WO2020243658A1 - Procédés en temps réel pour permettre à une rcp guidée par la précision d'améliorer le résultat neurologique et de prédire une lésion cérébrale après une lésion ischémique et une reperfusion - Google Patents

Procédés en temps réel pour permettre à une rcp guidée par la précision d'améliorer le résultat neurologique et de prédire une lésion cérébrale après une lésion ischémique et une reperfusion Download PDF

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WO2020243658A1
WO2020243658A1 PCT/US2020/035440 US2020035440W WO2020243658A1 WO 2020243658 A1 WO2020243658 A1 WO 2020243658A1 US 2020035440 W US2020035440 W US 2020035440W WO 2020243658 A1 WO2020243658 A1 WO 2020243658A1
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cbf
brain
cmro
ratio
cerebral
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PCT/US2020/035440
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English (en)
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Robert H. WILSON
Christian CROUZET
Yama AKBARI
Bernard Choi
Bruce J. Tromberg
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The Regents Of The University Of California
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Priority to EP20813099.7A priority Critical patent/EP3975970A4/fr
Priority to JP2021569885A priority patent/JP2022534386A/ja
Priority to US16/985,113 priority patent/US20200367761A1/en
Publication of WO2020243658A1 publication Critical patent/WO2020243658A1/fr
Priority to US17/377,123 priority patent/US20210338092A1/en
Priority to US17/534,986 priority patent/US20220079840A1/en
Priority to US17/690,866 priority patent/US20220192919A1/en
Priority to US17/706,217 priority patent/US20220223257A1/en
Priority to US17/735,903 priority patent/US20220262496A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H31/00—Artificial respiration or heart stimulation, e.g. heart massage
    • A61H31/004—Heart stimulation
    • A61H31/005—Heart stimulation with feedback for the user
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0033—Features or image-related aspects of imaging apparatus classified in A61B5/00, e.g. for MRI, optical tomography or impedance tomography apparatus; arrangements of imaging apparatus in a room
    • A61B5/004—Features or image-related aspects of imaging apparatus classified in A61B5/00, e.g. for MRI, optical tomography or impedance tomography apparatus; arrangements of imaging apparatus in a room adapted for image acquisition of a particular organ or body part
    • A61B5/0042—Features or image-related aspects of imaging apparatus classified in A61B5/00, e.g. for MRI, optical tomography or impedance tomography apparatus; arrangements of imaging apparatus in a room adapted for image acquisition of a particular organ or body part for the brain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0075—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/026—Measuring blood flow
    • A61B5/0261—Measuring blood flow using optical means, e.g. infrared light
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/40—Detecting, measuring or recording for evaluating the nervous system
    • A61B5/4058—Detecting, measuring or recording for evaluating the nervous system for evaluating the central nervous system
    • A61B5/4064—Evaluating the brain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4848—Monitoring or testing the effects of treatment, e.g. of medication
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/026—Measuring blood flow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14542—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring blood gases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H2230/00—Measuring physical parameters of the user
    • A61H2230/20—Blood composition characteristics
    • A61H2230/207—Blood composition characteristics partial O2-value
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H2230/00—Measuring physical parameters of the user
    • A61H2230/25—Blood flowrate, e.g. by Doppler effect

Definitions

  • the present invention relates to medical devices and methods for rapidly assessing ischemic brain damage and prognosing neurological recovery during onset of injury, during intervention (e.g., during resuscitation), or immediately after reperfusion.
  • CA Cardiac arrest
  • CPR cardiopulmonary resuscitation
  • the prior art typically uses either cerebral perfusion or oximetry, or it may rely on peripheral blood pressure/oxygenation. For instance, hemodynamic status is typically monitored in emergency and intensive care settings by measuring blood pressure and blood gas concentration from the radial or femoral artery. However, these measurements occur distant from the brain and are often not informative of cerebral hemodynamic processes. Thus, the prior art attempts to quantify cerebral perfusion and metabolism struggle to do so sufficiently and quickly enough to enable the clinician to take early action. [0006] Further still, methods for direct measurement of oxygen consumption in the brain are typically invasive and do not provide any information about perfusion. Techniques for non-invasive CBF measurement do not have the temporal resolution required to monitor rapid changes in cerebral perfusion and metabolism.
  • CBF cerebral blood flow
  • StO 2 brain tissue oxygenation
  • CMRO 2 cerebral metabolic rate of oxygen
  • ECoG cerebral electrical activity
  • Embodiments of the invention are given in the dependent claims.
  • Embodiments of the present invention can be freely combined with each other if they are not mutually exclusive.
  • the present invention provides near-continuous measurements to enable assessment of rapid dynamic changes that may be critical for improved diagnosis and prognosis. These changes may be measured as rapidly as within the first minute post-resuscitation.
  • the present invention incorporates perfusion and oximetry together to quantify cerebral metabolism and flow-metabolism coupling/decoupling at specific time windows after ischemia and reperfusion, which serve as a critical, unique distinction as cerebral ischemia can lead to autonomic dysregulation, not just deficits in perfusion or oxygenation individually.
  • the present invention in contrast, is a minimally- invasive approach that relies on optical signals from the body.
  • this technology may involve completely non-contact optical imaging approaches to monitor the brain.
  • this technology may involve fiber-optic probes that make contact with the skin surface to non-invasively measure changes in the underlying brain tissue.
  • cardiac arrest there are many different clinical scenarios in which the present invention can be used for rapid detection and characterization of cerebral ischemia critical for helping improve patient outcome. These applications include, but are not limited to: focal stroke, subarachnoid hemorrhage, traumatic brain injury, sleep apnea, and drug overdose.
  • the invention includes methods that calculate values of key parameters related to blood flow, oxygen consumption, tissue scattering, cytotoxic edema, perfusion/metabolism coupling/uncoupling, neurovascular coupling/uncoupling, and autonomic regulation in the brain following ischemia and reperfusion. These parameters can be used to diagnose the severity/duration of ischemia and prognose cerebral recovery.
  • the invention may also be used in conjunction with different modalities of neural stimulation, in cases where such stimuli are employed to drive reperfusion, enhance cerebral recovery, and/or test autoregulation.
