Abstract:
A method and apparatus for assessing tissue perfusion of a patient. The apparatus includes a probe for contacting the mucosa tissue in the upper respiratory/digestive tract of the patient, and a sensor coupled to the probe for directly detecting a pH measurement of the mucosa tissue and for generating an electrical signal in response to the detected pH measurement.  
     For the method of the invention, a probe capable of measuring pH is provided. The probe is placed in contact with the mucosa tissue in the upper respiratory/digestive tract of the patient. A pH measurement of the mucosa tissue is obtained. The pH measurement is converted into an indicator to a clinician representing a level of tissue perfusion.

Description:
BACKGROUND OF THE INVENTION  
         [0001]    The invention relates to assessing perfusion failure of a patient by measuring the pH of the mucosa tissue in the upper digestive/respiratory tract of the patient.  
           [0002]    Perfusion is defined as the flow of blood through the body to organs or tissues to supply nutrients and oxygen. Perfusion failure occurs when the flow of blood through the body is disrupted. Specifically, perfusion failure may be caused by bacteria and infection, by hemorrhage, or by coronary syndromes, such as myocardial infarction. Perfusion failure leads to the progressive deterioration of the cardiovascular functions of the body. If the perfusion failure can be corrected by the appropriate therapy, the perfusion failure is referred to as refractory shock. However, if the perfusion failure is irreversible and ultimately lethal, the perfusion failure is referred to as irreversible shock. Methods have been developed to detect and correct perfusion failure with the appropriate therapy during refractory shock, before the patient&#39;s condition deteriorates to irreversible shock.  
           [0003]    Perfusion failure can be detected by measuring systemic levels of blood gases. Systemic levels of blood gases provide an indication of perfusion failure throughout the body. One method of determining perfusion failure by measuring systemic levels of blood gases is to perform an arterial blood gas (ABG) analysis of the patient&#39;s blood. The ABG analysis produces five main measurements, including arterial pH, the arterial partial pressure of oxygen (P aO2 ), the arterial partial pressure of carbon dioxide (P aO2 ), oxygen saturation (S O2 ), and bicarbonate (HCO 3   − ) concentration. Although the ABG analysis is considered the most accurate way of detecting perfusion failure, it has several drawbacks. First, since the patient&#39;s blood must be drawn, the ABG analysis is highly invasive. Second, the ABG analysis only gives information intermittently when blood is drawn from the patient and then analyzed. Third, there is a substantial delay between the time the patient&#39;s blood is drawn and the time the ABG analysis results are available.  
           [0004]    Another method of determining perfusion failure by measuring systemic levels of blood gases is the use of a pulmonary artery catheter. For this method, a catheter is inserted directly into the pulmonary artery to take hemodynamic measurements, such as cardiac output, pulmonary artery occlusion pressure, and mixed venous oxygen saturation, along with blood gas measurements, such as arterial oxygenation, global oxygen delivery, and oxygen consumption. Even though these measurements provide useful information about systemic perfusion failure, the patient&#39;s condition may deteriorate considerably before changes in the systemic levels of blood gases reflect inadequate perfusion. Moreover, pulmonary artery catheters are highly invasive and have been associated with increased mortality rates, due to unintended arrhythmias, hemorrhage, thromboembolism, sepsis, and endocardial damage.  
           [0005]    Perfusion failure can also be detected by measuring the by-products of anaerobic metabolism in bodily tissues. The by-products of anaerobic metabolism are not carried away from bodily tissues as quickly during low blood flow states as during normal blood flow states. The build-up of by-products results in tissue acidosis, which is reflected in a decrease in the pH level of the tissue. Accordingly, a decrease in tissue pH correlates to perfusion failure.  
