MicroTransponder 10001001A Implantable Generator User Manual 26 0001 0000 ENG Rev A Serenity Implantable IFU

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Physician’s Manual
®
®
Paired VNS Therapy Serenity System Model 1000
Generator & Model 3000 Lead
For Healthcare Professionals
September 2012
CAUTION - Investigational Device. Limited by Federal (or United States) law to
investigational use.
NOTE: This identifies the parts included in this Physician’s Manual. The information contained in any
one part is not intended to serve as a substitute for a complete and thorough understanding of the
material presented in all of the physician’s manual sections for the Paired VNS Therapy Serenity System
and its component parts, nor does this represent full disclosure of all pertinent information concerning
use of this product, potential safety complications, or efficacy outcomes. Copies of all Paired VNS
Therapy Serenity System manuals must be included for full disclosure; copies are available from
MicroTransponder Inc.
Released Version A
26‐0001‐0000‐ENG © Copyright November 2012 MicroTransponder Inc. Austin, TX all rights reserved.
MicroTransponder, Paired VNS Therapy, Serenity System, are registered trademarks of
MicroTransponder. Inc.
Table of Contents
1. BRIEF DEVICE DESCRIPTION ............................................................ P. 5
1.1. Symbols and Definitions ..................................................................... P. 9
2. INTENDED USE / INDICATIONS ......................................................... P. 10
3. CONTRAINDICATIONS ......................................................................... P. 10
4. WARNINGS ........................................................................................... P. 10
5. PRECAUTIONS ..................................................................................... P. 13
5.1. General ...............................................................................................
5.2. Sterilization, Storage, and Handling ....................................................
5.3. Lead Evaluation and Connection ........................................................
5.4. Environmental and Medical Therapy Hazards ...................................
P. 13
P. 15
P. 15
P. 16
6. DETAILED DEVICE DESCRIPTION ..................................................... P. 19
6.1. Physical Characteristics ...................................................................... P. 19
6.2. Biological Compatibility ....................................................................... P. 19
6.3. Power Source....................................................................................... P. 19
7. DIRECTIONS FOR USE ........................................................................ P. 20
7.1. IPG Specifications and Product Information .......................................
7.2. Lead Specifications and Product Information ......................................
7.3 Operating Characteristics (Communication, Check Status, etc.) .........
7.4 IPG Replacement .................................................................................
7.5 Lead Lifetime and Replacement .........................................................
7.6 Signs of End of Life ..............................................................................
7.7. Replacement Based on Battery Status Indicators ..............................
P. 20
P. 22
P. 23
P. 27
P. 27
P. 27
P. 28
8. TROUBLESHOOTING ............................................................................ P. 28
9. SAFETY INFORMATION (from VNS Studies of Depression) ................ P. 29
9.1 Device Performance..............................................................................
9.2 Adverse Events .....................................................................................
9.3 Serious Adverse Events ........................................................................
9.4 Safety Considerations specific to depressed patients ..........................
9.5 AE Relationship to VNS Therapy and Duration of Events ....................
9.6 Severity .................................................................................................
9.7 VNS Therapy Continuation Rates .........................................................
P. 29
P. 29
P. 30
P. 32
P. 33
P. 34
P. 34
10.0 EPILEPSY SAFETY INFORMATION ................................................. P. 34
10.1 Device Performance............................................................................ P. 34
10.2 Adverse Events Observed in Studies ................................................. P. 34
10.3 Potential AEs....................................................................................... P. 36
11. BIBLIOGRAPHY ................................................................................... P. 37
12. GUIDELINES FOR PATIENT FOLLOW UP ......................................... P. 37
13. PATIENT COUNSELING INFORMATION ........................................... P. 38
14. MECHANISM OF ACTION .................................................................. P. 38
15. PHYSICIAN TRAINING/INFORMATION .............................................. P. 39
16. PAIRED VNS THERAPY SERENITY SYSTEM DEVICES .................. P. 39
2|Page
16.1 IPG Package Contents .......................................................................
16.2 Lead Package Contents .....................................................................
16.3 Other MicroTransponder Products .....................................................
16.4 Surgical Materials ...............................................................................
16.5 Open Package ...................................................................................
P. 39
P. 40
P. 40
P. 40
P. 40
17. RECOMMENDATIONS FOR IMPLANTATION .................................... P. 41
17.1. Check the Device and Input Patient Data ..........................................
17.2 Procedure Overview............................................................................
17.3 Prepare for Surgery.............................................................................
17.4 Lead and Pocket Location ..................................................................
17.5 Begin the Procedure ...........................................................................
17.6 Implant the Lead .................................................................................
17.7 Make a Tunnel and Pass the Lead .....................................................
17.8 Place the Electrodes ...........................................................................
17.9 Connect the Leads ..............................................................................
17.10 Test the Serenity System ..................................................................
P. 41
P. 42
P. 42
P. 43
P. 43
P. 44
P. 44
P. 45
P. 52
P. 55
18. INFORMATION AND SUPPORT .......................................................... P. 55
19. GLOSSARY .......................................................................................... P. 57
3|Page
List of Figures & Tables
Figure 1.1 – Device Placement and Treatment Set-up . . . . . . . .
P. 6
Figure 1.2 – Implantable Pulse Generator (IPG). . . . . . . . . . . . . .
P. 7
Figure 1.3 – Programming Interface . . . . . . . . . . . . . . . . . . . . . . .
P. 8
Figure 6.1 – X-Ray Identification . . . . . . . . . . . . . . . . . . . . . . . . . .
P. 20
Table 7.1 – Characteristics of Single Use IPG . . . . . . . . . . . . . . . .
P. 21
Table 7.2 – IPG Electrical Characteristics . . . . . . . . . . . . . . . . . . .
P. 21
Figure 7.1 – VNS Lead . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
P. 22
Table 7.3 – Characteristics of VNS Lead . . . . . . . . . . . . . . . . . . . . .
P.23
Figure 7.2 – Stimulation Waveform . . . . . . . . . . . . . . . . . . . . . .
P. 25
Table 9.1 – D-02 Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . .
P. 29
Table 9.2 – Serious Adverse Events . . . . . . . . . . . . . . . . . . .
P. 31
Table 10.1 – Epilepsy Study AEs . . . . . . . . . . . . . . . . . . . . . . . . . .
P. 36
Figures 17.1 – Placement of IPG and Lead . . . . . . . . . . . . . . . . . . . .
P.43
Figure 17.2 – Electrode Placement . . . . . . . . . . . . . . . . . . . . . . . . .
P. 44
Figure 17.3 – Position of Tube and Lead Connector . . . . . . . . . . .
P. 45
Figure 17.4 – VN Anatomy and Placement of Lead . . . . . . . . . . . .
P. 46
Figure 17.5 – Electrode Polarity . . . . . . . . . . . . . . . . . . . . . . . . . . . .
P. 47
Figure 17.6 – Spread the Helical Electrode . . . . . . . . . . . . . . . . . . .
P. 48
Figure 17.7 – Turn the Helical Electrode . . . . . . . . . . . . . . . . . . . . . .
P. 48
Figure 17.8 – Placement of the Turn . . . . . . . . . . . . . . . . . . . . . .
P. 48
Figure 17.9 – Starting to Wrap the Electrode . . . . . . . . . . . . . . . .
P. 49
Figure 17.10 – Partial Wrap of the Electrode around the Nerve . . . . .
P. 49
Figure 17.11 – Placement of the Proximal Portion of the Helical Electrode P. 49
Figure 17.12 – Placement of Electrodes and Anchor Tether . . . . . . . .
P. 50
Figure 17.13 – Use of Tie-Downs in Electrode Placement . . . . . . . . . .
P. 51
Figure 17.14 – Strain Relief Loop . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . P. 52
Figure 17.15 – IPG receptacle and Setscrew . . . . . . . . . . . . . . . . . . . . .
P. 52
Figure 17.16 – Hex Screwdriver Position . . . . . . . . . . . . . . . . . . . . . . . .
P. 53
Figure 17.17 – Lead Insertion . . . . . . . . . . . . . . . . . . . . . . . .
P. 54
4|Page
1. BRIEF DEVICE DESCRIPTION
The Paired VNS Therapy Serenity System is an active implantable device that is
comprised of four main components: (1) an Implantable Pulse Generator (IPG), (2) an
implantable lead, (3) Tinnitus Application & Programming software (TAPS), and (4) a
Wireless Transmitter (WT, a communication and trigger system). The IPG and lead
comprise the implantable components; the TAPS and WT comprise the non-implantable
components.
The Paired VNS Therapy Serenity System, when used as intended, provides a drugfree way to treat chronic tinnitus by pairing tone therapy with Vagus Nerve Stimulation
(VNS). The lead electrodes are attached to the left vagus nerve in the neck. The lead
is tunneled from the neck to the pectoral region, where it is connected to the IPG, and
the IPG is surgically placed subcutaneously (or sub-muscularly) in the pectoral region.
The Tinnitus Application & Programming Software (TAPS), via the Wireless
Transmitter,, allows the physician to program the output settings of the IPG, including
amplitude, frequency, and pulse width, to stimulate the vagus nerve while
simultaneously providing tones through a laptop and headphones to the patient’s ears.
Once the physician and site personnel have set the system settings and verified
operation, the patient will be trained in proper use of the device to initiate daily
stimulation at their own home.
The complete device system, called the Serenity
System, is shown in Figure 1.1. The IPG is seen in figure 1.2.
5|Page
Figure 1.1
(A) Device Placement, (B) In-Office Set-up, and (C) Home Set-up
A.
B.
C.
6|Page
Figure 1.2
Implantable Pulse Generator (IPG)
The IPG and Lead are described in detail throughout this manual. The Wireless
Transmitter and TAPS are described in further detail in the Paired VNS Therapy
Serenity Non-Implantable Physician’s Manual. However, since an understanding of the
complete system is helpful for understanding the implantable components, the Wireless
Transmitter and TAPS are summarized further below.
Wireless Transmitter (WT)
The WT has a cable with a USB connector that plugs into the laptop and converts the
information from TAPS into a radio-frequency (RF) signal that is transmitted to the IPG.
The WT converts the digital signals from the computer and software into RF signals that
can be transmitted through the air and skin to the device and also receives RF signals
back from the IPG. The IPG then translates the signal and acts on the commands given
to it from TAPS. The WT will have a cable of at least 6 feet long and will communicate
with the device at up to 1 meter from the WT. It is powered via the USB connection and
does not require any additional power source, such as battery, or additional power
connection. The WT is shown in Figure 1.3.
7|Page
Figure 1.3
Wireless Transmitter
Tinnitus Application & Programming Software (TAPS)
The TAPS allows the physician to control the tone frequencies, amplitude and relative
timing of the tones to the stimulation, in addition to setting the IPG stimulation
parameters. The TAPS also stores the therapy history. The TAPS (loaded and tested
on a provided laptop), headphones, and WT will be taken home by the patient, so that
therapy can be continued at home. When taken home, most features of the software
shall be locked out so that the patient cannot change the stimulation parameters or tone
therapy, but only initiate a therapy session. The TAPS system also allows the status of
the IPG to be checked for battery level, lead impedance, etc.
8|Page
1.1. Symbols and Definitions
This physician’s manual and accompanying device labeling use these symbols and
definitions:
Notice for reader to pay special attention to details that follow
SN
Serial Number
Use by / Expiration Date (last day of indicated month)
Single Use Only / Do Not Reuse
Date of Manufacture
+XXX °F -XX °C -XX °F
Storage Temperature
Contents Sterilized by Ethylene Oxide
No MRI
Consult Instructions for Use Sidebar Note (cross-references and
other useful information)
Non-Pyrogenic
RX Only Prescription Statement Symbol – US Federal law restricts
this device to sale or use by or on the order of a physician.
9|Page
2.0 INTENDED USE / INDICATION
The MicroTransponder Paired VNS Therapy Serenity System is intended to be used to
simultaneously stimulate the vagus nerve and provide tones to the ears in order to
reduce or eliminate a patient’s perception of tinnitus (ringing in the ears).
3.0 CONTRAINDICATIONS
•
Vagotomy—The Paired VNS Therapy Serenity System cannot be used in patients after
a bilateral or left cervical vagotomy.
•
Diathermy—Do not use shortwave diathermy, microwave diathermy, or therapeutic
ultrasound diathermy (hereafter referred to as diathermy) on patients implanted with a Paired
VNS Therapy Serenity System. Diagnostic ultrasound is not included in this contraindication.