  • the invention may be used to quantitatively characterize the brain’s response to the neural stimulus, the brain’s degree of autoregulation, and/or the effectiveness of the stimulation technique.
  • One of the unique and inventive technical features of the present invention is that it provides continuously-updating, quantitative metrics of brain dysfunction by using cerebral blood flow and metabolism parameters together. Without wishing to limit the invention to any theory or mechanism, this feature is important because the autoregulation of the brain is disrupted during ischemia so these parameters may be critical for improved diagnosis and prognosis, and may be further used to inform treatment.
  • CBF/CMRO 2 is indicative of CA duration/severity and prognostic (with 87% accuracy) of short-term neurological recovery measured by the initiation of ECoG activity (e.g. the time that ECoG activity resumes).
  • the present invention monitors both cerebral blood flow and metabolism immediately after resuscitation, which is counterintuitive to popular belief.
  • the present invention has surprisingly found that by monitoring CBF and CMRO 2 , a metric can be calculated that can provide information about the severity of brain damage. Furthermore, when this metric is obtained during a critical window after resuscitation, it has a higher accuracy that allows for early prognosis and prescribing of proper treatment to improve the patient’s recovery.
  • FIG.1A is a non-limiting flow diagram embodiment according to a method of the present invention.
  • FIG. 1B shows an experimental set-up of the present invention comprising instrumentation for high-speed LSI and SFDI.
  • Spatially-modulated LEDs and a sCMOS camera were used for SFDI.
  • An 809 nm laser and 60 fps camera were used for LSI.
  • the rapid LSI and SFDI system was integrated into an“animal intensive care unit” setup for monitoring the response of the brain to CA and CPR in a preclinical rat model.
  • a craniectomy was performed to expose a ⁇ 6 mm x 4 mm region of the brain for imaging, and four ECoG electrodes were implanted for monitoring cerebral electrical activity.
  • FIG.1C shows representative maps of CBF and brain oxygenation in a CA/CPR experiment. Notable differences in CBF and oxygenation (StO 2 ) were imaged during four phases: baseline, CA, hyperemic response to CPR, and post-hyperemic hypoperfusion. At baseline, normal cerebral perfusion and oxygenation were observed. During CA, blood flow was completely absent from the brain and cerebral oxygenation dropped rapidly, indicative of oxygen consumption. During post-ROSC hyperemia, states of hyper-perfusion and hyper-oxygenation were observed. During hypoperfusion, CBF stabilized at a level below baseline, yet increased metabolic activity was observed, reflected by a reduction in oxygenation.
  • FIG.2 shows different phases of CBF and metabolism observed during isoflurane washout and subsequent onset of CA.
  • CBF green
  • oxy-hemoglobin concentration ctHbO 2 , red
  • deoxy-hemoglobin concentration ctHb, blue
  • CMRO 2 magenta
  • FIG. 3 shows CBF (green), oxy-hemoglobin concentration (ctHbO 2 , red), deoxy- hemoglobin (ctHb, blue), and rCMRO 2 (magenta), averaged over a region of interest for the same rat as in FIG.2, during CPR (orange shaded window), hyperemia (Phase III), and hypoperfusion (Phase IV).
  • CBA green
  • oxy-hemoglobin concentration ctHbO 2 , red
  • deoxy- hemoglobin ctHb, blue
  • rCMRO 2 magenta
  • Flow-metabolism coupling (denoted as“coupling” in the figure) is defined as a period of concomitant changes in CBF and CMRO 2 with similar slopes.
  • Flow-metabolism uncoupling (denoted as“uncoupling” in the figure) is defined as a period during which CBF and CMRO 2 have opposite slopes or one has a nonzero slope and the other has roughly zero slope.
  • FIG. 4A shows CBF and CMRO 2 for a representative rat with short CA (5 min asphyxia) having an early, temporally-synchronous (coupled) recovery of CBF and CMRO 2 in the post-ROSC period.
  • FIG. 4B shows CBF and CMRO 2 for a representative rat with prolonged CA (7 min asphyxia) having a delayed recovery of CBF and CMRO 2 in the post-ROSC period with periods of decoupling between CBF and CMRO 2 temporal dynamics (shaded box).
  • FIG. 4C shows StO 2 , SFI, and CMRO 2 for a representative rat with good EEG activity 30 min post-CPR, where CMRO 2 follows flow during reperfusion (box).
  • FIG. 4D shows StO 2 , SFI, and CMRO 2 for a representative rat with poor EEG activity 30 min post-CPR, where CMRO 2 becomes decoupled from flow during reperfusion (box).
  • FIGs. 5A-5B show a CBF/CMRO 2 ratio during the first minute after resuscitation for 5 rats with shorter CA (5 min asphyxia; solid lines) and 5 rats with prolonged CA (7 min asphyxia; dashed lines).
  • the ratio of CBF/CMRO 2 can be used to retrospectively determine severity of CA and simultaneously provide a preliminary prediction of expected outcome. This ratio does not require any pre-ROSC information, making it well-suited for potential translation to emergency response and intensive care settings.
  • the time window of ⁇ 0.5-2 min post-ROSC is the most useful for CA severity assessment and prognosis.
  • FIGs.6A and 6B show CBF and CMRO 2 , normalized to the corresponding value at 15 sec post-ROSC, for the first 5 min post-ROSC for representative rats with shorter CA and longer CA, respectively.
  • CBF exceeds CMRO 2 during first 5 min post-ROSC for a representative rat with short (5 min) CA, but not for prolonged (7 min) CA.
  • FIG. 6C shows that the ratio of the areas under the CBF and CMRO 2 curves (AUC).
  • AUC the ratio of the areas from 15 sec - 3 min post-ROSC is significant (*, p ⁇ 0.02 from Wilcoxon rank-sum test) for distinguishing rats that underwent short CA from those with prolonged CA.
  • the CBF and CMRO2 Prior to the AUC calculation, the CBF and CMRO2 were normalized to their values at 15 sec post-ROSC. No pre-ROSC information was required for this calculation.
  • FIG. 7 shows CBF, measured at 30 sec post-ROSC and normalized to its value at 15 sec post-ROSC.
  • CBF at 30 sec post-ROSC predicted first ECoG burst to within 16% over the full cohort of rats in the study (5 min and 7 min asphyxia times). No pre-ROSC information was required for this calculation. This correlation vanished within 2 min after ROSC.
