MONITORING AUTOREGULATION

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of Provisional Application No. 62/186,458, entitled "SYSTEM AND METHOD OF MONITORING

AUTOREGULATION," filed June 30, 2015, and U.S. Application No. 15/194,122, entitled "SYSTEM AND METHOD OF MONITORING AUTOREGULATION," filed June 27, 2016, which are herein incorporated by reference in their entirety for all purposes.

BACKGROUND

[0002] The present disclosure relates generally to medical devices and, more particularly, to systems and methods of monitoring autoregulation.

[0003] This section is intended to introduce the reader to various aspects of art that may be related to various aspects of the present disclosure, which are described and/or claimed below. This discussion is believed to be helpful in providing the reader with background information to facilitate a better understanding of the various aspects of the present disclosure. Accordingly, it should be understood that these statements are to be read in this light, and not as admissions of prior art.

[0004] In the field of medicine, medical professionals often desire to monitor certain physiological parameters of their patients. In some cases, clinicians may wish to monitor a patient's autoregulation. Autoregulation is a physiological process that attempts to maintain an optimal cerebral blood flow to supply appropriate levels of oxygen and nutrients to the brain. During autoregulation, cerebral arterioles dilate or constrict to maintain optimal blood flow. For example, as cerebral pressure decreases, cerebral arterioles dilate in an attempt to maintain blood flow. As cerebral pressure increases, cerebral arterioles constrict to reduce the blood flow that could cause injury to the brain. If the patient's autoregulation process is not functioning properly, the patient may experience inappropriate cerebral blood flow, which may have negative effects on the l patient's health. In particular, a drop in cerebral blood flow may cause ischemia, which may result in tissue damage or death of brain cells. An increase in cerebral blood flow may cause hyperemia, which may result in swelling of the brain or edema.

[0005] Some existing systems for monitoring autoregulation may determine a patient's autoregulation status based on various physiological signals. For example, existing systems may determine a patient's autoregulation status based on a correlation between a change in blood pressure and a change in oxygen saturation. However, such a correlation may be subject to various sources of error. Accordingly, the autoregulation status determined by such existing systems may be inaccurate or unreliable.

BRIEF DESCRIPTION OF THE DRAWINGS

[0006] Advantages of the disclosed techniques may become apparent upon reading the following detailed description and upon reference to the drawings in which:

[0007] Fig. 1 is a block diagram of an embodiment of a system for monitoring a patient's autoregulation;

[0008] Fig. 2 is an example of a graph illustrating a linear correlation between oxygen saturation values and blood pressure values;

[0009] Fig. 3 is an example of a series of graphs illustrating blood pressure, oxygen saturation, a cerebral oximetry index (COx), a phase map, and a phase difference over time;

[0010] Fig. 4 is an example of a series of graphs illustrating a correlation between COx and a phase difference over time;

[0011] Fig. 5 is a process flow diagram of a method of monitoring autoregulation based at least in part on a phase difference between an oxygen saturation signal and a blood pressure signal, in accordance with an embodiment;

[0012] Fig. 6 is a process flow diagram of a method of determining a confidence level related to the COx based at least in part on a comparison of the COx to a phase difference between an oxygen saturation signal and a blood pressure signal, in accordance with an embodiment; [0013] Fig. 7 is an example of a series of graphs illustrating blood pressure, oxygen saturation, a phase map, and a synchrosqueezed phase map;

[0014] Fig. 8 is a process flow diagram of a method of monitoring autoregulation using a synchrosqueezed cross-wavelet transform, in accordance with an embodiment; and

[0015] Fig. 9 is an embodiment of a display configured to display various information related to an autoregulation status of a patient.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

[0016] One or more specific embodiments of the present techniques will be described below. In an effort to provide a concise description of these embodiments, not all features of an actual implementation are described in the specification. It should be appreciated that in the development of any such actual implementation, as in any engineering or design project, numerous implementation-specific decisions must be made to achieve the developers' specific goals, such as compliance with system-related and business-related constraints, which may vary from one implementation to another.

Moreover, it should be appreciated that such a development effort might be complex and time consuming, but would nevertheless be a routine undertaking of design, fabrication, and manufacture for those of ordinary skill having the benefit of this disclosure.

[0017] A physician may monitor a patient's autoregulation through the use of various monitoring devices and systems. In some cases, a patient's autoregulation may be monitored by correlating measurements of the patient's blood pressure (e.g., arterial blood pressure) with measurements of the patient's oxygen saturation (e.g., regional oxygen saturation). A cerebral oximetry index (COx) may be derived based at least in part on a linear correlation between the patient's blood pressure and oxygen saturation. However, the COx may be adversely affected by noise in the physiological signals, and/or may be adversely affected by other sources of error, such as a number of data points used in its computation, a gradient of a regression line, or the like. Thus, the COx may not accurately reflect the patient's autoregulation status.

[0018] In view of the foregoing, it may be desirable to determine (e.g., determine and/or assign) a confidence level (e.g., statistical confidence level, confidence measure, confidence metric, or quality metric) related to the COx. Accordingly, provided herein are systems and methods that enable determination of a confidence level of the COx. The confidence level may relate to, and provide some indication of, the accuracy and/or reliability of the COx (and thus, of the patient's autoregulation status). In certain embodiments, a system may determine the confidence level based at least in part on a phase difference between the blood pressure signal and the oxygen saturation signal. In particular, the phase difference between the blood pressure signal and the oxygen saturation signal may enable the system to determine that certain portions of the COx are reliable and/or accurate. The phase difference between the blood pressure signal and the oxygen saturation signal may also enable the system to identify certain portions of the COx that are unreliable and/or inaccurate.

[0019] In some embodiments, the system may be configured to provide information indicative of the confidence level to a user. For example, the system may provide a confirmation (e.g., via a display) that the autoregulation status is reliable if the COx is determined to have a high confidence level. In some cases, the system may discard portions of the COx that are determined to be unreliable or may take other remedial actions to provide accurate autoregulation information to the user, as discussed in more detail below. Such systems and methods may in turn provide improved patient monitoring and patient care.

