Percutaneous Neurostimulation to Treat Paroxysmal Sympathetic Hyperactivity in Children

Study Overview
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Brief Summary
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Survivors of severe brain injury, such as lack of oxygen or severe traumatic brain injury, frequently experience Paroxysmal Sympathetic Hyperactivity (PSH). PSH is characterized by disabling symptoms such as a fast heart rate, high blood pressure, rapid breathing, rigidity, tremors, and sweating due to uncontrolled sympathetic hyperactivity in the nervous system. Effective treatment is necessary to decrease secondary brain injury, prevent weight loss from increased metabolic demand and reduce suffering. Currently, a combination of medications to slow down the sympathetic nervous system, muscle relaxants, anti-anxiety drugs, gabapentin, and narcotics are used to treat PSH. The sudden, recurrent attacks of PSH often require repeated rescue medications and multiple drugs with a high risk of side effects. Non-drug treatments for PSH may revolutionize treatment. The novel and non-invasive Percutaneous Electrical Nerve Field Stimulation (PENFS) device is an attractive and potentially effective treatment option for PSH. PENFS, applied to the external ear, has been shown to be effective for conditions such as abdominal pain, narcotic withdrawal, and cyclic vomiting syndrome, all which have similar symptoms to PSH. Therefore, the hypothesis is PENFS could be effective in the treatment of PSH. The electrical current delivered by the PENFS device is thought to increase parasympathetic activity by stimulating a branch of the vagus nerve. PENFS was shown to decrease central sympathetic nervous system activity by 36% within 5 minutes of being placed in the ear of a rat model. Similar central inhibition could improve symptoms of PSH. This pilot study aims to evaluate the feasibility of performing an efficacy trial of PENFS for children with PSH.

