Q&A

We have learnt that many of our users have that “one special” question that they would like to ask. So we have tried to collate all the questions that we have been asked over the years into one place in order to assist all of our users. If there is a question that is till unanswered, pls contact us at [email protected];

CCI is a correlation Index between Mean Arterial Pressure (MAP) changes and Cerebral Flow Index (CFI) changes. It indicates the response of cerebral blood flow to changes in systemic blood pressure, thus may imply on the patient’s auto-regulatory state.

The c-FLOW™ Monitor mentioned above is not cleared for sale with the Autoregulation indication.

A high CCI value (close to 100) stands for high correlation between MAP changes and CFI changes meaning that CFI behaves similarly to MAP and each MAP modification is followed by a corresponding CFI change. Lower CCI values (close to 0) indicate that there is no correlation between MAP and CFI behaviors. That is to say that though MAP might be changing significantly, CFI will not change accordingly. It is well known that this is the case when cerebral autoregulation is intact.

The c-FLOW™ Monitor mentioned above is not cleared for sale with the Autoregulation indication.

CCI monitoring is continuous, however a value will be displayed on the screen only when a significant MAP change exists. CCI represents the correlation between MAP changes and CFI changes. Thus, when there is no change in MAP, CCI value cannot be evaluated.

The c-FLOW™ Monitor mentioned above is not cleared for sale with the Autoregulation indication.

The CCI parameter is calculated in real time based on synchronic MAP and CFI values. However, a processing delay exists, due to device’s data collection for the CCI calculation.

The c-FLOW™ Monitor mentioned above is not cleared for sale with the Autoregulation indication.

If you wish to display CCI values when they are absent, a MAP change should be enforced. An induced MAP challenge (either using drugs or other techniques) for a period of over 1 min should assist and activate the CCI values during the manipulation period.

The c-FLOW™ Monitor mentioned above is not cleared for sale with the Autoregulation indication.

Introduced at the 12th Annual Neurocritical Care Meeting in Seattle in late 2014, the c-FLOW™ is a non-invasive, continuous, real-time, bedside stand-alone tissue/ cerebral blood flow monitor used to assist in understanding patient’s tissue / brain perfusion status. The c-FLOW™ is a non-invasive monitor of deep tissue microcirculation blood flow, used to monitor relative changes in blood flow. Its interface with the patient consists of maintenance-free disposable “Smart-Pads” and the operation of the system does not require additional personnel, as the bedside nurse can operate it with minimal training. Information presented on the monitor’s screen provides nurses and physicians with timely indications of changes in blood flow, enabling timely and effective decisions by the clinical staff. The operation of the c-FLOW™ Blood Flow Monitor is based on Ornim Medical’s patented technology, UTLight™.

The revolutionary UTLight™ technology utilizes weak acoustic beams to identify light emerging from deep tissue layers. Neurocritical Care physicians, intensivists, surgeons, anesthesiologists and other medical professionals may use the information provided by the c-FLOW™ Blood Flow Monitor, in conjunction with other available monitoring systems, to determine critical changes in tissue microcirculatory blood flow levels and to improve patient care.

The c-FLOW™ monitor detects changes in cerebral blood flow that may have a negative effect on a patient’s outcome. It may also indicate the state of autoregulation when compared to changes in Mean Arterial Pressure. The use of the c-FLOW™ monitor will assist in the dynamic management of blood pressure, CO2, ICP and other factors influencing CBF and cerebral tissue perfusion. This dynamic management is important in tailoring treatment in the ICU for TBI, SAH, ICH and stroke patients and in the OR for a wide range of patients including CVS, aortic, valves repairs, CEA and various high risk procedures where cerebral perfusion may be disturbed.

Unlike most other organs which can tolerate brief hypoxia, the brain requires a steady delivery of oxygen and glucose. This is accomplished primarily through carefully controlled Cerebral Blood Flow (CBF). Underscoring the importance of CBF are the observations that the adult human brain uses about 20% of cardiac output and that blood normally takes up about 10% of the intracranial space. iAbout 20% of the oxygen and 25% of the glucose consumed by the human body are dedicated to cerebral functions, yet the brain represents only 2% of the total body mass. While the brain is a high energy-consuming organ, it contains little energy reserves and is therefore highly dependent upon the uninterrupted supply of energy substrates from the circulation. Impairment in this process results in perturbation of neurological function as severe as loss of consciousness, and coma within minutes.

In practice, CBF is determined by a number of factors, such as the viscosity of blood, diameter of blood vessels. The net pressure of the flow of blood into the brain, known as Cerebral Perfusion Pressure (CPP), is determined by the difference between arterial pressure entering the brain and intracranial pressure. Under normal conditions, a variety of autoregulatory mechanisms maintain CBF in the necessary range.

CBF is tightly regulated to maintain constant blood flow and meet the brain’s metabolic demands and on average, s maintained at a flow of 50mL of blood per 100g of brain tissue per minute. iiBlood flow in excess (hyperemia) can raise intracranial pressure (ICP) and compress critical brain structures, including those that control heart rate and respiration. At the same time, insufficient perfusion leads to ischemia, a biochemical cascade characterized by insufficient oxygen delivery, insufficient energy substrates delivery and metabolite clearance. Since neuronal metabolic pathways require the ongoing presence of oxygen (carried by hemoglobin in the blood) and glucose, if the ischemic state is not rapidly reversed, tissue death ensues which could lead to neural impairment. For this reason, in conditions such as shock, stroke, and traumatic brain injury, it is critical for caregivers to have ongoing understanding of CBF that will facilitate educated interventions to maintain CBF.

For these reasons, monitoring of cerebral blood flow is a real clinical need. Currently, physicians have limited tools to assess tissue perfusion to guide treatment accordingly. Cerebral blood oximetry is often used as a proxy for blood flow; this does not necessarily represent actual CBF, however. For instance when metabolic demand increases, blood flow increases too, while tissue microcirculatory oximetry decreases due to higher consumption. Suffice it to say that cerebral oximetry is a nuanced measure that can be challenging to interpret, if not misleading. Therefore, the ideal tool should be a direct CBF monitor, simple, and non-invasive providing a reading of tissue perfusion parameters in a relatively rapid and inexpensive fashion.

Flow is an actionable parameter, put simply, and physicians can manipulate blood flow by varying blood pressure, ventilation and medication. Feedback on these changes is imperative for management of blood pressure during cardio-pulmonary bypass and management of brain injured patients. According to the Brain Trauma Foundationiii guidelines for management of Cerebral Perfusion Pressure (CPP), ancillary monitoring of CBF, oxygenation and metabolism can facilitate CPP management.

Physicians care about flow: Monitoring Cerebral Blood Flow (CBF) is importantiv for managing patients suffering from head trauma, stroke or even under general anesthesia. In many such cases, changes in oximetry are used as a proxy to reflect changes in the underlying flow. Instead, Ornim’s UTLight™ technology provides this parameter directly. Recent studies have explored the use of Near Infrared Spectroscopy (NIRS) in assessing technology in assessing patient changes when regional blood flow is a primary concern for physicians. In many such cases, changes in oximetry are used as a proxy to reflect changes in the underlying flow.

Assessing Autoregulation function requires continuous monitoring of CBF: Impaired cerebral Autoregulation may predispose to stroke injury in patients undergoing cardio-pulmonary bypass surgeryv. Ornim’s technology provides continuous, real-time readings of changes in CBF, and combined with blood pressure or ICP readings can be used to assess Autoregulation function.

Oximetry is not a direct surrogate for blood flow: Changes in oxygen saturation may not reflect changes in blood flow, and may not be in the same directionvi. A vessel occlusion will lead both to a decrease in target tissue oximetry and blood flow. However, as a septic patient’s tissue oxygen demand grows, oximetry readings should decrease, whereas blood flow will likely increase to accommodate. Changes in oximetry are not always as dramatic as changes in flow. The flow parameter can provide an early indicator of possible changes in a patient’s status. On the other hand, rCBF, as tracked by the Cerebral Flow Index (CFI), is simple and easy to interpret. Flow is negatively affected strictly by insufficient arterial inflow, reduction of venous outflow, or impairment of autoregulation.

In the original Danish Study, Schytz et alvii found that the measurement of flow was of vital importance. This study, which utilized Xenon-SPECT flow measurements, clearly demonstrated that oximetry alone provides only a partial and narrow view of the actual changes in oxygen delivery to the tissue. This study has shown that in healthy volunteers it is not possible to obtain reliable reflections of changes in CBF using conventional NIRS oximetry. If this holds true in healthy volunteers, how much more so in patients with a presenting condition?