  • FIG. 8 shows a plot which illustrates that CMRO2 values measured in anesthetized rats without need for a physiological perturbation correlate well with values measured using the previous“zero-flow” perturbation method.
  • This result demonstrates an additional embodiment of the invention whereby measurements of CMRO2 in absolute physiological units can be obtained rapidly for any state of the subject (e.g., baseline, during injury, during intervention, during recovery) without need for measurement of the other states or need for performing a dynamic maneuver to perturb the physiology of the subject.
  • This allows for longitudinal comparison between subjects and a given subject at multiple discrete time points separated by hours, days, months, or even years, using the perturbation-free metric of absolute CMRO2 described here.
  • FIG. 9 shows an embodiment where cerebral blood flow data (speckle flow index; SFI) from laser speckle imaging (LSI) is combined with tissue absorption and scattering data (absorption coefficient mua, reduced scattering coefficient mus') from spatial frequency domain imaging (SFDI) to correct the SFI measurement for the effect of absorption and scattering and fit for a blood flow parameter in absolute physiological units.
  • SFI serum flow index
  • tissue absorption and scattering data absorption coefficient mua, reduced scattering coefficient mus'
  • SFDI spatial frequency domain imaging
  • the parameter is directed flow speed v c (units of mm/s).
  • the parameter is Brownian diffusion coefficient D b (units of mm 2 /s).
  • FIG.10 shows an embodiment where the displayed equation is used to perform the fitting procedure to extract the blood flow parameter (e.g., v c or D b ) in absolute physiological units.
  • the variable K is the measured speckle contrast obtained from LSI
  • the variable G1 is a function of the blood flow parameter (e.g., v c or D b ) and the tissue absorption and scattering coefficients measured with SFDI.
  • the equation may be solved for Brownian diffusion coeff D B , directed-flow term v c , or both.
  • FIG.11 shows an embodiment where the blood flow parameter (e.g., v c or D b ) is combined with the tissue oxy-hemoglobin and deoxy-hemoglobin concentrations measured with SFDI to calculate the cerebral metabolic rate of oxygen (CMRO 2 ) in absolute physiological units (e.g., uM O 2 / min).
  • CMRO 2 cerebral metabolic rate of oxygen
  • FIG. 12 shows an embodiment where the top equation is used to calculate the absolute CMRO 2 using blood flow and hemoglobin parameters multiplied by a coefficient (alpha).
  • Slide 17 shows how the (alpha) coefficient is determined by using a "zero-flow" boundary condition (e.g., start of asphyxia in cardiac arrest preclinical experiments), where blood flow is temporarily stopped and the metabolism of oxygen during this "zero-flow” state is attributed completely to the rate of change of deoxy-hemoglobin in the tissue.
  • the CMRO 2 expression shortly before this "zero-flow” condition is initiated (left hand side of equation) is set equal to the CMRO 2 expression shortly after this "zero-flow” condition is initiated (right hand expression).
  • This boundary condition equation is then solved to obtain the value of the coefficient (alpha), which is inserted back into the top equation to calculate the CMRO 2 in absolute physiological units (e.g., uM O 2 / min).
  • FIG. 13 shows an embodiment where the rate of change of deoxy-hemoglobin concentration in the tissue during the "zero-flow" period is modeled by fitting a sigmoid function to the measured data and then linearizing this sigmoid over a defined time window (which can have the duration shown in the figure or a shorter or longer duration).
  • the rate of change of deoxy-hemoglobin during the zero-flow period is calculated by choosing the endpoints of the linear period manually and calculating the mean rate of change over that period by calculating the slope of the line segment connecting those two endpoints.
  • FIG. 14 shows another embodiment where the absolute CMRO2 is calculated without the need for a "zero-flow" condition, thereby significantly reducing the perturbative effect on the tissue.
  • a dimensional analysis technique is used to combine the blood flow term (in absolute physiological units; e.g., D b or v c as described above) with the deoxy-hemoglobin concentration in the tissue and a parameter (delta) describing the mean penetration depth of the light in the tissue.
  • This embodiment was compared with one of the embodiments using the zero-flow condition, showing good agreement between the absolute CMRO 2 values for rats during a baseline period under anesthesia (FIG.8).
  • FIG. 15 shows an embodiment of the invention where an oxyhemoglobin perfusion rate *during the first 30 seconds of CPR* is calculated by measuring the oxyhemoglobin concentration with SFDI and determining the mean area under the curve during that time range.
  • This figure shows, surprisingly, that a higher perfusion rate of oxygenated hemoglobin over the *first 30 seconds* of CPR exhibited a significant negative correlation with cerebral electrical recovery (ECoG information quantity) 90 min post-CPR. This result provides evidence that our technology can help to predict the brain's response to CPR, an area that is typically overlooked in current clinical practice.
  • FIG. 16 shows an embodiment where a ratio of two parameters measured continuously *during CPR* (in this case, CBF and brain tissue deoxy-hemoglobin concentration ctHb) is monitored to identify the time it takes for the ratio to reach its peak value.
  • the time (relative to the start of CPR) for this ratio to reach its peak value was strongly correlated with the CBF/CMRO 2 ratio 0.55 min *after* CPR.
  • This CBF/CMRO2 ratio in the initial minutes post-CPR was shown to be prognostic of cerebral electrical recovery, as seen in other embodiments described in this patent, and this figure shows that a ratio of this type can be predicted via ratiometric CBF/ctHb data obtained during CPR.
  • the present invention features a method of performing guided, brain-targeted cardiopulmonary resuscitation (CPR) on a subject.
  • CPR cardiopulmonary resuscitation
  • the method of the present invention may be able to direct CPR variables in real time based on brain oxygen supply and utilization.
  • Guided brain- targeted CPR may be advantageous because many CA patients suffer significant long- term neurological damage, likely in part because very little is known about how to optimize perfusion and metabolism of the brain during CPR within the critical first few minutes post-CPR.
  • CPR is not brain-targeted, as in the present invention, because standard CPR is focused nearly exclusively on the performance of the heart (using feedback given by monitoring of heart rate and peripheral blood pressure).
