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

Authors

  • James R. Miner MD,

    1. From the Department of Emergency Medicine, Hennepin County Medical Center (JRM), Minneapolis, MN; the Division of Emergency Medicine, Washington University School of Medicine (LML, DT), St. Louis, MO; the Rush University Medical Center (GSM), Chicago, IL; The University of Texas Health Science Center at Houston, The University of Texas Medical Branch at Galveston, Galveston, TX, and Dorrington Medical Associates, P.A. (JV), Houston, TX; and ElectroCore, LLC (TJH), Morris Plains, NJ.
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  • Lawrence M. Lewis MD,

    1. From the Department of Emergency Medicine, Hennepin County Medical Center (JRM), Minneapolis, MN; the Division of Emergency Medicine, Washington University School of Medicine (LML, DT), St. Louis, MO; the Rush University Medical Center (GSM), Chicago, IL; The University of Texas Health Science Center at Houston, The University of Texas Medical Branch at Galveston, Galveston, TX, and Dorrington Medical Associates, P.A. (JV), Houston, TX; and ElectroCore, LLC (TJH), Morris Plains, NJ.
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  • Giselle S. Mosnaim MD, MS,

    1. From the Department of Emergency Medicine, Hennepin County Medical Center (JRM), Minneapolis, MN; the Division of Emergency Medicine, Washington University School of Medicine (LML, DT), St. Louis, MO; the Rush University Medical Center (GSM), Chicago, IL; The University of Texas Health Science Center at Houston, The University of Texas Medical Branch at Galveston, Galveston, TX, and Dorrington Medical Associates, P.A. (JV), Houston, TX; and ElectroCore, LLC (TJH), Morris Plains, NJ.
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  • Joseph Varon MD,

    1. From the Department of Emergency Medicine, Hennepin County Medical Center (JRM), Minneapolis, MN; the Division of Emergency Medicine, Washington University School of Medicine (LML, DT), St. Louis, MO; the Rush University Medical Center (GSM), Chicago, IL; The University of Texas Health Science Center at Houston, The University of Texas Medical Branch at Galveston, Galveston, TX, and Dorrington Medical Associates, P.A. (JV), Houston, TX; and ElectroCore, LLC (TJH), Morris Plains, NJ.
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  • Daniel Theodoro MD,

    1. From the Department of Emergency Medicine, Hennepin County Medical Center (JRM), Minneapolis, MN; the Division of Emergency Medicine, Washington University School of Medicine (LML, DT), St. Louis, MO; the Rush University Medical Center (GSM), Chicago, IL; The University of Texas Health Science Center at Houston, The University of Texas Medical Branch at Galveston, Galveston, TX, and Dorrington Medical Associates, P.A. (JV), Houston, TX; and ElectroCore, LLC (TJH), Morris Plains, NJ.
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  • Thomas J. Hoffmann

    1. From the Department of Emergency Medicine, Hennepin County Medical Center (JRM), Minneapolis, MN; the Division of Emergency Medicine, Washington University School of Medicine (LML, DT), St. Louis, MO; the Rush University Medical Center (GSM), Chicago, IL; The University of Texas Health Science Center at Houston, The University of Texas Medical Branch at Galveston, Galveston, TX, and Dorrington Medical Associates, P.A. (JV), Houston, TX; and ElectroCore, LLC (TJH), Morris Plains, NJ.
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  • Presented at the Society of Critical Care Medicine annual meeting, San Diego, CA, January 2011.

  • Support for this study was provided by ElectroCore, LLC.

  • JM, LL, and JV received grant support from ElectroCore LLC; JM and DT served as paid consultants to ElectroCore LLC; and GM serves on the Scientific Advisory Board and has stock options in ElectroCore LLC. TH is an employee of ElectroCore LLC.

  • Supervising Editor: Gary B. Green, MD.

Address for correspondence and reprints: James R. Miner, MD; e-mail: miner015@umn.edu. Address for reprint requests: Thomas J. Hoffmann; e-mail: thomas@electrocoremedical.com.

