Abstract:
A method for determining the hemodynamic state of a subject. The method comprises (a) determining the cardiac power index (Cpi) and systemic vascular resistance index (SVRi) values of a plurality of patients who have been diagnosed as having a specified hemodynamic state; (b) determining the range of Cpi and SVRi paired values corresponding to each of the hemodynamic states; (c) determining the Cpi and SVRi paired value of the subject; (d) comparing the Cpi and SVRi paired value of the subject to the ranges of Cpi and SVRi paired values determined in step (b); and (e) determining the range of Cpi and SVRi paired values which is most similar to the Cpi and SVRi paired value of the subject. The hemodynamic state which corresponds to the range indicates the hemodynamic state of the subject.

Description:
FIELD OF THE INVENTION  
         [0001]    This invention relates to the determination of the hemodynamic state of a patient by use of parameters of cardiac and peripheral vascular performance.  
         BACKGROUND OF THE INVENTION  
         [0002]    The following references may be relevant to the understanding of the invention, and are referred to in the specification by number:  
           [0003]    1. Roul G, Moulichon M. E., Bareiss P, Gries P, Koegler A, Sacrez J, Germain P, Mossard J. M., Sacrez A,  Prognostic factors of chronic heart failure in NYHA class II or III: value of invasive exercise haemodynamic data.  Eur Heart J (1995); 16:1387-98.  
           [0004]    2. Marmor A, Schneeweiss A.  Prognostic value of noninvasively obtained left ventricular contractile reserve in patients with severe heart failure.  J Am Coll Cardiol (1997) Feb;29(2):422-8.  
           [0005]    3. Marmor A, Jain D, Cohen L S, Nevo E, Wackers F J, Zaret B L.  Left ventricular peak power during exercise: a noninvasive approach for assessment of contractile reserve.  J Nucl Med (1993) Nov;34(11):1877-85.  
           [0006]    4. Tan L B.  Cardiac pumping capability and prognosis in heart failure . Lancet (1986) 13(2):1360-63.  
           [0007]    5. Sharir T, Feldman M D, Haber H, Feldman A M, Marmor A, Becker L C, Kass D A.  Ventricular systolic assessment in patients with dilated cardiomyopathy by preload-adjusted maximal power—Validation and noninvasive application . Circulation (1994) May;89(5):2045-53.  
           [0008]    6. Tan L B.  Clinical and research implications of new concepts in the assessment of cardiac pumping performance in heart failure.  Cardiovasc Res (1987) Aug;21(8):615-22.  
           [0009]    7. Cotter G, Metzkor E, Kaluski E, Faigenberg Z, Miller R, Simovitz A, Shaham O, Margithay D, Koren D, Blatt A, Moshkovitz Y, Zaidenstein R, Golik A.  Randomized trial of high-dose Isosorbide Dinitiate plus low-dose Furosamide versus high-dose Furosamide plus low-dose Isosorbide Dinitrate in severe pulmonary oedema . Lancet. (1998); 351: 389-93.  
           [0010]    8. Cotter G, Kaluski E, Blatt A, Milovanov O, Moshkovitz Y, Zaidenstein R. Salah A, Alon D, Mihovitz Y, Metzger M, Vered Z, Golik A.  L - NMMA  ( a Nitric Oxide Synthase Inhibitor )  is Effective in the Treatment of Cardiogenic Shock . Circulation. 2000 Mar 28;101(12):1358-61.  
           [0011]    9. P. D. Sasieni,  Statistical Analysis of the performance of diagnostic tests  (Invited review), Cytopathology, 1999, 10,73-78.  
           [0012]    10. Jeroen G. Lijmer, Ben Willen Mol,Siem Heisterkamp, Gouke J. Bonsel, Martin H. Prins, Jan H. P., van der Meulen, Patrik M. M. Bossuyt.  Empirical Evidence of Design Related Bias in Studies of Diagnostic Tests,  JAMA, 1999, 282,11,1061-1066.  
           [0013]    11. SAS/STAT User&#39;s Guide, Version 6, Fourth Edition. Volume 1, Cary, N.C.:SAS Institute Inc., 1989.  
