Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/02—Detecting, measuring or recording for evaluating the cardiovascular system, e.g. pulse, heart rate, blood pressure or blood flow
  • A61B5/026—Measuring blood flow
  • A61B5/029—Measuring blood output from the heart, e.g. minute volume
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/02—Detecting, measuring or recording for evaluating the cardiovascular system, e.g. pulse, heart rate, blood pressure or blood flow
  • A61B5/026—Measuring blood flow
  • A61B5/0261—Measuring blood flow using optical means, e.g. infrared light
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/02—Detecting, measuring or recording for evaluating the cardiovascular system, e.g. pulse, heart rate, blood pressure or blood flow
  • A61B5/026—Measuring blood flow
  • A61B5/0275—Measuring blood flow using tracers, e.g. dye dilution

Definitions

• This invention pertains to the detection of parameters of cardiovascular system of a subject.
• Cardiac output is a central part of the hemodynamic assessment in patients having heart disease, acute hemodynamic compromise or undergoing cardiac surgery, for example. Cardiac output is a measure of the heart's effectiveness at circulating blood throughout the circulatory system. Specifically, cardiac output (measured in L/min) is the volume of blood expelled by the heart per beat (stroke volume) multiplied by the heart rate. An abnormal cardiac output is at least one indicator of cardiovascular disease.
• thermodilution technique The current standard method for measuring cardiac output is the thermodilution technique (Darovic, G.O. Hemodynamic monitoring: invasive and noninvasive clinical application. 2nd Ed. W.B. Saunders, 1995).
• the technique involves injecting a thermal indicator (cold or heat) into the right side of the heart and detecting a change in temperature caused as the indicator flows into the pulmonary artery.
• thermodilution technique involves inserting a flow-directed balloon catheter (such as a Swan-Ganz catheter) into a central vein (basilic, internal jugular or subclavian) and guiding it through the right atrium and ventricle to the pulmonary artery.
• the balloon catheter is typically equipped with a thermistor near its tip for detecting changes in blood temperature.
• a rapid injection of a bolus of chilled glucose solution (through a port in the catheter located in the vena cava near the right atrium) results in a temperature change in the pulmonary artery detected with the thermistor.
• the measured temperature change is analyzed with an external electronic device to compute the cardiac output.
• the algorithm implemented in this computation is typically a variant of the Stewart-Hamilton technique and is based on the theory of indicator mixing in stirred flowing media (Geddes LA, Cardiovascular devices and measurements. John Wiley & Sons. 1984).
• thermodilution measurements of cardiac output are disadvantageous for several reasons.
• thermodilution measurements of the cardiac output are too invasive to be performed in small children and infants.
• Another method used for measuring cardiac output is the dye indicator dilution technique.
• a known volume and concentration of indicator is injected into the circulatory flow.
• a blood sample is removed and the concentration of the indicator determined.
• the indicator concentration typically peaks rapidly due to first pass mixing of the indicator and then decreases rapidly as mixing proceeds in the total blood volume (-10 seconds; first pass concentration curve).
• indicator concentration slowly diminishes as the indicator is metabolized and removed from the circulatory system by the liver and/or kidneys (time depending upon the indicator used).
• a concentration curve can be developed reflecting the concentration of the indicator over time.
• the theory of indicator dilution predicts that the area under the first pass concentration curve is inversely proportional to the cardiac output.
• indicator dilution techniques have involved injecting a bolus of inert dye (such as indocyanine green) into a vein and removing blood samples to detect the concentration of dye in the blood over time.
• a bolus of inert dye such as indocyanine green
• blood samples are withdrawn from a peripheral artery at a constant rate with a pump.
• the blood samples are passed into an optical sensing cell in which the concentration of dye in the blood is measured.
• the measurement of dye concentration is based on changes in optical absorbance of the blood sample at several wavelengths.
• a variation on the dye-dilution technique is implemented in the Nihon Kohden pulse dye densitometer.
• blood absorbance changes are detected through the skin with an optical probe (Nihon Kohden website: http://kohden.co.jp/intl/ppms-ddg2001.html) using a variation of pulse oximetry principles.
• This variation improves on the prior technique by eliminating the necessity for repeated blood withdrawal.