Abstract

ACADEMIC EMERGENCY MEDICINE 2012; 19: 421–429 © 2012 by the Society for Academic Emergency Medicine

Abstract

Objectives:  This study assessed the feasibility of an investigational vagus nerve stimulation (VNS) device for treating acute asthma exacerbations in patients not responding to at least 1 hour of initial standard care therapy.

Methods:  This was a prospective, nonrandomized study of patients treated in the ED for moderate to severe acute asthma (forced expiratory volume in 1 second [FEV1] 25% to 70% of predicted). Treatment entailed percutaneous placement of an electrode near the right carotid sheath and 60 minutes of VNS and continued standard care. VNS voltage was adjusted to perceived improvement, muscle twitching, or adverse events (AEs). All AEs, vital signs, FEV1, perceived work of breathing (WOB), and final disposition were recorded.

Results:  Twenty-five subjects were enrolled. There were no serious AEs and no significant changes in vital signs. No subject required terminating VNS. One patient had minor bleeding from the procedure, and one had a hematoma and withdrew prior to VNS. AEs related to VNS were temporary and included cough (1 of 24), swallowing difficulty (2 of 24), voice change (2 of 24), and muscle twitching (14 of 24). These resolved when VNS ended. The FEV1 improved at 15 minutes (median = 15.8%, 95% confidence interval [CI] = 9.3% to 22.4%), 30 minutes (median = 21.3%, 95% CI = 8.1% to 36.5%), and 60 minutes (median = 27.5%, 95% CI = 11.3% to 43.5%). WOB improved at 15 minutes (median = 53.9%, 95% CI = 33.7% to 73.9%), 30 minutes (median = 69.1%, 95% CI = 56.4% to 81.8%), and 60 minutes (median81.0%, 95% CI = 68.5% to 93.5%).

Conclusions:  Percutaneous VNS did not result in serious AEs and was associated with improvements in FEV1 and perceived dyspnea. Percutaneous VNS appears to be feasible for use in the treatment of moderate to severe acute asthma in patients unresponsive to initial standard care treatment.

Despite improvements in diagnosis and treatment, asthma continues to impose a major health burden in the United States. According to a recent American Lung Association report,1 asthma was associated with 1.7 million emergency department (ED) visits and 444,000 hospitalizations annually.

Recently, the use of a novel vagus nerve stimulator for acute severe asthma exacerbations was reported.2 Neuronal mechanisms have long been recognized for their role in regulating bronchial airway tone,3–7 and their dysfunction has been associated with many symptoms of asthma.8–10 This neural regulation of bronchoconstriction is based on the excitatory efferent parasympathetic nerves evoking contractions and, in many species, sympathetic nerves evoking relaxation.11,12 However, bronchial sympathetic innervation is absent in humans.7 In its place, the inhibitory nonadrenergic noncholinergic (iNANC) nervous system, with neurotransmitters such as nitric oxide and vasoactive intestinal peptide, has been associated with relaxation responses.7,13–16

For the past 50 years, a useful tool for investigating the neural component of airway regulation has been the application of electrical stimulation to the cervical vagus nerve. Many studies reported that stimulation of the vagus nerve resulted in increased airway resistance and decreased compliance,17,18 leading to the generally accepted theory that vagus nerve stimulation (VNS) induces bronchoconstriction. However, an electrical stimulus signal that reduced histamine-induced bronchoconstriction in guinea pig and swine was recently described.19 Although the specific mechanism had not been confirmed, iNANC nerve responses or possibly adrenergic outflow from adjacent sympathetic innervated vasculature were suggested. Recent preliminary animal data,20 however, suggest that stimulation may activate afferent nerves, leading to catecholamine release from the adrenal medulla.

Here we report on a feasibility study for the use of an investigational percutaneous VNS device (RPS-1000 Resolve proximity system, ElectroCore LLC, Morris Plains, NJ) as an adjunct to standard therapy in patients with acute moderate to severe asthma exacerbations. The goal of our investigation was to determine the feasibility of using the device to treat patients with moderate to severe asthma exacerbations who had not adequately responded to the first hour of standard care therapy in the ED. The primary outcome measure was the occurrence of adverse events (AEs) during device placement, with the 60 minutes of VNS, and then subsequently. Secondary outcomes included the change in forced expiration volume in 1 second (FEV1) and perceived work of breathing (WOB) during the stimulation period.

