GB2377787A

GB2377787A - Determination of blood flow parameters

Info

Publication number: GB2377787A
Application number: GB0206066A
Authority: GB
Inventors: Samuel Nathaniel Olal Akinyemi
Original assignee: Individual
Current assignee: Individual
Priority date: 2001-03-14
Filing date: 2002-03-14
Publication date: 2003-01-22
Also published as: GB0206066D0

Abstract

Method and apparatus for evaluating blood flow parameters of a subject. Together with their associated correction factors, a database is created storing a pair of test meaurements for a parameter, the dominant pupils, with a factor, the value of which brings them physiologically close, but pathologically different, and, another factor which defines them to represent the stastical mode of that parameter. The dominant pupils create conditions for a 'Runner', a calibration unit and, prepares the measured and evaluated factors of a subject under review to be calibrated. Also stored in that database is the measured and evaluated factors which belong to a 'Runner' into ordered modes based upon the physiological and patho - physiological significance of a factor relative to all the others which determine the value of an evaluated parameter, to enable the creation of a correction factor algorithym, the blueprint, which is used to calibrate the evaluated parameter of a subject under review.

Description

DETERMINATION OF BLOOD FLOW PARAMETERS The present invention relates to a method and apparatus that allows the determination of certain parameters of blood carrying organs, namely the heart, brain, lungs, kidneys, the liver, the eyes, the placenta (in pregnant females) and blood itself The parameters include: cardiac output (which is defined as the volume of blood pumped from the heart per minute); the right pulmonary systolic artery pressure; the right pulmonary diastolic artery pressure; the mean pulmonary artery pressure; the left atrial pressure; central hepatic vein pressure; mean pulmonary capillary pressure; intracerebral pressure; intraocular pressure; urinary output; plasma osmolarity ; erythrocyte sedimentation rate; haematocrit haemoglobin concentration of blood; cation concentration of plasma (e. g. potassium and sodium); anion concentration of plasma (e. g. chloride and phosphates); products of metabolism (e. g blood glucose); blood oxygen tension (arterial and venous); blood carbon dioxide tension (arterial and venous); blood pH; stroke volume of the heart; surface area of the body; foetal distress index; and the pain index.

From Applicant's earlier International Patent Application WO 92/22871 and WO 01/86474 Al (line 14 of page 2, to, line 21 of page 4), it was disclosed that all the parameters listed above are determined from a limited number of actual measurements of the subject, most of which can be determined non-invasively, and with the minimum of time and pain. In particular, the measurements that are taken may include: from a sample of the subject's blood, either the plasma total proteins concentration (T) or the blood haematocrit (A) is determined in this improved method of the determination of blood flow parameters, and not both as earlier disclosed. The one can be derived from the other, and, calibrated for realtime values. It is preferred that when blood gas studies are required for a subject, the blood sample is used to measure only the blood haematocrit, because of the added bonus of other useful haematological results which will be required to complete a blood gas study; plasma total proteins concentration may be measured in grams/l00ml ; blood haematocrit may be measured as a percentage; oxygen saturation of the subject's blood (U), which may be measured as a percentage, using a standard oximeter; body temperature (Th) measured in degree centigrade; pulse rate (P) measured in beats per minute; systolic blood pressure (S), diastolic bood pressure (D), and mean arterial blood pressure, measured in mmHg; height (h) of the subject measured in cm; and, weight (w) of the subject measured in kg.

Using these actual measurements, other factors can be derived for use in the determination of the required parameters. The derived factors may include: derved plasma viscosity (Dpv)

derived plasma osmolarity (Dw) derived central venous pressure (Dcvp) derived cardiac output (Dco); and derived right ventricular pressure (Dsr).

An equation or algorithym is used, including some or all of the actual measurements for the subject and the derived factors, for each parameter to be determined.

If it were possible to measure simultaneously a subject's cardiac output by each of the known methods available in hospital practice (listed in the order of accuracy, and not availability), which are the: direct Fick method; thermodilution method (with a Swan Ganz catheterization) ; ultrasound probe method; and the oesophageal Doppler probe method; the individual results will be seen to vary by as much as some 60% of the direct Fick method, which is widely accepted to be the most accurate of the methods listed above. The other methods are practiced in hospitals because they will show the same trend in changes of cardiac output suffered by the subject. The evaluation of blood flow parameters using for an example some of the equations and algorithyms from the Applicant's earlier International Patent Application WO 92/22871 and WO 01/86474 Al, some of the times produced results which are inverse to what are expected, and, confirmed by all of the methods given above.

