Vagus Nerve Stimulation Treatment for Asthmatic Bronchoconstriction

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Project Summary The Specific Aim of this proposal is to test the feasibility of using vagus nerve stimulation (VNS) for treating asthma related airway constriction that is refractory to current treatments. There are approximately 25 million people with asthma in the US. About 15% percent of these asthma sufferers experience early and late phase severe asthmatic bronchoconstriction that is refractory to current medication. These patients account for more than half of health related asthma costs and the majority of its mortality. This patient population accounts for 4,700 emergency department visits per day, 1,200 hospitalizations per day, and more than 3,300 deaths annually. There is currently no treatment for people who suffer from uncontrolled asthma. Other percutaneous devices have proven effective for blocking the early phase of asthma attacks that are refractory to current therapy in an ED setting; but there is currently no effective VNS device for outside of the ED setting. In addition, the efficacy of their device for blocking the later phase of the asthma response is unknown. The late phase occurs in 50% of individuals and may account for extended stand and returns to the ED. Our goal is to provide patients with VNS for on-demand treatment of both the early- and late-asthma responses in order to drastically improve quality of life, prevent death, and to obviate the need for visiting the ED.However, before evaluating our method in humans, we must first determine if VNS is effective for halting both the early and the late phase of asthma. In this Phase I study, we will achieve our Specific Aim by evaluating the efficacy of VNS for blocking both early and late asthma responses in an ovalbumin (OVA)- sensitized guinea pig model of asthma. Guinea pigs are anesthetized with urethane (1.8 g/kg i.p.). Heart rate and blood pressure are measured via a carotid artery cannula. Both jugular veins are also cannulated for administration of drugs. The left vagus nerve will be isolated and immersed in a pool of mineral oil, and bipolar cuff electrode will be placed around the left cervical vagus. Animal's body temperature will be maintained at 37C using a heating blanket. Animals are paralyzed with succinylcholine (10 ml/kg/min, i.v.) and ventilated (tidal volume 1 ml/100 g body weight at 100 breaths per minute) via a tracheal cannula (using a constant volume pump, Harvard Apparatus Co, South Natick, MA). Bronchoconstriction (measured as an increase in pulmonary inflation pressure (Ppi) via a pressure transducer on a sidearm of the tracheal cannula) will be measured at stated time intervals after ovalbumin inhalation. Test of Feasibility: We must observe ≥ 35% (mean) reduction of max respiratory system resistance when OVA is combined with VNS in comparison to sham VNS. This value was chosen because it is both directly related to previously demonstrated pulmonary pressure change in guinea pigs and predictive of later clinically meaningful responses in humans.