[0020] FIG. 1 illustrates an embodiment of a system 10 for monitoring

autoregulation. As shown, the system 10 includes a blood pressure sensor 12, an oxygen saturation sensor 14 (e.g., a regional oxygen saturation sensor), a controller 16, and an output device 18. The blood pressure sensor 12 may be any sensor or device configured to obtain the patient's blood pressure (e.g., arterial blood pressure). For example, the blood pressure sensor 12 may include a blood pressure cuff for non-invasively monitoring blood pressure or an arterial line for invasively monitoring blood pressure. In certain embodiments, the blood pressure sensor 12 may include one or more pulse oximetry sensors. In some such cases, the patient's blood pressure may be derived by processing time delays between two or more characteristic points within a single plethysmography (PPG) signal obtained from a single pulse oximetry sensor. Various techniques for deriving blood pressure based on a comparison of time delays between certain components of a single PPG signal obtained from a single pulse oximetry sensor is described in U. S. Publication No. 2009/0326386, entitled "Systems and Methods for Non-Invasive Blood Pressure Monitoring," the entirety of which is incorporated herein by reference. In other cases, the patient's blood pressure may be continuously, non- invasively monitored via multiple pulse oximetry sensors placed at multiple locations on the patient's body. As described in U. S. Patent No. 6,599,251, entitled "Continuous Noninvasive Blood Pressure Monitoring Method and Apparatus," the entirety of which is incorporated herein by reference, multiple PPG signals may be obtained from the multiple pulse oximetry sensors, and the PPG signals may be compared against one another to estimate the patient's blood pressure. Regardless of its form, the blood pressure sensor 12 may be configured to generate a blood pressure signal indicative of the patient's blood pressure (e.g., arterial blood pressure) over time. As discussed in more detail below, the blood pressure sensor 12 may provide the blood pressure signal to the controller 16 or to any other suitable processing device to enable evaluation of the patient's autoregulation status.

[0021] As shown, the oxygen saturation sensor 14 may be a regional oxygen saturation sensor configured to generate an oxygen saturation signal indicative of blood oxygen saturation within the venous, arterial, and capillary systems within a region of the patient. For example, the oxygen saturation sensor 14 may be configured to be placed on the patient's forehead and may be used to calculate the oxygen saturation of the patient's blood within the venous, arterial, and capillary systems of a region underlying the patient's forehead (e.g., in the cerebral cortex). In such cases, the oxygen saturation sensor 14 may include an emitter 20 and multiple detectors 22. The emitter 20 may include at least two light emitting diodes (LEDs), each configured to emit at different wavelengths of light, e.g., red or near infrared light. In one embodiment, the LEDs of the emitter 20 emit light in the range of about 600 nm to about 1000 nm. In a particular embodiment, one LED of the emitter 20 is configured to emit light at about 730 nm and the other LED of the emitter 20 is configured to emit light at about 810 nm. One of the detectors 22 is positioned relatively "close" (e.g., proximal) to the emitter 20 and one of the detectors 22 is positioned relatively "far" (e.g., distal) from the emitter 22. Light intensity of multiple wavelengths may be received at both the "close" and the "far" detectors 22. For example, if two wavelengths are used, the two wavelengths may be contrasted at each location and the resulting signals may be contrasted to arrive at a regional saturation value that pertains to additional tissue through which the light received at the "far" detector passed (tissue in addition to the tissue through which the light received by the "close" detector passed, e.g., the brain tissue), when it was transmitted through a region of a patient (e.g., a patient's cranium). Surface data from the skin and skull may be subtracted out, to generate a regional oxygen saturation (rSC ) signal for the target tissues over time. As discussed in more detail below, the oxygen saturation sensor 14 may provide the regional oxygen saturation signal to the controller 16 or to any other suitable processing device to enable evaluation of the patient's autoregulation status. While the depicted oxygen saturation sensor 14 is a regional saturation sensor, the sensor 14 may be a pulse oximeter configured to obtain the patient's oxygen saturation or may be any suitable sensor configured to provide a signal indicative of the patient's blood flow. For example, the sensor 14 may be configured to emit light at a single wavelength (e.g., an isobestic wavelength) and to provide a signal indicative of blood flow.

[0022] In operation, the blood pressure sensor 12 and the oxygen saturation sensor 14 may each be placed on the same or different parts of the patient's body. Indeed, the blood pressure sensor 12 and the oxygen saturation sensor 14 may in some cases be part of the same sensor or supported by a single sensor housing. For example, the blood pressure sensor 12 and the oxygen saturation sensor 14 may be part of an integrated oximetry system configured to non-invasively measure blood pressure (e.g., based on time delays in a PPG signal) and regional oxygen saturation. One or both of the blood pressure sensor 12 or the oxygen saturation sensor 14 may be further configured to measure other parameters, such as hemoglobin, respiratory rate, respiratory effort, heart rate, saturation pattern detection, response to stimulus such as bispectral index (BIS) or

electromyography (EMG) response to electrical stimulus, or the like. While an exemplary system 10 is shown, the exemplary components illustrated in FIG. 1 are not intended to be limiting. Indeed, additional or alternative components and/or

implementations may be used.

[0023] As noted above, the blood pressure sensor 12 may be configured to provide the blood pressure signal to the controller 16, and the oxygen saturation sensor 14 may be configured to provide the oxygen saturation signal to the controller 16. In certain embodiments, the controller 16 is an electronic controller having electrical circuitry configured to process the various received signals. In particular, the controller 16 may be configured to process the blood pressure signal and the oxygen saturation signal to evaluate the patient's cerebral autoregulation status. Although the blood pressure sensor 12 and the oxygen saturation sensor 14 may be configured to provide their respective signals or data directly to the controller 16, in certain embodiments, the signals or data obtained by the blood pressure sensor 12 and/or the oxygen saturation sensor 14 may be provided to one or more intermediate processing devices (e.g., specialized monitor, such as a blood pressure monitor or an oxygen saturation monitor, or the like), which may in turn provide processed signals or data to the controller 16.