  • this embodiment “teaches away” from commonly-accepted CPR practices by providing a complementary CPR paradigm where continuous feedback on brain hemodynamics is incorporated into the CPR workflow to optimize CPR quality to target the brain in addition to the heart.
  • the present invention allows for evaluation of a brain which has experienced an ischemic event, prior to the return of spontaneous circulation (ROSC)
  • the present invention may feature a method of evaluating the cerebral blood flow, brain oxygen supply, and brain oxygen utilization after an ischemic event, prior to ROSC. This may be advantageous to diagnose severity and duration of injury (e.g., amount of“down-time” that has passed between when the event occurred and when the event was identified).
  • the present invention may require the determination of a brain perfusion value and a brain metabolism value.
  • brain perfusion values include, cerebral blood flow (CBF), speckle flow index (SFI), blood flow index (BFI), Brownian diffusion coefficient Db, and directed-flow coefficient vc.
  • brain metabolism values include, cerebral metabolic rate of oxygen (CMRO 2 ), deoxy-hemoglobin concentration ctHb, and brain oxygenation StO2.
  • the brain perfusion value and the brain metabolism value may each be a relative value in comparison to a baseline value, or alternatively, the brain perfusion value and the brain metabolism value may each be an absolute value. This allows for longitudinal comparison between subjects and a given subject at multiple discrete time points separated by hours, days, months, or even years, using the metric of absolute CMRO2. [0051] Referring now to FIG. 1A, the present invention may feature a method of determining brain damage severity and prognosing recovery after an ischemic event in a subject.
  • the method may comprise measuring cerebral blood flow (CBF), measuring cerebral oxygenation, determining a relative cerebral metabolic rate of oxygen (CMRO 2 ) using the measurements of CBF and cerebral oxygenation, and calculating a ratio of the CBF to CMRO 2 .
  • CBF cerebral blood flow
  • CMRO 2 relative cerebral metabolic rate of oxygen
  • the method may comprise resuscitating the subject after the ischemic event, measuring cerebral blood flow (CBF) and cerebral oxygenation within a specific period of time immediately post- resuscitation, determining a relative cerebral metabolic rate of oxygen (CMRO 2 ) using the measurements of CBF and cerebral oxygenation, calculating a ratio of CBF to CMRO 2 , and prescribing a treatment based on the CBF:CMRO 2 ratio.
  • the prescribed treatment may be a pharmaceutical composition, surgery, rehabilitative therapy, or a combination thereof.
  • the CMRO 2 may be calculated using the equation:
  • the CBF:CMRO 2 ratio taken within a specific period of time after resuscitating the subject can provide a severity assessment and recovery prognosis for the subject, thus the method can improve cerebral recovery of the patient.
  • the specific period of time is preferably less than 3 minutes, for example, 30-120 seconds.
  • the CBF:CMRO 2 ratio is at or below a first threshold, the ratio is indicative of ischemic damage. In one embodiment, this first threshold may be about 1-1.2. If the CBF:CMRO 2 ratio is above a second threshold that is higher than the first, the ratio is indicative of excess perfusion.
  • the second threshold may greater than or equal to 1, for example the second threshold is 1.2.
  • the method may further comprise measuring cerebral electrical activity as electrocorticography (ECoG) bursts immediately post-resuscitation.
  • EoG electrocorticography
  • the CBF:CMRO 2 ratio is predictive of ECoG burst time.
  • a higher CBF:CMRO 2 ratio immediately after resuscitation is associated with a shorter asphyxial cardiac arrest period and improved neurological outcome as measured by faster ECoG bursting.
  • the step of measuring CBF, cerebral metabolism, and ECoG bursts may comprise illuminating a target tissue of the subject using a laser light source of a laser speckle imaging (LSI) system, detecting remitted light from the target tissue using a first detector of the LSI system and recording measurements of the remitted light, projecting spatial frequency patterns of light onto the target tissue using a spatial light modulator coupled to a plurality of light emitting diodes (LEDs) of a spatial frequency domain imaging (SFDI) system, detecting backscattered light from the target tissue using a second detector of the SFDI system and recording measurements of the backscattered light, detecting cerebral electrical activity of the subject using electrodes of an ECoG system and recording ECoG burst frequency, calculating speckle flow index (SFI) values using the LSI measurements to obtain CBF measurements, and determining deoxyhemoglobin and hemoglobin concentrations from the SFDI measurements.
  • LSI laser speckle imaging
  • the relative CMRO 2 is calculated using the CBF measurements and deoxyhemoglobin and hemoglobin concentrations.
  • the method is non-invasive and can provide information about the brain in the immediate minutes post-reperfusion.
  • the ischemic event is cerebral ischemia caused by cardiac arrest, stroke or traumatic brain injury.
  • the ischemic event includes global ischemia from cardiac arrest.
  • the present invention features a system for determining brain damage severity and prognosing recovery after an ischemic event in a subject.
  • the system may comprise a means for measuring cerebral blood flow (CBF), a means for measuring cerebral metabolism, and a processing unit comprising a memory and a processor operatively coupled to the memory.
  • CBF cerebral blood flow
  • a processing unit comprising a memory and a processor operatively coupled to the memory.
  • the memory stores computer- readable instructions that when executed by the processor, causes the processor to perform operations comprising determining a relative cerebral metabolic rate of oxygen (CMRO 2 ) using the measurements of CBF and cerebral oxygenation, and calculating a ratio of the CBF to CMRO 2 .
  • the system may further comprise a means for measuring ECoG burst frequency for cerebral electrical activity, where the CBF:CMRO 2 ratio is predictive of ECoG burst time.
  • FIG. 1B An example of the system for determining brain damage severity and prognosing recovery after an ischemic event in a subject is shown in FIG. 1B.
  • the system may comprise a laser speckle imaging (LSI) system comprising a laser light source, a diffuser, and a first detector; a multispectral spatial frequency domain imaging (SFDI) system comprising a plurality of light emitting diodes (LEDs) of varying wavelengths, a spatial light modulator coupled to the LEDs, and a second detector; an electrocorticography (ECoG) system comprising a plurality of electrodes; and a processing unit comprising a memory and a processor operatively coupled to the memory, the LSI system, the SFDI system, and the ECoG system.
  • the laser light source may be an 809 nm laser.
