Carbon Dioxide Literature

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Biological Properties

  1. Gas readily diffuses through skin, especially when the skin is wet (Alkalay, Suetsugu, Constantine, & Stein, 1971; Bedu, Cheynel, Gascard, & Coudert, 1989; Vaupel, 1976)

  2. Solubility in various tissues - 30x more soluble than oxygen in water (Sutton, 2015)

  3. Sensed by cyclic-AMP (Buck & Levin, 2011)

Physiological Properties of Carbon Dioxide

  1. How produced in the body

    • Metabolic activity converts oxygen in the blood to ATP and CO2 – any physiology textbook

  2. How eliminated from the body

    • Normal respiratory ventilation – any physiology textbook

  3. Reduces inflammation

    • Moderates NF-kappa B (Keogh et al., 2017)

  4. Increases blood flow

    • Nitric oxide dependent (Carr, Graves, & Poston, 1993)

  5. Increases tissue oxygenation

    • Bohr effect (Duling, 1973; Sakai et al., 2011)

  6. Activates angiogenesis

    • Increases VEGF (Irie et al., 2005; Xu, Elimban, & Dhalla, 2017)

    • Skeletal muscle (Oe et al., 2011)

    • Fracture (Koga et al., 2014)

    • Nerve damage (Nishimoto et al., 2018)

    • Hyperglycemia capillary preservation (Matsumoto et al., 2019)

  7. Effect on oxidative state

    • Anti-oxidant (Bolevich et al., 2016)

  8. Reduces size of tumors

    • Moderates hypoxia inducible factor (HIF1) (Harada et al., 2013; Selfridge et al., 2016)

    • Moderates metalloproteases – MMP (Takeda et al., 2014)

  9. Releases VEGF in cultured endothelial cells (D’Arcangelo et al., 2000)

Reported Biological Responses – Transdermal Carbon Dioxide Treatment

  1. Hastens fracture closure – rat (Koga et al., 2014)

  2. Improves endurance – rat, human (Akamine & Taguchi, 1998; Ueha et al., 2017)

  3. Improves acceptance of skin flaps – rat (Saito et al., 2018)

  4. Reduces tumor growth – rat, mice(Harada et al., 2013; Iwata et al., 2016; Takeda et al., 2014)

  5. Enhances effectiveness of chemotherapy and radiation therapy – rat (Onishi, Y. et al., 2014; Onishi, Yasuo & Kawamoto, 2012)

  6. Improves blood flow and preserves tissue in peripheral vascular disease – human, rat (Fabry et al., 2009; Hartmann, Bassenge, Hartmann, & Hartmann, 1997; Izumi et al., 2015; Savin et al., 1995)

  7. Improves muscle recovery after nerve injury – rat (Nishimoto et al., 2018) 

  8. Improves wound healing – human (Persson & van der Linden, 2004; Wollina, Heinig, & Uhlemann, 2004)

  9. Preserves capillaries during hyperglycemia – rat (Matsumoto et al., 2019)

Reported Treatments – Hypoventilation Induced Hypercarbia

  1. Hypercapnia – elevated carbon dioxide levels in the blood

    • Improved blood flow and tissue oxygenation - (Akça et al., 2006; Akça et al., 2002; Jankov et al., 2006; Selfridge et al., 2016; Shigemura, Lecuona, & Sznajder, 2017; Sinclair et al., 2002; Wang, Su, Bruhn, Yang, & Vincent, 2008)

  2. Effects of Acidosis

    • How related to hypercarbia? Unknown if effects are due to hypercarbia or acidosis (Payen & Haloui, 2014)

Equine Ailments Likely To respond To Carbon Dioxide Therapy

  1. Laminitis – inflammation, poor blood flow, acute phase most sensitive to treatment

  2. Non-healing wounds – inflammation, poor blood flow

  3. Lymphangitis – inflammation, poor blood flow

  4. Sarcoid – MMP, inflammation

  5. Radiation dermatitis - antioxidant properties

Canine ailments likely to respond to carbon dioxide therapy

  1. Arthritis – inflammation, MMP

  2. Non-healing wounds – inflammation, poor blood flow

  3. Dermatitis – inflammation


Akamine, T. & Taguchi, N. (1998). Effects of an artificially carbonated bath on athletic warm-up. Journal of Human Ergology, 27(1/2), 22-29. doi:10.11183/jhe1972.27.22

