Abstract:
A device and a method for preventive treatment of evolving pulmonary edema in patients which are at risk of complication associated with pulmonary edema which is based on the monitoring of internal thoracic impedance of the patient. The device extracts the internal thoracic impedance from measured trans-thoracic impedance and is relatively immune to variations in skin/electrode interface impedance. The method includes identification of a stage of interstitial edema development before the appearance of a clinical indication and the beginning of an appropriate medicinal treatment in accordance to variations of the monitored internal thoracic impedance. The method also indicates the appropriate moment for terminating the medicinal treatment and can be applied when the patient and his treating physician are positioned at remote locations.

Description:
FIELD AND BACKGROUND OF THE INVENTION 
       [0001]    The present invention relates to a method of medical treatment in general and to a method for prevention the clinical onset of the alveolar pulmonary edema in patients suffering diseases which are complicated with this pathological condition. 
         [0002]    Pulmonary edema is an excessive accumulation of liquid in the lungs. It is a dangerous common complication of many, especially heart diseases (congestive heart failure, myocardial infarction, arterial hypertension, heart valves disease) and trauma, etc. 
         [0003]    Results of treatment of evolving pulmonary edema can be improved significantly if it starts as early as possible to the appearance of clinical indications, at the stage of interstitial edema. 
         [0004]    This is so because at the alveolar stage of pulmonary edema a vicious cycle has already started, it means that edematous liquid already fills lungs alveoli and forces them out of air. This impedes the blood O 2  saturation in the lungs and leads to general hypoxemia which may cause myocardial hypoxia with additional weakness of the cardiac muscle. 
         [0005]    This in turn increases further the heart failure and the subsequent increase of the accumulation fluid into the alveolus which further decreases blood O 2  saturation and vice versa. 
         [0006]    Early treatment intervention at the stage of interstitial edema before alveolar lung and vicious cycle starts have to prevent alveolar edema development and prevents its extremely painful and dangerous complications, thus for an efficient preventive treatment, pulmonary edema must be detected and treated in time, in its interstitial stage before the appearance of clinical signs. 
         [0007]    The mentioned above objects of early detection of the interstitial stage of evolving pulmonary edema, the early onset of its preventive treatment and the treatment termination can be achieved provided that there exists a method for continuous monitoring the lungs condition of patients suffering from diseases which pose a risk of the pulmonary edema development. 
         [0008]    Process of Pulmonary edema development is associated with fluid buildup in the lungs which causes therefore a decrease in electrical impedance across the lungs, a parameter which is termed herein after as lung impedance (LI). 
         [0009]      FIG. 1  shows a correlation between LI and the amount of water in the lungs, accordingly, a persistent decrease in LI is indicative of a buildup of electrically conductive fluid in the lungs. 
         [0010]    Thus, devices and method have been proposed to monitor the onset and advance of pulmonary edema by techniques of surface impedance plethysmography, in which the electrical impedance of the chest is measured by imposing an electrical current across the body via a set of attached electrodes and measuring the associated voltage difference which arises. 
         [0011]    A main problem for early prediction of pulmonary edema development in prior art surface methods and devices was inability to diagnose small changes in LI at the stage of interstitial congestion (preclinical stage) because of low sensitivity of most existing medical devices and lack of appropriate methodology. 
         [0012]    Typically, surface devices and methods in use today diagnose already existing alveolar edema and no method is available for prediction of the onset of pulmonary edema and for its preventive treatment. 
         [0013]    Generally, the LI has to be extracted from a measured trans-thoracic impedance which includes parasitic contribution such as electrode/skin contact impedance and the impedance of skin, hence allegedly a more accurate and sensitive measurement of LI can be achieved by the use of implanted electrodes, which usually have been inserted in the body for other reasons e.g. for the purpose of defibrillation or heart pacing). 
         [0014]    U.S. Pat. No. 6,595,927 to Pitts-Crick et al. describes a method and system for diagnosing and treating pulmonary congestion which is based on the deviation of a value of measured trans-thoracic impedance as by implanted electrodes from a background base-line. 