  • the plurality of LEDs comprises 655 nm, 730 nm, and 850 nm LEDs.
  • the memory can store computer-readable instructions that when executed by the processor, causes the processor to perform operations comprising recording ECoG burst frequency from the ECoG system, which correlates to cerebral electrical activity, recording measurements from the LSI system, calculating speckle flow index (SFI) values using the LSI measurements to obtain measurements of cerebral blood flow (CBF), recording measurements from the SFDI system, determining deoxyhemoglobin and hemoglobin concentrations from the SFDI measurements, calculating a relative cerebral metabolic rate of oxygen (CMRO 2 ) using the CBF measurements and deoxyhemoglobin and hemoglobin concentrations, and calculating a ratio of the CBF:CMRO 2 .
  • SFI speckle flow index
  • the CBF:CMRO 2 ratio can quantify a degree of mismatch between cerebral perfusion and metabolism, and also serve as a metric of cerebral autoregulation. For instance, within a specific period of time after resuscitation, the CBF:CMRO 2 ratio can be used to provide a severity assessment and recovery prognosis, as well as predict ECoG burst time.
  • the present invention may incorporate fiber-probe based methods to interrogate regions of the brain that are deeper beneath the surface.
  • non-invasive near-infrared spectroscopy (NIRS) and coherent optical fluctuation sensing techniques such as for example diffuse correlation spectroscopy (DCS) and Doppler-based techniques, may be applied to measure CBF and CMRO 2 immediately post-ROSC in CA patients.
  • NIRS near-infrared spectroscopy
  • DCS diffuse correlation spectroscopy
  • Doppler-based techniques may be applied to measure CBF and CMRO 2 immediately post-ROSC in CA patients.
  • the method may comprise illuminating a target tissue of the subject using the laser light source of the LSI system, detecting remitted light from the target tissue using the first detector of the LSI system and recording measurements of the remitted light, projecting spatial frequency patterns of light onto the target tissue using the spatial light modulator coupled to the plurality of light emitting diodes (LEDs) of the SFDI system, detecting backscattered light from the target tissue using the second detector of the SFDI system and recording measurements of the backscattered light, detecting cerebral electrical activity of the subject using the ECoG system and recording ECoG burst frequency, calculating SFI values using the LSI measurements to obtain CBF measurements, determining deoxyhemoglobin and hemoglobin concentrations from the SFDI measurements, calculating the relative CMRO 2 using CBF measurements and deoxyhemoglobin and hemoglobin concentrations, and calculating the CBF:CMRO 2 ratio.
  • the present invention uses metrics for both blood flow and oxygenation and combines them into a metabolic and flow-metabolism coupling/ uncoupling metric.
  • the present invention may also incorporate tissue scattering/cytotoxic edema parameters for improved quantitative characterization.
  • the present invention can quantify autonomic dysregulation in the brain by using flow and metabolism parameters in tandem.
  • the present invention requires no implantation, no exogenous contrast agents, and can even be non-contact in some manifestations.
  • the present invention features a method of performing guided, brain-targeted cardiopulmonary resuscitation (CPR) on a subject.
  • the method may comprise: performing CPR on the subject; simultaneously with CPR, evaluating cerebral blood flow, brain oxygen supply, or brain oxygen utilization by: determining a brain perfusion value; and determining a brain metabolism value; calculating a ratio R of the brain perfusion value and the brain metabolism value; and directing CPR or post-CPR treatment based on the value of R.
  • CPR may be iteratively directed based on the change of R over time.
  • CPR may be iteratively directed based on a comparison of R or a time- derivative of R to a threshold value.
  • the threshold value may be one.
  • the value of R may be determined dynamically and provide real time feedback.
  • the value of R may be initially determined within about 20 seconds of beginning CPR.
  • the value of R may be initially determined within about 2, 4, 6, 8, 10, 12, 14, 16, 18, 22, 24, 26, 28, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 175, 200, 250, 300, or more than 300 seconds of beginning CPR.
  • the value or change in value of R is used to determine a CPR variable.
  • CPR variables include, a chest compression rate, a chest compression depth, the frequency of ventilation, the depth of ventilation, how much oxygen is administered during each ventilation, if epinephrine should be administered, a dose of epinephrine to be administered, if electric shock should be administered, if a pharmaceutical should be administered, or a dose of pharmaceutical to be administered.
  • the brain perfusion value and the brain metabolism value may each be a relative value in comparison to a reference point or baseline value. In alternative embodiments, the brain perfusion value and the brain metabolism value may each be an absolute value.
  • Non-limiting examples of brain perfusion values include cerebral blood flow (CBF), speckle flow index (SFI), blood flow index (BFI), Brownian diffusion coefficient Db, directed-flow coefficient vc, or a combination thereof.
  • the brain metabolism value may be based on cerebral blood flow, brain oxygenation, a measured concentration of oxyhemoglobin, a measured concentration of deoxyhemoglobin, or a combination thereof.
  • Non-limiting examples of brain metabolism values include the cerebral metabolic rate of oxygen (CMRO 2 ), the deoxy-hemoglobin concentration ctHb, the tissue oxygenation StO2, or a combination thereof.
  • CMRO 2 cerebral metabolic rate of oxygen
  • a probe, a patch, or a sticker which attaches to the subject’s body may be used to determine the brain perfusion value, the brain oxygenation value, the brain metabolism value, or a combination thereof.
  • a method for guided CPR may include an initial step of fixing a patch to the subject’s head.
  • a method of the present invention may allow for a CPR pause time (for example, a pause time to check for a pulse) to be reduced or eliminated.
  • the present invention features a method of performing guided, brain-targeted cardiopulmonary resuscitation (CPR) on a subject.
  • the method may comprise: performing CPR on the subject; simultaneously with CPR, evaluating brain oxygen supply and utilization by: determining a brain perfusion value; and determining a brain metabolism value; and directing CPR based on both the brain perfusion value and the brain metabolism value.
  • the brain perfusion value and the brain metabolism value may be analysed as a coordinate (perfusion, metabolism) that uses both the magnitude of each value and the ratio between them to inform CPR.
  • the present invention features a method of performing guided, brain-targeted cardiopulmonary resuscitation (CPR) on a subject.