           [0014]    To date, no correlation has been found between invasive hemodynamic measurements and the clinical syndrome of patients with congestive heart failure (CHF) (1). In patients admitted with acute deterioration in cardiac function such as progressive dyspnea leading to pulmonary edema or cardiogenic shock, and even in patients with systolic chronic stable CHF, the measurement of cardiac index (CI) or systemic vascular resistance index (SVRi i ) has not provided any reliable diagnostic, therapeutic or prognostic value.  
           [0015]    SVR i  is a measure of the resistance of the vascular system to blood flow and is measured in Kg. * M 4 /sec 3  (=wood*M 2 ). In the cardiovascular system, SVR I =(mean arterial blood pressure (MAP)−right arterial pressure)/CI. If not obtainable, right arterial pressure may be estimated as 10-15% of MAP.  
           [0016]    Cardiac power index (Cp i ) is a measure of the contractile state of the myocardium and is measured in watts/M 2 . The measurement of Cp i  is a newly introduced concept in cardiology (2-6). It is based on the physical law of fluids where  
           Power=Flow X Pressure.  
           [0017]    In the cardiovascular system, Cp i  can be measured by replacing flow with cardiac index (CI) and pressure by the MAP.  
           [0018]    Therefore:  
           Cp i =CI X MAP.  
           [0019]    This measurement was partially used in the past (2-6) to evaluate the cardiac contractility of patients with CHF. It may be assumed that in patients with CHF, as Cp i  progressively decreases a compensatory increase of SVR i  occurs, and this increase is predictable within normal ranges. In addition, in patients with acute decrease in Cp i  this SVR i  response could be either (1) adequate—leading to a compensated or near compensated response, (2) excessive—leading to a significantly higher than required MAP increase, thereby leading to pulmonary edema, or (3) insufficient—leading to low MAP, inadequate perfusion of vital organs (brain, heart, kidneys) and cardiogenic shock.  
         SUMMARY OF THE INVENTION  
         [0020]    It is an object of the present invention to provide a method for determining the hemodynamic state of a patient.  
           [0021]    It is a further object of the invention to provide a method for monitoring changes in the hemodynamic state of a patient.  
           [0022]    Thus, the present invention provides a method for determining the hemodynamic state of a subject comprising:  
           [0023]    (a) determining the cardiac power index (Cp i ) and systemic vascular resistance index (SVR i ) values of a plurality of patients who have been diagnosed as having a hemodynamic state selected from the group consisting of systolic congestive heart failure (sCHF), pulmonary edema (PE), cardiogenic shock (CS), vasodilative shock (VS) and normal state;  
           [0024]    (b) determining the range of Cp i  and SVR i  paired values corresponding to each of said hemodynamic states;  
           [0025]    (c) determining the Cp i  and SVR i  paired value of said subject;  
           [0026]    (d) comparing the Cp i  and SVR i  paired value of said subject to the ranges of Cp i  and SVR i  paired values determined in step (b); and  
           [0027]    (e) determining the range of Cp i  and SVR i  paired values which is most similar to the Cp i  and SVR i  paired value of said subject, the hemodynamic state corresponding to said range indicating the hemodynamic state of said subject.  
           [0028]    It has now been surprisingly found that for a given patient, the values of the pair of parameters Cp i  and SVR i  are indicative of the hemodynamic state of the patient. In this specification, the term “paired values” will be used to indicate the Cp i  and SVR i  values of a given patient measured at essentially the same time.  
           [0029]    The method of the present invention enables the determination of the hemodynamic state of a patient by determining only two parameters, Cp i  and SVR i . These parameters may be determined either invasively, e.g. with a Swan-Ganz catheter or arterial line, or non-invasively, e.g. by Echo-doppler or non-invasive blood pressure measurement. The obtained values are then compared to a set of values previously compiled from patients with known hemodynamic states. The comparison may be carried out graphically, by eye, or by calculation (e.g. by computer). The range of Cp i  and SVR i  paired values which is most similar to the Cp i  and SVR i  paired value of said subject will indicate in which group the subject should be classified. Similarity may be determined by eye (for example when using a graph) or by known statistical methods.  