• this technique remains limited by the difficulty of separating absorbance changes due to the dye concentration changes from absorbance changes due to changes in blood oxygen saturation or blood content in the volume of tissue interrogated by the optical probe.
• Blood volume measures the amount of blood present in the cardiovascular system. Blood volume is also a diagnostic measure which is relevant to assessing the health of a patient. In many situations, such as during or after surgery, traumatic accident or in disease states, it is desirable to restore a patient's blood volume to normal as quickly as possible. Blood volume has typically been measured indirectly by evaluating multiple parameters (such as blood pressure, hematocrit, etc.). However, these measures are not as accurate or reliable as direct methods of measuring blood volume.
• Blood volume has been directly measured using indicator dilution techniques (Geddes, supra). Briefly, a known amount of an indicator is injected into the circulatory system. After injection, a period of time is allowed to pass such that the indicator is distributed throughout the blood, but without clearance of the indicator from the body. After the equilibration period, a blood sample is drawn which contains the indicator diluted within the blood. The blood volume can then be calculated by dividing the amount of indicator injected by the concentration of indicator in the blood sample (for a more detailed description see U.S. Pat. 6,299,583 incorporated by reference).
• the dilution techniques for determining blood volume are disadvantageous because they are limited to infrequent measurement due to the use of indicators that clear slowly from the blood.
• cardiovascular parameters such as cardiac output and blood volume.
• the present invention is directed to methods and systems for assessing cardiovascular parameters within the circulatory system using indicator dilution techniques.
• Cardiovascular parameters are any measures of the function or health of a subjects cardiovascular system.
• a non-invasive method for determining cardiovascular parameters is described.
• a non-invasive fluorescent dye indicator dilution method is used to evaluate cardiovascular parameters.
• the method is minimally invasive requiring only a single peripheral, intravenous line for indicator injection into the circulatory system of the patient. Further, it is preferable that only a single blood draw from the circulatory system of the patient be taken for calibration of the system, if necessary.
• cardiovascular parameters may be evaluated by measuring physiological parameters relevant to assessing the function of the heart and circulatory system. Such parameters include, but are not limited to cardiac output and blood volume.
• Such minimally invasive procedures are advantageous over other methods of evaluating the cardiovascular system.
• Second, such practical and minimally invasive procedures are within the technical ability of most doctors and nursing staff, thus, specialized training is not required.
• Third, this minimally invasive methods may be performed at a patient's bedside or on an out-patient basis.
• Third, methods may be used on a broader patient population, including patients whose low risk factors may not justify the use of central arterial measurements of cardiovascular parameters.
• these methods may be utilized to evaluate the cardiovascular parameters of a patient at a given moment in time, or repeatedly over a selected period of time.
• the dosages of indicators and other aspects of the method can be selected such that rapid, serial measurements of cardiovascular parameters may be made.
• These methods can be well suited to monitoring patients having cardiac insufficiency or being exposed to pharmacological intervention over time.
• the non-invasive methods may be used to evaluate a patient's cardiovascular parameters in a basal state and when the patient is exposed to conditions which may alter some cardiovascular parameters. Such conditions may include, but are not limited to changes in physical or emotional conditions, exposure to biologically active agents or surgery.
• modifications of the method may be undertaken to improve the measurement of cardiovascular parameters.
• modifications may include altering the placement of a photodetector relative to the patient or increasing blood flow to the detection area of the patient's body.
• the non-invasive method of assessing cardiovascular parameters utilizes detection of indicator emission, that is fluorescence, as opposed to indicator absorption.
• indicator emission may be detected in a transmission mode and/or reflection mode such that a broader range of patient tissues may serve as detection sites for evaluating cardiovascular parameters, as compared to other methods.
• measurements of indicator emission are more accurate than measurements obtained by other methods, as indicator emission can be detected directly and independent of the absorption properties of whole blood.
• a system for the non-invasive or minimally invasive assessment of cardiovascular parameters may include an illumination source for exciting the indicator, a photodetector for sensing emission of electromagnetic radiation from the indicator and a computing system for receiving emission data, tracking data over time and calculating cardiovascular parameters using the data.
• the methods and system described herein may be used to assess cardiovascular parameters of a variety of subjects.
• the methodology can be modified to examine animals or animal models of cardiovascular disease, such as cardiomyopathies.
