The Relationship Between Breathing, Pain, and Wound Healing

Title: Respiratory alkalosis may impair the production of vitamin D and lead to significant morbidity, including the fibromyalgia syndrome

Authors: Lewis JM, Fontrier TH, Coley JL.

Journal: Med Hypotheses. 2017 May;102:99-101. doi: 10.1016/j.mehy.2017.03.013. Epub 2017 Mar 8. PMID: 28478843.

Link to PubMed: Respiratory alkalosis may impair the production of vitamin D and lead to significant morbidity, including the fibromyalgia syndrome

Abstract: Hyperventilation caused by physical and/or psychological stress may lead to significant respiratory alkalosis and an elevated systemic pH. The alkalotic pH may in turn suppress the normal renal release of phosphate into the urine, thereby interrupting the endogenous production of 1,25-dihydroxyvitamin D (calcitriol). This could cause a shortfall in its normal production, leading to a variety of adverse consequences. It might partially explain the pathogenesis of acute mountain sickness, a treatable disease characterized by severe hyperventilation secondary to the hypoxia of high altitude exposure. Milder degrees of hyperventilation due to different forms of stress may produce other conditions which share characteristics with acute mountain sickness. One of these may be the fibromyalgia syndrome, a chronic painful disorder for which no satisfactory treatment exists. Should fibromyalgia and acute mountain sickness have a common etiology, may they also share a common form of treatment? Evidence is presented to support this hypothesis.

Title: Breathing evaluation and retraining as an adjunct to manual therapy

Authors: McLaughlin L, Goldsmith CH, Coleman K.

Journal: Man Ther. 2011 Feb;16(1):51-2. doi: 10.1016/j.math.2010.08.006. Epub 2010 Oct 8. PMID: 20933458.

Link to PubMed: Breathing evaluation and retraining as an adjunct to manual therapy

Abstract: Back and neck pain are extremely common reasons for patients seeking manual therapy treatment. Epidemiological evidence supports a link between breathing difficulties and back pain. Since trunk muscles perform both postural and breathing functions, it is theorized that disruption in one function can negatively impact the other. Altered breathing mechanics can change respiratory chemistry and therefore pH causing smooth muscle constriction, altered electrolyte balance and decreased tissue oxygenation. These changes can profoundly impact any body system. Increased excitability in the muscular and nervous systems may be most relevant to a manual therapist. Respiratory function can be tested via capnography which measures CO₂ at the end of exhale known as End Tidal CO₂ (ETCO₂). ETCO₂ closely reflects arterial CO₂ in people with normal cardiopulmonary function. A case series of twenty nine outpatients with neck or back pain who had plateaued with manual therapy and exercise were identified all of whom were found to have low ETCO₂. Breathing retraining improved ETCO₂, pain and function in all patients with 93% achieving at least a clinically important change in either pain or function. Screening for breathing dysfunction using capnography may improve patient outcomes in those patients where manual therapy, exercise and education do not provide full resolution of symptoms.

Title: Hypocapnia in women with fibromyalgia

Authors: Jonsson K, Pikwer A, Olsson EMG, Peterson M.

Journal: Scand J Pain. 2024 Jun 21;24(1). doi: 10.1515/sjpain-2024-0003. PMID: 38907689.

Link to full text: Hypocapnia in women with fibromyalgia

Abstract: Objectives: The purpose of this study was to investigate whether people with fibromyalgia (FM) have dysfunctional breathing by examining acid-base balance and comparing it with healthy controls. Methods: Thirty-six women diagnosed with FM and 36 healthy controls matched for age and gender participated in this cross-sectional study. To evaluate acid-base balance, arterial blood was sampled from the radial artery. Carbon dioxide, oxygen, bicarbonate, base excess, pH and lactate were analysed for between-group differences. Blood gas analyses were performed stepwise on each individual to detect acid-base disturbance, which was categorized as primary respiratory and possible compensation indicating chronicity. A three-step approach was employed to evaluate pH, carbon dioxide and bicarbonate in this order. Results: Women with FM had significantly lower carbon dioxide pressure (p = 0.013) and higher lactate (p = 0.038) compared to healthy controls at the group level. There were no significant differences in oxygen pressure, bicarbonate, pH and base excess. Employing a three-step acid-base analysis, 11 individuals in the FM group had a possible renally compensated mild chronic hyperventilation, compared to only 4 among the healthy controls (p = 0.042). Conclusions: In this study, we could identify a subgroup of individuals with FM who may be characterized as mild chronic hyperventilators. The results might point to a plausible dysfunctional breathing in some women with FM.