And, the evaluated value of the correction factor which is contributed by a 'Tertiary Key Factor', TKF, as defined in Applicant's earlier International Patent Application WO 01/86474 Al (lines 8 to 15 of page 15), to the final correction Factor kn as defined in Applicant's earlier International Patent Application WO 01/86474 Al (lines 1 to 17 of page 6) for the parameter being measured, from a subject under review, is often found to be disproportionate to its physiological or patho-physiological significance relative to the other'Tertiary Key Factors'that are listed for that parameter. It is possible that:

a) the disproportionality can arise in part by the exclusive use of the 'Primary Key Factor'and the'Secondary Key Factor'to enter for calibration an evaluated parameter from a subject under review in realtime as described in Applicant's earlier International Patent Application WO 01/86474 Al (lines 18 of page 6, to, line 9 of page 12). This method did not always relate to the clinical status of either the pupils from a'Class' (the calibration unit) or the subject under review ; b) and, the disproportionality can arise in part by the fact that, the greater the difference of the measured or evaluated value of a'Tertiary Key Factor'from a subject under review, is out of the range which has been defined by its assigned 'Class', the greater is the degree of disproportionality.

Therefore and, generally, the object of this improved method of determination of blood flow parameters in blood carrying organs is to increase the sensitivity of the apparatus.

According to one aspect of the present invention, the prior art problems are overcome by modifying the configuration and use of a'Class'. In another aspect, by modifying the means by which the parameter is determined, based on the difference between an actual measurement and a derived measurement when compared with the determined differences of values stored in the database.

An implementation of the present invention will now be described, with particular reference to the drawings, in which: Figure 1 shows a tree which illustrates the pathway required to arrive at a correction factor kn.

A database The'Primary Key Factor', PKF The value of this factor is the first to be used, to enter for calibration the evaluated parameter of a subject under review. The principles inherent in the use of a 'Primary Key Factor'as described in Applicant's earlier International Patent Application, WO 01/86474 Al (line 18 of page 6, to, line 6 of page 7) are being

adhered to. It is assumed that, the choice of a measured or evaluated factor will allow for the collection of a large population of variants, to span the full range of the physiological and patho-physiological changes of a parameter.

The configuration of a'Class', the'Dominant Pupils' While the'Primary Key Factor'enters the parameter of a subject under review for calibration, the'Secondary Key Factor'uses the value of a factor from that parameter to enter the evaluated measurement into a calibration unit (a'Class').

And, while adhering to the principiles inherent in the creation of a'Class'for the evaluation of a parameter as described in Applicant's earlier International Patent Application WO 01/86474 Al (line 7 of page 7, to, line 9 of page 12), this improved method of the determination of blood flow parameters utilizes: a) only a single'Class'which is defined by the value of an elected measured or evaluated CLa index which belong to the'Higher Class Pupil', HCP, and, the 'Lower Class Pupil', LCP, according to Applicant's earlier International Patent Application WO 01/86474 Al (line 12 of page 11, to, line 9 of page 12); b) accordingly, it is entered into each of the'Schools'in the database for a parameter. For descriptive purposes, the'Class'will be referred to as the'Dominant Pupils', DPs. It is not impossible to find the'Dominant Pupils'elected for a parameter to serve in the database of another parameter; c) and, it is preferred in this improved method of the determination of blood flow parameters that the following principles are adhered to when making the choice of the'Dominant Class'for a parameter: 1) for any of the parameters to be evaluated in the determination of blood flow parameters in blood carrying organs, it is preferred that the choice of a 'Primary Key Factor'is the factor Sp (and SPk for children), a measure of the mean systemic filling pressure, as defined in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 4 to 8 of page 8); and that for an example, the Sp (and Spk for children) values for the'Higher Class Pupil'and'Lower Class Pupil'have a difference in value which is either equal to or lower than some 0. 01 units;

2) that the choice of the'Secondary Key Factor'for the'School', is the pulse and pulse pressure product, [P (S-D)] ; and in the example of an adult, the value is in a range which is greater than 4000 but less than 5000; and thereby, placing the pupils within a value for what is generally considered to be the range of the (statistical) mode for cardiac output measurements of the adult in the general population of the healthy and sick for a defined region of the world, as in this example, the adult European living at sea level and not acclimatized to living either at high altitudes (greater than 3000m), or in hyperbaric chambers; 3) and that in accordance with the principles inherent in the use of a'Class' that is in a'School', the'Dominant Pupils'are used to evaluate the correction factor kps for each of the'Tertiary Key Factors'which have been listed for a parameter as described in Applicant's earlier International Patent Application, WO 01/86474 Al (line 10 of page 12, to, 19 of page 13). However, in this improved method of the determination of blood flow parameters, there are two distinct different applications of the use of the correction factor kps, which will be described later in this text.