           [0006]    One method of determining perfusion failure by measuring the by-products of anaerobic metabolism is gastric tonometry. Gastric tonometry takes advantage of the fact that during perfusion failure blood flow is directed away from the gastrointestinal (GI) tract to organs such as the heart and the brain. Gastric tonometry involves inserting a catheter down a nasal gastric tube into the patient&#39;s stomach. The catheter contains a gas-permeable silicone balloon filled with saline. While in the patient&#39;s stomach, the saline in the balloon is allowed to equilibrate with carbon dioxide, a byproduct of anaerobic metabolism. The catheter is removed from the patient&#39;s stomach, and the saline from the balloon is analyzed for its carbon dioxide level. Gastric tonometry provides accurate information about tissue-level perfusion failure, but it is a highly invasive procedure that requires a significant length of time for the saline in the balloon to equilibrate with the carbon dioxide in the stomach.  
           [0007]    Another less-invasive method of detecting perfusion failure by measuring the by-products of anaerobic metabolism is disclosed in U.S. Pat. No. 6,055,447. The &#39;447 Patent discloses a method and apparatus for assessing impairment of blood circulation of a patient by measuring the partial pressure of carbon dioxide in the patient&#39;s upper digestive/respiratory tract.  
         SUMMARY OF THE INVENTION  
         [0008]    During perfusion failure, the body automatically directs blood flow to the organs that need continuous blood flow to survive and away from the organs that do not need continuous blood flow to survive. As a result, the body directs blood flow to organs such as the heart, kidney, liver, adrenal glands, and brain, and away from the organs of the GI tract. With blood flow being directed away from the GI tract, the GI tract is the first portion of the body to suffer from inadequate tissue perfusion or ischemia. The term ischemia is defined as a decrease in the blood supply to a bodily organ, tissue, or part caused by constriction or obstruction of the blood vessels. Accordingly, if ischemia in the GI tract can be detected before systemic perfusion failure occurs, the clinician can take steps to prevent the patient from deteriorating into irreversible shock.  
           [0009]    In general, ischemia can be detected in tissues by measuring the pH level of the tissue. During perfusion failure, lactic acid, a by-product of anaerobic metabolism, is not carried away from tissues as quickly as during normal perfusion. The lactic acid builds up in the tissue, increasing the acidosis of the tissue. This increase in the acidosis of the tissue is reflected in a decrease in the pH of the tissue. The pH of the tissue is determined directly based on the level of H+ ions in the tissue. The pH of the tissue is determined directly from H +  ion concentration by the following equation: 
           pH=−log [H + ] 
           [0010]    The pH of the tissue can also be calculated indirectly from the partial pressure of carbon dioxide by the Henderson-Hasselbalch equation: 
           pH=6.1+(log[HCO 3   31  ]/α P CO2 ) 
           [0011]    where 6.1 is the logarithm of a carbonic acid constant; [HCO 3   −]  is the bicarbonate concentration of blood; α is a constant that relates the partial pressure of carbon dioxide to the concentration of carbon dioxide; and P CO2  is the partial pressure of carbon dioxide.  
           [0012]    In the GI tract, ischemia can be detected by determining intramucosal pH (pHi). The mucosa layer is the most proximal of the four layers of the GI tract. Below the mucosa layer is the submucosa layer. The arterial supply for GI tract perfusion flows through arterioles in the submucosa layer and through branches of the arterioles into the folds and projections, called villus, of the mucosa layer. Due to the flow of blood through the villus of the mucosa layer, ischemia of the GI tract can be detected by measuring the adequacy of perfusion in the tissue of the mucosa layer.  
           [0013]    Intramucosal pH (pHi) can be determined indirectly by measuring the partial pressure of carbon dioxide in the mucosa tissue and then calculating the pH using the Henderson-Hasselbalch equation as follows: 
           pHi=6.1+(log[HCO 3   − ]/α mucosal P CO2 ) 
           [0014]    where pHi is the calculated intramucosal pH; 6.1 is the logarithm of a carbonic acid constant; [HCO 3   −]  is the mucosal bicarbonate concentration, which is assumed to be equal to the arterial bicarbonate concentration; α is a constant that relates the mucosal partial pressure of carbon dioxide to the mucosal concentration of carbon dioxide; and mucosal P CO2  is the partial pressure of carbon dioxide in the mucosa tissue.  