It should be noted that many of the interventions offered by Covidien/Somanetics and CASMED to correct problems with cerebral oximetry are related to flow. Such interventions include increasing MAP or cardiac output. But with no proven correlation between flow and oximetry, how would a physician know how to treat a patient? The combination of this study and the results from the Xenon study Ornim has done which does show correlation between the CerOx™ flow parameter and the Xenon flow should be a strong driver for the recognition of the need for a flow parameter. While Ornim might not provide a treatment protocol, added information on a physician’s patient should help guide which intervention s/he chooses.

Understanding changes in tissue perfusion can assist physicians in focusing and tailoring treatments when the perfusion to a specific tissue is at stakeviii. Currently, there is no solution that enables localized flow monitoring continuously and non-invasively.

UTLight™ technology, developed by Ornim, utilizes laser light which is introduced into a tissue, much like other Near Infrared Spectroscopy (NIRS) based devices that monitor cerebral oximetry. However, only the c-FLOW™ monitor adds rapid, brief, focused pulses of ultrasound into the tissue over the volume of interest through which light passes. Propagating through tissue slower than the light does, these ultrasound pulses create an effect, similar to the Doppler Effect, on the light photons they encounter. As time progresses, the ultrasound pulse penetrates deeper into the tissue, and the phase of light emanating from this depth is shifted, or “tagged” accordingly, and can be identified later. Using this tagging mechanism, light collected by the monitor’s photoSensor can be filtered serially as a function of time, corresponding to relative depth, to analyze the photons emanating from a predetermined tissue volume, roughly 1cm3. The greater the flow, the greater the shift – the amount of this disturbance or shift is presented as Cerebral Flow Index (CFI).

The first unknown: the volume of tissue light collected emanates from or, the actual path length taken by photons. Reflected light may have come from skin, bone, or deeper tissue. The algorithmic calculations to attain an average depth in several devices may still be affected by skull size, skin pigmentation, and other factors, so physicians cannot always be sure which tissue they’re measuring.

The second unknown: the effect of other factors on the collected light signal. Changes in blood flow can greatly affect the quality of the oximetry signalix. And flow at shallower depths might affect the accuracy of the oximetry measurement from the target tissuex. Ornim’s UTLight™ technology solves both of these problems.

UTLight™ Flowmetry

NIRS-based technology provides a “clean” reflection of oxygen saturation in a patient’s microvasculature when tissue is static. Live tissue is never static; blood is moving all the time… and the higher the blood flow, the broader the Doppler shift of the scattered light. Current NIRS-based cerebral oximeters cannot assess this shift, and therefore cannot measure blood flow directly. The UTLight™ algorithm analyzes the Doppler shift of the tagged light signal to non-invasively determine a patient’s blood flow in the microcirculation underneath the Sensor.

The c-FLOW™ shines laser light into a tissue, much like other NIRS-based devices. However, only the c-FLOW™ adds rapid, brief, focused pulses of ultrasound into the tissue over the volume of interest through which light passes. As time progresses, the ultrasound pulse will penetrate deeper into the tissue, and the phase of light emanating from this depth will be shifted, or “tagged” accordingly, and can be identified later.

Using this tagging mechanism, light collected by the c-FLOW™ photoSensor can be filtered serially as a function of time, corresponding to relative depth, calculating flow can be done differently now, focusing the measurement only at a determined volume, we can forego assumptions about path length and light dissipation through the tissue. And, with a predetermined tissue volume, readings are almost unaffected by changes in surrounding blood flow or other tissue parameters such as skin color. This increases the confidence that oximetry measurements derive from the desired volume such as the brain or muscle tissue, by reducing contamination from tissue layers. In other words, c-FLOW™ reads dynamic information (Doppler shift equates to flow) rather than just the absorption. Secondly, it can screen out flow signal that originates from non-cerebral tissue layers, focusing on a deeper region of interest that correlates with cerebral microvasculature.

This gives the c-FLOW™ monitor the distinct advantage of being the only device on the market that directly measures flow continuously and non-invasively, rather than relying on a surrogate marker like oximetry.

Despite the tremendous growth in the field of NIRS-based regional oximetry monitoring, concerns have been raised regarding the accuracy of the measurement. Using algorithms and different “spacing” methods, regional oximeters attempt to target brain tissue, but in no instance is there a defined volume of tissue measured. Thus, often the light signal can be contaminated by superficial circulation and other factors, reducing physician confidence that oximetry measurements derive from the tissue of interest, the brain. In fact, recent studies have demonstrated that the cerebral oximeters of all three US industry manufacturers are affected by superficial blood flow, which contaminates the signal.

In addition, most cerebral oximeters claim to monitor “perfusion” though only displaying oximetry measurements. To better understand perfusion, physicians must not only monitor the amount of oxygen in the tissue, but the delivery of oxygen to the tissue, i.e. blood flow. While oximetry is often used as a proxy for blood flow, there are many clinical scenarios in which changes in flow will differ from oximetry in their dynamic response, magnitude of change and even with a different trajectory (where tissue oxygen demand increased resulting in high oxygen extraction [lower rSO2] and increased blood flow). Many of the interventions clinicians use to maintain and adjust tissue perfusion are based on changing blood flow rather than oxygen fraction.

The set depth for sampling is based on the majority of human skull thickness and distance from skin to cortex. Furthermore, we have successfully validated UTLight™ against other brain blood flow measurement modalities, in both animal and human models. Tight correlation was shown between the trends in Cerebral Flow Index (CFI) and flow data from:

  • Laser Doppler
  • Thermodiffusion Sensor
  • 133Xenon-SPECT
  • Transcranial Doppler

It is worth going into a bit of detail over one of our most key studies (the Denmark study):

A New Technology for Detecting Cerebral Blood Flow: A Comparative Study of Ultrasound Tagged NIRS and 133Xe-SPECT study. Neurocrit Care. 2012 Aug;17(1):139-45 . Henrik W. Schytz, Song Guo, Lars T. Jensen, Moshe Kamar, Asaph Nini, Daryl R. Gress, Messoud Ashina

In this study, UTLight™ was compared to isotopic Xenon Single-Positron Emission Computed Tomography (133Xe-SPECT), which is considered the “gold standard” for accurately measuring cerebral blood flow. Additionally, Diamox (acetazolamide), a potent carbonic anhydrase inhibitor, was injected during this study, causing dilation of the precapillary arterioles and increasing cerebral blood flow. Changes in CFI indeed correlated with changes measured by 133Xe-SPECT, and a significant increase in rCBF with Diamox administration was nicely demonstrated.

  • A defect in the skin, scalp or skull at the site of placement
  • The presence of hair follicles
  • An excessively thick skull
  • Brain tissue shifted out of reach of the UTLight™

In general water is translucent and does not affect the signal, so the changes seen are related to changes in CBF as a consequence of the changes in vasculature resistance. Good example will be brain swelling leading to increased ICP which overcomes vessels filling pressure – decrease in rCBF.

Edema is swelling of tissue caused by the accumulation of water inside or between cells. Edema of the brain (“cerebral edema”) can elevate the intracranial pressure (ICP). As with hydrocephalus, if the ICP becomes great enough, it can cause the microvasculature to collapse creating a limitation of blood flow. Cerebral edema occurs in three phases, all of which may be responsive to intervention:

  1. Acute Cytotoxic – cell membranes become damaged, allowing water to rush into cells, which then become swollen.
  2. Transitional – cells start recovering and healing their membranes, pumping water back out of their cells.
  3. Vasogenic – cells have healed their membranes and fluid is trapped between cells and around blood vessels.
  4. Evaluating the efficacy of cerebral edema countermeasures may be one use for the c-FLOW™.
  • CerOx™ Oximetry vs. Venous Oxygen Saturation

Jugular vein bulb oximetry (Animal): Data from Ornim’s non-invasive Sensor placed on the head was correlated with cerebral mixed venous-arterial saturation (ratio 75:25) measured by co-oximetry of the jugular vein bulb and carotid artery in a swine model during hypoxia and hyperoxia. 12 piglets were anesthetized, ventilated and monitored. The inspired oxygen fraction (FiO2) was lowered to induce hypoxia. Blood samples were drawn 1 minute before the end of each phase (total of 95 samples). O2 saturation was compared to jugular bulb saturation. A good correlation (r=0.85, p<0.001) was observed, that did not depend on subject’s variability.

Venous saturation (Healthy volunteers): The Sensor of the Ornim’s oximeter was placed over the forearm muscles. 20 healthy subjects performed a handgrip exercise during normoxic and hypoxic oxygen inhalation. Venous blood was sampled at the end of each phase of the protocol. Readings of the system significantly correlated with venous blood oxygen saturation as measured by a co-oximeter (r= 0.77, p<0.001).