Title: The role of carbon dioxide therapy in the treatment of chronic wounds

Authors: Brandi C, Grimaldi L, Nisi G, Brafa A, Campa A, Calabrò M, Campana M, D'Aniello C.

Journal: In Vivo. 2010 Mar-Apr;24(2):223-6. PMID: 20363999.

Link to full text: The role of carbon dioxide therapy in the treatment of chronic wounds

Abstract: A wound is defined as chronic when it does not heal according to the normal repair times and mechanisms. This particular condition may be principally due to local hypoxia. Carbon dioxide (CO(2)) therapy refers to the transcutaneous or subcutaneous administration of CO(2) for therapeutical effects on both microcirculation and tissue oxygenation. In this study, we report the clinical and instrumental results of the application of CO(2) in the therapy of chronic wounds. The study included 70 patients affected by chronic ulcers. The patients were selected by aetiology and wound extension and equally divided into two homogeneous groups. In group A, CO(2) therapy was used in addition to the routine methods of treatment for such lesions (surgical and/or chemical debridement, advanced dressings according to the features of each lesion). In group B, patients were treated using routine methods alone. Both groups underwent to instrumental (laser doppler flow, measurement of TcPO(2)), clinical and photographic evaluation. In the group that underwent subcutaneous treatment with CO(2) therapy, the results highlighted a significant increase in tissue oxygenation values, which was confirmed by greater progress of the lesions in terms of both healing and reduction of the injured area. Considering the safety, efficacy and reliability of this method, even if further studies are necessary, we believe that it is useful to include subcutaneous carbon dioxide therapy in the treatment of wounds involving hypoxia-related damage.

Title: Carboxytherapy: Controls the inflammation and enhances the production of fibronectin on wound healing under venous insufficiency

Authors: Brochado TMM, de Carvalho Schweich L, Di Pietro Simões N, Oliveira RJ, Antoniolli-Silva ACMB.

Journal: Int Wound J. 2019 Apr;16(2):316-324. doi: 10.1111/iwj.13031. Epub 2018 Nov 22. PMID: 30467979; PMCID: PMC7949331.

Link to full text: Carboxytherapy: Controls the inflammation and enhances the production of fibronectin on wound healing under venous insufficiency

Abstract: To examine the influence of carboxytherapy on wound healing under venous insufficiency, full‐thickness excisional wounds were created on Wistar rats. We used three groups with 32 rats each: Group (I): daily cleaning with 0.9% saline solution; Group Sulfadiazine (II): 1% silver sulfadiazine; and Carboxytherapy (III): subcutaneous application of 0.3 mL of carbon dioxide. The predetermined periods of analysis were the 3rd, 7th, 14th, and 30th day. The slides were stained with haematoxylin and eosin and Picrosirius red and submitted for immunohistochemistry. Groups II and III presented a statistically significant decrease in relation to the presence of neutrophilic and lymphocytic infiltrates. The presence of collagen significant increased in groups II and III. However, group III presented better organisation. Only group I maintained the neovascularisation until the 30th day. The new epithelium statistically significantly increased in groups II and III. On immunohistochemistry, regarding fibronectin expression, only group III demonstrated a statistically significant increase since the beginning of the healing process. Thus, the use of carboxytherapy promotes the formation of a tissue better structured and that may be an important resource for the treatment of wounds under venous insufficiency, especially those of recurrent re‐openings.

Title: Transdermal CO2 application in chronic wounds

Authors: Wollina U, Heinig B, Uhlemann C.

Journal: Int J Low Extrem Wounds. 2004 Jun;3(2):103-6. doi: 10.1177/1534734604265142. PMID: 15866797.

Link to PubMed: Transdermal CO2 application in chronic wounds

Abstract: Chronic wounds are a challenge to treatment. In this retrospective study, the effect of transdermal CO2 application on wound healing in chronic ulcers was investigated and compared to the effect of CO2 on acute surgical wounds. Eighty-six patients (52 females and 34 males) with chronic wounds of different origin except arterial occlusive disease were included. In addition, 17 patients (5 females, 12 males) with wide excision wounds after surgical therapy of acne inversa were considered. The indication for CO2 application was a wound at risk for infection. Treatment was performed with a Carboflow device once daily for 30 to 60 minutes. There was clinical evidence of improvement of granulation and reduction of discharge and malodor within 1 week of treatment in both chronic and acute wounds. Only 9 patients, all diabetics, needed an additional systemic antibiosis. The treatment was well tolerated. No adverse effects have been noted. Transdermal CO2 application is a useful method to reduce the risk of infection and improve wound healing in both chronic and certain acute wounds. Systematic prospective trials are needed.