Detailed Description
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Paroxysmal sympathetic hyperactivity - incidence, pathophysiology, diagnosis, treatment, prognosis and implications for treatment Paroxysmal sympathetic hyperactivity is frequently seen in survivors of acute severe brain injury (ASBI). It is most commonly associated with severe traumatic brain injury (sTBI) with a reported incidence of 10-20% among survivors of sTBI. Survivors of anoxic brain injury have a higher incidence of PSH (approximately 30%). The pathophysiology of PSH is incompletely understood. Current consensus is that it the result of disconnection between with neuroinhibitory higher centers in the diencephalon and the excitatory pathways in the brainstem and spinal cord (10). PSH is characterized by a constellation of symptoms such as tachycardia, tachypnea, hypertension, hyperthermia, rigidity, tremors, sweating, and pupillary dilation as a result of sympathetic hyperactivity due to the brain injury. Research on PSH has been hampered by lack of a uniform definition and use of various terms such as neurostorming, dysautonomia. Consensus diagnostic criteria and a scoring algorithm (CFS) were developed in 2014 (Table 1a,1b). This tool has 2 components - Clinical Feature Scale to score the severity of symptoms and Diagnosis Likelihood Tool (DLT) that lists the diagnostic features to help with initial diagnosis of PSH (Table 1b). The combined CFS and DLT scores are used to assess the likelihood of PSH (Table 1b). We will use a CFS+DLT cut-off of ≥ 10 to diagnose PSH. PSH increases the risk for secondary brain injury and is associated with worse functional outcomes, longer hospitalization and higher healthcare costs. Appropriate treatment of PSH is important for patient comfort and to prevent secondary brain damage. Currently, PSH is treated using a combination of multiple neurotropic medications (narcotics, benzodiazepines, sympatholytics, gabapentin, muscle relaxants etc.) that can result in complications due to their side effects such as excessive sedation, respiratory depression, drug dependence, and constipation. Some of these medications necessitate ICU stay due to their CNS depressant effects thus potentially increasing healthcare costs. There has been very little research into novel ways of treating PSH other than the use of various neurotropic medications. Measurement of autonomic function - HRV and Pupillometry Autonomic function can be evaluated clinically and is most commonly measured using heart rate variability (HRV). Established standards for measurement of HRV are available. HRV has been studied in various disease states in the intensive care environment such as post-acute MI, sepsis, multi-organ dysfunction, brain injury, and brain death. HRV is decreased or lost in severe disease and has been shown to be associated with increased mortality in the ICU. Higher sympathetic activity in severe disease states is associated with decreased HRV. HRV was shown to be significantly different between children and adults with ASBI and controls. Similarly, pupillary reactivity is also under autonomic control. Recently, pupillometry has also been used to measure autonomic activity. A pupillometer quantitatively measures pupil size (size, minimum size with light stimulus, % change in pupil size) and reactivity (constriction velocity, max constriction velocity, latency, dilation velocity) that can be compared to established norms and trended over time. These parameters have been shown to reflect sympathetic (dilation velocity) and parasympathetic system (% change in pupil size, latency, constriction velocity) activity and sympatho-parasympathetic balance (baseline pupil size). PSH, as the name implies, is associated with uncontrolled paroxysms of sympathetic activity that results in pupillary dilation among other symptoms. It is conceivable that an increase in parasympathetic activity would alter these parameters that could be compared using the patient as his/her own control. PENFS device - description, mechanism of action, and applications The PENFS (auricular neurostimulator) device is a novel, non-pharmacological therapy that has been effectively used for various conditions such as functional abdominal pain, chronic pain, and narcotic withdrawal. Recent data from CW also demonstrates efficacy in a pilot study for children with cyclic vomiting syndrome, with improvement in episode severity and frequency lasting an average 5 months (unpublished data). Cyclic vomiting syndrome (CVS) is a disorder of autonomic imbalance manifested by severe sympathetic hyperactivity. Symptoms of nausea/vomiting, pallor, diaphoresis, and tachycardia are similar to PSH. Many of the symptoms of narcotic withdrawal are also very similar to those of PSH including tachycardia, tachypnea, hypertension, fever, tremors, and sweating. Clonidine, an alpha-2 agonist with sympatholytic properties is commonly used as an adjunct in the treatment of narcotic withdrawal syndrome. Clonidine is also one of the first-line medications used for treatment of PSH. Thus, it is plausible that PENFS could be effective in treatment of PSH. The PENFS device is applied over the external ear and is continuously worn for 120 hours at a time. The electrical current stimulates the auricular branch of the vagus nerve (ABVN) and auricular branches of cranial nerves V, VII and IX. The nerves project to the various parts of the brain, including the brainstem nucleus tractus solitarius. fMRI scans in healthy human volunteers have shown significant activation of the central vagal projections by stimulating ABVN. Sympathoinhibition has been shown to be one of the primary mechanisms of action of the device in the various conditions for which it is used. Electrical stimulation of the tragus has been shown to cause central sympathoinhibition in rats by up to 36% within 5 minutes of stimulation. This central sympathoinhibition by the PENFS device could improve the symptoms of PSH. One of the advantages of PENFS in the treatment of PSH is that it is continuously active while it is worn thus providing symptomatic treatment throughout that period. This could help prevent or ameliorate the paroxysmal symptoms classically seen in PSH and thus reduce the need for rescue medications. The device also has been shown to have a relatively rapid onset of action. A recent study showed that the onset of action was rapid with 63% reduction in narcotic withdrawal score within 20 minutes of activation of the device and 85% reduction within 60 minutes. Thus, PENFS could offer a non-pharmacological tool for managing PSH, helping to decrease the need for maintenance and rescue medications and thus limiting the side effects of some of these medications. Decreased need for neurosedative medications could further decrease the length of ICU stay for these patients thus decreasing healthcare costs. The device is also well-tolerated without any serious adverse effects.

Official Title
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Percutaneous Neurostimulation for Treatment of Paroxysmal Sympathetic Hyperactivity in Children With Acute Severe Brain Injury

Conditions
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Paroxysmal Sympathetic Hyperactivity

Intervention / Treatment
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* Device: Percutaneous Electrical Nerve Field Stimulation (PENFS) device application


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children 2-17 years age with PSH due to ASBI PSH severity score > 6 (moderate severity) Glasgow Coma Scale < 15 Exclusion Criteria: age < 2 years (small ears thus less surface area to apply the leads) ear deformity or severe dermatitis of ear lobes, intractable seizures, heart block, patients with other implantable devices (cardiac pacemaker, vagal nerve stimulator, etc. known pregnancy