• the methodology of the present invention is advantageous for studying animals, such as transgenic rodents whose small size prohibits the use of current methods using invasive procedures.
• the present invention is also advantageous in not requiring anesthesia which can affect cardiac output measurements.
• the methodology can be modified for clinical application to human patients.
• the present invention may be used on all human subjects, including adults, juveniles, children and neonates.
• the present invention is especially well suited for application to children, and particularly neonates.
• the present technique is advantageous over other methods at least in that it is not limited in application by the size constraints of the miniaturized vasculature relative to adult subjects.
• Fig. 1 is a diagrammatic depiction of an example of one embodiment of the system of the present invention.
• Fig. 2 is a fluorescence intensity curve generated using one embodiment of the present invention.
• FIG. 3 is a diagrammatic depiction of an example of one embodiment of the present invention having a photodetector positioned on the ear skin surface.
• Fig. 4 is a diagrammatic depiction of a user interface of a cardiac output computer program useful in conjunction with this invention.
• the interface may depict information regarding values measured and converted from fluorescence to concentration, and parameters of the curve fit for the values obtained using the method or system.
• Fig. 5 is a depiction of a decay of fluorescence intensity curve as a function of time following injection of a 1 mg dose of ICG.
• Fig. 6 is a depiction of a calibration curve for blood ICG concentration as a function of transcutaneous ICG fluorescence.
• Fig. 7 is a depiction of cardiac output and aortic velocity measurements during one representative experiment.
• Fig. 8 is a depiction of cardiac output measurements derived from sites on the ear surface and on the exposed femoral artery during one experiment.
• Fig. 9 is a flow chart depicting one method of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
• the method and system of the present invention are for the evaluation of cardiovascular parameters of a subject using an indicator dilution technique.
• the method of this invention generally involves the injection of a selected amount of indicator into the bloodstream of the subject (Fig. 9).
• the indicator is illuminated using a first wavelength of excitation light selected cause the indicator to fluoresce and emit a second wavelength of light.
• a photodetector is placed near the subject for the detection of the intensity of the second wavelength of emitted light which is proportional to the concentration of the indicator circulating within the circulatory system. The photodetector transmits this intensity information to a computing system, which records and preferably maps the intensity curve of the indicator detected over time.
• the indicator concentration values increase to a peak rapidly after injection of the indicator. Then, the concentration values decrease rapidly, then more steadily as the indicator is diffused throughout the body and metabolized over time.
• a microprocessor driven computation then can calculate from the concentration curve, the patient's cardiac output and/or blood volume values. Additionally, values can be generalized repeatedly using this method, at intervals of about every 1-2 minutes.
• the indicators useful in this in invention are preferably inert and biocompatible in that they do not alter cardiovascular parameters, such as heart rate. Further, the indicator is preferably a substance that once injected, does not diffuse out of the vasculature of the cardiovascular system. Also, the indicator is preferably selected to be one which is metabolized within the body at a rate such that repeated measures using this method may be conducted at intervals of about 1-2 minutes. It is also desirable that the background levels of circulating indicator be cleared between intervals, although measurements may be taken when background levels are not zero. Finally, the indicator can be selected to be detectable by the photodetector system selected. [0037] In one embodiment, a non-invasive dye indicator dilution method may be used to evaluate cardiovascular function function.
• the dye indicator is fluorescent having an excitation wavelength and an emission wavelength in the near infrared spectrum, preferably about 750 nm to about 1000 nm, and more preferably about 750 nm to about 850nm.
• the indicator used is indocyanine green (ICG; purchased for example from Akorn, Decatur or Sigma, St. Louis, MO; commercial names: Diagnogreen ⁇ , ICGreen ⁇ , Infracyanine ⁇ , Pulsion ⁇ ).
• ICG has been previously been used to study the microcirculation of the eye, the digestive system and liver function (Desteil, T., J. M. Devoisselle, and S. Mordon. Fluorescence properties and metabolic features of indocyanine green (ICG) as related to angiography. Surv Ophthalmol 45, 15-27, 2000). ICG fluoresces intensely when excited at near infrared wavelengths.
• ICG in blood plasma has a peak fluorescence of about 810 to 830 ⁇ 10 nm with an optimal excitation wavelength of about 780 nm (Hollins, supra; Dorshow, supra).