Methods

Study Design

This was a prospective single intervention study of patients undergoing treatment for asthma in the ED or an urgent care clinic. Patients not responding to the initial hour of standard care were screened for potential inclusion. Subjects were enrolled at five sites, comprising four EDs and one urgent care clinic, between January 20, 2009, and August 24, 2010, under a Food and Drug Administration investigational device exemption. Institutional review board approval was obtained from each site. All participants provided informed consent. Patients were compensated a total of $200 for expenses and time related to study procedures.

Study Setting and Population

The study was carried out at five sites: Christus Santa Rosa Hospital, San Antonio, Texas; Dorrington Medical Associates, Houston, Texas; Hennepin County Medical Center, Minneapolis, Minnesota; Rush University Medical Center, Chicago, Illinois; and Washington University-Barnes-Jewish Hospital, St. Louis, Missouri.

Adult patients (age 18 to 65 years) presenting with moderate to severe acute asthma exacerbation (FEV1 25% to 70% of predicted), who received at least a 1 hour of standard care therapy without significant improvement and met inclusion and exclusion criteria, were approached for enrollment. Screening was performed by trained research assistants (RAs) on a continuous basis 24 hours a day during the study period. Failure to respond to the initial hour of therapy was defined as an improvement of <12% in FEV1 over the hour, an FEV1 <70%, and assessment by the investigator. Standard-care treatment for asthma included beta agonists, anticholinergics, supplemental oxygen, and oral or parenteral corticosteroids and was administered at the discretion of the treating physician. Other therapies, such as magnesium, were also used at the treating physician’s discretion. Patients with respiratory insufficiency not related to asthma, such as due to lung cancer, emphysema, and chronic obstructive pulmonary disease, were excluded, as were patients with compromised cervical anatomy such as from scarring, infection, or suspected carotid artery disease. Patients with coagulopathy, irregular heart rhythm, on pressor medication, pregnant, or unable to provide informed consent were also excluded. Screening failure patients were defined as patients screened for the study who did not subsequently meet inclusion or exclusion criteria.

Study Protocol

Device Description.  The investigational device is a neuromodulation system composed of an external signal generator, an electrode, and accessories. It is designed to deliver a specific electrical signal (25 Hz and 0.2-ms pulse width, 1–12 volt amplitude) to nerve and tissue structures in the neck for the purpose of reducing bronchoconstriction. The system is intended to be used by physicians who are experienced with both the placement of central venous access lines and the associated AEs. In this study, the device was placed by one of the investigators, each of whom had been trained in its placement using a central line placement simulation model (Blue Phantom, Redmond, WA).

Treatment entailed the percutaneous placement of an electrode near the right carotid sheath using anatomical landmarks and ultrasound guidance under sterile conditions. The device placement required only local anesthesia while the patient remained alert. Following a preliminary physical and ultrasound examination of the cervical anatomy, the patient was briefly lowered into a semirecumbent position for electrode insertion. With the carotid artery and jugular vein visualized using ultrasound, a 22-gauge finder needle was positioned posterior-lateral to the carotid sheath. A small (approximately 5 mm) incision was made to accommodate a 5F sheath introducer and the introducer was inserted parallel to the finder needle. The finder needle was removed, the electrode placed through the introducer, and the position confirmed with ultrasound (Figure 1). The introducer was then removed, the electrode was secured by a dressing, and stimulation commenced. The subject was then returned to an upright position. No other procedural anesthesia or sedation was used. Following VNS treatment, the electrode was withdrawn and the skin approximated using a butterfly bandage or single stitch.

Figure 1.

 Ultrasound image during device insertion. CA = carotid artery; IJ = internal jugular vein; SA = introducer/sheath assembly; T = trachea.

