Treatment of Frostbite Sequelae With Botulinum Toxin A

Summary

Background Digital vasospasm as part of frostbite sequelae is comparable to the vasospastic disorders found in Raynaud's phenomenon which has been successfully treated with Botulinum toxin type A injections in the palm of the hands. Aim of this pilot study To investigate the effect of Botulinum toxin type A for frostbite sequelae in the fingers. Hypothesis The null hypothesis which is that all study-subjects will have equal distribution of symptoms and measurements after treatment, regardless of injection with Botulinum toxin type A or placebo. Methodology A randomized, double-blind, placebo-controlled study design, The study population consists of four patients with frostbite sequelae. The patients are randomized to either treatment with Botulinum toxin type A or placebo Two patients in the primary treatment group will receive Botulinum toxin type A at their first injection at inclusion, while the two patients in the secondary treatment group will receive normal saline (placebo) as their first injection at inclusion. At 6 weeks follow up, the primary treatment group will receive their second injection of Botulinum toxin type A and the secondary treatment group now will receive their second injection, but this will be their first injection of Botulinum toxin type A. By using the described study-design, all participating soldiers will get treatment. However, the secondary treatment group will have a delayed onset of treatment with Botulinum toxin type A and serves as a control for the primary treatment group during the initial 6 weeks observation. Botulinum toxin A and placed will be injected near the neurovascular bundle at the A1 pulley in the palm of the hand using a total dosage 100 U per hand (concentration 50 U per ml), 8-12 U/ injection site. The effect of Botulinum toxin type A on subjective symptoms will be measured by Patients Subjective Symptom Score (PSSS) The effect of Botulinum toxin type A on peripheral microcirculation will be evaluated with dynamic infrared thermography (DIRT) of the dorsal side of the hands. Quantitative sensory testing will be used to evaluate the effect of Botulinum toxin type A on peripheral nerve function. Both DIRT and QST will be performed prior to the treatment with Botulinum toxin type A and placebo at the start of the pilot study, at 6 weeks as well as 6 weeks after the last injections. Statistical methods and data analysis will be performed according to the EMA guidelines for biostatistics. Statistical analysis will be performed according to the null hypothesis.

Timeline

Start

2022-11

Primary completion

2023-07

Completion

2024-06-10

Publications

• Background Schaefer G, Huguet J, Zhu SY, Plassmann P, Ring F. Adopting the DICOM standard for medical infrared images. Conf Proc IEEE Eng Med Biol Soc. 2006;2006:236-9. doi: 10.1109/IEMBS.2006.259523.
• Results Iorio ML, Masden DL, Higgins JP. Botulinum toxin A treatment of Raynaud's phenomenon: a review. Semin Arthritis Rheum. 2012 Feb;41(4):599-603. doi: 10.1016/j.semarthrit.2011.07.006. Epub 2011 Aug 24.
• Results Imray C, Grieve A, Dhillon S; Caudwell Xtreme Everest Research Group. Cold damage to the extremities: frostbite and non-freezing cold injuries. Postgrad Med J. 2009 Sep;85(1007):481-8. doi: 10.1136/pgmj.2008.068635.
• Results Fabregat G, De Andres J, Villanueva-Perez VL, Asensio-Samper JM. Subcutaneous and perineural botulinum toxin type a for neuropathic pain: a descriptive review. Clin J Pain. 2013 Nov;29(11):1006-12. doi: 10.1097/AJP.0b013e31827eafff.
• Results Norheim AJ, Mercer J, Musial F, de Weerd L. A new treatment for frostbite sequelae; Botulinum toxin. Int J Circumpolar Health. 2017;76(1):1273677. doi: 10.1080/22423982.2016.1273677.
• Results Segreto F, Marangi GF, Cerbone V, Persichetti P. The Role of Botulinum Toxin A in the Treatment of Raynaud Phenomenon. Ann Plast Surg. 2016 Sep;77(3):318-23. doi: 10.1097/SAP.0000000000000715.
• Results Arnold PB, Campbell CA, Rodeheaver G, Merritt W, Morgan RF, Drake DB. Modification of blood vessel diameter following perivascular application of botulinum toxin-A. Hand (N Y). 2009 Sep;4(3):302-7. doi: 10.1007/s11552-009-9169-8. Epub 2009 Feb 5.
• Results Ring EF, Ammer K. Infrared thermal imaging in medicine. Physiol Meas. 2012 Mar;33(3):R33-46. doi: 10.1088/0967-3334/33/3/R33. Epub 2012 Feb 28.
• Results Moreira DG, Costello JT, Brito CJ, Adamczyk JG, Ammer K, Bach AJE, Costa CMA, Eglin C, Fernandes AA, Fernandez-Cuevas I, Ferreira JJA, Formenti D, Fournet D, Havenith G, Howell K, Jung A, Kenny GP, Kolosovas-Machuca ES, Maley MJ, Merla A, Pascoe DD, Priego Quesada JI, Schwartz RG, Seixas ARD, Selfe J, Vainer BG, Sillero-Quintana M. Thermographic imaging in sports and exercise medicine: A Delphi study and consensus statement on the measurement of human skin temperature. J Therm Biol. 2017 Oct;69:155-162. doi: 10.1016/j.jtherbio.2017.07.006. Epub 2017 Jul 18.
• Results Maier C, Baron R, Tolle TR, Binder A, Birbaumer N, Birklein F, Gierthmuhlen J, Flor H, Geber C, Huge V, Krumova EK, Landwehrmeyer GB, Magerl W, Maihofner C, Richter H, Rolke R, Scherens A, Schwarz A, Sommer C, Tronnier V, Uceyler N, Valet M, Wasner G, Treede DR. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain. 2010 Sep;150(3):439-450. doi: 10.1016/j.pain.2010.05.002.
• Results Aru RG, Songcharoen SJ, Seals SR, Arnold PB, Hester RL. Microcirculatory Effects of Botulinum Toxin A in the Rat: Acute and Chronic Vasodilation. Ann Plast Surg. 2017 Jul;79(1):82-85. doi: 10.1097/SAP.0000000000001054.

Drugs

Indications