• ICG may be advantageous for use in this invention in remains intravascular because it is protein bound. ICG breaks down quickly in aqueous solution, and metabolites are not fluorescent, minimizing recirculation artifact and reducing the time period between which measurements can be made.
• the wavelength of emission of ICG is also within the optical window (750-1000 nm) in which living tissues are relatively transparent to light.
• Fluorescein in blood plasma has a peak fluorescence of about 518 ⁇ 10 nm with an optimal excitation wavelength of about 488 nm (Hollins, supra; Dorshow, supra).
• Rhodamine in blood plasma has a peak fluorescence of about 640 ⁇ 10 nm with an optimal excitation wavelength of about 510 nm.
• Indicator dosage The dosage of indicator is preferably selected such that an amount used is non-toxic to the subject, is present in the circulatory system for an amount of time adequate to establish an indicator concentration curve, but is metabolized in an amount of time such that repeated measurements can be conducted at intervals of about 1-2 minutes apart. Further, the indicator is preferably administered to the subject by injection into a vein.
• a dosage of about 0.005 mg/kg is preferable in that this dose leads to peak blood concentrations below 0.001 mg/ml.
• the measurement of the circulating indicator concentration is linearly related to the intensity of the emission wavelength detected.
• Dye dilution techniques have been applied in humans using indocyanine green as a dye.
• Living tissues of humans and animals are relatively transparent for near infrared wavelengths of light which allows for transmission of light across several mm of tissue and transcutaneous detection of the fluorescence emission of ICG.
• the use of dosages in the ranges stated above is additionally suitable for human use.
• Illumination Source The illumination sources useful in this invention are preferably selected to produce an excitation wavelength in the near infrared spectrum, preferably about 750nm to about 1000nm, and more preferably about 750 to about 850nm. This selection is advantageous in at least that most tissues are relatively transparent to wavelengths in this range.
• an indicator in the blood stream is excitable transcutaneously and indicator emission detected transcutaneously. Further, blood constituents do not fluoresce at these wavelengths, thus there is no other contributor to the measured fluorescence emission signal. Therefore, this method is advantageous in that at least the sensitivity of detection in this method is improved over other methods which measure indicator absorption, as opposed to emission.
• illumination sources which may be used in this invention include, but are not limited to lamps, light emitting diodes (LEDs), lasers or diode lasers.
• modifications to the system or illumination source may be altered to further to maximize the sensitivity or accuracy of the system for measuring indicator concentration.
• the excitation wavelength produced by the illumination source will be steady.
• the excitation wavelength produced by the illumination source can be modulated using a lock-in detection technique (Stanford Research Systems website: http://www.srsys.com/html/scientific.html, herein incorporated by reference).
• the illumination source may emit light in a periodic varying pattern having a fixed frequency and the emission recorded by the photodetector read at the same frequency to improve the accuracy of the readings.
• the periodic varying pattern and frequency can be selected to improve noise-rejection and should be selected to be compatible with the rest of the instrumentation (such as the light source and photodetector).
• the illumination source may be adapted to target a detection area of the subject's tissue from which emission wavelength intensity will be recorded.
• the illumination source may comprise an optic fiber for directing the excitation light to the detection area.
• the illumination source may comprise mirrors, filters and/or lenses for directing the excitation light to the detection area.
• the target detection area is that location of a subject's tissue which is exposed to the excitation wavelength of light and/or from which the emission wavelength light intensity output will be measured.
• the method of detection is non-invasive.
• a detection area is selected such that a photodetector can be placed in proximity to the detection area and emission wavelength light intensity measured.
• the photodetector is placed transdermally to at least one blood vessel, but more preferably a highly vascularized tissue area.
• detection areas include, but are not limited to fingers, auricles of the ears, nostrils and areas having non-kertanized epithelium (such as the nasal mucosa or inner cheek).
• the method of detection is minimally invasive.
• the photodetector can be placed subdermally (within or beneath the epidermis) and proximate to at least one blood vessel or in a perivascular position.
• the method of detection is invasive.
• the photodetector can be placed intravascularly to detect indicator emission, such as within an artery.
• the detection area may be arterialized during indicator emission detection.