Jugular vein bulb oximetry (Patients): CerOx™ saturation readings were compared to SjVO2 in a cohort of patients with severe brain injury admitted in a neurocritical care unit. In 10 out of 12 TBI patients, good quality continuous data was obtained from the CerOx™ monitor. Good quality jugular bulb venous data without evidence of non-cerebral contamination was obtained in 8 out of 11 patients. In a majority of patients a significant correlation (r=0.59, p<0.01) was found between ipsilateral CerOx™ measurements of cerebral tissue oxygenation and jugular bulb venous saturation (SjVO2).

  • Clinical Validation: CerOx™ Flow vs. Flow Monitors

Laser Doppler (Animal): A study was conducted aimed at demonstrating the capability of the CerOx™ 3210F to measure flow during pharmacologic and mechanical manipulations on systemic blood flow, and its equivalence to laser Doppler in detecting these manipulations. Study included 6 animals, with 65 manipulations of blood flow, by increasing and decreasing flow. Analysis included ROC analysis and agreement analysis using Cohen’s Kappa coefficient. ROC analysis for each type of manipulation showed the high discriminative power of the CerOx 3210F in detection of decreases and increases in tissue blood flow. The analysis of the difference between the Areas Under the Curve (AUCs) for Laser Doppler and CerOx 3210F measurements demonstrated that the CerOx™ 3210F is equivalent to Laser Doppler (LD) for detecting manipulations in blood flow. Analysis of agreement between Laser Doppler and CerOx™ revealed a significantly robust agreement between the two systems for detecting all events (Kappa = 0.79 p< 0.001).

CBF in traumatic brain injury patients: Data was collected on TBI patients, undergoing extensive neuromonitoring. CerOx™ signals corresponding to CBF were compared to invasive CBF measurements using a thermo-diffusion Sensor (Hemedex, MA). Readings of the two monitors were compared during physiologic challenges of hyperventilation. Hyperventilation challenges were performed to assess cerebral CO2 vasoreactivity.

  1. In 5 out of 6 patients good quality continuous flow data was obtained from the CerOx™ monitor
  2. Data from 10 hyperventilation challenges revealed a close correspondence between invasive measures of CBF (Hemedex) and the non-invasive CerOx™ monitor
  3. The Kappa measurement was statistically significant (p<0.001, Kappa=0.641)
  4. Clinical Applicability

Traumatic Brain Injury: The CerOx™ was used to monitor about 50 TBI patients in three leading hospitals (UCSF, CA UPenn, PA: and Hadassah MC, Israel) in neurointensive care settings. Observational studies included patients monitored with other invasive monitors (such as Jugular vein oximetry, Brain oxygen tension and CBF) that were monitored with the CerOx™ up to 7 days. Patient management was based on existing monitors. Following initial technical improvements, the usability of the system was acceptable and feasible in the neuro-ICU settings. Interim analysis of the data from 11 patients shows good correlation between CerOx™ saturation readings and SjVO2 readings. In addition, a good agreement between CerOx™ flow measurements and CBF by thermo-diffusion was observed.

Sub-Arachnoid Hemorrhage (SAH): Subarachnoid Hemorrhage patients, Hunton-Hess grade 3-5, in ICU settings were monitored. Initial experience with 10 patients, monitored for short periods of time, CerOx™ Sensors were tolerated by both awake and sedated patients. Initial data from these patients is currently analyzed. In the future, longer monitoring periods will be evaluated and compared to findings of CT-Perfusion. No adverse events were reported.

The US used hin the c-FLOW™ is unidirectional and used only for the purpose of light tagging. Therefore the signal we analyze is light which contrary to TCD/ US Doppler that transmit and receives sound. Transcranial Doppler works on the principle of listening for an ultrasound echo and measuring the Doppler shift of that echo. By determining the degree of shift, TCD estimates the velocity of blood flow in the artery undergoing insonation.

This velocity measurement can be useful to determine certain characteristics of the extracranial and intracranial blood vessels, and a variety of indices have developed around the Mean Flow Velocity parameter. This makes TCD particularly useful to detect the presence of certain conditions, such as cerebral arterial vasospasm or stenosis. Importantly, velocity does not equate to CBF, and it is possible to see an elevation in velocity in an vessel where there is decreased CBF.

Because bone degrades the quality of the echo that TCD requires, there are certain areas of the skull which are thinner and therefore more conducive to use. These windows are found at the orbits, the temporal fossae, and the foramen magnum at the base of the skull.

It is not necessary to obey these windows when using Ultrasound Tagged Light, because UTL does not listen for an echo. Instead, it uses ultrasound to knock photons out of phase, creating a Doppler shift in photons that is measurable. This is called the acousto-optic affect, a well described physical principle of the interaction between sound and light.

So while Transcranial Doppler is all about listening for a change in echo due to Doppler shift, c-FLOW™ is all about watching for a change in light patterns due to the effect of ultrasound.

Measuring a relative change in cerebral blood flow is of high clinical value and is useful as a gauge of the effect of clinical interventions or other changes occurring (example, re-occlusion of vessel in a stroke patient who underwent thrombolysis). The move towards personalized medicine supports this approach. It is important to note that every patient has his own baseline, and the c-FLOW™ bases its relative value based on the individual. And ultimately, it is the response of the relative index to therapeutic interventions that makes c-FLOW™ uniquely useful.

CFI – Cerebral Flow Index – represents changes in microcirculation blood flow in a non-invasive manner. It relates to changes in the measured UTLight™ as it returns to the Sensor, called a “photo-diode.” The greater the flow in the measured territory the more of the light is disturbed. When Interpreting the CFI, it is important to take into account the clinical scenario and the baseline number, then monitor as time progresses and follow the trends. CFI is a relative, unitless number, thus comparison can be made to a baseline number but not between different patients.

  • Cerebral monitoring:
    1. Continuous monitoring in the Neuro ICU
  • TBI patients for blood pressure and CPP management
  • Monitoring of ischemic stroke patients during and post revasculariztion using thrombolytic drugs or endovascular embolectomy
  • Monitoring subarachnoid hemorrhage patients, at risk of developing delayed vasospasm
    • Monitoring patients undergoing carotid endarterectomy c. Monitoring of pediatric and neonates in the ICU (future)
    • Monitoring brain perfusion during and post resuscitation post cardiac arrest e. Monitoring brain perfusion during CVS procedures
  • Muscle/tissue monitoring:
    • Plastic surgery – monitoring flap perfusion
    • Monitoring of vascular disease patients
  • Additional indications:
    • Monitoring of adequacy of hemodynamic resuscitation
    • Monitoring of brain perfusion during any type of CV surgery that may compromise cerebral perfusion
    • Surgery of the aortic arc d. Any type of HLM use
    • Controlled hypotension
  • Monitoring of brain perfusion/oxygenation during ECMO for non-cardiac diseases:
    • Monitoring of muscle blood flow in compartment syndrome
    • Monitoring of muscle blood flow after replantation of extremities
  • Groups of indications:
  • All indications (and more) of the above can be grouped into three distinct functional groups.
  • These groups also well define which clinicians will use the technology:
    • Monitoring of cerebral perfusion in cases of cerebral pathology (TBI, SAH, stroke, etc.)
    • Monitoring of cerebral perfusion in cases of non-neurological pathologies (e.g., cardiac surgeries, vascular surgery, shock/resuscitation, etc.)
    • Monitoring of non-cerebral tissue oxygenation and tissue blood flow d. Local disease (e.g. plastic/reconstructive surgery)
    • Systemic disease (e.g. hemodynamic shock)
    • Emergency medicine (out of hospital)

Sensor placement depends upon the vascular region of interest.

“Anterior circulation” is shorthand for blood flow in the territory of the internal carotid arteries. The main divisions include the paired middle cerebral arteries (MCAs) and anterior cerebral arteries (ACAs). “Posterior circulation” is shorthand for blood flow in the territory of the vertebrobasilar system. The main divisions include the posterior cerebral arteries (PCAs).

For most clinical conditions, monitoring will take place over the anterior circulation or at border-zone regions. The forehead is ideal for placing the Sensors if the anterior circulation is in question. In this case, Sensors are placed over the frontal region, just lateral to the midline and avoiding the frontal sinuses, which can degrade signal quality.

The Sensor can be placed over the occipital region to measure the posterior circulation, but any overlying hair must be shaved. It is important to note that hair follicles have the potential to degrade signal quality, so repositioning may be necessary until adequate signal is obtained.

Cerebral blood flow should be expected to drop because of decreased cerebral metabolism. But to what extent is unknown and probably varies from person to person. It might also vary with the degree and duration of cooling, but this is open to investigation.

Sensors contain highly valuable components, including the Doppler ultrasound transducer, the laser light emitter, and the light-detecting “photo-diode.” They do not contain the source (laser) and the Sensor (photo diode), but the optical fibers which lead the light to/from the tissue. This fact is important and explains the Sensor’s sensitivity and the special handling that it requires.