The'Runner' Other than the'Dominant Pupils'which feature in this improved method, all the other'Pupils'which are collected in the database for a parameter will be referred to individually as a'Runner', RNs, (or'Runners'where there is a plurality), for descriptive purposes in each of the'School'which exists for that parameter. And, each'Runner'will function totally independent of its neighbours when fully established to function in this improved method of determination of parameters of blood flow in blood carrying organs. The calibration unit in this improved method is a'Runner'and not a'Class'as described in Applicant's earlier International Patent Application, WO 01/86474 Al.

The'Universal Tertiary Key Factor'UTKF It is generally accepted that the result of the measurement of a single parameter, on its own, does not reflect exactly the true physiological or patho-physiological status of that subject. The diagnosis and judgement of the prognosis of an illness is made on a multiplicity of factors, which include the value of factors which relate to blood flow, haematology, biochemistry and the blood gas. These factors are being defined as the'Universal Tertiary Correction Factor', UTKF, by this

improved method. And, irrelevant to the parameter which is to be measured, the same'Universal Tertiary Correction Factors'are collected for: the'Dominant Pupils' (the'Higher Class Pupil'and the'Lower Class Pupil' which form the only'Class'in this improved method of the determination of blood flow parameters); the'Runners', RNs ; and for a subject under review.

For fonctional applications, it is preferred that the'Universal Tertiary Correction Factor'in the database for each parameter which can be evaluated by this improved method, is defined by the following, which may progress in turn from : a) a'Statement Tertiary Key Factor', STKF, to include all the measured and evaluated factors that is used in the algorithym to evaluate a parameter; b) a'Lesser Tertiary Key Factor', LTKF, to include all of the remaining factors from the list of the'Universal Tertiary Key Factor', UTKF, which do not appear in the list of the'Statement Tertiary Key Factor', STKF; and therefore, this list can vary in content from the evaluation of one parameter to another; c) and to a'Correction Factor Equation', CFQ, which may include one or more factors from the list of the'Statement Tertiary Key Factor', and the list of the 'Lesser Tertiary Key Factor' ; and therefore, this list can vary in content from the evaluation of one parameter to another. The correction factor Kc is described in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 10 to 11 of page 6) as a factor by which the evaluated parameter may be modified to calibrate the actual value, that is, CFQ = Kc While the choice of the'Tertiary Key Factors'for the'Universal Tertiary Key Factor'have not by any means been exhausted, the following is an example of those measured and evaluated factors which can be used to define: i) the'Universal Tertiary Key Factor', which are, the derived central venous pressure (Dcvp), the pulse rate (P), the pulse pressure (R), the derived plasma viscosity (Dpv), a derived measurement of the mean

systemic filling pressure (Sp or Spk), the derived right pulmonary artery systolic pressure (Dsr or Dsrk), the derived the right pulmonary artery diastolic pressure, (PaPd), the mean pulmonary artery pressure (PaPm), the derived cardiac output (Dco, Dcopu, or DcOk), the derived mean pulmonary capillary pressure (Mcp), the measured mean systemic arterial pressure (m), the derived plasma osmolarity (Dw), the measured plasma total proteins concentration (T), the derived haemoglobin concentration (Dhgb), the body temperature (Th), the body weight (w), the height of the subject (h), the measured arterial blood oxygen saturation (U) ; the derived stroke volume (Dsv), the derived oxygen content of arterial blood (dOFka), the derived oxygen content of venous blood (dOFkv), the derived carban dioxide content of arterial blood (dCOka), and the derived blood pH (DpH); ii) the'Statement Tertiary Key Factor', which are, the central venous pressure (Dcvp), the pulse rate (P), the pulse pressure (R), the derived plasma viscosity (Dpv), a derived measurement of the mean systemic filling pressure (Sp or Spk), and the derived cardiac output (Dco, Dcopu, or DCOk) iii) the'Lesser Tertiary Key Factor', which are, the derived right pulmonary artery systolic pressure (Dsr or Dsrk), the derived right pulmonary artery diastolic pressure, (PaPd), the mean pulmonary artery pressure (PaPm), the derived mean pulmonary capillary pressure (Mcp), the measured mean systemic arterial pressure (m), the derived plasma osmolarity (Dw), the measured plasma total proteins concentration (T), the derived haemoglobin concentration (Dhgb), the body temperature (Th), the body weight (w), the height of the subject (h), the measured arterial blood oxygen saturation (U), the derived stroke volume (Dsv), the derived oxygen content of arterial blood (dOFka), the derived oxygen content of venous blood (dOFkv), the derived carban dioxide content of arterial blood (dCOka), and the derived blood pH (DpH); iv) and the'Correction Factor Equation', which are, the central venous pressure (Dcvp), the pulse rate (P), the pulse pressure (R), the derived plasma viscosity (Dpv), a derived measurement of the mean systemic filling pressure (Sp or Spk), the derived cardiac output (Dco, Dcopu, or DCOk), and the correction factor DX (which can be evaluated according to the principles described in Applicant's earlier International Patent Application, WO 01/86474 Al (line 1 of page 15, to, line 19 of page 16).