Akça, O., Sessler, D. I., Delong, D., Keijner, R., Ganzel, B., & Doufas, A. G. (2006). Tissue oxygenation response to mild hypercapnia during cardiopulmonary bypass with constant pump output. British Journal of Anaesthesia, 96(6), 708-714.doi:10.1093/bja/ael093

Akça, O., Doufas, A. G., Morioka, N., Iscoe, S., Fisher, J., & Sessler, D. I. (2002). Hypercapnia improves tissue oxygenation. Anesthesiology, 97(4), 801-806. doi:10.1097/00000542-200210000-00009

Alkalay, I., Suetsugu, S., Constantine, H., & Stein, M. (1971). Carbon dioxide elimination across human skin. The American Journal of Physiology, 220(5), 1434. Retrieved from

Bedu, M., Cheynel, J., Gascard, J., & Coudert, J. (1989). Transcutaneous CO2 diffusion comparison between CO2 spa water and dry gas in royal thermal spa. In A. Strano, & S. Novo (Eds.), Advances in vascular pathology (pp. 1109-1113) Elsevier Science Publishers B. V. (Biomedical DIvision).

Bolevich, S., Kogan, A., Zivkovic, V., Djuric, D., Novikov, A., Vorobyev, S., & Jakovljevic, V. (2016). Protective role of carbon dioxide (CO2) in generation of reactive oxygen species. Molecular and Cellular Biochemistry, 411(1), 317-330. doi:10.1007/s11010-015-2594-9

Buck, J., & Levin, L. R. (2011). Physiological sensing of carbon dioxide/bicarbonate/pH via cyclic nucleotide signaling. Sensors (Basel, Switzerland), 11(2), 2112-2128. doi:10.3390/s110202112

Carr, P., Graves, J. E., & Poston, L. (1993). Carbon dioxide induced vasorelaxation in rat mesenteric small arteries precontracted with noradrenaline is endothelium dependent and mediated by nitric oxide. Pflügers Archiv : European Journal of Physiology, 423(3-4), 343-345. doi:10.1007/BF00374415

D’arcangelo, D., Facchiano, F., Barlucchi, L., Melillo, G., Illi, B., Testolin, L., Capogrossi, M. (2000). Acidosis inhibits endothelial cell apoptosis and function and induces basic fibroblast growth factor and vascular endothelial growth factor expression. Circulation Research: Journal of the American Heart Association, 86(3), 312-318. doi:10.1161/01.RES.86.3.312

Duling, B. R. (1973). Changes in microvascular diameter and oxygen tension induced by carbon dioxide. Circulation Research, 32(3), 370-376. doi:10.1161/01.RES.32.3.370

Fabry, Monnet, Schmidt, Lusson, Carpentier, Baguet, & Dubray. (2009). Clinical and microcirculatory effects of transcutaneous CO2 therapy in intermittent claudication. Randomized double-blind clinical trial with a parallel design. Vasa, 38(3), 213-224. doi:10.1024/0301-1526.38.3.213

Fitzgerald, L. R. (1957). Cutaneous respiration in man. Physiological Reviews, 37(3), 325. Retrieved from

Harada, R., Kawamoto, T., Ueha, T., Minoda, M., Toda, M., Onishi, Y., . . . Akisue, T. (2013). Reoxygenation using a novel CO2 therapy decreases the metastatic potential of osteosarcoma cells. Experimental Cell Research, 319(13), 1988-1997. doi:10.1016/j.yexcr.2013.05.019

Hartmann, B. R., Bassenge, E., Hartmann, M., & Hartmann, B. R. (1997). Effects of serial percutaneous application of carbon dioxide in intermittent claudication: Results of a controlled trial. Angiology, 48(11), 957-963. doi:10.1177/000331979704801104