A Sensor is therefore held in place against the scalp with a single-use “Smart-Pad” (Disposable), which adheres to the scalp. This allows for better positioning of the Sensor, and it also allows for better portability. If there is an emergent need for transport, for a study or the use of an MRI, the Sensor can easily be disconnected and then replaced at a later time. “Smart-Pads” should be replaced every 2-3 days.

Yes.

Only in rare cases where the Sensor interferes with the TCD window, it can be temporarily removed though this is not likely to be an issue if the Smart-Pad Disposables are placed on the forehead. In cases where a Smart Pad is placed over a temporal window, then the orbital window could be used instead; or the Sensor could be disconnected temporarily from the Smart-Pad Disposable.

Yes.

Electroencephalogram electrodes are passive and should not cause any interference, as long as they are not placed in the way of the Smart-Pad Disposables. It should be noted that Bovie digital electrocautery generators may cause temporary interference while in use.

Measuring a relative change in cerebral blood flow is of high clinical value and is useful as a gauge of the effect of clinical interventions or other changes occurring (example, re-occlusion of vessel in a stroke patient who underwent thrombolysis). The move towards personalized medicine supports this approach. It is important to note that every patient has his own baseline, and the c-FLOW™ bases its relative value based on the individual. And ultimately, it is the response of the relative index to therapeutic interventions that makes c-FLOW™ uniquely useful.

CFI – Cerebral Flow Index – represents changes in microcirculation blood flow in a non-invasive manner. It relates to changes in the measured UTLight™ as it returns to the Sensor, called a “photo-diode.” The greater the flow in the measured territory the more of the light is disturbed. When Interpreting the CFI, it is important to take into account the clinical scenario and the baseline number, then monitor as time progresses and follow the trends. CFI is a relative, unitless number, thus comparison can be made to a baseline number but not between different patients.

The c-FLOW™ shines laser light into a tissue, much like other NIRS-based devices. However, only the c-FLOW™ adds rapid, brief, focused pulses of ultrasound into the tissue over the volume of interest through which light passes. As time progresses, the ultrasound pulse will penetrate deeper into the tissue, and the phase of light emanating from this depth will be shifted, or “tagged” accordingly, and can be identified later.

Using this tagging mechanism, light collected by the c-FLOW™ photoSensor can be filtered serially as a function of time, corresponding to relative depth, calculating flow can be done differently now, focusing the measurement only at a determined volume, we can forego assumptions about path length and light dissipation through the tissue. And, with a predetermined tissue volume, readings are almost unaffected by changes in surrounding blood flow or other tissue parameters such as skin color. This increases the confidence that oximetry measurements derive from the desired volume such as the brain or muscle tissue, by reducing contamination from tissue layers. In other words, c-FLOW™ reads dynamic information (Doppler shift equates to flow) rather than just the absorption. Secondly, it can screen out flow signal that originates from non-cerebral tissue layers, focusing on a deeper region of interest that correlates with cerebral microvasculature.

This gives the c-FLOW™ monitor the distinct advantage of being the only device on the market that directly measures flow continuously and non-invasively, rather than relying on a surrogate marker like oximetry.

Despite the tremendous growth in the field of NIRS-based regional oximetry monitoring, concerns have been raised regarding the accuracy of the measurement. Using algorithms and different “spacing” methods, regional oximeters attempt to target brain tissue, but in no instance is there a defined volume of tissue measured. Thus, often the light signal can be contaminated by superficial circulation and other factors, reducing physician confidence that oximetry measurements derive from the tissue of interest, the brain. In fact, recent studies have demonstrated that the cerebral oximeters of all three US industry manufacturers are affected by superficial blood flow, which contaminates the signal.

In addition, most cerebral oximeters claim to monitor “perfusion” though only displaying oximetry measurements. To better understand perfusion, physicians must not only monitor the amount of oxygen in the tissue, but the delivery of oxygen to the tissue, i.e. blood flow. While oximetry is often used as a proxy for blood flow, there are many clinical scenarios in which changes in flow will differ from oximetry in their dynamic response, magnitude of change and even with a different trajectory (where tissue oxygen demand increased resulting in high oxygen extraction [lower rSO2] and increased blood flow). Many of the interventions clinicians use to maintain and adjust tissue perfusion are based on changing blood flow rather than oxygen fraction.

By developing c-FLOW™, Ornim provides physicians with a tool to improve personalized medicine, where the goal is to protect brain function and cells. Real-time feedback about changes in brain perfusion during therapy or triage will take blood pressure management from “guessing” to “knowing” brain perfusion! In addition the development of new therapies or medications, the provision of feedback on local brain perfusion can determine their effectiveness on-line and can provide a closed-loop feedback for treatment by using the Ornim product line, can impact humanity in several ways:

  • Reduction in disabilities and deaths resulting from secondary brain injury originating from insufficient blood supply in numerous situations, ranging from the battle field to the delivery room. Traumatic Brain Injury (TBI) for example, is the leading cause of death and disability in children and adults from ages 1 to 44. Brain injuries are most often caused by motor vehicle crashes, sports injuries, or simple falls at the playground, at work or in the home. Exposures to blasts are a leading cause of TBI among active duty military personnel in war zones. It is estimated that TBI related costs in the US healthcare systems are around $48B annually. Personalized patient management, based on Ornim’s monitoring platform is expected to reduce such costs by improving patient’s outcome post injury.
  • Improving the success rates of therapies for brain disorders, such as stimulation or medication: Neurological and psychiatric disorders cause suffering and disability to millions. The implications for patients and health companies alike are driving the search for more successful treatment alternatives based on neurostimulation and neuromodulation technologies. Non-invasive monitoring techniques enable measurement of brain physiology, and function that can be used for selecting a specific form of stimulation and optimizing its parameters and guidance and allow real-time feedback and control to achieve optimal treatment efficiency and improve patient’s personal response to the treatment protocol.
  1. Cerebral monitoring:
    • Continuous monitoring in the Neuro ICU
  2. TBI patients for blood pressure and CPP management
  3. Monitoring of ischemic stroke patients during and post revasculariztion using thrombolytic drugs or endovascular embolectomy
  4. Monitoring subarachnoid hemorrhage patients, at risk of developing delayed vasospasm
    • Monitoring patients undergoing carotid endarterectomy c. Monitoring of pediatric and neonates in the ICU (future)
    • Monitoring brain perfusion during and post resuscitation post cardiac arrest e. Monitoring brain perfusion during CVS procedures
  5. Muscle/tissue monitoring:
    • Plastic surgery – monitoring flap perfusion
    • Monitoring of vascular disease patients
  6. Additional indications:
    • Monitoring of adequacy of hemodynamic resuscitation
    • Monitoring of brain perfusion during any type of CV surgery that may compromise cerebral perfusion
    • Surgery of the aortic arc d. Any type of HLM use
    • Controlled hypotension
  7. Monitoring of brain perfusion/oxygenation during ECMO for non-cardiac diseases:
    • Monitoring of muscle blood flow in compartment syndrome
    • Monitoring of muscle blood flow after replantation of extremities
  8. Groups of indications:
  9. All indications (and more) of the above can be grouped into three distinct functional groups.
  10. These groups also well define which clinicians will use the technology:
    • Monitoring of cerebral perfusion in cases of cerebral pathology (TBI, SAH, stroke, etc.)
    • Monitoring of cerebral perfusion in cases of non-neurological pathologies (e.g., cardiac surgeries, vascular surgery, shock/resuscitation, etc.)
    • Monitoring of non-cerebral tissue oxygenation and tissue blood flow d. Local disease (e.g. plastic/reconstructive surgery)
    • Systemic disease (e.g. hemodynamic shock)
    • Emergency medicine (out of hospital)

Yes.

As an issue of practicality, focusing on carotid territory circulation maybe more widespread, since approximately 85% of strokes occur in the territory of the carotid arteries.

It is possible to monitor the flow in the territory of the vertebrobasilar system by placing the Sensor over the occipital regions. It should be noted that placing the Sensor posteriorly may create some technical challenges. Most patients will require shaving of the hair over the region of interest. And the Sensor may require repositioning in order to avoid hair follicles, which have the potential to degrade signal quality. Additionally, the Sensors ought to be placed above the level of the occipital ridge in order to ensure optimal depth of signal.