The ordered form of measured and evaluated factors of the'Statement Tertiary Key Factor'for a Parameter The ordered form of measured and evaluated factors of the'Statement Tertiary Key Factor'for a Parameter forms the basis for the creation of a calibration unit in this improved method of the determination of blood flow parameters. The principles of this ordered-form in the listing of a'Tertiary Key Factor'in a'Statement Tertiary Key Factor'and'Lesser Tertiary Key Factor'modes, once established, are to be identically reproduced in all the modes which exist for the evaluation of a parameter. This can be applied to : the'Dominant Pupils' the'Runners'in the database for the evaluation of a parameter; and for the measured and evaluated factors from a subject under review in realtime.

It is possible not to show any ordered form of seniority (or conversely inferiority) in the listing of factors (the TKF) for the'Statement Tertiary Key Factor'in the database for a parameter. In a preferred method, the ordered form of a'Statement Tertiary Key Factor'in the database for a parameter is determined as follows: 1) first by virtue of the algorithym which is used for the evaluation of the parameter; and for an example, the algorithym for the evaluation of the derived cardiac output (Dco), is not the same as that as for the evaluation of the derived right ventricular pressure (Dsr), these are different equations, as described in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 1 to 9 of page 10, and, lines 1 to 7 of page 11); 2) and, by the importance of a factor relative to the others in the algorithym to evaluate a parameter; an importance which is shown to influence the physiological or patho-physiological changes that has been suffered by the subject under review. In the following example of the algorithym used for the evaluation of the derived cardiac output measurement, the equation as described in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 1 to 9

of page 10), is not used to distinguish the varied form of heart failure, which are described as being either one, of left or right sided, or to be of both. In the following examples: a) in the choice for a left sided form of heart failure, this can be the measured factors which are required to evaluate the pulse and pulse pressure product; i. e. the measured pulse rate (P), the measured pulse pressure [ (S-D)] and, the evaluated (Pp), pulse and pulse pressure product [ (P (S-D)] itself. These are listed in the'Statement Tertiary Key Factor'before all other requirements to complete the algorithym for the evaluation of the derived cardiac output, which to follow those factors used in the algorithym, the preferred order is as follows from left to right: [ (P (S-D)] : P: R: Dco: Dpv: T: (3Hgb): Dw: wo. 425 : ho. 725 None of the above factors will be listed as a'Lesser Tertiary Key Factor'for the parameter, by virtue of its definition. And, by its definition, one or more from the list of both the'Statement Tertiary Key Factor'and'Lesser Tertiary Key Factor'can appear in the list for the'Correction Factor Equation'. b) and, in the choice for a right sided heart failure, this can be the measured and derived factors which are required to evaluate the derived right ventricular pressure; i. e. the measured and derived factors which are required to evaluate it are described in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 10 to line 12 of page 10). These are listed in the'Statement Tertiary Key Factor', which to follow those factors used in the algorithym, the preferred ordered form is as follows: Dcvp: m2 : [ (P (S-D)] : P: R: Dco: Dpv: T: (3Hgb): Dw: w0425 : ho. 725 and while none of these factors will be listed as a'Lesser Tertiary Key Factor' (by virtue of its definition), one or more from the list of both the'Statement Tertiary Key Factor'and'Lesser Tertiary Key Factor'can appear in the list for the 'Correction Factor Equation'. Note, that the derived central venous pressure (Dcvp) does not feature in the algorithym to evaluate cardiac output.

Use of the correction factor kps Once in a calibration unit, the first process within, is the use of the correction factor kps. While adhering to the principles of the use of the correction factor kps as described in Applicant's earlier International Patent Application, WO 01/86474 Al (line 10 of page 12, to, line 19 of page 13), it is possible to evaluate the value of the correction factor of each of the'Tertiary Key Factors', which in this improved method of the evaluation of a parameter, belong to the following: the'Runners'in the database for the evaluation of a parameter, with the results recorded in the database; and for a subject under review in realtime, with the results entered, for an example in the CPU of a microcomputer.

The use of the value for these evaluated correction factors will differ for a 'Runner', and a subject under review in realtime. Their use in this improved method will be explained later in this text.

Evaluating the value of the initial correction factor DX The initial correction factor DX is described in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 1 to 11 of page 15). There is just the one'Class'which is created for a parameter in this improved method, the 'Dominant Pupils'. Using values from the'Dominant Pupils', the initial correction factor DX is evaluated for: each of the'Runners'in the database for the evaluation of that parameter, with the results recorded in the database; and for a subject under review in realtime, with the results entered for an example in the CPU of a microcomputer.

