Patent Publication Number: US-7221969-B2

Title: Method and apparatus for determining cerebral oxygen saturation

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
   The present invention is related to that disclosed and claimed in prior International Application No. PCT/US98/25236 filed PCT on 25 Nov. 1998, and U.S. patent application Ser. No. 09/555,351 based thereupon, filed on May 26, 2000, entitled METHOD AND APPARATUS FOR MONITORING FETAL CEREBRAL OXYGENATION DURING CHILDBIRTH (now U.S. Pat. No. 6,381,480), and also to U.S. provisional Application No. 60/359,829 filed Feb. 27, 2002, entitled METHOD AND APPARATUS FOR DETERMINING CEREBRAL OXYGEN SATURATION, on which priority is hereby claimed. All such prior applications are incorporated herein by reference as completely as though set forth verbatim. 

   BACKGROUND OF THE INVENTION 
   In the first above-identified previously filed patent application, a new concept is disclosed for determining the state of hemoglobin oxygen saturation in brain tissue, particularly fetal brain tissue, that is especially useful during the critical time of childbirth. Basically, this approach utilizes the concept of injecting a very short pulse of light at a selected wavelength in the near-infrared range (e.g. one nanosecond (ns) in length) into the head via a fiberoptic cable optically coupled to the head, detecting the corresponding photons emerging from the head into an adjacent detector and fiberoptic cable after a first very short period (e.g., one ns) and then detecting emerging photons once again after at least one more very brief period (on the order of 4 to 5 ns). 
   The injected pulse of photons (sometimes referred to as a “bolus”) spreads out from the injection site in the form of a rapidly expanding “glowball,” due to the extensive amount of scatter which occurs in this medium (on average, photon direction becoming completely randomized after only 0.6 mm of travel), and this translates into photon pathlength. Therefore, the detection of differing amounts of photons leaving the head at different relatively short intervals corresponding to photon travel over different effective pathlengths within the brain, which represents, and characterizes, differing depths of photon travel within the brain tissue. Thus, the quantities of photons detected at different intervals in effect sample different depths of travel, and hence different volumes of brain tissue. As a result, mathematical processing and correlation of these differential results will be directly indicative of differing amounts of photon absorption at different depths, including the amount of photon reduction which results (for example) from absorption by hemoglobin molecules. By using selected wavelengths of injected light, the amount of hemoglobin oxygenation can thus be determined, due to the difference in oxygen absorption as opposed to reduced or non-oxygenated hemoglobin, on a wavelength-specific basis. 
   The aforementioned U.S. Pat. No. 6,381,480 discloses this technological concept in considerably greater detail, together with representative and then-contemplated preferred embodiments of apparatus and methodology for implementing the concept to create a useful fetal cerebral oximeter. As may be seen by further study of that patent, it will be seen that the disclosed apparatus basically includes a source of photons coupled to the head by a fiberoptic conductor which leads to an injection site (e.g., the forehead), plus a fiberoptic leading from a photon detection device that basically comprises at least two shuttered detectors which are gated open for a very brief period (on the order of ins) at specific time intervals after the instant of injection, preferably by using a trigger signal obtained from a fiberoptic conductor that transmits a small fraction of the photons emitted by the source to the shuttered detectors at different and specifically timed intervals. 
   SUMMARY OF THE INVENTION 
   The present invention comprises a new and improved method and apparatus for determining cerebral oxygenation based on the underlying concept of the aforementioned earlier patent, obtained by way of a novel implementation of such concept, and this forms the basis of the present patent, in which a disclosure is provided for a preferred embodiment of such implementation. 
   In one basic aspect, the present invention recognizes and provides a new processing methodology for oxygenation determination, in particular cerebral oxygenation as briefly noted above, based on the apprehension and discovery that time-based photon quantity determinations of the wavelength-specific light leaving the head of the patient may be significantly improved, and simplified, by determining the quantity of returning photons in at least one set of two different but closely spaced points in time following the instant of injection, and then taking the ratio of the determinations in each set, to thereby cancel and remove several important sources of error. 
   Furthermore, and in a more particular sense, the invention provides a novel and advantageous implementation of the methodology just described, by which the detection equipment is simplified and certain components shown in the implementation of U.S. Pat. No. 6,381,480 eliminated, thereby providing substantial economies of manufacture, with related reduction of costs to users of the technology. 