  • the method may comprise: performing CPR on the subject; simultaneously with CPR, evaluating brain oxygen supply and utilization by: determining a brain perfusion value; or determining a brain metabolism value; and directing CPR based on the brain perfusion value or the brain metabolism value.
  • the present invention features a method of evaluating the brain oxygen supply and utilization of a subject prior to, during, in response to, or after an ischemic event.
  • the method may comprise: determining a brain perfusion value; determining a brain metabolism value; and calculating a ratio R of the brain perfusion value and the brain metabolism value, wherein the value or change in value of R provides information on the relative oxygen supply and utilization of a brain of the subject.
  • R may be initially calculated prior to, or immediately after, return of spontaneous circulation (ROSC). According to a selected embodiment, R may be calculated during the administration of CPR to the subject.
  • the information on the cerebral blood flow, brain oxygen supply, brain oxygen utilization, or a combination thereof may be iteratively used to guide treatment of the subject.
  • the information on the cerebral blood flow, brain oxygen supply, brain oxygen utilization or a combination thereof may be used to diagnose a condition of the subject or provide prognostication of the patient’s cerebral recovery.
  • a laser speckle imaging (LSI) system or diffuse correlation spectroscopy (DCS) system or laser Doppler flowmetry (LDF) system may be used to determine the brain perfusion value.
  • a spatial frequency domain imaging SFDI
  • DOS diffuse optical spectroscopy
  • NIRS near-infrared spectroscopy
  • FDPM-DOS frequency-domain photon migration DOS
  • FDPM-NIRS frequency-domain photon migration NIRS
  • TR-DOS time-resolved diffuse optical spectroscopy
  • TR- NIRS time-resolved near-infrared spectroscopy
  • epidural screw electrodes were implanted for ECoG, and a partial craniectomy (4 mm right-to-left x 6 mm anterior-to- posterior) was performed to expose a portion of the right sensory and visual cortex for optical imaging.
  • epidural screw ECoG electrodes one of which is the reference electrode
  • Two of these electrodes were located toward the front of the brain (2 mm anterior to bregma, 2.5 mm lateral to bregma) over the motor cortices, one was located atop the visual cortex (5.5 mm posterior to bregma, 4 mm left of bregma), and the reference electrode was located in the posterior region of the brain (3 mm posterior to lambda), over the cerebellum.
  • the femoral artery was cannulated to enable arterial blood gas sampling as well as blood pressure monitoring while the femoral vein was cannulated to enable intravenous drug delivery.
  • the LSI system employed a long-coherence-length 809 nm laser as the light source. A diffuser was mounted between the laser and the tissue to obtain near-uniform illumination on the exposed brain region. The remitted light was then isolated with a laser line filter and images were acquired at 60 Hz using a CCD camera with an exposure time T of 10 ms. For each region of interest (ROI) selected within the craniectomy, mean speckle flow index (SFI) values were calculated and used to create time-resolved curves. Relative SFI curves were calculated using a sliding median filter of 10 s in length. Unless otherwise specified, the pre-asphyxial time period was chosen as baseline due to post-anesthesia emergence and consequent cerebral hyperemia.
  • ROI region of interest
  • SFI speckle flow index
  • a different time period e.g., post-CPR
  • the SFI obtained using these procedures was used as the measure of CBF in this report.
  • the SFDI setup used three light emitting diodes (LEDs, 655 nm, 730 nm, 850 nm) as light sources that were coupled into a spatial light modulator to project spatial frequency patterns of the light onto the tissue.
  • LEDs light emitting diodes
  • sCMOS scientific complementary metal-oxide semiconductor
  • the acquisition sequence DC projection, followed by a square-wave pattern at each of three spatial phases, repeated serially over all wavelengths was repeated to achieve an effective frame rate of ⁇ 14 Hz.
  • DCBF, DctHb, and DctHb tot are the changes in CBF, deoxy- hemoglobin, and total hemoglobin, respectively, relative to their baseline values (CBF 0 , ctHb 0 , ctHbtot 0 ).
  • the constants g r and g t are related to the venous and arterial contributions to hemoglobin content, and were set to 1.
  • the flow-metabolism ratio CBF/CMRO 2 was calculated at each time point by dividing the CBF value obtained with LSI by the CMRO 2 value obtained from Equation 1. This ratio was used to quantify flow-metabolism mismatch. Specifically, CBF/CMRO 2 > 1 corresponded to a mismatch for which CBF exceeded metabolic demand, and CBF/CMRO 2 ⁇ 1 represented a mismatch where CBF was insufficient to meet metabolic demand.
  • the periods of flow-metabolism coupling were defined as time windows during which CBF and CMRO 2 exhibited similar rates of change, and the periods of flow-metabolism uncoupling were defined as time windows during which the slopes of CBF and CMRO 2 had opposite signs, or where one slope was non-zero and the other was zero.
  • Electrocorticography EoG
  • Each screw electrode was connected to a Tucker-Davis Technologies (TDT) PZ2 preamplifier, which had a 0.35 Hz high-pass filter for detection of standard ECoG signals.
  • TDT Tucker-Davis Technologies
  • a noise test was performed to ensure that the signal-to-noise ratio was suitable for measurements.
  • Raw ECoG data were processed using custom MATLAB code. DC bias was removed by de-trending the data. Noise and artifacts across channels were reduced with common average referencing. A 60 Hz notch filter and a 1-150 Hz bandpass filter were applied to the data. To lessen computational burden, signals were downsampled to 600Hz.
  • ECoG burst frequency (defined as bursts/min) was used as a metric to quantify the extent of cerebral electrical recovery, which correlates to neurological outcome.
  • CA Cardiac Arrest
  • CPR Cardiopulmonary Resuscitation
  • the isoflurane level was decreased from 2.0% to 0.5-1.0% and the inhaled gas mixture changed from 50% O 2 + 50% N 2 to 100% O 2 .
  • isoflurane delivery was turned off and washed out by delivering room air (21% O 2 ).
  • This washout period is essential to mitigate effects of isoflurane on CBF and brain function.
  • a neuromuscular blocking agent (1 mL of 2 mg/kg Vecuronium; 1 mL of heparinized saline) was administered intravenously to provide the ventilator with complete control of respiration.
  • FIG. 1C shows representative maps of CBF and brain oxygenation during four distinct phases of the CA/CPR experiment.