           [0015]    Detecting ischemia by measuring the partial pressure of carbon dioxide and then calculating intramucosal pH with the Henderson-Hasselbalch equation is an indirect and possibly inaccurate method of detecting perfusion failure. The Henderson-Hasselbalch equation depends on two assumptions: first, that the intramucosal bicarbonate concentration is equal to the arterial bicarbonate concentration, and second, that the arterial bicarbonate concentration is constant. However, these assumptions are inaccurate during states of very low perfusion. Specifically, during partial or total GI tract ischemia, the mucosal bicarbonate concentration may be significantly lower than the arterial bicarbonate concentration. Moreover, the arterial bicarbonate concentration fluctuates significantly in very low perfusion states. As a result, the calculated intramucosal pH may be lower than the actual intramucosal pH. If the calculated intramucosal pH is lower than the actual intramucosal pH, perfusion failure may be indicated when perfusion failure is not actually occurring.  
           [0016]    Thus, a need exists for a minimally invasive method of providing information about tissue-level perfusion failure based on a direct measurement of the tissue pH level, rather than on an indirect or highly invasive determination of tissue perfusion.  
           [0017]    In order to avoid the inaccuracies associated with making a measurement of the partial pressure of carbon dioxide and then indirectly determining the pH level based on assumptions regarding the bicarbonate concentration, the present invention measures the H +  ion concentration of the mucosa tissue directly. The pH is determined directly from the H +  ion concentration for a more accurate result than when pH is calculated from the partial pressure of carbon dioxide.  
           [0018]    Accordingly, the invention is embodied in a device for assessing perfusion failure of a patient, including a probe for contacting the mucosa tissue in the upper digestive/respiratory tract of a patient, and a sensor coupled to the probe for directly detecting the pH of the mucosa tissue. Preferably, the sensor is either an ion-selective, field-effect transistor or an electrochemical sensor. Preferably, the sensor is not encapsulated within a permeable membrane. The device includes a holder for the probe to secure the probe to the patient.  
           [0019]    In another embodiment, the device includes a pH sensor and a second sensor for acquiring an end-tidal carbon-dioxide partial pressure measurement. The end-tidal carbon-dioxide partial-pressure measurement is used as a reference measurement to increase the accuracy of the pH measurement.  
           [0020]    In still another embodiment, the device includes additional sensors or sensor platforms for detecting not only pH and end-tidal carbon-dioxide partial-pressure, but also for detecting blood chemistry data and saliva chemistry data.  
           [0021]    The invention is also embodied in a new method of assessing tissue perfusion in a patient. The method includes the acts of providing a probe capable of measuring pH, placing the probe in contact with the mucosa tissue in the patient&#39;s upper digestive/respiratory tract, obtaining a pH measurement of the mucosa tissue, and converting the pH measurement into an indicator to a clinician representing the level of perfusion failure.  
           [0022]    In another embodiment, the method includes the acts of providing a sensor capable of measuring end-tidal carbon-dioxide partial-pressure, placing the probe in the patient&#39;s upper digestive/respiratory tract, obtaining an end-tidal carbon-dioxide partial-pressure measurement, and comparing the pH measurement to the end-tidal carbon-dioxide partial-pressure measurement in order to increase the accuracy of the pH measurement.  
           [0023]    In still another embodiment, the method includes the acts of providing additional sensors or sensor platforms for detecting not only pH and end-tidal carbon-dioxide partial-pressure, but also for detecting blood-chemistry data and saliva-chemistry data.  
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0024]    [0024]FIG. 1 illustrates a holder for a probe attached to a patient&#39;s mouth and coupled to a display unit.  
         [0025]    [0025]FIG. 2 is a flow chart illustrating one preferred embodiment of the method of the invention.  
         [0026]    [0026]FIG. 3 is a schematic illustrating the electrochemical embodiment of the sensor.  
         [0027]    [0027]FIG. 4 is a schematic illustrating the ion-selective, field-effect transistor embodiment of the sensor.  