   
     BRIEF DESCRIPTION OF THE DRAWINGS 
       FIG. 1  is a block diagram of the basic system and equipment disclosed in the aforementioned prior and related patent, corresponding to  FIG. 3  thereof; 
       FIG. 2  is an enlarged representation of an image intensifier as shown in the aforementioned prior and related patent, corresponding to  FIG. 4  thereof; 
       FIG. 3  is a simplified system block diagram illustrating a detection system in accordance with the present invention; 
       FIG. 4  is an enlarged, simplified drawing showing the image intensifier portion of the shutter detector, as utilized in accordance with the invention; 
       FIG. 5  is a schematic block diagram showing a preferred and more detailed embodiment of the present invention; and 
       FIG. 6  is a pictorial view showing an exemplary visual display for use in operating the system. 
   

   DESCRIPTION OF THE PREFERRED EMBODIMENTS 
   Inasmuch as an understanding of the present invention requires an understanding of the invention disclosed in the aforementioned prior related patent of the present inventors,  FIG. 1  herein depicts the overall system of a preferred embodiment then contemplated, and an abbreviated commentary with respect thereto follows. 
   A very short (on the order of ins) pulse of photons at a selected wavelength in the near infrared range is provided by a source  10  and is conducted to the head (“HEAD”) of the patient (fetus) by a fiberoptic cable  42  (photon travel designated “I” and shown with an arrow), and resulting photons exiting the head at brief intervals after that are detected at a point closely adjacent the point of entry at two (or more) closely spaced points in time (for example, on the order of 4 ns and 5 ns after injection). These detected photons are then coupled to a photon detection apparatus  20  that includes at least first and second shuttered detectors  22  and  24 , via a receiving fiberoptic cable  44  (labeled “O”), after passing through a lens  28 , partially reflecting mirrors  30  and  38 , an auxiliary shutter  32 , and a fluorescence-blocking filter  34 . The total flow of photons exiting the head via cable  44  is monitored by a photodiode detector  26 , to which a small fraction of such light is directed by partially reflecting mirror  38 . Shuttered detectors  22  and  24  are gated open by a small amount of the light from source  12 , via fiberoptic cables  46  and  48 , which are accurately cut to precise lengths that will provide the desired time delay for sampling the exiting photon stream after the instant of injection. 
   Accordingly, the shuttered detectors  22  and  24  provide outputs which represent the amount of photons exiting the head at the corresponding points in time, and by choosing wavelengths which are selectively absorbed by oxygenated and reduced hemoglobin, a precise and accurate determination of cerebral oxygenation may be obtained. In this regard, the longer the time delay from the instant of insertion, the deeper the photons will travel within the brain due to the effects of scatter, as noted above. Therefore, the longer this duration (and deeper the extent of travel), the more absorption these photons will incur before they exit the brain and skull, etc. For these reasons, it may be advantageous to implement more than one of the longer periods of delay, and also to utilize an alternating wavelength set, since this enables the determination of oxygenation with attendant suppression of subject-dependent parameters and variations in skin contact. 
