WO1990000367A1 - Management of hemodynamic state of a patient - Google Patents

Abstract

A therapeutic system provides a clinician with an appropriate course of treatment for a patient whose cardiovascular system is operating outside the normal range of values for the left cardiac work index (LCWI) and the systemic vascular resistance index (SVRI). The left cardiac work index and the systemic vascular resistance index are calculated from the cardiac index (CI) and mean arterial blood pressure (MAP) and are displayed as relative values so that the clinician can readily determine which of the vascular parameters are outside the normal range. Preferably, the cardiac index and the other cardiac parameters are measured by an electrical bioimpedance monitor (104) that provides continuous dynamic measurement of the parameters. The left cardiac work index and the systemic vascular resistance index are calculated by a personal computer (140) that displays the calculated parameters in an easily discernible manner.

Description

MANAGEMENTOFHEMODYNAMICSTATEOFAPATIENT

Notice Regarding Inclusion of Copyrighted Material A portion of the disclosure of this patent document contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure, as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever.

Background of the Invention The present invention relates to a method and apparatus for the non-invasive diagnosis and therapeutic management of patients having systemic hypertension or other critical illnesses, and, more particularly, to a method and apparatus for determining a therapy to achieve both a normotensive and normodynamic state or a selected stated dictated by conditions to increase the probability of survival after surgery, trauma, illness, or the like. Hypertension is typically diagnosed through a non- invasive measurement of systolic and diastolic arterial pressure values by a sphygmomanometer, and by comparing the obtained "blood pressure" values to values considered "normal" for that particular patient taking into consideration the sex, age and body habitus. Once diagnosed, hypertension today is predominantly treated by prescription of any of a variety of classes of drugs which are pharmacologically capable of reducing the measured blood pressure value. Hypertension is then considered under control when the measured arterial pressures reach the normal range.

Although the use of such single modality therapy is generally quite successful in achieving the desired variation in the measured blood pressure, it does not take into account the patient's status with regard to more important hemodynamic parameters, such as cardiac output. Hypertensive drugs can be prescribed which have the additional and unmeasured effect of simultaneously lowering cardiac output. Thus, notwithstanding attainment of the normotensive end goal of therapy, important hemodynamic deviations can remain, or eve^'ή be induced by the prescribed therapy. The resulting diminished perfusion could be reasons for so-called side effects of hypertension therapy, such as dizziness, impotence and general down feeling, which the patient typically did not experience prior to diagnosis and traditional treatment of hypertension. Hence, current hypertension therapy could lead to prolonged duration of the treatment, higher cost to the patien and/or medical insurance carrier, adverse side effects resulting in patient's noncompliance, and general lowerin of the patient's quality of life. The importance of precise differentiation betwee normotensive therapy and effects on the hemodynamic stat have recently been underscored by the work of .C. Shoemaker, M.D., Department of Surgery, UCLA Medica Center, in the postoperative critically ill patient. Whil studying postoperative, high-risk, critically ill survivor and non-survivors, Shoemaker found that, in general, th survivors' cardiovascular systems maintained mean arteria pressure at a normotensive level while increasing thei global blood flow to a cardiac index of greater than 4. liters/min/m² and maintaining it at that level throughou the postoperative period.

In contrast, the non-survivors did not experienc increased global blood flow during the postoperativ period. The non-survivors generally were normotensive an maintained blood flow at a cardiac index of 3. liters/min/m² which is considered normal for health adults.

The surgical wound requires significantly increase perfusion to facilitate healing and the removal of fluids Thus, in order to maintain adequate perfusion of al organs, the global blood flow must increase. If thi condition is not met, the brain will reduce flow t selected organs in order to maintain increased perfusion o the surgical site. The organs inadequately perfused wil eventually fail. Shoemaker found that the mean time a which the deaths of non-survivors occurred wa approximately 90 hours postoperatively as a result o single or multiple organ failure.

Subsequently, in a controlled study, Shoemaker prove that in patients who are not in hyperdynamic sepsis an whose cardiovascular systems cannot increase the level o global blood flow to a desired hyperdynamic level, prope immediate postoperative management through volum expansion, positive inotropic support and peripherall vasoactive therapy, resulting in a cardiac index greate than 4.5 liters/min/m² and normotension (mean arteria blood pressure approximately equal to 92 Torr) , wil substantially increase their chances to survive.

The implementation of the foregoing therapeutic goa has the potential for a dramatic reduction of postoperativ mortalities, estimated to be approximately 400,000 annuall in the U.S. alone.

Summary of the Invention There has been provided in accordance with one aspec of the present invention a method of achieving preselected hemodynamic state in a subject mammal typically a human patient. The preselected hemodynami state may be a state of normovole ia, normoinotropy an arterial normocapacitance, although the preselected stat may be another hemodynamic state, if indicated by th circumstances surrounding diagnosis and treatment. Th method comprises the steps of first determining the mea arterial pressure of the patient and then measuring th cardiac index of that patient. Left cardiac work inde (LCWI) is determined based upon the foregoing measure values, in accordance with the formula: LCWI = (MAP - PAOP) x CI x K wherein MAP represents mean arterial pressure, PAOP represents pulmonary artery occluded pressure, CI represents cardiac index and K is a constant. Typically, PAOP may be assumed to be" approximately 6 Torr. The patient's systemic vascular resistance index (SVRI) is additionally determined utilizing the measured values of mean arterial pressure and cardiac index, according to the formula:

. sv∞ = f" -_I ^cvp> * ⁸⁰

wherein CVP is central venous pressure, which typically may be assumed to be approximately 3 Torr. The obtained LCWI and SVRI values are thereafter compared to the values desired to be obtained in the patient, and a therapeutic dose of a pharmacologically active material is administered for altering these values to achieve the preselected hemodynamic state. In a case where the preselecte hemodynamic state in an adult patient comprises "arterial normocapacitance, the pharmacologically active material comprises a vasodilator if the systemic vascμlar resistanc index exceeds about 2030 dyn«sec/cm⁵m². Alternatively, i the systemic vascular resistance index is less than abou 2030 dyn«sec/cm⁵m², the pharmacologically active material comprises a vasoconstrictor.

In a case in which the end goal of therapy is achievin normovolemia and normoinotropy, the pharmacologically activ material comprises one which will have a volume expansio and/or positive inotropic effect if the left cardiac wor index is less than about 4.35 kg-m/m². Alternatively, volume reduction and/or negative inotropic therapy will b indicated in a patient having a left cardiac work index i excess of about 4.35 kg-m/m².

Further features and advantages of the presen invention will become apparent from the Detailed Descriptio of Preferred Embodiments which follows, when considere together with the attached figures. Brief Description of the Drawings Figure 1 illustrates the interrelationship betwee cardiac index, mean arterial pressure, systemic vascula resistance index and 'left cardiac work index in a huma adult.

Figure 2 illustrates the interrelationship betwee cardiac index, mean arterial pressure, systemic vascula resistance index and left cardiac work index in a huma adult showing the changes in the parameters caused b triple modal therapy (e.g., volume reduction/negativ inotropic/ vasodilation) .

Figure 3 illustrates the interrelationship betwee cardiac index, mean arterial pressure, systemic vascula resistance index and left cardiac work index in a huma adult showing the changes in the parameters caused b triple modal therapy including the stronger utilization o negative inotropes in conjunction with lowering the hear rate, supplemented by volume reduction.

Figure 4 illustrates a schematic representation of a electronic system to assist in providing the diagnostic an therapeutic information in accordance with the method o the present invention.

Figure 5 illustrates an exemplary data format for th serial output transmitted from the exemplary NCCOM^®3-R electrical bioimpedance monitor to the computer in Figur 4.

Figure 6 illustrates an exemplary system of th present invention that includes an automatic pressur measuring system. Figure 7 illustrates an exemplary system of th present invention that includes an alternative automati pressure measuring system that utilizes electrica bioimpedance techniques.

Figure 8 is a flow chart of an exemplary compute program algorithm for implementing the present invention.

Figure 9 illustrates an exemplary screen display tha utilizes bar graphs to display the parameters of th hemodynamic status of a patient's cardiovascular system for use in diagnostic evaluation of a patient.

Figure 10 illustrates an alternative screen display that utilizes cartesian graphs to display the hemodynamic status and the percentage deviation from a selected goal o a patient's cardiovascular system.

Figure 11 illustrates the cartesian graph scree display of Figure 10 for a patient having 43% relativ hypovolemia and/or hypoinotropy and arterial normocapacitance.

Figure 12 illustrates the cartesian graph scree display of Figure 11 for the same patient and the sam input parameters but with the coordinates of the grap adjusted for a therapeutic goal of increased oxyge perfusion, showing that, for this therapeutic goal, th patient has an increased percentage of relative hypovolemi and/or hypoinotropy and has relative arteria hypocapacitanc .

Detailed Description. of Preferred Embodiments The primary function of the cardiovascular system i transport of oxygen. Pulsatile pressure having a mea component (mean arterial pressure or MAP) develops as byproduct of the viscosity of blood pushed out of the lef ventricle and through the vasculature system which i characterized by a systemic vascular resistance (SVR) . Th systemic vascular resistance and mean arterial pressure ar related such that in the absence of corrective mechanisms a reduction in SVR through vasodilatation will result in reduction in pressure. However, it is generally recognize that the supply of oxygen to all tissue cells is a functio of global blood flow, i.e., cardiac output, and not bloo pressure as will become apparent.

Determination of MAP is typically achieved using sphygmomanometer to directly determine systolic an diastolic pressure, and solving the following equation:

^ _m SYSTOLIC - DIASTOLIC _{+ DIAST0LIC} _ MAP values may also be measured and displayed directly on automated blood pressure instruments using oscillometric principles.

