Patent Abstract:
a method for obtaining diagnostic information relating to the lungs of a subject includes directing into tissue of the lungs of the subject light of a first wavelength and detecting part of the light that has passed primarily through microcirculatory tissue of the lungs and generating a signal which is a function of intensity of the detected light . the signal is then processed to derive a ppg curve for pulmonary microcirculatory arteries . the method is implemented using various locations for a light source and a detector , including various combinations of positioning on the thoracic wall , insertion into the esophagus , and in some cases , insertion of a probe through the thoracic wall to a position adjacent to the pulmonary pleura . use of two different wavelengths allows derivation of mixed venous blood oxygen saturation .

Detailed Description:
in the current invention , a method is presented for the measurement of the pulmonary ppg signal , presenting the oscillations at the heart rate of the transmission of light through a region in the microcirculation of the pulmonary system . the pulmonary ppg signal can be utilized for the assessment of the cardiopulmonary circulatory system . it can also be used for the determination of the oxygen saturation in the pulmonary arteries , which is actually the oxygen saturation in mixed venous blood . the latter parameter enables the noninvasive ( or minimally invasive ) determination of cardiac output by the fick method . the conventional ppg technique is based on measurements in the arterial system of the systemic circulation conducting blood from the left ventricle to the different organs of the body , except the lungs . the blood volume in the systemic arteries increases by the blood which is ejected from the left ventricle during systole and decreases by the relatively constant blood flow through the capillaries to the veins . the lungs are supplied with venous blood from the right ventricle through the pulmonary artery and , similarly to the systemic circulation , the pulmonary arterial blood volume increases during systole and decreases during diastole . pulmonary blood volume increase during systole has been demonstrated in several prior studies , using several techniques , including n 2 o body plethysmography ( karatzas 1969 ), analysis of pulmonary arterial pressure curves ( her 1987 ), ecg - gated radionuclide scintigraphy ( nitzan 1992 , 1994 ), and cardiovascular magnetic resonance ( ugander 2009 ). one of these techniques ( her 1987 ) is invasive ; the other techniques require either special training of the examinees ( karatzas 1969 ), or a sophisticated imaging device ( nitzan 1992 , 1994 , ugander 2009 ). the present invention provides a pulmonary ppg method , in which the pulmonary blood volume increase during systole is detected by the resultant decrease in light transmission through the lungs — the method requires that light emitted from a light - source reaches the lungs and that the light transmitted through the lung tissue is detected . the light transmitted through the lung tissue oscillates at the heart rate , like the systemic ppg , and like the latter the pulmonary ppg is related to the blood volume change in the pulmonary arteries through equation 1 . like the systemic circulation the systolic blood volume change in the pulmonary arteries is related to the stroke volume and to the arterial compliance and small arteries resistance in the pulmonary system . hence the pulmonary ppg signal can provide information on these cardiovascular parameters in the cardio - pulmonary system . the present invention relates generically to any and all techniques in which a pulmonary ppg signal is derived from measurements of light transmission through microcirculatory tissue of the lungs , whether by non - invasive , minimally invasive or fully invasive procedures . while it is simple to achieve the ppg signal in the systemic circulation , because of the proximity of the tissue under examination to the skin , the achievement of the pulmonary ppg is significantly more difficult , since the lungs lay inside the thoracic wall . by way of exemplary but non - limiting preferred examples , the present invention will be exemplified herein with reference to four non - invasive or minimally invasive techniques that enable the measurement of the light transmitted through the pulmonary tissue , each of which is believed to be of value in its own right : 1 . a light source and a detector are applied to the thoracic wall of a patient and the detector measures the light which was emitted from the light source and transmitted through the thorax . see fig4 and 5 . the light source and the detector are separated by at least 20 mm so that the region of illumination overlaps a portion of the pulmonary microcirculation beneath the ppg probe . the technique is especially suitable for infants , whose thoracic wall is relatively thin . 2 . a light source and a detector are inserted into the esophagus and brought into close contact with its wall , in a site where the pulmonary tissue is in tight proximity to the esophageal wall , and the detector measures the light which was emitted from the light source and transmitted through the esophageal wall and part of the lungs . see fig6 . the light source and the detector are separated by at least 10 mm so that the region of illumination overlaps a portion of the pulmonary microcirculation in the neighborhood of the ppg probe . 3 . a light source is applied to the thoracic wall of a patient and a detector is inserted into the esophagus and brought into close contact with its wall in a site where the pulmonary tissue is in tight proximity to the esophageal wall . the detector measures the light which was emitted from the light source and transmitted through the thoracic wall and the esophageal wall and through part of the lungs . by suitable choice of the locations of the light - source and the detector the detected light is mainly affected by absorption in the pulmonary microcirculation and the contribution of the attenuation by other organs can be neglected . 