         [0028]    [0028]FIG. 5 is a perspective view of the holder of FIG. 1.  
         [0029]    [0029]FIG. 6 is a top view of the holder of FIG. 1.  
         [0030]    [0030]FIG. 7 is a side view of the holder of FIG. 1.  
         [0031]    [0031]FIG. 8 is a flow chart illustrating another preferred embodiment of the method of the invention. 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT  
       [0032]    Before one embodiment of the invention is explained in full detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the following drawings. The invention is capable of other embodiments and of being practiced or of being carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including” and “comprising” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.  
         [0033]    [0033]FIG. 1 illustrates a device  11  embodying the invention. The device  11  includes a probe  12 , a sensor  30  (shown in FIG. 7) coupled to the probe  12 , a holder  14  coupled to the probe  12 , and a display unit  16  coupled to the probe  12 . The display unit  16  may be a stand-alone unit dedicated solely to providing an indicator of tissue perfusion levels to a clinician. Alternatively, the display unit  16  may be part of a complete patient monitoring system.  
         [0034]    Before the preferred embodiments of the sensor  30  are described in detail, it should be understood that the use of any sensor to detect the pH of the mucosa tissue in the upper digestive/respiratory tract in order to assess perfusion failure is considered within the scope of the invention.  
         [0035]    In the most preferred embodiment of the invention, an ion-selective, field-effect transistor (ISFET) is used to detect the pH of the mucosa tissue. ISFETs are steady-state devices similar to metal-oxide semiconductor field-effect transistors (MOSFET). MOSFETs are composed of two diodes separated by a gate region. The gate is a thin insulator, usually silicon dioxide, upon which a metallic material is deposited. Voltage applied to the gate generates an electric field, and thus current flows between the drain and the source. ISFETs are similar to MOSFETS, except that the metal gate region is replaced with an ion-selective layer. Ions traveling through the ion-selective layer generate an electric field, and thus current flows between the drain and source.  
         [0036]    [0036]FIG. 4 is a schematic illustration of one embodiment of the sensor  30 . The sensor  30  is an ISFET and includes a gate  52 , an insulator  54 , an ion-selective surface  56 , a drain  58 , a source  60 , a reference electrode  62 , and a plurality of metal contacts  64 . The ion-selective surface  56  and the reference electrode  62  are in contact with the mucosa tissue  66 . The reference electrode  62  keeps a constant voltage potential V gs  against the mucosa tissue  66 , independent of the mucosa tissue composition. As H +  ions pass through the ion-selective surface  56 , a voltage potential is developed at the ion-selective surface  56  in response to the H +  ion concentration of the mucosa tissue  66 . The ion-selective surface  56  is not encapsulated by any permeable membranes, rather the surface itself is ion-selective. The voltage potential V ds  developed in response to the H +  ion concentration modulates the current between the drain  58  and the source  60 . As the voltage potential V ds  across the gate changes, the ISFET current I ds  flows. The voltage potential V ds  correlates to the pH of the mucosa tissue.  
         [0037]    [0037]FIG. 3 is a schematic illustration of another suitable sensor  30 . The sensor  30  shown in FIG. 3 is an electrochemical sensor. The electrochemical sensor  30  includes a voltmeter  32  coupled between a reference electrode  34  and a silver/silver-chloride reference wire  36 . A shielded lead  44  connects the reference wire  36  to the voltmeter  32 . The reference wire  36  is immersed within a buffer solution  38  with a constant pH level. Preferably, the buffer solution  38  is hydrochloric acid (HCl).  
         [0038]    A pH-sensitive glass membrane  40  encapsulates the reference wire  36  and the buffer solution  38 . Preferably, the glass membrane  40  is not encapsulated within an ion-selective permeable membrane. Ion-selective permeable membranes are not necessary in order to measure H +  ion concentration, as they are necessary to measure carbon dioxide concentration and other ion concentrations. Rather than having an ion-selective permeable membrane, the glass membrane composition itself is ion-selective. Preferably, the ion-selective composition of the glass membrane  40  is SiO 2  or Na 2 O.  