   The aforementioned shuttered detectors  22  and  24  must be very fast-acting, going from completely off to completely on in about ins, or less. Errors in turn-on relative to the instant of pulse injection cannot be tolerated even if amounting only to a few nanoseconds (i.e., one or more). A satisfactory shutter and detector can be implemented by using a fast, linear, focused-dynode PMT; however, in a preferred first embodiment, an image-intensifier of the type widely used in night-vision devices was utilized with good results, and a schematic cross section of a typical proximity-focused such image intensifier, as utilized in the earlier patent, is illustrated in  FIG. 2 . Basically, this device consists of an entrance window “A” having a photocathode  60  which is very sensitive to the wavelength-specific near-infrared light pulses to be utilized. A few hundred microns from the photocathode is the input face of a microchannel plate electron multiplier (MCP) labeled “B.” The electrons which emerge from the MCP are accelerated by appropriate bias voltages to impact a phosphor screen  62  deposited on the inside of an output window Such image intensifiers can be used as fast electronic imaging shutters by biasing the photocathode  60  by an appropriate positive electrical potential relative to the front of the MCP, and then applying a short negative pulse to momentarily turn the device “on.” As used in accordance with both the previous patent and the present invention, the shuttered detectors  22 ,  24  also include a photodiode coupled to the image-intensifier outer window “C” so that an electrical signal is obtained that corresponds to the image intensity appearing on output window “C”. As indicated previously, both of the shuttered detectors  22  and  24  (also designated “S 1 ” and “S 2 ,” “S 3 ”) of the previous patent would, of course, each include its own image intensifier for independent switching. 
   The speed with which an image intensifier can be turned on and off is limited by a phenomenon called “irising,” in which the peripheral image field appears first while the center of the field is still dark (off). The reason for this is that the photocathode material has a relatively high resistance per unit area and a distributed capacitance, principally to the front of the MCP, and an electrode ring  64  is used in such devices to apply the gating voltage. When a fast negative pulse is applied to the electrode ring  64 , it takes a finite if short time to charge the photocathode center relative to its periphery. Typically, this delay will be on the order of at least several nanoseconds, before the intensifier is fully turned on. The effects of such irising are negated as used in accordance in the present invention, since the image intensifier is only being used for shuttered light detection rather than imagery. Thus, by limiting the fiber optics applying the input photons to only the edge of the photocathode, adjacent the ring electrode  64 , the delay in fully turning on the center of the photocathode is made entirely irrelevant. 
   In accordance with the present invention, both the system (apparatus) and processing of the time-related detected photon signals are simplified and substantially improved. This is based on apprehension of the fact that a number of important sources of error may be cancelled by taking the ratio of the number or representative value of at least two bursts of mutually time-spaced returning photons, i.e., those leaving the head of the patient and being coupled to the photon detection apparatus  20  on fiber optical cable  44 , which are to be shutter-detected at points in time corresponding to two or more specifically designated time delays after introduction of the related wavelength-specific photons from source  10 . 
   More particularly, the number of photons (N) received after a first time delay (t) may be expressed as:
 
