Transdermal Carbon Dioxide (Cardiox) For The Treatment of Laminitis
Factors Supporting The Use of Transdermal Carbon Dioxide (Cardiox) For The Treatment of Laminitis
Richard Rivers, M.D., Ph.D
Johns Hopkins University
This paper presents some information about the pathology of laminitis, both acute and chronic. It then discusses some of the physiological effects of carbon dioxide and describes how elevated levels of carbon dioxide, achieved by diffusion through the skin, is predicted to have specific effects on inflammation, blood flow, and reactive oxygen species that will work together to improve laminitis.
Although there are many causes, and risk factors, for laminitis 5, a final common pathway to the generation of laminitis appears to be vasospasm of digital arteries and loss of blood flow to the lamina. This is followed by ischemia, and activation of hypoxic pathways. These pathological mechanism are further insulted by reperfusion injury once the arteries reopen and present oxygenated blood. Although challenging to detect, the acute process of digital vasospasm offers the best opportunity to treat and prevent progression to a chronic, debilitating, disease. The vasospasm associated with laminitis has been described to closely align with Raynaud’s disease in humans. The initial acute phase (4 to 60 hours), if detected, allows an opportunity for treatment with vasoactive medications to increase blood flow and reverse the ischemia.
Carbon dioxide applied through the skin has been shown to dramatically increase tissue blood flow, and improve tissue oxygenation. The mechanisms are well described in the microcirculation 2, and in human studies 8. Studies on the microcirculation show that carbon dioxide will increase blood flow, and tissue oxygenation, better than oxygen itself. While human studies show repeated exposure to transcutaneous carbon dioxide reverses the loss of digits and limbs caused by peripheral vascular disease, and it also improves the symptoms caused by Raynaud’s disease.
Vasospasm generates regions with low oxygen. Low oxygen increases hypoxia-inducible factor (HIF) that causes translation of proteins for protecting the cell during hypoxia, and ultimately, generating the proteins for apoptosis 4. This process also results in inflammation (pain and swelling). Transdermal carbon dioxide should affect all four mechanisms. It increases blood flow and tissue oxygenation, it decreases concentrations of HIF1alpha 7, and it directly decreases the main biological compound that regulates inflammation (NFkB) 6, just like other anti-inflammatory drugs such as aspirin.
A single treatment of CO2 may therefore have some immediate effects due its multiples actions. This may last a day, or longer. Like any other therapy however, it will wear off and there could even be a rebound response that may seem worse than when it was first applied. Only through repeated treatments will you see a more permanent effect because the therapy should cause new blood vessels to be formed with the expected permanent improvements in oxygen supply to the tissue and permanent decreases in inflammation.
Once the acute phase of laminitis passes the chronic phase begins with chronic inflammation, intense pain, and remodeling of the distal phalanx. Inflammation is a metabolically active process, requiring the synthesis of high levels of inflammatory enzymes and cytokines by the inflamed tissue cells. This leads to an increase in oxygen demand. In addition, metabolic requirements/oxygen demand at the inflamed site is increased by the influx of inflammatory cells. The hypoxia due to increase in demand during inflammation is worsened by disruption of oxygen delivery. This is particularly the case in chronic inflammation where the combination of prolonged inflammatory activity and associated fibrosis and thrombosis results in diminished blood (and consequently oxygen) supply to the site of inflammation 3. Therefore, a combination of increased oxygen consumption by inflamed resident cells and infiltrating immune cells along with a disrupted blood supply due to vascular dysfunction contributes to tissue hypoxia during chronic inflammation.
Although we have already described four potential pathways for effective CO2 therapy in the treatment of laminitis, there is one more. Many of the symptoms and biological responses during inflammation are mediated through the generation of reactive oxygen species (ROS). ROS may also be regenerated by a secondary potential mechanism of laminitis, called reperfusion injury. Tissue is ischemic during the vasospastic acute phase. When blood flow resumes, the availability of oxygenated blood will generate even more ROS. While ROS are important for some biological actions, and death of microorganisms, excessive ROS will destroy normal tissue through its caustic activity. Carbon dioxide has powerful role in reducing the ROS 1 so its presence should ameliorate the ROS activity. Thus, we now describe a fifth pathway for carbon dioxide to generate a positive response in the treatment of laminitis.
Together these studies highlight the complex and inter-related vasoactive and inflammatory signaling cascades that are initiated during laminitis. The use of carbon dioxide gas to treat this disorder offers numerous potentially effective modes of therapy. The precise dosing regimen in terms of application frequency, and duration, as it relates to the progression of the disease has yet to be studied, or defined.
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