Energy delivered by diathermy may be concentrated into or reflected by implanted products
such as the Paired VNS Therapy Serenity System. This concentration or reflection of
energy may cause heating.
Heating of the Paired VNS Therapy Serenity System resulting from diathermy could cause
temporary or permanent nerve, tissue, or vascular damage. This damage may result in pain
or discomfort, loss of vocal cord function, or even possibly death if there is damage to blood
vessels.
Because diathermy can concentrate or reflect its energy off any size implanted object, the
hazard of heating is possible when any portion of the Paired VNS Therapy Serenity System
remains implanted, including just a small portion of the Lead or electrode. Injury or damage
can occur during diathermy treatment whether the Paired VNS Therapy Serenity System is
turned “ON” or “OFF.”
Diathermy is further prohibited because it may also damage the Paired VNS Therapy
Serenity System components resulting in loss of therapy, requiring additional surgery for
system explantation and replacement. All risks associated with surgery or loss of therapy
would then be applicable.
Advise patients to inform all healthcare professionals that they should not be exposed to
diathermy treatment.
4.0 WARNINGS
Physicians should inform patients about all potential risks and adverse events discussed in
this physician’s manual.
•
Use—The Paired VNS Therapy Serenity System should only be prescribed and
monitored by physicians who have specific training and expertise in the management of tinnitus
and the use of this device. The System should only be implanted by physicians who are trained
10 | P a g e
in surgery of the carotid sheath and have received specific training in the implantation of this
device.
•
Not curative—Physicians should warn patients that the Paired VNS Therapy Serenity
System has not been determined to be a cure for tinnitus. Patients should be counseled to
understand that individual results will likely vary. Beneficial results might not become evident for
months or may never occur.
•
Unapproved uses—The safety and efficacy of the Paired VNS Therapy Serenity
System have not been established for uses outside the “Intended Use / Indications” section of
this physician’s manual, including (but not limited to) patients with:
•
Acute suicidal thinking or behavior
•
History of schizophrenia, schizoaffective disorder or delusional disorders
•
History of rapid cycling bipolar disorder
•
History of previous therapeutic brain surgery or CNS injury
•
Progressive neurological diseases other than tinnitus
•
Cardiac arrhythmias or other abnormalities
•
History of dysautonomias
•
History of respiratory diseases or disorders, including dyspnea and asthma
•
History of ulcers (gastric, duodenal, or other)
•
History of vasovagal syncope
•
Only one vagus nerve
•
Other concurrent forms of brain stimulation
•
Pre-existing hoarseness
•
Under 18 years of age
•
Worsening depression/suicidality—Patients being treated with adjunctive Paired VNS
Therapy who have moderate or severe depression should be observed closely for clinical
worsening and suicidality, especially at the time of Paired VNS Therapy stimulation parameter
changes or drug or drug dose changes, including either increases or decreases in the
stimulation parameters or concomitant treatments. Consideration should be given to changing
the therapeutic regimen of Paired VNS Therapy or concomitant treatments, including possibly
discontinuing Paired VNS Therapy or the concomitant therapy, in patients whose depression is
persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of
the patient’s presenting symptoms.
•
Dysfunctional cardiac conduction systems—The safety and effectiveness of the
Paired VNS Therapy Serenity System in patients with predisposed dysfunction of cardiac
conduction systems (re-entry pathway) have not been established. Evaluation by a cardiologist
is recommended if the family history, patient history, or electrocardiogram suggests an
11 | P a g e
abnormal cardiac conduction pathway. Serum electrolytes, magnesium, and calcium should be
documented before implantation. Additionally, postoperative bradycardia can occur among
patients with certain underlying cardiac arrhythmias. Post-implant electrocardiograms and holter
monitoring are recommended if clinically indicated.
It is important to follow recommended implantation procedures and intraoperative
product testing described in the Implantation Procedure part of this manual. During
intraoperative Lead Impedance Diagnostics of the Cyberonics VNS Therapy System,
infrequent incidents of bradycardia and/or asystole have occurred. Although these events
have not occurred during implantation of the MicroTransponder paired VNS Therapy Serenity
System, they are events that could possibly occur. If asystole, severe bradycardia (heart rate
< 40 bpm), or a clinically significant change in heart rate is encountered during a Lead
Impedance Check or during initiation of stimulation, physicians should be prepared to follow
guidelines consistent with Advanced Cardiac Life Support (ACLS).
Additionally, postoperative bradycardia can theoretically occur among patients with
certain underlying cardiac arrhythmias (although none have been reported with the Paired VNS
Therapy Serenity System). If a patient has experienced asystole, severe bradycardia (heart rate
< 40 bpm), or a clinically significant change in heart rate during a Lead Impedance Check at the
time of initial device implantation, the patient should be placed on a cardiac monitor during
initiation of stimulation.
The safety of this therapy has not been systematically established for patients
experiencing bradycardia or asystole during Paired VNS Therapy Serenity System
implantation.
•
Swallowing difficulties—Difficulty swallowing (dysphagia) may occur with active
stimulation, and aspiration may result from the increased swallowing difficulties. Patients with
pre-existing swallowing difficulties are at greater risk for aspiration. Appropriate aspiration
precautions should be taken for such patients.
•
Dyspnea or shortness of breath—Dyspnea (shortness of breath) may occur with
active Paired VNS Therapy. Any patient with underlying pulmonary disease or insufficiency,
such as chronic obstructive pulmonary disease or asthma, may be at increased risk for dyspnea
and should have their respiratory status evaluated prior to implantation and monitored following
initiation of stimulation.
•
Obstructive sleep apnea—Patients with obstructive sleep apnea (OSA) may have an
increase in apneic events during stimulation. Lowering stimulus frequency or prolonging “OFF”
time may prevent exacerbation of OSA. Vagus nerve stimulation may also cause new onset
sleep apnea in patients who have not previously been diagnosed with this disorder. It is
recommended that patients being considered for Paired VNS Therapy who demonstrate signs
or symptoms of OSA, or who are at increased risk for developing OSA, should undergo the
appropriate evaluation(s) prior to implantation.
None of the above three items (swallowing difficulties, dyspnea, obstructive sleep apnea)
should be issues for the Paired VNS Therapy Serenity System, since stimulation sessions only
occur for 2.5 hours while the patient is awake and for shorter periods (1/2 second vs. 30
seconds). However, this information is included for completeness since it is reported in
unpaired VNS Therapy use.
12 | P a g e
•
Device malfunction—Device malfunction could cause painful stimulation or direct
current stimulation. Either event could cause nerve damage and other associated problems.
Patients should be instructed to use the Magnet to stop stimulation if they suspect a
malfunction, and then to contact their physician immediately for further evaluation. Prompt
surgical intervention may be required if a malfunction occurs.
•
Magnetic resonance imaging (MRI)—Patients with the Paired VNS Therapy Serenity
System, or any part of the implanted Paired VNS Therapy Serenity System, should not have
MRI procedures performed. No testing has yet been completed on MRI compatibility of the
Paired VNS Therapy Serenity System. Therefore the Serenity System should be completely
explanted or removed prior to MRI being performed.
•
Excessive stimulation—Excessive stimulation at an excess duty cycle (when “ON” time
is greater than “OFF” time) has resulted in degenerative nerve damage in laboratory animals.
•
Device manipulation—Patients who manipulate the IPG and Lead through the skin
(Twiddler’s Syndrome) may damage or disconnect the Lead from the IPG and/or possibly cause
damage to the vagus nerve. Patients should be warned against manipulating the IPG and Lead.
Note: See the “Physician Training/ Information” section of the Implantation Procedure part of this
physician’s manual.
5.0 PRECAUTIONS
Physicians should inform patients about all potential risks and adverse events discussed in this
physician’s manual.
5.1 General
• Appropriate physician training is very important. Prescribing physicians should be
experienced in the diagnosis and treatment of tinnitus and should be familiar with the
programming and use of the Paired VNS Therapy Serenity System.
• Physicians who implant the Paired VNS Therapy Serenity System should be
experienced performing surgery in the carotid sheath and should be trained in the surgical
technique relating to implantation of the Paired VNS Therapy Serenity System.
• Use during pregnancy—The safety and effectiveness of the Paired VNS Therapy
Serenity System have not been established for use during pregnancy. There are no
adequate and well-controlled studies of Paired VNS Therapy in pregnant women.
• The Paired VNS Therapy Serenity System is indicated for use only in stimulating the left
vagus nerve in the neck area inside the carotid sheath. The Paired VNS Therapy Serenity
System is indicated for use only in stimulating the left vagus nerve below where the
superior and inferior cervical cardiac branches separate from the vagus nerve. The
safety and efficacy of the Paired VNS Therapy Serenity System have not been established
for stimulation of the right vagus nerve or of any other nerve, muscle, or tissue.
• It is important to follow infection control procedures. Infections related to any implanted
device are difficult to treat and may require that the device be explanted. The patient should
be given antibiotics preoperatively. The surgeon should ensure that all instruments are
sterile prior to the operation.
Frequent irrigation of both incision sites with generous amounts of bacitracin or equivalent
13 | P a g e
solution should be performed prior to closure. To minimize scarring, these incisions should
be closed with cosmetic closure techniques. Also, antibiotics should be administered
postoperatively at the discretion of the physician.
• Effects on other medical devices—The Paired VNS Therapy Serenity System has not
been tested with and may affect the operation of other implanted devices, such as cardiac
pacemakers and implanted defibrillators. Possible effects include, but are not limited to,
sensing problems and inappropriate device responses.
• Reversal of Lead polarity has been associated with an increased chance of
bradycardia in animal studies of unpaired VNS. It is important that the electrodes are
attached to the left vagus nerve in the correct orientation.
• The patient can use a neck brace for the first week to help ensure proper Lead
stabilization.
•
A reset of the device will program the device OFF (output current = 0.0 mA).
When an IPG is reset, its stimulation output is disabled (0.0mA); however, all settings and
device history are preserved. After a successful reset, the IPG stimulation output may be reenabled to resume operation at the previously programmed settings.
Note: For more information on diagnostic testing, see the “Troubleshooting” section.
• Laryngeal irritation may result from stimulation. Patients who smoke may have an
increased risk of laryngeal irritation.
• Potential effects of Lead breaks—Lead fractures may prevent patients from receiving
therapy. If a Lead fracture is suspected, perform diagnostic testing to evaluate continuity
within the system. If diagnostics suggest that a fracture is present, consider turning the
Serenity IPG to zero milliamps (0 mA) of output current. Continuing stimulation with a
fractured Lead may result in dissolution of the conductor material resulting in adverse
events, such as pain, inflammation, and vocal cord dysfunction. The benefits and risks of
leaving the Serenity IPG ON (actively stimulating) when a Lead fracture is present should be
evaluated and monitored by the medical professional treating the patient.
• Some complications may be associated with damage to the vagus nerve.
• Hoarseness may be caused by device malfunction, nerve constriction, or nerve fatigue.
Nerve constriction should be apparent within a few days after implantation and may require
explantation of the Lead. Nerve fatigue usually occurs after intense stimulation parameters
have been used, and might not be associated with any other adverse event. If fatigue is
suspected, the Serenity IPG should be turned OFF for several days until hoarseness
subsides.
• Persistent hoarseness not associated with stimulation suggests possible nerve irritation
and should be immediately investigated.
Trauma to the vagus nerve at the implantation site could result in permanent vocal cord
dysfunction.
5.2 Sterilization, Storage, and Handling
14 | P a g e
The IPG and Lead have been sterilized using ethylene oxide (EO) gas, and are supplied in a
sterile package to permit direct introduction into the operating field. An expiration (or use-before)
date is marked on each package. A sterilization process indicator is included in each package.
Products labeled as sterile should be used only if the color of the indicator is green or brown.
The implantable portions of the Paired VNS Therapy Serenity System are nonpyrogenic.
• Store the Paired VNS Therapy Serenity System between -20°C (-4°F) and +55°C
(+131°F). Temperatures outside this range can damage components.
• Do not store the Paired VNS Therapy Serenity System where it is exposed to water
or other liquids. Moisture can damage the seal integrity of the package materials.
• Do not implant a device if any of the following has occurred:
ƒ The device has been dropped, because dropping it could damage IPG components.
ƒ
The color of the sterilization process indicator within the inner package is not green
or brown for product sterilized by EO.