Methods of Measurement.  The primary study outcome measurements were AEs as determined by subject report to the investigator and the investigator’s examination of the subject. All AEs from the electrode placement procedure (including but not limited to diaphoresis, carotid artery or jugular vein puncture, damage to the vagus nerve, pneumothorax, scarring, and infection), VNS (including but not limited to dyspnea, bradycardia, nausea, hoarseness, swallowing difficulty, and muscle twitching), and asthma treatment were recorded. All other AEs related or unrelated to the study were recorded. Following treatment, subjects were evaluated for potential vagus nerve damage, including but not limited to hoarseness, swallowing or speaking difficulty, loss of gag reflex, and uneven tone in soft palate. Patients were questioned on whether they experienced any anticipated AEs, such as for VNS-induced muscle twitching, and asked to grade them as none, mild, moderate, or severe.

The secondary outcome measurements included changes in FEV1 as measured by spirometry and improvement in perceived WOB as measured on a 10-cm visual analog scale (VAS). FEV1 was assessed by trained RAs using a Piko meter (nSpire Health Inc., Longmont, CO). ED patients who met the study requirements and agreed to participate were instructed and evaluated on proper spirometry technique. Once enrolled, spirometry was limited to single exhalations at each observation point for all patients to minimize subject stress. The VAS consisted of a 10-cm line bounded by “normal breathing” at one end and “extreme difficulty breathing” on the other.21 This evaluation was amended to the original treatment protocol after the study had started by consensus of the investigators and was not performed on the first nine patients.

Participants were classified as responders and nonresponders for each outcome measurement. For FEV1, responders were defined by the protocol as achieving a clinically meaningful increase of ≥12%.22 For WOB, responders were defined post hoc by the investigators as achieving a decrease on VAS of 50% from baseline. Although there are some data suggesting a generally acceptable improvement in FEV1 that can be used to separate responders from nonresponders,22 this is not the case for the VAS WOB self-assessment tool. Since a clinically meaningful change has not been established for VAS WOB, we chose an improvement of 50% as a cutoff for distinguishing between responders and nonresponders.

After confirming eligibility and obtaining informed consent, the study protocol was initiated. All subjects continued to receive standard care therapy throughout the study. The device was then placed. Stimulation treatment commenced immediately after device placement, with voltage amplitude increased until the patient reported symptomatic improvement in breathing or noted muscle twitching or discomfort or a maximum voltage of 12 volts was reached. VNS was performed for 60 minutes, after which the electrode was removed. Subjects underwent monitoring of vital signs (blood pressure, heart rate, respiration rate, and oxygen saturation levels) at baseline (immediately before stimulation) and at 5, 10, 15, 30, and 60 minutes after initiation of VNS. The FEV1 and VAS were measured at baseline; at 15, 30, and 60 minutes; and at 30 minutes following device removal. Subjects remained under observation for AEs for 1 hour after the device was removed. The subject’s time in the ED or clinic and discharge status was recorded. All AEs and all treatments received by subjects during the study period were recorded.

Subjects returned after 7 days for examination by an investigator. The examination included stitch removal, if used, and evaluations for wound healing, indications of infection, scarring, signs of nerve damage, and any related and unrelated AEs. At 30 days posttreatment, the subjects completed a telephone interview to report any related or unrelated AEs, any indications of nerve damage, relative increase or decrease in the number of asthma attacks since treatment, and whether or not the subject would have the procedure again if symptoms recurred.

Data Analysis

Measurement outcomes are presented with descriptive statistics and using binomial exact 95% confidence intervals (CIs) for proportions and the 95% CI for Hodges-Lehman median differences for continuous data. This was a feasibility study to provide preliminary safety information for both the electrode placement procedure and the stimulation treatment. Sample size was restricted to 25 treatment participants by the Food and Drug Administration and was not powered by sample size determination for efficacy.

