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| ID | Type | Description | Link |
|---|---|---|---|
| MT24001.345 | Other Grant/Funding Number | Medical Technology Enterprise Consortium(MTEC)/Department of Defense |
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| Name | Class |
|---|---|
| United States Department of Defense | FED |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Epoprostenol | Active Comparator | Standard of care plus epoprostenol intravenous infusion titrated based on tolerability for 8 hours per day and up to 5 days of treatment. |
|
| Placebo (Normal Saline) | Placebo Comparator | Standard of care plus placebo infusion dosed and titrated to match epoprostenol infusion for 8 hours per day and up to 5 days of treatment. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Standard of care plus Epoprostenol infusion for 8 hours (hrs) per day up to 5 days maximum | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Amputation Rate | Amputation rate within 90 days of frostbite injury, defined as number of amputations per number of digits affected. | from enrollment to the end of treatment when client returns for clinic visit at 90 days. |
| Measure | Description | Time Frame |
|---|---|---|
| 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
Change in Hennepin Frostbite Score from admission to final healing to day 90 |
| Measure | Description | Time Frame |
|---|---|---|
| Hospital Length of Stay | Measure the total number of days each patient spent in the hospital. | from admission to day 90 |
| Mortality Rate | Measure the incidence of death within the patients admitted to the hospital, enrolled in this frostbite study, expressed as a rate or percentage. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Beth A Strimpel, MA, BSN, RN | Contact | 203-980-2209 | beth.a.strimpel@cuanschutz.edu | |
| Arek J Wiktor, MD, FACS | Contact | 303-724-1055 | arek.wiktor@cuanschutz.edu |
| Name | Affiliation | Role |
|---|---|---|
| Arek J Wiktor, MD, FACS | University of Colorado, Denver | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Colorado, Denver | Aurora | Colorado | 80045 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34139760 | Background | Endorf FW, Nygaard RM. Social Determinants of Poor Outcomes Following Frostbite Injury: A Study of the National Inpatient Sample. J Burn Care Res. 2021 Nov 24;42(6):1261-1265. doi: 10.1093/jbcr/irab115. | |
| 34964583 | Background | Update: Cold weather injuries, active and reserve components, U.S. Armed Forces, July 2016-June 2021. MSMR. 2021 Oct 1;28(10):2-10. |
| Label | URL |
|---|---|
| Veletri (epoprostenol). Package insert. Actelion Pharmaceuticals US, Inc.; 2020 | View source |
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Data will be shared with Department of Defense
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Participant will be randomized to either intervention or placebo
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Research Coordinators
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| Standard of Care + Placebo (Normal Saline)infusion for 8 hours per day up to 5 days maximum | Drug | 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. |
|
| from admission to final healing to day 90 |
| Preserved Digit Segments | Number of preserved digit segments from admission to final healing to day 90. | 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. | 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. | from admission to final imaging at day 7 |
| from admission to day 90 |
| Need for Skin graft procedures | The number of patients who had a skin graft | from admission to 90 days of frostbite injury |
| Need for Surgical Debridement | The number of patients who had a surgical debridement | from admission to day 90 |
| Need for surgical excision | The number of patients who had a surgical excision | from admission to day 90. |
| Need for surgical flap | The number of patients who had a surgical flap | from admission to day 90 |
| Long term outcome- Neuropathy level | The level of neuropathy as measured by the Qualitative Sensory Test(QST), performed at Day 90 after frostbite injury. The QST is a psychophysical test that assesses sensory nerve function by measuring a person's ability to detect stimuli such as heat, cold and vibration. It is used to detect nerve damage or dysfunction after frostbite. The TSA2Air devise is a hand- held device used to measure sensory nerve function. Generally, at the onset of a stimulus, an adaptation temperature between 30°C and 32°C is set (within this range, the subject should have neither a warm sensation or a cool sensation). For threshold measurement, temperature will then decrease or increase at a constant rate until a response from the subject or operator is received. Response can be recorded by either using the keyboard (operator or subject) or the Patient Response Unit (subject). The temperature at which the response was noted is saved, and the next cycle of stimuli starts. | from admission to 90 days after frostbite injury |