ƒ
The outer or inner storage package has been pierced or altered, because this could
have rendered it non-sterile.
The expiration (use-before) date has expired, because this can adversely affect the
device’s longevity and sterility.
Do not ultrasonically clean the IPG, because doing so may damage IPG components.
ƒ
•
• Do not re-sterilize any Paired VNS Therapy Serenity System product. Return any
opened devices to MicroTransponder.
The IPG and Lead are single-use-only devices. Do not re-implant an explanted IPG or Lead
for any reason, because sterility, functionality, and reliability cannot be ensured, and infections
may occur.
Note: See the exterior package label to ascertain the method of sterilization, which is indicated
by the EO sterility symbol (see “Symbols and Definitions” section of this manual).
Note: See the “Other environmental hazards” section of this manual.
Explanted IPGs and Leads should be returned to MicroTransponder for examination and
proper disposal. Before returning the IPG or Lead, disinfect the device components with
®
®
Betadine , Cidex soak, or other similar disinfectant, and double-seal them in a pouch or
other container properly labeled with a biohazard warning.
Do not incinerate the IPG; it contains a sealed chemical battery, and an explosion could result.
5.3. Lead Evaluation and Connection
• Do not use a lead other than the MicroTransponder Model 3000 Lead with the Serenity
IPG because such use may damage the IPG or injure the patient.
• Exercise extreme caution if testing the Lead using line-powered equipment because
leakage current can injure the patient.
15 | P a g e
• Do not insert a Lead in the IPG Lead receptacle(s) without first visually verifying that
the setscrew(s) is sufficiently retracted to allow insertion. Avoid backing the setscrew(s)
out further than needed for Lead insertion.
• To avoid damaging (stripping) the setscrew(s) and/or dislodging the setscrew plug(s),
insert the hex screwdriver into the center of the setscrew plug, keeping it perpendicular to
the IPG.
• Inserting the hex screwdriver into the septum can aid in relieving a vacuum that may be
created during lead insertion or withdrawal.
5.4. Environmental and Medical Therapy Hazards
Patients should exercise reasonable caution in avoiding devices that generate a strong electric
or magnetic field. If an IPG ceases operation while in the presence of electromagnetic
interference (EMI), moving away from the source may allow it to return to its normal mode of
operation.
5.4.1. Hospital and medical environments
Paired VNS Therapy Serenity System operation should always be checked by performing
device diagnostics after any of the procedures mentioned in this manual. Additional precautions
for these procedures are described below.
• For clear imaging, patients may need to be specially positioned for mammography
procedures because of the location of the IPG in the chest. (Most routine diagnostic
procedures, such as fluoroscopy and radiography, are not expected to affect system
operation.)
• Therapeutic radiation may damage the IPG’s circuitry, although no testing has been
done to date and no definite information on radiation effects is available. Sources of such
radiation include therapeutic radiation, cobalt machines, and linear accelerators. The
radiation effect is cumulative, with the total dosage determining the extent of damage. The
effects of exposure to such radiation can range from a temporary disturbance to permanent
damage, and may not be detectable immediately.
• External defibrillation may damage the IPG. Attempt to minimize current flowing
through the IPG and Lead system by following these precautions:
•
Position defibrillation paddles perpendicular to the IPG and Lead system and as
far from the IPG as possible.
•
Use the lowest clinically appropriate energy output (watt-seconds).
•
Confirm IPG function after any internal or external defibrillation.
•
Use of electrosurgery [electrocautery or radio frequency (RF) ablation devices] may
damage the IPG. During the VNS implantation procedure, do not use electrosurgical equipment
after the IPG has been introduced to the sterile field. When performing other surgical
procedures on a patient implanted with a Serenity IPG, attempt to minimize the current flowing
through the IPG and Lead system by following these precautions:
16 | P a g e
•
Position the electrosurgery electrodes as far as possible from the IPG and Lead.
•
Avoid electrode placement that puts the IPG or Lead in the direct path of current
flow or within the part of the body being treated.
•
Confirm that the IPG functions as programmed after electrosurgery.
• Electrostatic Discharge (ESD) may damage the IPG. Care should be taken when using
the hex screwdriver to avoid touching the metal shaft when the screwdriver is engaged with
the setscrew of the IPG. This shaft can serve as a path to conduct electrostatic discharges
into the device circuitry.
Caution: The patient should seek medical advice before entering environments that are
protected by a warning notice preventing entry by patients implanted with a cardiac pacemaker
or defibrillator.
• Extracorporeal shockwave lithotripsy may damage the IPG. If therapeutic ultrasound
is required, avoid positioning the area of the body where the IPG is implanted in the water
bath or in any other position that would expose it to ultrasound therapy. If that positioning
cannot be avoided, program the IPG output to 0 mA for the treatment, and then after
therapy, reprogram the IPG to the original parameters.
• If the patient receives medical treatment for which electric current is passed through the
body (such as from a TENS unit), either the IPG output should be set to 0 mA or function of
the IPG should be monitored during initial stages of treatment.
• Therapeutic ultrasound. Routine therapeutic ultrasound could damage the IPG and
may be inadvertently concentrated by the device, causing harm to the patient.
Magnetic resonance imaging (MRI) should not be performed.
Patients with an implanted device should not be exposed to the electromagnetic fields produced
by magnetic resonance imaging (MRI). Use of MRI may potentially result in system failure or
dislodgment, heating, or induced voltages in the IPG and/or lead. An induced voltage through
the IPG or lead may cause uncomfortable, “jolting” or “shocking,” levels of stimulation.
5.4.2. Home occupational environments
Properly operating microwave ovens, electrical ignition systems, power transmission lines, theftprevention devices, and metal detectors are not expected to affect the IPG. Similarly, most
routine diagnostic procedures, such as fluoroscopy and radiography, are not expected to affect
system operation. However, because of their higher energy levels, sources such as transmitting
antennas may interfere with the Paired VNS Therapy Serenity System. It is suggested that the
IPG be moved away from equipment—typically at least 1.8 meters (6 feet)—that may be
causing interference.
5.4.3. Cellular phones
Cellular phones should have no effect on IPG operation. Unlike an implanted pacemaker or
17 | P a g e
defibrillator, the IPG does not sense physiologic signals.
5.4.4. Other environmental hazards
Strong magnets, hair clippers, vibrators, loudspeaker magnets, Electronic Article Surveillance
(EAS) System tag deactivators, and other similar electrical or electro-mechanical devices, which
may have a strong static or pulsing magnetic field, can cause accidental closure of the reed
switch. Patients should be cautioned to keep such devices away from the IPG, typically at least
15 centimeters (6 inches) away.
5.4.5. Programming Software
The IPG can be programmed using TAPS. This software should be used on the provided laptop
or computer dedicated only to programming the Paired VNS Therapy Serenity System.
5.4.6. Implantable Pulse Generator (IPG) and EMI effects on other devices
The IPG should be moved—typically at least 1.8 meters (6 feet)—away from equipment with
which it may be interfering.
Programming or interrogating the IPG may momentarily interfere with other sensitive
electronic equipment nearby. The IPG is not expected to trigger airport metal detectors or
theft-protection devices that are further than about 1.8 meters (6 feet).
The IPG may affect the operation of other implanted devices, such as cardiac
pacemakers and implantable defibrillators. Possible effects include sensing problems and
inappropriate IPG responses.
The Magnet provided for activation or inhibition of the IPG may damage televisions, computer
disks, credit cards, and other items affected by strong magnetic fields.
5.4.8. Implantable Pulse Generator (IPG) disposal
• Do not incinerate the IPG, because it can explode if subjected to incineration or
cremation temperatures.
•
Return all explanted IPGs to MicroTransponder for examination and safe disposal.
• Do not implant an explanted IPG in another patient, because sterility, functionality, and
reliability cannot be ensured.
18 | P a g e
6.0 DETAILED DEVICE DESCRIPTION
6.1. Physical Characteristics
®
®
The titanium case of the Paired VNS Therapy Serenity System Model 1000 IPG is
hermetically sealed and leak-rate tested. Specially designed feedthroughs using platinum
conductors form the electrical connection from the connector blocks to the circuitry through the
hermetically sealed enclosure. The Model 1000 IPG accepts the single-pin Model 3000 Lead.
6.2. Biological Compatibility
Materials exposed to the subcutaneous environment are biologically compatible. All of these
materials have a long history in medical implants and have been found to be tissue compatible.
6.3. Power Source
The power source for the Model 1000 IPG is a Wilson Greatbatch Ltd, Model WG 9086, Li CfX Lithium / Carbon Monofluoride with an open-circuit voltage of 3.3V. The battery’s maximum
available capacity is approximately 2.5 Amp-hours. The voltage in this battery gradually
decreases as the battery nears its end of life (EOL).
The IPG can be identified on an x-ray film and will appear as shown in Figure 6.1. The serial
number and model number of the IPG are marked on its titanium case, but do not appear on the
x-ray film. The serial number and model number can be identified by interrogating the IPG with
the Programming Software.
19 | P a g e
Figure 6.1
X-Ray IPG identification
The radiograph in Figure 6.1 shows a Model 1000 IPG (and the provided screwdriver to the left). The
x-ray tag included uses the code MTI12, in which:
•
MTI = MicroTransponder Model 1000
•
12 = The year of manufacture
7. DIRECTIONS FOR USE
7.1. IPG Specifications and Product Information
The Paired VNS Therapy Serenity System IPG is a neurostimulator device similar to other
implanted neurostimulators such as the Cyberonics’ NeuroCybernetic Prosthesis or the
Medtronic’s DBS System. The IPG has a metal Titanium case or “can” that is hermitically
sealed and houses the electrical components of the device; a polyurethane header is attached
to the can and has feedthrough connectors that pass the electrical signal from inside the can to
the external lead connectors, while at the same time isolating the can from the stimulation
electrodes and providing EMI filtering.
The IPG also has an internal battery (primary cell – Li/CFx, Lithium/Carbon MonoFluoride) that
provides power to the electrical components. The IPG is programmable by the physician, and
provides stimulation at amplitudes of up to 3.5 mA, frequencies up to 30 Hz., pulse widths up to
1000 uSec, and stimulation durations of up to one minute. The device characteristics for the
20 | P a g e
Paired VNS Therapy System Serenity IPGs are presented in Table 7.1 and the full range of
settings is described in Table 7.2.
The IPG has been designed to accept the Cyberonics Model 304 Perennia lead
Table 7.1: Characteristics of the Single Use IPG
Size
Shape
Weight
Power Source
Housing (Can)
Header Material
48 mm wide x 62 mm tall x 11.5 mm thick
Rectangular with radius >= 2mm and no sharp
corners/edges
70 g
WG 9086, Li CfX - Lithium / Carbon
Monofluoride
Titanium
Epoxy Resin
Table 7.2: IPG: Electrical Characteristics
Parameter
Output Current
Frequency
Pulse Width
Range / Tolerance
0 to 3.5 mA in 0.1 mA steps; (+/- 0.1 mA <= 1
mA, +/-10% > 1 mA tolerance), with a
maximum 12 volts
1 to 30 Hz, with the following steps
(1,2,5,10,15,20,25,30); +/-1% tolerance
10 µs to 1000 µs with the following steps (10
us steps from 10 to 100, 25 µs steps from 100
to 500 µs, and 50 µs steps from 500 to 1000
µs) (+/- 2µS or 1% tolerance, whichever is
greater)
Duration
0.5 seconds to 60 seconds, in 1 seconds
steps, starting at 1 sec (e.g. 0.5, 1, 2, 3, etc.)
(+/- 1% tolerance)
Identification
factory-only programmed Model Number and
Unique Serial number that can be retrieved via
the RF communications, X-RAY ID tag (MTI)
Lead Measure
report the lead impedance from 250 Ohms to
10 K ohms with 20% accuracy
Output
Bipolar output; electrically floating can with at
least 10M ohm DC impedance to either + or –.
Upgradability
IPG firmware shall be wirelessly upgradeable
21 | P a g e
Note: See the Paired VNS Therapy Serenity Non-Implantable Physician’s Manual for more
information on TAPS, including a list of the requirements for the laptop to be used with this software.
* Latex is not included in any component of the Paired VNS Therapy Serenity System.