4 . a catheter with two optic fibers is inserted through the thoracic wall and brought into adjacent relation ( i . e ., with minimal intervening tissue ) with the pulmonary pleura , which covers the lung tissue . the light delivering element and light receiving element in the probe ( catheter ) are typically brought into contact with the pulmonary pleura or preferably into close proximity to the pulmonary pleura , without contacting it , in order to avoid harm to the vulnerable organ . one of the optic fibers conveys light from a light source into the lung tissue and the other one conveys light which was scattered by the tissue to a detector . both the light source and the detector are located out of the body . in the first three above - mentioned pulmonary ppg techniques , referred to herein as “ remote ppg techniques ”, the light , in its way to the pulmonary tissue , also passes through the thoracic wall or the esophageal wall , which are supplied by the systemic circulation . nevertheless , the main contribution to the ppg signal is by the pulmonary circulation , because the stroke volumes from the right and left ventricles are equal while the former is distributed in the relatively small pulmonary tissue volume and the latter is distributed in the relatively high systemic tissue volume . the relationship between the increase in pulmonary blood volume during systole and the right stroke volume ( which is the blood volume ejected from the right ventricle during systole ) was determined in several studies : it is 50 - 67 % of the total stroke volume ( karatzas 1969 , nitzan 1992 , 1994 , ugander 2009 , her 1987 ). hence the systolic blood volume increase in a volume element in the pulmonary circulation is much higher than in a typical volume element in the systemic circulation , enabling the pulmonary ppg measurement because of the depth of pulmonary tissue relative to the measurement surface in the remote ppg techniques , the light source and the detector are preferably separated by at least 10 mm in the esophageal probe and by at least 15 mm in the thoracic probe . in order to assess the contribution of the esophageal wall or the thoracic wall circulation to the ppg signal , a second detector can be attached to the esophageal wall or the thoracic wall , where the second detector and the light source are separated by less than 8 mm . in another technique for the assessment of the contribution of the esophageal wall circulation or the thoracic wall circulation to the ppg signal , a second light source is attached to the thoracic wall , where the second light source and the first detector are separated by less than 8 mm . light transmission measurement by a light - source and a detector of relatively short separation provides information of the tissue of short depth relative to the measurement surface . for a probe adjacent to the pulmonary pleura ( option 4 , above ), smaller spacing between the two optic fibers is preferably used in order to use a single penetrating catheter . in each of the remote pulmonary ppg techniques , the pathlength of the light is long , and in order to have significant amount of transmitted light intensity for the measurement , infrared light which is less absorbed than visible light , is preferred . fig1 a presents the extinction coefficients of oxi - and deoxi - hemoglobin . red light , in the wavelength region of 600 - 700 nm , is more absorbed by deoxi - hemoglobin , than infrared light , of 700 - 1000 nm wavelength . for a probe adjacent to the pulmonary pleura ( option 4 , above ), other wavelengths , such as visible wavelengths , may be used . parenthetically , it should be noted that the term “ light source ” is used herein to refer to the light delivering element from which light is released into the tissue . the “ light source ” thus defined may be a light generating element , such as a laser diode or led , brought directly to the required location for delivering light , or may be the end of an optic fiber , an applicator connected to such a fiber , or any other waveguide or the like that conveys light to the required site from one or more remotely located light generating device . similarly the term “ detector ” is used herein to refer to the light detecting element which detects the light scattered from the tissue . the “ detector ” thus defined may be an electro - optic light detecting element , such as a pin diode or avalanche photodiode , brought directly to the required site of measurement for detecting light , or may be the end of an optic fiber , an applicator connected to such a fiber , or any other waveguide or the like that conveys light to the more remotely electro - optic detecting element from the required site of measurement . similar to conventional pulse oximetry technique , which provides information on sao 2 via the measurement of systemic ppg in two wavelengths , the measurement of pulmonary ppg in two wavelengths provides information on the oxygen saturation of the arterial blood in the pulmonary tissue , svo 2 , which in fact is equal to the mixed venous blood saturation , smvo 2 . smvo 2 provides information on the adequacy of the systemic blood supply and is an essential component in the quantitative determination of cardiac output by the fick method , as mentioned in section 1 . 