Veno-venous extracorporeal blood phototherapy as treatment for carbon monoxide poisoning

一氧化碳（CO）中毒是中毒相关死亡的主要原因，在美国每年有超过20,000人到急诊室就诊。一氧化碳中毒的死亡率为1 - 3%，发病率高达40%。一氧化碳中毒存活下来的病人会有神经系统和心脏后遗症，这已被证明会增加长期死亡率。如果考虑到医院费用和收入损失，一氧化碳中毒的经济负担每年约为13亿美元。与吸入一氧化碳相关的毒性是由线粒体的氧气输送受损和ATP生成抑制引起的。与氧相比，CO对血红蛋白（Hb）结合位点的亲和力高250倍，导致组织缺氧。一氧化碳中毒治疗的主要目标是通过氧气尽快将一氧化碳从体内清除。通过氧与血红蛋白的竞争性结合，CO在肺中从血红蛋白中排出，然后呼出。呼吸室内空气、100%氧气或高压氧时的CO t1/2分别约为5小时、2小时和30分钟。不幸的是，由于需要将患者运送到配备专门设备的医疗中心，高压氧治疗经常被推迟。此外，高压氧可能并发气压损伤、氧中毒、癫痫发作和肺水肿。由于目前一氧化碳中毒患者治疗的这些局限性，需要新的治疗方法来改善结果。本课题的总体目标是设计和开发一种结合CO光解和体外氧合原理的大型人工肺单元，以提高CO中毒患者的CO去除率。在博士领导的初步研究中。Zazzeron和Zapol，我们设计并制造了一个小型的光体外一氧化碳去除（ecor）装置，提高了CO中毒大鼠的CO去除率。然而，原型装置将需要修改，以允许治疗更大的动物和最终的一氧化碳中毒患者。所需的变化包括更大的表面面积，用于气体交换和照明，以及适应更高血液流速的能力。在体外测试氧合性能和CO去除后，将在CO中毒绵羊模型中测试光- ecor装置去除血液中CO的能力。在这项研究结束时，我预计我们将有一个原型的静脉-静脉光ecor装置，可以有效地从包括人类在内的大型动物的血液中去除CO。

Carbon monoxide (CO) intoxication is a leading cause of poisoning related death and results in more than 20,000 visits to emergency departments in the United States each year. The mortality rate from CO poisoning is 1 – 3% and the rate of morbidity is as high as 40%. Patients who survive CO poisoning suffer from neurologic and cardiac sequelae, which have been shown to increase the long-term mortality. If one considers both hospital costs and lost earnings, the economic burden of CO intoxication is approximately 1.3 billion dollars each year. The toxicity associated with inhalation of CO is caused by the impairment of oxygen delivery to, and inhibition of ATP generation in, mitochondria. Compared to oxygen, CO has a 250-fold higher affinity for the binding site in hemoglobin (Hb) resulting in tissue hypoxia. The main goal of treatment for CO poisoning is to remove CO from the body as quickly as possible by oxygen. Through competitive binding of oxygen to Hb, CO is displaced from Hb in the lung and then exhaled. The CO t1/2 while breathing room air, 100% oxygen or hyperbaric oxygen is approximately 5 hours, 2 hours and 30 minutes respectively. Unfortunately, hyperbaric oxygen therapy is often delayed, because of the need to transport the patient to medical centers with specialized equipment. Furthermore, hyperbaric oxygen may be complicated by barotrauma, oxygen toxicity, seizures and pulmonary edema. Because of these limitations to the current treatment of patients with CO poisoning, new therapies are needed to improve outcomes.The overall objective of the current proposal is to design and develop a large artificial lung unit that combines the principles of CO photodissociation and extra-corporeal oxygenation to increase the rate of CO removal from patients with CO poisoning. In preliminary studies led by Drs. Zazzeron and Zapol, we designed and built a small photo- extracorporeal CO removal (ECCOR) device that increased the rate of CO removal from CO-poisoned rats. However, the prototypic device will require modifications to permit treatment of larger animals and ultimately patients with CO poisoning. The required changes include larger surface areas for gas exchange and illumination and the ability to accommodate a higher blood flow rate. After in-vitro testing of oxygenating performance and CO removal, the ability of the photo-ECCOR device to remove CO from blood will be tested in a sheep model of CO poisoning.By the end of this research fellowship, I anticipate that we will have a prototypic veno-venous photo-ECCOR device that can efficiently remove CO from the blood of large animals, including humans.