Methods and systems for photoacoustic monitoring using indicator dilution

A patient monitoring system may provide photoacoustic sensing based on an indicator dilution to determine one or more physiological parameters of a subject. The system may detect an acoustic pressure signal, which may include one or more thermo-dilution responses, one or more hemo-dilution responses, or a combination thereof. For example, a thermo-dilution indicator and/or a hemo-dilution indicator may be used to determine one or more hemodynamic parameters. In a further example, an isotonic indicator and a hypertonic indicator may be used to determine one or more hemodynamic parameters of the subject.

The present disclosure relates to monitoring physiological parameters, and more particularly relates to monitoring physiological parameters using indicator dilution and photoacoustic analysis.

SUMMARY

A physiological monitoring system may be configured to determine a physiological parameter of a subject, using photoacoustic analysis and a dilution response. The system may include a light source that may provide a photonic signal to a first blood vessel site of the subject, which may be, for example, an artery of the subject. The system may also include an acoustic detector that detects an acoustic pressure signal from the first blood vessel site, caused by the absorption of at least some of the photonic signal by one or more constituents at the first blood vessel site.

In some embodiments, a hemo-dilution indicator, thermo-dilution indicator, or both, may be provided to a blood vessel site of the subject, which may be, for example, a vein of the subject. The one or more indicators may include a dye indicator, a saline indicator, or any other suitable type of indicator. A photoacoustic signal derived from the acoustic pressure signal may include one or more responses corresponding to one or more respective indicators. Based at least in part on the one or more responses, the system may determine one or more physiological parameters of the subject. The physiological parameters may include hemodynamic parameters such as, for example, cardiac output, intrathoracic blood volume, intrathoracic circulatory volume, global end-diastolic volume, pulmonary circulatory volume, extravascular lung water, and/or other suitable parameters. In some embodiments, one or more characteristics may be derived from an acoustic pressure signal such as, for example, a value of the acoustic pressure signal, a value of a signal derived from the acoustic pressure signal such as a photoacoustic signal, an area under a dilution curve derived from the photoacoustic signal, a time, or a time difference, and may be used to determine the one or more physiological parameters.

In some embodiments, an isotonic indicator and a hypertonic indicator may be provided to the subject at a second blood vessel site, which may be, for example, a central vein. The photoacoustic signal may include a first response corresponding to the isotonic indicator and a second response corresponding to the hypertonic indicator. Based at least in part on the first and second response, the system may determine one or more physiological parameters of the subject. The physiological parameters may include hemodynamic parameters such as, for example, cardiac output and extravascular lung water. In some embodiments, at least one of the isotonic indicator and the hypertonic indicator comprises a dye indicator. In some embodiments, the system may generate a dilution curve, and determine the one or more physiological parameters based at least in part on the dilution curve.

DETAILED DESCRIPTION OF THE FIGURES

Photoacoustics (or “optoacoustics”) or the photoacoustic effect (or “optoacoustic effect”) refers to the phenomenon in which one or more wavelengths of light are presented to and absorbed by one or more constituents of an object, thereby causing an increase in kinetic energy of the one or more constituents, which causes an associated pressure response within the object. Particular modulations or pulsing of the incident light, along with measurements of the corresponding pressure response in, for example, tissue of the subject, may be used for medical imaging, physiological parameter determination, or both. For example, the concentration of a constituent, such as hemoglobin (e.g., oxygenated, deoxygenated and/or total hemoglobin) may be determined using photoacoustic analysis. In a further example, one or more hemodynamic parameters such as cardiac output, intrathoracic blood volume, intrathoracic circulatory volume, global end-diastolic volume, pulmonary circulatory volume, extravascular lung water, and/or any other suitable hemodynamic parameters may be determined using photoacoustic analysis and indicator dilution techniques.

A photoacoustic system may include a photoacoustic sensor that is placed at a site on a subject, typically the wrist, palm, neck, forehead, temple, or anywhere an artery or vessel is accessible noninvasively. In some embodiments, the photoacoustic techniques described herein are used to monitor large blood vessels, such as a major artery or vein which may be near the heart (e.g., the carotid or radial arteries or the jugular vein). The photoacoustic system may use a light source, and any suitable light guides (e.g., fiber optics), to pass light through the subject's tissue, or a combination of tissue thereof (e.g., organs), and an acoustic detector to sense the pressure response of the tissue induced by the light absorption by a blood vessel. Tissue may include muscle, fat, blood, blood vessels, and/or any other suitable tissue types. In some embodiments, the light source may be a laser or laser diode, operated in pulsed or continuous wave (CW) mode. In some embodiments, the acoustic detector may be an ultrasound detector, which may be suitable to detect pressure fluctuations arising from the constituent's absorption of the incident light of the light source.

In some embodiments, the light from the light source may be focused, shaped, or otherwise spatially modulated to illuminate a particular region of interest. In some arrangements, photoacoustic monitoring may allow relatively higher spatial resolution than line of sight optical techniques (e.g., path integrated absorption measurements). The enhanced spatial resolution of the photoacoustic technique may allow for imaging, scalar field mapping, and other spatially resolved results, in 1, 2, or 3 spatial dimensions. The acoustic response to the photonic excitation may radiate from the illuminated region of interest, and accordingly may be detected at multiple positions.

The photoacoustic system may measure the pressure response that is received at the acoustic sensor as a function of time. The photoacoustic system may also include sensors at multiple locations. A signal representing pressure versus time or a mathematical manipulation of this signal (e.g., a scaled version thereof, etc.) may be referred to as the photoacoustic (PA) signal. The PA signal may be derived from a detected acoustic pressure signal by selecting a suitable subset of points of an acoustic pressure signal. The PA signal may be used to calculate any of a number of physiological parameters, including a concentration of a blood constituent (e.g., hemoglobin), at a particular spatial location. In some embodiments, PA signals from multiple spatial locations may be used to construct an image (e.g., imaging blood vessels) or a scalar field (e.g., a hemoglobin concentration field). In some embodiments, an indicator such as, for example, a dye or saline solution may be introduced into the blood stream of a subject, and the PA system may be used to determine a concentration of a blood constituent, a concentration of an indicator, a relative temperature difference, any suitable characteristic of an indicator dilution response, any suitable hemodynamic parameters derived thereof, any other suitable parameter, or any combination thereof.

In some applications, the light passed through the tissue is selected to be of one or more wavelengths that are absorbed by the constituent in an amount representative of the amount of the constituent present in the tissue. The absorption of light passed through the tissue varies in accordance with the amount of the constituent in the tissue. For example, Red and/or infrared (IR) wavelengths may be used because highly oxygenated blood will absorb relatively less Red light and more IR light than blood with a lower oxygen saturation.

Any suitable light source may be used, and characteristics of the light provided by the light source may be controlled in any suitable manner. In some embodiments, a pulsed light source may be used to provide relatively short-duration pulses (e.g., nanosecond pulses) of light to the region of interest. Accordingly, the use of a pulse light source may result in a relatively broadband acoustic response (e.g., depending on the pulse duration). The use of a pulsed light source will be referred to herein as the “Time Domain Photoacoustic” (TD-PA) technique. A convenient starting point for analyzing a TD-PA signal is given by Eq. 1:
p(z)=Γμaφ(z)  1)
under conditions where the irradiation time is small compared to the characteristic thermal diffusion time determined by the properties of the specific tissue type. Referring to Eq. 1, p(z) is the PA signal (indicative of the maximum induced pressure rise, derived from an acoustic pressure signal) at spatial location z indicative of acoustic pressure, Γ is the dimensionless Grüneisen parameter of the tissue, μais the effective absorption coefficient of the tissue (or constituent thereof) to the incident light, and φ(z) is the optical fluence at spatial location z. The Grüneisen parameter is a dimensionless description of thermoelastic effects, and may be illustratively formulated by Eq. 2:

Γ=β⁢⁢ca2CP(2)
where Cais the speed of sound in the tissue, β is the isobaric volume thermal expansion coefficient, and CPis the specific heat at constant pressure. In some circumstances, the optical fluence, at spatial location z (within the subject's tissue) of interest may be dependent upon the light source, the location itself (e.g., the depth), and optical properties (e.g., scattering coefficient, absorption coefficient, or other properties) along the optical path. For example, Eq. 3 provides an illustrative expression for the attenuated optical fluence at a depth z:
φ(z)=φ0e−μeffz(3)
where φ0is the optical fluence from the light source incident at the tissue surface, z is the path length (i.e., the depth into the tissue in this example), and μeffis an effective attenuation coefficient of the tissue along the path length in the tissue in this example.

In some embodiments, a more detailed expression or model may be used rather than the illustrative expression of Eq. 3. In some embodiments, the actual pressure encountered by an acoustic detector may be proportional to Eq. 1, as the focal distance and solid angle (e.g., face area) of the detector may affect the actual measured PA signal. In some embodiments, an ultrasound detector positioned relatively farther away from the region of interest, will encounter a relatively smaller acoustic pressure. For example, the peak acoustic pressure signal received at a circular area Adpositioned at a distance R from the illuminated region of interest may be given by Eq. 4:
pd=p(z)f(rs,R,Ad)  (4)
where rsis the radius of the illuminated region of interest (and typically rs<R), and p(z) is given by Eq. 1. In some embodiments, the detected acoustic pressure amplitude may decrease as the distance R increases (e.g., for a spherical acoustic wave).