Irie, H., Tatsumi, T., Takamiya, M., Zen, K., Takahashi, T., Azuma, A., . . . Matsubara, H. (2005). Carbon dioxide-rich water bathing enhances collateral blood flow in ischemic hindlimb via mobilization of endothelial progenitor cells and activation of NO-cGMP system. Circulation, 111(12), 1523-1529. doi:10.1161/01.CIR.0000159329.40098.66

Iwata, E., Hasegawa, T., Takeda, D., Ueha, T., Kawamoto, T., Akisue, T., . . . Komori, T. (2016). Transcutaneous carbon dioxide suppresses epithelial-mesenchymal transition in oral squamous cell carcinoma. International Journal of Oncology, 48(4), 1493-1498. doi:10.3892/ijo.2016.3380

Izumi, Y., Yamaguchi, T., Yamazaki, T., Yamashita, N., Nakamura, Y., Shiota, M., . . . Iwao, H. (2014). Percutaneous carbon dioxide treatment using a gas mist generator enhances the collateral blood flow in the ischemic hindlimb. Journal of Atherosclerosis and Thrombosis, 22(1), 38-51. doi:10.5551/jat.23770

Jankov, R. P., Kavanagh, B. P., Teixeira, L., Kantores, C., McNamara, P. J., Engelberts, D., & Murthy, P. (2006). Therapeutic hypercapnia prevents chronic hypoxia-induced pulmonary hypertension in the newborn rat. The American Journal of Physiology, 291(5), L912. 

Keogh, C. E., Scholz, C. C., Rodriguez, J., Selfridge, A. C., von Kriegsheim, A., & Cummins, E. P. (2017). Carbon dioxide-dependent regulation of NF-kappaB family members RelB and p100 gives molecular insight into CO2-dependent immune regulation. The Journal of Biological Chemistry, 292(27), 11561-11571. doi:10.1074/jbc.M116.755090 [doi]

Koga, T., Niikura, T., Lee, S. Y., Okumachi, E., Ueha, T., Iwakura, T., . . . Kurosaka, M. (2014). Topical cutaneous CO2 application by means of a novel hydrogel accelerates fracture repair in rats. The Journal of Bone and Joint Surgery. American Volume, 96(24), 2077-2084. doi:10.2106/JBJS.M.01498

Matsumoto, T., Tanaka, M., Ikeji, T., Maeshige, N., Sakai, Y., Akisue, T., . . . Fujino, H. (2019). Application of transcutaneous carbon dioxide improves capillary regression of skeletal muscle in hyperglycemia. The Journal of Physiological Sciences, 69(2), 317-326. doi:10.1007/s12576-018-0648-y

Nishimoto, H., Inui, A., Ueha, T., Inoue, M., Akahane, S., Harada, R., . . . Sakai, Y. (2018). Transcutaneous carbon dioxide application with hydrogel prevents muscle atrophy in a rat sciatic nerve crush model. Journal of Orthopaedic Research, 36(6), 1653-1658. doi:10.1002/jor.23817

Oe, K., Ueha, T., Sakai, Y., Nikura, T., Lee, S. Y., Koh, A., . . . Kurosaka, M. (2011). The effect of transcutaneous application of carbon dioxide (CO2) on skeletal muscle. Biochemical and Biophysical Research Communications, 407(1), 148-152. doi:10.1016/j.bbrc.2011.02.128

Onishi, Y., Akisue, T., Kawamoto, T., Ueha, T., Hara, H., Toda, M., . . . Kurosaka, M. (2014). Transcutaneous application of CO2 enhances the antitumor effect of radiation therapy in human malignant fibrous histiocytoma. International Journal of Oncology, 45(2), 732-738. doi:10.3892/ijo.2014.2476

Onishi, Y., & Kawamoto, T. (2012). Transcutaneous application of carbon dioxide (CO2) enhances chemosensitivity by reducing hypoxic conditions in human malignant fibrous histiocytoma. Journal of Cancer Science & Therapy, 4(7) doi:10.4172/1948-5956.1000136

Payen, D., & Haloui, H. (2014). Acid-base status is an important factor for inflammation, but don't forget CO2. Critical Care (London, England), 18(6), 664. Retrieved from