1 . the current method for smvo 2 measurement in the pulmonary artery is invasive in the sense that it includes insertion of a swan - ganz balloon catheter in the pulmonary artery . smvo 2 is then measured , either intermittently , by extracting blood from the pulmonary artery or continuously , by means of oximetric measurements through optic fibers in the pulmonary artery blood . in another invasive technique , the oxygen saturation in the upper vena cava ( central venous oxygen saturation ) is measured . the invasive insertion of a catheter in the vena cava is of lower hazard than that through the right ventricle into the pulmonary artery , but the values of oxygen saturation in the two vessels may be different . several optical methods have been proposed for the non - invasive or minimally invasive measurement of oxygen saturation of blood within the pulmonary artery or in a central vein . these methods derive the required parameter from spectroscopic absorption measurements utilizing scattered light from the pulmonary artery or the central vein . the proposed various methods try to isolate the contribution of the scattered light from the pulmonary artery ( or the other vessel ) from that of the surrounding tissue . cheng et al in us patent no . us 2006 / 0253007 presented a method for the assessment of the oxygen saturation in a blood vessel such as the interior jugular vein by illuminating it from the skin . they suggest transmitting of the radiation into two regions , containing different portions of the target structure , for the isolation of the scattered radiation from the target vessel . they also suggest using ultrasound imaging for optimal placement of the optical transmitters and the receivers above the target structure . dixon in us patent no . us2010 / 0198027 proposed a non - invasive method for the determination of oxygen saturation of blood within a deep vascular structure . deep vascular structure are major blood vessels which are not superficially located , and include the inferior and superior vena cava , the right atrium , the right ventricle and central and peripheral parts of the pulmonary arteries . the method includes placing emitter and receiver elements of light oximeter device on the skin in the vicinity of the deep vascular structure of interest , wherein placement of the elements is achieved through matching of the plethysmography trace obtained from the oximeter device to known plethysrnography characteristics of the deep vascular structure . kohl et al in u . s . pat . no . 6 , 961 , 600b2 presented a minimally - invasive technique for the determination of mixed venous oxygen saturation by introducing catheter with an optical fiber in the bronchia , in the vicinity of the pulmonary artery . these inventions suggest measuring smvo 2 in the blood within the big arteries or veins , using non - invasive or minimally - invasive techniques , similar to the conventional invasive technique , which measures smvo 2 in the pulmonary artery . however , the measurement of smvo 2 by pulse oximetry , based on light scattering from big vessels is not accurate , as was found in the systemic circulation , that pulse oximetry cannot be used in the vicinity of big blood vessels ( mannheimer 2004 , reuss 2004 ). pulse oximetry in the systemic circulation has to be performed on the microcirculatory bed , and the same must be done in the pulmonary system . in preferred implementations of the present invention , the pulmonary pulse oximetry is preferably performed by illuminating the pulmonary tissue , while avoiding scattering of light from the major blood vessels in the thorax , which include the inferior and superior vena cava , the right atrium , the right ventricle and central and peripheral parts of the pulmonary arteries . certain embodiments of the present invention perform pulmonary pulse oximetry using pulmonary ppg signals in two wavelengths obtained by a ppg probe applied either on the thoracic wall or on the esophageal wall . as was explained above , two wavelengths in the infrared are preferably used for the measurement of the pulmonary ppg signals and svo 2 due to the long path of the light from the light - source to the detector . this is in contrast to the pulse oximetry in the systemic circulation , which is generally done by red and infrared light , taking the advantage of the relatively high difference between the values of the extinction coefficients of oxi - and deoxi - hemoglobin for red light ( see fig1 ). in the pulse oximetry in the systemic circulation the use of red light is possible because the pathlength required for measurements in skin is small , in the order of a few millimeters . similarly , in the fourth above - mentioned embodiment of the pulmonary pulse oximetry , which uses optic fibers to convey the light to and from the lung , the use of red light is possible . as was explained in section 1 . 3 , the pathlengths of the red and infrared light are significantly different , so that calibration by extracted arterial blood is required for the determination of the relationship between sao 2 and the measured parameter r derived from the two ppg signals . similarly , in the pulmonary pulse oximetry technique , if the difference between the pathlengths of the two wavelengths in the infrared is significant , calibration by extracted blood from the pulmonary artery is required . this calibration is typically not required in pulse oximeter which uses two wavelengths in the infrared region , if they are close enough so that the difference between their pathlengths can be neglected . it is therefore preferable to use two adjacent wavelengths in the infrared , of small difference between their pathlength , and use equation 9 , after neglecting the small difference in their pathlength or correcting it by a suitable correction factor ( see section 1 . 3 ). in the description of the pulse oximetry method presented above , svo 2 is obtained from r , which was defined as the ratio of the ratios δi a / i s for the two wavelengths . svo 2 can also be obtained from the ratio of two values of a parameter related to the change in the ppg signal for the two wavelengths , which can be different than δi a / i s . it can be chosen as ln ( i d / i s ) ( as in u . s . pat . nos . 4 , 773 , 422 and 4 , 167 , 331 ) or the derivative of i divided by i ( as in u . s . pat . no . 6 , 505 , 060 ). the esophageal pulmonary pulse oximetry presented in the current patent application differs from the esophageal pulse oximeters presented by atlee ( u . s . pat . no . 