Results

Characteristics of the Study Subjects

A total of 671 patients with asthma exacerbation were screened in the ED for inclusion in the study. Of these, there were 603 screening failures, 43 refusals, and 25 subjects enrolled. Screening failures included patients who responded to standard care within 1 hour or did not meet inclusion or exclusion criteria. Baseline demographics are reported in Table 1, and vital signs in Table 2. Medications received in the ED for asthma treatment received prior to enrollment included albuterol (median dose = 5 mg, 95% CI = 5 to 10 mg, range = 2.5 to 35 mg, n = 25), ipratropium (median dose = 0.5 mg, 95% CI = 0.5 to 1 mg, range = 0.5 to 1 mg, n = 22), and corticosteroids (median dose = 60 mg, 95% CI = 60 to 125 mg, range = 25 to 125 mg, n = 24). Two subjects (8%) received magnesium sulfate (2 g).

Table 1. 
Study Demographics
Characteristics 
  1. BMI = body mass index; FEV1 = forced expiratory volume in 1 second; IQR = interquartile range; WOB = work of breathing.

Age, median (range)41.0 (19–65)
BMI, median (range)30.2 (19–47)
Sex (%)
 Male36.0
 Female64.0
Race (%)
 White12.0
 Black or African American76.0
 Hispanic 4.0
 Asian0.0
 Native American4.0
 Other4.0
Smoking history (%)
 Current18.2
 Previous45.5
 Never36.4
Baseline airway assessment (median, IQR)
 Percent predicted FEV135.1 (29.2–48.0)
 WOB3.8 (1.4–7.1)
Table 2. 
Vital Signs
 Baseline5 minutes10 minutes15 minutes30 minutes60 minutes
  1. Values represent median (95% CI) range.

  2. MAP = mean arterial pressure; SpO2 = oxygen saturation.

Heart rate (beats/min)89.5 (81–99) 61–12589.5 (81–99) 62–11885.0 (78–91) 63–12280.5 (73–88) 63–12787.5 (78–97) 63–12089.0 (84–94) 68–122
MAP (mm Hg)95.0 (90–100) 65–12295.3 (90–101) 72–12392.3 (86–99) 71–12093.5 (88–99) 73–12693.8 (87–101) 73–13290.3 (83–98) 66–134
% SpO296.0 (95–97) 91–9995.5 (94–97) 92–9995.5 (94–97) 89–10096.0 (94–98) 88–10095.5 (94–97) 87–10097.0 (95–99) 91–100
Respiratory rate (breaths/min)20.0 (17–23) 13–3020.0 (17–23) 11–3119.5 (16–23) 12–3519.0 (16–24) 12–3318.0 (16–20) 87–10018.0 (17–19) 12–30

The median peak stimulation delivered was 4.4 volts (interquartile range [IQR] = 3.0 to 7.0 volts, range = 1 to 11.6 volts). No subject required termination of stimulation prior to the 60-minute end point. However, one of the 25 subjects withdrew from the study prior to insertion of the electrode.

Safety Endpoints

Anticipated Side Effects.  There were no reported incidences of increased dyspnea, nausea, or vomiting recorded. Treatment with the device stimulated coughing in one subject (4%, graded by the subject as moderate), temporary swallowing difficulty in two subjects (8%, both mild), temporary hoarseness or voice change in two subjects (8%, both mild), and minor muscle twitching in 14 subjects (56%, including eight mild, five medium, and one severe). These symptoms resolved through decreasing the device output as per protocol and did not recur during treatment. The degree of asthma exacerbation worsened in one of 24 subjects (FEV1 decreased from 44% to 40%). In addition, cardiovascular and respiratory vital signs were stable throughout the study (Table 2).

Risks Associated With the Device Placement Procedure.  The VNS electrode placement procedure had a median time from preparation to stimulation commencement of 9.5 minutes (range = 3 to 29 minutes). There were no instances of nerve damage or suspected damage. There was one occurrence of diaphoresis (4%), one instance of minor bleeding (4%) at the insertion site, and one hematoma (4%) during device placement. All events were resolved without additional intervention. The hematoma was reported as forming superficially after finder needle insertion, and the investigator decided not to place the electrode. The hematoma was about 3 cm in size and stopped expanding with 1 minute with local pressure. The hematoma had resolved at the 1-week posttreatment exam, and the subject did not report any other AEs.