  • Phase I baseline/washout
  • CBF and oxygenation were constant until isoflurane washout began, at which point the CBF and CMRO 2 both increased as the animal began to wake up.
  • Phase II CA
  • Phase III hyperemia
  • Phase IV hyperperfusion
  • CBF stabilized at a level below baseline, but oxygen extraction increased, leading to a decrease in brain oxygenation.
  • FIGs. 2-3 illustrate the dynamic relationship between CBF and CMRO 2 in a representative rat.
  • CBF green
  • deoxy- hemoglobin blue
  • CMRO 2 magenta
  • ECoG activity all increased during isoflurane washout.
  • Phase II ECoG showed electrocerebral silence within ⁇ 30 sec following onset of asphyxia concomitantly with a decrease in systemic blood pressure (c).
  • a large decrease in CBF, oxy-hemoglobin (red), and CMRO 2 was observed with a large ( ⁇ 50%) increase in deoxy-hemoglobin, as oxygen extraction occurred in the absence of perfusion.
  • Phase III ROSC was associated with a hyperemic state, yet electrocerebral silence persisted.
  • Phase IV CBF decreased to a stabilized level, deoxy-hemoglobin increased, and ECoG activity resumed.
  • Phase IV dynamics signified increased oxygen extraction relative to perfusion, coinciding with increased neuronal activity.
  • Five sub-phases were identified during Phase III (FIG. 3). During Phase III(a), which lasted for only ⁇ 1 min post-CPR, a transient increase in deoxy-hemoglobin, followed immediately by a transient decrease in CBF and CMRO 2 , was observed.
  • Phase III(b) CBF, oxy-hemoglobin, and CMRO 2 increased and deoxy- hemoglobin decreased.
  • Phase III(c) CMRO 2 and CBF continued to increase, but oxy-hemoglobin reached a plateau and deoxy-hemoglobin began to increase, in a manner similar to that seen in Phase I.
  • Phase III(d) CMRO 2 and deoxy- hemoglobin continued to increase, but oxy-hemoglobin slightly decreased while CBF reached a plateau.
  • Phase III(e) a noticeable transient decoupling between flow and metabolism was observed, as CMRO 2 reached a plateau while CBF decreased sharply.
  • Phase IV contains two main sub-phases. During Phase IV(a), CBF and CMRO 2 decrease sharply, oxy-hemoglobin continues to decrease gradually, and deoxy- hemoglobin increases. During Phase IV(b), CBF has stabilized at a level below pre-CA baseline and deoxy-hemoglobin gradually reaches a steady value. The end of hyperemia coincides with initial ECoG bursting and the transition between Phases III and IV, marked by the intersection of the CBF and CMRO 2 curves.
  • Flow-metabolism coupling and uncoupling post-CPR may be influenced by CA duration
  • FIGs. 4A and 4B show CBF and CMRO 2 for two representative rats: one with a 5 min asphyxial period and earlier time to initial ECoG burst frequency (4A), and one with a 7 min asphyxial period and delayed recovery of burst frequency (4B).
  • the CBF and CMRO 2 dynamics are coupled throughout the reperfusion period. This similarity in the CBF and CMRO 2 lineshapes, with the magnitude of the CBF change exceeding the magnitude of the CMRO 2 change, is similar to that observed in stimulus-evoked CBF and CMRO 2 measurements in healthy subjects.
  • FIG. 5A shows the CBF/CMRO 2 ratio during the first minute after resuscitation for 5 rats with shorter CA (5 min asphyxia; solid lines) and 5 rats with prolonged CA (7 min asphyxia; dashed lines).
  • a threshold can be placed on the value of CBF/CMRO 2 in the window of ⁇ 0.5-1 min post-resuscitation (vertical line at CBF/CMRO 2 ⁇ 1 in FIG. 5B) to separate the rats with shorter CA from the rats with prolonged CA.
  • the CBF/CMRO 2 ratio can be used for assessment of the severity (duration) of CA, without any prior knowledge of the cardiac or hemodynamic history of the patient.
  • This threshold makes sense physically, because CBF/CMRO 2 ⁇ 1 can be thought of as a marker of flow-metabolism mismatch (i.e. CBF is insufficient to meet metabolic demand).
  • the CA severity assessment capability of the CBF/CMRO 2 ratio vanished within 3 min of ROSC.
  • a second threshold can be placed at CBF/CMRO 2 ⁇ 1.2 to differentiate between rats with poor short-term recovery (longer time to ECoG bursting) and those with good short-term recovery (shorter time to ECoG burst), independent of CA duration.
  • FIGs. 6A and 6B show CBF and CMRO 2 , normalized to the corresponding value at 15 sec post-ROSC, for the first 5 min post-ROSC for representative rats with shorter CA (6A) and longer CA (6B).
  • FIG.6C shows that the ratio of the areas under the CBF and CMRO 2 curves from 0.25-3 min post-ROSC was statistically significant for distinguishing between shorter CA and prolonged CA.
  • FIG. 7 shows that CBF alone, measured within the first minute post-ROSC and normalized to its value at 15 sec post-ROSC, can be employed to predict time of initial ECoG burst.
  • this metric predicted first ECoG burst to within 16% over the entire cohort of rats, including both shorter and prolonged asphyxia times. This result suggests that the lower the CBF after completion of CPR, the longer it will take for the brain’s electrical activity to resume.
  • the present invention has found that deviations of the CBF/CMRO 2 ratio from unity within the first minute post-ROSC can assess CA severity (asphyxia duration) and predict cerebral electrical recovery (time to first ECoG burst).
  • the CBF/CMRO 2 ratio at 1 min post-ROSC is predictive of ECoG burst time with 87% accuracy (Table 1).
  • CA patients typically suffer pronounced and prolonged brain damage due to cerebral ischemia. For patients who undergo out-of-hospital CA, 68% of fatalities are attributed primarily to ischemia-related brain injury, and fewer than 9% survive with “Good or Moderate Cerebral Performance” (defined as Cerebral Performance Category 1 or 2).