The set depth for sampling is based on the majority of human skull thickness and distance from skin to cortex. Furthermore, we have successfully validated UTLight™ against other brain blood flow measurement modalities, in both animal and human models. Tight correlation was shown between the trends in Cerebral Flow Index (CFI) and flow data from:

  • Laser Doppler
  • Thermodiffusion Sensor
  • 133Xenon-SPECT
  • Transcranial Doppler

It is worth going into a bit of detail over one of our most key studies (the Denmark study):

A New Technology for Detecting Cerebral Blood Flow: A Comparative Study of Ultrasound Tagged NIRS and 133Xe-SPECT study. Neurocrit Care. 2012 Aug;17(1):139-45 . Henrik W. Schytz, Song Guo, Lars T. Jensen, Moshe Kamar, Asaph Nini, Daryl R. Gress, Messoud Ashina

In this study, UTLight™ was compared to isotopic Xenon Single-Positron Emission Computed Tomography (133Xe-SPECT), which is considered the “gold standard” for accurately measuring cerebral blood flow. Additionally, Diamox (acetazolamide), a potent carbonic anhydrase inhibitor, was injected during this study, causing dilation of the precapillary arterioles and increasing cerebral blood flow. Changes in CFI indeed correlated with changes measured by 133Xe-SPECT, and a significant increase in rCBF with Diamox administration was nicely demonstrated.

Stroke is the clinical syndrome of neurological deficits that occur when blood flow to the brain and spinal cord is interrupted long enough to cause damage to the tissue. Stroke can be:

  • Ischemic – due to a lack of blood flow
  • Hemorrhagic – due to rupture of a blood vessel inside the brain
  • These should be differentiated from-
  • Subdural hematoma (SDH) – Venous bleeding around the brain due to rupture of a vein
  • Epidural hematoma (EDH) – Arterial bleeding around the brain due to rupture of an artery
  • Subarachnoid hemorrhage (SAH) – Arterial bleeding into the folds of the brain and the base of the skull. The most common cause is trauma, followed by a ruptured aneurysm

A Transient Ischemic Attack (TIA) is the temporary neurological deficit that occurs when an artery to the brain or spinal cord is blocked temporarily. The clot clears before damage can be done, and neurological function returns to normal.

Ischemic Stroke Classification:

The TOAST classification comes from the stroke study titled “Trial of Org 10172 in Acute Stroke

Treatment”. This study gave us a common language to use to speak about the origin of clots

causing stroke:

  • “Atherothromboembolic” – large blood vessels
  • “Lacunar” – small penetrating arteries deep in the brain
  • “Cardioembolic” – heart valves or chambers
  • “Other” – Either more than one of the above, or very rare causes
  • “Unknown” – Truly no clear explanation

Can we monitor lacunar strokes with c-FLOW™?

It is possible that lacunar strokes, which occur deep inside the brain may be too small or deep to be monitored with c-FLOW™. However, blood clots that cause lacunar strokes can back up into the larger arteries, blocking them off. The impairment of rCBF at that point may be detectable and able to be monitored by c-FLOW™. The monitor is designed to monitor regional CBF. Thus we use the monitor to inform us on changes in blood flow at the regions adjacent to the stroke which occurs in response to the insult. So if there is an inflammatory response, edema, elevated ICP leading to decrease or increase of CBF which will be picked up by the device.

Strokes and mechanical clot removal:

Embolectomy is the mechanical retrieval of a blood clot from artery. This blood clot has “embolized” or traveled from a source upstream, such as a heart valve.

Thrombectomy is the mechanical removal of a thrombus, or a blood clot from an artery or vein. Typically these blood clots form “in situ” or at the site they are found, often because the blood is too thick or because there is a defect in the blood vessel itself.

Measurement of efficacy of flow restoration has been demonstrated with c-FLOW™ in the acute clinical setting.

The accepted practice for maintaining brain oxygen delivery satisfied is by maintaining Cerebral Perfusion Pressure (CPP) above 70mmHg. CPP is the difference between the Mean Arterial Pressure (MAP) and ICP. CPP is used mainly to understand cerebral blood flow as the key component in perfusion. In order to determine it, an ICP monitor has to be inserted into the brain. This is an invasive procedure. Current ICP monitors suffer from drift in accuracy over time. Also, after up to 5 days, they carry a risk of infection and have to be taken out. Moreover, the value of

70mmHg is an upper limit, and lower values may be tolerated. This is due to the unknown degree of loss of autoregulation that is prevalent in such patients, especially TBI patients. Measuring changes in blood flow directly, non-invasively and accurately, to indefinite periods of time, will be a great benefit to patients in detecting deterioration, providing physicians with an indication of autoregulatory function and patient’s response to treatment. In many cases it will alleviate the need to insert ICP and calculate CPP

The c-FLOW™ monitor can alert surgeons and anesthesiologists to low cerebral blood flow, warranting the insertion of a shunt or increasing blood pressure. Furthermore it can alert to reperfusion injury.

With pathology of an atherosclerotic plaque narrowing the lumen of the carotid artery, the goal of CEA is to remove the obstruction and restore blood flow to the brain. During CEA, temporary cross-clamping of the internal carotid artery (ICA) is an integral part of the surgery relying on perfusion from other vessels which may be also occluded or narrowed. This can produce brain ischemia in patients with poor collateral flow. The perioperative stroke rate after CEA can be as high as 5%, a situation that renders intraoperative brain monitoring of special interest.xiii Available

tools include Transcranial Doppler (TCD), which cannot be used in 20% of patients and requires technical skills, EEG, and Cerebral Oximetry (rSO2), each with their own limitations. Overall, some studies indicate that utilizing a decrease in cerebral rSO2 of 12% is a reliable, sensitive, and relatively specific threshold for brain ischemia secondary to ICA clamping and necessitates shunt placement or other pharmacological or physiological intervention.

Postoperative neurological complication after CEA can be related to rebound increases in cerebral blood flow (CBF) after surgical repair of carotid stenosis (reperfusion injury). Impaired autoregulation as a consequence of chronic brain ischemia with a rapid restoration of regional perfusion can generate a hyperperfusion syndrome characterized in severe cases by intracerebral hemorrhage. The c-FLOW™ monitor can track blood flow bilateratly during clamping and following release and provide an indication whether collateral flow to the operated hemisphere is efficient, whether autoregulation is intact and alert to hyperperfusion following surgery.

First, cerebral autoregulation is the way that the brain ensures a constant, even supply of blood flow to the tissues by altering flow at the microvasculature. Regulation of flow occurs at the pre-capillary arterioles. These small vessels are part of the microvasculature. They dilate and constrict in response to many factors, including systemic mean arterial pressure (MAP). The reason autoregulation takes place is to make sure that the brain capillaries do not receive too little nor too much flow. In order to determine whether autoregulation is intact, it is necessary to measure two variables at the same time:

  1. Mean Arterial Pressure (MAP) – usually with an arterial catheter or blood pressure cuff.
  2. Cerebral Blood Flow (CBF) – in our case, with c-FLOW™�.

If the CBF stays the same despite changes in MAP, then autoregulation is intact. In other words, regardless of what the systemic blood pressure is doing, the CBF stays constant because the pre-capillary arterioles are doing their job.

If the CBF varies in tandem with changes in MAP, then autoregulation is impaired. In this situation, the precapillary arterioles have lost their ability to properly manage flow, and the capillaries are seeing the same pressure as the rest of the system. Loss of autoregulation is a hazardous situation for the brain, because it puts the brain tissue at increased risk of damage from too little or too much flow.

Common causes of impaired autoregulation include:

  • Chronic uncontrolled hypertension
  • Ischemic stroke
  • Traumatic Brain Injury
  • Chronic low flow due to a severely narrowed cerebral artery
  • Anesthetic use
  • Cardiopulmonary bypass

Autoregulation Literature:

A Novel Cerebral Flow Monitor for Detecting Autoregulation – Animal Study. Moshe Kamar, Asaph Nini, Ilan Breskin, Avihai Ron, Limor Barkan, Zmira Silman, Adi Tzalach, Michal Balberg.

  • CerOx™ Oximetry vs. Venous Oxygen Saturation

Jugular vein bulb oximetry (Animal): Data from Ornim’s non-invasive Sensor placed on the head was correlated with cerebral mixed venous-arterial saturation (ratio 75:25) measured by co-oximetry of the jugular vein bulb and carotid artery in a swine model during hypoxia and hyperoxia. 12 piglets were anesthetized, ventilated and monitored. The inspired oxygen fraction (FiO2) was lowered to induce hypoxia. Blood samples were drawn 1 minute before the end of each phase (total of 95 samples). O2 saturation was compared to jugular bulb saturation. A good correlation (r=0.85, p<0.001) was observed, that did not depend on subject’s variability.

Venous saturation (Healthy volunteers): The Sensor of the Ornim’s oximeter was placed over the forearm muscles. 20 healthy subjects performed a handgrip exercise during normoxic and hypoxic oxygen inhalation. Venous blood was sampled at the end of each phase of the protocol. Readings of the system significantly correlated with venous blood oxygen saturation as measured by a co-oximeter (r= 0.77, p<0.001).