7.2 Lead Specifications and Product Information
The Lead is similar to other vagus nerve leads such as the Cyberonics Model 304. The Lead
delivers the electrical signal from the Serenity IPG to the vagus nerve, is insulated with silicone
and is bifurcated at the nerve end to provide bipolar stimulation. It has two helical electrodes
(nerve cuffs) and an anchor tether, which are coiled around the left vagus nerve. The connector
end of the Lead is tunneled subcutaneously to the IPG pocket. The lead is available in both a
43 cm and 85 cm length. The lead length and serial number are indicated on the tag inside the
connector of the lead.
The lead and identification tag are shown below in Figure 7.1 A, B and C; Table 7.3 shows lead
characteristics.
Figure 7.1
A. VNS Lead
B. Close-up of both ends
C. Lead Identification Tag
22 | P a g e
Cuff Diameter
(mm)
Lead Length
(cm)
Serial Number
23 | P a g e
Table 7.3: Characteristics of VNS Lead
Total Length
Outer Material (insulation)
Lead body diameter
Conductor coil
Connector – Outer Material
Connector - Connector Pin
Connector - Connector Ring
Resistance
Helical Cuff material
Helical Coil Separation
Cuff Diameter
43 cm or 86 cm
Silicone
2 mm
MP-35N Alloy, quadfilar
Silicone
300 series stainless steel; 1.6 mm diameter
300 series stainless steel; 2.67 mm diameter
< 200 Ohms (43 cm), < 400 Ohms (86 cm)
Pt/Ir alloy and silicone
8 mm center to center
2 mm
Tie Downs
Four silicone tie downs
7.3. Operating Characteristics
7.3.1. Communicating with the Paired VNS Therapy Serenity System
7.3.1.1. TAPS
The IPG can be programmed with the Paired VNS Therapy System Serenity TAPS
Software.
TAPS is used on a computer supplied by MicroTransponder that is dedicated only to
programming the Paired VNS Therapy Serenity System. More information on TAPS can be
found in the Paired VNS Therapy System Serenity Non-Implantable Physician’s Manual.
7.3.1.2. Wireless Transmitter
A Wireless Transmitter connected to a compatible computer running the Programming Software
is needed to communicate with the IPG (see the Paired VNS Therapy Serenity System NonImplantable Physician’s Manual for a list of compatible computers).
7.3.1.3. Prompts and messages
After the program has been initiated, the software screens display prompts and messages to aid
in communicating with the IPG.
7.3.1.4. Communication
The IPG “listens” for a communication signal from the Wireless Transmitter.
Communication usually takes less than two (2) seconds, but may be prolonged or
interrupted in the presence of electromagnetic interference (EMI). The IPG listens for and
implements interrogations, parameter programming instructions, requests for Device
Diagnostics testing, and Device History inquiries.
In response, the IPG transmits information on the stimulation parameter settings, lead
24 | P a g e
impedance, and battery status information. Each time these data are transmitted by the IPG,
they are saved by the Programming Software to a database.
In addition to the Programming Software and Wireless Transmitter combination, a Magnet can
be used for one-way communication to the IPG by activating a reed switch in the electronic
circuitry. The Magnet can be used to temporarily inhibit stimulation, depending on how the
Magnet Mode is configured in TAPS.
7.3.1.5. Typical Parameters
After the IPG has been programmed, the stimulation will be initiated by the Programming
Software in accordance with the programmed settings for the length of time designated by the
physician. Typically, settings are 0.8 mA, 30 Hz, 100 µSec, ½ second ON, 30 Seconds OFF,
and 2.5 hours total treatment time. An audio tone is synchronized with the VNS signal (so a ½
second tone is played while the ½ second VNS pulse occurs); this tone is played by the
computer and the Programming Software through the headphones and delivered to the patient’s
ears. This treatment session is typically given once per day and typically lasts 2.5 hours (150
minutes). The specific settings are programmed by the physician or audiologist. The patient
may then start a daily session from their own home, using their own patient programming
system. Stimulation duty cycles greater than 50% shall be inhibited.
7.3.1.6. Stimulation Inhibition via Magnet Application
A magnet is provided to the patient to inhibit stimulation in the unlikely event that stimulation is
too strong or becomes uncomfortable or there is some device malfunction while the patient is at
home between sessions. The site will also have a magnet available during the rehabilitation
session so that stimulation can be easily aborted. The user should place the magnet over their
chest where the IPG is located and hold the magnet in place. The device should not stimulate
while the magnet is in place. If at home, the patient should then contact their physician or
audiologist for an immediate appointment so that the device can be further tested.
7.3.1.7. IPG interrogation
The IPG can be interrogated to determine the present settings of the stimulation parameters.
7.3.1.8. Programmable parameters
A graphic representation of VNS (Figure 7.2) depicts the relationship of the programmable
parameters. Each parameter can be independently programmed, thereby offering multiple
setting combinations from which the physician may select optimal stimulation for the patient.
Figure 7.2 shows that the output pulse can be varied both by amplitude (output current) and
duration (pulse width). The number of output pulses delivered per second determines the
frequency.
25 | P a g e
Figure 7.2
Stimulation Waveform
The typical VNS session for tinnitus rehabilitation will be 150 minutes.
7.3.1.9 Parameter settings and battery life
When selecting a combination of parameter settings for stimulation, the physician should also
consider that some combinations, such as higher output currents and longer On-Times, would
decrease battery life faster than others.
7.3.2. Paired VNS Therapy System Serenity Magnet
The main use of the magnet is to temporarily inhibit stimulation. This is done by placing the
magnet over the chest where the IPG is implanted. Stimulation is inhibited for as long as the
magnet is placed over the IPG.
7.3.3. Device History
The Device History consists of the IPG serial number, model number, the patient ID, tone
therapy, and other information pertinent to diagnostic and programming events. Use the TAPS
to access and view Device History information.
7.3.4. Check Impedance
In the Status portion of the Program Implant menu, the lead impedance can be checked by
selecting the Check button. When the Check button is selected the IPG delivers a small
current to assess Lead impedance. High lead impedance is defined as any value >= 10,000
ohms. Low lead impedance is defined as any value <= 600ohms.
Caution: Possible cases of high lead impedance readings are thought to include: fibrosis
between the nerves and the electrode, Lead discontinuity, or Lead disconnection from the IPG.
Caution: possible causes of low lead impedance are thought to include: short circuit condition
within the lead or a defective IPG.
26 | P a g e
7.3.4.1. High Lead impedance: possible implications
High Lead impedance (≥10,000 Ohms), in the absence of other device-related complications, is
an indication that it is difficult for the IPG to deliver the programmed output current, and that the
battery may therefore not last as long as typical. In conjunction with the patient’s failure to feel
stimulation, High Lead Impedance may indicate a Lead wire fracture or other type of electrical
discontinuity in the Lead. Patients experiencing high Lead impedance, no sensation of
stimulation, and an increase in tinnitus symptoms should be further evaluated for possible Lead
replacement.
7.3.4.2. Low Lead Impedance: possible implications
Low Lead impedance (≤600 Ohms) likely indicates the existence of a short-circuit condition,
although an impedance value of greater than 600 Ohms does not exclude the possibility. A
sudden decrease in impedance value in combination with device-related complications (e.g.,
increase in tinnitus symptoms or painful stimulation; patient perception of feeling erratic, limited,
or no stimulation) may also indicate a short-circuit condition in the Lead.
7.3.5. Implantable Pulse Generator (IPG) battery longevity
7.3.5.1. Battery longevity and programmed setting choices
The anticipated longevity of the IPG battery varies, depending on the choice of programmed
settings. Higher output currents, frequencies, pulse widths, and duty cycles generally deplete
the battery over a shorter period of time than lower settings. Generally, the increase in battery
depletion rate is proportional to the increase in the programmed setting.
Other factors, such as the Lead impedance and, if applicable, magnet usage, also affect the
anticipated longevity of the IPG battery. The anticipated battery longevity decreases as Lead
impedance increases. Although 1.5 k to 3 kOhms may be typical Lead impedance at
implantation, the impedance may increase to 3 k to 5 kOhms during the life of the implant.
The approximate battery longevity predicted is greater than 5 years at programmed settings of
1.5 mA in to 3K ohm load, 50 Hz, 500 µS PW, 0.5 S pulse train, and a separation of 15 S
between pulse trains. Because of the number of possible parameter combinations, it is
impractical to provide the projected life for all possible combinations. Increasing settings
(output current, pulse width, duty cycle) will decrease battery life. As impedance increases
battery life also decreases.
Caution: Undeliverable output currents—
Programming the IPG to a high output current that cannot be delivered due to a high Lead
impedance may disproportionately increase the battery depletion rate and should be avoided.
Caution: Battery evaluation at cold temperatures—Low storage temperatures may affect the
battery status indicators. In such cases, the battery status indicators should be re-evaluated
27 | P a g e
using the System Diagnostics or Generator Diagnostics after the IPG has been at room or body
temperature for 30 minutes.
7.3.5.2. Battery status indicators
The Programming Software will display warning messages after an interrogation or
programming of the IPG if the battery is nearing its depletion. The first indication is an
Elective Replacement Indicator (ERI) flag, which indicates less than 15% of the battery life is left
(likely nine [9] months or less). The final indication is an End of Life (EOL) flag, which indicates
less than 5% of the battery life is left. It is recommended that IPG replacement start being
considered at ERI. Please refer to the Paired VNS Therapy Serenity System Non-Implantable
Physician’s Manual for additional information in these indicators.
7.4 Implantable Pulse Generator (IPG) Replacement
All Paired VNS Therapy Serenity IPGs eventually require surgical replacement as a result of
battery depletion. IPG replacement does not, of itself, require Lead replacement unless a Lead
discontinuity is suspected. IPG replacement or removal requires dissection to the IPG’s pocket,
with care being taken not to damage or cut the Lead. Replacement of the IPG only typically
requires 30 minutes or less; replacement of the entire system typically requires approximately
90 minutes.
7.5 Lead Lifetime and Replacement
A Lead requires replacement when a Lead discontinuity is suspected. An increase in clinical
signs and symptoms may signal a need for Lead replacement. Events that can shorten the life
expectancy of the Lead are as follows:
•
Blunt trauma to the neck and/or any area of the body beneath which the Lead is
implanted
•
Twisting or picking (Twiddler’s Syndrome) at either the implanted Lead or the IPG
•
Improper surgical implantation of the Paired VNS Therapy Serenity System, including
(but not limited to) providing an inadequate strain-relief loop, placing sutures directly on the
Lead body rather than using the tie-downs, and suturing the Lead body to muscle.
Caution: Lead replacement or removal—Replacing or removing Leads because of lack of
efficacy is a medical judgment that includes the patient’s desires and health status, and must
be carefully weighed against the known and unknown risks of surgery. At present, no known
long-term hazards or risks are associated with leaving the Lead implanted, beyond those
already mentioned in this multi-part physician’s manual. All precautions and contraindications
still should be observed (see “Troubleshooting”, Section 8 below).
7.6 Signs of End of Life
The most common reason for the absence of stimulation is battery depletion, although there
28 | P a g e
may be other reasons. When end of life (EOL) occurs, the IPG will disable stimulation and no
output will be delivered. If the IPG is not explanted or replaced at EOL, the battery voltage will
continue to gradually decrease and communication with the IPG may not be possible.
7.7 Replacement Based on Battery Status Indicators
The TAPS battery status indicators provide warnings that an IPG battery should be monitored more
frequently, is near EOL, or has reached EOL. Once these warning messages appear, see
recommendations in the Paired VNS Therapy Serenity Non-Implantable Physician’s Manual.
8. TROUBLESHOOTING
This section provides troubleshooting instructions in two parts: (1) in the Operating Room (OR)
and (2) at patient follow-up visits.
A communication problem can cause an error message (such as “There is an error establishing
communication with the device” or “Failed to retrieve diagnostic data”) during:
• Interrogation
•
Programming of parameters or implant date/patient code
•
Diagnostic testing indicated by the message, Communication “FAULT”
Failure of the IPG and Wireless Transmitter to clearly communicate with each other to
interrogate, program, or run diagnostic tests can be attributed to several factors:
Movement of the Wireless Transmitter away from the IPG during communication
Improper cable connection between the Wireless Transmitter and
Programming Computer
Electromagnetic interference (EMI), i.e., OR lights, Programming Computer
IPG battery at end of life (EOL)
Defective Wireless Transmitter
Defective Programming Computer
Defective IPG
The most common cause of difficulties are connection issues. Verify that the Wireless
Transmitter connector is correctly inserted into the computer’s USB port. Refer to the Paired
VNS Therapy Serenity Non-Implantable Physician’s Manual for further details. Communication
problems are often intermittent and are rarely related to the IPG. The surrounding environment
can often cause these problems.