. There currently exist about eight practical methods of measuring cardiac output, including three indicator dilution methods (known as FICK, dye and ther odilution) , three methods which allow visualization of heart chambers and a subsequent calculation of stroke volume and cardiac output (cine-angiography, gated pool radionuclides, echocardiography) and two other methods (Doppler ultrasound and electrical bioimpedance) . The only absolutely accurate blood flow measurement method, not mentioned above, is a calibrated cylinder to collect blood and a stopwatch. Of course, each of the foregoing methods is characterized by a unique balance of accuracy, invasive/non-invasive nature, and patient risk, as will be appreciated by one of skill in the art.

Although any of the foregoing known methods of determining cardiac output may by used, the mechanics of each being well known in the art, it is preferred in the context of the present invention to non-invasively and continuously monitor cardiac output through the use of an instrument such as the NCCOM.3-R7 manufactured by BoMed® Medical Manufacturing Ltd. in Irvine, California, which is the subject matter of U.S. Patent No. 4,450,527, which is incorporated herein by reference. This instrument has been determined to exhibit the same accuracy as any of the available alternative methods, while accruing the substantial advantage of being a non-invasive technique. In addition to determining cardiac output, several additional parameters can be measured noninvasively utilizing the NCCOM 3-R7, as a result of its use of Thoracic Electrical Bioimpedance (TEB) technology. TEB measures total electrical impedance of the thorax which is called TFI (Thoracic Fluid Index) and which is volume dependent. TFI has a normal range in males between 20 and 33 Ohms and in females between 27 and 48 Ohms. A lower TFI value indicates an excess of fluids (more conductive thorax) .

TEB also measures two parameters which are related to measurement of contractility. Index of Contractility, (IC) , is a volume-dependent measure of the contractile state and ACI (Acceleration Index) is a volume-independent measure of the inotropic state. The normal range for IC in a human adult falls between about 0.033 to about 0.065/sec, and the normal range for ACI is between about 0.5 and about 1.5/sec². TEB measurements may conveniently be performed using the BoMed NCCOM 3-R7, and provide useful supporting data as will be discussed.

Once MAP and CI are known, two additional important hemodynamic parameters can be determined. The first is the systemic vascular resistance index (SVRI) defined by the arithmetic ratio of the arterial-venous pressure difference and an indexed blood flow in accordance with the following equation:

SVRI = <**» ∞) ^{X 80} (2)

In this equation, CVP is central venous pressure measure in Torr, 80 is a constant of proportionality and CI is th cardiac index. Since the value of cardiac output (CO) is direct function of body mass, its normalized value, e.g., cardiac index (CI) is a more appropriate indicium fo assessing adequacy of perfusion. Similarly, with systemi vascular resistance being flow dependent and, therefore, body size-dependent, its direct use is unhelpful fo absolute quantification of the normal levels of arteria capacitance. Thus, its indexed value, SVRI, will b discussed herein. If cardiac index (CI) is used as i Equation (2), the equation will directly provide th indexed parameter SVRI. The NCC0M^®3-R7, for example allows a clinician to enter either the patient's bod weight or the patient's body surface are'] to provide basis for calculating the indexed outputs. The data obtained through Equation (2) will not b subject to a significant error if CVP = 3 Torr is assume to be a typical value in the usual patient. In some cases of course, the CVP can vary ^"from as low as about 0 (zero Torr to as high as about 10 Torr under different hemodynami conditions. Minor variations from 3 Torr are generall insignificant since CVP is subtracted from the much large MAP which may range from approximately 93 Torr in th normotensive patient to as high as 120 Torr as in Example (described hereinafter) , or higher in a hypertensiv patient.

A second important hemodynamic parameter that can b calculated once MAP and CI are known, is the left cardia work index (LCWI) defined by the arithmetic product of th pump's pressure contribution and blood flow as expressed i the following equation:

LCWI = (MAP - PAOP) x CI x 0.0144 kg-m/m² (3 wherein PAOP is pulmonary artery occluded pressure in Torr CI is cardiac index in liters/min/m², and 0.0144 is constant of proportionality. In the typical patient, th PAOP will be approximately 6 Torr, and this value may b ordinarily assumed without subjecting the data to an significant error. However, a patient's actual PAOP ca vary sufficiently to justify determination of the actua PAOP value for use in Equation (3) under conditions of pum failure. In such a case, the actual PAOP can be determine invasively using a thermodilution catheter.

Depending upon oxygen demand, the heart has capability to vary cardiac output by a factor of 10, al within the life-sustaining range, throughout which MAP i maintained by the brain at a fairly constant level due t several biofeedback mechanisms with different tim constants. Thus, the brain continually re-evaluate Equation (2) to maintain MAP constant, and a decrease i SVRI (increase in global oxygen demand) must be met by a equal percentage increase of CI (increase in oxyge delivery) in order to maintain MAP constant. Thus, th brain attempts to maintain MAP constant by simultaneousl varying SVRI by vasoactivity and output of the pump b heart rate, preload, contractility and afterload. Essential hypertension, as generally understood today is probably caused by a gradual increase of stiffness o arterial walls which results in an increase in vascula impedance, or by a gradual decrease of vascula capacitance, e.g., gradual vasoconstriction. Both case result in an increase of SVRI. In order to provide adequat perfusion, (which, for an adult is approximatel

3.5 liters/min/m²), under conditions of an elevated SVRI the brain must permit a rise in MAP to accommodate Equatio

(2) . This is a hemodynamic explanation of essenti hypertension.

Since, in the case of essential hypertension, the bo must increase MAP in order to provide, adequate perfusio the worst choice of therapy would be to prescribe drugs lower MAP (which the clinician can easily measure) an unfortunately also simultaneously lower CI (which t clinician typically does not measure) . The resulti diminished perfusion could be reasons for the so-call side effects of hypertension therapy including dizzines impotence and general down feeling, which the patient oft did not experience prior to institution of the hypertensi therapy.

The end goal of essential hypertension therapy shou therefore be to lower the blood pressure to an acceptabl e.g., normotensive level, while maintaining adequa perfusion. This cannot be accomplished by measuring me arterial pressure alone, but must also involve t determination of the deviation, if any, from arteri normocapacitance and normσvolemia and/or normoinotrop based upon measured values for MAP and cardiac index. The mutual interrelationships between MAP, CI, LC and SVRI for the supine resting adult, defined by Equatio (2) and (3) above, are illustrated in Figure 1. Since M and CI can be directly measured, they become coordinates o the orthogonal system while LCWI and SVRI become th derived parameters. From this chart, the approximat values of LCWI and SVRI can^* be visually observed withou the necessity of going through the foregoing equations.

The range of normal MAP, illustrated in Figure 1 a numeral 10, and the range of normal CI 12 define two mai perpendicular axes of an ellipse 14 encompassing the loc of all normotensive and normodynamic patients. The cente 16 of the ellipse 14 represents an ideal mean-mean valu and could be considered an appropriate end goal of therap for patients whose data describes a point outside of th normal ranges. Since the ideal MAP and CI are described i terms of ranges, however, and not absolute values, the dat derived from a normotensive and normodynamic patient wil define a point on Figure 1 which may be anywhere withi ellipse 14. Ellipse 14 reflects the empirically derive data that MAP_mean equals 92 Torr, with a range o normotension from about 84 to about 100 Torr depending o the hemodynamic state. In addition, the CI_mean equal 3.5 liters/min/m², with a normodynamic range of from abou 2.8 to about 4.2 liters/min/m² in the resting human adul depending upon the hemotensive state.

The LCWI lines 18 run from the upper left of Figure to the lower right. The particular LCWI lines (no illustrated) which are tangent to the ellipse 14 define th bounds of the normal range of LCWI for adult humans. Th SVRI lines 20 run from the upper right of Figure 1 to th lower left. Similarly, the particular SVRI lines (no illustrated) which are tangent to the ellipse 14 (no illustrated) define the bounds of the normal range of SVR for human adults. Although literature-published data o normal ranges of LCWI and SVRI, based on demographic dat collected by any particular author, can vary considerably the following are believed representative of significantly large population and have, therefore, bee incorporated into Figure 1: LCWϊmean ⁼ 4-35 kg-m/m² normal LCWI range is between about 3.3 and 5.3 kg«m/m²; SVRI_{me n} = 2030 dyn*sec/cm⁵m²; and the normal SVRI range i between about 1660 and 2580 dyn-sec/cm⁵m². For neonata patients, the normal LCWI range is between about 2.5 an 5 4.0 kg-m/m², and the normal SVRI'range is between about 95 and 1500 dyn»sec/cm⁵m².

The loci of constant LCWI (the hyperbola 18) simultaneously represent the isovolemiσ and/or isoinotropi lines. Hence, the LCWI line passing through the center o

10. the ellipse 14 (LCWI = 4.35 kg»m/m²) is the line o normovolemia and/or nor oinotropy. A patient who is in th center of the normotensive and the normodynamic ranges i also normovolemic and normoinotropic.

The foregoing results from the fact that the heart i

15 neither a constant volume nor a constant pressure pump. B circulating non-compressible fluid through the system whic exhibits a given, value of SVRI, it creates MAP with certain level of arterial distention. For example consider a patient exhibiting a starting stat

20 corresponding to point 16 on Figure 1 wherei CI - 3.5 liters/min/m², MAP = 92 Torr, and SVRI = 203 dyn-sec/cm⁵m². If the system would vasoconstrict t SVRI = 2440 dyn-sec/cm⁵m², MAP would increase in an attemp to maintain an adequate level of perfusion. If th

25 circulation level would remain the sam (CI = 3.5 liters/min/m²), MAP would increase to 110 Tor (point 22 on Figure 1) , causing additional arteria distention through an increase in intravascular pressure hence an increase of volume. On the other hand, if th

30 system would maintain the same volume while vasoconstrictin to SVRI = 2440 dyn-sec/cm⁵m² level, it would reach MAP = 10 Torr (point 24 on Figure 1) but would have to simultaneousl decrease CI to 3.2 liters/min/m². LCWI = 4.35 kg-m/m² is therefore, a line of a constant volume.