5 , 329 , 922 ) and kyriacou et al ( kyriacou 2006 ), for the measurement of sao 2 in the systemic microcirculation of the esophagus . accordingly , the distance between the light source and the detector was less than 8 mm enabling the measurement of the ppg signal in the esophageal wall , where the light source and the detector were applied . the two light sources in each wavelength in the esophageal systemic pulse oximeters are required for the increase the ppg signal , while the two detectors in each wavelength in the esophageal pulmonary pulse oximeters are required for the differentiation between the contributions of the systemic and the pulmonary circulations to the ppg signal . an esophageal systemic pulse oximetry , based on fiber - optic reflectance sensor was presented by phillips et al ( phillips 2011 ) and an apparatus for measuring the oxygen saturation level of blood at an internal measurement site , based also on fiber - optic reflectance pulse oximetry was presented by phillips et al in us patent 2008 / 0045822 . in the former device , the distance between the ends of the detector and the light - sources optic fibers was 4 mm . in the latter apparatus the optical centers of the first and second optical fibers are separated by at least 1 mm at their distal ends . a short distance , of few mms , between the detector and the light - sources or between the ends of the optic fibers of the detector and the light - sources is required for measuring the light absorption in the tissue in contact to the pulse oximeter . in both articles and in the patent application the light - sources included a red emitter , which is highly absorbed in the tissue and can therefore be used only for measurements in tissue of short distance to the pulse oximeter , like the esophageal wail . in the pulmonary pulse oximeter the light - sources emit infrared light and the light sources - detector separation is higher than 10 - 20 mm , to allow penetration of light to depth of 10 - 20 mm relative to the measurement surface , which contains pulmonary tissue . it should be noted that the pulse oximeter presented by phillips et al in their us patent 2008 / 0045822 was also suggested for the measurement of oxygen saturation in internal tissue like brain , but the probe must be inserted through the skull and applied adjacent to the brain surface in order to measure the oxygen saturation in the brain blood . the preferred pulse oximeter is a device , which includes two laser diodes of two peak wavelengths in the infrared region and of narrow spectrum and a detector which can detect , for each wavelength , the transmitted light through a portion of the thorax . the light from the laser diodes is conveyed to the thoracic wall by an optic fiber and the light transmitted through the thorax is conveyed to the detector by another optic fiber . for each laser diode a ppg curve is obtained and from each of the two ppg curves the ratio between the ppg pulse amplitude and its baseline is derived . the ratio r of the two values of this amplitude - to - baseline ratio for the two wavelengths is calculated and svo 2 is determined from the equation the value of the extinction coefficients for oxygenated blood c o and for deoxygenated blood ε d can be retrieved from the literature data - bases , for each peak wavelength . another preferred pulse oximeter is an esophageal probe which includes the tips of two optic fibers , one of them conveying infrared light from two laser diodes of two peak wavelengths in the infrared region and of narrow spectrum and the second optic fiber conveying light to a detector . the probe is applied to the esophageal wall , in close proximity to the lung tissue . the two optic fiber tips are separated by more than 10 mm , so that a significant quantity of the light reaching the detector have been scattered by the lung tissue and the ppg pulse will mainly represent the blood volume changes in the pulmonary circulation . for each laser diode a ppg curve is obtained and from each of the two ppg curves the ratio between the ppg pulse amplitude and its baseline is derived . the ratio r of the two values of this amplitude - to - baseline ratio for the two wavelengths is calculated and svo 2 is determined from the equation the value of the extinction coefficients for oxygenated blood ε o and for deoxygenated blood ε d can be retrieved from the literature data - bases , for each peak wavelength . in another preferred embodiment svo 2 is obtained from the ratio of two values of a parameter related to the change in light transmission for the two wavelengths , and this parameter can be different than amplitude - to - baseline ratio . it can be chosen as ln ( i d / i s ) or the derivative of i divided by i . in another preferred embodiment light emitting diodes ( leds ) are used instead of laser diodes and inserted directly into the esophagus with no need for optic fibers . the emission spectrum of led is broad , so that the calculation of the mean extinction coefficients over the spectrum band of the emitted light is required . in another preferred embodiment the leds with narrow - band filter are used , so that the calculation of the mean extinction coefficients over the spectrum band of the emitted light is simpler and more accurate . in another preferred embodiment the pulmonary ppg signal is obtained from several pulmonary ppg pulses , summed together , where the start of each ppg pulse is determined by the corresponding ppg pulse of the systemic circulation . in another preferred embodiment the pulmonary ppg signal is obtained during specific phase of the respiration . in another preferred embodiment the pulmonary ppg signal is obtained during the time of minimal movement of the lungs , such as at end expiration or at end inspiration . 1 . l yoshiya , y . shimady and k . tanake , 1980 . spectrophotometric monitoring of arterial oxygen saturation on the fingertip . med . biol . eng . comput . 18 : 27 - 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