Transcutaneous Application of Gaseous CO2

Study Overview
=================
Brief Summary
-----------------
The research is designed to evaluate influence of transcutaneous application of CO2 (carbon dioxide) on peripheral diabetic neuropathy. Transcutaneous application of CO2 is known to have immediate effect on vasodilatation and elevates oxygen release from Hb via the Bohr effect. After repetition of the therapies neoangiogenesis is induced. Impairment of microcirculation is one of the causes of diabetic peripheral neuropathy and improvement in circulation could have positive effect also on peripheral neuropathy. In order to evaluate the effect of transcutaneous application of CO2 on peripheral neuropathy in diabetic patients the investigators designed a randomised double blind clinical trial.

Detailed Description
-----------------
Transcutaneous application of gaseous CO2 showed to be a successful adjuvant therapy in treatment of chronic wounds in diabetic patients (PMID: 32633896). During that research patients reported improvement in peripheral sensation after treatment. Therefore, in order to investigate the influence of transcutaneous application of gaseous CO2 in peripheral diabetic neuropathy the investigators designed a randomised double blind research. 60 diabetic patients with peripheral diabetic neuropathy will be randomised in study and control group. Study group will receive 20 treatments with CO2 (each workday for 4 weeks). Lower part of the body is inserted into therapeutic wrap that is filled with 99.9% CO2 gas for 45 minutes. The same approach will be used in control group but in their case the therapeutic wrap will be filled with air. In both groups investigator will evaluate vibration sensation, monofilament test and temperature of the big toe before first and after 4 weeks of treatment. Patients as well as investigator (doctor) will be blind for the group belonging of the patients. The medical nurse performing all the therapies will randomise the patients using random number generator into study and control group. The nurse will be the only one knowing group belonging of the patients until the obtained results from both groups will be compared.

Official Title
-----------------
The Effect of Transcutaneous Application of Gaseous CO2 on Diabetic Symmetrical Peripheral Neuropathy - A Double Blind Randomized Clinical Trial

Conditions
-----------------
Peripheral Diabetic Neuropathy

Intervention / Treatment
-----------------
* Other: Transcutaneous CO2 application
* Other: Placebo treatment


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: patients with diabetes and peripheral symmetrical diabetic neuropathy with unilateral chronic wound, without previous amputations with scores above 3 on the Michigan Neuropathy Scoring Instrument Exclusion Criteria: diabetic patients with asymmetrical peripheral neuropathy patients with severe comorbidities: deep vein thrombosis, chronic kidney diseases grade III and IV, chronic heart diseases NYHA (New York Heart Association) III and IV, patients with known malignant diseases, patients with progressive infection, signs of systemic infection with elevated inflammatory markers or osteomyelitis

Ages Eligible for Study
-----------------
Minimum Age: 30 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The use of transcutaneous application of gaseous CO2 for treatment of diabetic peripheral neuropathy. A double blind clinical trial. Control group receives placebo treatment.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CO2 treated<br>Patients receiving treatment with transcutaneous application of gaseous CO2 on lower limbs | Other: Transcutaneous CO2 application<br>* Patients lie on examination tables. Lower extremities of the patients are isolated in a therapeutic wrap (single use, low-density, made from biocompatible polyethylene), sealed at the waist. After this, air is first pumped out of the therapeutic wrap, then the wrap was filled with 99.9% CO2 gas. The therapy lasts for 45 minutes. Each patient from the study group will receive CO2 therapies - four weeks (meaning 20 CO2 therapies that were performed on workdays only).<br>|
| Placebo Comparator: control<br>Patients receiving placebo treatment with air on lower limbs | Other: Placebo treatment<br>* Each patient from control group will have therapeutic wrap filled with air instead of CO2. Patients from control group will also receive 20 therapies (4 weeks on workdays only), that will also last 45 minutes.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Vibration sensation | Vibration sensation is performed using a 128 Hz tuning fork on 5 standard points on each foot (on the skin above a bony prominence the first metatarsophalangeal joint (MPT), the apex of the hallux, malleolus, diaphysis of tibia and tibia tuberosity). Results are presented as number of points (out of 10) with no vibration sensation. | before first therapy with CO2 or placebo and after 4 weeks of therapy with CO2 or placebo | 
| Change in Monofilament test | Monofilament testing is performed using Semmes Weinstein Monofilament (SWM) 10 g on 8 standard points on each foot (on the plantar surface of the great toe, third and fifth toe, on the plantar surface of the first, third and fifth metatarsal head, on the plantar arch and on the plantar surface of the calcaneus). Results are presented as number of points (out of 16) with no sensation. | before first therapy with CO2 or placebo and after 4 weeks of therapy with CO2 or placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in skin temperature | the temperature measured with infrared thermometer on the plantar of the big toes using infrared thermometer. Temperature measurement was standardized - before treatment (in order to exclude increased temperature during the CO2 therapy due to vasodilatation). Patients are left to lie on the examination table, barefoot for 20 minutes to adjust to the room temperature. | before first therapy with CO2 or placebo and after 4 weeks of therapy with CO2 or placebo | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
peripheral diabetic neuropathy, transcutaneous CO2 application