<\

35 Patients having an LCWI value lower than abou

4.35 kg-m/m^ are either hypovolemic or hypoinotropic, or combination of both. Conversely, if the patient's LC value is higher than about 4.35 kg-m/m², the patient' heart is not only burning a greater amount of oxygen bu the patient is also hypervolemic or hyperinotropic, or combination of both. The volemic and inotropic status of patient are masked by each other on Figure l whe considering the patient's MAP and CI alone. However, whether a deviation in LCWI is due to an abnormal volemi or inotropic state can be differentiated throug consideration of the supporting TEB data, as illustrated i Example 1.

The LCWI hyperbolas 18 are marked in Figure 1 both b their respective kg»m/m² value and by the percentag deviation from normovolemia and/or normoinotropy. Th negative deviations represent hypovolemia and/o hypoinotropy, whereas the positive deviations represen hypervolemia and/or hyperinotropy. Figure 1 illustrate 20% increments in deviations of hyper/ hypovolemia and/o hyper/hypoinotropy, since the volemic and inotropi deviation is more important in diagnostic and therapeuti decision-making than the abstract LCWI value.

The foregoing ellipse 14 in Figure 1 is based upon th data obtained from normal adult patients. A simila ellipse 19 can be constructed for neonatal infants base upon a range of CI = 4.2 ± 20% liters/min/m² and a range o MAP = 60 ± 10% Torr. A line (not shown) connecting th centers of the ellipse 14 for adults and the ellipse 19 fo neonates would reflect the effects of aging on hemodynami parameters. Any of a number of additional ellipses coul be constructed for any age group. For example, an ellips (not shown) defining the empirically observed normotensiv and normodynamic ranges in premature infants would be belo and slightly to the right from the neonate ellipse. Ellipses for pediatric patients, depending upon their age, would appear between the ellipse 14 for adults and th ellipse 19 for neonates.

The SVRI line 20 passing through a specific patient' , point (located at the intersection of his/her MAP and C values) represents the direction of the highest gradient o the hemodynamic response to fluid expansion/reductio and/or to inotropic therapy and provides the vectoria direction of that specific therapy. For example, volum expansion and/or positive inotropic therapy will move th patient's point along the SVRI line toward upper right i Figure 1, whereas volume reduction and/or negative inotropi therapy will move the patient's point toward the lower lef of the chart in Figure 1. The SVRI lines 20 on Figure 1 also represent th arterial isocapacitance lines. Arterial capacitance is physical description of the state of vasoactivity hypocapacitance represents a vasoconstricted arterial bed whereas hypercapacitance represents a vasodilated arteria bed. The SVRI line 20 passing through the center 16 of th normotensive/normodynamic ellipse 14 drawn on Figure (SVRI = 2030 dyn*sec/cm⁵m²) represents the line of arteria normocapacitance. (A normotensive and normodynamic patien also exhibits arterial normocapacitance.) The LCWI line 1 passing through a specific patient's point represents th highest gradient of change of vasoactivity, hence th vectorial direction of the peripheral vasoactivity therapy

The SVRI values higher than about 2030 dyn*sec/cm⁵m correspond to states of arterial hypocapacitance. Suc patients will require peripheral vasodilatation therapy t rectify their arterial capacitance deviation. The SV values lower than the arterial normocapacitance line val represent arterial hypercapacitances. The patients wi these values of SVRI will require periphera vasoconstriction to render them arterially normocapacitiv Again, the negative deviations of SVRI represent arteri hypocapacitances (vasoconstricted system) , the positi deviations represent arterial hypercapacitances (vasodilat system) . From the discussion above, it is clear that volu expansion and positive inotropic therapy both have the sa vectorial effect (up and to the right along the patient SVRI line) . Similarly, the volume reduction and negativ inotropic therapies mask each other with the same vectoria effect (down and to the left along the patient's SVR line) . If a mean normotensive and normodynamic state (th center 16 of the ellipse 14) is the therapeutic goal, th use of volume expansion or volume reduction therapy as single modality therapy is only appropriate on patients wh happen to exhibit arterial normocapacitance (SVRI = 203 dyn-»sec/cm⁵m²) and whose only hemodynamic abnormality is deviation from normovolemia. A similar statement is vali for a supplemental inotropic therapy, which can be used t augment inadequate hemodynamic response to volum expansion/reduction.

Similarly, the use of a single modality peripherall vasoactive therapy can only be appropriate for a patien whose hemodynamic points happen to fall along th normovolemic and/or no rmoinotrop ic lin (LCWI - 4.35 kg.m/m²).

However, considering statistical distribution of a infinite number of MAP and CI pairs, a vast majority o patient points will fall outside of these two specifi lines related to a single modality therapy. These patient will require a complex, multi-component volemic an cardioactive drug therapy. In accordance with th invention disclosed herein, it becomes clear that the firs goal of such therapy should be to correct any flui deficiency or excess, and the second goal should be t choose proper drug therapy which will institute a norma (or selected) hemodynamic condition. For these patients in whom single modality therapy i inappropriate, therapy should be initiated which will giv rise to vectorial components on Figure 1 parallel with eac set of SVRI and LCWI lines, such that when vectoriall added, will render the patient normotensive an normodynamic. Thus, the correct therapy will result in vectorial sum of effects of volume expansion and/o reduction, together with positive and/or negative inotropi therapy and a vectorial sum of vasodilatation and/o vasoconstriction that will move the patient's point t within the ellipse 14. The specific percentage deviatio from the ideal goal of therapy which can be derived fro Figure 1 will assist the clinician to quantify th titration of that specific therapeutic component.

The following two examples illustrate the efficacy o utilizing the method of the present invention in one commo class of hemodynamic deviation which could benefit fro correct non-invasive assessment — the treatment o essential hypertension. The examples involve two patient who were both undergoing treatment for hypertension fo over one year but remained hypertensive and were both a approximately the same level of MAP though each in different cardiodynamic state. Thus, they each required completely different choice of therapy.

EXAMPLE 1

Male patient, 61 years old, height 173 cm, weigh 78 kg, was first diagnosed hypertensive 13 years ago. H had been taking orally, once a day for the last thre months, INDERIDE LA 80/50 mg (a long-acting combination o beta blockers and diuretics) . The INDERIDE replaced t previous therapy which involved the use of diuretics f many years. The main reason for the change in prescripti was the side effects of the simple diuretic therapy, su as cold extremities, which improved after switching INDERIDE. The INDERIDE therapy lowered MAP into the 1 Torr level from the MAP = 133 Torr level (190/105 Tor which the patient would attain without medication. T therapy never lowered the value of his arterial pressu below MAP = 110 Torr. The patient's hemodynamic a cardiodynamic state was measured with Bomed's NCCOM^®3- and a sphygmomanometer. This state is shown at the poi identified by reference numeral 26 in Figure 2, whi corresponds to a MAP of 110 Torr (hypertensive) and CI of 2.6 liters/min/m² (hypodynamic) . The supporting T measurements were TFI = 29.8 ohm, IC = 0.038/sec ACI = 1.05/sec², and HR = 58 beat/ in.

The physiologic interpretation of point 26 deriv from Figure 2 is relative^" hypovolemia and/or relati hypoinotropy 10%, relative arterial hypocapacitance 60 The TEB data above confirm normal inotropic state (a norm ACI value) pointing to relative hypovolemia as t contributor to the 10% deviation. However, the major 6 physiologic deviation is excessive vasoconstriction f which this patient has not been treated at all.

After the data analysis, the patient was administer 50 mg of CAPOTEN . (peripheral vasodilator) , and a n measurement of his hemodynamic parameters was performed s hours later (estimated half-time of CAPOTEN) . This n measurement is expressed as a movement of his hemodynam state from the initial state — point 26 to point 28 Figure 2. The new data relating to the patient's conditi following administration of CAPOTEN are:

MAP. 92 Torr (mean normotensive) CI 3.4 liters/min/m² (normodynamic)

TFI 28.4 ohm

IC 0.043/sec

ACI 1.18/sec²

HR 69 beats/min. The patient is now both normotensive and normodynami and has been maintained in this state by staying on t original prescription of INDERIDE LA 80/50 once a da supplemented by CAPOTEN 50 mg taken twice daily. Thi triple modality therapy (volume reduction/negativ inotropic/ vasodilatation) is, according to analysis of t statistical distribution of patient points on Figure l, t most often required therapy for treatment of hypertensio though currently seldom practiced. Potential fine-tuni of the therapy in this patient could require a reduction o titration of diuretics to 25 mg/day. EXAMPLE 2

Female patient, 44 years old, height 153 cm, weight 47 kg, treated for severe hypertension for 12 months. Most recently, she has been taking CALAN SR 240 mg (calcium channel blocker) and HYDROCHLOROTHIAZIDE 25 mg (diuretic) daily. The therapy never reduced her MAP below 110 Torr. She also complained about several side effects.

The patient's hemodynamic state was measured with the same instrumentation as in Case 1. Her hemodynamic state is expressed as point 30 in Figure 3:

MAP 120 Torr

CI 4.9 liters/min/m²

TFI 24.4 ohm

IC 0.081/sec ACI 2.28/sec²

HR 73 beats/min

The position of point 30 in Figure 3 show^'s a 15 deviation toward arterial hypercapacitance and 90% towar hypervolemia and/or hyperinotropy. The supporting TEB dat above document that (a) the patient is hyperdynamic (CI an SI values much higher than their normal range) , (b) hypervolemic (TFI value is significantly below normal rang for females indicating an excess of fluids) , and (c hyperinotropic (ACI and IC values higher than their norma range) . The 90% increase of LCWI also demonstrates potential long-term problem of the patient's condition excessive work of the pump (excessive myocardia consumption) . In the absence of the knowledge that th patient is hyperdynamic, she could never have been treate correctly.