In some embodiments, a modulated CW light source may be used to provide a photonic excitation of a tissue constituent to cause a photoacoustic response in the tissue. The CW light source may be intensity modulated at one or more characteristic frequencies. The use of a CW light source, intensity modulated at one or more frequencies, will be referred to herein as the “Frequency Domain Photoacoustic” (FD-PA) technique. Although the FD-PA technique may include using frequency domain analysis, the technique may use time domain analysis, wavelet domain analysis, or any other suitable analysis, or any combination thereof. Accordingly, the term “frequency domain” as used in “FD-PA” refers to the frequency modulation of the photonic signal, and not to the type of analysis used to process the photoacoustic response.

Under some conditions, the acoustic pressure p(R,t) at detector position R at time t, may be shown illustratively by Eq. 5:

p⁡(R,t)~p0⁡(r0,ω)R⁢ⅇ-ⅈω⁡(t-τ)(5)
where r0is the position of the illuminated region of interest, ω is the angular frequency of the acoustic wave (caused by modulation of the photonic signal at frequency ω), R is the distance between the illuminated region of interest and the detector, and τ is the travel time delay of the wave equal to R/ca, where cais the speed of sound in the tissue. The FD-PA spectrum p0(r0,ω) of acoustic waves is shown illustratively by Eq. 6:

p0⁡(r0,ω)=Γμa⁢ϕ⁡(r0)2⁢(μa⁢ca-ⅈω)(6)
where μacarepresents a characteristic frequency (and corresponding time scale) of the tissue.

In some embodiments, a FD-PA system may temporally vary the characteristic modulation frequency of the CW light source, and accordingly the characteristic frequency of the associated acoustic response. For example, the FD-PA system may use linear frequency modulation (LFM), either increasing or decreasing with time, which is sometimes referred to as “chirp” signal modulation. Shown in Eq. 7 is an illustrative expression for a sinusoidal chirp signal r(t):

r⁡(t)=sin⁡(t⁡(ω0+b2⁢t))(7)
where ω0is a starting angular frequency, and b is the angular frequency scan rate. Any suitable range of frequencies (and corresponding angular frequencies) may be used for modulation such as, for example, 1-5 MHz, 200-800 kHz, or other suitable range, in accordance with the present disclosure. In some embodiments, signals having a characteristic frequency that changes as a nonlinear function of time may be used. Any suitable technique, or combination of techniques thereof, may be used to analyze a FD acoustic pressure signal. Two such exemplary techniques, a correlation technique and a heterodyne mixing technique, will be discussed below as illustrative examples.

In some embodiments, the correlation technique may be used to determine the travel time delay of the FD-PA signal. In some embodiments, a matched filtering technique may be used to process a PA signal. As shown in Eq. 8:

Bs⁡(t-τ)=12⁢π⁢∫-∞∞⁢H⁡(ω)⁢S⁡(ω)⁢ⅇⅈω⁢⁢t⁢ⅆω(8)
Fourier transforms (and inverse transforms) are used to calculate the filter output BS(t−T), in which H(ω) is the filter frequency response, S(ω) is the Fourier transform of the PA signal s(t), and T is the phase difference between the filter and signal. In some circumstances, the filter output of expression of Eq. 8 may be equivalent to an autocorrelation function. Shown in Eq. 9:

S⁡(ω)=12⁢π⁢∫-∞∞⁢s⁡(t)⁢ⅇ-ⅈω⁢⁢t⁢ⅆt(9)
is an expression for computing the Fourier transform S(ω) of the PA signal s(t). Shown in Eq. 10:
H(ω)=S*(ω)e−iωτ(10)
is an expression for computing the filter frequency response H(ω) based on the Fourier transform of the PA signal s(t), in which S*(ω) is the complex conjugate of S(ω). It can be observed that the filter frequency response of Eq. 10 requires the frequency character of the PA signal be known beforehand to determine the frequency response of the filter. In some embodiments, as shown by Eq. 11:

B⁡(t)=∫-∞∞⁢r⁡(t′)⁢s⁡(t+t′)⁢ⅆt′(11)
the known modulation signal r(t) may be used for generating a cross-correlation with the PA signal. The cross-correlation output B(t) of Eq. 11 is expected to exhibit a peak at a time t equal to the acoustic signal travel time τ. Assuming that the temperature response and resulting acoustic response follow the illumination modulation (e.g., are coherent), Eq. 11 may allow calculation of the time delay, depth information, or both.

In some embodiments, the heterodyne mixing technique may be used to determine the travel time delay of the FD-PA signal. The FD-PA signal, as described above, may have similar frequency character as the modulation signal (e.g., coherence), albeit shifted in time due to the travel time of the acoustic signal. For example, a chirp modulation signal, such as r(t) of Eq. 7, may be used to modulate a CW light source. Heterodyne mixing uses the trigonometric identity of the following Eq. 12:
sin(A)sin(B)=½[cos(A−B)−cos(A+B)]  (12)
which shows that two signals may be combined by multiplication to give periodic signals at two distinct frequencies (i.e., the sum and the difference of the original frequencies). If the result is passed through a low-pass filter to remove the higher frequency term (i.e., the sum), the resulting filtered, frequency shifted signal may be analyzed. For example, Eq. 13 shows a heterodyne signal L(t):

L⁡(t)=〈r⁡(t)⁢s⁡(t)〉≅〈Kr⁡(t)⁢r⁡(t-Rca)〉=12⁢K⁢⁢cos⁡(Rca⁢bt+θ)(13)
calculated by low-pass filtering (shown by angle brackets) the product of modulation signal r(t) and PA signal s(t). If the PA signal is assumed to be equivalent to the modulation signal, with a time lag R/cadue to travel time of the acoustic wave and amplitude scaling K, then a convenient approximation of Eq. 13 may be made, giving the rightmost expression of Eq. 13. Analysis of the rightmost expression of Eq. 13 may provide depth information, travel time, or both. For example, a fast Fourier transform (FFT) may be performed on the heterodyne signal, and the frequency associated with the highest peak may be considered equivalent to time lag Rb/ca. Assuming that the frequency scan rate b and the speed of sound caare known, the depth R may be estimated.

In some embodiments, a photoacoustic signal may be used with Eq. 1 to determine an absorption coefficient μa. When a suitable light source is used (e.g., a photonic signal at 905 nm), tHb may be determined based on the value of the absorption coefficient and one or more pre-defined parameters. In some embodiments, a photonic signal may include light have two different wavelengths (e.g., one of which may be 905 nm), and blood oxygen saturation may be determined based on photoacoustic signals corresponding to the each wavelength of the photonic signal. In some embodiments, a light source may provide a photonic signal including light having a wavelength at an isobestic point where light absorption of oxy and de-oxy hemoglobin are substantially equal (e.g., at about 808 nm).

FIG. 1is a perspective view of an embodiment of a physiological monitoring system10. System10may include sensor unit12and monitor14. In some embodiments, sensor unit12may be part of a photoacoustic monitor or imaging system. Sensor unit12may include a light source16for emitting light at one or more wavelengths, which may but need not correspond to visible light, into a subject's tissue. Light source16may provide a photonic signal including any suitable electromagnetic radiation such as, for example, a radio wave, a microwave wave, an infrared wave, a visible light wave, ultraviolet wave, any other suitable light wave, or any combination thereof. A detector18may also be provided in sensor unit12for detecting the acoustic (e.g., ultrasound) response that travels through the subject's tissue. Any suitable physical configuration of light source16and detector18may be used. In an embodiment, sensor unit12may include multiple light sources and/or acoustic detectors, which may be spaced apart. System10may also include one or more additional sensor units (not shown) that may take the form of any of the embodiments described herein with reference to sensor unit12. An additional sensor unit may be the same type of sensor unit as sensor unit12, or a different sensor unit type than sensor unit12(e.g., a photoplethysmograph sensor). Multiple sensor units may be capable of being positioned at two different locations on a subject's body.

In some embodiments, system10may include two or more sensors forming a sensor array in lieu of either or both of the sensor units. In some embodiments, a sensor array may include multiple light sources, detectors, or both. It will be understood that any type of sensor, including any type of physiological sensor, may be used in one or more sensor units in accordance with the systems and techniques disclosed herein. It is understood that any number of sensors measuring any number of physiological signals may be used to determine physiological information in accordance with the techniques described herein.

In some embodiments, sensor unit12may be connected to and draw its power from monitor14as shown. In another embodiment, the sensor may be wirelessly connected to monitor14and include its own battery or similar power supply (not shown). Monitor14may be configured to calculate physiological parameters based at least in part on data relating to light emission and acoustic detection received from one or more sensor units such as sensor unit12. For example, monitor14may be configured to determine cardiac output, intrathoracic blood volume, intrathoracic circulatory volume, global end-diastolic volume, pulmonary circulatory volume, extravascular lung water, any other suitable hemodynamic parameters, or any combination thereof. Further, monitor14may be configured to determine pulse rate, blood pressure, blood oxygen saturation (e.g., arterial, venous, or both), hemoglobin concentration (e.g., oxygenated, deoxygenated, and/or total), any other suitable physiological parameters, or any combination thereof. In some embodiments, calculations may be performed on the sensor units or an intermediate device and the result of the calculations may be passed to monitor14. Further, monitor14may include a display20configured to display the physiological parameters or other information about the system. In the embodiment shown, monitor14may also include a speaker22to provide an audible sound that may be used in various other embodiments, such as for example, sounding an audible alarm in the event that a subject's physiological parameters are not within a predefined normal range. In some embodiments, the system10includes a stand-alone monitor in communication with the monitor14via a cable or a wireless network link.

