Carbon Dioxide Literature

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; Oe et al., 2011)

  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)

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; Irie et al., 2005; Izumi et al., 2014; 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

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.

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

To download this list click here.