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，并且在美国每年导致超过20，000次急诊就诊。CO中毒的死亡率为1 - 3%，发病率高达40%。一氧化碳中毒后幸存的患者会出现神经和心脏后遗症，这会增加长期死亡率。如果考虑到住院费用和收入损失，每年一氧化碳中毒的经济负担约为13亿美元。与吸入CO相关的毒性是由线粒体的氧输送受损和ATP生成抑制引起的。与氧气相比，CO对血红蛋白（Hb）中的结合位点具有高250倍的亲和力，从而导致组织缺氧。治疗CO中毒的主要目的是通过氧气尽快将CO从体内清除。通过氧与Hb的竞争性结合，CO从肺中的Hb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，高压氧治疗经常被延迟，因为需要将患者运送到具有专门设备的医疗中心。此外，高压氧可能并发气压伤、氧中毒、癫痫发作和肺水肿。由于这些限制，目前的治疗与CO中毒的患者，需要新的治疗方法，以改善outcomes.The总体目标，目前的建议是设计和开发一个大型的人工肺单位，结合CO光解和extra-coronary氧合的原则，以增加CO中毒患者的CO去除率。在Zazzeron和Zapol博士领导的初步研究中，我们设计并建造了一个小型的光体外CO去除（ECCOR）装置，该装置增加了CO中毒大鼠的CO去除率。 然而，原型装置将需要修改，以允许治疗较大的动物，并最终与CO中毒的患者。所需的变化包括用于气体交换和照明的更大表面积以及适应更高血液流速的能力。在氧合性能和CO去除的体外测试之后，photo-ECCOR装置从血液中去除CO的能力将在CO中毒的绵羊模型中进行测试。在本研究奖学金结束时，我预计我们将拥有一个原型静脉-静脉photo-ECCOR装置，它可以有效地从大型动物（包括人类）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.