Jugular vein bulb oximetry (Patients): CerOx™ saturation readings were compared to SjVO2 in a cohort of patients with severe brain injury admitted in a neurocritical care unit. In 10 out of 12 TBI patients, good quality continuous data was obtained from the CerOx™ monitor. Good quality jugular bulb venous data without evidence of non-cerebral contamination was obtained in 8 out of 11 patients. In a majority of patients a significant correlation (r=0.59, p<0.01) was found between ipsilateral CerOx™ measurements of cerebral tissue oxygenation and jugular bulb venous saturation (SjVO2).

  • Clinical Validation: CerOx™ Flow vs. Flow Monitors

Laser Doppler (Animal): A study was conducted aimed at demonstrating the capability of the CerOx™ 3210F to measure flow during pharmacologic and mechanical manipulations on systemic blood flow, and its equivalence to laser Doppler in detecting these manipulations. Study included 6 animals, with 65 manipulations of blood flow, by increasing and decreasing flow. Analysis included ROC analysis and agreement analysis using Cohen’s Kappa coefficient. ROC analysis for each type of manipulation showed the high discriminative power of the CerOx 3210F in detection of decreases and increases in tissue blood flow. The analysis of the difference between the Areas Under the Curve (AUCs) for Laser Doppler and CerOx 3210F measurements demonstrated that the CerOx™ 3210F is equivalent to Laser Doppler (LD) for detecting manipulations in blood flow. Analysis of agreement between Laser Doppler and CerOx™ revealed a significantly robust agreement between the two systems for detecting all events (Kappa = 0.79 p< 0.001).

CBF in traumatic brain injury patients: Data was collected on TBI patients, undergoing extensive neuromonitoring. CerOx™ signals corresponding to CBF were compared to invasive CBF measurements using a thermo-diffusion Sensor (Hemedex, MA). Readings of the two monitors were compared during physiologic challenges of hyperventilation. Hyperventilation challenges were performed to assess cerebral CO2 vasoreactivity.

  1. In 5 out of 6 patients good quality continuous flow data was obtained from the CerOx™ monitor
  2. Data from 10 hyperventilation challenges revealed a close correspondence between invasive measures of CBF (Hemedex) and the non-invasive CerOx™ monitor
  3. The Kappa measurement was statistically significant (p<0.001, Kappa=0.641)
  4. Clinical Applicability

Traumatic Brain Injury: The CerOx™ was used to monitor about 50 TBI patients in three leading hospitals (UCSF, CA UPenn, PA: and Hadassah MC, Israel) in neurointensive care settings. Observational studies included patients monitored with other invasive monitors (such as Jugular vein oximetry, Brain oxygen tension and CBF) that were monitored with the CerOx™ up to 7 days. Patient management was based on existing monitors. Following initial technical improvements, the usability of the system was acceptable and feasible in the neuro-ICU settings. Interim analysis of the data from 11 patients shows good correlation between CerOx™ saturation readings and SjVO2 readings. In addition, a good agreement between CerOx™ flow measurements and CBF by thermo-diffusion was observed.

Sub-Arachnoid Hemorrhage (SAH): Subarachnoid Hemorrhage patients, Hunton-Hess grade 3-5, in ICU settings were monitored. Initial experience with 10 patients, monitored for short periods of time, CerOx™ Sensors were tolerated by both awake and sedated patients. Initial data from these patients is currently analyzed. In the future, longer monitoring periods will be evaluated and compared to findings of CT-Perfusion. No adverse events were reported.

NCCU

SAH – detect changes in regional CBF when vasospasm occurs

TBI – detect changes in CBF when ICP changes or a change in CPP occurs when Autoregulation is disturbed Stroke – monitor for revascularization and re-occlusion. Prognosticate stroke outcome in response to treatment Post cardiac arrest – cerebral blood flow status during cooling and rewarming

Operating Room

SAH Vascular surgeon

  • Monitor for blood flow to revascularized areas
  • Monitor for low perfusion, need for shunt in CEA and alert for overflow
  • Monitor changes in blood supply in PVD pre and post-surgery
  • Monitor for compartment syndrome

Plastic surgery

  • monitor for tissue blood supply after flap reconstruction (free and rotational)
  • Orthopedics
  • Monitor CBF using beach chair position
  • Monitor for compartment syndrome

CVS

  • Blood pressure management
  • Assist in determining pump “flow”
  • Alert for CBF changes due to surgery related issues (i.e. cannula kink etc.)

Anesthesia

  • Optimize blood pressure to maintain adequate CBF
  • Effect of different anesthesia drugs and manipulations on CBF
  • Monitor for post anesthesia CBF effects
  • Alert for changes in tissue blood flow in ICU sepsis patients
  • Monitor for blood flow changes related to patient positioning, such as beach chair position

Trauma

  • Optimize blood pressure to maintain adequate CBF
  • Effect of different anesthesia drugs and manipulations on CBF
  • Alert for changes in tissue blood flow in the hemorrhagic and shock patients
  • Early detection of sepsis
  • Monitor for compartment syndrome

Emergency Room

  • OCPR- feedback on the efficacy of resuscitation in delivering blood to the brain
  • Assist in differentiating stroke from intoxicated patients
  • Early detection of sepsis
  • Monitor for decreasing tissue blood flow to detect compartment syndrome
Department Patient population Indication
ER CPR Adequate resuscitation
OR Brain revascularization(CEA) Adequate collateral, upstream flow
Major cardio – vascular surgery Adequate tissue oxygenation and perfusion.Indication of Autoregulation
Angio suite Brain revascularization(stroke) Adequate collateral, upstream flow
Neuro ICU RevascularizationTBI, ICP patients, ICH, SAH Post procedure monitoringBrain oxygenation
Cardiac ICU CPR Adequate resuscitation
General ICU CPR Adequate resuscitation
Sepsis Adequate tissue perfusion

Common denominator – Blood Pressure management

Seeing is believing – The ability to see into the brain like never before

  • Detect cerebral blood flow in
    • Acute ischemic stroke – To better understand CBF and help guide therapeutic decisions with respect to revascularization.
    • Perihematomal penumbra – To better guide management of blood pressure and CPP,
    • Cerebrovascular disease – To better understand the effect of vasoactive therapy or revascularization on brain’s microcirculation.
    • Traumatic brain injury – To better guide management of blood pressure and CPP. .
    • Delayed cerebral ischemia due to vasospasm after subarachnoid hemorrhage – To help guide decisions about blood pressure management. To better understand the effect of vasoactive therapy or revascularization on brain’s microcirculation..
    • Cerebrovascular procedures – To help guide decision making when it comes to intracranial or extracranial revascularization, such as Carotid Endarterectomy or percutaneous angioplasty and stenting.
    • Cardiac Arrest – To assess adequacy of chest compressions; and to determine sufficiency of cerebral blood flow in the setting of anoxic encephalopathy and during post cardiac arrest cooling and rewarming.
  • Detect muscle blood flow
    • Tissue flaps – to monitor for graft vascular occlusion/ insufficiency / tissue perfusion compromise
    • Compartment syndrome – To monitor for critical ischemia due to compartment syndrome and assist in determining the need for intervention

Vascular limb ischemia – To assist in determining the need for revascularization and limb salvage procedure. To monitor surgery impact on blood restoration, tissue perfusion, compartment syndrome and reperfusion syndrome

  • Perioperative determination of autoregulation, facilitating personalized care of blood pressure and anesthetic drugs to maintain adequate CBF during surgery.
  • Intraoperative surveillance for cerebral perfusion during variety of high risk surgeries where it is known that patients are at risk for brain and other systemic complications.
    • Carotid endarterectomy – May suggest the need for shunt, management of blood pressure when augmenting collateral flow
    • Cardiac bypass – manage pump flow, blood pressure, ventilator CO2 and other parameters affecting CBF
    • Procedures requiring beach chair position – alert for changes in CBF following lengthy procedures in this position to avoid stroke and other cognitive impairments
    • Any operative procedure which might compromise cerebral blood flow
  • Surveillance at the bedside for changes in brain blood flow that might compromise patient outcomes.
  • Easy use, ability to start monitoring immediately without need for intervention.Improvement in decision making.

Unlike most other organs which can tolerate brief hypoxia, the brain requires a steady delivery of oxygen and glucose. This is accomplished primarily through carefully controlled Cerebral Blood Flow (CBF). Underscoring the importance of CBF are the observations that the adult human brain uses about 20% of cardiac output and that blood normally takes up about 10% of the intracranial space. iAbout 20% of the oxygen and 25% of the glucose consumed by the human body are dedicated to cerebral functions, yet the brain represents only 2% of the total body mass. While the

brain is a high energy-consuming organ, it contains little energy reserves and is therefore highly dependent upon the uninterrupted supply of energy substrates from the circulation. Impairment in this process results in perturbation of neurological function as severe as loss of consciousness, and coma within minutes.