In some embodiments, sensor unit12may be communicatively coupled to monitor14via a cable24. Cable24may include electronic conductors (e.g., wires for transmitting electronic signals from detector18), optical fibers (e.g., multi-mode or single-mode fibers for transmitting emitted light from light source16), any other suitable components, any suitable insulation or sheathing, or any combination thereof. In some embodiments, a wireless transmission device (not shown) or the like may be used instead of or in addition to cable24. Monitor14may include a sensor interface configured to receive physiological signals from sensor unit12, provide signals and power to sensor unit12, or otherwise communicate with sensor unit12. The sensor interface may include any suitable hardware, software, or both, which may be allow communication between monitor14and sensor unit12.

In the illustrated embodiment, system10includes a multi-parameter physiological monitor26. The monitor26may include a cathode ray tube display, a flat panel display (as shown) such as a liquid crystal display (LCD) or a plasma display, or may include any other type of monitor now known or later developed. Multi-parameter physiological monitor26may be configured to calculate physiological parameters and to provide a display28for information from monitor14and from other medical monitoring devices or systems (not shown). For example, multi-parameter physiological monitor26may be configured to display an estimate of a subject's extravascular lung water, cardiac output, and hemoglobin concentration generated by monitor14. Multi-parameter physiological monitor26may include a speaker30.

Monitor14may be communicatively coupled to multi-parameter physiological monitor26via a cable32or34that is coupled to a sensor input port or a digital communications port, respectively and/or may communicate wirelessly (not shown). In addition, monitor14and/or multi-parameter physiological monitor26may be coupled to a network to enable the sharing of information with servers or other workstations (not shown). Monitor14may be powered by a battery (not shown) or by a conventional power source such as a wall outlet.

FIG. 2is a block diagram of a physiological monitoring system, such as physiological monitoring system10ofFIG. 1, which may be coupled to a subject40in accordance with an embodiment. Certain illustrative components of sensor unit12and monitor14are illustrated inFIG. 2.

Sensor unit12may include light source16, detector18, and encoder42. In some embodiments, light source16may be configured to emit one or more wavelengths of light (e.g., visible, infrared) into a subject's tissue40. Hence, light source16may provide Red light, IR light, any other suitable light, or any combination thereof, that may be used to calculate the subject's physiological parameters. In some embodiments, a Red wavelength may be between about 600 nm and about 700 nm. In some embodiments, an IR wavelength may be between about 800 nm and about 1000 nm. In embodiments where a sensor array is used in place of a single sensor, each sensor may be configured to provide light of a single wavelength. For example, a first sensor may emit only a Red light while a second may emit only an IR light. In a further example, the wavelengths of light used may be selected based on the specific location of the sensor. In a further example, one or more sensors may provide light at about 730 nm, about 810 nm, and/or about 900 nm.

It will be understood that, as used herein, the term “light” may refer to energy produced by electromagnetic radiation sources. Light may be of any suitable wavelength and intensity, and modulations thereof, in any suitable shape and direction. Detector18may be chosen to be specifically sensitive to the acoustic response of the subject's tissue arising from use of light source16. It will also be understood that, as used herein, the “acoustic response” shall refer to pressure and changes thereof caused by a thermal response (e.g., expansion and contraction) of tissue to light absorption by the tissue or constituent thereof.

In some embodiments, detector18may be configured to detect the acoustic response of tissue to the photonic excitation caused by the light source. In some embodiments, detector18may be a piezoelectric transducer which may detect force and pressure and output an electrical signal via the piezoelectric effect. In some embodiments, detector18may be a Faby-Pérot interferometer, or etalon. For example, a thin film (e.g., composed of a polymer) may be irradiated with reference light, which may be internally reflected by the film. Pressure fluctuations may modulate the film thickness, thus causing changes in the reference light reflection which may be measured and correlated with the acoustic pressure. In some embodiments, detector18may be configured or otherwise tuned to detect acoustic response in a particular frequency range. Detector18may convert the acoustic pressure signal into an electrical signal (e.g., using a piezoelectric material, photodetector of a Faby-Pérot interferometer, or other suitable device). After converting the received acoustic pressure signal to an electrical, optical, and/or wireless signal, detector18may send the signal to monitor14, where physiological parameters may be calculated based on the photoacoustic activity within the subject's tissue40. The signal outputted from detector18and/or a pre-processed signal derived thereof, will be referred to herein as a photoacoustic signal.

In some embodiments, encoder42may contain information about sensor unit12, such as what type of sensor it is (e.g., where the sensor is intended to be placed on a subject), the wavelength(s) of light emitted by light source16, the intensity of light emitted by light source16(e.g., output wattage or Joules), the mode of light source16(e.g., pulsed versus CW), any other suitable information, or any combination thereof. This information may be used by monitor14to select appropriate algorithms, lookup tables and/or calibration coefficients stored in monitor14for calculating the subject's physiological parameters.

Encoder42may contain information specific to subject40, such as, for example, the subject's age, weight, and diagnosis. This information about a subject's characteristics may allow monitor14to determine, for example, subject-specific threshold ranges in which the subject's physiological parameter measurements should fall and to enable or disable additional physiological parameter algorithms. Encoder42may, for instance, be a coded resistor that stores values corresponding to the type of sensor unit12or the type of each sensor in the sensor array, the wavelengths of light emitted by light source16on each sensor of the sensor array, and/or the subject's characteristics. In some embodiments, encoder42may include a memory on which one or more of the following information may be stored for communication to monitor14: the type of the sensor unit12; the wavelengths of light emitted by light source16; the particular acoustic range that each sensor in the sensor array is monitoring; the particular acoustic spectral characteristics of a detector; a signal threshold for each sensor in the sensor array; any other suitable information; or any combination thereof.

In some embodiments, signals from detector18and encoder42may be transmitted to monitor14. In the embodiment shown, monitor14may include a general-purpose microprocessor48connected to an internal bus50. Microprocessor48may be adapted to execute software, which may include an operating system and one or more applications, as part of performing the functions described herein. Also connected to bus50may be a read-only memory (ROM)52, a random access memory (RAM)54, user inputs56, display20, and speaker22.

RAM54and ROM52are illustrated by way of example, and not limitation. Any suitable computer-readable media may be used in the system for data storage. Computer-readable media are capable of storing information that can be interpreted by microprocessor48. This information may be data or may take the form of computer-executable instructions, such as software applications, that cause the microprocessor to perform certain functions and/or computer-implemented methods. Depending on the embodiment, such computer-readable media may include computer storage media and communication media. Computer storage media may include volatile and non-volatile, removable and non-removable media implemented in any method or technology for storage of information such as computer-readable instructions, data structures, program modules or other data. Computer storage media may include, but is not limited to, RAM, ROM, EPROM, EEPROM, flash memory or other solid state memory technology, CD-ROM, DVD, or other optical storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, or any other medium that can be used to store the desired information and that can be accessed by components of the system.

In the embodiment shown, a time processing unit (TPU)58may provide timing control signals to light drive circuitry60, which may control the activation of light source16. For example, TPU58may control pulse timing (e.g., pulse duration and inter-pulse interval) for TD-PA monitoring system. TPU58may also control the gating-in of signals from detector18through amplifier62and switching circuit64. The received signal from detector18may be passed through amplifier66, low pass filter68, and analog-to-digital converter70. The digital data may then be stored in a queued serial module (QSM)72(or buffer) for later downloading to RAM54as QSM72is filled. In some embodiments, there may be multiple separate parallel paths having components equivalent to amplifier66, filter68, and/or A/D converter70for multiple light wavelengths or spectra received. Any suitable combination of components (e.g., microprocessor48, RAM54, analog to digital converter70, any other suitable component shown or not shown inFIG. 2) coupled by bus50or otherwise coupled (e.g., via an external bus), may be referred to as “processing equipment.”

In the embodiment shown, light source16may include modulator44, in order to, for example, perform FD-PA analysis. Modulator44may be configured to provide intensity modulation, spatial modulation, any other suitable optical signal modulations, or any combination thereof. For example, light source16may be a CW light source, and modulator44may provide intensity modulation of the CW light source such as using a linear sweep modulation. In some embodiments, modulator44may be included in light drive60, or other suitable components of physiological monitoring system10, or any combination thereof.

In some embodiments, microprocessor48may determine the subject's physiological parameters, such as SpO2, SvO2, oxy-hemoglobin concentration, deoxy-hemoglobin concentration, total hemoglobin concentration (tHb), pulse rate, cardiac output, intrathoracic blood volume, intrathoracic circulatory volume, global end-diastolic volume, pulmonary circulatory volume, extravascular lung water, and/or other physiological parameters, using various algorithms and/or lookup tables based on the value of the received signals and/or data corresponding to the acoustic response received by detector18. Signals corresponding to information about subject40, and particularly about the acoustic signals emanating from a subject's tissue over time, may be transmitted from encoder42to decoder74. These signals may include, for example, encoded information relating to subject characteristics. Decoder74may translate these signals to enable the microprocessor to determine the thresholds based at least in part on algorithms or lookup tables stored in ROM52. In some embodiments, user inputs56may be used to enter information, select one or more options, provide a response, input settings, provide any other suitable inputting function, or any combination thereof. User inputs56may be used to enter information about the subject such as, for example, age, weight, height, diagnosis, medications, treatments, and so forth. In some embodiments, display20may exhibit a list of values, which may generally apply to the subject, such as, for example, age ranges or medication families, which the user may select using user inputs56.

