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Human Algometer - Prototype Development

Requirements & Specifications Document

I. Prototype Description & Objective The algometer represents the integration of neurospecific electrical sensory stimulation and near infra-red spectroscopy response signals under programmable, automated control of evaluation cycles established to:

A. Provide an objective measure of response to known intensity of stimulus that affect sensory nerve fibers and allow the determination of the stimulus detection threshold. Such measure is especially suitable for use in non-verbal patients but with utility for verbal patients of all ages,

B. Provide a diagnostic characterization of stimulus response (e.g., neuropathic pain, hyperalgesia etc.), and

C. Provide an objective measure of analgesic impact on stimulus detection threshold. D. With repeated measures of analgesic impact, determine the onset of tolerance or

opioid induced hyperalgesia.

II. Background Technology of the Functional Components

The algometer is comprised of three “functionalities” or components to be housed in one test/monitor unit:

A. Neurostimulator

In order to deliver stimulus at frequencies known to cause depolarization of specific sensory nerve fibers (C fiber, Aδ fiber, and Aβ fibers), we will use the sine-wave electrical frequencies indicated in the table below The electrical stimulation paradigm that will be incorporated in the algometer is the delivery of specific frequencies (Hz) of electrical stimulation at variable intensities (mA) to an area of a patient’s body (e.g. finger) to selectively test the three pain fiber pathways (termed C, Aδ and Aβ). In adults when the median nerve is stimulated, perception of these frequencies occurs at the following average intensities: 0.5 mA (5Hz, C fiber), 0.85 mA (250 Hz, Aδ fiber) and 2.3 mA (2000 Hz, Aβ fiber).

Fiber Prevalence Myelination Diameter(µm)

Stimulation (Hz)

Conduction Velocity

(m/s)

Lidocaine Blockade

Onset (min)

C (slow pain) 80% No 0.2-1.5 5 0.3-1.5 4

Aδ (fast pain) 10% Yes 2-5 250 12-30 6

Aβ (light touch) 10% Yes 5-12 2000 30-75 11

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There is an FDA approved device (Neurometer) that uses this paradigm of electrical stimulation. It is used for an electrodiagnostic test that objectively evaluates sensory nerve functional integrity by measuring neuroselective current perception threshold (CPT) as an indication of pain perception threshold (PPT), the point at which a current stimulus begins to become painful. CPT/PPT has been shown to be helpful in the diagnosis of neuropathies and to have low variability among adults. The original device received FDA approval in 1986. For this prototype, we will only require the ability to deliver these three frequencies at variable intensity under programmed control. More information on the physiological basis and clinical uses of the original neurometer is found in the attached reference document (Neurometer Clinical & Research Update Booklet.pdf).

B. Near Infrared Spectrometer (NIRS) & Cerebral Oximetry NIRS consists of a system of disposable tranducers (sensors or “optodes”) capable of producing optical signals in the 650 – 1000 nm range from light emitting diodes situated adjacent to detectors that receive the non-absorbed reflected photons from placement over the cerebral cortex of the patient, converting that data into electrical signals which are then sent through pre-amplifiers to a monitor that interprets these signals into a meaningful hemodynamic measure. By employing several wavelengths and time resolved (frequency or time domain) and/or spatially resolved methods, aspects of hemodynamic relevance (e.g. blood flow, volume and oxygenation) can be quantified. Recent data have demonstrated the utility of NIRS to discriminate “pain” signals in the somatosensory cortex of neonates. In this regard, NIRS functionality will be incorporated into the algometer to assess individual sensory fiber responses to neurostimulation. Contrary to vocalization in response to the electrical stimulation (i.e. “I feel that”, “this is painful”) commonly used for diagnostic purposes in adults, the algometer will use changes in the somatosensory cortex oxygenation as measured by NIRS as the physiologic evidence of stimulus detection. These changes in turn can also be utilized to represent the detection of noxious stimuli and could be altered by clinical interventions such as analgesics. In assessing pain signals, NIRS is to be configured to measure physiological (hemodynamic) changes in cerebral (somatosensory) responses to various stimuli including those provided by electrical stimulation at different frequencies (5, 250, and 2000Hz) and those often delivered during the course of clinical care such as venipuncture, endotracheal tube suctioning, dressing changes. The occipital cortex, as it has no pain related representation, will be used as the control site for NIRS changes that can occur and are non-pain related. Current interpretation of differential NIRS absorption data into values such as oxygen saturation or blood flow will not be required in this prototype. Instead, the intensity of stimulus (electrical or otherwise) that elicits differential responses in the NIRS measurements (such as the raw data for the photonic absorption of oxy-hemoglobin (HbO2) and deoxy-hemoglobin (Hb) respectively) will define a stimulus detection threshold (SDT) and can be synthesized into a “pain score”.