This is not a preferred method because it does not address the limitations of disproportionality which this improved method proves to overcome. A preferred method will be described later in this text.

Evaluating the value of the correction factor for a'Tertiary Key Factor' The factor kps which is evaluated for all the'Tertiary Key Factors'of a parameter for the'Dominant Pupils'as described earlier in this text. With the kps value of each factor from a'Universal Key Factor'mode evaluated for the'Dominant Pupils', it is possible, according to the principles outlined in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 12 of page 15, to, line 15 of page 19), to evaluate the value, (the value which any of those'Tertiary Key Factors'will contribute to the final correction factor Kn for a parameter) for each of the factors listed in the'Statement Tertiary Key Factor'and the'Lesser Tertiary Key Factor'modes for: i) a'Runner', with a value in the database for each of the measured or evaluated factors for the parameter, and, the value of the initial correction factor DX which has been evaluated for that parameter; ii) and from a subject under review in realtime, with a value entered into the CPU of a microprocessor for each of the measured or evaluated factors of the parameter, and, the value of the initial correction factor DX which has been evaluated for that parameter.

To adhere to the principles described in Applicant's earlier International Patent Application, WO 01/86474 Al (line 8 of page 15, to, line 19 of page 16), the value of the initial correction factor DX is modified in accordance with the kps value of the'Tertiary Key Factors'. For an example, in the following algorithym copied from Applicant's earlier International Patent Application, WO 01/86474 Al (line 15 of page 19), the measured or evaluated value of a'Tertiary Key Factor'from a 'Runner'or the subject under review is below the values for the'Higher Class Pupil'and'Lower Class Pupil'from those stored values for the'Dominant Pupils'in the database for a parameter:

D/= D, Y-/ (L-M/M wherein Dut ils the initial evaluated correction factor required by the evaluated parameter of a'Runner'or a subject under review;

QuL is the measured or evaluated value of a'Tertiary Key Factor'of the'Lower Class Pupil'from the'Dominant Pupils' ; QuX is the measured or evaluated value of a'Tertiary Key Factor'from a'Runner' or a subject under review; and, kps for the factor has been evaluated from stored factors of the'Dominant Pupils'.

Creating notated values of'Tertiary Key Factor'in the database for a parameter The application of the use of notated values in the database for the evaluation of a parameter applies only to the evaluated value of each of the'Tertiary Key Factors' which has been listed for a'Runner'. These factors belong to its'Statement Key Factor'and its'Lesser Key Factor'modes.

In Applicant's earlier International Patent Application, WO 01/86474 Al, the 'Primary Key Factor'and the'Secondary Key Factor'were used to establish a range (the calibration unit) in which to place the realtime measurement of a parameter for calibration.

In this improved method of determination of blood flow parameters in blood carrying organs, the range is established by the use of notated values in the database for a parameter. The notation translates to the value of the correction factor of each of the factors listed by the'Statement Key Factor'and'Lesser Key Factor'modes of a'Runner'. Whereas the correction factor evaluated could be an addition or subtraction, the following is an example of a preferred notation stored in the database for an evaluated parameter, when the value is expressed as: O. On infers a result which is between 0. 01 and 0.0999 O. n infers a result which is between 0.1 and 0.999 I. ne-03 infers a result which is between 0.001 and 0.00999 I. ne-04 infers a result which is between 0.0001 and 0.000999

1. n infers a result which is between 1 and 9.999 10. n infers a result which is between 10 and 99.999 The use of'Runners'as a Calibration unit It is possible to create a calibration unit for this improved method of the determination of blood flow parameters, by the combined use of the following: a) by the use of the factors as listed for a parameter in its'Statement Tertiary Key Factor'and the'Lesser Tertiary Key Factor'modes in an ordered form of seniority (or inferiority) as described earlier in this text; b) by evaluating the correction factor for each of these'Tertiary Key Factors' in the'Statement Tertiary Key Factor'and the'Lesser Tertiary Key Factor'modes of the parameter, as described earlier in this text; c) by applying the form of notation for the value of an evaluated factor as described earlier in this text.

The following is an example of two adjacent'Runners'from the database created for the evaluation of a parameter, in which the seniority, the preferred ordered form, is established as follows: 'Runner', RNs (1) 'Statement Tertiary Key Factor'

(Sp +] On) Ox-I. n 4 (Dcvp + C. ) : P-7. -o ; +0. 0 : (D- /: ? + lO.- < CQjc-l. ne-04) 6Qcv 'Lesser Tertiary Key Factor' D-70. .-M-0. ) ; 77-C. ).-Dco-7. " : cp-0. .--7. p .' + 7. -0.: (T + 7. ne-03) : (Hgb + l. ne-03) : (w-c. O : + 7. ne-03) 'Runner', RNs (2) 'Statement Tertiary Key Factor'