           [0030]    The known hemodynamic states used in the method of the invention are: (1) systolic or compensated CHF (sCHF). This group also includes hypertensive patients (HTN), due to their similar hemodynamic profile and small number in the study; (2) PE; (3) CS; (4) vasodilative or septic shock (VS); and (5) a group termed “normal” which represents patients who do not suffer from CHF. The last group consists of normal patients, i.e. with an SVR i  of approximately 15-35 wood*M 2  and a Cp i  above 190 watt/M 2 .  
           [0031]    The position of the patient&#39;s paired Cp i  and SVR i  values provide an indication as to how to treat the patient. For example, if the paired values are located in the range of values typical of cardiogenic shock, it would be advisable to administer to the patient a treatment which will boost vascular resistance (8). On the other hand, if the paired values are located in the range of values typical for pulmonary edema, it would be advisable to administer to the patient a treatment which will decrease vascular resistance (7).  
           [0032]    Changes in the condition of the patient due either to the natural progression of the disease or to therapeutic treatment, may be easily monitored using the method of the invention by following the change in position of the paired Cp i  and SVR i  values of the patient with respect to the predetermined set of values. In this way, the effectivity of a treatment may be assessed. Thus, the method of the invention may have significant therapeutic implications through pharmaceutical manipulation of SVR i  by vasodilators (nitrates, endothelin antagonists) or vasoconstrictors (L-NMMA, vasopresin).  
           [0033]    A graph prepared according to the method of the invention may appear, for example, on the display of a monitor, so that the measured Cp i  and SVR i  values of a patient can be immediately plotted on the graph in order to determine the patient&#39;s “real time” condition.  
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0034]    In order to understand the invention and to see how it may be carried out in practice, a preferred embodiment will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:  
         [0035]    [0035]FIG. 1 shows CI (litter/minute/M 2 ) in the six following diagnosed groups: CS, PE, HTN, sCHF, normal and VS;  
         [0036]    [0036]FIG. 2 shows Pulmonary Capillary wedge pressure (mmHg) in the 6 groups;  
         [0037]    [0037]FIG. 3 shows Cpii (watt/M 2 ) in the 6 groups;  
         [0038]    [0038]FIG. 4 shows SVRii (wood*M 2 ) in the 6 groups; and  
         [0039]    [0039]FIG. 5 is a graph in which the Y-axis indicates Cp i  units (in watts/M 2 ) and the X-axis indicates SVR i  units (Wood*M 2  units). The graph (also termed in this specification a “nomogram”) is used for classification of the hemodynamic status of patients and may be constructed by a method of statistical analysis according to one embodiment of the method of the invention. Normal patients are indicated by (Δ), PE patients are indicated by (□), CS patients are indicated by (O), VS patients are indicated by (*) and sCHF and HTN patients are indicated by (). 
     
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS  
     Example 1  
       [0040]    Determination of hemodynamic state by graphic means  
         [0041]    Patients and Methods.  
         [0042]    Hemodynamic data was obtained in patients undergoing right heart catheterization.  
         [0043]    Inclusion Criteria:  
         [0044]    All patients who were diagnosed by conventional clinical criteria (see below) as having systolic CHF (sCHF), hypertensive crisis, acute pulmonary edema (PE), vasodilative shock or cardiogenic shock were included.  
         [0045]    Exclusion Criteria:  
         [0046]    Significant valvular disease, significant brady- or tachy-arrhythmias or renal failure (creatinine&gt;2.5 mg/dl).  
         [0047]    Clinical Diagnosis Criteria:  
         [0048]    1) Systolic CHF: Patients admitted for invasive hemodynamic assesment due to CHF exacerbation, defined as clinical symptoms and signs of CHF, NYHA class III-IV, accompanied by EF&lt;35% on echocardiography and not treated with any oral drugs for 6 hours or intravenous drugs for the last 2 hours; not fulfilling the criteria for cardiogenic shock or pulmonary edema.  