N∝TS e −ρσ(λ,f)ct   Eq. 1
 
where:
         T=transmission at the fiberoptic-skin interface   S=sensitivity of the shuttered-detector   ρ=density of hemoglobin molecules (α) to blood density   σ=cross-section of a hemoglobin molecule at wavelength A and fractional oxygen f   c=velocity of photons in tissue   t=time delay from injection       

   If, in the expression set forth above, ρ is in units of molecules per cubic centimeter and σ is in units of square centimeters, then ρσ is the familiar linear absorption coefficient “μ” in units of inverse centimeters. Likewise, if c is units of centimeters per second and t is units of seconds, then ct is the pathlength in units of centimeters. 
   Using the basic expression set forth above as Equation 1, the number of photons received at a second time delay t is expressed as follows:
 
N′∝T′S′ e −ρσ(λ,f)   ct′   Eq. 2
 
   By dividing Equation 2 by Equation 1, we get the following ratio: 1    1  Note that the differential pathlength, ΔP=c(t′−t), is known exactly. 
   
     
       
         
           
             
               
                 
                   
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   As can be seen from Equation 3 above, variations in the coupling of the fiber optics with the skin are cancelled, since with these very short times T′=T. Referring back to  FIG. 1  and the accompanying discussion, it will of course be understood that each of the shuttered detectors  22 ,  24  will have its own characteristic sensitivity S, S′; however, in accordance with the invention, it is observed that if these two quantities could be made equal, they would also cancel, making the solution of the equation that much simpler. This novel and useful concept is accomplished in accordance with the present invention, and accomplished in a most effect way; i.e., a single image detector is utilized to switch each of the time-delayed photon quantities exiting the head of the patient, that carry the oxygen-related hemoglobin absorption information which is desired. 
   As indicated above, the shuttered detectors  22 ,  24  utilized in the preferred embodiment include a proximity-focused image intensifier, the output light from which is measured by a photodetector (as referred to above, and as described in detail in the prior patent identified above which is incorporated herein by reference). As disclosed in the prior patent, the termination of the fiber optic cable, (i.e. cable  44 , as seen in  FIG. 1 ) conducting the photons from the head is positioned at the edge of the image intensifier&#39;s photocathode to speed its response to the gating pulse by minimizing the distributed resistance and capacitance inherent in the thin photocathode, which causes the “irising” effect noted above. In accordance with the invention, a single image intensifier is utilized to provide two correlated but separate simultaneously acting shutters, by bringing a second fiberoptic cable (designated  144  in  FIGS. 3 and 4 ) from the head of the patient to the same image intensifier, but positioning its termination at the side of the photocathode opposite that where cable  44  is terminated (i.e., 180° therefrom). By using this arrangement, all that is required to make the device operate as a pair of separate or detectors is the presence of a second photodetector ( 66 ,  68 ) on the image intensifier&#39;s output side ( FIG. 4 ). These two photodetectors must be arranged to separately view the images appearing on the ends of the two input fiber optic cables  44 ,  144 , as they appear separately mapped on the image intensifier output screen  62 . In this regard, it should be pointed out that by utilizing this inventive concept, the same image intensifier may be utilized to provide even more than two such shutters, or optical switches. 2    2  The only limitation is the angular spatial resolution of the image intensifier around the edge of the photocathode and the corresponding map on the output screen. An inexpensive “streak camera” device could be built using a large number of input fibers each with small, uniformly stepped delays. 
     FIG. 3  provides a schematic representation of such an improved, simplified system, and the image intensifier portion thereof, comparable to that shown in  FIG. 4  of the referenced prior patent and  FIG. 2  herein, is shown in  FIG. 4  herein. As will be seen from  FIG. 3  herein, the photon detection fiberoptic  44 ,  144  extending from the head of the patient to the shuttered detector  22 ,  24  may advantageously be implemented by use of a single bifurcated or branched fiberoptic cable, one branch forming cable  44  and the other forming cable  144 . Also, as schematically illustrated in  FIG. 4  herein, and as noted above, photon input cable  44  is directly aligned with an output location of the image intensifier that is coupled to its own photodetector, designated  66  herein, and photon delivery cable  144  is directly aligned with an image-intensifier output coupled to its own photodetector, designated here  68 . Accordingly, the burst of photons to be detected at a first time interval following the instant of photon injection, t, is indicated by the arrow  100 , and the other such burst, at time t′ following injection, is indicated by the other such arrow, designated  200 . As shown in this example, where two separate branches carrying differently timed photon bursts (or images) are being switched by a single image intensifier, the input and output cables or other such optical connectors are preferably disposed 180° from each other around the edge of the photocathode. Of course, if a greater number of photon bursts was being detected, a corresponding greater number of separate cable branches would be used and each would be correspondingly equally spaced from the others around the edge of the photocathode. 