[0024] In some embodiments, the controller 16 may be configured to determine a cerebral oximetry index (COx) based on the blood pressure signal and the oxygen saturation signal. The COx is indicative of vascular reactivity, which is related to cerebral blood vessels' ability to control proper blood flow, via vasoconstriction (a narrowing of the blood vessel) and/or vasodilation (expansion of the blood vessel), for example. Thus, the COx is also indicative of whether the patient's autoregulation is impaired. The controller 16 may derive the COx by determining a linear correlation between blood pressure measurements and oxygen saturation measurements. The linear correlation may be based on a Pearson coefficient, for example. The Pearson coefficient may be defined as the covariance of the measured blood pressure (e.g., arterial blood pressure) and oxygen saturation divided by the product of their standard deviations. The result of the linear correlation may be a regression line between oxygen saturation measurements and blood pressure measurements, and the slope of the regression line may be indicative of the patient's autoregulation status. In one implementation, a regression line with a relatively flat or negative slope (e.g., regional oxygen saturation remains the same or decreases after blood pressure increases) may suggest that cerebral

autoregulation is working properly, while a regression line with a positive slope (e.g., regional oxygen saturation increases after blood pressure increases) may suggest that the cerebral autoregulation is impaired.

[0025] With the foregoing in mind, FIG. 2 is an example of a graph 40 illustrating a linear correlation between blood pressure measurements 42 (e.g., arterial blood pressure measurements) and oxygen saturation measurements 44. The result of the linear correlation may be a regression line 46 between the blood pressure measurements 42 and the oxygen saturation measurements 44, and the slope of the regression line 46 may be indicative of the patient's autoregulation status. In the illustrated example, the slope of the regression line 46 is negative and, thus, the COx value is between -1 and 0, which as discussed above, may indicate proper autoregulation. In such cases, the controller 16 may- determine that the patient's cerebral autoregulation is functioning properly and may generate and/or output an appropriate signal indicative of the patient's autoregulation status to the output device 18, for example. However, when the regression line 46 has a positive slope and the COx value is between 0 and 1 or above some predetermined threshold between 0 and 1 (e.g., 0.1, 0.2, 0,3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0,9), the controller 16 may determine that the patient's autoregulation is impaired and may generate and/or output the appropriate signal indicative of the patient's autoregulation status.

[0026] As discussed in more detail below, the controller 16 may also determine a phase difference between the blood pressure signal and the oxygen saturation signal. In such cases, the controller 16 may utilize the phase difference to determine whether the COx value is reliable or unreliable. In particular, a phase difference of approximately zero and/or a substantially constant phase difference may indicate correlation between the blood pressure signal and oxygen saturation signal, and thus, may indicate impaired autoregulation. However, a phase difference of approximately +/- % radians, and/or a rapidly varying and/or a randomly distributed phase difference, may indicate intact autoregulation. That is, the patient's blood flow (e.g., as indicated by the oxygen saturation signal) does not correlate with or is not driven by the patient's blood pressure, but rather, is controlled by the patient's autoregulation system to maintain appropriate blood flow. Thus, the phase difference may also be used to determine whether certain COx values, or portions of a CO signal generated based on such values, are reliable or unreliable. For example, if the COx signal over a time period indicates intact

autoregulation (e.g., the COx is between -1 and 0), but the phase difference over the time period indicates impaired autoregulation (e.g., the phase difference is approximately 0 and/or constant), the controller 16 may determine that the corresponding portion of the COx signal is unreliable. In this way, the phase difference may enable the controller 16 io identify portions of the COx signal that are adversely affected by noise or processing errors, and which are therefore unreliable. In certain embodiments, the controller 16 may be configured to remove or discard the unreliable portions of the COx signal and/or take other appropriate remedial actions, as discussed in more detail below.

[0027] Returning to FIG. 1, in the illustrated embodiment, the controller 16 includes a processor 24 and a memory device 26. The controller 16 may also include one or more storage devices. The processor 24 may be used to execute software, such as software for carrying out any of the techniques disclosed herein, such as processing the blood pressure signals and/or oxygen saturation signals, determining a phase difference, analyzing the phase difference, determining the COx, determining a confidence level of the COx, carrying out appropriate remedial actions, and so forth. Moreover, the processor 24 may include multiple microprocessors, one or more "general-purpose" microprocessors, one or more special-purpose microprocessors, and/or one or more application specific integrated circuits (ASICS), or some combination thereof. For example, the processor 24 may include one or more reduced instruction set (RISC) processors.

[0028] The memory device 26 may include a volatile memory, such as random access memory (RAM), and/or a nonvolatile memory, such as ROM. The memory device 26 may include one or more tangible, non-transitory, machine-readable media collectively storing instructions executable by the processor 24 to perform the methods and control actions described herein. Such machine-readable media can be any available media that can be accessed by the processor 24 or by any general purpose or special purpose computer or other machine with a processor. The memory device 26 may store a variety of information and may be used for various purposes. For example, the memory device 26 may store processor-executable instructions (e.g., firmware or software) for the processor 24 to execute, such as instructions for carrying out any of the techniques discloses herein, such as processing the blood pressure signal and/or the oxygen saturation signal, determining a phase difference, analyzing the phase difference, determining the COx, determining a confidence level of the COx, and/or taking appropriate remedial actions (e.g., output a visual or audible indication that the autoregulation status is unavailable or unreliable, block output of the COx, or the like). The storage device(s) (e.g., nonvolatile storage) may include read-only memory (ROM), flash memory, a hard drive, or any other suitable optical, magnetic, or solid-state storage medium, or a combination thereof. The storage device(s) may store data (e.g., the blood pressure signal, the oxygen saturation signal, the COx, the phase map, the phase difference, etc.), instructions (e.g., software or firmware for processing the blood pressure signal and/or the oxygen saturation signal, determining a phase difference, analyzing the phase difference, determining the COx, determining a confidence level of the COx, and/or taking appropriate remedial actions), predetermined thresholds, and any other suitable data.