(Sp + 10. n) : (COx + 1. ne-04 Dcvp + O. n) : (P-l. ne-03) : (R+O. On) : (Dpv + O. n) : (Sp + lO. n) : (COx + I. ne-D4) j

'Lesser Tertiary Key Factor'

D-70. .-P-C. .-P/M-C. ).- Dco-7. -.-cp-7. -c ; (Dsr-10. n) : (PaPd-0. n) : (PaPm-0. n) : (Dco-1. ne-04) : 6Kc2-1. n (m-I. ne-04) : (L) w + I. ne-3 -7. - - + 7. n-.- + 7. - : + l. ne-03) : (-C. On) :.- + 7. ne-03) Earlier in this text an ordered form of seniority (or inferiority) has been described for the factors listed in the'Statement Tertiary Key Factor'and the'Lesser Tertiary Key Factor'modes in the database for a parameter. In the above example of two adjacent'Runners', the ordered form of seniority will progress as follows: i) from the first factor listed in the'Statement Tertiary Key Factor'mode; and this is the factor Dcvp (the derived central venous pressure) in the above example, and; ii) to the last factor listed in the'Lesser Tertiary Key Factor'mode; and this the factor h (the measured height of the'Runner').

To follow the principles which have been outlined above, it follows that in the above example, the seniority of the two adjacent'Runners'is determined by the notated value for the factor Dcvp, which is the first listed difference to be found in the'Statement Tertiary Key Factor'mode (which as defined in Applicant's earlier International Patent Application, WO 01/86474 Al, is a'Primary Key Factor').

From the example, with a value for Dcvp of O. n, 'Runner'2 gains seniority over 'Runner'I with a value of Dcvp ofO. On.

There are other factors in the example above which have different values between the two'Runners', and, like the evaluated parameter Dcvp they have been underlined: a) the notated value for the derived plasma viscosity, Dpv; b) the notated value for the evaluated and calibrated cardiac output, Dco; c) the notated value for the mean capillary pressure, Mcp;

d) the notated value for the plasma osmolarity.

And, if the notated value for the evaluated parameter Dcvp had been identical for the two'Runners'in the above example, the determination of seniority will pass to the next in the list, which is the derived plasma viscosity, Dpv, (which as defined in Applicant's earlier International Patent Application, WO 01/86474 Al, is a 'Secondary Key Factor'). In the above example, the use of the difference in the notated value of the correction factors gives seniority to'Runner'2 ; i. e. that an added value may judged to be superior to that of the subtracted value of a factor.

And, in another example, if no differences in the notated value for a factor is found in the'Statement Key Factor'mode for a parameter (which from the example given above the notated value for the derived cardiac output of two adjacent'Runners'in the database for a parameter has been assumed to be equal, which as noted above they are not), the search for differences will pass into the'Lesser Tertiary Key Factor'mode to arrive at the first registered difference to be found in the notated value of the factor Mcp (the derived mean capillary pressure). Accordingly, with a greater notated value,'Runner'1 will gain seniority over'Runner'2 when listed in the database for the parameter; wherein as in the above example, both notated values are to be subtracted from the final correction factor for the parameter.

Applying the principles as described above in the inverse will create a database of 'Runners'in an ordered form of inferiority for a'School'. It is possible to create a 'School'which has at least double the capacity for calibration by the superior numbers of'Runners'over the numbers of'Classes'in a'School'as described in Applicant's earlier International Patent Application, WO 01/86474 Al. This improved method contributes to the increased sensitivity of an apparatus, which for an example is used to determine parameters of blood flow in blood carrying organs.

Creating a'Correction Factor Equation for a'Runner' In this improved method of the determination of blood flow parameters, a method by which the sensitivity of the apparatus is further enhanced, is in the use of a 'Correction Factor Equation'a factor by which the evaluated parameter from a 'Runner'is modified to calibrate this to the actual value; this is equivalent in value

for the parameter, as the factor Y,,,, as described earlier in this text, CFQ = Kc The knowledge of a subject's medical history and treatment regime at the time a parameter is being evaluated facilitates the creation of a'Correction Factor Equation'which may relate to the physiological or patho-physiological changes being suffered by the'Runner'. This knowledge is transferred to the value of the correction factors, adjusting them to match the significance which that factor will contribute to the final correction factor to be made to the evaluated parameter. The 'Correction Factor Equation'of a'Runner'is stored in the database for a parameter in a notated form. In the following example of two adjacent and, completely labelled'Runners' (as above) in the database for the evaluation of a parameter, the notation of a'Correction Factor Equation', CFQ, may take the following form : 'Runner', RNs (1) 'Statement Tertiary Key Factor'