         [0049]    2) Pulmonary edema: patients admitted due to clinical symptoms and signs of acute pulmonary congestion accompanied by findings of lung edema on chest X-Ray and O 2  saturation&lt;90% on room air by pulse oxymetery during invasive measurements.  
         [0050]    3) Cardiogenic shock: Systolic blood pressure&lt;100 mmHg for at least one hour after percutaneous revascularization due to an acute major coronary syndrome not responsive to revascularization, mechanical ventilation, Intra-Aortic Balloon-Pump (IABP), IV fluids administration and dopamine of at least 10 μg/kg/min and accompanied by signs of end organ hypoperfusion but not accompanied by fever&gt;38° or a systemic inflammatory syndrome.  
         [0051]    4) Vasodilative shock: Systolic blood pressure&lt;100 mmHg accompanied by fever&gt;38°, systemic inflammatory syndrome and signs of end organ hypoperfusion for at least 3 hours not responsive to IV fluids and IV dopamine of at least 10 μg/kg/min.  
         [0052]    5) Hypertension: MAP&gt;135 mmHg without signs of end-organ hypoperfusion, ischemia or pulmonary edema These patients were included in the sCHF group.  
         [0053]    Hemodynamic Variables assesment:  
         [0054]    In all patients the hemodynamic variables were obtained during right heart catheterization using a Swan-Ganz cathteter placed under fluroscopic guidence. All measurments were obtained while patients were at least 30 seconds without IABP while on the same treatment used at the time the clinical diagnosis was made.  
         [0055]    CI was measured by thermodilution using the mean of at least 3 consecutive measurements within a range of &lt;15%. In Normal subjects, right heart catheterization was not performed due to ethical concerns. The values used in this cohort were obtained by standard non-invasive cuff blood pressure measurement and evaluation of CI by the FDA-approved NICaS 2001, a non-invasive on-line cardiac output monitor (Cohen J A, Arnaudov D, Zabeeda D, Schlthes L, Lashinger J, Schachner A.  Non-invasive measurment of cardiac output during coronary artery bypass grafting . Eur. J. Card. Thoracic Surg. 1998; 14: 64-9). Therefore, wedge pressure was not assessed in normal subjects. Instead, we used standard values documented in the litterature (Lange R A, Hillis L D.  Cardiac catheterization and hemodynamic assessment . In: Topol E J; Textbook of Cardiovacular Medicine).  
         [0056]    Hemodynamic variables calculation:  
         [0057]    Cp i  was determined as MAP×CI and SVR i  was determined as (MAP−right atrial pressure)/CI. As right atrial pressure was not measured in normal subjects, it was estimated to be 10% of MAP.  
         [0058]    Results:  
         [0059]    One hundred consecutive patients (56 patients with systolic CHF, 5 patients with HTN crisis, 11 patients with pulmonary edema, 17 patients with cardiogenic shock and 11 patients with vasodilative shock) and twenty healthy volunteers were enrolled in the study. The mean CI, wedge pressure, MAP, SVR i  and Cp i  according to clinical diagnosis are presented in Table 1 and as box-plots in FIGS.  1 - 4 . Since the number of patients with hypertensive crisis (HTN) was too small to yield a statisticaly meaningful analysis, they were incorporated into the systolic CHF group for all further analysis.  