[0029] As shown, the system 10 includes the output device 18. In some

embodiments, the controller 16 may be configured to provide signals indicative of the patient's autoregulation status to the output device 18. As discussed in more detail below, the controller 16 may be configured to generate an alarm signal indicative of the patient's autoregulation status and to provide the alarm signal to the output device 18. The output device 18 may include any device configured to receive signals (e.g., the signal indicative of the patient's autoregulation status, the alarm signal, the signal indicative of a confidence level, or the like) from the controller 16 and visually and/or audibly output information indicative of the patient's autoregulation status (e.g., the COx, the COx signal, the phase difference, the confidence level of the COx, an alarm, or the like). For instance, the output device 18 may include a display configured to provide a visual representation of the patient's autoregulation status, the COx, and/or the confidence level as determined by the controller 16. Additionally or alternatively, the output device 18 may include an audio device configured to provide sounds in accordance with the patient's autoregulation status, the COx, and/or the confidence level. The output device 18 may be any suitable device for conveying such information, including a computer workstation, a server, a desktop, a notebook, a laptop, a handheld computer, a mobile device, or the like. In some embodiments, the controller 16 and the output device 18 may be part of the same device or supported within one housing (e.g., a computer or monitor).

[0030] As noted above, a phase difference between the blood pressure signal and the oxygen saturation signal may be indicative of the patient's autoregulation status. Thus, in accordance with certain embodiments of the present disclosure, the phase difference may be utilized to determine a confidence level related to the COx. The phase difference may be determined in any of a variety of manners. For example, in some embodiments, the phase difference may be determined based on a cross-wavelet transform of the blood pressure signal and the oxygen saturation signal. With the foregoing in mind, FIG. 3 is an example of a series of graphs illustrating a blood pressure signal 60, an oxygen saturation signal 62, a cerebral oximetry index (COx) 64, a phase map 66 (i.e., a phase map generated from a cross-wavelet transform of the blood pressure signal 60 and the oxygen saturation signal 62), and a phase difference 68 (i.e., a phase difference at a characteristic frequency over time). The phase map 66 is indicative of the phase difference between the blood pressure signal and the oxygen saturation signal across a range of scales (or frequencies) and temporal locations. In the illustrated embodiment, a characteristic frequency level of 0.0033Hz is shown by a line 70 drawn across the phase map 66, and the phase difference 68 is derived from the cross-wavelet transform at the characteristic frequency level (e.g., 0.0033Hz or any suitable characteristic frequency). The characteristic frequency level may be predetermined (e.g., stored in the memory device 26 and accessed by the processor 24) and/or may be selected by a user (e.g., via inputs communicatively coupled to the controller 16).

[0031] The wavelet function used to calculate the phase difference may be selected to optimize the temporal or frequency support required for the desired resolution and/or smoothing. In some embodiments, a low oscillation wavelet may be utilized. For example, FIG. 3 illustrates a low oscillation Morlet wavelet with a central frequency (coo) of 3 radians per second, which may provide sufficient resolution. In certain

embodiments, a low oscillation wavelet with a central frequency of approximately 1, 2, 3, or 4 radians per second may be utilized to calculate the phase difference. In some embodiments, a low oscillation wavelet with a central frequency of less than

approximately 5 radians per second may be utilized, as high central frequencies may cause the phase information to become smoothed over time and provide insufficient resolution for evaluation of the COx and/or the patient's autoregulation. Although the examples provided herein relate to wavelet transforms, it should be understood that any techniques, including any suitable complex transform (e.g., a Fourier transform), may be utilized to determine a phase difference between the blood pressure signal and the oxygen saturation signal. [0032] FIG. 4 illustrates an example of correlations between the COx 64 and the phase difference 68. In sections 76, regions 80 of approximately zero phase difference generally correlate with regions 82 of high COx values. When the phase difference is approximately zero and/or stable over a period of time coinciding with a high or positive COx value (e.g., between 0 and 1), as in sections 76, the controller 16 may determine that the COx value has a high confidence level (and thus, that the patient's autoregulation is impaired). Additionally, in section 78, a region 84 of a phase difference of approximately π radians generally correlates with a region 86 of near-zero COx values. When the phase difference is approximately +/- π radians over a period of time coinciding with a low or negative COx value (e.g., between -1 and 0), the controller 16 may determine that the COx value has a high confidence level (and thus, that the patient's autoregulaton is intact). On the other hand, if the phase difference does not corroborate the COx as set forth above, the controller 16 may determine that the COx value has a low confidence level or is unreliable. Accordingly, the phase difference 68 may be useful in providing a confidence level for the COx 64.

[0033] As discussed in more detail below, the controller 16 may be configured to remove or discard unreliable COx values (e.g., COx values having a low confidence level) and/or take other appropriate remedial action when the COx value is unreliable. For example, the controller 16 may not output the COx signal 64 or the signal indicative of the patient's autoregulation status while the phase difference does not corroborate the COx. In some cases, the controller 16 may cause the output device 18 to display a blank display screen or provide an appropriate visual or audible indication that the COx signal 64 is unavailable. In certain embodiments, the controller 16 may hold or maintain the COx value immediately preceding the segment determined to be unreliable, and thus may cause the output device 18 to show the most recent reliable COx signal 64 for a set period of time or until the phase difference indicates that the COx is reliable. In some embodiments, the controller 16 may be configured to average the unreliable COx value(s) with the most recent reliable COx value(s), and may cause the output device 18 to provide an appropriate visual or audible indication of this average COx value. In some embodiments, when the controller 16 determines that the phase difference corrobates the COx (e.g., a high confidence level in the COx), the controller 16 may cause the output device 18 to provide a visual or audible indication of the patient's autoregulation status and/or that the COx signal 64 is reliable.

