The Specific Aim of this proposal is to test the feasibility of using vagus nerve stimulation (VNS) fortreating asthma related airway constriction that is refractory to current treatments. There are approximately 25million people with asthma in the US. About 15% percent of these asthma sufferers experience early and latephase severe asthmatic bronchoconstriction that is refractory to current medication. These patients account formore than half of health related asthma costs and the majority of its mortality. This patient population accountsfor 4,700 emergency department visits per day, 1,200 hospitalizations per day, and more than 3,300 deathsannually. 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 thatare refractory to current therapy in an ED setting; but there is currently no effective VNS device for outside ofthe ED setting. In addition, the efficacy of their device for blocking the later phase of the asthma response isunknown. The late phase occurs in 50% of individuals and may account for extended stand and returns to theED. Our goal is to provide patients with VNS for on-demand treatment of both the early- and late-asthmaresponses in order to drastically improve quality of life, prevent death, and to obviate the need for visiting theED.However, before evaluating our method in humans, we must first determine if VNS is effective for haltingboth the early and the late phase of asthma. In this Phase I study, we will achieve our Specific Aim byevaluating 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 measuredvia a carotid artery cannula. Both jugular veins are also cannulated for administration of drugs. The left vagusnerve will be isolated and immersed in a pool of mineral oil, and bipolar cuff electrode will be placed around theleft cervical vagus. Animal's body temperature will be maintained at 37?C using a heating blanket. Animals areparalyzed with succinylcholine (10 ml/kg/min, i.v.) and ventilated (tidal volume 1 ml/100 g body weight at 100breaths per minute) via a tracheal cannula (using a constant volume pump, Harvard Apparatus Co, SouthNatick, MA). Bronchoconstriction (measured as an increase in pulmonary inflation pressure (Ppi) via apressure transducer on a sidearm of the tracheal cannula) will be measured at stated time intervals afterovalbumin inhalation. Test of Feasibility: We must observe ? 35% (mean) reduction of max respiratory system resistancewhen OVA is combined with VNS in comparison to sham VNS. This value was chosen because it is bothdirectly related to previously demonstrated pulmonary pressure change in guinea pigs and predictive of laterclinically meaningful responses in humans.
This is a proposal to develop an on-demand treatment for both immediate and long-lasting symptoms ofasthma using vagus nerve stimulation. There are 25 million Americans with asthma and approximately 15% donot respond to current methods of treatment. The proposed therapy seeks to mitigate debilitating symptomsand restore quality of life to patients suffering from uncontrolled asthma.