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Prospective unblinded pilot study to evaluate the feasibility of use of a peripheral neurostimulator for treatment of paroxysmal sympathetic hyperactivity in children with acute severe brain injury
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Percutaneous Electrical Nerve Field Stimulation (PENFS) device application<br>The peripheral neurostimulator, PENFS device, will be placed over the external ear of enrolled patients. The device will continuously stay in place for 120 hours. | Device: Percutaneous Electrical Nerve Field Stimulation (PENFS) device application<br>* PENFS device will be used to treat children with paroxysmal sympathetic hyperactivity (PSH) due to acute severe brain injury.<br>* Other names: Peripheral neurostimulator;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of children enrolled (Ages 2-17) with acute severe brain injury (ASBI) and Paroxysmal Sympathetic Hyperactivity (PSH) to use the Percutaneous Electrical Nerve Field Stimulation (PENFS) device for treatment | Number of patients enrolled | Up to 192 hours. | 
| Study retention for those children enrolled with acute severe brain injury (ASBI) and Paroxysmal Sympathetic Hyperactivity (PSH) to use the Percutaneous Electrical Nerve Field Stimulation (PENFS) device for treatment | Percentage of patients who complete the study | Up to 192 hours. | 
| Device tolerability for those children enrolled with acute severe brain injury (ASBI) and Paroxysmal Sympathetic Hyperactivity (PSH) to use the Percutaneous Electrical Nerve Field Stimulation (PENFS) device for treatment | Percentage of patients withdrawn due to device intolerability | Up to 192 hours. | 
| Capturing at least 80 percent of scoring events to assess pediatric Paroxysmal Sympathetic Hyperactivity (PSH) symptoms using the Clinical Feature Severity (CFS) scoring tool | The CFS will be administered by trained bedside nurses to capture PSH severity in enrolled patients before, during and after initiation of PENFS device treatment. The CFS is a composite measure of Heart Rate, Respiratory Rate, Systolic Blood Pressure, Temperature, Sweating and Posturing. The Scoring is as follows: 0 Nil; 1-6 Mild; 7-12 Moderate; and >=13 Severe. Percentage of CFS scores collected. | Up to 192 hours. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change from baseline of the Clinical Feature Scale (CFS) measured throughout the study to 192 hours after device placement | The CFS is a composite measure of Heart Rate, Respiratory Rate, Systolic Blood Pressure, Temperature, Sweating and Posturing designed to measure the severity of Paroxysmal Sympathetic Hyperactivity (PSH). The Scoring of PSH is as follows: 0 Nil; 1-6 Mild; 7-12 Moderate; and >=13 Severe. The before and after (192hrs) will be analyzed along with the trend in score over time. | 0 hours before device placement, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours,120 hours-device discontinuation, 132 hours, 144 hours, 156 hours, 168 hours, 180 hours, 192 hours | 
| Measure a change in maintenance and rescue medication use for treatment of PSH | Maintenance medications and the number of doses and type of rescue medications administered will be collected for enrolled patients every 24 hours. These will be compared to a historical cohort of PSH patients (2-17 years old) identified using the ICU Neurology database from January 2018 - August 2021. The association of the CSF score and the number of doses of maintenance and rescue medications will be summarized with a spearman correlation coefficient and exact 95% Confidence intervals (CI). | 0-24hours, 25-48hours, 49-72hours, 73-96hours, 97-120hours | 
| Measure pupil size (mm) to determine the change in autonomic response | The device will be tested to determine if it results in higher parasympathetic activity due to stimulation of the auricular branch of the vagus nerve. This will be assessed by using pupillometry to measure pupil size during the 12-hour period before and after initiation of PENFS therapy. Pupillometry is standard of care for monitoring ASBI patients. Enrolled patients would have pupillometry readings available even prior to initiation of PENFS. | -12 hours (12 hours before placement), Time 12 hours (12 hours after placement) | 
| Measure pupil's constriction velocity (mm/sec) to determine the change in autonomic response | The Percutaneous Electrical Nerve Field Stimulation (PENFS) device will be tested to determine if it results in higher parasympathetic activity due to stimulation of the auricular branch of the vagus nerve. This will be assessed by using pupillometry to measure the constriction velocity during the 12-hour period before and after initiation of PENFS therapy. Pupillometry is standard of care for monitoring ASBI patients. Enrolled patients would have pupillometry readings available even prior to initiation of PENFS. | -12 hours (12 hours before placement), Time 12 hours (12 hours after placement) | 