Calibration device80, which may be powered by monitor14via a communicative coupling82, a battery, or by a conventional power source such as a wall outlet, may include any suitable signal calibration device. Calibration device80may be communicatively coupled to monitor14via communicative coupling82, and/or may communicate wirelessly (not shown). In some embodiments, calibration device80is completely integrated within monitor14. In some embodiments, calibration device80may include a manual input device (not shown) used by an operator to manually input reference signal measurements obtained from some other source (e.g., an external invasive or non-invasive physiological measurement system).

The acoustic signal attenuated by the tissue of subject40can be degraded by noise, among other sources. Movement of the subject may also introduce noise and affect the signal. For example, the contact between the detector and the skin, or the light source and the skin, can be temporarily disrupted when movement causes either to move away from the skin. Another potential source of noise is electromagnetic coupling from other electronic instruments.

Noise (e.g., from subject movement) can degrade a sensor signal relied upon by a care provider, without the care provider's awareness. This is especially true if the monitoring of the subject is remote, the motion is too small to be observed, or the care provider is watching the instrument or other parts of the subject, and not the sensor site. Processing sensor signals may involve operations that reduce the amount of noise present in the signals, control the amount of noise present in the signal, or otherwise identify noise components in order to prevent them from affecting measurements of physiological parameters derived from the sensor signals.

FIG. 3is an illustrative signal processing system300in accordance with an embodiment that may implement the signal processing techniques described herein. In some embodiments, signal processing system300may be included in a physiological monitoring system (e.g., physiological monitoring system10ofFIGS. 1-2). In the illustrated embodiment, input signal generator310generates an input signal316. As illustrated, input signal generator310may include pre-processor320coupled to sensor318, which may provide input signal316. In some embodiments, pre-processor320may be a photoacoustic module and input signal316may be a photoacoustic signal. In an embodiment, pre-processor320may be any suitable signal processing device and input signal316may include one or more photoacoustic signals and one or more other physiological signals, such as a photoplethysmograph signal. It will be understood that input signal generator310may include any suitable signal source, signal generating data, signal generating equipment, or any combination thereof to produce input signal316. Input signal316may be a single signal, or may be multiple signals transmitted over a single pathway or multiple pathways.

Pre-processor320may apply one or more signal processing operations to the signal generated by sensor318. For example, pre-processor320may apply a predetermined set of processing operations to the signal provided by sensor318to produce input signal316that can be appropriately interpreted by processor312, such as performing A/D conversion. In some embodiments, A/D conversion may be performed by processor312. Pre-processor320may also perform any of the following operations on the signal provided by sensor318: reshaping the signal for transmission, multiplexing the signal, modulating the signal onto carrier signals, compressing the signal, encoding the signal, and filtering the signal.

In some embodiments, input signal316may be coupled to processor312. Processor312may be any suitable software, firmware, hardware, or combination thereof for processing input signal316. For example, processor312may include one or more hardware processors (e.g., integrated circuits), one or more software modules, and computer-readable media such as memory, firmware, or any combination thereof. Processor312may, for example, be a computer or may be one or more chips (i.e., integrated circuits) such as, for example, a field programmable gate array (FPGA), micro-controller, or digital signal processor (DSP). Processor312may, for example, include an assembly of analog electronic components. Processor312may calculate physiological information. For example, processor312may perform time domain calculations, spectral domain calculations, time-spectral transformations (e.g., fast Fourier transforms, inverse fast Fourier transforms), any other suitable calculations, or any combination thereof. Processor312may perform any suitable signal processing of input signal316to filter input signal316, such as any suitable band-pass filtering, adaptive filtering, closed-loop filtering, any other suitable filtering, and/or any combination thereof. Processor312may also receive input signals from additional sources (not shown). For example, processor312may receive an input signal containing information about treatments provided to the subject. Additional input signals may be used by processor312in any of the calculations or operations it performs in accordance with processing system300.

In some embodiments, all or some of pre-processor320, processor312, or both, may be referred to collectively as processing equipment. For example, processing equipment may be configured to amplify, filter, sample and digitize input signal316(e.g., using an analog to digital converter), and calculate physiological information from the digitized signal.

Processor312may be coupled to one or more memory devices (not shown) or incorporate one or more memory devices such as any suitable volatile memory device (e.g., RAM, registers, etc.), non-volatile memory device (e.g., ROM, EPROM, magnetic storage device, optical storage device, flash memory, etc.), or both. In some embodiments, processor312may store physiological measurements or previously received data from signal316in a memory device for later retrieval. In some embodiments, processor312may store calculated values, such as pulse rate, blood pressure, blood oxygen saturation (e.g., arterial, venous, or both), hemoglobin concentration (e.g., oxygenated, deoxygenated, and/or total), cardiac output, intrathoracic blood volume, intrathoracic circulatory volume, global end-diastolic volume, pulmonary circulatory volume, extravascular lung water, or any other suitable calculated values, or combinations thereof, in a memory device for later retrieval.

Processor312may be coupled to output314. Output314may be any suitable output device such as one or more medical devices (e.g., a medical monitor that displays various physiological parameters, a medical alarm, or any other suitable medical device that either displays physiological parameters or uses the output of processor312as an input), one or more display devices (e.g., monitor, PDA, mobile phone, any other suitable display device, or any combination thereof), one or more audio devices, one or more memory devices (e.g., hard disk drive, flash memory, RAM, optical disk, any other suitable memory device, or any combination thereof), one or more printing devices, any other suitable output device, or any combination thereof.

It will be understood that system300may be incorporated into system10(FIGS. 1 and 2) in which, for example, input signal generator310may be implemented as part of sensor unit12(FIGS. 1 and 2) and monitor14(FIGS. 1 and 2) and processor312may be implemented as part of monitor14(FIGS. 1 and 2). In some embodiments, portions of system300may be configured to be portable. For example, all or part of system300may be embedded in a small, compact object carried with or attached to the subject (e.g., a watch, other piece of jewelry, or a smart phone). In some embodiments, a wireless transceiver (not shown) may also be included in system300to enable wireless communication with other components of system10(FIGS. 1 and 2). As such, system10(FIGS. 1 and 2) may be part of a fully portable and continuous physiological monitoring solution. In some embodiments, a wireless transceiver (not shown) may also be included in system300to enable wireless communication with other components of system10. For example, pre-processor320may output signal316(e.g., which may be a pre-processed photoacoustic signal) over BLUETOOTH, IEEE 802.11, WiFi, WiMax, cable, satellite, Infrared, any other suitable transmission scheme, or any combination thereof. In some embodiments, a wireless transmission scheme may be used between any communicating components of system300.

It will also be understood that while some of the equations referenced herein are continuous functions, the processing equipment may be configured to use digital or discrete forms of the equation in processing the acquired PA signal.

FIG. 4shows an illustrative photoacoustic arrangement400, in accordance with some embodiments of the present disclosure. Light source402, controlled by a suitable light drive (e.g., a light drive of system300or system10, although not shown inFIG. 4), may provide photonic signal404to subject450. Photonic signal404may be attenuated along its pathlength in subject450prior to reaching site408of blood vessel452, and may be attenuated across blood vessel452. It will be understood that photonic signal404may scatter in subject450and need not travel as a constant, well-formed beam as illustrated. Also, photonic signal404may generally travel through and beyond site408, although not illustrated inFIG. 4. A constituent of the blood in blood vessel452such as, for example, hemoglobin, or an injected indicator (e.g., a dye) may absorb at least some of photonic signal404at site408. Accordingly, the blood may exhibit an acoustic pressure response via the photoacoustic effect, which may act on the surrounding tissues of blood vessel452. Acoustic detector420may detect acoustic pressure signals410traveling though tissue of subject450, and output (not shown) a photoacoustic signal that may be processed by suitable processing equipment. Changes in some properties of the blood in blood vessel452at site408may be detected by acoustic detector420. For example, a reduced hemoglobin concentration or reduced temperature at the monitoring site may cause a reduced acoustic pressure signal to be detected by acoustic detector420. In some embodiments, bolus dose460, which may include a suitable indicator, may be introduced to the blood of patient450at a suitable blood vessel site (not shown inFIG. 4). Acoustic detector420may detect the transient changes in the hemoglobin concentration (“hemo-dilution”) and/or temperature (“thermo-dilution”) at site408due to passage of bolus dose460through site408. In some embodiments (not shown), multiple monitoring sites may be used to detect changes in hemoglobin concentration, temperature, or both. As bolus dose460travels through the circulatory system of subject450, diffusion, mixing (e.g., within a heart chamber), or both may spread the hemoglobin concentration and temperature profiles axially (i.e., in the direction of flow) and radially (i.e., normal to the direction of flow). It will be understood that hemo-dilution refers to the dilution of blood constituents caused by the bolus dose, and thermo-dilution refers to the combined effects of blood constituent dilution and temperature change, both caused by the bolus dose. In some embodiments, by using a thermo-dilution indicator, a temperature change may be enhanced by hemo-dilution (e.g., when the temperature change and the dilution change both cause the photoacoustic signal to either increase or decrease), and accordingly may be detected by a system having relatively less temperature sensitivity.

Dilution techniques using a bolus dose may be used to determine, for example, cardiac output (CO), intrathoracic blood volume (ITBV), intrathoracic circulatory volume (ITCV), global end-diastolic volume (GEDV), pulmonary circulatory volume (PCV), extravascular lung water (EVLW), and/or other hemodynamic parameters.