                                     TABLE 1                           The means and standard deviations of various parameters in       the 5 diagnosis groups            GROUP   No. Obs.   Variable   Mean   Std. Dev.               CHF   61   SVRiI    44.8666667    8.0327015               CPI   210.6833333   60.1848823               WEDGE    25.5166667    7.1556347               MAP   101.1833333   17.9806786               CI    2.0611667    0.3313153       Pulmonary   11   CVRI    88.1818182   16.7380894       Edema       CPI   182.2727273   57.3673965               WEDGE    32.7272727    8.6033820               MAP   131.3636364   12.6828445               CI    1.3727273    0.3196589       Normal   20   SVRiI    25.1500000    4.0817308               CPI   280.0000000   35.7402913               WEDGE   —   —               MAP    87.9000000    8.8549718               CI    3.2000000    0.3568871       Septic Shock   11   SVRiI    11.8181818    1.1241158               CPI   358.1818182   56.4921555               WEDGE    11.3636364    7.6976974               MAP    68.1818182    5.4372453               CI    5.2181818    0.5344496       Cardiogenic   17   SVRiI    55.6375000   31.0761833       Shock       CPI    98.9375000   34.9866046               WEDGE    23.3125000    6.5086481               MAP    72.1875000   11.2973079               CI    1.4218750    0.6426427                  
 
         [0060]    Hemodynamic Variables:  
         [0061]    1) Cardiac Index (CI) (FIG. 1): The mean values of CI were significantly lower in patients with systolic CHF, pulmonary edema and cardiogenic shock compared to normals and higher in patients with vasodilative shock. ROC analysis found the cut-off point of CI&lt;2.7 Lit./min./M 2  useful for the determination that a patient has any kind of heart failure (either systolic CHF, pulmonary edema or cardiogenic shock)(sensitivity=1, specificity=0.99). However, values between 1.2-2.7 Lit./min./M 2  could be found in all patients with systolic CHF, 73% of patients with pulmonary edema and 47% of patients with cardiogenic shock. Moreover, the mean CI of patients in pulmonary edema and cardiogenic shock was found to be almost identical (1.4±0.4 vs 1.35±0.7 L/min/M 2 , p=ns).  
         [0062]    2) Mean Arterial Blood Pressure (MAP): As compared to normals, the mean values of MAP were significantly higher in patients with pulmonary edema and by definition, higher in patients with HTN crisis and lower in vasodilative and cardiogenic shock. Despite this, large areas of overlap were found regarding MAP measurments between pulmonary edema, systolic CHF and HTN crisis (MAP&gt;100 mmHg) and between systolic CHF, cardiogenic shock and vasodilative shock (MAP&lt;100 mmHg).  
         [0063]    3) Pulmonary capillary wedge pressure (FIG. 2): As compared to normals, the mean wedge pressure was significantly higher in patients with systolic CHF and pulmonary edema and lower in patients with vasodilative shock. The analysis was based on the normal values for wedge pressure reported in the literature (&lt;12 mmHg (8))(p=0.001). However, the overlap of wedge pressure values among the groups was very extensive. Values between 12-38 mmHg were found in 82% of patients with systolic CHF, 64% of patients with pulmonary edema, 76% of patients with cardiogenic shock, and 18% of patients with vasodilative shock.  
         [0064]    4) Cardiac Power index (FIG. 3): As compared to normals, the mean values of Cp i  were low in patients with systolic CHF and pulmonary edema, extremely low in patients with cardiogenic shock and high in patients with HTN crisis and vasodilative shock. However, some overlap was encountered among the 5 groups. Values of 200 to 300 Watt/M 2  were measured in 75% of normal people, 39% of patients with systolic CHF, 27% of patients with pulmonary edema, 18% of patients with vasodilative shock but none of the patients with cardiogenic shock (in whom Cpi was consistently below 170 Watt/M 2 .  
         [0065]    5) Systemic Vascular Resistence Index (FIG. 4): As compared to normals, the mean values of SVR i  were significantly higher in patients with systolic CHF and HTN crisis, extremely high in patients with pulmonary edema and lower in patients with vasodilative shock. ROC analysis found the cut-off point of SVR i &lt;35 wood*M 2  to be useful in discriminating normal subjects from patients with any CHF syndrome (specificity=1, sensitivity=0.95). Also, SVR i  was found instrumental in the diagnosis of pulmonary edema: all patients with this clinical syndrome had SVR i &gt;67 wood*M 2  while SVR i  values in all other patients as well as normal subjects were significantly lower than this value.  
         [0066]    Cpi/SVRi graph (FIG. 5):  
         [0067]    Distributions of SVR i  and Cp i  were highly skewed, whereas log(SVR i ) and Log(CP i ) were less skewed. Therefore, for her analysis only Log of the indices was used. However, the graph was constructed using values translated back from the Log values.  