| Measure the pupil's dilation velocity (mm/sec) to determine the change in autonomic response | The Percutaneous Electrical Nerve Field Stimulation (PENFS) device will be tested to determine if it results in higher parasympathetic activity due to stimulation of the auricular branch of the vagus nerve. This will be assessed by using pupillometry to measure the dilation velocity during the 12-hour period before and after initiation of PENFS therapy. Pupillometry is standard of care for monitoring ASBI patients. Enrolled patients would have pupillometry readings available even prior to initiation of PENFS. | -12 hours (12 hours before placement), Time 12 hours (12 hours after placement) | 
| Measure the change in Heart Rate Variability (HRV) parameter: Standard Deviation of NN Intervals (SDNN) (msec) to determine the change in autonomic response with Percutaneous Electrical Nerve Field Stimulation (PENFS) use | The Percutaneous Electrical Nerve Field Stimulation (PENFS) device will be tested to determine if it results in higher parasympathetic activity due to stimulation of the auricular branch of the vagus nerve. This will be assessed by measuring SDNN as part of evaluation of HRV during the 12-hour period before and after initiation of PENFS therapy. Higher scores are better as evidenced by greater HRV. | -12 hours (12 hours before placement), Time 12 hours (12 hours after placement) | 
| Measure the change in the Heart Rate Variability (HRV) parameter: Root Mean Square of the Successive Differences (RMSSD) to determine the change in autonomic response with the Percutaneous Electrical Nerve Field Stimulation (PENFS) device use | The Percutaneous Electrical Nerve Field Stimulation (PENFS) device will be tested to determine if it results in higher parasympathetic activity due to stimulation of the auricular branch of the vagus nerve. This will be assessed by measuring RMSSD as part of evaluation of HRV during the 12-hour period before and after initiation of PENFS therapy. Higher scores are better as evidenced by greater HRV. | -12 hours (12 hours before placement), Time 12 hours (12 hours after placement) | 
| Measure the change in the Heart Rate Variability (HRV) parameter: Total power (TP) (ms^2) to determine the change in autonomic response with Percutaneous Electrical Nerve Field Stimulation (PENFS) use | The PENFS device will be tested to determine if it results in higher parasympathetic activity due to stimulation of the auricular branch of the vagus nerve. This will be assessed by measuring Total power (TP) as part of evaluation of HRV during the 12-hour period before and after initiation of PENFS therapy. | -12 hours (12 hours before placement), Time 12 hours (12 hours after placement) | 
| Measure the change in the Heart Rate Variability (HRV) parameter: High Frequency (HF) (ms^2) to determine the change in autonomic response with Percutaneous Electrical Nerve Field Stimulation (PENFS) use | The PENFS device will be tested to determine if it results in higher parasympathetic activity due to stimulation of the auricular branch of the vagus nerve. This will be assessed by measuring High Frequency (HF) as part of evaluation of Heart Rate Variability (HRV) during the 12-hour period before and after initiation of PENFS therapy. Higher values are better. | -12 hours (12 hours before placement), Time 12 hours (12 hours after placement) | 
| Measure the change in the Heart Rate Variability (HRV) parameter Low frequency (LF) to determine the change in autonomic response with Percutaneous Electrical Nerve Field Stimulation (PENFS) use | The PENFS device will be tested to determine if it results in higher parasympathetic activity due to stimulation of the auricular branch of the vagus nerve. This will be assessed by measuring Low Frequency (LF) (ms^2) as part of evaluation of HRV during the 12-hour period before and after initiation of PENFS therapy. Higher values are better. | -12 hours (12 hours before placement), Time 12 hours (12 hours after placement) | 
| Measure the change in the Heart Rate Variability (HRV) parameter: Low Frequency: High Frequency (LF:HF) ratio to determine the change in autonomic response with Percutaneous Electrical Nerve Field Stimulation (PENFS) use | The PENFS device will be tested to determine if it results in higher parasympathetic activity due to stimulation of the auricular branch of the vagus nerve. This will be assessed by measuring LF:HF ratio as part of evaluation of HRV during the 12-hour period before and after initiation of PENFS therapy. A higher number indicates increased sympathetic activity or reduced parasympathetic activity. | -12 hours (12 hours before placement), Time 12 hours (12 hours after placement) | 
| Measure the change in the HRV parameter: Mean Heart Rate (Mean HR) (beats per minute/bpm) to determine the change in autonomic response with Percutaneous Electrical Nerve Field Stimulation (PENFS) use | The PENFS device will be tested to determine if it results in higher parasympathetic activity due to stimulation of the auricular branch of the vagus nerve. This will be assessed by measuring the change in (Mean HRT) Mean Heart Rate as part of evaluation of HRV during the 12-hour period before and after initiation of PENFS therapy. Normal HRT is between 60-90 beats per minute. | -12 hours (12 hours before placement), Time 12 hours (12 hours after placement) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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peripheral neurostimulator, pediatric, acute severe brain injury