A bolus dose of an indicator may cause the properties at a photoacoustic monitoring site to change in time as the bolus dose passes the site. Introduction of the indicator may alter one or more properties of the blood that interacts with the indicator (e.g., blood near the bolus dose). An indicator introduced as a bolus dose may be selected to have one or more properties that allow the bolus dose to be distinguished from a subject's un-dosed blood. For example, an indicator may be selected which has particular absorption properties at one or more particular wavelengths (e.g., a dye indicator such as indocyanine green dye), and the photoacoustic monitoring system may monitor the presence of the indicator by providing a photonic signal at the one or more particular wavelengths and detecting an acoustic pressure signal having a dye indicator dilution response. In a further example, an indicator may be selected to dilute blood of a subject but not substantially absorb the photonic signal. The photoacoustic monitoring system may then accordingly monitor the blood (e.g., hemoglobin) rather than the indicator, to detect dilution. In a further example, an indicator having a temperature different from the temperature of the subject's un-dosed blood may be introduced into a subject's bloodstream (e.g., a “hot” or “cold” indicator, relative to the blood temperature). The photoacoustic monitoring system may then accordingly monitor the bloodstream temperature at the monitoring site, or the combined effects of hemo-dilution and thermo-dilution achieved by the bolus dose. In some embodiments, an indicator may have more than one property that may be distinguished from a subject's blood. For example, a cold dye indicator may be introduced to the subject's bloodstream, which may allow hemo-dilution and thermo-dilution effects to be detected. In some embodiments, more than one indicator may be introduced to the subject's bloodstream, each indicator having particular properties that may be unique relative to the other indicators. For example, an isotonic indicator and a hypertonic indicator may be introduced into a subject's bloodstream. In a further example, a cold isotonic indicator and a dye indicator may be introduced into a subject's bloodstream.

FIG. 5shows an illustrative indicator arrangement500, in accordance with some embodiments of the present disclosure. In some embodiments, an indicator may be provided to the circulatory system of a subject to aid in determining one or more physiological parameters. For example, a saline solution may be injected into a subject's circulatory system at blood vessel site510using needle502. Blood vessel site510may be located at any suitable portion of a subject's circulatory system such as a vein, an artery, a capillary, or other suitable location. For example, blood vessel site510may be a central vein of the subject. Portion520of the subject's circulatory system shown illustratively inFIG. 5may include heart chambers, arteries, veins, capillaries, any other suitable parts of the circulatory system, or any combination thereof. As the indicator travels along portion520, in the direction of the motion arrows, the concentration and/or temperature profile of may change. For example, panel550shows an illustrative dilution curve time series as detected at site552, relatively near site510. Panels560and570each show illustrative time series of dilution curves at sites562and572, respectively, both downstream from site552. The dilution curve shown in panel560is relatively flattened in time compared to the dilution curve shown in panel550. The dilution curve shown in panel570is relatively flattened in time compared to the dilution curve shown in panel560. The flattening may be due to diffusion and mixing of the indicator with the subject's blood. The area under the time series of panels550,560, and570may be, but need not be, the same and may depend on the indicator type, travel time, site location, and other suitable variables. The phrase “dilution curve” as used herein shall refer to a time series, continuous or discrete, indicative of dilutive effects of an indicator on the concentration of blood constituents and/or blood temperature. For example, a dilution curve may include a time series of concentration or changes thereof of a blood constituent, an indicator, or both. In a further example, a dilution curve may include a time series of temperature, or change in temperature, of blood of the subject at a monitoring site.

In some embodiments, an indicator may be introduced to a vena cava or other vein. A photoacoustic monitoring system may be used to non-invasively detect the presence of the indicator in an arterial vessel (e.g., pulmonary artery, brachial artery, carotid artery, aorta) of the subject. The blood travels from the venous system to the right atrium and then ventricle, from which it is pumped to the lungs via the pulmonary arteries. Transport of water and other substances between the lungs and blood vessels occurs at the lung tissue. Accordingly, lung water may diffuse to the blood stream, depending upon the chemical potential difference of water between the lung tissue and the blood stream. Oxygenated blood leaving the lung tissue and returning to the heart is pumped by the left atrium and ventricle to the body via the aorta and other suitable portions of the arterial system of the subject. Characteristics of a measured dilution curve may provide an indication of CO of the subject. The dilatory effects of the indicator in the blood may depend on the interaction in the lung tissue, and may provide an indication of parameters such as, for example, EVLW. Properties of the subject's vasculature may be determined based at least in part on the measured dilution curves.

Isotonic and Hypertonic Indicators

In some embodiments, more than one indicator may be introduced to the subject's circulatory system at the same time or in succession. For example, in some embodiments, an isotonic indicator (e.g., 0.9% w/v saline) and a hypertonic indicator (e.g., 5% w/v saline) may be introduced in succession, and respective dilution curves may be measured for both indicators. Shown inFIG. 6are illustrative dilution curves602and652for isotonic and hypertonic saline indicators, respectively, in accordance with some embodiments of the present disclosure. The abscissa of each of illustrative plots600and650are shown in units of time, while the ordinate of each of illustrative plots600and650are shown in arbitrary units. In some embodiments, dilution curves such as, for example, dilution curves602and652may be time series in units of indicator concentration, tHb, temperature, photoacoustic signal, change in tHb, change in temperature, change in photoacoustic signal, or any other suitable units indicative of an indicator dilution response.

Plot600shows dilution curve602indicative of introduction of an isotonic indicator to a subject's bloodstream. Dilution curve602is unipolar, and exhibits a peak604, followed by a gradual steadying to a steady-state value. Because the isotonic indicator includes water having a chemical potential approximately equal to that of, for example, water in the lung tissue, the net diffusion of the indicator out of the vessel is zero.

Plot650shows dilution curve652indicative of introduction of a hypertonic indicator to a subject's bloodstream. Dilution curve652is bipolar, and exhibits a peak654, followed by a trough656, and then a gradual steadying to a steady-state value. Because the hypertonic indicator includes water having a chemical potential less than that of, for example, lung tissue, the net diffusion of the indicator out of the vessel may be nonzero. Water diffuses from the lung tissue to the blood, due to the imbalanced chemical potential of water across the permeable lung/vessel interfaces. This interaction may reduce the chemical potential of water in the lung tissue. Peak654indicates the increased dilution due to the indicator and the water transferred from the lung in the bloodstream. Accordingly, as the bolus dose of indicator travels away from the lung tissue via the pulmonary vein, blood with reduced indicator content, upstream of the bolus dose, reaches the lung tissue. The chemical potential imbalance then reverses, and water diffuses to the lung tissue from the blood. Trough656indicates the decreased dilution due to the transport of water from the bloodstream to the lung tissue. In some circumstances, the effect of the indicator may be reduced as time progresses, due to mixing and/or bio-regulation, illustratively indicated by the gradual return of dilution curves602and652to a steady-state, or near steady-state, condition.

FIG. 7shows a plot700of an illustrative time domain photoacoustic signal702, including a response corresponding to an isotonic indicator, in accordance with some embodiments of the present disclosure. Photoacoustic signal702may be a pre-processed and/or processed signal derived from the output of an acoustic detector. For example, photoacoustic signal702may include sample points corresponding to a maximum acoustic response for each light pulse (e.g., an acoustic pressure peak value), at a particular time lag corresponding to a particular spatial location (e.g., a particular blood vessel). The abscissa of plot700is shown in units of time, while the ordinate of plot700is shown in units proportional to voltage. A light source is used to provide a photonic signal to a first site of a circulatory system, causing a photoacoustic response of constituents in the circulating blood at that site. An acoustic detector is used to detect acoustic pressure signals caused by the photonic signal at the first site, and output photoacoustic signal702. An isotonic indicator is injected as a bolus dose into the circulating blood at a second site. As the bolus dose travels past the first site, the hemoglobin concentration at the first site temporarily decreases. Trough704indicates the dilatory effects of the bolus dose of isotonic indicator. The acoustic detector detects a reduced acoustic pressure signal caused by the reduced hemoglobin concentration. The effect of the indicator may be detected as a trough in the acoustic pressure signal corresponding to the passing of the bolus dose through the first site. Note that photoacoustic signal702may be indicative of tHb, exhibiting a substantially steady-state baseline and trough704indicative of the presence of the indicator (e.g., a reduction of tHb via displacement by the indicator). Note that a plot of indicator concentration as a function of time may exhibit a peak, corresponding to a steady-state tHb value minus an instantaneous tHb value. A dilution curve may include either a peak or a trough depending upon the species monitored and the units used in calculation.

FIG. 8shows an illustrative plot800of two total hemoglobin concentration time series as respective isotonic and hypertonic indicators pass a photoacoustic detection site, in accordance with some embodiments of the present disclosure. The abscissa of plot800is shown in units of time, and the ordinate of plot800is shown in units of total hemoglobin concentration, although any suitable units may be used in accordance with the present disclosure. Time series802and804may be pre-processed and/or processed signals derived from the output of an acoustic detector. For example, time series802and804may each include sample points corresponding to a maximum acoustic response for each light pulse (e.g., an acoustic pressure peak value), at a particular time lag corresponding to a particular spatial location (e.g., a particular blood vessel). Time series802is total hemoglobin concentration as the isotonic indicator travels through the photoacoustic detection site. Alternatively, if the indicator concentration were shown rather than tHb, it may exhibit a peak rather than a trough, corresponding to the shaded area820. Time series804is total hemoglobin concentration as the hypertonic indicator travels through the photoacoustic detection site. The variable t as shown inFIG. 8represents time relative to each response, and not an absolute time scale. For example, the time origin for both responses may be zero, and they may be plotted on the same axis even though the indicators were introduced at different times. The variable τ as shown inFIG. 8represents the mean transit time difference between the two responses.