A communication problem causes an error message (such as “Data transmission error between
programmer and device”) during interrogation, when programming of parameters or implant
date/patient code, or when receiving “FAULT” results on a diagnostic test. Performing these
29 | P a g e
steps may restore communication.
If communication was possible before the IPG was inserted into the chest pocket, but is not
possible with the IPG inside the pocket, verify that the Wireless Transmitter is within 3-feet of the
IPG.
•
Programming, interrogating, or completing diagnostic tests in an area with EMI may be
difficult or impossible. The problem can usually be resolved by repositioning the patient, the
Wireless Transmitter, or source of EMI.
9. SAFETY INFORMATION (from VNS Studies of Depression)
Except where noted otherwise, the safety information presented in this section derives from the
Cyberonics’ pivotal (D-02) study of VNS for depression. Although from a different indication
(depression), and using a different device (Cyberonics’ VNS Therapy device), the information
from this study is included here because it is thought to be representative of possible adverse
events expected with paired VNS Therapy for tinnitus using the Serenity System. The
information provided on VNS Therapy for depression consists of both an acute and a long-term
phase showing adverse event and safety data when treating people with chronic or recurrent
treatment-resistant depression.
9.1.
Device Performance
The VNS Therapy System performed according to its specifications. Most device issues were
communication difficulties resolved by repositioning the Programming Interface or replacing the
Programming Interface batteries. One high Lead impedance occurred requiring replacement; a
Lead break due to fatigue at the electrode bifurcation was noted. Most device complaints were
resolved on the day of initial complaint.
9.2.
Adverse Events
The number (and percentage) of subjects reporting an adverse event during the 0-3 month period
and during the 9-12 month period of the pivotal (D-02) study is depicted in Table 9.1 for the most
commonly reported adverse events. Adverse events were coded using the COSTART 5
dictionary. Note that some subjects may have reported multiple events.
Table 9.1
D-02 Adverse Events
Adverse Event
0-3 Months (N=232)
Voice Alteration
Increased Cough
Neck Pain
Dyspnea
Dysphagia
135 (58.2%)
55 (23.7%)
38 (16.4%)
33 (14.2%)
31 (13.4%)
9-12 Months (N=209)
113 (54.1%)
13 (6.2%)
27 (12.9%)
34 (16.3%)
9 (4.3%)
30 | P a g e
Paresthesia
Laryngismus
Pharyngitis
Nausea
Pain
Headache
Insomnia
Palpitation
Chest Pain
Dyspepsia
Hypertonia
Hypesthesia
Anxiety
Ear Pain
Eructation
Diarrhea
Dizziness
Incision Site Reaction
Asthma
Device site reaction
Device Site Pain
Migraine Headache
26 (11.2%)
23 (9.9%)
14 (6.0%)
13 (5.6%)
13 (5.6%)
12 (5.2%)
10 (4.3%)
9 (3.9%)
9 (3.9%)
8 (3.4%)
6 (2.6%)
6 (2.6%)
5 (2.2%)
5 (2.2%)
4 (1.7%)
4 (1.7%)
4 (1.7%)
4 (1.7%)
4 (1.7%)
4 (1.7%)
9 (4.3%)
10 (4.8%)
11 (5.3%)
4 (1.9%)
13 (6.2%)
8 (3.8%)
2 (1.0%)
6 (2.9%)
4 (1.9%)
4 (1.9%)
10 (4.8%)
2 (1.0%)
6 (2.9%)
6 (2.9%)
2 (1.0%)
3 (1.4%)
2 (1.0%)
3 (1.4%)
4 (1.7%)
4 (1.7%)
2 (1.0%)
2 (1.0%)
It is important to note that subjects often had comorbid illnesses and almost all study subjects
were also receiving antidepressant and other drugs that could have contributed to these events.
9.2.1. Discontinuation due to adverse events
By the time all continuing subjects in the pivotal (D-02) study had at least 1 year of VNS
Therapy, 3% (8/235) of the subjects had discontinued VNS Therapy for an adverse eventrelated reason. The reasons for these eight discontinuations included one case each of suicide,
implant-related infection necessitating device removal, hoarseness, lightheadedness, postoperative pain, chest and arm pain, sudden death (of unknown cause), and worsening
depression (reported by the investigator as an adverse event rather than as lack of efficacy).
9.3.
Serious Adverse Events (SAEs)
9.3.1. SAEs
The SAEs described in this section are based on investigator reports from the pivotal (D-02)
study from study initiation through the data cutoff date for submission; the data cutoff date
included the entire period of evaluation for subjects who did not complete 12 months of VNS
Therapy and included a minimum of 12 months of evaluation during VNS Therapy for all
subjects who continued the study for 12 months or longer.
During the pivotal (D-02) study, 12 SAEs were considered related to the implant procedure
(wound infection, asystole, bradycardia, syncope, abnormal thinking, vocal cord paralysis,
aspiration pneumonia, voice alteration, device site reaction [two reports], acute renal failure, and
urinary retention). During the acute phase of the D-02 study, investigators did not report any
31 | P a g e
SAE to be related to stimulation. During the long-term phase of the D-02 study, eight SAEs were
considered at least possibly related to stimulation (sudden death of unknown cause, syncope
(two reports), dizziness, a manic depressive reaction in a subject with bipolar disorder,
hemorrhage GI, paresthesia, and an incident of worsening depression. Table 9.2 displays all the
SAEs reported during the D-02 study prior to the data cutoff date, regardless of relationship to
implantation or stimulation.
Table 9.2
Event
Serious Adverse Events (SAEs)
Acute (N=235)
No. of Events
Long Term (N=233)
No. of Subjects
No. of Events
No. of Subjects
5/7
11
62
31
Suicide Attempt
Syncope
Dehydration
1/1
Wound Infection
1/0
Cholecystitis
0/1
1/0
Convulsion
Device Site
Reaction
2/0
Pneumonia
0/1
Abdominal Pain
Accidental Injury
Chest Pain
Overdose
Peritonitis
Sudden
Unexplained
VNS(N=119)/Sham(N=116)
Worsening
Depression
Gastro Disorder
Abnormal
Thinking
32 | P a g e
Death
Suicide
1/0
Surgical
Procedure
1/0
Asystole
1/0
Bradycardia
1/0
Cholelithiasis
Constipation
Myasthenia
0/1
Confusion
1/0
Dizziness
Drug
Dependence
Manic
Depression
Somnolence
0/1
Aspiration
Pneumonia
1/0
Voice Alteration
0/1
Acute Renal
Failure
0/1
1/0
Vocal Cord
Paralysis
Breast Cancer
Enlarged
Uterine Fibroid
Urinary
Retention
9.3.2. Deaths
33 | P a g e
Four deaths occurred during the pivotal (D-02) study: one after the subject had given consent,
but before the subject was implanted; the second, a suicide; the third, a death of unknown
cause; and the fourth, a subject who developed multi-organ failure.
9.3.3. Unanticipated adverse device effects
Two events in the pivotal (D-02) study met criteria for an unanticipated adverse device effect
(UADE)—see Glossary for definition. Both these events were non-specific complications of
surgery related to the implant procedure and occurred before stimulation began. One UADE
was an episode of acute renal failure thought to be secondary to antibiotic administration, and
the other was an episode of altered mental status thought to be due to perioperative narcotic
administration.
9.4.
Safety Considerations Specific to Depressed Patients
Two specific safety concerns in the use of all antidepressant therapies are the precipitation of
manic or hypomanic episodes and the possible effect of antidepressant therapy on suicidal
ideation and behavior.
9.4.1. Antidepressant treatments and manic or hypomanic reaction
Although patients with bipolar disorder experience manic episodes as the cardinal feature of
their disorder, effective antidepressant therapies themselves can occasionally precipitate a
manic or hypomanic episode. Antidepressant therapies can also occasionally precipitate a
manic or hypomanic episode in patients without a prior history of mania who are being treated
for a major depressive episode.
9.4.1.1.
Manic reactions
In the pivotal (D-02) study, six hypomanic or manic reactions were identified according to DSM
IV criteria or the Young Mania Rating Scale (YMRS). Five were observed in subjects with a
known history of prior hypomanic or manic episodes. One of the events was considered serious
and the subject was hospitalized.
9.4.2. Suicidal ideation, suicide attempts, suicide, and worsened depression
Suicidal ideation was analyzed by examining the HRSD24 Item 3 scores. At 12 months of VNS
Therapy, 90% of the subjects in the pivotal (D-02) study showed either improvement (56%) or
no change (34%) in their Item 3 scores. During the acute D-02 study, 2.6% of the sham subjects
and 1.7% of the stimulation subjects increased their Item 3 score by 2 or more points, indicative
of an increase in suicidal ideation. During the long-term D-02 phase, 2.8% of the subjects had
an increase in their Item 3 score by at least 2 points at 12 months compared to baseline. In a
non-randomized control group of subjects treated with standard antidepressant therapies
without VNS Therapy (the D-04 study population), 1.9% of the subjects had an increase of at
least 2 points. Based on the occurrence of any increase in Item 3 score from baseline to 12
months, 10% of the D-02 subjects had an increase compared to 11% of the D-04 population.
Conversely, 27% of the D-02 subjects decreased their score by at least 2 points at 12 months
compared to baseline, whereas only 9% of the D-04 subjects did.
Suicide attempts and completed suicides in the D-02 and D-04 studies indicate that suicide
attempts in the VNS population (D-02) were similar to rates in a similarly depressed population
that did not receive VNS Therapy (D-04), with 2.4% and 2.5% attempts per patient years,
respectively.
34 | P a g e
In the acute phase of the D-02 study, there were 12 reports of worsening depression, 5 in the
stimulation group (5 of 119 subjects) and 7 in the sham group (7 of 116 subjects). One of the
treatment-group reports occurred prior to stimulation initiation. Following acute phase exit and
during the long-term phase of stimulation, 62 events were reported in 31 subjects. The number
of episodes of worsening depression per subject ranged from 1 to 6. Although specific rates of
worsening depression (and other safety endpoints) were not collected during the D-04 study,
“hospitalizations for psychiatric illness,” which might be a reasonable surrogate for worsening
depression, were recorded. The rate of this event was 0.237 events per patient-year in the D-04
group compared to 0.293 events of worsening depression per patient-year in the D-02 group.
9.5.
Adverse Event (AE) Relationship to VNS Therapy and Duration of Events
The pivotal (D-02) study investigators determined whether an adverse event (AE) was possibly,
probably, or definitely related to implantation of, or stimulation by, the VNS Therapy IPG and
Lead.
9.5.1 AE related to implantation
Because all eligible study subjects in the pivotal (D-02) study were implanted with the VNS
Therapy™ System device, no control was available to assess whether an adverse event was
related to the surgery. Investigators, therefore, determined which adverse events were related
to implantation. The events reported as related to implantation and occurring in at least 10% of
the subjects who received VNS Therapy System implants in the pivotal (D-02) study were
device site pain (23%), device site reaction (14%), incision pain (36%), dysphagia (11%),
hypesthesia (11%), pharyngitis (13%), voice alteration (33%), and incision site reaction (29%).
9.5.2. Duration of implant-related adverse events
Many of the individual incidences of the most common implantation-related AEs resolved within
30 days. Hypesthesia (generally described as a localized numbness) and voice alteration,
however, tended to be more persistent in some individuals. For example, in 17 of 24 reports of
implantation-related hypesthesia, the event continued beyond 3 months. Hypesthesia would be
an expected side effect of nerve injury during surgery. The persistence of voice alteration in
some subjects is difficult to assess because it could represent surgical injury to the innervation
of the larynx, but vagus nerve stimulation itself can cause voice alteration.
9.5.3. Stimulation-related adverse events
Among AEs judged by investigators to be stimulation-related in the D-02 study acute phase
treatment group, seven events occurred at a frequency of 10% or greater: voice alteration
(55%), cough increased (24%), dyspnea (19%), neck pain (16%), dysphagia (13%), laryngismus
(11%), and paresthesia (10%).
9.6.
Severity of Adverse Events
Investigators rated adverse events as mild, moderate, or severe according to the protocol
definitions: mild events were transient and easily tolerated by the subject; moderate events
caused discomfort and interrupted usual activities; severe events caused considerable
interference with the subject’s usual activities.