   With further reference to the system of the aforementioned prior patent, and as noted above, the two (or more) shuttered detectors  22 ,  24  are gated by a small portion of the input photon burst from source  10  (laser  12 ), by using two different fiberoptic cables (there designated  46  and  48 ) having two different lengths, so that the shuttered detectors are gated on at different points in time, thereby sampling or detecting the photons leaving the head at two different points in time, in effect taking “snapshots” at those points in time. In accordance with the present invention, the single shuttered detector  22 ,  24  is gated at a single point in time, utilizing a portion of the photons from the source directed toward the head. Although the single shuttered detector  22 ,  24  thus operates at a single and brief point in time, the different photon quantities which it detects at that single point in time actually emanate from the head of the patient at two closely spaced but different points in time, due to the precisely cut input cables  44  and  144 . Thus, the outputs from the shuttered detectors which are applied to photodetectors  66  and  68  are specifically different, and comparatively unique, notwithstanding the fact that the shuttered detector is operated only a single time to switch photon inputs that occurred at different points in time. 
   As an example of such a system, assume that the source (laser)  12  produces the photon pulse at t=0 and the fiber optic conducting the light to the head ( 42 ) is 10 ns long. Assume the fiberoptic receiving the photons  44 ,  144  from the head is split into two cables (bifurcated) going to opposite points on the edge of the image intensifier photocathode, as described above, but with one of the branches cut to be 6 ns and the other branch 7 ns long. If the gating fiber ( 47 ) between the laser  12  and the shuttered detector  22 ,  24  is 21 ns long and cable branch  44  is 6 ns long while branch  144  is 7 ns long, the photons arriving over the 6 ns fiber ( 44 ) will have left the head 5 ns after injection while the photons arriving over the 7 ns fiber ( 144 ) will have left the head 4 ns after injection. Accordingly, with this system, the ratio of the two signals from the corresponding photodetectors  66 ,  68  will be independent of both time and amplitude (“jitter”) in the shuttered detector gate, since S′=S. 
   Further improvements or enhancements in the system described in the previous patent are as follows. The first such feature, also comprising a part of the present invention, relates to the characteristics of the input and output fiberoptic cables, herein designated  42  and  44 ,  144  respectively. While it is obvious that the core material of these fibers should not scatter light, some such scattering is unavoidable. The very large injection pulse from the laser ( 12 ) initiates “reverberation” from scattering and reflection at the fiber ends that may persist long enough to interfere with the measurement of delayed light. Unlike the causes of this problem, its solution is not obvious; however, one measure which will or may help is to have the core material be deliberately partially absorbing. While the signal light passes through the fibers once, the reverberating light takes a longer path and will be discriminated against by such absorption. 
   The other item or feature has to do with insuring that the pulses used to gate the single shuttered ( 22 ,  24 ) detector on are of uniform amplitude. As indicated above, the photocathode of the image intensifier is biased off prior to the time of arrival of the laser-generated injection pulse (by a large positive voltage, which keeps the photoelectrons from getting to the microchannel plate), and it is only turned on (made negative) several nanoseconds later to measure the very small amount of delayed light from the head of the patient or test subject. However, the photocathode tends to “remember” the large initial pulse and release some electrons to the microchannel plate when turned on, even if there is no delayed light. This phenomenon was referred to as “persistence” in the prior patent referred to above. 