In some embodiments, one or more characteristics may be derived from one or both responses. For example, the flow rate of a particular indicator may be formulated as shown by:
{dot over (V)}Ci={dot over (N)}(14)
where {dot over (V)} is the volumetric flow rate of blood (e.g., volume/time, assumed here to be constant in time), Ciis the concentration of indicator i (e.g., mole/volume, equivalent to the reduction in tHb using suitable assumptions), and {dot over (N)} is the molar flow rate of molecule i (e.g., mole/time). Defining the cardiac output CO to be equal to volumetric flow rate {dot over (V)}, and referencing time series802, the following Eq. 15 may be derived by integrating both sides of Eq. 14 in time:

C⁢⁢O=NA(15)
where cardiac output CO is proportional to the total isotonic indicator amount introduced N (e.g., moles, equivalent to the time integral of {dot over (N)}), and A is given by:
A=∫Cidt(16)
where A may be equivalent to the area820bounded by time series802and the steady tHb value. If the ordinate of plot800were shown in units other than concentration, a constant of proportionality may be required in Eq. 16 if time series values are used. Under some circumstances, cardiac output may be equal to the ratio of isotonic indicator amount introduced and the area bounded by the time series and the steady tHb value, while in other circumstances the equality of Eqs. 15-16 may be replaced by the proportionality symbol ∝ (e.g., to account for density differences). Area A is an illustrative example of a characteristic derived from a response to an indicator.

In a further example, EVLW may be formulated based on both time series802and804, as shown by Eq. 17:
EVLW=CO*ΔτMT(17)
where CO is the cardiac output, and ΔτMTis the mean transit time difference between the isotonic and hypertonic indicator dilution curves. The mean transit time of an indicator dilution curve may be based on any suitable reference point of the curve. The mean transit time for a dilution curve may be calculated using Eq. 18:

τMT=τ0+∫Ci*(t-τ0)⁢ⅆt∫Ci⁢ⅆt(18)
where τ0is the time after introduction of the indicator when the indicator is detected at the PA monitoring site, and Ciis the indicator concentration.

In a further example, a vascular permeability metric vp may be defined as:
vp=τ2−τ1(19)
where τ2is the peak time of time series804, and τ1is the time where time series802and804cross. In some circumstances, vascular permeability may provide an indication and/or measure of the possibility of a capillary leak and the possibility of fluid accumulating outside of the blood vessels.

In a further example, EVLW may be determined based on an osmotic response (e.g., the transfer of water and salt between the blood and lungs due to a chemical potential difference) of the subject using an isotonic and hypertonic indicator. EVLW may be determined using the following Eq. 20, for the hypertonic indicator:

E⁢⁢V⁢⁢L⁢⁢W=Πb⁡(Δ⁢⁢n3c-Δ⁢⁢E⁢⁢V⁢⁢L⁢⁢W3)ΔΠb,3(20)
where Πbis the steady state osmolarity of the subject's blood (e.g., before introduction of the hypertonic indicator), ΔΠb,3is the change in the osmolarity of subject's blood at time τ3, Δn3is the total amount of salt transferred from the subject's blood to the subject's lungs at time τ3, c is the concentration of solutes in the EVLW, and ΔEVLW3is the total change in extravascular lung water at time τ3. The time τ3is the time, referenced to zero at the beginning of the response, when the EVLW and blood have the same osmotic pressure for the hypertonic indicator.

In some embodiments, a thermo-dilution indicator may be introduced to the subject's circulatory system at a suitable location. For example, in some embodiments, a saline solution having a temperature less than that of a subject's blood may be introduced, and one or more dilution curves may be measured at one or more respective locations in the subject's vasculature. The Grüneisen parameter of the subject's blood may depend on temperature linearly according to the illustrative empirical relation:
Γ=mT+b(21)
where m is a slope and b is an intercept. Accordingly, Eq.
1 may be rewritten as follows:
p(z,T)=Γ(T)μaφ(z).  (22)
Showing that as the temperature at the photoacoustic monitoring site changes, the acoustic pressure signal may change accordingly. Introduction of thermo-dilution indicator may be used to determine cardiac output, ITCV, PCV, and/or GEDV, for example.

In some embodiments, cardiac output CO may be calculated using:

C⁢⁢O=K⁢(Tb,0-Ti,0)⁢Vi∫(Tb,0-Tb⁡(t))⁢ⅆt(23)
where K is a proportionality constant (e.g., including the effects of specific gravity and heat capacity of blood and/or the indicator), Tb,0is the initial blood temperature at the time and site of injection, Ti,0is the initial indicator temperature, Viis the volume of injected indicator, and Tb(t) is the blood temperature at time t, as measured using the photoacoustic technique. Note that the moles of injected indicator may be used rather than Viin some cases, with a suitable adjustment of the proportionality constant K to include the indicator concentration (e.g., mole/volume). In some embodiments, an expression such as, for example, Eq. 22 may be solved for temperature as a function of photoacoustic signal, and the function may include one or more parameters that may depend on tissue properties and/or system properties. Accordingly, a photoacoustic monitoring system (e.g., system10ofFIGS. 1-2or system300ofFIG. 3) may use one or more references such as pre-defined constants, reference PA signals, correlations, or look-up tables to determine a temperature, or change thereof, from a detected acoustic pressure signal. In some embodiments, a photoacoustic monitoring system may be calibrated for a particular subject or particular monitoring site of a subject. In some embodiments, a photoacoustic monitoring system may use a thermo-dilution indicator response and a body-temperature hemo-dilution indicator response (e.g., to de-couple the temperature and concentration effects) to determine a temperature or change thereof.

In some embodiments, ITCV may be calculated using:
ITCV=CO*τMT(24)
where CO is cardiac output (e.g., which may be calculated using Eq. 23), and τMTis the mean transit time of the thermo-dilution curve. The mean transit time for a thermo-dilution indicator may be calculated using:

τMT=τ0+∫(Tb,0-Tb⁡(t))*(t-τ0)⁢ⅆt∫(Tb,0-Tb⁡(t))⁢ⅆt(25)
where τ0is the time after introduction of the indicator when the indicator is detected at the PA monitoring site, and (Tb,0−Tb(t)) is the difference in initial and instantaneous blood temperature of the thermo-dilution curve. In some embodiments, in which a thermo-dilution indicator may be used, a circulatory volume may be equivalent to a thermal volume.

In some embodiments, PCV may be calculated using:
PCV=CO*τDS(26)
where CO is the cardiac output, and τDSis the downslope time of the thermo-dilution curve. In some embodiments, the downslope time may be determined as the time interval of the linear decay of the indicator response (e.g., downslope of a peak), from about 80% of the peak value to about 20% of the peak value. In some circumstances, downslope time may provide an indication and/or measure of the washout of the indicator, which may depend on the volume which the indictor dilutes.

In some embodiments, GEDV may be calculated using:
GEDV=ITCV−PCV  (27)
which may be indicative of the blood volume included in the ITCV.

In some embodiments, EVLW may be calculated using:
EVLW=ITCV−ITBV  (28)
where ITBV may be calculated from GEDV, which may be calculated using Eq. 27. For example, ITBV may be directly proportional to GEDV, with a proportionality constant of order one (e.g., a constant of 1.25). Accordingly, in some embodiments, ITCV, PCV, GEDV, ITBV, and EVLW may be determined based on a thermo-dilution indicator.

In some embodiments, both a thermo-dilution indicator and a hemo-dilution indicator may be introduced to the subject's circulatory system at suitable locations and times. For example, in some embodiments, a saline solution having a temperature less than that of a subject's blood may be introduced, and a dye indicator such as indocyanine green dye may be introduced. Accordingly, two or more dilution curves may be measured at one or more locations in the subject's vasculature, indicative of the hemo-dilution and thermo-dilution indicators. Any of the properties that may be calculated using Eqs. 21-27 may be calculated using the thermo-dilution indicator. In some embodiments, ITBV may be calculated using the hemo-dilution curve, as shown by:
ITBV=CO*τMT(29)
where CO is the cardiac output (e.g., calculated using Eq. 15 or 23), and τMTis the mean transit time of the hemo-dilution curve (e.g., calculated using Eq. 18).

In some embodiments, EVLW may be calculated from the thermo-dilution curve and hemo-dilution curve using:
EVLW=ITCV−ITBV  (30)
wherein ITCV may be calculated from the thermo-dilution curve (e.g., using Eq. 24), and ITBV may be calculated from the hemo-dilution curve (e.g., using Eq. 29).

Any of the thermal-dilution and hemo-dilution techniques, using one or more indicators, including the use of an isotonic and a hypertonic indicator, may be used alone or in combination with other techniques. Accordingly, any of Eqs. 14-30 may be used alone or in concert to determine physiological information of a subject such as a physiological parameter.FIGS. 9-12include flowcharts of illustrative steps for implementing the aforementioned techniques. In some embodiments, other information may be determined based on indicator dilution techniques (e.g., using an indocyanine green indicator, liver function and/or total blood volume may be determined).