• conditions resulting in detection area arterialization include, but are not limited to heating or exposure to biologically active agents which effect sympathetic system blockade (such as lidocaine).
• Photodetector The detection of indicator emission can be achieved by optical methods known in the art. Measurement of indicator concentration can be made by administering a detectable amount of a dye indicator and using a non- invasive, minimally invasive or intravascular procedures, preferably for continuous detection. Preferably, the photodetector is positioned proximately to the detection area of the subject. The photodetector may be positioned distally or proximately to the site of the illumination source.
• fluorescent light is emitted from the indicator with the same intensity for all directions (isotropy). Consequently, the emission of the dye can be detected both in "transmission mode" when the excitation light and the photodetector are on opposite sides of the illuminated tissue or in "reflection mode” when the excitation and the photodetector are on the same side of the tissue. This is advantageous over other methods at least in that the excitation light and emitted light can be input and detected from any site on the body surface and not only optically thin structures.
• Photodetectors which are useful in this invention are those selected to detect the quantities and light wavelengths (electromagnetic radiation) emitted from the selected indicator. Photodectors having sensitivity to various ranges of wavelengths of light are well known in the art.
• modifications to the system are made to further enhance the sensitivity or accuracy of the system for measuring indicator concentration.
• the detection system can incorporate a lock-in detection technique.
• a lock-in amplifier can be used to modulate the source of light emission at a specific frequency and to amplify the output of the photodetector only at that frequency. This feature is advantageous in at least that it further improves the sensitivity of the system by reducing signal to noise and allows detection of very small amounts of fluorescence emission.
• a photomultiplier tube is utilized as or operably connected with another photodetector to enhance the sensitivity of the system.
• additional features such as filters, may be utilized to minimize the background of the emission signals detected. For example, a filter may be selected which corresponds to the peak wavelength range or around the peak wavelength range of the indicator emission.
• the detected electromagnetic radiation is converted into electrical signals by a photoelectric transducing device which is integral to or independent of the photodetector. These electrical signals are transmitted to a microprocessor which records the intensity of the indicator emission as correlated to the electrical signal for any one time point or over time. (For an example of such a device see U.S. Pat. 5766125, herein incorporated by reference.)
• the method is further minimally invasive in requiring only a single peripheral blood draw from the circulatory system be taken for calibration purposes.
• indicator concentration is preferably being measured continuously and non-invasively using a photodetector.
• one blood sample from the subject may be withdrawn for calibration of the actual levels of circulating indicator with the indicator levels detected by the system.
• a blood sample may be drawn from the subject at a selected time period after the administration of the indicator into the blood stream.
• the blood sample may then be evaluated for the concentration of indicator present by comparison with a calibration panel of samples having known indicator concentrations. Evaluation of the indicator concentration may be made spectrophotometrically or by any other means known in the art.
• the concentration-fluorescence curve is linear and it crosses the origin of the axes, that is the fluorescence is zero when the concentration is zero. Therefore a single measurement point suffices to define the calibration curve, and no further blood samples need be taken.
• the fluorescence of some indicators does not substantially vary from patient to patient and that the skin characteristics are relatively constant for large classes of patients.
• the fluorescence in the blood of the patient measured from a given site on the body surface can be converted in an absolute measurement of ICG concentration, once the curve of indicator concentration vs. fluorescence is defined for that site of measurement.
• This method and system may be utilized to measure several cardiovascular parameters. Once the system has been calibrated to the subject (where necessary) and the indicator emission detected and recorded over time, the computing system may be used to calculate cardiovascular parameters including cardiac output and blood volume.
• Cardiac output calculations In some embodiments, the cardiac output is calculated using equations which inversely correlate the area under the first pass indicator emission curve (magnitude of intensity curve) with cardiac output. Cardiac output is typically expressed as averages (L/min). The general methods have been previously described (Geddes, supra, herein incorporated by reference).
• the descending limb of the curve is plotted semilogrithmically to identify the end of the first pass of indicator. For example, the descending limb of the curve may be extrapolated down to 1% of the maximum height of the curve. The curve can then be completed by plotting values for times preceding the end time. Finally, the area under this corrected curve is established and divided by the length (time) to render a mean height. This mean height is converted to mean concentration after calibration of the detector. The narrower the curve, the higher the cardiac output; the wider the curve, the lower the cardiac output. Several variations of this calculation method are found, including methods that fit a model equation to the ascending and descending portions of the indicator concentration curve.