Analysis of the data corresponding to point 30 o Figure 3 clearly points toward a therapy which shoul include (a) stronger utilization of negative inotropes i conjunction with (b) lowering heart rate, supplemented b (c) volume reduction. The patient was administered INDERIDE LA 80/50 mg The patient's parameters were then measured again after 2 hours. The new hemodynamic data are expressed as movemen of the patient's hemodynamic^" point from the point 30 t point 32 in Figure 3. The patient's data corresponding t point 32 were:

MAP 93 Torr (normotension)

CI 4.1 liters/min/m²

TFI 28.6 ohm (now within normal range) IC 0.071/sec

ACI 1.86/sec²

HR: 58 beats/ in

The patient began taking INDERIDE LA 80/50 mg once day and was maintained normotensive and normodynamic However, during twice-daily blood pressure measurements, i was noted that 12 hours after taking the drug, her MA decreased to a value of MAP = 90 Torr, while 24 hours late (at the time of taking another dose) , it was consistentl at a value of MAP = 98 Torr. She was metabolizing the dru at a faster rate, causing larger periodic variation of th drug level in her system. To prevent such a hemodynami variation, the prescription was split and skewed by 1 hours. INDERAL LA 80 mg is now taken once a day and th diuretic (50 mg) taken also once a day, though 12 hour later. The patient's MAP is maintained this way at 93 Tor level, and the patient is hemodynamically stable withou the side effects reported on the initiation of this study.

The preceding case studies illustrate the prope measurement and identification of a patient's hemodynami and physiologic state in accordance with the method of th present invention. This can be easily accomplished and th deviation from the ideal state clearly defined. Th patient can be treated so as to achieve an ideal (o selected) hemodynamic state in real time. Significantly the important results of the described method are obtainabl based upon non-invasive physiologic and hemodynami measurements.

Description of An Exemplary Electronic System fo Implementing the Method of the^" Present Invention Figure 4 is a schematic representation of an exemplar electronic system for implementing the method of the prese invention. As illustrated, a patient 100 is electricall connected to an electrical bioimpedance monitor (EBM) 104 which, preferably, is an NCCOM 3-R7 noninvasive continuo cardiac output monitor manufactured by BoMed Medic Manufacturing Ltd. of Irvine, California. The electric bioimpedance monitor 104 is connected to the patient 100 v a first electrical conductor 110 connected to a fir connector 111, a second electrical conductor 112 connect to a second connector 113, a third electrical conductor 1 connected to a third connector 115, and a fourth electric conductor 116 connected to a fourth connector 117. T first electrical conductor 110 is connected to a first pa of electrodes 120a and 120b that are positioned on the ne of the patient 100 at the intersection of a line encircli the root of the neck with the frontal plane of the patie 100 (the frontal plane is an imaginary plane, dividing t anterior and posterior sections of the neck and shoulder the patient 100) . Thus, the two electrodes 120a and 12 are positioned approximately 180* apart around t circumference of the neck. The second electrical conduct 112 is connected to a second pair of electrodes 122a a 122b that are positioned on the patient's neck approximate 5 centimeters directly above the first pair of electrod 120a and 120b. The third electrical conductor 114 connected to a third pair of electrodes 124a and 124b th are positioned on the patient's thorax along the mi axillary line at the xiphoid process level with t electrode 124a positioned approximately 180" apart from t electrode 124b. The fourth electrical conductor 116 electrically connected to a fourth pair of electrodes 12 and 126b that are positioned on the patient's thor approximately 5 centimeters directly below the third pai of electrodes 124a and 124b. It should be understood tha the positioning of the electrodes can be varied t accommodate bandages and other obstructions so long as th electrodes in each pair of electrodes are approximatel 180* apart. Other electrode combinations (e.g., ban electrodes, and the like) can also be used.

The electrical bioimpedance monitor 104 includes serial data output connector 130 which is electricall connected via a serial data line 132 to a computer 140 such as an IBM PC, XT, AT, or the like. Other computer can also be advantageously used. The computer 140 i connected to a keyboard 142 and to a monitor 144 tha operate in known conventional manners. Preferably, th computer 140 is also connected to a printer 146. Th computer 140 receives serial data from the electrica bioimpedance monitor 104, processes the data and display the processed data on the monitor and the printer. Th details of the data received from the electrica bioimpedance monitor 104 and the processing functions o the computer 140 will be discussed in additional detai below. It should be understood that a parallel dat connection can also be used between the electrica bioimpedance monitor 104 and the computer 140 in alternativ embodiments of the invention.

The electrical bioimpedance monitor 104 furthe includes a set of electrical output connectors 150 tha provide an ECG compatible output signal thereon. The EC compatible output signal is connectable to a conventiona ECG monitoring device 152 via an ECG cable 154. As will b discussed below, the ECG compatible output signal i selectably representative of the electrical activity of th patient's heart or the electrical bioimpedance measurements

The electrical bioimpedance monitor 104 preferabl further includes an ECG input connector 160 that i connectable to a set of conventional ECG electrodes (no shown) on the patient 100 via a set of ECG input lines 162. The electrical bioimpedance monitor 104 operates in known manner to derive significant cardiac information fro the electrical bioimpedance changes that occur during eac cardiac cycle. Briefly, ^•*- the electrical bioimpedanc monitor 104 operates by generating a high frequency substantially constant current that is provided as a output from the connectors 113 and 117 (labeled as CIO t represent the current injection outputs) . The constan current is coupled to the patient via the second conducto 112 and the fourth conductor 116 and is injected into th body of the patient 100 between the second pair o electrodes 122a and 122b and the fourth pair of electrode 126a and 126b so that the current flows through th patient's thorax between the two pairs of electrodes. Th constant current causes a voltage to be induced in th patient's thorax that is proportional to the electrica impedance of the thorax. The induced voltage is sense between the first pair of electrodes 120a and 120b and th third pair of electrodes 126a and 126b. The sensed voltag is conducted to the electrical bioimpedance monitor 104 vi the first conductor 110 and the third conductor 114 and i provided as an input to the electrical bioimpedance monito 104 via the connectors 111 and 115 (labeled as SVI t represent the sensed voltage input) . The electrica bioimpedance monitor 104 converts the sensed voltage into representation of the electrical bioimpedance of the thora The electrical bioimpedance as a function of time i referred to as Z(t) . The representation of the electric bioimpedance is available as an output on a connector 162. The electrical impedance of the thorax depends upon number of factors, one of which is the quantity of blood the vasculature system of the thorax which chang throughout each cardiac cycle. The electrical impedan changes caused by the blood in the thorax are time-varyi and can be detected by differentiating the detected sens voltage to provide a representation of the differentiat electrical bioimpedance (i.e., dZ/dt) which includes bo changes caused by blood flow in the thorax and change caused by respiration and other more slowly changin factors.

The NCCOM^Θ3-R7 processes the differentiate 5 bioimpedance information and provides a processed signal that represents the electrical bioimpedance changes (dZ/dt) caused by blood flow. The processed dZ/dt signal is selectably provided as an output signal from the electrical bioimpedance monitor 104 on a dZ/dt output connector 164 s

10. that the dZ/dt signal can be provided as an input to a oscilloscope (not shown) or other suitable equipment fo monitoring the dZ/dt signal.

The electrical bioimpedance monitor 104 can als derive an ECG signal from voltages present on the fou

15 input lines 110, 112, 114 and 116. The ECG signal whic represents the electrical activity of the patient's hear can also be sensed by the four pairs of electrodes describe above. The ECG signals can be separated from the sense voltage proportional to the electrical bioimpedance sinc 0 the injected constant current signal is a relatively hig frequency (e.g., 50-100 kHz) and the ECG signals generate by the heart have a considerably lower frequency content. Thus, suitable filters can be used to separate the tw signals. Alternatively, in the event that a suitable ECG 5 signal cannot be derived from the electrical input signals on the four lines 110, 112, 114 and 116, the ECG inpu connector 160 can be connected to suitably positione electrodes (not shown) to obtain an ECG input signal. Th ECG signal derived from the four input lines 110, 112, 114,

30 and 116, or the ECG signal derived from a separate EC signal on the ECG input connector 160 is selectably outpu as an ECG compatible output signal on the set of ECG outpu connectors 150 that can be recorded and displayed on the EC monitoring device 152. The preferred embodiment of th

35 electrical bioimpedance monitor 104 (e.g., the NCCOM^®3-R7) preferably includes a switch (not shown) to switch th output signal on the set of ECG output connectors 150 fro the ECG signal to a signal representative of the processed dZ/dt signal. For example, in the preferred embodiment, the output signal has a magnitude of 1 millivolt for each oh per second of change in the' electrical bioimpedance. signal of this magnitude is compatible with the range o input voltages that can be provided as inputs to conventional ECG monitor.

The electrical bioimpedance monitor 104 furthe processes the differentiated electrical bioimpedanc information and the ECG information and calculate additional cardiovascular system information that is derive from the differentiated electrical bioimpedance informatio and the ECG. In particular, the electrical bioimpedanc monitor 104 calculates the pre-ejection period (PEP) , whic is measured between the onset of Q of the QRS complex of th ECG signal to the opening of the aortic valve) , and th ventricular ejection time (VET) , which is measured betwee the opening and the closing of the aortic valve. Th ventricular ejection time is a direct measure of th duration of the mechanical systole of the patient's heart From these two calculated parameters, the electrica bioimpedance monitor 104 calculates the systolic time rati (STR) as follows:

STR « PEP/VET (4 The calculated systolic time ratio is displayed and i provided as an output parameter from the electrica bioimpedance monitor 104.