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Emitter

Scalp

Brain

Emitter

Conventional NIRS cerebral oximeters use a single emitter and two detectors for the optical measurements (e.g. Somanetics). The mean penetration depth of the photons is proportional to the distance between the emitting source and receiving detector. Consequently the detector (scalp or near detector) located closer to the light source measures saturations within the scalp, whereas the detector located further away measures both cerebral as well as scalp saturations (brain or far detector). For example, hemoglobin molecules within capillary red blood cells are measured by each detector at the wavelengths of 730-775 nm (deoxyhemoglobin), 810nm (total hemoglobin) and 850-900nm (oxyhemoglobin). The optical measurement from the shorter path (representing extracranial blood oxygen) is subtracted from the longer path (representing intracranial and extracranial blood oxygen) to isolate measurements for intracranial blood oxygen. Any surface and shallow tissue variation between the two detector sites can introduce error into the measurement.

An alternative is a dual emitter and dual detector sensor topology (e.g. Nonin Medical) to provide improved accuracy and repeatability by removing the error due to skin coupling or surface and shallow tissue variations. Using three alternating wavelengths in the 700 to 900 nanometer range, dual emitters create pairs of reflected light paths

through surface tissue to the shallow receiver and through the cerebral cortex to the far receiver. The system algorithm first uses the dual emitter architecture to remove surface effects that modulate light amplitude and then uses the shallow path to remove the surface tissue components from the deep path signals — resulting in a cerebral cortex measurement that is unaffected by intervening tissue or surface effects. The example below is of hemodynamic responses in neonates to heel lance. Stimulus-response latencies vary by age in neonates from approximately 9-20s. Data are from Slater et. al. J. Neuroscience 26: 3662 (2006). Details are provided in the attached paper.

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Hemodynamic response in the youngest infant. A sample trace in the youngest infant (25+5 weeks PMA) is shown, demonstrating the evoked change in [HbT] in the contralateral and ipsilateral somatosensory cortex after a painful stimuli given at t=20 s. Sampling frequency, 6 Hz.

Hemodynamic Response: sample trace in a single infant (29+5 weeks PMA) demonstrating an evoked change the somatosensory cortex. Stimulus given at t=20s. Sampling frequency, 2 Hz.

C. Computer Circuitry and Software The third component of functionality in the algometer prototype consists of the circuitry and software that controls and integrates the delivery and termination of stimulus (frequency, intensity, duration, and duty cycle), with the detection of the response (changes in intracerebral oxygenation). The program will provide a user interface such that the characteristics of the stimulus and the respective response can be visualized . The software is to be configured to:

1) Contain experimental protocols that allow for variation in stimulus type (electrical, clinical stimulation), frequency, intensity, duration, duty cycle, and will be stored in a spreadsheet format. This file contains the permutation of electrical stimulus frequencies, minimum and maximum amperages for each frequency, as well as the duration and pause timings for each stimulus.

2) The program provides visual feedback to the user as to the electrical stimulus

frequency, intensity, and repetition. The investigator can manually stop a stimulus (due to missed responses detection), inform the program of false response detection, or abort the entire procedure if necessary. A handheld remote control and display device allows a single person to operate the system while still paying close attention to the patient.

3) Perform looped stimulus-response evaluation tests of various stimulus

(electrical or clinical)in patients under conditions of administration or withdrawal of analgesic therapeutics,

4) synthesize NIRS data into a meaningful stimulus detection threshold (SDT)

store and/or transmit relevant patient data as well as necessary threshold notifications and alarms.

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Lastly the prototype design will be considered in two form factors:

1) Fully wired, all stimulus and response leads are wired directly back to the control unit (Figure 1a), or

2) where the stimulus and response leads go to a wireless control/transmitter unit (placed in proximity to the patient) which functions to transmit control commands and data to/from the monitor within a reasonable range (e.g. to a rack unit, rolling unit, and or to a nurses station or any combination thereof) thus providing an enhanced aspect of ambulatory care (Figure 1b).