[0034] Furthermore, in certain embodiments, the phase difference may be utilized to weight the COx values within a moving average. For example, high confidence (e.g., greater than approximately 50, 90, 95, or 99 percent) COx values may receive a relatively higher weight than low confidence (e.g., less than approximately 50, 90, 95, or 99 percent) COx values in an ensemble averaging technique. In some embodiments, the weight applied to the COx values may be on a sliding scales, such that intermediate confidence (e.g., greater than approximately 50, 90, or 95 percent) COx values receive a relatively lower weight than high confidence COx values and a relatively higher weight than relatively low confidence COx values. In some embodiments, the desired level of confidence may be predetermined (e.g., stored in the memory device 26) and/or selected (e.g., via inputs coupled to the controller 16) by a user. In some embodiments, a trigonometric function may be utilized to compensate for phase wrap and to bound the value used to indicate correlation, thus making it easier to identify regions of various phase differences. For example, a cosine of the phase difference will provide a value of 1 for phase differences of approximately 0 and will provide a value of -1 for phase differences of approximately +/- π radians. Such values may be further transformed to alter the limits of the function output (e.g., 0.5*(cos(cp)+l)) to limit the output to 0 to 1 to facilitate identification of regions of various phase differences.

[0035] Although certain examples provided herein utilize the phase difference to assess the quality of the COx, in some embodiments, the phase difference may be used to determine a confidence level for other measures of autoregulation, such as a mean velocity index (Mx) and/or a pressure reactivity index (PRx). Thus, a phase difference of approximately zero and/or a substantially constant phase difference may provide high confidence in the Mx and/or the PRx indicating impaired autoregulation, while a phase difference of approximately +/- π radians, and/or a rapidly varying and/or a randomly distributed phase difference, may provide high confidence in the Mx and/or the PRx indicating intact autoregulation. In a similar manner as discussed above with respect to COx, low confidence in the Mx and/or the PRx may be indicated if the phase difference does not corroborate the Mx and/or the PRx values. Furthermore, while the examples provided herein utilize the phase difference to assess the quality of the COx value and/or other autoregulation metrics, in some embodiments, the phase difference may be used to directly monitor the patient's autoregulation. For example, if the phase difference is approximately zero and/or generally stable over a period of time, the controller 16 may determine that the patient's autoregulation is impaired, and if the phase difference is approximately +/- π radians, and/or rapidly varying and/or randomly distributed, over a period of time, the controller 16 may determine that the patient's autoregulation is intact.

[0036] FIGS. 5, 6, and 8 are flow charts illustrating various methods for monitoring autoregulation, in accordance with the present disclosure. The methods include various steps represented by blocks. It should be noted any of the methods provided herein, may be performed as an automated procedure by a system, such as system 10. Although the flow charts illustrate the steps in a certain sequence, it should be understood that the steps may be performed in any suitable order and certain steps may be carried out

simultaneously, where appropriate. Further, certain steps or portions of the methods may be performed by separate devices. For example, a first portion of the method may be performed by the controller 16, while a second portion of the method may be performed by the sensor 14. In addition, insofar as steps of the methods disclosed herein are applied to the received signals, it should be understood that the received signals may be raw signals or processed signals. That is, the methods may be applied to an output of the received signals.

[0037] FIG. 5 is a process flow diagram of a method 100 of monitoring autoregulation based at least in part on a phase difference between the oxygen saturation signal and the blood pressure signal, in accordance with an embodiment. Some or all of the steps of the method 100 may be implemented by the controller 16 (e.g., the processor 24 of the controller 16) of FIG. 1, for example, to determine whether the patient's autoregulation is impaired and/or to take an appropriate remedial action (e.g., output a visual or audible indication that the autoregulation status is unavailable or unreliable, block output of the COx, or the like). In step 102, the controller 16 may receive the blood pressure signal (e.g., arterial blood pressure signal). In some embodiments, the controller 16 may receive the blood pressure signal from the blood pressure sensor 12, as set forth above. In step 104, the controller 16 may receive the oxygen saturation signal. In some embodiments, the controller 16 may receive the oxygen saturation signal from the oxygen saturation sensor 14, as set forth above.

[0038] In step 106, the controller 16 may determine a phase difference between the blood pressure signal and the oxygen saturation signal. As set forth above, the controller 16 may determine the phase difference using any of a variety of suitable techniques. For example, in some embodiments, the controller 16 may calculate the phase difference using a cross-wavelet transform, as discussed above. In step 108, the controller 16 may determine the patient's autoregulation status based at least in part on the phase difference. As previously noted, the controller 16 may utilize the phase difference to directly monitor the patient's autoregulation status. In such cases, an approximately zero and/or constant phase difference may indicate impaired autoregulation, while a phase difference of +/- π radians, and/or a rapidly varying and/or randomly distributed phase difference, may indicate properly functioning autoregulation. In certain embodiments, the phase difference may be used in conjunction with one or more autoregulation measurements, such as COx, Mx, and/or PRx, to determine the patient's autoregulation status. For example, in some such embodiments, the phase difference may be used to determine a confidence level of the COx, Mx, and/or PRx as part of the autoregulation analysis, as set forth in more detail with respect to FIG. 6

[0039] In step 109, the controller 16 may provide an indication of the patient's autoregulation status to the output device 18. For example, in some cases, the controller 16 may cause the output device 18 to provide a visual and/or audible indication of proper autoregulation if the phase difference is approximately +/- π radians, and/or a rapidly varying and/or randomly distributed. Furthermore, the controller 16 may cause the output device to 18 to provide a signal indicating impaired autoregulation if the phase difference is approximately zero and/or constant. Additional or alternative steps related to indications provided to the output device 18 are discussed below with respect to FIG. 6.