         [0039]    The pH-sensitive glass membrane  40  and the reference electrode  34  are in contact with the mucosa tissue, represented by sample  42 , which has an unknown pH. The reference electrode  34  keeps a constant voltage potential against the sample  42 , independent of the sample composition. In response to the difference in pH of the buffer solution  38  and the sample  42 , a direct voltage is developed between the inside and outside of the glass membrane  40 . The voltage is caused by an ion exchange at each surface of the glass membrane  40  between the metal ions of the glass and the H +  ions of the solutions. The approach of H +  ions to the outside of the membrane  40  causes the silicate structure of the glass to conduct a positive charge into the buffer solution  38  inside the membrane  40 . The ion exchange across the glass membrane  40  is controlled by the concentration of H +  ions in each solution, and thus, the pH of each solution. The change in the voltage potential between the reference electrode  34  and the reference wire  36  is sensed by the voltmeter  32 . If the concentration of H +  ions in both solutions is the same, the potential difference across the glass membrane and the output of the voltmeter  32  is zero volts. Thus, the output of the voltmeter  32  correlates to the pH of the mucosa tissue, represented by sample  42 .  
         [0040]    In another preferred embodiment, the device  11  includes a sensor for acquiring an end-tidal carbon-dioxide partial-pressure (P etCO2 ) measurement. A P etCO2  sensor suitable for use in the present invention is disclosed in U.S. patent application Ser. No. 09/477,914 entitled “Low Cost Main Stream Gas Analyzer System,” and is incorporated herein by reference.  
         [0041]    In still another preferred embodiment of the invention, the device  11  includes additional sensors or sensor platforms for acquiring blood-chemistry and/or saliva-chemistry data from the patient. In order to implement the additional sensors into a platform sensor package, preferably one or more ISFETs capable of detecting multiple species of ions and molecules are fabricated onto one silicon chip.  
         [0042]    Preferably, the additional sensors are capable of detecting the blood chemistry data that is normally gathered in an arterial blood gas (ABG) analysis. The additional sensors are preferably capable of detecting at least one of pH, the partial pressure of oxygen (P O2 ), the partial pressure of carbon dioxide (P CO2 ), bicarbonate, hematocrit, hemoglobin, oxygen saturation (S O2 ), electrolyte concentration, and metabolite concentration. The additional sensors are preferably capable of detecting electrolytes including at least one of sodium, potassium, calcium, and chloride. The additional sensors are preferably capable of detecting metabolites including at least one of glucose, lactate, creatinine, and urea. The additional sensors are also preferably capable of detecting saliva chemistry data including at least one of cholesterol, lactate, electrolytes, illegal or abused drugs, glucose, bone markers, cystic fibrosis, HIV, and pregnancy.  
         [0043]    FIGS.  5 - 7  illustrate the preferred embodiment of the holder  14 . Before the preferred embodiment of the holder  14  is described in detail, it should be understood that the holder  14  could be constructed in any configuration and of any material capable of placing the sensor or sensors in contact with the mucosa tissue in the patient&#39;s upper digestive/respiratory tract.  
         [0044]    Referring to FIGS.  5 - 7 , the holder  14  preferably includes an inner holder portion  90  and an outer holder portion  92  coupled to the inner holder portion  90  by a resilient connecting member  102 . The inner holder portion  90  includes an outer surface  93  and a groove  94  formed in the outer surface  93 . The probe  12  is positioned within the groove  94 . The inner holder portion  90  also includes a first end  96  and a second end  98 . The first end  96  is a projection for use by the clinician to grasp the holder  14 . The second end  98  is a gradually downward-sloping projection that is positioned within the patient&#39;s mouth, preferably in contact with the patient&#39;s cheek. As illustrated in FIG. 7, the sensor  30  is coupled to the second end  98 . The sensor  30  is positioned to contact the mucosa tissue within the patient&#39;s mouth.  