Either unit will be designed only for single patient use and dedicated evaluation protocols. It is not intended to monitor more than one patient at a time. Leads and sensors requiring adhesive attachment will be “disposable”. III. Additional Technical Specifications

A. Neurostimulator • Output Frequencies: 5, 250 and 2000 Hz (non-variable), serial (as opposed to parallel

stimulation outputs) • Output Current (Intensity): 0 – 10 mA constant AC (sinusoidal, single 180 degree or 360 degree) • Output Increments : 0.05 – 0.25 mA (adjustable) • Output Resolution : 0 – 40 µA (+/- 20 μA, p<0.006) • Output Intervals : dependent upon response detection latency • Output Duration: < 200 milliseconds (adjustable) • Calibration: Digital quartz

As part of the prototype development agreement, we will provide a Neurometer Model CPT/C from Neurotron, Inc. (Baltimore, MD) and its technical manual for testing and engineering design considerations. We or the prototype developer can obtain the necessary cables and disposable electrodes for initial testing:

Neurometer® CPT® Electrode Cables are lightweight lead wires terminated with spring loaded molded electrode holders. Item No.: CBEX-4A Electrode Cable. Length: 36 inches. Goldtrode® Disposable Electrodes provide a consistent, distortion free interface between the neuroselective electrical stimuli and skin. The 22k gold plated electrodes are paired together using a flexible spreader to standardize the distance between them. They are cupped to accommodate sufficient Goldtrode® electrode gel to maintain a consistent output current density for reliable, repeatable results. These are disposable electrodes designed for single-use only.

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B. NIRS General specifications across manufacturers • Light source: Light/laser emitting diodes (LEDs) modulated at 2kHz • Examples: 730 and 810nm (Somanetics); 690, 780, 805, and 850nm (CAS Medical

Dual Channel); 730, 810, and 880nm (Nonin Medical Dual Emitter); 775, 810, and 850nm (Hamamatsu, Japan/EU); 780, 805nm and 830nm (Shimadzu, Japan)

• Photo detector: Photodiode (monolithic) • Patient irradiation level: Class I (FDA Safe Level) • Measurement method: Spatially resolved spectroscopy • Sample interval: variable depending on neurostimulation cycle and NIRS response

latency. As part of the prototype development agreement, we will provide an INVOS® Model 5100C Cerebral Oximeter from Somanetics, Inc. (Troy, MI), now a wholly owned subsidiary of Covidien, and its technical manual for testing and engineering design considerations. The unit consists of the monitor, 2 preamplifiers with cables, and reusable sensor cables. It is the current plan to utilize the commercially available, disposable NIRS sensors from Somanetics. These come in adult, child and neonatal sizes. We or the prototype developer can obtain the necessary disposable one-time use sensors:

SAFB-SM Disposable OxyAlert™ NIRSensor Adult (>40 kg) SomaSensor® for Infants and Neonates

An alternative disposable sensor is available from Nonin Medical (Plymouth, MN) as part of their Model 7600 regional oximeter and 8000CA sensor with dual emitter and dual detector system. We however cannot provide the Model 7600 at this time.

C. Software A possible software process flow is depicted in Figure 2. Protocols could consist of the following:

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1. Exogenous Stimulus Evaluation: Noxious stimuli (e.g. heel lance, intravenous needle, etc.) common to pediatric treatments are introduced and NIRS responses are recorded directly without neuroselective fiber stimulation. These protocols will build a database of elevated somatosensory responses and establish a “pain index” or scale. From this scale, a stimulus detection threshold (SDT) can be established that provides “sub-pain” fiber assessment (See Figure 3). NIRS signals from the control (occipital) regions of the brain can be utilized to further discriminate true pain related signals from other brain activity.

2. Baseline Fiber Response & SDT Validation:

Baseline fiber activity can be monitored in the absence of neuroselective fiber stimulation. In addition, tactile stimulation (e.g. alcohol swipe, etc.) can be introduced and NIRS responses recorded and compared to Aβ fiber stimulation at 2000 Hz as outlined below. The neurostimulation/response evaluation cycles repeat until a desired (defined) response is achieved. Each “loop” consists of a change in intensity at constant frequency followed by an appropriate latency period for the NIRS response. As intensity at any one frequency increases, NIRS response will be considered “maximal” for SDT if that response exceeds the predetermined SDT threshold. A repeat of that frequency/intensity could occur to validate that threshold response within an acceptable variance. Repeating the intensity looping for the remaining frequencies will follow. Once all three frequency cycles have occurred, this protocol will end (See Figure 3).

3. Analgesic Evaluation

Once the pain scale, baseline and SDT validation are performed, post-procedural (e.g. surgery, burn, abrasion, fracture, etc.) administration of analgesics and assessment of therapeutic efficacy can be determined over time and after repeated analgesic administrations (See Figure 4).

D. General Speicifications

FDA Device Class: II (likely) Dimensions Monitor: preferably within 16” W x 8” H x 10” D Weight: < 5 lbs desirable unless on roller stand Monitor Cables: ≤ 15 ft. (if to preamplifiers as on Somanetics) Sensor Cables: ≤ 18 - 24 in. Preamplifiers need not be separate from the monitor/control unit.