FIG. 9is a flow diagram900of illustrative steps for determining a physiological parameter from an acoustic pressure signal having an indicator dilution response, in accordance with some embodiments of the present disclosure.

Step902may include a suitable light source (e.g., light source16of system10) of system300providing a photonic signal to a subject. The light source may be a pulsed light source, continuous wave light source, any other suitable light source, or any combination thereof. In some embodiments, modulator44may be used to modulate the photonic signal of the light source. In some embodiments, the photonic signal may be focused or otherwise spatially modulated. For example, the photonic signal may be focused on or near a blood vessel, which may contain blood that absorbs at least some of the photonic signal, causing a relatively stronger photoacoustic response and accordingly a stronger photoacoustic signal than surrounding tissue.

Step904may include system300detecting an acoustic pressure signal having an indicator response. In some embodiments, an acoustic detector such as, for example, an ultrasound detector of system300may detect the acoustic pressure signal. The acoustic detector may output an electrical signal to suitable processing equipment of system300. The acoustic pressure signal may be detected as a time series (e.g., in the time domain or sample number domain), and processed as a time series, as a spectral series (e.g., in the frequency domain), any other suitable series, or any combination thereof. In some embodiments, pre-processor320may pre-process the detected acoustic pressure signal. For example, pre-processor320may perform filtering, amplifying, de-multiplexing, de-modulating, sampling, smoothing, any other suitable pre-processing, or any combination thereof. The acoustic pressure signal may include a hemo-dilution and/or thermo-dilution response characterized by a temporal peak or trough in concentration, temperature, any other suitable property of the monitoring site, any changes thereof, or any combination thereof. In some embodiments, processor312may use a peak finding technique to locate a peak and/or trough. For example, processor312may locate a maximum or minimum in the photoacoustic signal, locate a zero in the first derivative of the photoacoustic signal, perform any other suitable peak finding technique, or any combination thereof. The peak finding technique may operate on only a subset of the photoacoustic signal. For example, the peak finding algorithm may only start looking for a peak and/or trough after a predetermined time or sample number from the introduction of the indicator. In some embodiments, processor312and/or pre-processor320may generate a photoacoustic signal from a time series of peak values in a detected acoustic pressure signal, occurring at a particular time lag indicative of a spatial location, resulting from the photoacoustic response to the photonic signal.

Step906may include system300determining one or more physiological parameters of the subject based at least in part on the indicator dilution response detected at step904. Physiological parameters may include hemoglobin, blood oxygen saturation, CO, ITBV, ITCV, GEDV, PCV, EVLW, any other suitable hemodynamic parameters, any other suitable physiological parameters, any physiological modulations thereof, or any combination thereof. In some embodiments, step906may include processor312determining one or more characteristics based at least in part on the indicator dilution response. Processor312may determine characteristics such as particular values of the acoustic pressure signal or values of a signal derived thereof (e.g., a tHb value), areas under or between signals (e.g., integrals), temporal values or differences (e.g., as shown by Eqs. 18, 19, and 25), any other suitable characteristics, or any combination thereof. For example, processor312may calculate one or more physiological parameters using any or all of Eqs. 14-16, 18, and 23-29, based on a detected indicator dilution response. In some embodiments, an acoustic pressure signal may be influenced by arterial pulsations and/or respiratory synchronous variations, or other biological modulations. In some such embodiments, system300may use a spectral filter (e.g., a notch filter, a high-pass filter) to reduce the influence of these biological modulations that typically occur over larger time scales than the time scales of an acoustic pressure signal. For example, system300may apply a spectral filter to a photoacoustic signal derived from an acoustic pressure signal, to filter out pulsatile components.

FIG. 10is a flow diagram1000of illustrative steps for determining a physiological parameter from an acoustic pressure signal having a first and a second response, in accordance with some embodiments of the present disclosure.

Step1002may include a suitable light source (e.g., light source16of system10) of system300providing a photonic signal to a subject, at a monitoring site. The light source may be a pulsed light source, continuous wave light source, any other suitable light source, or any combination thereof. In some embodiments, modulator44may be used to modulate the photonic signal of the light source. In some embodiments, the photonic signal may be focused or otherwise spatially modulated. For example, the photonic signal may be focused on or near a blood vessel, which may contain blood that absorbs at least some of the photonic signal, causing a relatively stronger photoacoustic response and accordingly a stronger photoacoustic signal than surrounding tissue. In some embodiments, step1002may include providing the photonic signal at two particular times to monitor the respective first and second responses. For example, the photonic signal of step1002may be provided in response to the introduction of an indicator, at a suitable time to monitor the response at the monitoring site of the subject. In some embodiments, step1002may include providing the photonic signal steadily, and using processor equipment to locate the response in the time series.

Step1004may include system300detecting an acoustic pressure signal having a first and a second response. In some embodiments, an acoustic detector such as, for example, an ultrasound detector of system300may detect the acoustic pressure signal. The acoustic detector may output an electrical signal to suitable processing equipment of system300. The acoustic pressure signal may be detected as a time series (e.g., in the time domain or sample number domain), and processed as a time series, as a spectral series (e.g., in the frequency domain), any other suitable series, or any combination thereof. In some embodiments, pre-processor320may pre-process the detected acoustic pressure signal. For example, pre-processor320may perform filtering, amplifying, de-multiplexing, de-modulating, sampling, smoothing, any other suitable pre-processing, or any combination thereof. In some embodiments, processor312and/or pre-processor320may generate a photoacoustic signal from a time series of peak values in a detected acoustic pressure signal, occurring at a particular time lag indicative of a spatial location, resulting from the photoacoustic response to the photonic signal. The photoacoustic signal may include a first and a second response, which may be hemo-dilution and/or thermo-dilution responses. The responses may be characterized by a temporal peak or trough in the photoacoustic signal, a concentration time series derived thereof, a temperature time series derived thereof, any other suitable signal, any changes thereof, or any combination thereof. In some embodiments, processor312may use a peak finding technique to locate a peak and/or trough. For example, processor312may locate a maximum or minimum in the photoacoustic signal, locate a zero in the first derivative of the photoacoustic signal, perform any other suitable peak finding technique, or any combination thereof. The peak finding technique may operate on only a subset of the photoacoustic signal. For example, the peak finding algorithm may only start looking for a peak and/or trough after a predetermined time or sample number from the introduction of the respective indicator.

Step1006may include system300determining one or more physiological parameters of the subject based at least in part on the first and/or second responses detected at step1004. Physiological parameters may include hemoglobin, blood oxygen saturation, CO, ITBV, ITCV, GEDV, PCV, EVLW, any other suitable hemodynamic parameters, any other suitable physiological parameters, any physiological modulations thereof, or any combination thereof. In some embodiments, step1004may include processor312determining one or more characteristics based at least in part on the first and/or second responses. Processor312may determine characteristics such as particular values of the acoustic pressure signal or values of a signal derived thereof (e.g., a tHb value), areas under or between signals (e.g., integrals), temporal values or differences (e.g., as shown by Eqs. 18, 19, and 25), any other suitable characteristics, or any combination thereof. For example, processor312may calculate one or more physiological parameters using any or all of Eqs. 14-20, and 23-30, based on detected first and/or second responses. More particularly, processor312may calculate EVLW from an isotonic indicator dilution response and a hypertonic indicator dilution response using Eq. 17. Also more particularly, processor312may calculate ITBV, ITCV, and EVLW from a hemo-dilution response and a thermo-dilution response using Eqs. 29-30.

FIG. 11is a flow diagram1100of illustrative steps for determining a physiological parameter from an acoustic pressure signal having a first and second response, corresponding to respective isotonic and hypertonic indicators, in accordance with some embodiments of the present disclosure.

Step1102may include a suitable light source (e.g., light source16of system10) of system300providing a photonic signal to a subject, at a first site. The light source may be a pulsed light source, continuous wave light source, any other suitable light source, or any combination thereof. In some embodiments, modulator44may be used to modulate the photonic signal of the light source. In some embodiments, the photonic signal may be focused or otherwise spatially modulated.

Step1104may include providing an isotonic indicator to a subject at a second site, at a first time. In some embodiments, a bolus dose of the isotonic indicator may be injected using a hypodermic needle, inserted into a blood vessel of the subject. The bolus dose may include, for example, a volume on the order of ten milliliters. Such a dose applied to the central vein may dilute the blood inside the heart up to ten percent. In some embodiments, the bolus dose of isotonic indicator may be introduced at substantially the same temperature of the subject at the second site. In some embodiments, the bolus dose of isotonic indicator may be introduced at a temperature different from the temperature of the subject at the second site (e.g., the bolus dose may be relatively warmer or cooler).

Step1106may include providing a hypertonic indicator to a subject at or near the second site, at a second time. In some embodiments, a bolus dose of the hypertonic indicator may be injected using a hypodermic needle, inserted into a blood vessel of the subject. The bolus dose may include, for example, a volume on the order of ten milliliters. The second time may be before or after the first time (i.e., the introduction of the isotonic and hypertonic indicators may be in any suitable order). In some embodiments, the bolus dose of hypertonic indicator may be introduced at substantially the same temperature of the subject at the second site. In some embodiments, the bolus dose of hypertonic indicator may be introduced at a temperature different from the temperature of the subject at the second site (e.g., the bolus dose may be relatively warmer or cooler). The bolus dose of hypertonic indicator may be introduced at a temperature the same as, or different from, the temperature of the bolus dose of isotonic indicator of step1104.