Treatment Failures.  There were two device failures and one operator error failure. One subject was treated with 3.4 volts of stimulation and had an elevated FEV1 at 30 minutes (36.4%), but then the electrode was dislodged. The second subject was treated with 5.0 volts, FEV1 had increased by 19.2% at 15 minutes, but the electrode was also dislodged. The operator error occurred after 15 minutes of treatment (2.9 volts) without FEV1 improvement. The operator omitted entering the device’s lockout code and could not increase voltage. The unit was then turned off and the device removed.

Secondary Outcome Measurements

Spirometry.  In addition to failing to show significant improvement in symptoms with at least 1 hour of standard care therapy as assessed by the treating physician, 17 of the 24 subjects were also evaluated by spirometry during this preenrollment screening period. The spirometry results were consistent with the physician’s evaluation and indicated no improvement in FEV1 prior to VNS (median predicted screening = 38.9% [95% CI = 31.1% to 46.5%] vs. baseline 34.1% [95% CI = 28.0% to 40.2%]; Figure 2). After initiation of VNS treatment, the median airway assessment as measured by FEV1 increased at each time point (Figures 2 and 3). At 15 minutes, FEV1 increased by median of 15.8% (95% CI = 9.3% to 22.4%, range = −19% to 58%, n = 24). FEV1 continued to increase at 30 minutes (median FEV1 = 23.7%, 95% CI = 8.1% to 36.5%, range = −16% to 75%, n = 22), and at 60 minutes (median FEV1 = 27.5%, 95% CI = 11.3% to 43.5%, range = −9% to 98%, n = 21). FEV1 remained improved at 30 minutes posttreatment (median = 40.4%, 95% CI = 21.4% to 59.4%, range = −9% to 163%, n = 20).

Figure 2.

 Median percent predicted FEV1 results obtained during screening. FEV1 = forced expiration volume in 1 second; SOC = standard care.

Figure 3.

 Spirometry results reported as the median percent change in FEV1 from baseline (median, 95% CIs; n = 24). FEV1 = forced expiratory volume in 1 second.

Subjects were then compared to determine the relative percentage of treatment responders (≥12% FEV1 improvement). At 15 minutes, 54.2% (n = 24); at 30 minutes, 77.3% (n = 22); and at 60 minutes, 81.0% (n = 21) were classified as FEV1 responders. At 30 minutes poststimulation treatment, 80.0% (n = 20) were classified as FEV1 responders.

Work of Breathing.  Sixteen subjects completed the WOB assessment (Figure 4). At 15 minutes, the VAS evaluation indicated an improvement (decrease) in WOB by a median 53.9% (95% CI = 33.7% to 73.9%, n = 16). WOB continued to improve at 30 minutes (median = 69.7%, 95% CI = 56.4% to 81.8%, n = 15) and at 60 minutes (median = 81.0%, 95% CI = 68.5% to 93.5%, n = 14). WOB remained improved at 30 minutes posttreatment (median = 85.4%, 95% CI = 67.4% to 100%, n = 14). The subjects were then compared to determine the relative percentage of treatment responders (>50% improvement). Fifty percent were classified as responders at 15 minutes, 80.0% at 30 minutes, and 85.7% at 60 minutes. At 30 minutes posttreatment, 85.7% were classified as responders.

Figure 4.

 WOB. Visual analog scale WOB reported as the median percent improvement in breathing ability from baseline (median, 95% CIs; n = 16). WOB = work of breathing.

Posttreatment Follow-up.  All 25 subjects were examined by the investigator at 1 week postprocedure. There were no instances of wound healing complications or indications of potential nerve damage. There were two reports of minor AEs, one for pain, and one for “twinges.” Both involved the insertion site and resolved by the second day. At the 1-month telephone interview, two subjects were lost to follow-up. There were no AEs or nerve complications reported. Subsequent frequency of asthma attacks were reported by 16 subjects: eight reported a reduction in frequency with no attacks during this period, six reported no change and no attacks, and two reported no change and one attack. Twenty-one of 23 subjects reported that they would have the treatment procedure again if symptoms recurred.