| Long term outcome: Neuropathy Level | The Neuropathic Pain Diagnostic Questionnaire (DN4) is a questionnaire that measures the presence and severity of neuropathy on a scale from 0 to 10. Ten questions are asked. A yes answer is 1 point, and a no answer is 0 points. The lower the score, the better the outcome. This questionnaire is given at the Burn Clinic return visit, 90 days after frostbite injury. | from admission to 90 days after frostbite injury |
| Functional Ability -Quick Disabilities of Arm, Shoulder, Hand (DASH) | The Quick DASH questionnaire for arms and shoulders and hand mobility. Each question has a scale rating from No difficulty, mild difficulty, moderate difficulty, severe difficulty, or unable to do task. It also asks about pain levels ranging from none (0), mild (1), moderate (2), severe (3) to extreme (4). | from admission to 90 days after frostbite injury |
| Functional Ability - Lower Extremity Functional Scale (LEFS) | The Lower Extremity Functional Scale (LEFS) is a questionnaire that scores for all 20 items to get a total score between 0 and 80. Each item is scored on a 5-point scale from 0 (extreme difficulty or unable to perform) to 4 (no difficulty). A higher LEFS score indicates better lower extremity function | from admission to 90 days after frostbite injury |
| Quality of Life - Five-level EuroQol five-dimensional questionnaire(EQ-5D-5L) | The EQ-5D-5L is a generic health questionnaire that measures health-related quality of life by asking respondents to rate their current health status across five dimensions:
For each dimension, respondents choose from five (5) levels of severity, indicating no, slight, moderate, severe, or extreme problems. The questionnaire also includes a visual analogue scale (VAS), where individuals rate their overall health from 0 (worst possible) to 100 (best possible). | from admission to 90 days after frostbite injury |
| Return to Work | Return to work is a yes/no question determining if the subject has returned to work (if working prior to hospitalization) at day 90 after discharge. The answers provided are yes, no, did not work/attend school previously or unknown. | from discharge to 90 days after frostbite injury |
| University of Colorado, Denver | Aurora | Colorado | 80045 | United States |
| 29931369 | Background | Nygaard RM, Endorf FW. Frostbite in the United States: An Examination of the National Burn Repository and National Trauma Data Bank. J Burn Care Res. 2018 Aug 17;39(5):780-785. doi: 10.1093/jbcr/irx048. |
| 10733441 | Background | Badesch DB, Tapson VF, McGoon MD, Brundage BH, Rubin LJ, Wigley FM, Rich S, Barst RJ, Barrett PS, Kral KM, Jobsis MM, Loyd JE, Murali S, Frost A, Girgis R, Bourge RC, Ralph DD, Elliott CG, Hill NS, Langleben D, Schilz RJ, McLaughlin VV, Robbins IM, Groves BM, Shapiro S, Medsger TA Jr. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med. 2000 Mar 21;132(6):425-34. doi: 10.7326/0003-4819-132-6-200003210-00002. |
| 28018840 | Background | Young A, Namas R, Dodge C, Khanna D. Hand Impairment in Systemic Sclerosis: Various Manifestations and Currently Available Treatment. Curr Treatm Opt Rheumatol. 2016 Sep;2(3):252-269. doi: 10.1007/s40674-016-0052-9. Epub 2016 Jul 19. |
| 19147617 | Background | Kowal-Bielecka O, Landewe R, Avouac J, Chwiesko S, Miniati I, Czirjak L, Clements P, Denton C, Farge D, Fligelstone K, Foldvari I, Furst DE, Muller-Ladner U, Seibold J, Silver RM, Takehara K, Toth BG, Tyndall A, Valentini G, van den Hoogen F, Wigley F, Zulian F, Matucci-Cerinic M; EUSTAR Co-Authors. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis. 2009 May;68(5):620-8. doi: 10.1136/ard.2008.096677. Epub 2009 Jan 15. |
| 39874231 | Background | Del Galdo F, Lescoat A, Conaghan PG, Bertoldo E, Colic J, Santiago T, Suliman YA, Matucci-Cerinic M, Gabrielli A, Distler O, Hoffmann-Vold AM, Castellvi I, Balbir-Gurman A, Vonk M, Ananyeva L, Rednic S, Tarasova A, Ostojic P, Boyadzhieva V, El Aoufy K, Farrington S, Galetti I, Denton CP, Kowal-Bielecka O, Mueller-Ladner U, Allanore Y. EULAR recommendations for the treatment of systemic sclerosis: 2023 update. Ann Rheum Dis. 2025 Jan;84(1):29-40. doi: 10.1136/ard-2024-226430. Epub 2025 Jan 2. |