In practice, CBF is determined by a number of factors, such as the viscosity of blood, diameter of blood vessels. The net pressure of the flow of blood into the brain, known as Cerebral Perfusion Pressure (CPP), is determined by the difference between arterial pressure entering the brain and intracranial pressure. Under normal conditions, a variety of autoregulatory mechanisms maintain CBF in the necessary range.

CBF is tightly regulated to maintain constant blood flow and meet the brain’s metabolic demands and on average, is maintained at a flow of 50mL of blood per 100g of brain tissue per minute. iiBlood flow in excess (hyperemia) can raise intracranial pressure (ICP) and compress critical brain structures, including those that control heart rate and respiration. At the same time, insufficient perfusion leads to ischemia, a biochemical cascade characterized by insufficient oxygen delivery, insufficient energy substrates delivery and metabolite clearance. Since neuronal metabolic pathways require the ongoing presence of oxygen (carried by hemoglobin in the blood) and glucose, if the ischemic state is not rapidly reversed, tissue death ensues which could lead to neural impairment. For this reason, in conditions such as shock, stroke, and traumatic brain injury, it is critical for caregivers to have ongoing understanding of CBF that will facilitate educated interventions to maintain CBF.

For these reasons, monitoring of cerebral blood flow is a real clinical need. Currently, physicians have limited tools to assess tissue perfusion to guide treatment accordingly. Cerebral blood oximetry is often used as a proxy for blood flow; this does not necessarily represent actual CBF, however. For instance when metabolic demand increases, blood flow increases too, while tissue microcirculatory oximetry decreases due to higher consumption. Suffice it to say that cerebral oximetry is a nuanced measure that can be challenging to interpret, if not misleading. Therefore, the ideal tool should be a direct CBF monitor, simple, and non-invasive providing a reading of tissue perfusion parameters in a relatively rapid and inexpensive fashion.

Flow is an actionable parameter, put simply, and physicians can manipulate blood flow by varying blood pressure, ventilation and medication. Feedback on these changes is imperative for management of blood pressure during cardio-pulmonary bypass and management of brain injured patients. According to the Brain Trauma Foundationiii guidelines for management of Cerebral Perfusion Pressure (CPP), ancillary monitoring of CBF, oxygenation and metabolism can facilitate CPP management.

Physicians care about flow: Monitoring Cerebral Blood Flow (CBF) is importantiv for managing patients suffering from head trauma, stroke or even under general anesthesia. In many such cases, changes in oximetry are used as a proxy to reflect changes in the underlying flow. Instead, Ornim’s UTLight™ technology provides this parameter directly. Recent studies have explored the use of Near Infrared Spectroscopy (NIRS) in assessing technology in assessing patient changes when regional blood flow is a primary concern for physicians. In many such cases, changes in oximetry are used as a proxy to reflect changes in the underlying flow.

Assessing Autoregulation function requires continuous monitoring of CBF: Impaired cerebral Autoregulation may predispose to stroke injury in patients undergoing cardio-pulmonary bypass surgeryv. Ornim’s technology provides continuous, real-time readings of changes in CBF, and combined with blood pressure or ICP readings can be used to assess Autoregulation function.

Oximetry is not a direct surrogate for blood flow: Changes in oxygen saturation may not reflect changes in blood flow, and may not be in the same directionvi. A vessel occlusion will lead both to a decrease in target tissue oximetry and blood flow. However, as a septic patient’s tissue oxygen demand grows, oximetry readings should decrease, whereas blood flow will likely increase to accommodate. Changes in oximetry are not always as dramatic as changes in flow. The flow parameter can provide an early indicator of possible changes in a patient’s status. On the other hand, rCBF, as tracked by the Cerebral Flow Index (CFI), is simple and easy to interpret. Flow is negatively affected strictly by insufficient arterial inflow, reduction of venous outflow, or impairment of autoregulation.

In the original Danish Study, Schytz et alvii found that the measurement of flow was of vital importance. This study, which utilized Xenon-SPECT flow measurements, clearly demonstrated that oximetry alone provides only a partial and narrow view of the actual changes in oxygen delivery to the tissue. This study has shown that in healthy volunteers it is not possible to obtain reliable reflections of changes in CBF using conventional NIRS oximetry. If this holds true in healthy volunteers, how much more so in patients with a presenting condition?

It should be noted that many of the interventions offered by Covidien/Somanetics and CASMED to correct problems with cerebral oximetry are related to flow. Such interventions include increasing MAP or cardiac output. But with no proven correlation between flow and oximetry, how would a physician know how to treat a patient? The combination of this study and the results from the Xenon study Ornim has done which does show correlation between the CerOx™ flow parameter and the Xenon flow should be a strong driver for the recognition of the need for a flow parameter. While Ornim might not provide a treatment protocol, added information on a physician’s patient should help guide which intervention s/he chooses.

c-FLOW™ measures microvascular cerebral blood flow at or just deep to the cortex of the brain. Proximal flow monitoring at large vessels such as that gained by TCD is less sensitive to distal changes at the microvasculature where it is thought to be the most sensitive to flow perturbations.

Yes.

As an issue of practicality, focusing on carotid territory circulation maybe more widespread, since approximately 85% of strokes occur in the territory of the carotid arteries.

It is possible to monitor the flow in the territory of the vertebrobasilar system by placing the Sensor over the occipital regions. It should be noted that placing the Sensor posteriorly may create some technical challenges. Most patients will require shaving of the hair over the region of interest. And the Sensor may require repositioning in order to avoid hair follicles, which have the potential to degrade signal quality. Additionally, the Sensors ought to be placed above the level of the occipital ridge in order to ensure optimal depth of signal.

Using the UTLight™ technology allows us to take measurements reliably at different depths. (Currently only one depth is presented, but post processing allows us to focus on different depths). When a specific region of interest is selected, ultrasound-tagged photons traveling through that region are distinguished from photons traveling through more superficial layers of tissue. There is no “contamination” from light traveling through other layers.

Rather than measuring surface area, c-FLOW™ measures a specific volume of brain tissue. The volume measured is 1 Cubic Centimeter (1 cm3).

Hematoma will absorb the light and will not allow any readings. A hematoma also can push on the brain enough to shift it away from the region of interest. So placing the Sensor over this area will not yield a true signal. It is advisable though that adjacent areas may be monitored for changes in CBF as a consequence of the hematoma.

Other conditions that may limit the effectiveness of c-FLOW™ may include:

  • Subdural hygroma or arachnoid cycts (collections of cerebrospinal fluid that push on the brain)
  • Epidural hematoma (an arterial collection of blood just deep to the skull)
  • Significant cerebral atrophy (brain shrinkage)
  • Anything else causing a mass-like effect, distorting the contour of the brain (such as a brain tumor).

It is conceivable that regions adjacent to a compressive hematoma or other space-occupying lesion might be at risk for reduced rCBF. Additionally, in cases of increased cerebrovascular resistance or increased intracranial pressure, the distal, microvascular flow might be reduced.

The clinician should use clinical judgment and rely on neuro images (such as a head CT or brain MRI) in order to make a determination whether their patient is a suitable candidate for rCBF monitoring with c-FLOW™.

Hydrocephalus is the inappropriate accumulation of cerebrospinal fluid (CSF) within the brain. The CSF circulates throughout the brain, normally draining into the veins around the base of the brain. When the exit pathway is blocked, CSF backs up. However, the brain generally doesn’t know how to stop producing the fluid, so it continues to accumulate, eventually increasing the intracranial pressure (ICP).

At a certain point, ICP elevation causes the microvasculature to collapse, limiting cerebral blood flow. This critical change ought to be detectable by c-FLOW™, at which time countermeasures can be put into effect.

  • A defect in the skin, scalp or skull at the site of placement
  • The presence of hair follicles
  • An excessively thick skull

Brain tissue shifted out of reach of the UTLight™

Since it may not always be practical to monitor patients with subarachnoid hemorrhage for an extended period of time, c-FLOW™ may be used in a more tactical fashion to assess the effect of efforts to treat vasospasm when it occurs.

Typically, most patients go through changes in their neurological exam or elevation of the mean flow velocity measured by TCD. These signal that vasospasm may be starting, and this would be the correct time to place the c-FLOW™ while confirmatory testing is done. Then ongoing monitoring to assess treatment effect may be beneficial.

Encephalopathy is a malfunction of the brain, causing deterioration of brain function. If it occurs acutely in the hospital setting, it usually manifests as “delirium.” There are many causes of encephalopathy, and in some instances, cerebral blood flow may be affected. There may be a role, therefore, in monitoring with c-FLOW™, though clinical trials have not been performed in this setting.

In general water is translucent and does not affect the signal, so the changes seen are related to changes in CBF as a consequence of the changes in vasculature resistance. Good example will be brain swelling leading to increased ICP which overcomes vessels filling pressure – decrease in rCBF.

