Neurostimulation for Asthma

Abstract

Asthma is a debilitating and life-threatening disorder resulting in 2 million emergency room visits each year and 500,000 hospital admissions. Asthma is characterized, in part, by smooth muscle contraction, which narrows the airways in a response to a variety of stimuli, including neural input, allergens, and irritants. Several animal models, including swine and guinea pig models, have demonstrated that electrically stimulating the vagus nerve can reduce bronchoconstriction by as much as 70%. Human clinical trials with both percutaneously inserted electrodes and a transcutaneously applied electrical signal have improved forced expiratory volume in 1 s (FEV1) and work of breathing (WOB) in patients experiencing acute asthma exacerbations. Although further blinded clinical studies are necessary, there clearly exists value in vagus nerve stimulation (VNS) as an alternate treatment for bronchoconstriction.

Keywords

Airway reactivity, Asthma, Bronchoconstriction, Bronchospasm, Neuromodulation, Vagus nerve stimulation, VNS

Outline
Introduction 1339
Asthma: The Scope of the Problem 1339
Basic Science 1340
- Clinical Results With Vagus Nerve Stimulation for Bronchoconstriction 1341
- The Mechanism of Vagus Nerve Stimulation on Airway Reactivity 1345
Conclusion 1345
References 1345

Introduction

When one considers electricity a digital drug , it becomes evident that any innervated organ should be amenable to neuromodulation. The field of neuromodulation is expanding greatly, with novel targets constantly being explored, from cardiac disease to urinary incontinence. Spinal cord stimulation (SCS) for pain and deep brain stimulation (DBS) for motor dysfunction, such as Parkinson’s disease, are considered mainstream therapies for those disorders. Novel neuromodulatory targets that include the pulmonary system, previously not thought to be amenable to neuromodulation interventions, are under study.

Vagus nerve stimulation (VNS), which has been used to treat epilepsy since the 1990s, is being considered for people with a variety of disorders such as headaches, inflammatory disorders such as rheumatoid arthritis and inflammatory bowel disease, neurologic disorders including anxiety, depression, and posttraumatic stress disorder, sleep disorders, fibromyalgia, stroke, bleeding diatheses, metabolic disorders such as diabetes mellitus, and airway reactivity. Historically, disorders associated with these diseases have not been considered amenable to neurostimulation.

Asthma: The Scope of the Problem

Asthma is a chronic, long lasting, inflammatory disease of the lung and airways, characterized by reversible bronchoconstriction in response to noxious stimuli. This is mediated by airway smooth muscle contraction and the release of mucus, which leads to airway narrowing. Asthma is classically considered to have both an inflammatory and a neural component. In stress-induced asthma for example, an anxiety attack will trigger the release of histamine and leukotrienes, which can trigger the narrowing of airways ( ). Local anesthetics can be used to blunt airway reactivity, when administered either locally or systemically ( ).

Asthma and airway reactivity is an enormous problem. In recent decades, both asthma prevalence and incidence have been increasing worldwide. According to the World Health Organization, asthma affects over 334 million people worldwide. In the United States, per the National Health Interview Survey (NHIS)-2012, about 26 million people (8%) suffer from current asthma. It is the most common chronic disease in childhood, affecting an estimated 7 million children. Asthma is a significant public health problem, which often requires the use of emergency care, sometimes including hospital admission, and is responsible for a high number of missed school and/or workdays. Two-hundred and fifty thousand annual deaths are attributed to the disease. According to the Centers for Disease Control, asthma costs the American economy 56 billion dollars each year.

Traditional treatments for asthma include beta agonists and inhaled and systemic steroids. There are emerging biologic therapies targeting cytokines and cytokine receptors. None of these treatments work exceedingly well, and systemic steroids, which have significant systemic side effects, should only be used in later stages of the disease. An approach that could rapidly and sustainably reduce bronchoconstriction has the potential to revolutionize the treatment of bronchoconstriction and improve the quality of life for millions with asthma. Previously published literature, in a variety of species, support investigation of VNS with the interplay of neural pathways and receptors that control airway smooth muscle tone.

Basic Science

Autonomic innervation of the airways modulates both contraction and relaxation of airway smooth muscle, which in turn dictates airway diameter ( ). In some asthmatics, dysfunction of parasympathetic activity is thought to be the primary mechanism of enhanced bronchoconstriction ( ), which may explain why there often is a common coexistence of gastroesophageal reflux and asthma in many individuals ( ).

Parasympathetic nerves that release acetylcholine (Ach) activate muscarinic receptors on airway smooth muscle that induce contraction, resulting in bronchoconstriction. Parasympathetic nerves themselves express histamine receptors that can augment the release of Ach. In a study by , a well characterized guinea pig model of airway constriction was used to determine if specific, low voltage, electrical stimuli could be applied directly to the vagal nerves to reduce histamine-induced bronchoconstriction. Guinea pigs were anesthetized with urethane and ventilated through a tracheostomy with continuous measurement of pulmonary inflation pressure (PIP). Elevations in PIP are reflective of airway constriction. The animals received repetitive challenges of intravenous histamine, which induced transient and consistent increases in PIP. In this model, histamine predominantly increases PIP, due to stimulation of vagal parasympathetic, efferent fibers ( ), resulting in enhanced Ach release, which facilitates airway smooth muscle constriction. Electrical stimulation with a range of amplitudes and varied voltages (0.4–1.5 V), along with other set parameters (25 Hz, 0.2 ms, pulse duration), chosen and based on working off of successful vagal neuromodulation used in humans for the treatment of epilepsy and depression ( ), and was subsequently modified to optimize treatment for airway reactivity. These low-voltage stimuli alone had no effect on PIP, but significantly attenuated histamine-induced increases in PIP. These results were then confirmed in a small number of swine to demonstrate applicability to larger animals ( ; Fig. 111.1 ).

A subsequent study was performed in guinea pigs using pharmacological inhibitors and ligation of the vagal nerves to identify the mechanism by which low voltage, VNS attenuates histamine-induced increases in PIP, either cephalad or caudal to the location of stimulation, The pharmacologic inhibitors tested in different groups of animals included N _G-nitro- l -arginine methyl ester ( l -NAME) (50 mg/kg i.v.) (inhibitor of nitric oxide synthase), guanethidine (10 mg/kg i.v.) (decreases catecholamine release from sympathetic nerves), or propranolol (1 mg/kg i.v.) (an antagonist of β-adrenoceptors). Plasma levels of catecholamines were measured at baseline and during low-voltage VNS. Systemic changes in blood pressure confirmed adequate dosing of l -NAME and guanethidine, yet neither of these inhibitors blocked the ability of low-voltage VNS to attenuate histamine-mediated increases in PIP. In contrast, pretreatment with propranolol completely eliminated the effectiveness of low-voltage VNS ( Fig. 111.2 ).