[0040] FIG. 6 is a process flow diagram of a method 110 of determining a confidence level related to the COx based at least in part on a comparison of the COx to a phase difference between an oxygen saturation signal and a blood pressure signal, in accordance with an embodiment. Some or all of the steps of the method 110 may be implemented by the controller 16 (e.g., the processor 24 of the controller 16) of FIG. 1, for example, to determine whether the patient's autoregulation is impaired. In step 112, the controller 16 may receive the blood pressure signal (e.g., arterial blood pressure signal). In some embodiments, the controller 16 may receive the blood pressure signal from the blood pressure sensor 12, as set forth above. In step 114, the controller 16 may receive the oxygen saturation signal. In some embodiments, the controller 16 may receive the oxygen saturation signal from the oxygen saturation sensor 14, as set forth above.

[0041] In step 116, the controller 16 may determine the COx based on the linear correlation between blood pressure measurements of the blood pressure signal and the oxygen saturation measurements of the oxygen saturation signal, in step 118, the controller 16 may determine a phase difference between the blood pressure signal and the oxygen saturation signal. The phase difference may be determined via any suitable technique, including those discussed above with respect to FIGS. 2-5, for example. In step 120, the controller 16 may compare the COx to the phase difference. As noted above, regions of high or positive COx values (e.g., between 0 and 1) are expected to correlate with regions of approximately zero and/or constant phase difference.

Additionally, regions of near-zero and/or low COx values (e.g., between -1 and 0) are expected to correlate with regions of a phase difference of approximately +/- π radians and/or a rapidly varying and/or randomly distributed phase difference.

[0042] In step 122, the controller 16 may determine a confidence level related to the COx based at least in part on the comparison between the phase difference and the COx. For example, when the phase difference is approximately zero over a period of time coinciding with a high or positive COx value (e.g., between 0 and 1), the controller 16 may determine that the COx value has a high confidence level (e.g., greater than approximately 50, 90, 95, or 99 percent), and thus, that the patient's autoregulation is impaired. Similarly, when the phase difference is approximately +/- π radians over a period of time coinciding with a low or negative COx value (e.g., between -1 and 0), the controller 16 may determine that the COx value has a high confidence level (e.g., greater than approximately 50, 90, 95, or 99 percent), and thus, that the patient's autoregulaton is intact. However, if the phase difference does not corroborate the COx as set forth above, the controller 16 may determine that the COx value has a low confidence level (e.g., less than approximately 50, 90, 95, or 99 percent) or is unreliable.

[0043] in step 124, the controller 16 may provide an indication of autoreguiation status. For example, the controiler 16 may cause the output device 18 to provide a visual or audible indication of the autoreguiation status (e.g., functioning or impaired), the COx, the phase difference, and/or a confidence level, in some cases, when the controller 16 determines that the phase difference corrobates the COx, the controller 16 may cause the output device 18 to provide a visual or audible indication that the signal indicative of the patient's autoreguiation status and/or the COx signal 64 has a high confidence level and/or is reliable. In certain embodiments, while the phase difference does not corroborate the COx, the controller 16 may not output the COx signal 64 and/or the signal indicative of the patient's autoreguiation status. Additionally or alternatively, the controller 16 may cause the output device 18 to display a blank display screen or provide an appropriate visual or audible indication that the COx signal 64 is unavailable.

Additionally or alternatively, the controller 16 may hold or maintain the COx value immediately preceding the segment determined to be unreliable, and thus may cause the output device 18 to show the most recent reliable COx signal 64 for a set period of time or until the phase difference indicates that the COx is reliable. Additionally or alternatively, the controller 16 may be configured to weight the COx value(s) based on the phase difference and/or average the unreliable COx value(s) with the most recent reliable COx value(s), and may cause the output device 18 to provide an appropriate visual or audible indication of this average COx value.

[0044] In some embodiments, additional or alternative processing techniques may be utilized to determine the patient's autoreguiation status. For example, cross-wavelet transform components may be reassigned via a synchrosqueezing process to facilitate determination of the patient's autoreguiation status and/or to facilitate determination of a confidence level related to the COx. With the foregoing in mind, the cross-wavelet transform of two signals (f and g) may be expressed in complex exponential form as:

CrWTf,g(a,b) = \Tf(a,b)\ \T _g (a,b)\ '%(α ) )) (i ) where a and b are scale and time variables, respectively, T/(a,b) and T _g (a,b) are the wavelet coefficients of the time series f(t) and g(t), respectively, and ^< t ^> _g ^(a>¾) - ^< l ^{> a>¾)} is the phase angle. As shown by Equation 1, the phase angle ( ^< t ^> _g ^(a>¾) - ^< l ^{> a>¾)} ) of the cross-wavelet transform reflects the phase difference between transforms of the individual signals (e.g., the phase difference by which f(t) leads g(t) at the given scale and time. Therefore, the cross- wavelet transform phase may provide a phase difference map between the two signals over a range of scales (or frequencies) and temporal locations. In some embodiments, components in the cross-wavelet transform domain may be reassigned through synchrosqueezing.

Synchrosqueezing may identify an instantaneous frequency for each point in the transform domain as follows: (2) where a and b are scale and time variables, respectively, and φ is the phase angle. The derivative of the phase angle with respect to time is the frequency of phase cycling corresponding to the transform component at that point in the transform domain and may be used to move transform components to a new location corresponding to ft.