         [0015]    U.S. Pat. No. 7,272,443 to Xiaoyi et al. describes the detection of overloads in liquid levels in the thorax and in ventricular myocardial mass of a patient as a result of the pulmonary edema, by impedance measurement across implanted electrodes, 
         [0016]    U.S. Patent application No. 2002 01123674 to Picchi et al. describes a bioelectric impedance measurement by which is carried out by electrodes which are implanted in the lung tissue and which are supposed to overcome all drawbacks of prior LI measurements. 
         [0017]    A description of using implanted electrodes to measure LI in order to follow the fluid status and thus the early monitoring pulmonary edema development is given in the publication; “Intrathoracic Impedance Monitoring in Patients With Heart Failure, Correlation With Fluid Status and Feasibility of Early Warning Preceding Hospitalization” by Chenk-Man Yu et al. (Circulation, Aug. 9, 2005; 112: 841-846). 
         [0018]    Documentation which describes LI measurement with auxiliary electrode which are disposed across a chest of a patient includes Japanese Patent No. 200128748 to I. Tetsuya, which shows a lung water amount display device to detect the onset of pulmonary edema, and U.S. Pat. No. 7,096,061 to S. Arad which measure the trans thoracic impedance with auxiliary electrodes embedded in a chest belt. 
         [0019]    Conclusions drawn from this collective prior art are: firstly, that while LI measurement with implanted electrode may provide the fluid status in the lung already in early stages of its accumulation, no such reliable and sensitive enough non invasive technique for LI measurement did exist. 
         [0020]    Secondly, that regardless the LI measurement technique, no coherent method of preventive treatment for pulmonary edema exists which takes care of all the aspects of the episode and in particular the determination of the interstitial stage of evolving (onset) of pulmonary edema and the exact moment for impedance-guided starting a preventive treatment, the effect of medicine administered and determining of treatment termination. 
         [0021]    The drawbacks associated with the use of implanted electrode for LI measurements (such as e.g. the implantation being an invasive procedure which is costly and causes inconvenience to the patient and which has low inherent sensitivity because electrode configuration inside the chest), have been recently removed when a device and a method for stable impedance plethysmography was described in U.S. Pat. No. 5,749,369 to P. Rabinovich et al., which is incorporated herein by reference for all purpose as if fully set forth herein. 
         [0022]    The “369” patent, teaches a device in which at least two sets of electrodes are used, the first set of so called measuring electrodes, measures the thoracic impedance across two electrodes which are attached to opposite side of the patient chest, while the other set of electrodes so called references electrodes, measures the skin/electrode impedance which is included in the measured thoracic impedance across the first set of electrodes. 
         [0023]    Subtracting the anterior and posterior skins electrode contact impedance from the impedance measured between the measuring electrodes yields corrected impedance whose change over time accurately reflects the change over time of the internal impedance of the biological object. 
         [0024]    The present invention uses the “369” device to introduce a fundamental change in pulmonary edema treatment concept which takes care of all the aspects of the episode and in particular the determination of the interstitial stage of evolving of pulmonary edema and the exact moment for starting a preventive treatment, the effect of medicine administered and determining of treatment termination. 
       SUMMARY 
       [0025]    The present invention includes a device and method for prediction of alveolar stage of the pulmonary edema in absence of clinical signs in patients with diseases which render a risk of pulmonary edema development, for the preventive treatment and determination of individual doses of the administered medicines and for a knowledgeable decision of the treatment termination. 
         [0026]    In accordance to the present invention there is provided a method for preventive treatment for pulmonary edema in a patient comprising the step of: (a) monitoring an internal thoracic impedance Z ITI  (which approximates LI) of the patient, (b) establishing an initial value of (Z ITI ) i  to said Z ITI , (c) beginning a medical treatment against edema by administering the patient at least a first dose of medication when a value of said Z ITI  dropped beneath a threshold value while continuing monitoring and updating said Z ITI  and, (d) deciding on further treatment possibilities in accordance to said updated value of said Z ITI  wherein said possibilities are selected from the group consisting of administering an additional amount of said at least first dose of medicine, increasing the administered amount of medicine, administering a different medicine and termination of the treatment. 