| 28096285 | Background | Sitbon O, Vonk Noordegraaf A. Epoprostenol and pulmonary arterial hypertension: 20 years of clinical experience. Eur Respir Rev. 2017 Jan 17;26(143):160055. doi: 10.1183/16000617.0055-2016. Print 2017 Jan. |
| 31326282 | Background | McIntosh SE, Freer L, Grissom CK, Auerbach PS, Rodway GW, Cochran A, Giesbrecht GG, McDevitt M, Imray CH, Johnson EL, Pandey P, Dow J, Hackett PH. Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Treatment of Frostbite: 2019 Update. Wilderness Environ Med. 2019 Dec;30(4S):S19-S32. doi: 10.1016/j.wem.2019.05.002. Epub 2019 Jul 17. |
| 36444642 | Background | Bello JW, Rickrode GA, Harlan NP, Buckey JC. Systemic Prostacyclin Analogues for Frostbite Require Careful Monitoring. J Burn Care Res. 2023 Mar 2;44(2):487-488. doi: 10.1093/jbcr/irac178. No abstract available. |
| 15733628 | Background | Bouhassira D, Attal N, Alchaar H, Boureau F, Brochet B, Bruxelle J, Cunin G, Fermanian J, Ginies P, Grun-Overdyking A, Jafari-Schluep H, Lanteri-Minet M, Laurent B, Mick G, Serrie A, Valade D, Vicaut E. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain. 2005 Mar;114(1-2):29-36. doi: 10.1016/j.pain.2004.12.010. Epub 2005 Jan 26. |
| 15042521 | Background | Tan G, Jensen MP, Thornby JI, Shanti BF. Validation of the Brief Pain Inventory for chronic nonmalignant pain. J Pain. 2004 Mar;5(2):133-7. doi: 10.1016/j.jpain.2003.12.005. |
| 35969437 | Background | Kamstra RJM, Boorsma A, Krone T, van Stokkum RM, Eggink HM, Peters T, Pasman WJ. Validation of the Mobile App Version of the EQ-5D-5L Quality of Life Questionnaire Against the Gold Standard Paper-Based Version: Randomized Crossover Study. JMIR Form Res. 2022 Aug 11;6(8):e37303. doi: 10.2196/37303. |
| 15671616 | Background | Ogawa A, Matsubara H, Fujio H, Miyaji K, Nakamura K, Morita H, Saito H, Kusano KF, Emori T, Date H, Ohe T. Risk of alveolar hemorrhage in patients with primary pulmonary hypertension--anticoagulation and epoprostenol therapy. Circ J. 2005 Feb;69(2):216-20. doi: 10.1253/circj.69.216. |
| 28778759 | Background | Lindford A, Valtonen J, Hult M, Kavola H, Lappalainen K, Lassila R, Aho P, Vuola J. The evolution of the Helsinki frostbite management protocol. Burns. 2017 Nov;43(7):1455-1463. doi: 10.1016/j.burns.2017.04.016. Epub 2017 Aug 1. |
| 36482743 | Background | Murphy J, Endorf FW, Winters MK, Rogers C, Walter E, Neumann N, Weber L, Lacey AM, Punjabi G, Nygaard RM. Bleeding Complications in Patients With Severe Frostbite Injury. J Burn Care Res. 2023 Jul 5;44(4):745-750. doi: 10.1093/jbcr/irac180. |
| 34021017 | Background | Poole A, Gauthier J, MacLennan M. Management of severe frostbite with iloprost, alteplase and heparin: a Yukon case series. CMAJ Open. 2021 May 21;9(2):E585-E591. doi: 10.9778/cmajo.20200214. Print 2021 Apr-Jun. |
| 35870081 | Background | Crooks S, Shaw BH, Andruchow JE, Lee CH, Walker I. Effectiveness of intravenous prostaglandin to reduce digital amputations from frostbite: an observational study. CJEM. 2022 Sep;24(6):622-629. doi: 10.1007/s43678-022-00342-9. Epub 2022 Jul 23. |
| 21226604 | Background | Cauchy E, Cheguillaume B, Chetaille E. A controlled trial of a prostacyclin and rt-PA in the treatment of severe frostbite. N Engl J Med. 2011 Jan 13;364(2):189-90. doi: 10.1056/NEJMc1000538. No abstract available. |
| 26948558 | Background | Cauchy E, Davis CB, Pasquier M, Meyer EF, Hackett PH. A New Proposal for Management of Severe Frostbite in the Austere Environment. Wilderness Environ Med. 2016 Mar;27(1):92-9. doi: 10.1016/j.wem.2015.11.014. |
| 37045447 | Background | Wibbenmeyer L, Lacey AM, Endorf FW, Logsetty S, Wagner ALL, Gibson ALF, Nygaard RM. American Burn Association Clinical Practice Guidelines on the Treatment of Severe Frostbite. J Burn Care Res. 2024 May 6;45(3):541-556. doi: 10.1093/jbcr/irad022. |
| ID | Term |
|---|---|
| D005627 | Frostbite |
| ID | Term |
|---|---|
| D000067390 | Cold Injury |
| D014947 | Wounds and Injuries |
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| ID | Term |
|---|---|
| D059039 | Standard of Care |
| D006643 | Histidine-tRNA Ligase |
| ID | Term |
|---|---|
| D019984 | Quality Indicators, Health Care |
| D011787 | Quality of Health Care |
| D006298 | Health Services Administration |
| D017530 | Health Care Quality, Access, and Evaluation |
| D000604 | Amino Acyl-tRNA Synthetases |
| D019729 | Carbon-Oxygen Ligases |
| D008025 | Ligases |
| D004798 | Enzymes |
| D045762 | Enzymes and Coenzymes |
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