There are five main phases to this study. The first phase is baseline testing, second
phase is temporary implant, third phase is post-temporary implant mapping/treatment,
fourth phase is permanent implant, and fifth phase is post-permanent implant treatment.
During each of the three phases, subjects will have laboratory testing sessions and daily
home training sessions. o The frequency of the sessions may vary based on individual
circumstances. The baseline training sessions are expected to occur with a minimum
frequency of once every month and may extend up to a maximum frequency of two times a
week. The specific frequency for each participant will be determined by the PI based on
individual participant needs and the extent of injury. As this is a feasibility study,
the phases are designed to select for subjects that will be most responsive and will
benefit from this strategy.
Phase 1. Screening and Baseline testing/training (up to 6 months, UCLA Semel Institute
for Neuroscience and Human Behavior), the purpose of which is to ensure that each subject
begins with the full benefits achievable by standard rehabilitative respiratory therapy
and has stable baseline of function before they begin epidural stimulation. 12 subjects
will undergo this phase. Maximum inspiratory and expiratory pressure, resting spontaneous
respiratory activity, and respiratory muscle EMG will be measured during this phase.
Subjects on ventilator assist mode (unless or until they can sustain adequate respiration
on their own) will be monitored via pneumotachometer for respiratory frequency changes.
Additionally, subjects will undergo motor and sensory testing. The subjects must show
stable respiratory function before implantation, therefore if a subject is showing small
improvements at 3 months the subject will continue training until they have reached their
maximal effect from training (up to 6 months). Subjects that show stable baseline at 3
months will proceed to Phase 2. If a subject's health worsens, including non-respiratory
functioning, subject will be assessed by appropriate physician and testing will be held
until subject's health has improved and maintains stable for at least 2 months. Subjects
will obtain preoperative clearance and general anesthesia clearance in preparation for
Phase 2.
Phase 2. Temporary Implant (1 day, 24 hours overnight stay, UCLA Medical Center, Santa
Monica). Subjects will undergo temporary stimulator implant surgery. CT scan may be
collected prior for surgical planning if needed by PI. Up to 9 subjects with most
connectivity and evidence of response to baseline testing will undergo this phase from
the pool of 12 subjects in Phase 1 above. The electrode that will be used will be the
same one that will be applied in subsequent permanent trial Phase 4, however a temporary
connector will be placed to an external battery source and no permanent battery will be
implanted. Connectivity of subject will be based on motor evoked potentials and
somatosensory evoked potentials done during baseline testing and evaluated by a clinical
neurophysiologist
Phase 3. Post-temporary implant mapping/treatment. Respiratory ability will be assessed.
Respiratory rehabilitation regimen with the stimulator will be used to re-enable
respiratory function. The length of time of this phase will be dependent on the
participant's response (as explained below) to the implant. The paddle will remain
implanted until a comprehensive assessment of the participant's respiratory response is
conducted by PI. Should the participant fail to exhibit a measurable respiratory
response, the explantation of the paddle electrodes may be performed by the PI, provided
that it is deemed safe to proceed. Extent and amplitude of evoked responses and motor
pools activated from electrode pairs will be analyzed through EMG obtained. Response to
the temporary stimulator implant will be based on tidal volume and spontaneous
respiratory rate and respiratory muscle EMG. The same 9 subjects from Phase 2 will
undergo this phase. Maximum inspiratory and expiratory pressure, and respiratory muscle
EMG measurements will also be collected during this Phase.
Phase 4. Permanent implant procedure (1 day, 24 hours overnight stay, UCLA Medical
Center, Santa Monica). Subjects will undergo stimulator implant surgery. Up to 6 subjects
with most connectivity and evidence of response to baseline testing will undergo this
phase from the pool of 9 subjects in Phase 3 above. The functional respiratory circuit
connectivity of the subject will be based on implanted spinal cord stimulator-induced
spinal evoked respiratory muscle potential changes. Response to stimulator
implant-induced respiratory facilitation will be evaluated based on intraoperative minute
ventilation, tidal volume, and respiratory muscle EMG before and after the spinal
stimulation. Subjects will be monitored overnight following surgery as a pre-cautionary
measure. Ventilated subjects undergoing surgery are not at an increased risk over
non-ventilated subjects.