Persson, M., & van der Linden, J. (2004). Wound ventilation with carbon dioxide: A simple method to prevent direct airborne contamination during cardiac surgery? Journal of Hospital Infection, 56(2), 131-136. doi:10.1016/j.jhin.2003.10.013

Saito, I., Hasegawa, T., Ueha, T., Takeda, D., Iwata, E., Arimoto, S., . . . Komori, T. (2018). Effect of local application of transcutaneous carbon dioxide on survival of random-pattern skin flaps. Journal of Plastic, Reconstructive & Aesthetic Surgery, 71(11), 1644-1651. doi:10.1016/j.bjps.2018.06.010

Sakai, Y., Miwa, M., Oe, K., Ueha, T., Koh, A., Niikura, T., . . . Kurosaka, M. (2011). A novel system for transcutaneous application of carbon dioxide causing an "artificial bohr effect" in the human body. PloS One, 6(9), e24137. doi:10.1371/journal.pone.0024137

Savin, E., Bailliart, O., Bonnin, P., Bedu, M., Cheynel, J., Coudert, J., & Martineaud, J. (1995). Vasomotor effects of transcutaneous CO2 in stage II peripheral occlusive arterial disease. Angiology, 46(9), 785-791. doi:10.1177/000331979504600904

Selfridge, A. C., Cavadas, M. A. S., Scholz, C. C., Campbell, E. L., Welch, L. C., Lecuona, E., . . . Taylor, C. T. (2016). Hypercapnia suppresses the HIF-dependent adaptive response to hypoxia. The Journal of Biological Chemistry, 291(22), 11800-11808. doi:10.1074/jbc.M116.713941.

Shigemura, M., Lecuona, E., & Sznajder, J. I. (2017). Effects of hypercapnia on the lung. The Journal of Physiology, 595(8), 2431-2437. doi:10.1113/JP273781

Sinclair, S. E., Kregenow, D. A., Lamm, W. J. E., Starr, I. R., Chi, E. Y., & Hlastala, M. P. (2002). Hypercapnic acidosis is protective in an in vivo model of ventilator-induced lung injury. American Journal of Respiratory and Critical Care Medicine, 166(3), 403-408. doi:10.1164/rccm.200112-117OC

Sutton, I. (2015). Solubility of O2, N2, H2 and CO2 in water. Process risk and reliability management (2nd Edition ed., pp. 209-239) Elsevier. Retrieved from

Takeda, D., Hasegawa, T., Ueha, T., Imai, Y., Sakakibara, A., Minoda, M., . . . Komori, T. (2014). Transcutaneous carbon dioxide induces mitochondrial apoptosis and suppresses metastasis of oral squamous cell carcinoma in vivo. PloS One, 9(7), e100530. doi:10.1371/journal.pone.0100530

Ueha, T., Oe, K., Miwa, M., Hasegawa, T., Koh, A., Nishimoto, H., . . . Sakai1, Y. (2017). Increase in carbon dioxide accelerates the performance
of endurance exercise in rats. J Physiol Sci, DOI: 10.1007/s12576-017-0548-6

Vaupel, P. (1976). Effect of percentual water content in tissues and liquids on the diffusion coefficients of O2, CO2, N2, and H2. Pflugers Archiv : European Journal of Physiology, 361(2), 201-204. doi:10.1007/BF00583467

Wang, Z., Su, F., Bruhn, A., Yang, X., & Vincent, J. (2008). Acute hypercapnia improves indices of tissue oxygenation more than dobutamine in septic shock. American Journal of Respiratory and Critical Care Medicine, 177(2), 178-183. doi:10.1164/rccm.200706-906OC

Wollina, U., Heinig, B., & Uhlemann, C. (2004). Transdermal CO2 application in chronic wounds. The International Journal of Lower Extremity Wounds, 3(2), 103-106. doi:10.1177/1534734604265142

Xu, Y., Elimban, V., & Dhalla, N. S. (2017). Carbon dioxide water-bath treatment augments peripheral blood flow through the development of angiogenesis. Canadian Journal of Physiology and Pharmacology, doi:10.1139/cjpp-2017-0125

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