   Two operating parameters appear to be most important in eliminating this ‘persistence’. Firstly, the larger the “off” bias, the better. In the particular implementation described and illustrated, increasing the “off” bias from +170 to +190 volts appears to reduce the persistence by two orders of magnitude. Secondly, it is important to control the amplitude of the larger negative gate “on” pulse so that it does not take the photocathode more than 20 v negative. Therefore, for a +190 volt “off” bias in this implementation, the gate “on” pulse peak amplitude should be very close to −210 v. Since the gate pulse is derived directly from a photodiode which is driven by a fraction (delayed) of the laser pulse, its reproducibility depends on the laser pulse amplitude stability. Since the laser&#39;s stability is much less than the 2% needed to hold the on voltage to 20%, it is believed advantageous to use avalanche transistors to completely isolate the laser-generated photodiode gate pulse from the image intensifier photocathode. The photodiode will trigger an avalanche breakdown in a string of transistors that will then generate their own gate pulses with amplitudes that are independent of the laser output stability. Based on measurements taken of representative circuits, the avalanche transistor breakdown occurs in less than ins. (For a reference with respect to avalanche transistors, see Jinyuan L. Bing S. Zenghu C; “ High voltage fast ramp pulse generation using avalanche transistor ,” Rev. Sci. Inst 69, 3066–67, 1998). 
     FIG. 5  is a schematic block diagram showing a preferred and more particular embodiment of the overall system of the invention shown in  FIG. 3 . The laser system  12  for the preferred embodiment shown in  FIG. 5  consists of a flashlamp-excited Nd:YAG laser with its 5 ns output pulses of infrared light (1064 nm) closely coupled to a second harmonic generator (“SHG”), which converts the wavelength to green light (532 nm) and width to 4 ns. 3 . The pulse of light from the SHG is then closely coupled to an optical parametric oscillator (OPO)  13  where the wavelength is tuned to the range of 700 to 950 nm depending on the angle of its internal prism with pulse widths of 3 ns. The pulse of infrared photons from the OPO  13  (or laser) is divided into four parts 4 . Most such photons go to the head via the delivery fiber  42 . Another part of them goes to a super diode  50  which triggers the avalanche gate  52 , turning on the shuttered detector  22 ,  24 . The third photon pickoff goes to another super diode  54 , which signals the computer  56  to start a new data point sequence. A fourth photon part goes to the CCD spectrometer  58 , which measures the wavelength of the photons in the pulse.  3  Another useful source is a Quantel Nd:YAG laser 4  Actually, more laser pulse pickoffs may also be used—notably to drive a Pockels Cell used to quench the tail of the pulse. 
   With further reference to  FIG. 5 , light emerging from the head is carried to the shuttered detector inputs by two fibers  44 ,  144  that differ in length by ins. The two electrical equivalent outputs from the shuttered detector  22 ,  24  are sampled and digitized, and coupled to the computer  56  by appropriate components  70 ,  72 , as labeled, under the control of the console computer and associated software. 
     FIG. 6  is a pictorial view showing an exemplary display-type user interface for use in operating a system in accordance with the invention. The system gathers data in a “list” mode. That is, for each laser ( 12 ) pulse the computer ( 56 ) saves the time, the signal and reference data for the two PMT&#39;s, the amplitude and wavelength of the pulse from the OPO, and several bits of “housekeeping” data. This data is binned (made into a histogram) on the fly to build up an absorption spectrum of the chromophores within the glowball and displayed on the computer monitor. 
   In the operator interface display shown in pictorial view  FIG. 6 , the box at top left (“VR 6 ”) sets the laser operating parameters. The middle box (“Status”) displays the system status, and the box at the right (“Power Supplies”) allows the operator to set the power supply voltages. The dynamic display on the lower left (“OPO”) continuously shows the wavelength of each pulse and allows the wavelength range to be set. The display at lower right (“Data”) continuously scrolls the outputs of the two channels. 
   As will now be readily apparent to those skilled in the art, a highly novel and advantageous improvement is provided herewith, both in connection with the particular fetal cerebral oximeter apparatus which forms the primary focus of this patent, and also, in a broader sense, in connection with the gating of such optical systems generally; i.e. the use of a single image intensifier that simultaneously sequentially gates a plurality of different optical circuits also has substantial potential advantage for various different applications. Consequently, both such aspects are to be considered part of this invention, as are the two other aspects set forth immediately above. 
   It is believed that those skilled in the art will readily recognize the novel and unobvious character of the inventions disclosed above, and also recognize the wide scope of applicability and high degree of advantage which they possess and provide. Of course, the above description is to be considered that of preferred embodiments only. Modifications and variations of this and other such embodiments may well occur to those skilled in the art and to those who make or use the invention after learning of it through access to such preferred embodiments. Accordingly, it is to be understood that the embodiment shown in the drawings and described above is merely for illustrative purposes and should not be used to limit the scope of the invention, which is to be interpreted according to the principles of patent law, including the doctrine of equivalents.