• the curve may not return to zero after the end of the first pass due to a residual concentration of indicator recirculating in the system. Subsequent calculations of cardiac output from the curve may then account for this recirculation artifact by correcting for the background emission, prior to calculating the area under the curve.
• This system is advantageous over the known methods in that at least the emission magnitude of intensity is being directly measured and no measurement of hemoglobin nor accommodation for hemoglobin absorbance or need be made.
• blood volume calculations may be measured independently or in addition to the cardiac output. General methods of measuring blood volume are known in the art.
• circulating blood volume may be measured using a low dose of indicator which is allowed to mix within the circulatory system for a period of time selected for adequate mixing, but inadequate or the indicator to be completely metabolized. The circulating blood volume may then be calculated by back extrapolating to the instant of injection the slow metabolic disappearance phase of the concentration curve detected over time (Bloomfield, D.A. Dye curves: The theory and practice of indicator dilution. University Park Press, 1974).
• Alternative methods of calculation include, but are not limited to those described in U.S. Pat Nos. 5,999,841 , 6,230,035 or 5,776,125, herein incorporated by reference.
• This method and system may be used to examine the general cardiovascular health of a subject.
• the method may be undertaken one time, such that one cardiac output and or blood volume measurement would be obtained.
• the method may be undertaken to obtain repeated or continuous measurements of cardiovascular parameters over time. Further, repeated measures may be taken in conditions where the cardiovascular system is challenged such that a subject's basal and challenged cardiovascular parameters can be compared.
• Challenges which may be utilized to alter the cardiovascular system include, but are not limited to exercise, treatment with biologically active agent which alter heart function (such as epinephrine), parasympathetic stimulation (such as vagal stimulation), injection of liquids increasing blood volume (such as colloidal plasma substitutes) or exposure to enhanced levels of respiratory gases.
• FIG. 1 A schematic of one embodiment of a system 10 useful in the present invention is shown in FIG. 1.
• the system comprises an illumination source 12 here a 775 nm laser selected to emit a excitation wavelength of light 14 which maximally excites ICG, the indicator selected.
• the illumination source 12 is positioned proximately to the subject 16, such that the excitation wavelength of light 14 shines transdermally onto the indicator circulating in the bloodstream.
• the system also comprises a photodetector 20 placed in proximity to the subject's skin surface 18 for detection of the indicator emission wavelength 22.
• a filter 24 may be used for isolating the peak wavelength at which the indicator emits, being about 830 nm.
• the photodetector 20 is operably connected to a microprocessor 26 for storing the electronic signals transmitted from the photodetector 20 over time, and generating the indicator concentration curve (FIG. 2).
• the microprocessor 26 may regulate the illumination source to coordinate the excitation and detection of emission from the indicator, for example using a modulation technique.
• the microprocessor may also comprise software programs for analyzing the output obtained from the detector 20 such that the information could be converted into values of cardiac output or blood volume, for example and/or displayed in the form of a user interface.
• a non-invasive indicator detection system 10 of the invention was used to repeatedly monitor cardiac output.
• a fiber optic 12b transmitted light from illumination source 12a to the subject's skin 18.
• a second fiber optic 20b, positioned near the skin 18 transmitted the emitted light to a photodetector 20.
• the indicator was intravenously injected.
• a body portion which included blood vessels near the surface of the skin, was irradiated with a laser.
• a characteristic fluorescence intensity/ concentration curve was obtained upon excitation with laser light at about 775 nm and detection of the fluorescence at about 830 nm. From this information cardiac output and blood volume for the subject was calculated.
• the system used for this method may comprise a variety of additional components for accomplishing the aims of this invention.
• non- invasive detection is described for monitoring of indicators within the circulatory system of the patient. Modifications of the detectors to accommodate to various regions of the patient's body or to provide thermal, electrical or chemical stimulation to the body are envisioned within the scope of this invention.
• calibration of the system may be automated by a computing system, such that a blood sample is drawn from the patient after administration of the indicator, concentration detected and compared with known standards and/or the emission curve.