         [0068]    The distributions of the two log-parameters were different between groups. However, neither of the individual parameters enabled separation among the five groups, as shown in Table 2. 
                                                                                                                     TABLE 2                           Number of Observations Classified into the Correct Clinical Group       Using Log(Cpi) or Log(SVRi) only.                Cardio-                           By Clinical   genic   Systolic       Pulmonary   Septic           diagnosis→   Shock   CHF   Normal   Edema   Shock   Total                    (1) Classification using Log(CPi) only.       By       Parameters↓            Cardiogenic   13    4   0   0   0   17       Shock       Systolic CHF   1   44    14    0   2   61       Normal   0   9   8   0   3   20       Pulmonary   1   9   1   0   0   11       Edema       Septic Shock   0   0   3   0   8   11            (2) Classification using Log(SVIRi) only.       By       Parameters↓            Cardiogenic   2   12    1   2   0   17       Shock       Systolic CHF   0   58    3   0   0   61       Normal   0   3   17    0   0   20       Pulmonary   2   0   0   9   0   11       Edema       Septic Shock   0   0   0   0   11    11                  
 
         [0069]    These data suggested that the separation may be obtained using two dimensional discriminant analysis. We used classical discriminant analysis for Normal distributions with unequal covariance matrices because the small numbers of observations in two groups prevented from using more flexible kernel functions.  
         [0070]    Due to large variability of variances of the parameters in the five groups, we could not suppose equal covariance matrices in the groups. (The test of homogeneity of within covariance matrices gives P&lt;0.0001).  
         [0071]    Classification using the nomogram.  
         [0072]    In order to determine the state of a patient, his Cp i  and SVR i  are determined, and the paired values are plotted on a graph, e.g. FIG. 5. The location of the measured paired values on the graph indicates which clinical condition may be assigned to the patient.  
         [0073]    The vascular response to decreased cardiac performance is crucial in determining the clinical syndrome of CHF. Insufficient SVRi increase may cause cardiogenic shock while excessive vasoconstriction will induce progressive pulmonary congestion resulting in frank pulmonary edema. The exact mechanism of deterioration of each patient can be determined using measurements of CI and MAP and a simple nomogram. This can have extensive therapeutic implication through pharmaceutical manipulation of SVRi. For example, ISDN can be used to move patients from PE to cCHF, and 1-NMMA can be used to move patients from cardiogenic shock.  
       Example II  
       [0074]    Determination of hemodynamic state using statistical analysis  
         [0075]    Another embodiment of the method of the invention will be illustrated by means of the example given below. However, it will be clear to the skilled man of the art that other embodiments using other statistical methods of analysis are possible.  
         [0076]    1. Data  
         [0077]    Statistical Methods:  
         [0078]    The five clinical groups were compared with regard to all parameters using a one-way Analysis of Variance. The Ryan-Einot-Gabriel-Welsch Multiple Range Test was used for pair-wise comparisons between the groups, while Dunnett&#39;s T test was used to compare all groups to the healthy controls.  
         [0079]    A one-sample t-test was performed to compare mean Wedge pressure in each group to the wedge pressure of normal people (less than 12 mmHg).  
         [0080]    In order to determine the usefulness of the hemodynamic parameters to discriminate between the clinical syndromes, ROC curves, derived from a Logistic regression model were applied to the data to determine the best cutoff point of various parameters in terms of highest sensitivity and specificity.  
         [0081]    Cpi/SVRi normogram:  
         [0082]    A classification rule was developed using second order discriminant analysis. Firstly both variables (CP i  and SVR i ) were transformed into Log scale for better approximation to normality. Since the number of patients with HTN was small, they were incorporated into the systolic CHF group. The classification used two steps. In the first step the rule separated three classes: Vasodilative shock Cardiogenic shock and combined group, which includes Normal patients, systolic CHF and Pulmonary Edema (N-C-P). If after the first step the patient was defined as N-C-P, the second classification was used for separation among Normal, Systolic CHF and Pulmonary Edema subgroups.  
