Factors supporting the transdermal use of pharmacopeial carbon dioxide for the treatment of laminitis
This paper presents some information about the pathology of acute and chronic laminitis. 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, are predicted to have specific effects on inflammation, blood flow, and reactive oxygen species that will work together to alleviate laminitis.
Although there are many causes, and risk factors, for laminitis ,5 a final common pathway to the disorder appears to be the disruption of blood flow to the digital arteries and loss of blood flow to the lamina. This is followed by two more pathways to laminitis: ischemia, and activation of hypoxia. These pathological mechanisms are further compounded 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 onset phase (4 to 60 hours), if detected, provides 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 blood flow to the tissues, bringing necessary nutrients such as glucose and improving tissue oxygenation. The mechanisms are well described in both the microcirculation2 and human studies.8 Studies of the microcirculation show that carbon dioxide increases both blood flow and tissue oxygenation better than oxygen itself. Although human studies show that repeated exposure to transcutaneous carbon dioxide reverses the loss of digits and limbs caused by peripheral vascular disease, it also improves the symptoms caused by Raynaud’s disease.
A single treatment of carbon dioxide may therefore have some immediate effects because of its multiple actions. These effects may last a day or longer. As with any other therapy, however, the effects will wear off, and there could even be a rebound response that may seem worse than when the carbon dioxide was first applied. Only through repeated treatments will there be a more permanent effect because the therapy should cause new blood vessels to form with the expected permanent improvements in oxygen supply to the tissue and a permanent reduction in inflamma tion.
Once the acute phase of laminitis passes, the chronic phase begins with lasting 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 process leads to an increase in oxygen demand. In addition, metabolic requirements/oxygen demand at the inflamed site are increased by the influx of inflammatory cells. The hypoxia that results from the increase in demand during inflammation is worsened by the disruption of oxygen delivery. This is particularly the case in chronic inflammation in which the combination of prolonged inflammatory activity and associated fibrosis and thrombos is 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 hypoxia in the tissue during chronic inflammation.
We have described four potential pathways for effective carbon dioxide therapy in the treatment of laminitis: (i) increase tissue blood flow, (ii) improvement of tissue oxygenation, (iii) decrease concentrations of HIF1alpha, and (iv) decrease the main biological compound that regulates inflammation, but there is one more. Many of the symptoms and biological responses that occur during inflammation are mediated through the generation of reactive oxygen species (ROS). ROS may also be regenerated by a secondary mechanism that could potentially lead to laminitis called reperfusion injury, which develops in the following way. Tissue is ischemic during the vasospastic acute phase. When blood flow resumes, the availability of oxygenated blood will generate even more ROS. Although ROS are important for some biological actions and cause the death of microorganisms, excessive ROS will destroy normal tissue through its caustic activity. Carbon dioxide has a powerful role in reducing the ROS,1 so its presence should ameliorate the ROS activity, a fifth pathway for carbon dioxide to generate a positive response in the treatment of laminitis.
Together, the studies cited in this paper 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 pathways to effective 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.
Visit the "How it works” section on this website to review several case studies in which pharmacopeial carbon dioxide successfully treated laminitis.
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