[0045] With the foregoing in mind, FIG. 7 is an example of a series of graphs illustrating a blood pressure signal 150, an oxygen saturation signal 152, a COx signal 154, a phase map 156 (i.e., CrWT phase, a phase map generated from a cross-wavelet transform of the blood pressure signal 150 and the oxygen saturation signal 152), and a synchrosqueezed cross-wavelet transform 158 (i.e., Synchro-CrWT) at a zero-frequency level. As discussed above, an approximately zero and/or constant phase difference between the blood pressure signal 150 and the oxygen saturation signal 152 may indicate impaired autoregulation, while a phase difference of +/- π radians, and/or a rapidly varying and/or randomly distributed phase difference, may indicate properly functioning autoregulation. In the synchrosqueezed cross-wavelet transform 158, stable phase differences between the blood pressure signal 150 and the oxygen saturation signal 152 manifest as significant energy at the zero-frequency le vel, thereby facilitating identification of regions of stable, or relatively constant, phase differences, in some embodiments, energies at, or around zero phase, may be normalized by dividing by a total energy in the signal, or within a sub-band of the signal. [0046] Features of the synchrosqueezed cross-wavelet transform 158 may be utilized to evaluate the patient ^' s autoregulation status. For example, in some embodiments, the controller 16 may determine that a patient's autoregulation system is impaired if the synchrosqueezed cross-wavelet transform indicates significant energy at the zero- frequency level, such as in regions 160. In some cases, the controller 16 may determine that a patient's autoregulation system is intact if the synchrosqueezed cross-wavelet transform lacks regions of region 162, or otherwise indicates a phase difference of approximately +/- π radians, and/or a rapidly varying and/or randomly distributed phase difference,

[0047] Furthermore, in some embodiments, the synchrosqueezed cross-wavelet transform may be utili zed to determine a confidence level of the COx. As noted above, regions of approximately zero and/or constant phase difference are expected to correlate with regions of high or positive COx values. Additionally, regions having a phase difference of approximately +/- π radians, and/or a rapidly varying and/or randomly distributed phase difference, are expected to correlate with regions of low or negative COx values. Accordingly, when the synchrosqueezed cross-wavelet transform includes significant energy at the zero-frequency level over a period of time coinciding with a high or positive COx value (e.g., between 0 and 1), such as in regions 160, the controller 16 may determine that the COx value has a high confidence level (e.g., greater than 50, 90, 95, or 99 percent), and thus, that the patient's autoregulation is impaired. Similarly, when the synchrosqueezed cross-wavelet transform indicates low energy at the zero-frequency level, such as in region 162, and/or a rapidly vary ing and/or randomly distributed phase difference over a period of time coinciding with a low or negative COx value (e.g., between -1 and 0), the controller 16 may determine that the COx value has a high confidence level (e.g., greater than 50, 90, 95, or 99 percent), and thus, that the patient's autoregulaton is intact. On the other hand, if the synchrosqueezed cross-wavelet transform does not corroborate the COx as set forth above, the controller 16 may determine that the COx value has a low confidence level (e.g., less than 50, 90, 95, or 99 percent) or is unreliable. Accordingly, the synchrosqueezed cross-wavelet transform may be useful in providing a confidence level for the COx 154 and for evaluating the patient's autoregulation status. [0048] As noted above, a low oscillation Morlet wavelet with a central frequency (coo) of 3 radians per second may be utilized to provide sufficient resolution in the cross- wavelet transform and/or synchrosqueezed cross-wavelet transform. In certain embodiments, a low oscillation wavelet with a central frequency of approximately 1, 2, 3, or 4 radians per second may be utilized. In some embodiments, a low oscillation wavelet with a central frequency of less than approximately 5 radians per second may be utilized as high central frequencies may cause the phase information to become smoothed over time and provide insufficient resolution for evaluation of the patient's autoregulation.

[0049] FIG. 8 is a process flow diagram of a method 170 of monitoring autoregulation using a synchrosqueezed cross-wavelet transform, in accordance with an embodiment. Some or all of the steps of the method 170 may be implemented by the controller 16 (e.g., the processor 24 of the controller 16) of FIG. 1, for example, to determine whether the patient's autoregulation is impaired. In step 172, the controller 16 may receive the blood pressure signal (e.g., arterial blood pressure signal). In some embodiments, the controller 16 may receive the blood pressure signal from the blood pressure sensor 12, as set forth above. In step 174, the controller 16 may receive the oxygen saturation signal. In some embodiments, the controller 16 may receive the oxygen saturation signal from the oxygen saturation sensor 14, as set forth above.

[0050] In step 176, the controller 16 may determine the COx based on the linear correlation between blood pressure measurements of the blood pressure signal and the oxygen saturation measurements of the oxygen saturation signal, in step 178, the controller 16 may calculate a cross-wavelet transform of the blood pressure signal and the oxygen saturation signal. In step 180, the controller 16 may calculate the

synchrosqueezed cross-wavelet transform. In step 182, the controller may determine a confidence level associated with the COx based at least in part on the synchrosqueezed cross-wavelet transform. As noted above, regions of high or positive COx values (e.g., between 0 and 1) are expected to correlate with regions of approximately zero and/or constant phase difference (e.g., regions of high energy in the zero-frequency level of the synchrosqueezed cross-wavelet transform). Additionally, regions of near-zero and/or low COx values (e.g., between -1 and 0) are expected to correlate with regions of a phase difference of approximately +/- π radians and/or a rapidly varying and/or randomly distributed phase difference.

[0051] Thus, when the synchrosqueezed cross-wavelet transform includes significant energ at the zero-frequency level over a period of time coinciding with a high or positive COx value (e.g., between 0 and 1), the controller 16 may determine that the COx value has a high confidence level (e.g., greater than 50, 90, 95, or 99 percent), and thus, that the patient's autoregulation is impaired. Similarly, when the synchrosqueezed cross-wavelet transform indicates low energy at the zero-frequency level and/or a rapidly varying and/or randomly distributed phase difference over a period of time coinciding with a low or negative COx value (e.g., between -1 and 0), the controller 16 may determine that the COx value has a high confidence level (e.g., greater than 50, 90, 95, or 99 percent), and thus, that the patient's autoregulaton is intact. On the other hand, if the synchrosqueezed cross-wavelet transform does not corroborate the COx as set forth above, the controller 16 may determine that the COx value has a low confidence level (e.g., less than 50, 90, 95, or 99 percent) or is unreliable.

