PRE-CLINICAL & CLINICAL STUDIES

Studies have shown that the vagus nerve is an important component in mediating smooth muscle constriction. Clinical data suggests that Vagus Nerve Stimulation (VNS) can safely induce significant bronchodilation during an asthma exacerbation and may serve as an efficacious treatment for bronchoconstriction1.

Several pre-clinical and clinical studies have been conducted to define the mechanism of action and magnitude and duration of the effect on bronchoconstriction. In several guinea pig & swine studies the treatment system showed significant effectiveness in reducing bronchoconstriction by >60%.

The vagus nerve is an important structure in parasympathetic and sympathetic tonal balance that mediates smooth muscle activity. The following clinical and animal studies demonstrate the ability of vagus nerve stimulation (VNS) to modulate vagal nerve activity to safely alleviate smooth muscle constriction.

  • Summary of Pre-Clinical & Clinical Findings
    • Vagal Nerve Stimulation (VNS) inhibits bronchoconstriction through an afferent pathway, causing an endogenous release of catecholamines.
    • There was no clinically significant change in heart rate or blood pressure in studies of the company’s proprietary electrical stimulation waveform [of the AlphaCore] on guinea pigs, dogs, and humans.
    • Percutaneous devices demonstrated clinically significant improvement in Forced Expiratory Volume (FEV1) and Work Of Breathing (WOB).
    • Non Invasive Vagus Nerve Stimulation (nVNS) is as effective as albuterol at 2 hrs in treating asthma exacerbations.
    • Preliminary animal and clinical data suggest that nVNS may provide an effective option for treating bronchoconstriction in patients who cannot tolerate the adverse cardiac effects of albuterol or other inhaled short-term beta-agonists or whose airway resistance is too high to get adequate benefit from inhaled medications in a timely manner.
    • These data, suggest that the AlphaCore™ device is a safe and effective treatment for acute bronchoconstriction associated with reactive airway diseases (e.g., asthma exacerbations).

Mark Pawanker, R., Canonica, G.W., Holgate, S.T., Locke, R.F. World Allergy Organization (WAO) White Book on Allergy. World Allergy Organization. 2011.

 

Clinical Study Content

Summary: Inhibition of Histamine-induced Bronchoconstriction in Guinea Pig and Swine by Pulsed Electrical Vagus Nerve Stimulation¹

The goal of this study was to determine whether applying a low-voltage electrical signal to the vagus nerve could reduce histamine-induced bronchoconstriction in swines and guinea pigs. Sixteen guinea pigs were anesthetized and had bipolar electrodes positioned on the cervical vagus nerves.

Intravenous histamine was titrated to elicit a moderate 2–4 cm H2O increase in pulmonary inflation pressure (Ppi). Histamine was then administered with or without concurrent VNS. The peak change in Ppi following a histamine challenge was reduced in the guinea pigs by VNS stimulation by approximately 60%.

Figure 1. VNS inhibits histamine-induced bronchoconstriction.

Similar results were confirmed in a study in swine indicating VNS is applicable to larger animals. These studies suggest that VNS can reduce bronchoconstriction and may prove useful as a therapy in the treatment of reactive airway disease.

¹Hoffman, T.J., Mendez, S., Staats, P., Emala, C.W., Guo, P. Neuromodulation: Technology at the Neural Interface 2009.

 

Summary: Low Voltage Vagal Nerve Stimulation Reduces Bronchoconstriction in Guinea Pigs through Catecholamine Release²

The purpose of this study was to determine the mechanism of action by which VNS reduces bronchoconstriction in guinea pigs. To test whether VNS acted through an efferent or afferent vagal pathway, investigators ligated the vagal nerves either rostral or caudal to the electrode. Tying the vagus nerves caudal had no effect (Figure 2).