The electrical bioimpedance monitor 104 derives th heart rate period (HRP) from the ECG signal. The hear rate (HR) is derived from the heart rate period in a know manner (e.g., HR - 60/HRP) . In addition, the heart rat period can be used in combination with the ventricula ejection time (VET) to calculate the ejection ratio (ER) a follows: ER(%) = (100 x VET)/HRP (5 The electrical bioimpedance monitor 104 furthe calculates the thoracic fluid index (TFI) which is a valu that represents the total resistance of the thorax to th flow of the high frequency, constant current injected int the thorax as measured by the electrical bioimpedanc monitor 104. Typical values for the thoracic fluid inde vary from 20-33 ohms for male adults and 27-48 ohms fo female adults and children.

The electrical bioimpedance monitor 104 calculates th ejection velocity index (EVI) which is the maximum value o the rate of change of thoracic impedance change (i.e. EVI = (dZ/dt)_max) during the systolic upstroke. Th ejection velocity index corresponds to the peak ejectio velocity and the peak flow in the descending thoraci aorta, and is directly related to the heart's contractilit when it is normalized by the thoracic fluid index. Th peak ejection velocity is measured in centimeters pe second and the peak flow is measured in milliliters pe second. The ejection velocity index represents these tw parameters in ohms per second. Because of the variabilit of the thoracic fluid index during a long range therapeuti procedure, the ejection velocity index alone is generall not usable to assess changes in a patient's inotropi state. Thus, the exemplary electrical bioimpedance monito 104 (i.e., the NCC0M^®3-R7) calculates the index o contractility (IC) as the ratio of the ejection velocit index to the thoracic fluid index (i.e., IC = EVI/TFI) The index of contractility is displayed and is provided a an output parameter from the electrical bioimpedanc monitor 104.

The electrical bioimpedance monitor 104 calculates displays and provides as an output signal on the seria data line 132 a digital output signal that represents th stroke volume (SV) of the patient's heart. The strok volume is calculated from the above-described parameters a follows:

SV = VEPT x VET x (EVI/TFI) = VEPT x VET x IC (6 where VEPT is the physical volume of the electricall participating tissue in the thorax in milliliters. Th parameter VEPT is calculated as VEPT = (L³/*4«25), where is the equivalent thoracic length in centimeters that i derived from the patient's height and body weight which ar entered as input parameters by the clinician. Since strok volume is a function of body mass, in most diagnostic an therapeutic procedures a normalized stroke index (SI) i desirable. The stroke index is determined by dividing th stroke volume by the patient's body surface area, calculate from the patient's height and weight, to obtain the strok index normalized by body surface area, or by dividing th stroke volume by the patient's weight to obtain the strok index normalized by weight. The electrical bioimpedance monitor 104 calculates displays and provides as a digital output signal th cardiac output (CO) in liters per minute. The cardia output is calculated from the stroke volume and the hear rate as follows: CO = SV x HR (7

Cardiac output expresses the perfusion capability of th patient's heart. The resting cardiac output of a patien is a function of the patient's body mass. In order to b able to compare the adequacy of oxygen delivery o individuals of different body masses, the cardiac output i preferably normalized by body surface area or body weigh to obtain the cardiac index (CI) . The cardiac index b body surface area (CIBSA) i*³ obtained by dividing t cardiac output by the calculated body surface area deriv from the height and weight parameters input -by t clinician. The cardiac index by weight (CI_weight) calculated by dividing the cardiac output by the patient' weight. The electrical bioimpedance monitor 104 selectab provides either the cardiac output or one of the t cardiac indices as a display and output parameter.

4> Another parameter that is calculated, displayed an provided as an output is the peak flow (PF) which is calculated from the thoracic volume VEPT and the index o contractility IC as follows: ^{'•*■•*•} PF - VEPT x IC x CONSTANT (8) where CONSTANT is a dimensionless constant that is derived empirically. For example, in exemplary adult patients the constant is approximately 2.0. Peak flow represents the highest rate of left-ventricular volumetric delivery durin the ejection phase of the cardiac cycle in illiliters pe second. Peak flow is linked directly to the ejection phase contractility of the heart and as such is dependent on volemic status. Peak flow is one parameter that describes left ventricular performance. Alternatively, the electrical bioimpedance monitor 104 calculates, displays and outputs the peak flow index (PFI) which is the peak flow normalized by body surface area or body weight, depending" upon which o the two indexing systems is selected.

The electrical bioimpedance monitor 104 als calculates, displays and provides as a digital output signal the ejection fraction (EF) which is calculated from the ratio of the pre-ejection period PEP to the ventricula ejection time VET. The ejection fraction is typicall expressed as a percentage. The calculation is performed internally to the electrical bioimpedance monitor 104 i accordance with the following equation:

EF ■ 0.84 - (0.64 x (PEP/VET)) (9) where the two constants have been derived empirically. The ejection fraction represents the volumetric emptyin efficiency of the left ventricle, and thus represents the percentage of total volume contained in the ventricle just before the beginning of the systolic phase.

The electrical bioimpedance monitor 104 furthe calculates, displays and outputs^' the end-diastolic volum (EDV) which is volume of blood remaining in the heart a the end of the diastolic portion of the cardiac cycle an is calculated as the stroke volume divided by the ejectio fraction. In other words:

EDV - SV/EF (10) where EDV is in milliliters. The end-diastolic volume i preferably indexed by body surface area or body weight fo comparison between patients. The indexed end-diastoli volume is referred to as the end-diastolic index (EDI) an is calculated as:

^EDIBSA - EDV/BSA (11a) EDIWEIGHT - EDV/WEIGHT (lib) where EDIjgsa is in milliliters per square meter, and wher EDI_weight is in milliliters per kilogram.

The inotropic state of the left ventricle of th patient's heart (i.e., its contractile state), represente by the index of contractility (IC) , is dependent upon th fluid volume, the preload of the heart and the afterload o the heart. In contrast, the initial acceleration of th blood from the left ventricle of the heart takes place i the first 10-20 milliseconds after the aortic valve open and is related to the left ventricular impulse. The initia acceleration is substantially less load dependent and i thus more closely defines the inotropic state of th patient's vasculature system. As discussed above, th dZ/dt signal in ohms per second is processed by th electrical bioimpedance monitor 104 as an ohmic image o blood flow (milliliters per second) and blood velocit (centimeters per second) . The maximum rate of change o dZ/dt (i.e., d²Z/dt _max) represents the ohmic counterpar of the acceleration of the blood. This parameter divide by the thoracic fluid index (TFI) is calculated an displayed as the acceleration index (ACI) . In other words ACI = d²Z/dt² _max/TFI. The acceleration index is als provided as a serial data output parameter on the seria data line 130. The electrical bioimpedance monitor 104 of th preferred embodiment of the apparatus of the presen invention calculates the foregoing parameters and display selected ones of the parameters on a display panel (no shown) that is included as part _t of the electrica bioimpedance monitor 104. Furthermore, the calculate parameters are provided as serial output signals on th serial output connector 130 and thus as inputs to th computer 140 via the serial data line 132. In th exemplary electrical bioimpedance monitor 104 describe herein (i.e., the NCCOM 3-R7) , the output signals on th serial output connector 130 are provided in conventiona RS-232 format at 9600 baud. Preferably, the output dat format . is as illustrated in Figure 5, with each characte of data comprising a start bit, seven data bits, a parit bit (set to provide even parity in the preferre embodiment) , and two stop bits. Other suitable formats ca be used. It should be understood that the preferred forma for the transmitted data is the standard ASCII codes fo the numeric characters and the punctuation.

In the preferred embodiment incorporating th NCCOM^β3-R7, the parameters can be provided as output signal in at least two different formats referred to as the FAS mode and the SLOW mode. In the slow mode, the electrica bioimpedance monitor 104 transmits eleven of the parameter described above in sequence, a character at a time, an outputs the calculated parameters on the serial data lin 132 once for every sixteen heart beats. The electrica bioimpedance monitor 104 preferably outputs the averag values of the parameters over the sixteen heartbeats. Fo example, in one exemplary embodiment, the following forma for the transmission of the SLOW mode parameters is used:

:CO SV EDV PF EF HR TFI IC ER STR ACI HOUR:MIN where the first eleven parameters are defined as discusse above, ^"jand HOUR and MIN are the twenty-four hour time o day entered into the electrical bioimpedance monitor 10 and updated in accordance with a real-time clock within th electrical bioimpedance monitor 104. Preferably, the hou and minute information is transmitted only once ever minute rather than every transmission. The first colon i the transmission is used to indicate the beginning of transmission sequence. Other delimiters could of course b used. The first colon can be distinguished from the colo between the. hour and minute portion of the time portion a being preceded by a space rather than a number. Thus, th computer 140 can readily use the first colon to synchroniz with the serial data from the electrical bioimpedanc monitor 104. Preferably, the data is output from th electrical bioimpedance monitor 104 as a series of digit only. The dimensions and the expected ranges are known b the software algorithms in the computer 140. It should b understood that the transmitted data comprises numeri data, which may include a decimal point, separated by blan spaces (hexadecimal 20) , and delimited by the colons.

Alternatively, the SLOW mode parameters are output ollows:

:CI SI EDI PFI EF HR TFI IC ER STR ACI HOUR:MIN wherein the cardiac index (CI) , the stroke index (SI) , t end-diastolic index (EDI) and the peak flow index (PFI) a substituted for their respective unindexed values. T indexing can be in accordance with body surface area weight, as discussed above.