         [0045]    The outer holder portion  92  includes a first end  104  and a second end  106 . The first end  104  is a projection for use by the clinician in conjunction with the first end  96  of the inner holder portion  92  to grasp the holder  14 . The second end  106  is a gradually upward-sloping projection that is positioned outside the patient&#39;s mouth, preferably in contact with the cheek-area of the patient&#39;s face. The space  108  between the second end  98  of the inner holder portion  90  and the second end  106  of the outer holder portion  92  is such that the holder  14  remains secured to the patient&#39;s cheek.  
         [0046]    Preferably, the holder  14  is constructed from a soft, pliable material that easily conforms to the patient&#39;s anatomy while remaining rigid enough to secure the holder  14  to the patient&#39;s face. Preferably, the material for the holder  14  is biocompatible.  
         [0047]    [0047]FIG. 2 is a flow chart illustrating the method of the invention. Referring to FIGS. 1 and 2, the holder  14  coupled to the probe  12  is positioned  20  on the patient. Preferably, the holder  14  is attached to the patient&#39;s cheek, and when in the appropriate position, presents the sensor  30  in contact with the oral mucosa tissue of the patient  10 . In other embodiments (not shown), the holder  14  may be attached to the patient&#39;s lip or under the patient&#39;s tongue. Referring to FIGS.  5 - 7 , in order to attach the holder  14 , the clinician grasps the holder  14  by the first end  96  of the inner holder portion  90  and by the first end  104  of the outer holder portion  92 . The clinician then positions the second end  98  of the inner holder portion  90  within the patient&#39;s mouth, preferably so that the sensor  30  is in contact with the mucosa tissue inside the patient&#39;s cheek. At the same time the clinician positions the second end  106  of the outer holder portion  92  outside the patient&#39;s mouth, preferably so that the second end  106  is in contact with the cheek area of the patient&#39;s face.  
         [0048]    Still referring to FIGS. 1 and 2, the sensor  30  within the probe  12  measures  22  the pH by detecting the H +  ion concentration of the mucosa tissue in the patient&#39;s mouth. The sensor  30  generates  24  an electrical signal in response to the detected pH. The signal is converted  26  into an indicator of the level of perfusion. The indicator of the level of perfusion is displayed  28  to a clinician on display unit  16 .  
         [0049]    [0049]FIG. 8 is a flow chart illustrating another preferred embodiment of the method of the invention including the additional step of acquiring a P etCO2  measurement. Generally, mucosa tissue pH correlates to arterial perfusion, while P etCO2  correlates to pulmonary perfusion. In order to compare the arterial and pulmonary levels of perfusion failure, the mucosa tissue pH measurement is compared to the P etCO2  measurement. Thus, the comparison between the pH and P etCO2  measurements helps to provide a more accurate assessment of systemic perfusion failure.  
         [0050]    Referring to FIGS. 1 and 8, the holder  14  coupled to the probe  12  is positioned  70  on the patient  10 . Preferably, probe  12  includes both a pH sensor  30  and a P etCO2  sensor (not shown). Preferably, the holder  14  is attached to the patient&#39;s cheek. In other embodiments (not shown), the holder  14  may be attached to the patient&#39;s lip or under the patient&#39;s tongue. The pH sensor  30  measures  72  the pH of the mucosa tissue, and the P etCO2  sensor measures  72  the P etCO2  level of the air expired by the patient. The P etCO2  measurement is compared to the pH measurement and used as a reference to determine the accuracy of the pH measurement. If the mucosa tissue pH measurement is significantly different from the P etCO2  measurement, which may occur in very low perfusion states, the pH measurement can be taken again  72  or the P etCO2  measurement can be relied upon to indicate the level of perfusion failure. Once the pH measurement is accurate, the sensors generate  76  an electrical signal in response to the detected pH and P etCO2 . The signal is converted  78  into an indicator of the level of perfusion. The indicator of the level of perfusion is displayed  80  to a clinician on display unit  16 .  
         [0051]    Various features and advantages of the invention are set forth in the following claims.