(Dcvp + O. On) : (P-l. ne-03) : (R+O. On) : Dpv-M. n) : (Sp + lO. n) : (Dco -l. ne-04) 'Lesser Tertiary Key Factor' --70. .: (PaPd-0. n) : (PaPm-C. n).: cp-M : (m-7. ne-04) : + 7. ne-o) .-+7. -o.-, + 7. -0.--O. C ; + 7. - 'Correction Factor Equation' Dcvp. inv : P : R : Dpv. inv : Sple2 : Dco. e3 : DX= Kc 'Runner', RNs (2) 'Statement Tertiary Key Factor'

(Dcvp + O. M).- P-7. -.-+0. .-Dpv + C. .- 7 + O. n) : (Sp + lO. n) : (Dco-l. ne- 'Lesser Tertiary Key Factor' D-7C. ) ; P-C. ).- P/M-C. ; My ?-7. -0 ; -7. -o) ; w + I. ne-03) : (T+ I. ne-03) : (Hgb + I. ne-03) : (w-C. On) : (h + I. ne-03) 'Correction Factor Equation'

Dcvp : P : R : Dpv.-Sp/e2inv : Deo. e3. DX = Kc To retain the properties of reproducibility for this improved method of the determination of blood flow parameters, it is possible to adjust the value of an evaluated factor by shifting the decimal point up or down, to increase or decrease respectively its value. For an example, in the above'Correction Factor Equations' : i) the derived parameter Dcvp from the'Correction Factor Equation'for 'Runner'2 is not qualified by a notated value; the value of its evaluated correction factor is not adjusted; accordingly, the factors P, R and Dpv, by the registered notation will not also be adjusted. For an explanation, the factors Dcvp (an evaluated parameter), P, R and Dpv (in the failing heart) have values which are considered in this example not to be disproportionate and judged to be clinically significant; ii) also from the'Correction Factor Equation'for'Runner'2, the factor Sp is

qualified and notated as Sp/e2inv, the value of the evaluated correction factor is adjusted ; given the example of a value +17. 6, the applied correction factor will be - 0. 176, and note the inversion which is carried in the'Correction Factor Equation' for this factor. For an explanation, the Sp value of + 17. 6 is judged clinically to be grossly disproportionate to a final correction factor Kc which has a value of some 0.67 for an example. Also, in this healthy subject, the value of the factor Sp is considered not to be clinically significant; iii) the factor Dco is qualified and notated as Dco. e3, the value of the evaluated correction factor is adjusted, given the example of a value +0. 0009, the applied correction factor will be +0. 9 ; for an explanation here, the value of the factor COx is judged clinically to contribute more to the final correction factor from the value ofK : for'Runner'2, and not so for'Runner'1 with a value of-0. 9; iv) the value of the correction factor DX which is to be entered into a 'Correction Factor Equation'does not involve any of the factors which belong to a 'Runner'. The correction factor DX in the'Correction Factor Equation'for a parameter is evaluated from an algorithym which involves measured and evaluated factors of the subject under review in realtime and the'Dominant Pupils'in the database for that parameter.

Application of the correction factor DX in this improved method And, DX is the initial correction factor for the evaluated parameter, as defined in Applicant's earlier International Patent Application, WO 01/86474 Al (page 15, to, line 19 of page 16). To overcome the limitations of disproportionality, while retaining the properties of reproducibility in this improved method of the determination of blood flow parameters, the algorithym for the correction factor DX, is modified as in the following example: A) a DX algorithym as given in Applicant's earlier International Patent Application, WO 01/86474 Al (line 5 of page 15),

DXH = KCH- (HCLa-XCLa) (K, H-KCL) D (HCLA-LCLA) CZ-CZ

B) a DX algorithym elaborated for this improved method,

DXHB = (KL * (KcH/XCLa))- (HCLa-XCLa) (KrH-K L) (HCL-LCLa) 7CZ-ZCZ)

wherein in the above algorithym B, the value of the factors, 1) HCLa, KcH, KcL are recorded measured and evaluated values from the 'Dominant Pupils'stored in the database for a parameter ; 2) DX value for a'Runner', is the factor DXRHB ; and, that for the subject under review is the factor DXSHB ; 3) and XCLa is the value of a measured or evaluated factor which is: a) either the recorded value for a'Runner' ; and, given an evolved'Correction Factor Equation', the final correction factor which is listed in the database for this 'Runner'is given in this improved method by the algorithym : Kc= Dcvp : P : R : Dpv.-Sp/e2inv : Dco. e3 : ZMB b) and, by the application of the principles inherent in the creation of a 'Correction Factor Equation', which has been described earlier in this text, the knowledge of the value of jMTB and the clinical status of the'Runner'has resulted in the'Correction Factor Equation'for'Runner'2,

which is given by the the algorithym:

CFQ= Dcvp : P : R : Dpv : Sp/e2inv : Dco. e3 : DXSHB = Kn wherein the factor Kn is as described in Applicant's earlier International Patent Application, - WO 01/86474 Al (lines 11 to 21 of page 5); this is better elaborated in the description for the determination in realtime of a parameter for a subject under review.