Title: The impact of CO2 dry baths on subpopulations of NK and NK-T lymphocytes, cytotoxic activity, level of inflammation and pain management in elderly with musculosceletal syndromes - a pilot study

Authors: Kallistratos, E., Toliopoulos, I., Fragkoraptis, D., Gerou, S., & Fragkoraptis, E.

Journal: Experimental Medicine 1, no. 1 (2009).

Link to EBSCO: The impact of CO2 dry baths on subpopulations of NK and NK-T lymphocytes, cytotoxic activity, level of inflammation and pain management in elderly with musculosceletal syndromes - a pilot study

Abstract: Background - Aim of the study The effects of carbon dioxide-rich water bathing have been investigated in clinical research; CO2 is assumed to exert a direct action on vascular smooth muscles, induce vasodilatation and activate thermoreceptors of the skin. Our overall aim is to test our hypothesis that dry CO2 treatment's rehabilitative effect is achieved by using its immune boosting, anti-inflammatory and anti-depressive elements to encage the elderly's pathophysiologic mechanisms capable of supporting a repaired and significantly improved function. In particular, the present study compared the post-therapy effects with pre-therapy baseline of the treatment measuring immune mediated response, the levels of biochemical markers for chronic inflammatory conditions and assessing clinically the short - term effectiveness of pain management in a group of elderly with musculoskeletal syndromes. Material and Methods Repeated artificial CO2 dry treatments were performed on 37 volunteers with musculoskeletal pain disorders. Group A (intervention) comprised 27 patients (12 men and 15 women) and group B (placebo) tracked 10 patients (5 men and 5 women). Each patient was covered with a specific plastic hypoallergic bag up to neck level and underwent the treatment for 45 min. In group A the bag was filled with CO2 gas and in the placebo group B the bag was filled with fresh air only. The DCDB( Dry Carbon Dioxide Bath) treatment was performed for 17 consecutive days. Blood samples were drawn before and after the intervention period. The selected parameters included white blood cells, cytotoxicity, lymphocytes, NK, NK-T cells, β-endorphin, substance P and neurokinin A. Repeated measurements were made in heart frequency, arterial blood pressure and body temperature at the beginning and after all sessions. Results In the intervention group, a significant decrease was detected in the diastolic arterial pressure (only in women) and in the heart rate. Significant increase was measured in the white blood cells count, lymphocytes count (in men), NK-T cells count, the cytotoxicity measurements, β-endorphin and substance P levels as well as the neurokinin A levels in men. Interestingly, the intervention group members reported a kind of profound euphoria which remained during the intervention period and lasted for at least one month. The increase of Substance P and neurokinin A in the intervention group was not followed by any increase of pain intensity. In the control group, the parameters related to the arousal of the immune system remained unaffected but the levels of substance P and neurokinin A rose more sharply than in group A. Conclusions Dry CO2 bath seems to stimulate short-term immuneboosting responses that last during and after the intervention period. The rise in the endorphin levels explains the euphoric sensation reported by the intervention group patients. The effects of dry CO2 on the parasympathetic nervous system are induced probably via hemodynamic mechanisms; for the hemodynamic responses triggering, a direct action of dry CO2 on specific CO2-receptors in the skin is a possible physiologic pathway.

Title: The effect of transcutaneous application of gaseous CO2 on diabetic chronic wound healing-A double-blind randomized clinical trial

Authors: Macura M, Ban Frangez H, Cankar K, Finžgar M, Frangez I.

Journal: Int Wound J. 2020 Dec;17(6):1607-1614. doi: 10.1111/iwj.13436. Epub 2020 Jul 7. PMID: 32633896; PMCID: PMC7949258.

Link to full text: The effect of transcutaneous application of gaseous CO2 on diabetic chronic wound healing-A double-blind randomized clinical trial

Abstract: Chronic wounds in diabetics are difficult to treat, therefore, adjuvant therapies have been investigated. Bathing in CO2 -rich water (spa therapy) has been known in Europe for decades for its positive effect on peripheral vascular disorders. Recently, much effort has been invested in developing optimal application methods of CO2 . Uses include subcutaneous injections of CO2 , bathing in CO2 -enriched water, and transcutaneous application of CO2 . To verify the effect of transcutaneous application of gaseous CO2 on the healing of chronic diabetic wounds, a randomized double-blind clinical research was designed. The research included 30 and 27 wounds in the study and control groups, respectively. In addition to standard treatment, patients in the study group received 20 therapies with medical-grade CO2 gas and the control group received the same treatment with air. Results showed significantly faster healing in the study group: 20 of the 30 wounds in the study group were healed compared with none in the control group. Mean wound surface and volume in the study group was reduced significantly (surface: 96%, P = .001, volume: 99%, P = .003) compared with a small reduction in the control group (surface: 25%, P = .383, volume: 27%, P = .178). Considering our results, transcutaneous application of gaseous CO2 is an effective adjuvant therapy in diabetic chronic wound treatment.

