite Center 3. Cauchy Grade 2-4 frostbite injury 4. Admission within 72 hours post-rewarming Exclusion Criteria: 1. Patients unable to initiate therapy within 72 hours post-rewarming 2. Unsalvageable frostbite as defined by obvious necrosis of tissue, wet gangrene, or other condition requiring amputation (within the first week) 3. Anticipated death within 48 hours of admission 4. Pregnant or breastfeeding patients 5. Prisoners 6. Inability to obtain consent from patient or legally authorized representative (LAR) or proxy 7. Not a good candidate for treatment per treating physician or investigator 8. Patients with known allergy/hypersensitivity to epoprostenol 9. Current or planned receipt of other prostaglandin analog (iloprost and treprostinil) 10. Known congestive heart failure due to severe left ventricular systolic dysfunction (New York Heart Association (NYHA) class III/IV) 11. Known right heart failure (RHF) 12. Hypotension unresponsive to fluids and discontinuation of concomitant anti-hypertensives (mean arterial pressure (MAP) \< 65 mmHg) 13. Known pulmonary hypertension

Outcomes

Primary Outcomes

Amputation Rate

Amputation rate within 90 days of frostbite injury, defined as number of amputations per number of digits affected.

Time frame: from enrollment to the end of treatment when client returns for clinic visit at 90 days.

Secondary Outcomes

Hennepin frostbite score change

The Hennepin Frostbite score is a standardized, clinical tool used to quantify injury and tissue loss of frostbite injury. It assigns a numerical value to each digit, phalanx or limb affected, based on clinical appearance or absence of blood flow. The scale is classified from 0 to 3. 0 = absence of uptake 1. low uptake 2. normal uptake 3. high uptake Studies show patients with an absence (0) or low (1) uptake predicted amputation with high specificity. Change in Hennepin Frostbite Score from admission to final healing to day 90

Time frame: from admission to final healing to day 90

Preserved Digit Segments

Number of preserved digit segments from admission to final healing to day 90.

Time frame: from admission to final healing to Day 90

Change in Perfusion Imaging (fluorescence intravenous indocyanine green)

Change in perfusion imaging from admission to final imaging. SPY Portable Handheld Imaging System (SPY -PHI) fluorescence intravenous imaging is a near-infrared (NIR) imaging technology using indocyanine green (ICG) dye to provide real-time, high-resolution visualization of blood flow, tissue perfusion, and lymphatic vessels. It enables physicians to immediately assess tissue viability and vascularity. Physicians select a region of interest of uninjured tissue as baseline perfusion (for example 100%), and then a relative percentage value (0-100%) is obtained for affected tissue. Studies have identified a perfusion cut-off value of 33% (using SPY-QP) to determine tissue viability, with some studies showing a high negative predictive value (up to 91-93%) for identifying ischemic tissue. Data on affected tissue perfusion and location will be serially recorded every other day throughout the treatment period. A higher score means a better outcome.

Time frame: from admission to final imaging at day 7

Change in Technetium Bone Scans

Technetium-99m bone scans for frostbite measure tissue perfusion, viability, and deep-tissue/bone infarction. They use a triple-phase technique to distinguish viable from necrotic (dead) tissue, providing early prognosis, identifying regions suitable for thrombolytic therapy, and determining the necessary amputation level. These scans are superior to initial clinical exams, which may not show true tissue damage for weeks. The scale we are using ranges from 5 options - worst outcome is completely absent perfusion, then decreased activity/perfusion, questionable or possible decreased activity, hyperfusion/increased blood flow, to the best possible outcome, which is no abnormality/no problems.