Discussion

This is the first study to demonstrate that percutaneous VNS treatment is feasible in patients who fail to adequately respond to standard care therapy for moderate to severe acute asthma in the ED. Although the percutaneous VNS procedure is new, it was readily performed by physicians experienced with placing central venous access lines under ultrasound guidance. Although the patients in this study received standard care prior to VNS, spirometry indicated that the patients were not responding within the initial hour of standard care therapy. Placement of the stimulus electrode and VNS did not result in any serious AEs and was associated with improved FEV1 and perceived WOB. These improvements were maintained at the 30-minute-posttreatment evaluation.

Asthma is a heterogeneous disease with patients differing in degrees of airway inflammation, mucus plugging, and responsiveness to β2-adrenergic and corticosteroid medication. Despite continued research into new pharmaceutical therapies and the development of diagnostic and treatment guidelines,23 a significant number of adult patients presenting to the ED with acute asthma exacerbation are poor responders, and either require prolonged stays in the ED or are admitted to the hospital. In two North American studies, 20% of the adult asthma ED patients required hospital admission.24,25 Not surprisingly, increased exacerbation severity resulted in greater hospitalization rates.25 Therefore, new treatments that can be used concomitantly with current therapies may improve patient outcomes, reduce ED utilization time and resources, and possibly prevent hospital admissions.

This was a feasibility study designed to evaluate safety of an investigational VNS device for treating patients with acute asthma exacerbation. Our study excluded patients who responded to standard care therapy over a preenrollment assessment period of at least 1 hour, thereby selecting patients who were not responding to initial treatment. Thus, it was in these acute asthma patients who were not responding to initial standard care that the treatment appeared to show benefit.

This feasibility study provided preliminary safety information regarding percutaneous vagal nerve electrode placement and VNS. We did not detect any episodes of increased tachycardia, bradycardia, or hypotension during or after treatment, and there were no long-term AEs reported at 7 or 30 days posttreatment. It also indicated that the VNS treatment was associated with rapid (observed within 15 minutes) and clinically meaningful improvements which continued over the 60-minute stimulation period and 30 minutes posttreatment.

The basis for this feasibility study arose from animal data that demonstrated VNS with this signal reduced bronchoconstriction in guinea pigs and in swine.19 However, it was necessary to confirm safety of VNS treatment in a clinical setting in light of previous reports linking vagus nerve activity to bronchoconstriction26 and implanted vagus nerve stimulators with dyspnea in some patients treated for seizures27–29 or depression.30 In addition, the vagus nerve innervates the heart, raising concerns that stimulation could trigger cardiac symptoms.31,32 In this feasibility study, the electrical VNS did not alter baseline cardiovascular measurements and appeared to relieve bronchoconstriction and improve dyspnea (Figures 2 and 3). Despite ultrasound guidance and investigators skill in placing central venous access lines, vascular puncture remains a risk. In the 25 patients enrolled, there was one instance where the 22-gauge finder needle produced a superficial hematoma that did not result in long-term AEs.

This feasibility study was not designed to establish the underlying mechanism that resulted in the improvement in FEV1 and WOB. In previous animal studies, a low-voltage VNS signal had induced small but significant increases in blood pressure and heart rate and attenuated histamine-induced bronchoconstriction responses.19,20 In contrast, stimulation at substantially higher voltages could induce bradycardia and bronchoconstriction.17,18,33,34 The low-voltage VNS bronchodilation and the high-voltage VNS bradycardia with bronchoconstriction responses could be differentiated, however, by investigating the stimulation pathway rather than the applied voltages. When a ligature was placed cephalic to the electrode, thereby blocking afferent but preserving efferent nerve transmission, the bradycardia and bronchoconstriction responses were unaffected (unpublished data). When a ligature was placed on the vagus nerve caudal to the electrode, only afferent nerve transmission remained. With caudal ligation, the bradycardia and bronchoconstriction responses were eliminated, but reduction in the histamine bronchoconstriction response (bronchodilation) was preserved. These experiments indicate that the bronchodilation and bradycardia responses are independent. It also suggests that the bronchodilation is through afferent nerves.