• software may be used in conjunction with the microprocessor to aid in altering parameters of any of the components of the system or effectuating the calculations of the cardiovascular parameters being measured. Further, software may be used to display these results to a user by way of a digital display, personal computer or the like.
• the fluorescence intensity trace (indicator concentration recording) was measured transcutaneously at the level of the rat's ear using reflection mode detection of emission (FIG.2).
• the initial rapid rise and rapid decay segments of the fluorescence intensity trace represent the first pass of the fluorescent indicator in the arterial vasculature of the animal. Such a waveform is characteristic of indicator dilution techniques.
• This portion of the recording is analyzed with one of several known algorithms (i.e. Stewart Hamilton technique) to compute the "area under the curve" of the fluorescence intensity trace while excluding the recirculation artifact.
• Indicator concentration C(t) was computed from the fluorescence y(t) using one of two calibration methods.
• Transcutaneous in vivo fluorescence was calibrated with respect to absolute blood concentrations of ICG, using a few blood samples withdrawn from a peripheral artery after bolus dye injection of ICG. The blood samples were placed in a fluorescence cell and inserted in a tabletop fluorometer for measurement of their fluorescence emission. The fluorescence readings were converted into ICG concentrations using a standard calibration curve established by measuring with the tabletop fluorometer the fluorescence of blood samples containing known concentrations of ICG.
• An alternative calibration procedure which avoids blood loss uses a syringe outfitted with a light excitation - fluorescence detection assembly.
• the syringe assembly was calibrated once before the cardiac output measurements by measuring ICG fluorescence in the syringe for different concentrations of ICG dye in blood contained in the barrel of the syringe.
• a blood sample was pulled in the syringe during the slow decay phase of the fluorescence trace, that is the phase during which recirculating dye is homogeneously mixed in the whole blood volume and is being slowly metabolized.
• the fluorescence of that sample was converted to concentration using the syringe calibration curve and then related to the transcutaneous fluorescence reading. So long as the ICG concentrations in blood remain sufficiently low ( ⁇ 0.001 mg/ml), a linear relationship can be used to relate fluorescence intensity to concentration.
• Either one of these calibration methods can be developed on a reference group of subjects to produce a calibration nomogram that would serve for all other subjects with similar physical characteristics (i.e., adults, small children etc.). This is advantageous over prior methods at least in that an additional independent measurement of the blood hemoglobin concentration for computation of the light absorption due to hemoglobin is not required.
• a sample method and system for measuring cardiac output and blood volume Experiments have been performed in New Zealand White rabbits (2.8 - 3.5 Kg) anesthetized with halothane and artificially ventilated with an oxygen-enriched gas mixture (Fio2 ⁇ 0.4) to achieve a Sao2 above 99% and an end-tidal C02 between 28 and 32 mm Hg (FIG. 4).
• the left femoral artery was cannulated for measurement of the arterial blood pressure throughout the procedure.
• a small catheter was positioned in the left brachial vein to inject the indicator, ICG. Body temperature was maintained with a heat lamp.
• Excitation of the ICG fluorescence was achieved with a 780 nm laser (LD head: Microlaser systems SRT-F780S-12) whose output was sinusoidally modulated at 2.8 KHz by modulation of the diode current at the level of the laser diode driver diode (LD Driver: Microlaser Systems CP 200) and operably connected to a thermoelectric controller (Microlaser Systems: CT15W).
• LD head Microlaser systems SRT-F780S-12
• LD Driver Microlaser Systems CP 200
• CT15W thermoelectric controller
• the near- infrared light output was forwarded to the animal preparation with a fiber optic bundle terminated by a waterproof excitation-detection probe.
• the fluorescence emitted by the dye in the subcutaneous vasculature was detected by the probe and directed to a 830 nm interferential filter (Optosigma 079-2230) which passed the fluorescence emission at 830 ⁇ 10 nm and rejected the retro-reflected excitation light at 780 nm.
• the fluorescence intensity was measured with a photomultiplier tube (PMT; such as Hamamatsu H7732-10MOD) connected to a lock-in amplifier (Stanford Research SR 510) for phase-sensitive detection of the fluorescence emission at the reference frequency of the modulated excitation light.
• the output of the lock-in amplifier was displayed on a digital storage oscilloscope and transferred to a computer for storage and analysis.