Preferably, additional patient information, such the patient's sex, identification number, height, weigh VEPT (thoracic volume) , and calculated body surface ar (BSA) , are also transmitted from the electrical bioimpedan monitor 104 to the computer 140. Preferably, the addition patient information is transmitted only once at t beginning of the data transmission as these paramete should not change for a patient during a diagnostic sessio In the FAST mode, the calculated parameters a transmitted once for each heart beat. Because of t transmission rates and the time required to perform th calculations, in the FAST mode, only six of the foregoin parameters are transmitted. For example, the followin exemplary format is used for unindexed parameters: : CO SV EDV PF EF HR HOUR:MIN

Alternatively, the indexed parameters can be transmitted a follows:

: CI SI EDI PFI EF HR HOUR:MIN

As with the SLOW mode, the hour and minute information i preferably transmitted only once per minute rather than i every transmission. Furthermore, the other patien parameters and identification information, discussed above are preferably transmitted once at the beginning o diagnostic session. Additional information regarding the operation of th exemplary NCCOM^β3-R7 electrical bioimpedance monitor i sensing the electrical bioimpedance changes and calculatin the above-described parameters can be found in "NCCOM^®3-R CARDIOVASCULAR MONITOR OPERATOR'S MANUAL," available fro BoMed^® Medical Manufacturing Ltd., 5 Wrigley Street, Irvine California 92718.

One additional input to the computer 140 is require in order to complete the system of the present invention As discussed above, the mean arterial blood pressure (MAP is a factor in the determination of the appropriat therapeutic procedure to return the patient to a norma range of conditions for the patient's vasculature system The mean arterial blood pressure can be provided as a input by a number of different methods. One of the simples and most straight forward apparatus and methods fo inputting the mean arterial blood pressure to the compute 140 is to measure the mean arterial blood pressure using conventional occlusive cuff to determine the systolic an diastolic pressures, calculating the mean arterial bloo pressure in accordance with the Equation 1, above as:

^ _m SYSTOLIC - DIASTOLIC _{+ DIASTQLIC (1)}

The result of the calculation is then entered into th computer 140 using the keyboard 142. This combination o apparatus and method has the disadvantage of requirin manual input from a clinician with the accompanyin possibility of introducing error into the computer 140 Furthermore, this combination of method and apparatus doe not lend itself to automatic monitoring of the condition o the patient's vasculature system. Thus, it is preferabl that an automated system be used for measuring the patient' mean arterial blood pressure and providing it as an input t the computer 140.

A number of systems are available for automaticall measuring a patient's blood pressure and providing it as a input to the computer 140. One such system is described i United States Patent No. 4,677,984, which is incorporate herein in its entirety. The system disclosed in Unite

States Patent No. 4,677,984 is illustrated in simplifie form in Figure 6. As illustrated, the system includes a automatic cuff pressure generator 200 controlled by processor 204. The pressure is selectively coupled to a occlusive cuff 210. The system further includes an EC monitoring device 212 to sense the occurrence of an R-wav in the ECG signal of the patient. The system includes pressure transducer 214 detects transitions in the pressur in the occlusive cuff 210 caused by the passage of a bolu of blood beneath the cuff 210 when the arterial pressur exceeds the cuff pressure during a cardiac cycle. Th transitions are timed with respect to the occurrence of t

R-wave of the ECG to maintain a record of the pressu transitions as the pressure on the occluding bladder systematically decreased or increased. The record pressure transitions and times are used to reproduce t arterial blood pressure waveform from which the me arterial blood pressure can be calculated. In the presen invention, the processor 204 of Figure 6 provides an outpu signal representing the mean arterial blood pressure tha is provided as an input signal to the computer 140 o Figure 4. This connection is shown as a dashed line 220 i Figures 6 and 4. In a fully integrated system, th computer 204 used to record the pressure transitions an times advantageously can be the same computer 140 tha receives the serial data information from the electrica bioimpedance monitor 104.

The pressure can also be measured using electrica bioimpedance techniques as set forth in allowed U.S. Paten Application Serial No. 111,699, filed on October 21, 1987 and assigned to the assignee of this application, and whic is incorporated herein by reference. This system i illustrated in part in Figure 7. As illustrated in Figur 7, the automatic blood pressure measuring system includes pair of electrical bioimpedance measuring devices, one o which is the electrical bioimpedance monitor 104, disclose and described above. A second electrical bioimpedanc measuring device 230 is connected to a set of curren injecting electrodes 232a and 232b and a set of curren sensing electrodes 234a and 234b on the calf of th patient's leg that defines a second body segment fo bioimpedance sensing. The second electrical bioimpedanc device 230 can be a much simpler device than the electrica bioimpedance monitor 104, as it is only necessary to detec the peak on the change in the electrical bioimpedance i the patient's leg. As described in U.S. Patent Applicatio Serial No. 111,699, a computation circuit 240 receives th dZ/dt output signals from the electrical bioimpedanc monitor 104 and the electrical bioimpedance measurin device 230 and calculates the time delay (i.e., th arterial pulse propagation delay) between the peaks in th two dZ/dt signals. The computation circuit 240 uses th measured time delay to determine the mean arterial bloo pressure therefrom. As set forth in U.S. Paten Application Serial No. 111,699, the time delay and th spacing of the second body segment of the leg from the firs body segment of the patient's thorax provide sufficien information from which the ^"mean arterial blood pressur (MAP) can be calculated. The computation block 24 advantageously provides the calculated mean arterial bloo pressure as an output on a line 250 which is connected to a input to the computer 140. Thus, the mean arterial bloo pressure is provided as an input to the computer 140. I should be understood that the computation block 240 ca advantageously be a microprocessor or other programmabl computation device. Although shown as a single serial dat line 250, it should be understood that the data can b transmitted from the computation block 240 to the compute 140 via a parallel data bus, for example.

Other known automatic or manual methods and apparatu can be used to measure the mean arterial blood pressure an provide it as an • input to the computer 140 for use i calculating the therapeutic information, as will b described hereinafter.

The computer 140 uses the data information from th electrical bioimpedance monitor 104 and the mean arteria blood pressure provided as a data input from the keyboar 142 or from the automated system of Figure 6 or Figure 7 An exemplary flow chart for the operation of the compute 140 is illustrated in Figure 8. Description of the Flow Chart of the Computer Algorithms

As illustrated in Figure 8, the computer 140 i programmed with an algorithm 300 that includes an entr block 310 wherein the program begins. Thereafter, th algorithm enters a first activity block 314 in which t program is initialized. The program requests variou parameters from the clinician including the patient's na and other identification information. Thereafter, t algorithm enters a second activity block 318 in which t computer inputs data that represents the mean arteri blood pressure (MAP) . The MAP data can be entered from t keyboard 142 when the MAP is provided by manual methods an apparatus. Alternatively, the MAP can be provided as direct digital input from the automated blood pressur measuring system of Figure" 6 or the automated bloo pressure measuring system of Figure 7, as discussed above. After entering and storing the MAP, the computer algorith enters a decision block 322 wherein the algorithm monitor waits for an interrupt indicating that new data has begu to arrive on the serial data input lines from the electrica bioimpedance monitor 104, that the clinician has entered command from the keyboard 142, or that other real-tim activities have occurred that must be handled, such as th clock interrupt internal to the computer 140. So long as n interrupt has occurred, the algorithm will reenter th decision block 322.

When an interrupt occurs, the algorithm will enter process block 330 wherein it processes the interrupt an branches to the appropriate routine determined by th nature of the interrupt. The various routines are shown a three generalized routines. If the interrupt is an interna computer interrupt, such as the real-time clock interrupt, the algorithm enters an activity block 334 wherein th internal computer interrupts are processed in know conventional manners. These interrupts are handled in conventional manner by the disk operating system (DOS) o other system level programs provided with the computer 140. Thus, the handling of these interrupts is transparent to th algorithm itself and control is returned from the activit block 334 back to the decision block 322 where the algorith awaits the next interrupt.

If the interrupt is a keyboard entry interrupt, th algorithm enters an activity block 340 wherein the dat entered via the keyboard 142 is provided as an input to th algorithm for further processing. For example, the dat can indicate that the clinician desires to re-initializ the algorithm. Thus, a path is illustrated that return the algorithm control back to the first activity block 31 wherein the algorithm is re-initialized. The data can als indicate an update of the patient's mean arterial bloo pressure. Thus, a path is illustrated from the activit block 340 to the second activity block 318 wherein the MA 5 is updated. It should be understood that in the embodimen of Figure 6 or the embodiment of Figure 7, wherein the MA is generated automatically, an interrupt from the externa computer 210 (Figure 6) or the computer 220 (Figure 7 causes the computer 140 to input the MAP data from th

ICC corresponding external computer.

The keyboard entry can also be a request to terminat the program. Thus, a path is provided from the keyboar entry activity block 340 to a program termination bloc 344. Other keyboard entries could of course envisioned

15 However, rather than attempt to enumerate all possibl entries, a path is illustrated from the keyboard entr activity block 340 back to the decision block 322 wherei the algorithm waits for the next interrupt.

The third general type of interrupt is generated whe

2:0 serial data inputs are received from the electrica bioimpedance monitor 104. As set forth above, th electrical bioimpedance monitor 104 periodically output the calculated parameters of the vasculature system to th computer 140. When the serial data is received by th

25 computer 140, an interrupt is generated and the algorit enters an activity block 350 wherein the computer inpu the data from the electrical bioimpedance monitor 104 Thereafter, the algorithm enters an activity block 35 wherein the computer 140 calculates the systemic vascul

30 resistance index (SVRI) in accordance with the Equation (2 as follows:

SVRI = <*** - g^P> * ⁸⁰ (

35 As discussed above, CVP is the central venous pressu which is estimated to be approximately 3 Torr. The cardi index (CI) is one of the parameters received on the seri data line 132 from the electrical bioimpedance monitor 10 The dimensions of SVRI resulting from the above calculatio is in dyn»sec/cm⁵m², also referred to herein as fluidi ohms per square meter (F.Ohms/m²) .

After calculating the SVRI, the algorithm enters a activity block 358 wherein the computer 140 calculates the left cardiac work index (LCWI) in accordance with Equation (3) as follows:

LCWI •= (MAP - PAOP) x CI x 0.0144 kg«m/m² (3)

As discussed above, PAOP is pulmonary artery occluded pressure in Torr, CI is the cardiac index in liters/min/m², and 0.0144 is a constant of proportionality. As further discussed above, in the typical patient, the PAOP will be approximately 6 Torr, and this value may be ordinarily assumed without subjecting the data to any significant error. However, a patient's actual PAOP can var sufficiently to justify determination of the actual PAO value for use in Equation (3) under conditions of pump failure. In such a case, the actual PAOP is entered via the keyboard 142 by the clinician. The dimensions of LCWI resulting from the above calculation are in kilograms per square meter (kg-m/m²) .