Keywords: CO2 therapy; carboxy therapy; chronic wound treatment; diabetic chronic wound; diabetic foot ulcer; transcutaneous CO2 application.

Title: Effect of Transcutaneous Application of Carbon Dioxide on Wound Healing, Wound Recurrence Rate and Diabetic Polyneuropathy in Patients with Neuropathic, Ischemic and Neuroischemic Diabetes-Related Foot Ulcers

Authors: Bulum T, Poljičanin T, Badanjak A, Držič J, Metelko Ž.

Journal: Life (Basel). 2025 Apr 7;15(4):618. doi: 10.3390/life15040618. PMID: 40283172; PMCID: PMC12028706.

Link to full text: Effect of Transcutaneous Application of Carbon Dioxide on Wound Healing, Wound Recurrence Rate and Diabetic Polyneuropathy in Patients with Neuropathic, Ischemic and Neuroischemic Diabetes-Related Foot Ulcers

Abstract: (1) Background: Diabetes-related foot ulcers (DFUs) are a severe complication of diabetes mellitus (DM), with a five-year mortality rate of around 40%. Our study aimed to explore the effects of transcutaneous application of carbon dioxide (CO2 therapy) on DFU healing and recurrence rate, as well as diabetic polyneuropathy. (2) Methods: Adults with at least one chronic DFU were invited to undergo 20 50-min-long CO2 therapies within 4 weeks. After the completion of the last CO2 therapy, the effect of the therapies on wound healing and diabetic polyneuropathy was assessed, and 1 year later, we evaluated the incidence rate of DFU recurrence. (3) Results: Thirty-five subjects with DM and forty DFUs (ischemic: 15, neuropathic: 8, neuroischemic: 17) participated in our trial. After 4 weeks, 67.5% of all DFUs healed, whereas the reduction of the surface area of the unhealed wounds (74.0% ± 22.3%) was statistically significant. The restoration of protective sensations was also statistically significant. All unhealed wounds received standard care and healed within 2 additional weeks. The recurrence rate after 1 year was 17.5%. None of the patients required antibiotic treatment, hospitalization, or amputation. (4) Conclusion: CO2 therapy is a promising therapeutic intervention for treating DFUs and improving diabetic polyneuropathy.

Keywords: CO2 therapy; diabetes-related foot ulcer; diabetic foot; distal symmetrical polyneuropathy; loss of protective sensation; transcutaneous CO2 application; wound healing.

Title: Pain in the elderly: Prospective study of hyperbaric CO2 cryotherapy (neurocryostimulation)

Authors: Chatap G, De Sousa A, Giraud K, Vincent JP; Acute Pain in the Elderly Study Group.

Journal: Joint Bone Spine. 2007 Dec;74(6):617-21. doi: 10.1016/j.jbspin.2006.10.011. Epub 2007 Jul 19. PMID: 17897861.

Link to PubMed: Pain in the elderly: Prospective study of hyperbaric CO2 cryotherapy (neurocryostimulation)

Abstract: Objective: To evaluate the analgesic effects of hyperbaric CO(2) cryotherapy in elderly inpatients.

Methods: An open-label prospective study was conducted in two geriatrics departments in patients with a broad range of pain characteristics. Each patient underwent a physical evaluation followed by hyperbaric CO(2) cryotherapy sessions, whose spacing and number were at the discretion of the physiotherapist. Patients completed a 100-mm visual analog scale for pain severity before and after the sessions.

Results: We included 51 patients, who were treated between May 2 and June 30, 2005. Mean age was 83.7years, and the female-to-male ratio was 4/1. The patients had acute or chronic pain whose origin was usually musculoskeletal (80.3%) or neurological (18.6%). Pain scores decreased significantly after four sessions, from 52mm to 13mm (P<0.001) in patients with acute pain and from 45mm to 13mm (P<0.001) in those with chronic pain.

Conclusion: Hyperbaric CO(2) cryotherapy is an innovative tool that should be incorporated within the non-pharmacological armamentarium for achieving pain relief in older patients.