• the model fit (white trace) is performed from the time point for which the fluorescent ICG is first detected to a point on the decaying portion of the trace that precedes the appearance of recirculating indicator (identified from the characteristic hump after the initial peak in the experimental trace).
• the model equation is used to estimate the "area under the curve" for the indicator dilution trace.
• the theory of indicator dilution technique predicts that the area under the concentration curve is inversely proportional to the cardiac output (Q): m/ ⁇ o C ⁇ dt.
• m is the mass amount of injected indicator and C(t) is the concentration of indicator in the arterial blood at time t.
• the program also fits the slow decaying phase of the measurement to a single exponential to derive the circulating blood volume from the value of the exponential fit at the time of injection.
• the estimated cardiac output is 509 ml/min and the circulating blood volume is 184 ml, in the expected range for a 3 Kg rabbit.
• This computer program is advantageous in that it improved the ability to verify that the experimental measurements are proceeding as planned or to correct without delay any measurement error or experimental malfunction.
• Indicator dosage In this experiment is was found that a dose of about 0.015 mg injected ICG was optimal in this animal to allow for detection of an intense fluorescence dilution curve and at the same time rapid metabolic disposal of the ICG. Further, with this small dose cardiac function measurements could be performed at about intervals of less than about every 4 minutes.
• Detector placement Defined fluorescence readings were obtained by positioning the detection probe above the skin surface proximate to an artery or above tissue, such as the ear or the paw arterialized by local heating.
• FIG. 5 shows the transcutaneous ear fluorescence intensity (in V) as a function of time (in s) after the high dose (1 mg) ICG injection during the calibration sequence.
• FIG. 5 shows the characteristic first order exponential decay of ICG in blood as the dye is being metabolized.
• FIG. 6 shows the ICG concentration (in mg/ml) as a function of the in vivo fluorescence for the same example and the same time points. For the range of concentrations used in these studies, ICG concentration and transcutaneous fluorescence were linearly related. The calibration line passes through the origin of the axes since there is no measured fluorescence when the ICG blood concentration is 0.
• the experimental preparation described in the preceding section includes two measurement sites for the fluorescence dilution traces: a transcutaneous site at the level of the ear central bundle of blood vessels and the exposed femoral artery.
• the ear vasculature is arterialized by local heating.
• the cardiac output estimates obtained from the peripheral non-invasive (transcutaneous) measurement site were compared with estimates obtained by interrogating a major artery.
• FIG. 8 shows the time course of the cardiac output measurements obtained from the ear site and from the exposed femoral artery in a representative experiment during control conditions (C), intense then mild vagal stimulation (S,l and S,M), and post-stimulation hyperemia (H). Near-identical estimates of the cardiac output are obtained from the two sites during all phases of the study.
• two illumination + detection fiber optic probes were used: one probe was placed on or above the ear middle vessel bundle and the other probe was placed in proximity to the dissected left femoral artery. Local heating to 44 degrees centigrade arterialized the ear vasculature.
• vagal stimulation which reduces the cardiac output
• saline infusion which increases the circulating volume and cardiac output.
• the right vagal nerve was dissected to position a stimulating electrode. Stimulation of the distal vagus results in a more or less intense decrease of the heart rate that depends on the stimulation frequency and voltage (1 ms pulses, 3 to 6 V, 10 to 30 Hz).
• the cardiac output and aortic flow velocity also decrease during vagal stimulation even though less markedly than the heart rate decreases because the stroke volume increases.
• Saline infusion at a rate of 15-20 ml/min markedly increases the cardiac output.
• FIG. 7 shows the time course of the cardiac output and aortic velocity measurements in one experiment including control conditions (C), intense then mild vagal stimulation (S,l and S,M), and saline infusion (I).

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• 2002
  • 2002-05-21 US US10/153,387 patent/US6757554B2/en not_active Expired - Lifetime
  • 2002-05-22 JP JP2002590811A patent/JP2004528917A/ja active Pending
  • 2002-05-22 WO PCT/US2002/016197 patent/WO2002094085A2/en not_active Ceased
  • 2002-05-22 AU AU2002310038A patent/AU2002310038A1/en not_active Abandoned
• 2004
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• 2009
  • 2009-09-22 US US12/564,769 patent/US20100022898A1/en not_active Abandoned

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