Most adverse events for the feasibility (D-01) study and pivotal (D-02) study were mild or
moderate. Because the pivotal (D-02) study included a sham-control group, further analysis of
severity rating was performed. After 3 months of treatment, there were 280 (43%) adverse
events that were categorized as mild, 293 (45%) as moderate, and 73 (11%) as severe in the
sham-control group. The active VNS Therapy group had 360 (47%) adverse events categorized
35 | P a g e
as mild, 349 (45%) as moderate, and 61 (8%) as severe.
9.7.
VNS Therapy Continuation Rates
Of the 295 subjects implanted during both the feasibility (D-01) and pivotal studies (D-02), 270
subjects (92%) were still receiving VNS Therapy at 12 months and 242 subjects (82%) were still
receiving VNS Therapy at 24 months. This is similar to the epilepsy continuation rates; 12- and
24-month continuation rates of 95% and 83% were seen, respectively, for the subjects
implanted in the epilepsy preapproval trials.
10.0 SAFETY INFORMATION (from VNS Studies of Epilepsy)
The Cyberonics’ VNS Therapy™ System for refractory epilepsy was implanted in 454 patients in
five clinical studies involving 611 devices (some patients had IPG replacements). As of August
1996, total VNS Therapy exposure in these 454 patients was 901 device-years. Individual
patient exposure averaged 24 months, with a range of eight days to 7.4 years.
A total of nine patients died during these five studies. One patient died from each of the
following: thrombotic thrombocytopenic purpura, drowning, aspiration pneumonia, pneumonia,
and renal failure associated with drug and alcohol ingestion. No cause of death was apparent
for the other four deaths, which may be classified as sudden unexpected death in epilepsy
(SUDEP). None of these deaths were attributed by the investigators to the VNS Therapy
System.
10.1. Device Performance
The VNS Therapy System performed according to its specifications. Most device issues were
communication difficulties resolved by repositioning the Programming Interface or replacing the
Programming Interface batteries. One high Lead impedance occurred requiring replacement; a
lead break due to fatigue at the electrode bifurcation was noted. Most device complaints were
resolved on the day of initial complaint.
10.2. Adverse Events Observed in Studies
Included among the five clinical trials were two randomized, blinded, active control trials (Study
E03 and E05), which involved 314 patients and the implantation of 413 devices, yielding a total
VNS Therapy System exposure (inclusive of long-term follow up) of 591 device years. These
trials form the basis of the rates of observed adverse events. Table 1 contains only a partial list
of the more common and expected observed adverse events associated with the VNS Therapy
System. A comprehensive listing of adverse events observed in studies is available by study
from the Clinical Research department at MicroTransponder®.
Table 10.1 reports the adverse events from these studies during the randomized phase
(approximately a 14-week observation period) and randomized phase plus long-term follow up
(> 3 months) through August 1996. The most common side effect associated with stimulation
was hoarseness (voice alteration), which, depending on device settings, can be severe to barely
perceptible. Hoarseness is reported to occur primarily during the ON period of stimulation.
36 | P a g e
Table 10.1
Epilepsy Study Adverse Events
Randomized + Long-term Follow-up (>3 months)
N=314 Patients, 591 Device Years
Adverse
Events
No. of
Patients1
Serious AEs3
Surgery
Related
Stimulation
Related
Non-serious AEs
Voice
Alteration
Increased
Coughing
Pharyngitis
Paresthesia
Dyspnea
Dyspepsia
Nausea
Laryngismus
Randomized Phase,
HIGH only, 152 Patients
% of
Patients2
Number of
Events
Events/DeviceYear
Number of
Patients
% of Patients
13
4.1
13
0.0222
N/A
N/A
1.2
0.007
0.7
156
50
720
1.228
91
60
129
41
456
0.772
57
38
84
87
55
36
59
10
27
28
18
12
19
3.2
182
377
55
98
154
30
0.308
0.638
0.093
0.166
0.261
0.051
36
32
32
22
21
24
21
21
15
14
5.9
1 – Number of patients reporting the event at least once.
2 – Percentage of patients reporting the event at least once.
3 – Included infection, nerve paralysis, hypesthesia, facial paresis, left vocal cord paralysis, left facial
paralysis, left hemidiaphragm paralysis, left recurrent laryngeal nerve injury, urinary retention, and lowgrade fever.
10.3 Potential AEs
Adverse events reported during clinical studies as statistically significant are listed below in
alphabetical order:
Ataxia (Loss of the ability to coordinate muscular movement), Dyspepsia
(indigestion), Dyspnea (difficulty breathing, shortness of breath), Hypesthesia
(impaired sense of touch), Increased coughing, Infection, Insomnia (inability to
sleep), Laryngismus (throat, larynx spasms), Muscle movement or twitching
generally associated with stimulation, Nausea, Pain, Paresthesia (prickling of the
skin), Pharyngitis (inflammation of the pharynx, throat), Voice alteration
(hoarseness), Vomiting
Other potential adverse events possibly associated with surgery or stimulation include, but are
not limited to, the following:
Aspiration (fluid in the lungs), Blood clotting, Choking sensation, Damage to
nerves or vasculature in the surgical area, including the carotid artery and jugular
vein, Device (IPG and/or Lead) migration or extrusion, Dizziness, Dysphagia
(Difficulty Swallowing), Duodenal ulcer, gastric ulcer, Ear pain, Facial flushing,
Facial paralysis, paresis, Foreign body reaction to implants, including possible
tumor formation, Formation of fibrous tissue, pockets of fluid, Heart rate and
rhythm changes, Hiccuping, Incision site pain, Irritability, Laryngeal irritation
(sore, painful throat), Left hemidiaphragm paralysis, Left recurrent laryngeal
nerve injury, Left vocal cord paralysis, Low-grade fever, Muscle pain, Neck pain,
37 | P a g e
Nerve injury, Painful or irregular stimulation, Seroma, Skin, tissue reaction,
Stomach discomfort, Tinnitus (ringing in the ears), Tooth pain, Unusual scarring
at the incision site, Urinary retention, Vagus nerve paralysis, Weight change,
Worsening of asthma and bronchitis.
Although the pilot study of VNS for tinnitus did not show any worsened tinnitus, in the absence
of any definitive data, it is possible that device use could worsen tinnitus, or that worsening of
tinnitus could occur if the device stops.
11.
BIBLIOGRAPHY
A bibliography of animal, clinical, and mechanism of action studies is available from
MicroTransponder® on request.
12.
GUIDELINES FOR PATIENT FOLLOW UP
During the first few weeks after implantation, the patient should be seen to confirm wound
healing and proper Serenity System operation. During initial programming, the output current
should be programmed to start at nominal parameters (0 mA) and then be slowly increased in
0.10 mA increments until the patient feels the stimulation at a comfortable level. The target
output current is 0.8 mA, however patients who cannot tolerate this level should have the
highest tolerable level below this amount. Patients who are receiving replacement IPGs should
also be started at nominal parameters, with 0.1 mA-step increases to allow re- accommodation.
After proper training, the patient may return frequently during the first week or two of device use,
so that the physician/audiologist may review the patient’s computer records and verify proper
device use; retraining and further follow-up should occur if indicated.
At each patient visit, the IPG should be checked, using the appropriate version of the TAPS.
After reprogramming and/or diagnostics testing, data can be printed out and filed. These data
can be used for comparison with a patient’s own records to evaluate the Paired VNS Therapy
Serenity System, to confirm proper Paired VNS Therapy Serenity System functioning, and to
assess the need for reprogramming. However, all information is also kept in the TAPS
database, and can be reviewed within the TAPS program.
Paired VNS Therapy Serenity System treatment should not be uncomfortable, nor should it
cause bothersome side effects. Patients should be observed for the first stimulation period or
after any stimulation setting adjustment to make certain that they are comfortable with the
programmed stimulation.
The subsequent follow-up schedule and the nature of each examination should be determined
by the physician on the basis of patient response to and tolerance of the implant. In all other
respects, follow-ups should be performed in accordance with the standard medical practice for
patients with tinnitus.
In the event intolerable adverse events are reported, physicians should always try reducing the
output current (mA) as a means of eliminating or reducing the severity of an event. Additionally,
physicians should instruct patients or caregivers on the application of the Magnet to turn the IPG
off (output current 0 mA) if an adverse event becomes intolerable.
MicroTransponder strongly encourages physicians to keep all medications stable for the first
38 | P a g e
three months of stimulation before attempting to reduce or change a patient’s medication.
Paired VNS Therapy System treatment should not be uncomfortable, nor should it cause
bothersome side effects. Patients should be instructed and shown how to place the magnet
over their device in order to stop stimulation. It should be verified that the patient can do this
during the first session when stimulation is started; it should also be verified that the patient is
given a magnet to take home with them for this use.
13.
PATIENT COUNSELING INFORMATION
In the unlikely event of uncomfortable adverse events, continuous stimulation, or other
malfunction, the patient must be advised to hold or tape the Magnet directly over the implanted
IPG to prevent additional stimulation. If patients or caregivers find this procedure necessary,
they should immediately notify the patient’s physician.
Patients should also be instructed that they should not manipulate the device or lead through
their skin, as this could damage the device. Pulling on the lead may move the electrode on the
nerve, and cause possible nerve damage. Additionally, patients should not pick at their surgical
scars.
14.
MECHANISM OF ACTION
The precise mechanism(s) by which Paired VNS Therapy exerts its tinnitus action is unknown.
Previous animal studies of VNS enhanced learning demonstrated the principle that one can
open a window of enhanced learning by VNS. The use of VNS therapy is based on animal and
clinical observations that VNS can indeed improve learning and memory in normal animals and
humans (Clark et al., 1995). Importantly, the VNS parameters that have been found to be most
effective in rats are also the most effective parameters to use in humans (Clark et al., 1999).
VNS has also been shown to improve motor performance in rat models of percussion brain
injury (Smith et al., 2005; Clough et al., 2007).
These studies did not pair the stimulation specifically with desired learning tasks. The current
approach takes advantage of this window by specifically pairing tones with very short periods
(such as 0.5 seconds) of VNS.
It is generally accepted that tinnitus arises from hyperactivity of neurons in the central auditory
system subsequent to central or peripheral auditory system damage (Norena and Eggermont,
2003; Rajan and Irvine, 1998; Seki and Eggermont, 2003; Kaltenbach et al., 2007; Bauer et al.,
2008). Human and animal studies have shown that neurons deprived of auditory input begin to
respond to the same frequencies as neighboring neurons that receive input from undamaged
parts of the cochlear (Rajan et al., 1993; Dietrich et al., 2001; Syka, 2002). This change in
neuronal behavior results in a dramatic increase in the number of neurons that respond to a
narrow range of frequencies. When the number of neurons that respond to a given frequency
increases beyond some critical level, synchronous spontaneous activity sets in, which is thought
to account for tinnitus (Eggermont and Roberts, 2004; Muhlnickel et al., 1998; Møller, 2006).
39 | P a g e
Current treatments for tinnitus are not very effective and no current treatment has been shown
to reverse the pathological plasticity that gives rise to tinnitus (Flor et al., 2004; Tyler et al.,
1984; Searchfield et al., 2007; Szczepaniak and Møller, 1995; Darlington and Smith, 2007; Tyler
et al., 2007; Miyamoto and Bichey, 2003; Steenerson and Cronin, 2003; Kleinjung et al., 2007).
A treatment that reversed the underlying pathology would be expected to be very effective. Our
studies suggest that targeted manipulation of neural plasticity can reverse the pathological
plasticity and decrease the symptoms of tinnitus (Engineer et al., 2011). Our approach is to
greatly speed up the rehabilitation process by using VNS to briefly put the brain into a receptive
state during which associated stimuli can drive therapeutic neural plasticity.
15.
PHYSICIAN TRAINING / INFORMATION
All Paired VNS Therapy Serenity System programming should be performed by or under the
supervision of a physician familiar with the use and operation of the Programming Software.
Training Materials
Physicians implanting the Paired VNS Therapy Serenity System should be thoroughly familiar
with all associated training materials, including:
Product labeling for the IPG, Lead, and accessories, including physician and patient
manuals and directions for use
“Implant Guide for the Paired VNS Therapy Serenity System” training manual and other
brochures
16.