         [0083]    All calculations were performed by SAS 6.12 [SAS Institute Inc., Cary, N.C.] using procedures FREQ, MANS, GLM, DISCRIM, GPLOT.  
         [0084]    2. Classification rule.  
         [0085]    A. Classification using calculations.  
         [0086]    Step 1. Calculate three values v1, v2, v3 according to the formulas below.  
           v 1 =LCPi 2*21.54+2* LCPi*LSVRi* 10.61 +LSVRi 2*59.44− LCPi* 305.24 −LSVRi* 417.70+1408.89  
           v 2 =LCPi   2 *10.12+2* LCPi*LSVRi* 5.67− LSVRi 2*4.99− LCPi* 135.81− LSVRi* 90.11+482.61  
           v 3 =LCPi 2*7.29 +LCPi*LSVRi* 2.57+ LSVRi 2*4.09− LCPi*  97.41− LSVRi* 58.22+368.16  
         [0087]    Classify the patient  
         [0088]    into the group ‘Vasodilative shock’, if v1 is the smallest value  
         [0089]    into the group ‘Cardiogenic Shock’, if v2 is the smallest value  
         [0090]    if v3 is the smallest value go to step 2  
         [0091]    Step 2. Calculate three values v4, v5, v6 according to the formula below.  
           v 4 =LCPi 2*6.45−2* LCPi*LSVRi* 0.45+ LSVRi 2*16.01− LCPi* 65.16− LSVRi*  116.53+391.67  
           v 5 =LCPi 2*17.75+2* LCPi*LSVRi* 26.56 +LSVRi 2*54.27− LCPi* 420.26− SVRi* 758.55+2775.78  
           v 6 =LCPi 2*32.95+2* LCPi*LSVRi* 3.09 +LSVRi 2*19.72− LCPi* 390.74− LSVRi* 161.49+1355.57  
         [0092]    Classify the patient  
         [0093]    into the group ‘Systolic CHF’, if v4 is the smallest value among v4, v5, v6 and LSVRi&lt;Log(67)  
         [0094]    into the group ‘Pulmonary Edema’, if v5 is the smallest value among v4, v5, v6 and LSVRi&gt;Log(67)  
         [0095]    into the group ‘Normal’, if v6 is the smallest value among v4, v5, v6  
         [0096]    The value of SVRi=67 was used to separate patients with systolic CHF from patients with pulmonary edema since the group of ‘pulmonary edema’ was rather small and by classifying these patients according to the usual rule we did not receive a separating line for Cpi measures&gt;250 Watt/M 2 . Therefore, the line of SVRi=67 wood*M 2  was used as an approximation of the classification results.  
         [0097]    3. Classification results.  
         [0098]    The results of the application of the classification rule to the sample are presented in Table 3. 
                                             TABLE 3                           Number of Observations Classified into the Correct       Clinical Group using both Log(SVR i ) and Log(CP i ).                Cardio-                           By Clinical   genic   Systolic       Pulmonary   Septic           diagnosis→   Shock   CHF   Normal   Edema   Shock   Total               By                               Parameters↓       Cardiogenic   15    2   0   0   0   17       Shock       Systolic CHF   0   60    1   0   0   61       Normal   0   0   20    0   0   20       Pulmonary   2   0   0   11    0   11       Edema       Septic Shock   0   0   0   0   11    11                  
 
         [0099]    4. Performance of the classification rule.  
         [0100]    The performance of the diagnostic procedure with only two possible results and two classes of patients usually is expressed by using measures like positive (negative) predictive value (9) or diagnostic odds ratio(10). For more complex tests with many outcomes and many classes of patients the overall performance may be expressed through the difference between proportion of erroneously classified patients with and without using the test. This measure is usually called as Lambda assymmetric (R|C), where R (rows) is the true group and C (column) is a group where the patient was classified. For our data, Lambda (R|C)=0.95 (S.D.(Lambda)=0.03) which corresponds to the 3 errors of classification according to the classification rule, instead of 59 errors of classification according to the prior probabilities of the groups.