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User Interface Display: Touch screen command Patient ID and data inputs Program(s) call ups & initiation Event marking (possible Event List - pre-stored for easy call up) Manual override Alarms (adjustable volumes) Run summary (graphics) Diagnostics: Automatic self-tests Export Options Patient “Pain” Response System Display Numerical Value: 0 – 100% or similar index History: (retrievable): up to 24 hrs increments Trend Analysis: Graphics enabled (real time, history and trend) Temperature Operating: 0 to 40° C (+32 to +104° F) Storage: -40 to 70° C (-40 to +158° F) Humidity: 10 – 90% non-condensing Altitude: Up to 12,000 feet Power Requirements and Supply External: 120/240 VAC, 50/60 Hz Battery Life: (if stand alone) > TBD hrs. (based upon weight/size considerations) Fuse: F2.5A, 250V (likely) Internal Storage: RAM: 4GB HD: ≤ 250 GB Output: USB 2.0 (minimum) Network connector (RJ-45) RS-232 IEEE 1394 Wireless 802.11a/b/g/n (optional) Secure Digital (SD), MiniSD, CompactFlash, Type I/II PCMCIA or equivalent (optional) Bluetooth® wireless (optional) with signal strength indicator

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E. Prototype Development Timeline

The preferable delivery date for the completed prototype (“alpha”) is no later than March 28, 2011. Given the turnaround time, the primary goal is to determine that all technologies can be feasibly integrated and signal/response validation be completed to an acceptable degree, either through synthetic response generation models but preferably with a minimum proof-of-principal human (adult volunteer) data. In the latter respect, all technologies need not be necessarily packaged into a single form factor, however, the design considerations for such should be sufficiently developed to assure a reasonable timeline to alpha production. The quote to achieve the above may be phased. If phased, please detail phase milestones, required involvement of resources and consultation on our part for each phase, as well as milestone expenses. Deadline for submission of prototype bid: January 5, 2011. Please feel free to contact us if there are any questions regarding this requirements document. All questions may be directed to: Dr. Larry Mahan 202-476-5024 (office) lmahan@cnmc.org 202-236-9075 (mobile)

5Hz

250Hz

2000Hz Somatosensory

pain signals

Sequentialpain fiber“queries”

AδC AβC +/-Aδ +/-Aβ +/-

Neuro-stimulator(stimulus)

NIRS(response)

control

• Diagnostics• Pain Management

& Compliance• EHR

SDT

1

2

43

5

6

The Human AlgometerRequirements & Specifications – Figure 1a

Clinical Stimuli

5Hz

250Hz

2000Hz Somatosensory

pain signals

Sequentialpain fiber“queries”

AδC AβC +/-Aδ +/-Aβ +/-

The Human Algometer

NIRS(response)

control

• Diagnostics• Pain Management

& Compliance• EHR

SDT

Requirements & Specifications – Figure 1b

1

2

43

5

6Neuro-stimulator(stimulus)

Clinical Stimuli

Set first stimulus frequency

Turn stimulus off

Wait 60 sec

Increment stimulus intensity

Neurostimulation LoopFigure 2

Set stimulus intensity (initial)

Detect NIRSSignal?

Yes

No

Turn stimulus off

Initiate stimulus

Has __ timeexpired?

No

Yes

No

Wait __ sec

Yes No

Set next stimulus

frequency

Is NIRSresponse

+/-10% prior?

Last stimulus

frequency?

Notify end of protocol

YesNo

Wait ___ sec Store patient data

Is stimulus intensity > max?

Yes

Noxious Stimuli Threshold

SDT

Noxious StimuliIntroduction

Pain - SDTDetermination

100

75

50

25

0

Baseline & ControlDetermination

SDT ValidationTime (sec/min)

Alarm 1

Alarm 2

Notify 1

Notify 2

Aδ

C

Aβ

Set thresholdvalue/range

5Hz200 Hz2000Hz“loops”

Baseline Activity

Protocol Examples – Pain & SDT EvaluationRequirements & Specifications – Figure 3

Noxious Stimuli Threshold

SDT

Post-surgicalEvaluation

AnalgesicAdministration

AnalgesicEvaluation

100

75

50

25

0

AnalgesicBreakthrough

AnalgesicAdministration

AnalgesicEvaluation

Time (min) Time (min)Time (hrs) Time (hrs)

5Hz200 Hz2000Hz“loops”

Alarm 1

Alarm 2

Notify 1

Notify 2

Baseline Activity

Aδ

C

Aβ

Protocol Examples – Analgesic EvaluationRequirements & Specifications – Figure 4