PAIRED VNS THERAPY SERENITY SYSTEM DEVICES
16.1
IPG Package Contents
The IPG package contains the following:
1 MicroTransponder ® Paired VNS Therapy Serenity Implantable Pulse Generator (IPG)
1 hex screwdriver
Documentation
• Note: Ensure that at least one back-up IPG is available before starting the procedure.
40 | P a g e
16.2
Lead Package Contents
The Lead package contains the following:
1 VNS Therapy Lead
4 (or more) silicone tie-downs
Documentation
Note: Ensure that at least one back-up Lead is available before starting the procedure.
16.3
Other MicroTransponder Products
16.4
1 Paired VNS Therapy Serenity System Wireless Transmitter (non-sterile)
1 Laptop preloaded with TAPS.
MTI-approved Headphones
Surgical Materials
The following is a list of additional materials typically used during the
VNS Therapy implantation procedure:
16.5
Sterile Laser Arm Bag or equivalent (optional, Programming System typical
distance of 3 meters may preclude need for the sterile bag)
Vessel loops and/or silicone sheet for manipulation of the vagus nerve
(suggested but optional)
Blunt dissection tool (such as blunt forceps, blunt scissors – surgeons decision)
Sterile tube for ease of moving the connector end of the leads from the neck
incision to the chest incision (optional; surgeon may prefer other tool or method)
To Open the Sterile Package
Before the package is opened, it should be examined carefully for evidence of damage or
compromised sterility. If the outer or inner package has been opened or damaged,
MicroTransponder cannot guarantee sterility of the IPG or Lead, and it should not be used if the
sterile package has been opened or damaged. An opened or damaged product should be
returned to MicroTransponder.
To open the package, do the following:
1. Grasp the tab, and peel back the outer cover.
2. Observing sterile technique, lift out the sterile inner tray.
3. Grasp the inner tray’s tab, and carefully peel off the inner cover to expose the contents
without dropping them.
- The sterile Lead package should only be opened after exposing the vagus nerve and selecting
the MicroTransponder Lead that best fits.
41 | P a g e
- Tie downs could potentially fall out of package, carefully remove the lead to maintain control of
these.
- Caution: Do not use the package if it has been exposed to extreme temperatures or if there is
any indication of external damage or damage to the package seal. Instead, return it unopened
to MicroTransponder.
17.
RECOMMENDATIONS FOR IMPLANTATION
In general, implantation of the Paired VNS Therapy Serenity System is similar to accepted
practice for implantation of other implantable devices. The most novel portion of the surgery is
the placement of the electrodes and the subcutaneous routing of the Lead connector and body
over the clavicle. Although the surgical approach and techniques will vary with the preference of
the implanting physician this part of the physician’s manual provides recommendations for
implantation, along with a detailed description of the order of placement of the helical electrodes
and the anchor tether and other essential steps.
Critical to the long-term success of the implant are proper techniques both for the attachment of
the electrodes and the anchor tether to the left vagus nerve, and for the provision of adequate
strain relief below and above the sternocleidomastoid muscle.
It is recommended that the Lead body be coiled and placed in the chest pocket underneath or to
the side of the IPG; placement above the generator may cause damage to the lead body during
generator replacement, and is therefore not recommended.
Adequate exposure of the vagus nerve (>3 cm) facilitates placement of the electrodes on the
nerve. Stretching the nerve or allowing it to dry during implantation may result in temporary
swelling of the nerve. Constriction of the nerve or other nerve damage may result in vocal cord
dysfunction.
After the electrodes are placed on the nerve, the electrode-nerve interface impedance is tested
by connecting the Lead directly to the IPG and performing a Lead Impedance Check.
17.1. Check the device and Input Patient Data
To ensure proper device communication, using TAPS, check the IPG by communicating with it
while still in the sterile package. [See the Paired VNS Therapy Serenity Non-Implantable
Physician’s Manual for a detailed explanation or the Programming Software instruction card
(handheld) for a quick reference.]
Using TAPS, input the patient identification into the IPG. [See the Paired VNS Therapy Serenity
Non-Implantable Physician’s Manual for a detailed explanation.]
42 | P a g e
17.2. Procedure Overview
The following overview summarizes the recommended sequence for implanting the Lead:
1. Expose the left carotid sheath and left vagus nerve.
2. Create a pocket in the chest for the IPG.
3. Tunnel the Lead connector and body subcutaneously from the neck to the IPG pocket in the
chest.
4. Attach the electrodes and anchor tether to the left vagus nerve.
5. Secure the Lead parallel to the nerve using the provided tie-downs, do not suture around or
on the lead body itself as it may damage it.
6. Form the strain relief bend and strain relief loop and secure using the provided tie-downs.
7. Attach the Lead connector to the IPG.
8. Visually verify that the connector pin is fully inserted, tighten the setscrews.
9. Perform Lead Impedance Check
10. Place the IPG in the chest pocket, with the extra coiled lead body underneath or to the side
of the IPG, not above it.
11. Secure the IPG to fascia; do not place sutures directly around or on the Lead.
12. Perform the second Lead Impedance Check.
13. Check the IPG to verify current is 0.0 mA.
14. Irrigate the incision site with bacitracin or other solution.
15. Close the incisions.
17.3 Prepare for Surgery
The surgeon should verify that the IPG and lead are compatible. MicroTransponder
recommends that the patient be given antibiotics preoperatively and that both incision sites be
irrigated frequently with generous amounts of bacitracin or equivalent solution prior to closure.
(These incisions should be closed with cosmetic closure techniques to minimize scarring.) Also,
antibiotics should be administered postoperatively at the discretion of the physician.
43 | P a g e
17.4
Lead and Pocket Location
The IPG is usually implanted just below the clavicle in a subcutaneous pocket in the left upper
chest. Suggested placement for the Lead is the area of the left vagus nerve half-way between
the clavicle and the mastoid process, with the Lead subcutaneously tunneled between the
incision site in the neck and the pocket formed in the upper chest (see Figure 17.1). It is
recommended that both the Lead body and the IPG be positioned on the left side of the body.
Figure 17.1
17.5
Placement of IPG and Lead
Begin the Procedure
While the specific surgical approach and techniques for implanting the Lead will vary with the
physician performing the implant, the following detailed instructions are provided for guidance:
1. After administering appropriate anesthesia to the patient, expose the left carotid sheath as it
extends along the anterior border of the sternocleidomastoid muscle.
2. Locate and expose at least 3 centimeters (1.18 inches) of the left vagus nerve. The
recommended stimulation site is a 3-cm section of the vagus nerve, approximately half-way up
between the clavicle and the mastoid process, where it is clear of branches (below where the
superior and inferior cervical cardiac branches separate from the vagus nerve—see Figure 17.2
44 | P a g e
and Figure 17.4). The nerve usually lies in a posterior groove between the carotid artery and
internal jugular vein.
Figure 17.2
Electrode Placement
3. Create a subcutaneous pocket in the chest below the clavicle for the IPG.
17.6 Implant the lead
Caution: Do not expose the Lead to dust or other similar particulates, because its
silicone insulation can attract particulate matter.
Caution: Do not soak the Lead in saline or similar solution before implanting it,
because this may cause the insulated portions of the connector pin to swell and
become difficult to insert into the IPG.
17.7 Make a tunnel and pass the Lead
The surgeon should use blunt dissection to create a subcutaneous tunnel or pathway from the
neck incision to the chest incision. The lead connector end can then be passed from the neck to
chest incision using a sterile bag or sterile tube. Although the connector can be passed after the
electrode has been placed on the nerve and secured, MicroTransponder recommends that the
connector be passed first, in order to avoid the possibility of accidentally putting tension on the
electrodes or nerve while passing the lead connectors.
Caution: To maximize system performance and minimize possible mechanical damage to the
nerve or Lead, pay careful attention to Lead routing, Lead stabilization, and electrode placement.
45 | P a g e
Caution: Never route the Lead through muscle.
Caution: Never suture the Lead or Lead body to muscle tissue.
Caution: Always use the tie-downs.
Caution: Do not place sutures directly on the Lead body. Doing so may result in insulation
damage or wire failure, causing premature failure of the Lead.
To pass the tube, do the following:
Figure 17.3 Position of Tube and Lead Connector(s) (Example is shown with a tube,
although a sterile bag could be used instead).
1. With the tube or bag in place between the two incisions, carefully insert the Lead
connector(s) inside the end of the tube or bag at the neck incision.
2. Carefully pull the tube or bag and Lead connector(s), from the neck incision end until the
lead connector(s) completely exit(s) the chest incision.
3. Remove the Lead connector(s) from the sleeve, leaving the electrode array at the neck
incision site.
4. Discard the tube or bag after use.
17.8 Place the Electrodes
It is very important that the surgeon implanting the Paired VNS Therapy Serenity System be
familiar with vagus nerve anatomy, particularly the cardiac branches. The Lead electrodes must
not be placed on either the superior or the inferior cervical cardiac branches. Place the Lead
below where the superior and inferior cardiac branches separate from the vagus nerve.
Stimulation of either of these two branches during the Lead Impedance Check may cause
bradycardia and/or asystole. Careful dissection laterally on the vagus nerve should aid the
46 | P a g e
physician in determining proper electrode placement. In most but not all patients, the main
vagus nerve is the largest of the three nerves. Figure 17.4 shows the correct anatomical
placement of the helices.
Caution: Attachment of Lead electrodes must not involve the superior cervical cardiac branch
or the inferior cervical cardiac branch of the vagus nerve. Place the electrodes below where
these two branches separate from the vagus nerve.
Caution: When flushing the nerve and neck incision site, be careful not to use a cold solution.
Solutions not at body temperature may cause temporary bradycardia or other cardiac effects.
Caution: Excessive manipulation of the vagus nerve during placement of the Lead can result in
noticeable post-operative hoarseness. Under most circumstances, this condition will resolve
without additional medical intervention within three to four weeks, depending on the degree of
stress applied to the nerve during surgery. MicroTransponder does not recommend that
stimulation treatment be initiated until this condition has resolved, since it could aggravate the
condition.
Figure 17.4
Vagus Nerve Anatomy and Placement of the Lead
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The helical electrodes and anchor tether are coiled around the nerve, beginning with the
electrode that is farthest from the Lead bifurcation (with a blue suture embedded in the helical
material). This electrode should be nearest (proximal to) the patient’s head.
Depending on the surgeon’s preference, the helices can alternately be placed by putting the
anchor tether on first (distal to head), next placing the electrode closest to the Lead bifurcation
(with white suture), and then placing the electrode farthest from the Lead bifurcation (with blue
suture). The polarity of stimulation does not change (see Figure 17.5). The following
instructions show placement beginning with the electrode farthest from the Lead bifurcation
(blue suture).
Figure 17.5
Electrode Polarity
The helical electrodes can be placed on the nerve as described below. As an alternative, each
helical electrode can be placed underneath the nerve before it is spread. A silicone sheet may
be useful to separate the nerve from tissue during the procedure.
1. Place the first helical electrode (negative electrode with the green suture, which will be the
closest to the head) in the following manner:
a.
With forceps, gently pull each end of the helix, using the attached sutures to spread the
helix (see Figure 17.6).
Caution: The suture may become dislodged from the helical electrode if product labeling is not
followed, i.e., grasping the elastomer and suture to manipulate the helical electrode onto the
nerve.
Caution: The Lead and helical electrodes are very delicate. Take care not to stretch, pinch, or
crush the helical electrodes when using forceps. Take care to not over-straighten or stretch the
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helices when coiling them around the nerve, because doing so may damage the electrode or
tether. Use soft rubber vessel loops or equivalent to raise, or lift the nerve, if necessary.
Figure 17.6
Spread the Helical Electrode
b.
Starting with the opened helical electrode spread directly above and parallel to the
exposed nerve, turn the helical electrode clockwise at a 45 degree angle to the nerve (see
Figure 17.7).
Fig. 17.7
Turn the Helical Electrode
c.
Place the turn of the helical electrode where the Lead wire connects to the helical
electrode (the section with the metal ribbon) onto the nerve (see Figure 17.8).
Fig. 17.8
Placement of the Turn
d. Pass the distal suture portion of the helical electrode under the nerve and back around so
that it encircles the nerve (see Figure 17.9 and Figure 17.10).
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Figure 17.9
Starting to Wrap the Electrode
Figure 17.10 Partial Wrap of the Electrode around Nerve
e.