After calculating the left cardiac work index, the algorithm enters an activity block 370 wherein the computer 140 branches to a selected one of an activity block 374 or an activity block 378 wherein the computer provides a visual display of the calculated data. Two primary alternative data displays are advantageously provided in the preferred embodiment of the present invention. The selection of which type of display to provide is one of the selections that can be entered via the keyboard when the computer 140 is in the activity block 340. Other types of displays can also be advantageously provided. After providing an updated display as an output in either the activity block 374 or the activity block 378, the algorithm returns to the decision block 322 to await the next interrupt. Additional details regarding the two primary types of displays generated in accordance with the present invention are illustrated in Figures 9 and 10, and are described hereinafter.

One of the two primary ^"displays is provided when the computer enters the activity block 374. The displa associated with the activity block 374 is illustrated i Figure 9. In Figure 9, the cardiovascular and hemodynami data are displayed as a bar chart comprising a series o ten bar graphs. The bar chart of Figure 9 is referred t as the diagnostic chart as it allows the clinician t quickly review ten parameters reflecting the hemodynami state of the patient's cardiovascular system.

In the exemplary display of Figure 9, the bar graph are horizontal and the length of the bar graph in th horizontal direction represents the magnitude of th corresponding parameter.

As illustrated in Figure 9, the bar graphs are labele with the abbreviations for each of the parameters, a introduced above. In addition, in order to assist th clinician in quickly perceiving the significance o parameter that is outside the indicated normal range, th bar graphs preferably include a translation of the variou parameters into more readily understood terms. The cardia index (CI) is referred to as the GLOBAL FLOW and has th dimensions of liters/min/m².

Four of the parameters relate to the pump performance

The stroke index (SI) is referred to as the PUMP PERFORMANC and has the dimensions of milliliters/m². One modulato that affects pump performance is the end diastolic inde (EDI) which is referred to as the PRELOAD and has th dimensions of milliliters/m². The index of contractilit (IC) and the acceleration index (ACI) are both shown a CONTRACTILITY parameters. The index of contractility i dependent upon fluid volume and has the dimensions 1/sec The acceleration index is dependent upon the inotropic stat of the patient's vasculature system and has the dimension of 1/sec². The systemic vascular resistance index (SVRI) i referred to as the AFTERLOAD of the heart and has th dimensions of fluid ohms/m².

The left cardiac work index (LCWI) is referred to a the CARDIAC WORK and represents the amount of work th heart has to expend in order to deliver the blood flow. The left cardiac work index has the dimensions of kg-m/m².

The ejection fraction (EF) is referred to a the PUM EFFICIENCY and is expressed as a percentage.

In the preferred embodiments of the present invention, the thoracic fluid index (TFI) from the NCCOM^®3-R7 is inverted and displayed as thoracic fluid conductivity (TFC) (i.e., TFC - 1/TFI) . The thoracic fluid conductivity has normal range of 0.030 to 0.050 mhos (i.e., 1/ohms) . I Figure 9, the thoracic fluid conductivity is referred to as the THORACIC FLUIDS. By using the conductivity, increasin amount of fluids results in increased conductivity and thus results in a shift in the bar graph to the right. Thus, the clinician perceives an increase (movement to the right) of the bar graph as an increase in the patient's fluids. The mean arterial blood pressure (MAP) is displayed as the lowermost bar graph in Figure 9 and is dimensioned i Torr.

As illustrated, the magnitude of each of the foregoin parameters is displayed both as a numeric value and as a length on the corresponding bar graph. The bar graph fo each of the parameters further includes a pair of line perpendicular to the bar graph (i.e., a pair of vertical lines 380 and 382, as illustrated for the bar graph for th cardiac index) which delineate the range of "normal" values for the parameter. (It should be understood that on a vide display monitor, the vertical lines can be highlighted wit a different color or brightness level so that they are more readily discernible.) For example, the bar graph for the cardiac index (CI) is shown as having the first vertical line 380 at a magnitude of 2.8 liters 'min/m², representin the lower limit of the "normal" range, and having the secon vertical line at a magnitude of 4.2 liters/min/m², representing the upper limit of the "normal" range. Thus, clinician can easily determine which of the parameters ar outside the normal range. For example in Figure 9, it ca be seen that the magnitudes of the systemic vascula resistance index (SVRI) and the mean arterial blood pressur are greater than the normal ranges for those parameters, an the magnitudes of the cardiac index (CI) and the index o contractility (IC) are less the normal range. In contras the remaining six parameters are within their normal ranges Preferably, the bar graphs representing the parameter are scaled so that the vertical lines for each of the ba graphs, with the exception of the mean arterial pressur bar graph, are vertically aligned with respect to eac other, as illustrated in Figure 9, to assist the clinicia in quickly recognizing which of the parameters are above o below their respective "normal" ranges. Because of th large magnitude in the range of the mean arterial bloo pressure, the vertical lines representing its "normal limits are not aligned with the vertical lines of the othe parameters.

The heart rate (HR) , the patient's height, patient' weight and patient's date of birth are displayed in t display format of Figure 9 as numeric parameters witho corresponding bar graphs. The display format can al include other patient identification information and da storage identification.

When the computer 140 enters the activity block 37 it provides the alternative primary display illustrated Figure 10, which displays the hemodynamic status of t patient's cardiovascular system. Unlike the display Figure 9, the display of Figure 10 provides an alphanumer display of five of the above-described parameters, name the cardiac index (CI) , the mean arterial blood pressu (MAP) , the left cardiac work index (LCWI) , the system vascular resistance index (SVRI) and the heart rate (HR) .

The display of Figure 10 is distinguished from t display of Figure 9 in that the cardiac ilndex (CI) and t mean arterial blood pressure (MAP) are also displayed as cartesian graph. The cardiac index is on the X-axis (i.e. the horizontal axis) and the mean arterial blood pressur is on the Y-axis (i.e., the vertical axis). The cartesia graph of Figure 10 generally corresponds to the, graphs o Figures 1, 2 and 3, and has an ellipse 400 that represent the range of normal combinations of magnitudes of th cardiac index and the mean arterial blood pressure. I Figure 10, the ellipse 400 has a center 404 (i.e., th intersection of its major and minor axes) at a cardia index of 3.5 liters/min/m², and at a mean arterial bloo pressure of 92 Torr.

In addition to the ellipse 400, the cartesian graph o Figure 10 includes a first curve 410 and a second curve 41 (both shown as dotted lines) that intersect at the cente 404 of the ellipse 400. The curve 410 represents th normal left cardiac work index (LCWI) , which in the displa of Figure 10 is equal to approximately 4.35 kg«m/m². Th curve 414 represents the normal systemic vascular resistanc index (SVRI) , which in the display of Figure 10 is equal t approximately 2030 fluidic ohms per square meter.

The cartesian graph of Figure 10 further includes a indicator 420 that represents the patient's cardiac inde and the patient's mean arterial blood pressure, and als represents the patient's left cardiac work index an systemic vascular resistance index. As illustrated for a exemplary patient having the parameters illustrated i Figures 9 and 10, the patient's cardiac index (CI) is 2. liters/min/m², which is below the normal range of values and the patient's mean arterial blood pressure is 135 Tor which is considerably above the normal range of values. I addition, the patient's left cardiac work index (LCWI) i 5.0 kilograms per square meter, which is at the high end o the normal range for that parameter. The patient' systemic vasculaj.j resistance index (SVRI) is 3870 fluidi ohms/m², which is considerably greater than the norma range. By observing the position of the indicator 420 wit respect to the ellipse 400 and with respect to the firs curve 410 and the second curve 414, the clinician ca readily perceive which of the four parameters differ fro the normal values for the parameters. In order to assist the clinician in quantitativel analyzing the displayed data, the display of Figure 1 further includes an alphanumeric display of the percentag deviation of the calculated left cardiac work index and th systemic vascular resistance index from the normal value and indicates whether the parameters are greater than o less than the normal values. For example, in Figure 10 the left cardiac work index is approximately 15 percen below a normal value of approximately 4.35 kg-m/m², whic represents relative hypervolemia or relative hyperinotropy The systemic vascular .resistance index is 91 percent abov a normal value of approximately 2030 dyn*sec/cm⁵m² (i.e. 2030 F.Ohms/m²), which represents relative hypocapacitance.

The cartesian graph display of Figure 10 is referre to as the therapeutic management chart. The clinician ca use the information displayed in the therapeutic managemen chart of Figure 10 in combination with the diagnostic char of Figure 9 to determine a proper course of therapy, a discussed above in connection with Figures 1, 2 and 3. Fo example, the clinician will observe that the patient wil require therapy that increases the patient's arteria capacitance to reduce the systemic vascular resistanc index. In addition, the patient will likely requir therapy that increases either or both the patient's flui volume or the patient's inotropy. For example, th acceleration index (ACI) parameter in Figure 9 indicate that the patient's inotropic state is substantially normal In contrast, the volume-dependent index of contractilit (IC) parameter is below normal and indicates that th patient is hypovolemic. Thus, the proper therapy for t exemplary patient having these parameters should increase the patient's fluid volume. This is consiste with the bar graph of the thoracic fluid conductivity i Figure 9 which is at the low end of the normal range.