         [0027]    In accordance to the present invention there is provided a device for predicting of evolving of pulmonary edema in a patient which is based on measurements of internal thoracic impedance of the patient, the device comprising: (a) a first measuring electrode and a second measuring electrode to be attached to a patient outer skin, (b) a first set and a second set of reference electrodes to be attached to a patient outer skin, each set among said first set and second set of reference electrodes consist of a first electrode and a second electrode, (c) a first impedance measuring circuit for measuring a first impedance across said first and said second measurement electrodes, (d) a first impedance measuring assembly to evaluate a first contact impedance across contact of said first measuring electrode with said skin of said patient, (e) a second impedance measuring assembly to evaluate a second contact impedance across contact of said second measuring electrode with said skin of said patient, (f) a mechanism to calculate said internal thoracic impedance by subtracting a value which equals to the sum of said first contact impedance and said second contact impedance from said first impedance and, (g) a transmitter to transmit said values of said internal thoracic impedance. 
         [0028]    In accordance to the present invention there is provided a system for preventing pulmonary edema comprising of: (a) a device for prediction of pulmonary edema in a patient which is based on measurements of internal thoracic impedance of the patient, (b) a transmitting unit to deliver data including values of said measured internal trans-thoracic impedance and, (c) a receiver to accept said delivered data. 
         [0029]    It is an object of the present invention to introduce a novel and effective method of a preventive treatment of pulmonary edema. 
         [0030]    It is another object of the present invention to introduce a method for early detection of an interstitial stage of an interstitial stage of evolving pulmonary edema prior to appearance of clinical indications. 
         [0031]    It is yet another aim of the present invention to introduce a method to enable a knowledgeable decision on the termination of medical treatment of pulmonary edema. It is still another aim of the present invention to enable a patient to get a treatment to evolving pulmonary edema by a remote physician. 
         [0032]    Other benefits of the present invention will become evident in conjunction with the accompanying figures. 
     
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         [0033]      FIG. 1  shows a correlation between water content in the lungs and the lung&#39;s electrical impedance (LI). 
           [0034]      FIG. 2  shows a bock diagram of an edema guard monitor (EGM) in accordance to the present invention, 
           [0035]      FIG. 3  shows a block diagram of an internal thoracic impedance measuring unit in EGM unit shown in  FIG. 2 , 
           [0036]      FIG. 4  shows electrode configuration needed for internal thoracic impedance measurement by the unit shown in  FIG. 3 , 
           [0037]      FIG. 5  shows a graphically, stages in pulmonary edema treatment in accordance to the present invention and, 
           [0038]      FIG. 6  shows a flowchart of the stages of evolving pulmonary edema treatment in accordance with the present invention. 
       
    
    
     DESCRIPTION OF PREFERRED EMBODIMENTS 
       [0039]    The present embodiments herein are not intended to be exhaustive and to limit in any way the scope of the invention; rather they are used as examples for the clarification of the invention and for enabling of other skilled in the art to utilize its teaching. 
         [0040]      FIG. 2  depicts a block diagram of an edema guard monitor (EGM) device  30 , suitable for the implementation of the method of the present invention. 
         [0041]    In  FIG. 2 , device  30  includes an impedance measuring unit  31  and a telemetry unit  32  to transmit and receive data either via interface  33  which physically connects device  30  to an external processor or telephone line (not shown) or by a wireless transmitter  34  via a wireless link to a computer or a cellular device (not shown). 
         [0042]    Impedance measuring unit  31  can be any prior art measuring device (outside the body or implanted) which has the appropriate measuring range, stability and resolution to extract LI from trans-thoracic measurement, preferably unit  31  consist of impedance measuring unit  340  shown in  FIG. 6  in the “369” patent which is depicted in  FIG. 3 . 