There are other possible mechanisms that may explain how the VNS may have reduced the bronchoconstriction in acute asthma exacerbation patients who did not respond to initial standard care. In asthma patients, sympathetic activity is important for maintaining airway caliber.35 Although sympathetic nerves are absent in the human airway, adrenergic modulation may be possible through local release of norepinephrine from the well-innervated pulmonary vasculature or from sympathetic innervation of vagal ganglia. This norepinephrine may potentially bind to β2-adrenoceptors on airway smooth muscle to induce bronchodilation or to modulate cholinergic neurotransmissions in human airways via prejunctional inhibitory α2-adrenoceptors.36 Alternatively, stimulation may activate iNANC nerves and release of nitric oxide to relax pulmonary smooth muscle.37,38 Another possibility is that afferent VNS triggered catecholamine release from the adrenal medulla.

In many species, including humans, the density of β-adrenoceptors in the lungs is higher than in any other tissue36 and blocking these receptors with drugs, such as propranolol, worsens airway obstruction in people with asthma.39–42 In animal studies, propranolol has been shown to inhibit the benefit of VNS in reducing bronchoconstriction.20 Asthma patients have also been reported to be more sensitive to endogenous epinephrine,43 and at physiologic concentrations treatment with an epinephrine infusion can induce bronchodilation in a dose-dependent manner and at a dose below that which affects blood pressure and heart rates.44,45 Furthermore, β-adrenoceptors have a higher affinity for epinephrine (Kd = 0.8 μmol/L) than for the sympathetic neurotransmitter norepinephrine (Kd = 10 μmol/L).46 The adrenal medulla is the primary source of epinephrine. Thus, it is possible that this afferent pathway, with signaling through the central nervous system and a sympathetic response from the adrenal medulla, may be the mechanism of action for the bronchodilation reported in this study.

Limitations

This was a preliminary feasibility study with methodologic limitations. As a nonblinded study, treatment bias may have influenced patient selection. Also, any placebo effect on the VNS treatment outcomes was not evaluated. The small number of study subjects did not permit calculation of an accurate rate of the AEs that would be expected in the general target patient group or detection of rare but more serious AEs. A definitive clinical trial or registry will be needed to confirm safety. In terms of effectiveness, the spirometry methodology used to evaluate efficacy could have a negative effect on the study, since it required the patients to consistently perform forced expirations with maximal effort to achieve a true FEV1 value. This potentially underestimated efficacy, because subjects might be hesitant to comply due to the electrode placement procedure and because the exertion might result in movement of the electrode in their neck. Indeed, two patients did not complete the entire 60 minutes of treatment due to dislodgement of the electrode, and it is possible that in general practice, without dedicated research staff at the patient’s bedside, this number would be much higher. An improved method of securing the electrode could potentially improve this in future trials.

The WOB assessment was added after the study had started. During enrollment of the initial patients into the study, it became apparent that the patients had a wide variety of skill levels using the Piko meter, but that more extensive training than was done during the screening was not compatible with the time frame of this study from presentation to data collection. We therefore added the subjective measure of WOB to assess how patients perceived their respiratory status. In addition, this perception was an aspect of the stimulation voltage (which was adjusted to perceived improvement or the development of symptoms from the electrical stimulation), and it was felt that these data could provide information on the electrode placement procedure.

Finally, there was no comparison (control) group against which to assess the degree of improvement in the two respiratory outcome measures. When combined with the small number of subjects, caution should be exercised in the interpretation of the FEV1 and WOB findings.

Conclusions

Percutaneous vagus nerve stimulation did not result in any serious adverse events in the 25 subjects in this study, although it did result in some minor adverse events related to electrode placement and stimulation. In this feasibility study, vagus nerve stimulation was associated with improvements in FEV1 and perceived work of breathing in patients undergoing treatment for moderate to severe acute asthma exacerbations in the ED who did not respond to initial standard care therapy. Percutaneous vagus nerve stimulation may be feasible for use in the treatment of moderate to severe acute asthma in patients unresponsive to initial standard care treatment, and further investigation in a significantly larger study population is warranted.

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