Step1108may include system300detecting an acoustic pressure signal having a first and a second response, corresponding to the isotonic and hypertonic indicators. In some embodiments, an acoustic detector such as, for example, an ultrasound detector of system300may detect the acoustic pressure signal. In some embodiments, processor312and/or pre-processor320may generate a photoacoustic signal from a time series of peak values in a detected acoustic pressure signal, occurring at a particular time lag indicative of a spatial location, resulting from the photoacoustic response to the photonic signal. The acoustic detector may output an electrical signal to suitable processing equipment of system300. In some embodiments, the first and second responses may be detected as peaks or troughs in the photoacoustic signal, distinguishable from a baseline photoacoustic signal.

Step1110may include system300determining one or more characteristics based at least in part on the first and/or second response. Processor312may determine characteristics such as particular values of the acoustic pressure signal or values of a signal derived thereof, areas under or between dilution curves, temporal values or differences, any other suitable characteristics, or any combination thereof. For example, a mean transit time may be determined using any of Eqs. 18 or 25. In a further example, a mean transit time difference may be determined using Eq. 18. In a further example, an integral may be determined using Eq. 16. In a further example, a crossing time may be determined such as variable τ1used in Eq. 19. In a further example, a time associated with a peak value may be determined such as variable τ2used in Eq. 19. In a further example, a time difference may be determined using Eq. 19.

Step1112may include system300determining one or more physiological parameters of the subject based at least in part on the one or more characteristics of step1110. Physiological parameters may include hemoglobin, blood oxygen saturation, CO, ITBV, ITCV, GEDV, PCV, EVLW, any other suitable hemodynamic parameters, any other suitable physiological parameters, any physiological modulations thereof, or any combination thereof. For example, processor312may calculate one or more physiological parameters based on suitable characteristics using any or all of Eqs. 14-20.

FIG. 12is a flow diagram1200of illustrative steps for determining a physiological parameter from an acoustic pressure signal having a hemo-dilution and/or thermo-dilution response, in accordance with some embodiments of the present disclosure.

Step1202may include a suitable light source (e.g., light source16of system10) of system300providing a photonic signal to a subject, at a monitoring site. The light source may be a pulsed light source, continuous wave light source, any other suitable light source, or any combination thereof. In some embodiments, modulator44may be used to modulate the photonic signal of the light source. In some embodiments, the photonic signal may be focused or otherwise spatially modulated.

Step1204may include determining which indicators are to be introduced to the subject. One or more thermo-dilution indicators, one or more hemo-dilution indicators, or combinations thereof, may be introduced to the subject. In some embodiments, system300may determine which indicators to introduce to the subject. For example, in order to determine a particular physiological parameter, system300may determine that particular indicator(s) are required. In some embodiments, step1204may be performed by a user, who may input one or more commands (e.g., selections from a pull-down menu, entry of a text indication) into a suitable user interface (e.g., user inputs56of system10). In some embodiments, system300may be configured to detect a particular response (e.g., thermo-dilution or hemo-dilution), and accordingly step1204need not be performed because no determination is required.

Step1206may include providing one or more thermo-dilution indicators to the subject at an indicator site, and then system300detecting a resulting thermo-dilution response of an acoustic pressure signal at step1208based at least in part on the photonic signal of step1202. In some embodiments, a bolus dose of the thermo-dilution indicator may be injected using a hypodermic needle, inserted into a blood vessel of the subject. The bolus dose may include, for example, a volume on the order of ten milliliters. In some embodiments, the bolus dose of thermo-dilution indicator may be introduced at a temperature different from the temperature of the subject at the indicator site (e.g., the bolus dose may be relatively warmer or cooler). The thermo-dilution indicator may be an isotonic indicator, a hypertonic indicator, a hypertonic indicator, a dye indicator, any other suitable indicator, or any combination thereof. In some embodiments, an acoustic detector such as, for example, an ultrasound detector of system300may detect the acoustic pressure signal at step1208. The acoustic detector may output an electrical signal to suitable processing equipment of system300. In some embodiments, processor312and/or pre-processor320may generate a photoacoustic signal from a time series of peak values in a detected acoustic pressure signal, occurring at a particular time lag indicative of a spatial location, resulting from the photoacoustic response to the photonic signal. In some embodiments, the thermo-dilution response may be detected as a peak or trough in the photoacoustic signal, distinguishable from a baseline photoacoustic signal.

Step1210may include providing one or more hemo-dilution indicators to the subject, and then system300detecting a resulting hemo-dilution response of an acoustic pressure signal at step1212based at least in part on the photonic signal of step1202. In some embodiments, a bolus dose of the hemo-dilution indicator may be injected using a hypodermic needle, inserted into a blood vessel of the subject. The bolus dose may include, for example, a volume on the order of ten milliliters. The bolus dose of hemo-dilution indicator may be, but need not be, introduced at the same temperature as the temperature of the subject at the indicator site. The hemo-dilution indicator may be an isotonic indicator, a hypertonic indicator, a hypertonic indicator, a dye indicator, any other suitable indicator, or any combination thereof. In some embodiments, an acoustic detector such as, for example, an ultrasound detector of system300may detect the acoustic pressure signal at step1212. The acoustic detector may output an electrical signal to suitable processing equipment of system300. In some embodiments, processor312and/or pre-processor320may generate a photoacoustic signal from a time series of peak values in a detected acoustic pressure signal, occurring at a particular time lag indicative of a spatial location, resulting from the photoacoustic response to the photonic signal. In some embodiments, the hemo-dilution response may be detected as a peak or trough in the photoacoustic signal, distinguishable from a baseline photoacoustic signal.

Step1214may include system300detecting a thermo-dilution response and a hemo-dilution response of an acoustic pressure signal based at least in part on the photonic signal of step1202, resulting from respective thermo-dilution and hemo-dilution indicators provided at steps1206and1210. In some embodiments, bolus doses of the thermo-dilution and hemo-dilution indicators may be injected using one or more hypodermic needles, inserted into one or more blood vessels (or sites thereof) of the subject. Each bolus dose may include, for example, a volume on the order of ten milliliters. In some embodiments, an acoustic detector such as, for example, an ultrasound detector of system300may detect the acoustic pressure signal at step1208. The acoustic detector may output an electrical signal to suitable processing equipment of system300. In some embodiments, processor312and/or pre-processor320may generate a photoacoustic signal from a time series of peak values in a detected acoustic pressure signal, occurring at a particular time lag indicative of a spatial location, resulting from the photoacoustic response to the photonic signal. In some embodiments, the thermo-dilution and hemo-dilution responses may be detected as peaks or troughs in the photoacoustic signal, distinguishable from a baseline photoacoustic signal. In some embodiments, the thermo-dilution indicator and hemo-dilution indicator may be introduced to the subject at different times and/or locations. For example, a particular time interval between the thermo-dilution and hemo-dilution indicators may be used to prevent mixing of the indicators and corresponding composite effects.

Step1216may include system300determining one or more characteristics based at least in part on the detected responses of any of steps1208,1212, and1214. In some embodiments, the one or more characteristics may depend on the type of indicator that is provided (e.g., at steps1206and/or1210). Characteristics may include particular values of the acoustic pressure signal or values of a signal derived thereof (e.g., a photoacoustic signal), areas under or between dilution curves, temporal values or differences, any other suitable characteristics, or any combination thereof. For example, one or more thermo-dilution indicators may be used, and the one or more characteristics may include a mean transit time (e.g., as included in Eqs. 24 and 25), a downslope time (e.g., as included in Eq. 26), and an integral of a portion of a dilution curve (e.g., as included in Eq. 23). In a further example, one or more hemo-dilution indicator may be used, and the one or more characteristics may include a mean transit time (e.g., as included in Eqs. 18 and 29), a time difference (e.g., as included in Eqs. 17 and 19), and an integral of a portion of a dilution curve (e.g., as included in Eq. 16). In a further example, a thermo-dilution indicator and a hemo-dilution indicator may be used, and the one or more characteristics may include a mean transit time (e.g., as included in Eqs. 18, 24, 25 and 29), a downslope time (e.g., as included in Eq. 26), a time difference (e.g., as included in Eqs. 17, 19 and 23), and an integral of a portion of a dilution curve (e.g., as included in Eq. 23).

Step1218may include system300determining one or more physiological parameters of the subject based at least in part on the one or more characteristics of step1216. Physiological parameters may include hemoglobin, blood oxygen saturation, CO, ITBV, ITCV, GEDV, PCV, EVLW, any other suitable hemodynamic parameters, any other suitable physiological parameters, any physiological modulations thereof, or any combination thereof. For example, processor312may calculate one or more physiological parameters based on suitable characteristics using any or all of Eqs. 14-20 and 23-30.

In the foregoing flowcharts, an acoustic pressure signal having one or more indicators is detected. In some embodiments, the system (e.g., system300) may continuously detect the acoustic pressure signal and continuously analyze the photoacoustic signal to identify the one or more indicator responses. In some embodiments, the system may only detect and analyze the acoustic pressure signal in response to a user input. For example, the user may press a key on the monitor shortly before the one or more indicators are injected. In some embodiments, the system may be communicatively coupled to the injection apparatus and therefore may automatically know when the one or more indicators are injected and when to detect the acoustic pressure signal. For example, the injection apparatus may transmit a signal to the system each time there is an injection. As another example, the system may control the injection apparatus and instruct the injection apparatus when to perform an injection.