[0052] in step 184, the controller 16 may provide an indication of autoregulation status. For example, the controller 16 may cause the output device 18 to provide a visual or audible indication of the autoregulation status (e.g., functioning or impaired), the COx, the phase difference, the phase map, the cross-wavelet transform, the synchrosqueezed cross-wavelet transform, and/or a confidence level, in some cases, when the controller 16 determines that the synchrosqueezed cross-wavelet transform corrobates the COx, the controller 16 may cause the output device 18 to provide a visual or audible indication that the signal indicative of the patient's autoregulation status and/or the COx signal 64 has a high confidence level and/or is reliable. In certain embodiments, while the

synchrosqueezed cross-wavelet transform does not corroborate the COx, the controller 16 may not output the COx signal 64 and/or the signal indicative of the patient's

autoregulation status. Additionally or alternatively, the controller 16 may cause the output device 18 to display a blank display screen or provide an appropriate visual or audible indication that the COx signal 64 is unavailable. Additionally or alternatively, the controller 16 may hold or maintain the COx value immediately preceding the segment determined to be unreliable, and thus may cause the output device 18 to show the most recent reliable COx signal 64 for a set period of time or until the phase difference indicates that the COx is reliable. Additionally or alternatively, the controller 16 may be configured to weight COx value(s) based on the synchros queezed cross-wavelet transform and/or to average the unreliable COx value(s) with the most recent reliable COx value(s), and may cause the output device 18 to provide an appropriate visual or audible indication of this average COx value.

[0053] FIG. 9 is an embodiment of a display 190 configured to display various information related to an autoregulation status of a patient. The display 190 may be part of and/or may include any of the features of the output device 18, discussed above.

Furthermore, the display 190 may display any of the information related to the patient's autoregulation status set forth above. Various wavelet-based techniques for evaluating a patient's autoregulation status are disclosed herein. In some embodiments, a wavelet cross- correlation (WCC) measure may additionally or alternatively be used to monitor the relationship between blood pressure and oxygen saturation, and thereby, to evaluate the patient's autoregulation status. For example, the WCC may exhibit a first peak at 0.33Hz and a second peak at 0. lHz. In healthy patients with properly functioning autoregulation systems, the first peak may disappear during a head-up maneuver, while the second peak may shift to higher wavelet scales. However, in patients with impaired autoregulation systems, there may not be a significant peak at 0.33Hz, and the peak at 0. lHz may not shift significantly during the maneuver. Thus, the WCC may be useful in monitoring the patient's autoregulation status. Accordingly, in some embodiments, information indicative of the WCC may be displayed on the display 190. In certain embodiments, a WCC plot may show relative degrees of correlation via distinct contours and/or colors, as shown in region 192 of the display 190. In some embodiments, a plurality of colors (e.g., 2, 3, 4, 5, or more) may show multiple degrees of correlation. In some embodiments, two colors may be utilized to indicate whether the WCC is above or below a predetermined threshold of correlation (e.g., a first color is used in a first portion 194 of the WCC above the predetermined threshold and a second color is used in a second portion 196 of the WCC below the predetermined thereshold).

[0054] In some embodiments, a time at which a maximum correlation in the WCC at a particular scale (e.g., characteristic frequency or other frequency band suitable for evaluating autoregulation status, such as scales corresponding to waves between 20 to 250 second periods) or scales may be displayed on the screen of the display 190. In certain

embodiments, the scales may be selected and/or input by a user (e.g., via inputs coupled to the controller 16 and/or the display 190). In some embodiments, the scales may be predetermined (e.g., stored on the memory device 26) and utilized by the controller 16 during evaluation of the patient's autoregulation status. The display 190 may display the band of interest, or the display 190 may display a wider range of frequencies while highlighting the band of interest, as shown in region 198 of the display.

[0055] In certain embodiments, the controller 16 may cause a summed or characteristic value of WCC to be displayed on the display 190, as shown in region 200 of the display 190. A region over which the characteristic value is calculated may be selected by the user (e.g., by specifying the region on a touch sensitive display). In some embodiments, the region over which the characteristic value is calculated is determined automatically (e.g., based on areas associated with high levels of correlation, such as greater than 10, 20, 30, 40, 50, 60, 70, 80, 90 percent, or more, and/or areas encompassing predetermined and/or selected scales of interest).

[0056] In some embodiments, the controller 16 may cause the display 190 to update the WCC plot and/or the WCC value in real time, or at predetermined periods (e.g., every 5, 10, 20, or 30 seconds). The displayed information may be based on the latest calculated values representative of those collected during a previous update period (e.g., a median or a mean of the values collected during the time since the last update). In some embodiments, only zero-time delay values may be used to determine autoregulation status, and a graph of such WCC values against scale (or characteristic frequency) may be displayed, as shown in region 202 of the display 190. It should be understood that the display 190 may be configured to display all or some of the information illustrated in FIG. 8, and in any suitable arrangement. Although examples provided herein relate to providing information indicative of the WCC on the display 190, it should be understood that, additionally or alternatively, an audible indication of such information may be provided via one or more speakers, for example. [0057] While the disclosure may be susceptible to various modifications and alternative forms, specific embodiments have been shown by way of example in the drawings and have been described in detail herein. However, it should be understood that the embodiments provided herein are not intended to be limited to the particular forms disclosed. Rather, the various embodiments may cover all modifications, equivalents, and alternatives falling within the spirit and scope of the disclosure as defined by the following appended claims. Further, it should be understood that certain elements of the disclosed embodiments may be combined or exchanged with one another.