Phase 5. Post-permanent implant mapping/treatment (up to 12 months, UCLA Semel Institute
for Neuroscience and Human Behavior) in which the electrode pair or pairs that maximally
activate the largest number of respiratory motor pools will be identified based on the
extent and amplitude of evoked responses in the respiratory muscles. Connectivity of
subject will be based on motor evoked potentials and somatosensory evoked potentials done
during baseline testing and evaluated by a clinical neurophysiologist. Response to
respiratory training will be evaluated based on pulmonary function tests (including tidal
volume, maximum inspiratory and expiratory effort, spontaneous respiratory activity) and
respiratory muscle EMG. Once optimal parameters have been identified, electrode pairs
that allow subjects to manipulate their respiratory frequency with concomitant
diaphragm/intercostal EMG activity, subjects will be allowed to use stimulator at home
(daily, with identified parameters) with respiratory training in addition to weekly (or
monthly) testing. Each subject will undergo stimulation up to twice a week in the clinic
and daily (with identified parameters) up to 12 months. Extent and amplitude of evoked
responses and motor pools activated from electrode pairs will be analyzed through EMG.
Respiratory rehabilitation regimen with the stimulator will be used to re-enable
respiratory function. 6 subjects will be tested up to twice weekly in the clinic for up
to 2 hours per session. Pulmonary function tests (including maximum inspiratory and
expiratory pressure, resting spontaneous pressure, and initiated breaths) will be
evaluated weekly or monthly. Post-implant MEP/SSEP, SCIM3, FIM, ISNCSCI, SCI-QOL testing
will be conducted at a minimum of one timepoint during this phase of the study. For
patients with a ventilator, home use will involve turning on the stimulator, breathing
with the ventilator, and turning the sensitivity of ventilator assist mode up, working to
strengthen the muscles for initiated breaths. The same 6 subjects from Phase 4 will
undergo this phase.
Timeline. The study is a safety and feasibility trial. This is a single arm implantation
of permanent electrode to assess safety and early efficacy of cervical spinal epidural
stimulation to improve respiratory function. It is conducted over a period of up to 6
months or 21 months in 1, 2, or 3 periods, respectively: Phase 1. Baseline training (up
to 6 months), Phase 2. Temporary Trial Implant (1 day), Phase 3. Post-temporary trial
implant treatment (the length of time of this phase will be dependent on participant's
response to the implant), Phase 4. Permanent Implant (1 day, with up to 2 months for
surgical recovery), Phase 5. Post-permanent implant treatment (up to 12 months).
Therefore, 12 subjects will be involved for up to 6 months, while 9 subjects will be
involved for up to 7 months, and 6 subjects involved for up to 21 months (18 months of
testing with up to 2 months recovery).
Home Use. To ensure safety, the ventilator will provide support for the patient during
home use with stimulator turned on, just as it does when epidural stimulation is not on.
The patient will not be completely disconnected to the ventilator unless independence
from the ventilator is achieved through a gradual and very closely supervised weaning
process in which the patient will demonstrate stable O2 saturation and adequate minute
ventilation through the stages of weaning. Weaning (and evidence of improved respiratory
muscle function) will consist of gradually reducing the level of support delivered by the
ventilator while requiring that as weaning occurs, the patient maintains stable minute
ventilation on his own.
To ensure safety, these weaning maneuvers will be conducted only with respiratory
therapist being present, and an AMBU bag with supplemental O2 will be available.
Additionally, for safety, the caregiver will obtain heart rate, blood pressure,
temperature at 15 min intervals and O2 saturation continuously, or when there is a change
in the ventilator setting. Additionally this will be performed only when the subject is
fully conscious, awake, and following commands.