         [0043]    In  FIG. 3 , impedance measuring unit  31  includes: a current source  300 ; a commutator  302  for alternately connecting current source  300  to a distinct electrical circuit; a rectifier  304  for obtaining the absolute value of the signals representing the voltage drops across the various electrodes in a preferred configuration that will be detailed below; an analog to digital converter  306  for converting the signals to a digital form; an arithmetic-logic unit  310  for carrying out calculations; a data-storage unit  312  for storing data during the monitoring period; a display unit  314 ; an alarm unit  316 ; and a control unit  308  for controlling the operation of commutator  302 , arithmetic-logic unit  310 , data storage unit  312 , and display unit  314 . Arithmetic-logic unit  310  is electrically connected to data-storage unit  312 , display unit  314 , and alarm unit  316 . Unit  31  is powered by means of a power supplier  318 . 
         [0044]    When using a device according to the present invention, electrical source  300  is alternately connected to each of the electrode pairs shown in  FIG. 4  by means of commutator  302 . The signal representing the voltage drop of a specific electrical circuit is fed into rectifier  304  which provides the absolute value of such voltage drop. An analog to digital converter converts the obtained signal to a digital form. The obtained signal is fed into arithmetic logic unit  310  and stored in data-storage unit  312 . Then, control unit  308  orders commutator  302  to connect electrical source  300  to the next electrical circuit. 
         [0045]    After storage unit  312  has received data from each of the seven electrical circuits, arithmetic logic unit  310  calculates an internal thoracic impedance ZIT, according to the method which will be described below. 
         [0046]    Preferably, the process described above is carried out periodically, so that arithmetic logic unit  310  simultaneously calculates the values of the internal thoracic impedance Z ITI  as well as changes in Z ITI . The change in Z ITI  may be calculated, for example, as the difference between the last value and the initial value or as a percentage from the initial value. The results of the calculations are transmitted to display unit  314 , to data storage unit  312 , and to alarm unit  316 . 
         [0047]    In the event that the value of Z ITI  has decreased below a critical value, and/or in the event that the change in Z ITI  has exceeded a critical value, alarm unit  316  is activated. 
         [0048]    Data storage unit  312  may provide data for analysis during the monitoring period so as to monitor the progress of the disease. 
         [0049]    Electrodes for trans thoracic impedance measurement and for Z ITI  evaluation, either implanted or surface electrodes are booked to unit  31  via suitable connector (not shown) and are attached to patient body  10  in any configuration known in the art, preferably, electrode configuration  40  shown in  FIG. 4  and which is used in conjunction with measuring unit  31  is employed. 
         [0050]    In configuration  40 , measurement electrodes  1  and  2  are placed on opposite sides of the thorax of a patient  10 . Electrode  1  is placed at the point of intersection of the right 3-intercostal space and the right mid clavicle line of patient  10 . Measurement electrode  2  is placed on the back of patient  10 , at the point of intersection of the right 8-intercostal space and the right scapular line. 
         [0051]    Reference electrodes  3  and  5  are placed on opposite sides of electrode  1 , and reference electrodes  4  and  6  are placed on opposite sides of electrode  2 . 
         [0052]    The internal thoracic impedance Z ITI  is automatically calculated by device  31  as described in the “369” patent from the trans thoracic impedance measured between electrodes  1  and  2 ; Z 1,2 . 
         [0053]    Z 1,2  includes the skin and the electrode/skin contact impedances of both electrode  1  and electrode  2 , hence in order to extract Z ITI  from measured Z 1,2  these impedance contributions are subtracted from Z 1,2  as follows: 
         [0054]    Assume Z i,j  denotes the impedance measured between electrode i and electrode j as shown in  FIG. 4 , then 
         [0000]        Z   ITI   =Z   1,2 −½( Z   1,5   +Z   1,3   −Z   3,5 )−½( Z   2,4   +Z   2,6   −Z   4,6 ) 
         [0055]    This is so because the term ½(Z 1,5 +Z 1,3 −Z 3,5 ) represents the skin and skin/electrode contact impedance of electrode  1  and the term ½(Z 2,4 +Z 2,6 −Z 4,6 ) represents the skin and skin/electrode contact impedance of electrode  2 . 
         [0056]    Z ITI  obtained according to the procedure described above was found to be a drift free value. 