  • Cerebral Performance Category 1 or 2 “Good or Moderate Cerebral Performance”
  • Cerebral perfusion/metabolism mismatch can predict ischemic injury or perfusion damage to prognosticate neurological recovery and inform treatment
  • An optimal CBF range to promote cerebral recovery following ischemic injury, such as CA, is defined not by the CBF alone, but by the amount of perfusion relative to cerebral metabolism. Determining this optimal balance of flow-metabolism matching to allow optimal neurovascular coupling is especially critical during periods of cerebral autonomic dysregulation, which occurs after acute brain injury (including ischemic injury and traumatic brain injury). Therefore, measuring CBF and CMRO 2 in tandem is crucial, and the CBF/CMRO 2 ratio may be used to indicate ischemic damage (CBF/CMRO 2 ⁇ 1) or excess perfusion (CBF/CMRO 2 >>1).
  • CBF/CMRO 2 ratio that exceeds 1 in the first few minutes post-CPR; this ratio may need to be much greater than 1 to indicate perfusion injury.
  • a CBF/CMRO 2 ratio that is even slightly below 1 (or, in fact, slightly above 1) may indicate risk of ischemic injury, as animals with delayed ECoG bursting had CBF/CMRO 2 ⁇ 1.2 at this early time point.
  • the significant prognostic metrics in this experiment were all found at time points within ⁇ 3 min post- ROSC. After that time window ended, these metrics lost their prognostic significance.
  • peripheral blood pressure may be decoupled from CBF, measurements of CBF are not typically combined with cerebral oximetry, and there is often a significant time delay between ROSC and measurements of cerebral perfusion.
  • Continuously monitoring CBF and CMRO 2 immediately post- ROSC may provide real-time feedback to clinicians to optimize treatment and improve cerebral recovery for CA patients.
  • the present invention has quantified the highly-dynamic relationship between CBF and brain metabolism (CMRO 2 ) in a preclinical model of CA and CPR.
  • the present invention may be of great potential importance in a clinical scenario where a CA patient presents to first responders, emergency medicine physicians, or intensive care physicians who may lack knowledge of the exact time when CA occurred prior to achieving return of spontaneous circulation (ROSC). Since the perfusion and metabolism metrics reported here only require knowledge of CBF and CMRO 2 in the first minute post-CPR, these metrics can help inform urgent clinical decision making in the critical period immediately post-CPR. [00126] EXAMPLE 2
  • LSI Laser Speckle Imaging
  • SFI Speckle Flow Index
  • a , s brain absorption and reduced scattering coefficients
  • SFDI Spatial Frequency Domain Imaging
  • the wavelength-dependent a was analyzed to obtain concentrations (mM) of oxygenated and deoxygenated hemoglobin in the brain tissue (ctHbO 2 and ctHb, respectively).
  • the present example features a multimodal diffuse optical technique to rapidly measure cerebral metabolic rate of oxygen (CMRO 2 ) in quantitative physiological units (mM O 2 consumed per minute) without needing to induce a physiological perturbation.
  • CMRO 2 cerebral metabolic rate of oxygen
  • the technique was validated in a preclinical rat model and may be translatable for clinically-compatible measurements.
  • the technique may allow for characterization of baseline CMRO 2 values to enable subject-to-subject comparison and longitudinal comparison without requiring dynamic experiments (e.g., gas challenges).
  • the term“about” refers to plus or minus 10% of the referenced number.
  • descriptions of the inventions described herein using the phrase “comprising” includes embodiments that could be described as“consisting essentially of” or“consisting of”, and as such the written description requirement for claiming one or more embodiments of the present invention using the phrase“consisting essentially of” or“consisting of” is met.

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Abstract

Une plate-forme d'imagerie optique multimodale est utilisée pour obtenir des mesures incompatibles du métabolisme de perfusion cérébrale pour une évaluation rapide d'une lésion cérébrale aiguë, une rétroaction en cours (en temps réel) pour optimiser la réanimation cardiopulmonaire afin d'améliorer le résultat neurologique et le pronostic rapide de récupération. Une lumière constituée de plusieurs longueurs d'onde et types est administrée au tissu, celle-ci étant ensuite absorbée et diffusée par des constituants tissulaires tels que des constituants sanguins et cellulaires. Une partie de cette lumière rediffuse vers la surface, où elle est capturée par un détecteur. Les données ainsi obtenues sont traitées pour obtenir des paramètres de flux sanguin et d'oxygénation du sang, ainsi que de diffusion tissulaire. Ces paramètres sont ensuite combinés pour calculer des mesures de couplage/découplage du métabolisme et du métabolisme du flux, qui sont utilisées pour déterminer une lésion ischémique, un besoin en cours pour un flux sanguin optimal et une oxygénation optimale du sang, et pour prédire la récupération cérébrale chez des patients présentant une lésion cérébrale aiguë pendant et immédiatement après un arrêt cardiaque, un accident vasculaire cérébral, une lésion cérébrale traumatique, etc.
PCT/US2020/035440 2018-09-21 2020-05-29 Procédés en temps réel pour permettre à une rcp guidée par la précision d'améliorer le résultat neurologique et de prédire une lésion cérébrale après une lésion ischémique et une reperfusion WO2020243658A1 (fr)

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JP2021569885A JP2022534386A (ja) 2019-05-29 2020-05-29 正確にガイドされるｃｐｒが神経学的結果を改善し脳損傷を予測することを可能にするリアルタイムの方法
US16/985,113 US20200367761A1 (en) 2019-04-01 2020-08-04 Portable device for quantitative measurement of tissue autoregulation and neurovascular coupling using eeg, metabolism, and blood flow diagnostics
US17/377,123 US20210338092A1 (en) 2019-04-01 2021-07-15 Portable device for quantitative measurement of tissue autoregulation and neurovascular coupling using eeg, metabolism, and blood flow diagnostics
US17/534,986 US20220079840A1 (en) 2018-09-21 2021-11-24 Real-time methods to enable precision-guided cpr to improve neurological outcome and predict brain damage after ischemic injury and reperfusion
US17/690,866 US20220192919A1 (en) 2018-09-21 2022-03-09 Real-time methods to enable precision-guided cpr to improve neurological outcome and predict brain damage after ischemic injury and reperfusion
US17/706,217 US20220223257A1 (en) 2018-09-21 2022-03-28 Generation of personalized neuroprotective and cardioprotective nutrition programs featuring caloric restriction
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