Figure 2. Tying vagal nerves caudal to electrodes does not block VNS

However, when the vagus nerves were ligated rostral to the electrodes, VNS no longer inhibited histamine-induced bronchoconstriction (Fig. 3). These unexpected findings suggest that VNS inhibits bronchoconstriction through an afferent, rather than efferent pathway.

Figure 3. Tying vagal nerves rostral to electrodes blocks VNS

In another experiment, the β-blocker propranolol was shown to inhibit the VNS effect suggesting a role for catecholamines in the mechanism of VNS bronchoprotection (Fig. 4). This was further supported by the measurement of elevated serum catecholamines after VNS, which correlated with the degree of suppression of the histamine-induced constriction.

Figure 4. Propranolol inhibits VNS

The results from these studies suggest that relief from airway constriction through VNS may result from a parasympathetic-sympathetic reflex arc. An afferent signal travels up to the central nervous system, causing a sympathetically-mediated release of catecholamines. Catecholamines relax smooth muscles in the airway, relieving bronchoconstriction.

²Hoffman, T.J., Simon, B.J., Zhang, Y., Emala, C.W. Respir Physiol Neurobiol. 2012 (In press).Hoffman, T.J., Simon, B.J., Zhang, Y., Emala, C.W. Respir Physiol Neurobiol. 2012 (In press).

 

Summary: Development of Non-Invasive Vagal Nerve Stimulator for Treatment of Acute Asthma Exacerbations³

A proprietary, non-invasive VNS (nVNS) device (AlphaCore™) was developed and tested in an established hypersensitive beagle asthma model to confirm that it had a similar safety and efficacy profile as the pVNS device described above Dogs were subjected to methacholine (Mch) challenges inducing about a 100% increase in airway resistance.  Dogs were then treated with the AlphaCore™ device for 2 minutes and repeatedly challenged with the same dose of Mch at 1, 15 and 30 min and every 30 min thereafter for up to 2 hours. Changes in airway resistance, BP and HR were monitored during nVNS.

In a second experiment propranolol was given by i.v. prior to either albuterol or nVNS Treatment with AlphaCore™ resulted in a significant reduction in methacholine-induced bronchoconstriction, which occurred within 1 minute of nVNS and lasted for up to 2 hours, with no significant changes in BP or HR. These results are comparable to historical results with albuterol in the same model (Fig. 7). Further, propranolol inhibited the effects of albuterol and nVNS, suggesting that the mechanism of nVNS involves β-receptor stimulation through the release of catecholamines.

Figure 7 Effects of nVNS and albuterol on methacholine challenges in hypersensitive beagles

³Simon, B.J., Majdanska, J., Hoffmann, T.J., Lovelace Respiratory Research Institute (LRRI) et.al. European Respiratory Society Meeting, Kos, Greece 2011./p>

 

Summary: Feasibility of Percutaneous Vagus Nerve Stimulation for the Treatment of Acute Asthma Exacerbations 4

The purpose of this study was to investigate both the safety and efficacy of VNS delivered through a percutaneous electrode (pVNS) for the treatment of acute asthma exacerbations. The study subjects were limited to consenting adult patients with no further respiratory problems or other pre-existing medical conditions. 24 ED patients (ages 18-65 years) who failed to respond to one hour of standard of care (SOC) were treated with the percutaneous placement of an electrode near the right carotid sheath and then administered 60 minutes of pVNS and SOC. They were compared with a non-randomized control group of 57 subjects.

The primary study outcome measures included adverse events, Force Expiratory Volume in 1 sec (FEV1), and improvement in perceived Work of Breathing (WOB) measured on a visual analogue scale. Stimulation for 60 minutes showed remarkable improvement in both FEV1 (Fig. 5) and WOB (Fig. 6) without serious adverse events

Figure 5 Mean improvement in FEV1

Figure 6 Mean improvement in WOB

 

4 Miner, J.R., Lewis, L.M., Mosnaim, G.S., Varon, J., Theodoro, D. Hoffman, T.J. Acad Emerg Med. In Press 2012.