         [0057]    An important point to notice is that though Z ITI  may differ from the lung impedance (LI) because contribution of other inner tissues to the impedance, changes in Z ITI  of a patient posed at risk of pulmonary edema will nearly exclusively reflect the changes in LI because the impedance of the other inner tissues stay about constant. 
         [0058]    It should be noted that other combinations of inter-electrode impedances which can be used to evaluate Z ITI  do not limit the present invention and are included within the scope thereof. 
         [0059]    When a prediction of a patient at home, in hospital or in a health care center suggests a suspicion for an illness which may induce development of pulmonary edema when clinical signs for pulmonary edema are yet absent, the patient is attached to EGM  30  and monitoring of Z ITI  begins. 
         [0060]    It should be noted however that the method described below is not limited to EGM  30 , rather it can be implemented with other suitable device for impedance plethysmography and by using different electrodes (regardless whether external or implanted) which measure Z ITI  or its equivalent 
         [0061]    Measurements of Z ITI  should be taken repetitively, e.g. at least each 30 minutes. The average value of initially measured Z ITI  is designated as (Z ITI ) i  and serves as a reference point to which further measured Z ITI  are compared. 
         [0062]    Applicants of the present invention correlated quantitatively the value of Z ITI  to stages in the evolution of pulmonary edema, their finding are shown in graph  50  of  FIG. 5  where the changes of Z ITI  of a patient which develops pulmonary edema with time are shown. 
         [0063]    Stages of early prediction, subsequent treatment and terminating the treatment of evolving pulmonary edema which are based on continuously or periodically monitoring Z ITI  as described above, are shown in  FIG. 5  as well. 
         [0064]    In graph  50 , Z ITI  data is shown by error bars. The flat segment  51  in the value of Z ITI  reflects the stage prior to interstitial edema from which a reference base line and the value of (Z ITI ) i  is deduced, the beginning of the stage of interstitial edema is indicated by a decrease in Z ITI . 
         [0065]    The intensifying of interstitial edema which is shown in section  52  has no clinical signs but is detectable by the monotonically drop in Z ITI . 
         [0066]    Z ITI  values which correspond to a relative decrease of less than 12% then the value of (Z ITI ) i  reflect interstitial pre-clinical (as revealed by X-rays investigation) stages of evolving pulmonary edema which are not dangerous to the patient while a decrease of beyond about 12% from the value of (Z ITI ) i  indicates a stage of transformation from interstitial edema to alveolar edema (which is also observed by X-rays investigation), this stage has also no clinical signs. 
         [0067]    When alveolar lung edema initiates, Z ITI  decreases by at least about 17% then the initial (Z ITI ) i . 
         [0068]    Applicants of the present invention disclose that the most effective preventive treatment for evolving pulmonary edema is accomplished if medical treatment starts at the preclinical stage, preferably at the stage of interstitial edema, hence a threshold of about 12% in the relative decrease of Z ITI  with respect to (Z ITI ) i  as indicated by the line designating 0.88(Z ITI ) i  shown in  FIG. 5 , is selected for the instant of the beginning of medical treatment for evolving pulmonary edema. 
         [0069]    It should be noted however, that the exact value of the threshold does not limit the present invention and different values for said threshold can be used as a function of the state of health of the patient such as e.g. Z ITI  values of between about 10% to about 15% lower then the value of (Z ITI ) i . 
         [0070]    If the threshold value of Z ITI  has been reached a treatment which is based on the administration of the proper medication begins. This moment is indicated by arrow  55  in  FIG. 5 , if within a next preselected period of time, e.g. within half an hour since said administration of the medication the value of Z ITI  further decreases in spite the treatment, a more aggressive dose of medication, or another medication are administered as shown by arrow  56  in  FIG. 5 . 
         [0071]    If on the other hand, as a result of the administration of the medications, variations in the value of Z ITI  reverse direction and the value of Z ITI  increases as shown in sections  53  and  54  in  FIG. 5 , said administration should be continued until the value Z ITI  of closely meets the value of (Z ITI ) i , Then the treatment is terminated as shown in arrow  57  in  FIG. 5 . 