Pass the proximal suture portion of the helical electrode under the nerve and back
around so that it encircles the nerve (see Figure 17.11).
Figure 17.11 Placement of the Proximal Portion of the Helical Electrode
2. Repeat steps 1a through 1e for the middle helical electrode (the positive electrode with the
white suture).
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3. Next, place the third helical electrode (with blue suture but without any electrode portion)
around the nerve, following the same general steps as for the other two helices.
4. After all three helices have been coiled around the nerve, verify that the Lead body exits
each helical electrode in the same direction and that the Lead bodies are aligned parallel to
each other and to the nerve. The correct placement of the two helical electrodes and
anchor tether is shown in Figure 17.12.
Figure 17.12 Placement of Electrodes and Anchor Tether
Caution: Sutures that are part of the Lead (embedded in the helices of the electrodes and
anchor tether) are meant to assist in helical electrode placement around the vagus nerve. These
sutures should not be tied to each other or around the nerve, since this may cause nerve
damage.
Caution: Proper techniques for attaching the electrodes and the anchor tether to the left vagus
nerve are critical to the long-term success of the implant
NOTE: Provide Proper Strain Relief
After attaching the two electrodes and the anchor tether, form a strain relief bend and a strain
relief loop in the Lead to provide adequate slack and allow for neck movement.
1. To form the strain relief bend [see Figure 17. 12 above], do the following:
a. Form the Lead body into a 3-cm (1.18 in) strain relief bend with at least an additional 1 cm
(.39 in) of Lead routed parallel to the nerve. The parallel portion can be placed in a
pocket formed adjacent to the anchor tether.
b. Loosely attach the 3-cm strain relief bend to the adjacent fascia with tie-downs and then
route the Lead over the muscle. The first tie-down should be positioned laterally to the
anchor tether (see Figure 17.13). Five tie-downs are provided in the Lead package.
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Caution: Proper techniques for providing adequate strain relief below and above the
sternocleidomastoid muscle are critical to the long-term success of the implant.
Caution: The Lead and Lead wire may fracture if the recommended strain relief is not
provided.
Figure 17.13 Use of Tie-Downs in Electrode Placement
Caution: Sutures that are part of the Lead coil are meant to assist in electrode placement
around the left vagus nerve. These sutures should not be tied to each other since this may
cause nerve damage.
Caution: The Lead and its electrodes are very delicate, and care should be taken not to over
stretch or crush the helices.
2. To form the strain relief loop (see Figure 17.14), do the following above the
sternocleidomastoid muscle:
a.
In the neck, form the Lead into a large subcutaneous loop.
b.
Loosely attach it to fascia with a tie-down before routing the Lead over the clavicle. This
strain relief loop should be large enough to provide several inches/centimeters of Lead
extension when the neck is turned to its maximum stretched positions.
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Figure 17.14 Strain Relief Loop
Caution: Leave enough extra Lead on both sides of the clavicle to prevent the tension over
the clavicle from damaging the Lead.
Caution: Placing the sutures directly on the Lead body may result in insulation damage or wire
failure, causing premature failure of the Lead. Use only supplied tie-downs to secure the Lead.
17.9 Connect the Lead
To connect the Lead directly to the IPG:
1. Look inside the IPG Lead receptacle(s) to verify that no obstruction exists and that the
setscrew(s) has been backed out adequately to allow full insertion of the connector pin(s). Avoid
backing the setscrew(s) out further than needed for Lead insertion (see Figure 17.15). The
figure is intended to show the contrast between a blocked and a clear receptacle, and applies to
single or dual pin headers.
Figure 17.15 IPG Receptacle and Setscrew
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2. Keep the hex screwdriver perpendicular to the IPG while inserting the hex screwdriver
through the center of the setscrew plug to vent back pressure accumulated during Lead
insertion.
Caution: In the steps below, always push down on the hex screwdriver while turning it
clockwise until it clicks (begins ratcheting) while ensuring that it is fully inserted in the
setscrew. Also, the hex screwdriver must be inserted into the center of the silicone rubber
setscrew plug and kept perpendicular to the IPG to avoid stripping the setscrew and/or
dislodging the setscrew plug.
Caution: When using the hex screwdriver, grasp it by the handle only, as shown in Figure
17.16. Do not grasp any other portion of the hex screwdriver during use, as this may affect its
proper function. Touching the metal shaft while the hex screwdriver is engaged with the
setscrew can conduct an electrostatic discharge into the device circuitry and may damage the
IPG.
Caution: Do not use electrosurgical equipment after the IPG has been introduced to the sterile
field. Exposure to this equipment may damage the IPG.
Figure 17.16 Hex Screwdriver Position
When using the single-receptacle MicroTransponder IPG and MicroTransponder singlepin Lead, insert the Lead connector pin fully into the IPG header (Fig. 17.17, three images).
To allow escape of the back pressure created by insertion, leave the tip of the hex
screwdriver in the slit in the setscrew plug.
Caution: To avoid backing the setscrew out completely when loosening during surgery, use
no more than two counterclockwise turns
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Figure 17.17 Lead Connector(s) Prior to Insertion and Fully Inserted
4. With the hex screwdriver still inserted through the setscrew plug, verify that the connector pin
is fully inserted. The pin should be visible in the area at the back end of the setscrew connector
block. If it is not, remove the pin. To loosen the setscrew, engage the hex screwdriver into the
setscrew, and turn it counterclockwise until the connector pin can be fully inserted. Avoid backing
the setscrew out further than needed for Lead insertion.
5. After verifying that the connector pin has been fully inserted, tighten the setscrew by
engaging it with the hex screwdriver and turning the hex screwdriver clockwise until it begins to
click. Always push in on the hex screwdriver while turning it to ensure that the hex screwdriver is
fully inserted in the setscrew.
Caution: It is important to do the following:
•
•
•
•
Ensure that the Lead receptacle(s) is clean and free of obstruction.
Carefully insert the Lead connector pin(s) into the Lead receptacle(s) without bending
the Lead connector(s).
Visually inspect that the connector pin(s) is clean and completely inserted.
Electrical connection to the IPG is not established until the setscrew is completely
tightened with the hex screwdriver. Failure to make a good connection can result in
HIGH impedance during a Lead Impedance Check or erratic stimulation at varying
intensity due to rapid, unpredictable changes in Lead impedance, which is expected to
adversely affect device effectiveness and may have serious safety consequences.
55 | P a g e
•
Gently grasp and pull on Lead connector boot (the thick section of the Lead) to verify the
Lead is properly secured inside the Lead receptacle. Do not pull on Lead body (thin
section) or use excessive pull force, because doing so may cause Lead damage.
17.10 Test the Serenity System
The Lead Impedance Check, which should be conducted first, is performed with the Lead and
the IPG connected. Thus, if the Lead Impedance Check is successful, both components are
working properly. However, if the Lead Impedance Check fails, either of the two components
could be defective, or there may not be a good electrical connection between the IPG and the
Lead connector pin(s). If a defective component is suspected in the IPG, disconnect the Lead,
reconnect to another IPG, and then retest the system again using the Lead Impedance Check.
Caution: During the intraoperative Lead Impedance Check, infrequent incidents of bradycardia
and/or asystole may occur. If asystole, severe bradycardia (heart rate <40 bpm), or a clinically
significant change in heart rate is encountered during a Lead Impedance Check or during
initiation of stimulation, physicians should be prepared to follow guidelines consistent with
Advanced Cardiac Life Support (ACLS).
Additionally, postoperative bradycardia can occur among patients with certain underlying
cardiac arrhythmias. If a patient has experienced asystole, severe bradycardia (heart rate <40
bpm), or a clinically significant change in heart rate during a Lead Impedance Check at the time
of initial device implantation, the patient should be placed on a cardiac monitor during initiation
of stimulation.
The safety of this therapy has not been systematically established for patients experiencing
bradycardia or asystole during VNS Therapy System implantation.
18. INFORMATION AND SUPPORT
If there are questions regarding use of the Paired VNS Therapy Serenity System or any of its
accessories, contact MicroTransponder:
MicroTransponder, Inc.
2802 Flintrock Trace, Suite 226
Austin, TX 78738
Phone: 512-371-4160
Fax: 888-822-5206 or 214-299-8660.
For 24-hour Clinical and Technical Support, call:
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Telephone: 512-371-4160
Internet
www.microtransponder.com
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19. GLOSSARY
AE (adverse event) - Any symptom, sign, illness, or experience that develops or worsens in
severity and/or frequency during the course of the study (i.e., any changes from baseline)
D-01, D-02, D-04 clinical studies (depression studies)- Clinical trials conducted by
Cyberonics. The D-01 and D-02 studies used VNS Therapy in patients with chronic or recurrent
treatment-resistant depression. The D-04 study was a long-term, prospective, observational
study of patients with chronic or recurrent treatment-resistant depression who were being
treated with standard antidepressant treatments, but not VNS Therapy.
Electrode – The mechanical and electrical interface of the Paired VNS Therapy Serenity
System to the vagus nerve. The electrode is part of the Lead.
EMI - Electromagnetic interference
EOL – End of Life – The TAPS software displays an EOL indicator when there is less than 5%
of the battery remaining. EOL indicates that the IPG will cease to function in the very near
future.
ERI – Elective Replacement Indicator – The TAPS software displays an ERI indicator when
there is less than 15% of the battery remaining. This is a warning to the user that the IPG is
quickly approaching EOL and may stop functioning in the near future.
FDA – US Food and Drug Administration
High Lead impedance - Resistance to the flow of output current produced by the IPG, caused
by any of the following: possible fibrosis between the nerve and electrode, dry nerve (during
surgery), Lead fracture, Lead disconnection from the Pulse Generator, or high battery
impedance approaching end of service.
IPG – Implantable Pulse Generator – The stimulator portion of the Paired VNS Therapy
Serenity system, typically implanted in the chest below the clavicle. The IPG provides
stimulation to the vagus nerve through a connected Lead and Lead electrode.
Lead - An implantable part of the VNS Therapy System; delivers electrical impulses from the
IPG to the electrodes attached to the vagus nerve; contains flexible conductive wires within a
bio-compatible insulating sheath.
LIMIT output current - Output current other than that which was programmed; not a sole
indicator of a device malfunction.
Low Lead impedance - Lower than expected resistance to the flow of output current produced
by the IPG potentially caused by a short-circuit condition resulting from a break within the Lead
body or connector boot.
MRI - Magnetic resonance imaging
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MR Unsafe - An item that poses hazards in all MRI environments
Output current - Amount of electrical current delivered in a single pulse of a stimulation,
measured in mA.
Paired VNS Therapy® - VNS delivered by MicroTransponder’s Paired VNS Therapy Serenity
System. The Serenity system pairs VNS with tone therapy.
Pulse width - Duration of a single pulse within a stimulation, measured in μsec.
SAE (serious adverse event) - Any adverse event that resulted in any of the following
outcomes: death, a life threatening adverse experience, in-patient hospitalization or
prolongation of existing hospitalization, a persistent or significant disability/incapacity, a
congenital anomaly/birth defect, or any medical intervention that prevents one of the above.
Serenity – Trade name of the Paired VNS for tinnitus system
Signal frequency - Repetition rate of pulses in a stimulation; measured in number of pulses per
second (Hz).
Signal OFF time - Interval between stimulations when there is no stimulation; measured in
minutes.
Signal ON time - Length of time the programmed output current is delivered (not including
ramp-up and ramp-down times); measured in seconds.
TAPS (tinnitus application & programming software) – Software that allows the physician or
healthcare worker to set the VNS setting and initiate stimulation paired with tones.
UADE (unanticipated adverse device effect) - Any serious adverse effect on health or safety
or any life-threatening problem or death caused by, or associated with, a device, if that effect,
problem, or death was not previously identified in nature, severity, or degree of incidence in the
investigational plan or application (including a supplementary plan or application); also, any
other unanticipated serious problem associated with a device that relates to the rights, safety, or
welfare of patients.
Vagus nerve - Either of the pair of tenth cranial nerves arising from the medulla and supplying
mainly the viscera, especially with autonomic sensory and motor fibers
VNS - Vagus Nerve Stimulation
VNS Therapy® - VNS delivered by Cyberonics’ VNS Therapy System. Paired VNS Therapy is
delivered by the MicroTransponder Serenity System.
WT – Wireless Transmitter – A radio frequency device that connects via a USB plug to the
computers USB port and provides communication with the IPG, used in conjunction with TAPS.
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