Edema is swelling of tissue caused by the accumulation of water inside or between cells. Edema of the brain (“cerebral edema”) can elevate the intracranial pressure (ICP). As with hydrocephalus, if the ICP becomes great enough, it can cause the microvasculature to collapse creating a limitation of blood flow. Cerebral edema occurs in three phases, all of which may be responsive to intervention:

  1. Acute Cytotoxic – cell membranes become damaged, allowing water to rush into cells, which then become swollen.
  2. Transitional – cells start recovering and healing their membranes, pumping water back out of their cells.
  3. Vasogenic – cells have healed their membranes and fluid is trapped between cells and around blood vessels.
  4. Evaluating the efficacy of cerebral edema countermeasures may be one use for the c-FLOW™.

Stroke is the clinical syndrome of neurological deficits that occur when blood flow to the brain and spinal cord is interrupted long enough to cause damage to the tissue. Stroke can be:

  • Ischemic – due to a lack of blood flow
  • Hemorrhagic – due to rupture of a blood vessel inside the brain
  • These should be differentiated from-
  • Subdural hematoma (SDH) – Venous bleeding around the brain due to rupture of a vein
  • Epidural hematoma (EDH) – Arterial bleeding around the brain due to rupture of an artery
  • Subarachnoid hemorrhage (SAH) – Arterial bleeding into the folds of the brain and the base of the skull. The most common cause is trauma, followed by a ruptured aneurysm

A Transient Ischemic Attack (TIA) is the temporary neurological deficit that occurs when an artery to the brain or spinal cord is blocked temporarily. The clot clears before damage can be done, and neurological function returns to normal.

Ischemic Stroke Classification:

The TOAST classification comes from the stroke study titled “Trial of Org 10172 in Acute Stroke

Treatment”. This study gave us a common language to use to speak about the origin of clots

causing stroke:

  • “Atherothromboembolic” – large blood vessels
  • “Lacunar” – small penetrating arteries deep in the brain
  • “Cardioembolic” – heart valves or chambers
  • “Other” – Either more than one of the above, or very rare causes
  • “Unknown” – Truly no clear explanation

It is possible that lacunar strokes, which occur deep inside the brain may be too small or deep to be monitored with c-FLOW™. However, blood clots that cause lacunar strokes can back up into the larger arteries, blocking them off. The impairment of rCBF at that point may be detectable and able to be monitored by c-FLOW™. The monitor is designed to monitor regional CBF. Thus we use the monitor to inform us on changes in blood flow at the regions adjacent to the stroke which occurs in response to the insult. So if there is an inflammatory response, edema, elevated ICP leading to decrease or increase of CBF which will be picked up by the device.

Strokes and mechanical clot removal:

Embolectomy is the mechanical retrieval of a blood clot from artery. This blood clot has “embolized” or traveled from a source upstream, such as a heart valve.

Thrombectomy is the mechanical removal of a thrombus, or a blood clot from an artery or vein. Typically these blood clots form “in situ” or at the site they are found, often because the blood is too thick or because there is a defect in the blood vessel itself.

Measurement of efficacy of flow restoration has been demonstrated with c-FLOW™ in the acute clinical setting.

Monitoring brain perfusion is highly important for assessment of real-time treatment effectiveness, allowing early intervention for non-responders, hemorrhagic transformation or re-occlusion. The wide availability of c-FLOW™ may increase the number of patients treated with IV- tPA.

Stroke affects more than 700,000 individuals annually in the United States. Treatment with tissue Plasminogen Activator (tPA) is associated with improved outcome in acute ischemic stroke. Yet this treatment can be given within a short time window of up to 6 hours from initial symptoms. tPA is administered either intra-arterial in the CATH lab or intravenously, where an angiogram suite facility is not available. Only 3-5% of all stroke patients receive this treatment annually).1

Rymner MM, Akhtar N, Martin C, Summers D. Mo Med. 2010 Sep-Oct;107(5):333-7.

For SAH patients where the major concern is vasospasm and delayed cerebral ischemia, the c-FLOW™ will enable continuous, reliable, non-invasive monitoring of changes in cerebral blood flow and may enable earlier initiation of treatment, potentially improving outcome for these patients.

The major complication of SAH is cerebral vasospasm, affecting as many as 70% of patients who survive the initial insult in the following 7-14 days. Vasospasm carries a risk for further morbidity and mortality. It is diagnosed in responsive patients by repeating neurological examination. In unconscious patients the only way to follow patients is by performing Transcranial Doppler ultrasound (TCD) at least once daily. Using the c-FLOW™ monitor, it was possible to identify events of significant low flow.

Use of the c-FLOW™ during and post CPR will provide feedback as to the adequacy of brain resuscitation, as indicated by a change in cerebral perfusion.

The phrase cardio-pulmonary cerebral resuscitation, first coined by the late Peter Safar, is now recognized as the key principle ensuring an adequate resuscitation- the goal of all resuscitations is to perfuse and save the brain. Using the c-FLOW™ monitor will ensure this goal by showing caregivers resumption of perfusion directly with an instant, noninvasive device. Currently, tissue perfusion and oxygenation is monitored using end tidal CO2, an indirect, non-prevalent method.

The c-FLOW™ monitor can alert surgeons and anesthesiologists to low cerebral blood flow, warranting the insertion of a shunt or increasing blood pressure. Furthermore it can alert to reperfusion injury.

With pathology of an atherosclerotic plaque narrowing the lumen of the carotid artery, the goal of CEA is to remove the obstruction and restore blood flow to the brain. During CEA, temporary cross-clamping of the internal carotid artery (ICA) is an integral part of the surgery relying on perfusion from other vessels which may be also occluded or narrowed. This can produce brain ischemia in patients with poor collateral flow. The perioperative stroke rate after CEA can be as high as 5%, a situation that renders intraoperative brain monitoring of special interest.xiii Available

tools include Transcranial Doppler (TCD), which cannot be used in 20% of patients and requires technical skills, EEG, and Cerebral Oximetry (rSO2), each with their own limitations. Overall, some studies indicate that utilizing a decrease in cerebral rSO2 of 12% is a reliable, sensitive, and relatively specific threshold for brain ischemia secondary to ICA clamping and necessitates shunt placement or other pharmacological or physiological intervention.

Postoperative neurological complication after CEA can be related to rebound increases in cerebral blood flow (CBF) after surgical repair of carotid stenosis (reperfusion injury). Impaired autoregulation as a consequence of chronic brain ischemia with a rapid restoration of regional perfusion can generate a hyperperfusion syndrome characterized in severe cases by intracerebral hemorrhage. The c-FLOW™ monitor can track blood flow bilateratly during clamping and following release and provide an indication whether collateral flow to the operated hemisphere is efficient, whether autoregulation is intact and alert to hyperperfusion following surgery.

First, cerebral autoregulation is the way that the brain ensures a constant, even supply of blood flow to the tissues by altering flow at the microvasculature. Regulation of flow occurs at the pre-capillary arterioles. These small vessels are part of the microvasculature. They dilate and constrict in response to many factors, including systemic mean arterial pressure (MAP). The reason autoregulation takes place is to make sure that the brain capillaries do not receive too little nor too much flow. In order to determine whether autoregulation is intact, it is necessary to measure two variables at the same time:

  1. Mean Arterial Pressure (MAP) – usually with an arterial catheter or blood pressure cuff.
  2. Cerebral Blood Flow (CBF) – in our case, with c-FLOW™�.

If the CBF stays the same despite changes in MAP, then autoregulation is intact. In other words, regardless of what the systemic blood pressure is doing, the CBF stays constant because the pre-capillary arterioles are doing their job.

If the CBF varies in tandem with changes in MAP, then autoregulation is impaired. In this situation, the precapillary arterioles have lost their ability to properly manage flow, and the capillaries are seeing the same pressure as the rest of the system. Loss of autoregulation is a hazardous situation for the brain, because it puts the brain tissue at increased risk of damage from too little or too much flow.

Common causes of impaired autoregulation include:

  • Chronic uncontrolled hypertension
  • Ischemic stroke
  • Traumatic Brain Injury
  • Chronic low flow due to a severely narrowed cerebral artery
  • Anesthetic use
  • Cardiopulmonary bypass

Autoregulation Literature:

A Novel Cerebral Flow Monitor for Detecting Autoregulation – Animal Study. Moshe Kamar, Asaph Nini, Ilan Breskin, Avihai Ron, Limor Barkan, Zmira Silman, Adi Tzalach, Michal Balberg.

  • John’s Hopkins University
  • Harvard University
  • University of Pennsylvania
  • Washington University (St. Louis)
  • University of California San Francisco
  • University of New Mexico
  • Columbia, New York
  • UWO, Ontario, Canada