         [0072]    The method which was detailed above is summarized in flowchart  60  shown in  FIG. 6 . 
         [0073]    In flowchart  60 , the method starts in measuring Z ITI  repeatedly each time interval T and logging the measured values as shown in stage  61 . The method continues to stage  62  where a value of (Z ITI ) i  is established from the initial measurements which were taken. 
         [0074]    In stage  63  which proceeds, it is inspected whether Z ITI  decreases, if Z ITI  does not decrease for a sufficient time, the Doctor may decide on treatment termination (or prohibiting treatment initiation in this case) as shown in stage  70 , otherwise it is probed whether Z ITI  reached the threshold value of 0.88(Z ITI ) i  needed for treatment initiation as shown in stage  64 . 
         [0075]    If Z ITI  reached or passed said threshold, treatment begins as shown in stage  66 , if it did not, treatment will not yet be started. 
         [0076]    Stage  67  which proceed, probes whether Z ITI  increases as a result of the applied treatment. If it increased it will be checked whether the value of Z ITI  nearly reached again that of (Z ITI ) i  and if so, treatment ends (subjected to the doctor approval) as shown in stage  70   
         [0077]    If however Z ITI  does not increase, stage  68  probes its value in order to decide on a more aggressive treatment designated as stage  69 , which should be executed in case Z ITI  reached or passed a second threshold value of 0.83(Z ITI ) i . 
         [0078]    When an improvement is observed as a result of the aggressive treatment and the value of Z ITI  is no more smaller then about 0.88(Z ITI ) i , the treatment can be alleviated to the level which corresponds to stage  66 . 
         [0079]    The treatment ends, in subjection to the doctor approval when the value of Z ITI  returns to the value of (Z ITI ) i  as shown in stage  70 . 
         [0080]    A preferred implementation of the present invention is occurs when the patient and the doctor who predicts the patient&#39;s evolving pulmonary edema are located in remote places, e.g. at different department of a hospital, at two different hospitals, or when the patient resides at home while the doctor which is positioned remotely orders on its emergent hospitalized in accordance to the value of the Z ITI  which he receives from telemetry unit  32  of device  30 . 
         [0081]    Such information can be transferred via any known wired or wireless mechanism of data-link such as modem, cellular, internet or RF communication. 
       EXAMPLE 
       [0082]    The utility of the present invention is demonstrated by the following example: 
         [0083]    68 patients with acute myocardial infarction were admitted to 3 cardiology departments in Israel. All 68 patients suffered from acute myocardial infarction (AMI). The inclusion criterion to the test were absents of clinical and Roentgenological signs of lung edema at the beginning of monitoring and the decrease of the value of Z ITI  value by 12% (and more) compared to the value of (Z ITI ) i  during the monitoring. According X-ray examinations all patients were at interstitial stage of evolving pulmonary edema. 
         [0084]    The 68 patients were then divided into 2 groups of 34 patients each. The first group of 34 patients was treated immediately after the value of Z ITI  decreased beyond the said 12% threshold (Preventive Treatment Group-PT group). The remaining 34 patients were treated conventionally, i.e. only after the appearance of Pulmonary Edema clinical signs (No-preventative Treatment Group—NPT group). Such parameters as mean age, the male/female ratio, height, weight and initial Z ITI  were identical in two groups. 
         [0085]    The pulmonary edema did not develop in 29 of 34 patients who received the preventive treatment (PT group) and developed in mild form in the remaining 5 patients of this group. No fatal outcomes were observed. X-ray examinations have confirmed absence alveolar edema in 29 patients without clinical signs of edema and development alveolar edema in 5 rest patients. 
         [0086]    The pulmonary edema was developed in all 34 patients who have not received the preventive treatment (NPT group) with 4 fatal cases (p&lt;0.001). In all patients were found signs of alveolar edema on X-ray examinations. 
         [0087]    While the invention has been described with respect to a limited number of embodiments, it will be appreciated that many variations, modifications and other applications of the invention may be made without departing from the scope and spirit of the invention.