As discussed above, the end goal of the therapy is no always necessarily within" the normal ranges of th displayed parameters. For example, a patient recoverin from major surgery or certain illnesses may requir additional oxygen to assure successful recovery. Th clinician can use the displays of Figures 9 and 10 t determine a course of treatment in which the cardiovascula system is operated with parameters outside the normal rang to enhance the patient's recovery. For example, it is preferable that a post-surgical course of therapy include modality to cause the patient to be relatively hypervolemi to increase the oxygen-carrying capability of the patient's system. In preferred embodiments of the present invention, the clinician can select an alternative display mode i which the "normal" cardiac index, systemic vascula resistance index and left cardiac work index are adjusted t set a new goal for the patient's volume/ inotropy and th patient's arterial capacitance in accordance with results o the study by W.C. Shoemaker. In other words, a goal is se to increase the oxygen perfusion of the tissues. This is illustrated in Figures 11 and 12 which illustrate tw exemplary cartesian displays for the same patient. In Figure 11, the above-described normal ranges fo the cardiac index, the systemic vascular resistance inde and the left cardiac work index are used to define the ellipse 400, the first curve 410 and the second curve 414. The measured parameters are displayed alphanumerically t the left of the graph and the indicator 420 is located to

_; show that the blood pressure is low, the cardiac index is low, the left cardiac work index is low (indicating eithe relative hypovolemia and/or relative hypoinotropy) , and that the systemic vascular resistance index is "normal" (indicating normocapacitance) . Thus, the indicated therap would be to increase the volume and/or the inotropy. Th location of the indicator 420 on the normocapacitance curve does not indicate any therapy related to the capacitance.

Figure 11 should be contrasted with Figure 12 which illustrates the same parameters for a patient recovering from surgery, or the like. The "normal" values for the cardiac index, the systemic vascular resistance index and the left cardiac work index have been adjusted upward in Figure 12 to represent a therapeutic goal that will result in increased oxygen perfusion of the tissues. For example, the normal range of the cardiac index (CI) is shown as being approximately 3.8 to 5.2 liters/min/m² rather than 2.8 to 4.2 liters/min/m². Similarly, a curve 410' for the left cardiac work index (LCWI) , representing the "normovolemia/normoinotropic," condition has been shifte to approximately 5.55 kg-m/m²; and a curve 414' for th systemic vascular resistance index, representing th "normocapacitance" condition has been shifted t approximately 2690 F.Ohms/m² (2690 dyn»sec/cm⁵m²) . Thus, as illustrated by the location of the indicator 420' i Figure 12, the post-operative patient is 55 percen relatively hypovolemic and the therapeutic modality t expand the patient's fluid volume should be increased wit respect to the corresponding treatment for the normal goal illustrated in Figure 11. At the same time, the patien should be vasodilated in response to the 26 percent relativ hypocapacitance according to the new system vascula resistance index goal in order to increase the intravascula space for the acceptance of additional fluids.

As set forth above, the electronic system of th present invention preferably includes the printer 146. Th i printer is preferably capable of printing graphic images o the screen displays of Figures 9 and 10 to provide permanent record of the screen displays so that they may b coapared to analyze the results of a course of therapy ove a period of time. In addition, the computer 140 preferabl includes long term data storage capabilities (i.e., a har disk drive and/or a floppy disk drive) so that the dat collected during a diagnostic session can be saved an displayed contemporaneously with the data collected during current diagnostic session. Thus, the clinician can observ the results of the previously" prescribed therapy and modif the therapy, as needed, in order to achieve the desired en results.

Although this invention has been described in terms of certain preferred embodiments, other embodiments that are apparent to those of ordinary skill in the art are also within the scope of this invention. Accordingly, the scope of the invention is intended to be defined only by reference to the appended claims.

Claims

CLAIMS:

1. A system for determining the hemodynamic state o a mammal, characterized by: means (104) for measuring the cardiac index of th mammal and providing the cardiac index as a digita output signal; means (204) for measuring the mean arterial bloo pressure (MAP) of the mammal; a computational system (140) that receives sai digital output signal representing said cardiac inde as a first input and that receives a second inpu representing said mean arterial blood pressure, sai computational system calculating the left cardiac wor index (LCWI) and the systemic vascular resistanc (SVRI) of the mammal in accordance with the followin equations:

LCWI = (MAP - PAOP) x CI x K

SVRI ■= ((MAP-CVP) x L)/CI wherein PAOP represents the pulmonary occlude pressure of the mammal and CVP represents the centra venous pressure of the mammal, said PAOP and said CV being constants that are provided as additional input to the computational system; and wherein K and L ar predetermined constants, said computational syste providing said calculated LCWI and SVRI as huma readable output data, said computational system (140 further providing a display of said calculated LCWI an SVRI as graphs.

2. The system as defined in Claim 1, wherein sai means (104) for measuring the cardiac index of the mamma is an electrical bioimpedance monitor (104) that sense changes in the electrical bioimpedance of the mammal durin each cardiac cycle and that calculates the cardiac index o the mammal from said sensed changes.

3. The system as defined in Claim 1, wherein sai graphs include a cartesian graph with the cardiac index a one axis and the mean arterial blood pressure on the othe axis, said graph further including curves (410, 410', 414 414') illustrating the normal values of LCWI and SVRI and a indicator (420, 420') showing the location of th calculated values of LCWI and SVRI with respect to th curve (410, 410', 414, 414').

4. The system as defined in₍ Claim 3, furthe including a display of percent deviation of said calculate

LCWI and SVRI from said normal values of LCWI and SVRI.

5. A method of achieving a preselected hemodynami state in a subject mammal, characterized by the steps of:

(a) determining the subject's mean arteria pressure (MAP) ;

(b) measuring the subject's cardiac index (CI) ;

(c) determining the subject's left cardiac wor index (LCWI) utilizing the measured MAP and CI value according to the formula: ^" LCWI = (MAP - PAOP) x CI x K wherein PAOP represents pulmonary artery occlude pressure and K is a constant;

(d) determining the subject's systemic vascula resistance index utilizing the measured MAP and C values according the formula:

SVRI - (MAP - CVP) x L

wherein SVRI represents the systemic vascula resistance index, CVP is central venous pressure and is a constant; and

(e) administering a therapeutic dose of pharmacologically active material for altering th LCWI and SVRI values to achieve in the subj ect preselected hemodynamic state.

6. A method of achieving a preselected hemodynamic state as defined in Claim 5, wherein the subject is an adul human.

7. A method of achieving a preselected hemodynami state as in Claim 6, wherein the preselected hemodynami state comprises a systemic vascular resistance index o approximately 2030 dyn*sec/cm⁵m², and a left cardiac wor index of approximately 4.35 kg*m/m².

8. A method of achieving a preselected hemodynami state as defined in Claim 7, wherein the pharmacologicall active material comprises a vasodilator if the systemi vascular resistance index is greater than about 203 dyn*sec/cm⁵m².

9. A method of achieving a preselected hemodynami state as defined in Claim 7, wherein the pharmacologicall active material comprises a vasoconstrictor if the systemi vascular resistance index is less . than about 203 dyn*sec/cm⁵!!!².

10. A method of achieving a preselected hemodynami state as defined in Claim 5, wherein the patient is an adul human and the preselected hemodynamic state^' comprises systemic vascular resistance index within the range of fro about 1700 to about 2650 dyn*sec/cm⁵m⁵.

11. A method of achieving a preselected hemodynami state as defined in Claim 5, wherein the patient is an adul human and the preselected hemodynamic state comprises a lef cardiac work index within the range of from about 3.3 t about 5.3 kg*m/m².

12. A method of achieving a preselected hemodynami state as defined in Claim 5, wherein the patient is neonatal infant human and the preselected hemodynamic stat comprises a systemic vascular resistance index within th range of from about 950 to about 1500 dyn*sec/cm⁵m².

13. A method of achieving a preselected hemodynami state as defined in Claim 5, wherein the patient is neonatal human infant and the preselected hemodynamic state comprises a left cardiac work index within the range of from about 2.5 to about 4.0 kg*m/m²

14. A method of determining and correcting deviations from normovolemia in a subject mammal, characterized by the steps of:

(a) determining the subject's mean arterial pressure (MAP) ;

(b) measuring the subject's cardiac index (CI) ; (c) determining deviation from normovolemia by utilizing the measured values of MAP and CI according to the formula: deviation = (MAP - PAOP) x CI x K 4.35 kg*m/m^ wherein PAOP is the pulmonary artery occluded pressure and K is a constant; and

(d) increasing fluid volume if deviation is less than 1.0, and decreasing fluid volume if deviation is greater than 1.0.

15. A method of achieving a preselected hemodynamic state in a mammal, characterized by the steps of: determining mean arterial pressure in the mammal; measuring cardiac index in the mammal; determining a first deviation, if any, from a preselected volemic state; determining a second deviation, if any, from a preselected capacitive state; and administering a therapeutic dose of at least one pharmacologically active material for altering the first and second deviations to achieve a preselected hemodynamic state.

16. A method of achieving a preselected hemodynamic state as defined in Claim 15, wherein the preselected volemic state is normovolemic.

17. A method of achieving a preselected hemodynami state as defined in Claim 15, wherein the preselecte capacitive state is normocapacitive.

18. A method of achieving a preselected hemodynami state as defined in Claim 15, wherein the preselecte hemodynamic state comprises normovolemia, normoinotropy an arterial normocapacitance.

19. A method of achieving a preselected hemodynami state as defined in Claim 18, wherein the preselecte hemodynamic state comprises a mean arterial pressure o from about 84 to about 100 Torr.

20. A method of achieving a preselected hemodynami state as defined in Claim 16, wherein the volemic state i measured as the left cardiac work index and ranges fro approximately 3.3 to 5.3 kg*m/m².

21. A method of achieving a preselected hemodynami state as defined in Claim 15, further comprising the step prior to the administering step, of selecting pharmacologically active material for reducing th deviation from the preselected volemic state.

22. A method of achieving a preselected hemodynami state as defined in Claim 15, wherein the mammal is a hum adult in postoperative recovery and the preselect hemodynamic state comprises normotension and hyperdynam global blood flow.