Calibration of an evaluated Parameter from a Subject under Review Assuming that all the required measurements which will include that from a blood sample (for either the plasma total proteins concentration or the blood haematocrit) for a subject under review in realtime, have been made as described in Applicant's earlier International Patent Application, WO 01/86474 Al (line 20 of page 13, to, line 5 of page 14); the following is an example of the evaluation in realtime of a parameter for a subject under review, made according to the principles which have been described for this improved method in the foregoing text. a) the evaluated Parameter from a Subject under Review is entered into a 'School'to access the'Runners'in the database for that parameter, using for an example the evaluated values of the pulse and pulse pressure product (Pp) as the 'Primary Key Factor' ; b) the'Runners'in the database have established an ordered form of seniority of the factors listed in its'Statement Tertiary Key Factor'and'Lesser Tertiary Key Factor'modes. To follow this dictation by the'Runners'in this 'School', the measured and evaluated factors from the subject under review are presented in the same ordered form, as in the following example for a parameter: Factors as listed for the'Runners'from a'School'in the database 'Statement Tertiary Key Factor'

Dcvp : P : R : Dpv : Sp : Dco messer Tertiary Key Factor' Dsr : PaPd : ; M ?.-/ .-Z.-T : Hgb.-w : h

Factors as presented for the Subject under review, 'Statement Tertiary Key Factor' Dcvp: P: R: Dpv: Sp: Dco Zesser Tertiary Key Factor' Dsr: PaPd: PaPm : Mcp: m: Dw: T: Hgb: w: h c) the'Runners'in the database have established an ordered form of seniority of the factors listed in its'Statement Tertiary Key Factor'and'Lesser Tertiary Key Factor'modes; also they have recorded against each of these factors, the value of the evaluated correction factor which has been evaluated by the application of the principles inherent in the use of the correction factor kps as outlined earlier in this text, for this improved method. The notated form of these values have been recorded in the database for the parameter under evaluation, which to use as an example of a'Runner'from the'School', is as follows: 'Runner' 'Statement Tertiary Key Factor'

(Dcvp + O. M).P-7.-o.-+C..-Dpv + 0. : + 7 ; Dco + J. ne-04) 7, ee 7/ 7 Tc' 'Lesser Tertiary Key Factor' 'Lesser Tertiary Key Factor' (Dsr-lO. n) : (PaPd-O. n) : (PaPm-O. n) : (Mcp-I. ne-03) : (m-I. ne-04) : (Dw + l. ne-03) : (T + I. ne-03) : (Hgb + l. -o ; (-C. C.- (% + l. ne-03) d) and for the subject under review, also, by the application of the principles inherent in the use of the correction factor kps as outlined earlier in this text of this improved method, the correction factor for those factors which are listed in the 'Statement Tertiary Key Factor'and'Lesser Tertiary Key Factor'modes are evaluated, and the values recorded against each of these factors, as in the following example: Realtime measurement of a parameter for a Subject under review, 'Statement Tertiary Key Factor'

(Dcvp + 0. 2) : (P-0. 006) : (R+C. 01) : (Dpv-0. 2) : (Sp + 13. 6) : (Dco + 0. CC 'Lesser Tertiary Key Factor' (Dsr : P-C. 3 : (PaK-0. 223) - (Mcp + 0. 44) : -0. 0002) : p + 0. 441 : ( (Dw-O. 0053).- (T+ 0. 015) : (Hb + 0. 076 : (w-0. 033).- -C. 009) e) in the above example, the'Runner'has established a range for each of the factors, using the principles which have been described earlier in the text of this improved method. Assuming that the best match of the'Runner'and the subject under review has been made, under the conditions which exist in the database for the parameter under evaluation. In the above example, to follow the ordered form of seniority, the judgement was based upon the following factors:

'Runner'Subject Dcvp+O. n derived central venouss pressure +0.2 P-I. ne-03 measured pulse rate-0. 006 R+O. On measured pulse pressure +0.01 Sp + lO. n derived mean systemic filling pressure +13.6 Dsr-lO. n derived right ventricular systolic pressure-12. 3 PaPd-O. n derived right ventricular diastolic pressure-0. 3 PaPm-O. n derived mean right ventricular pressure-0. 223 Dco-l. ne-04 derived cardiac output-0. 0002 m - 1. ne-04 derived mean systemic arterial pressure-0. 0002 w-O. On measured weight-0. 033 f) the'Runner'has an evaluated calibration algorithym, the'Correction Factor Equation, which is given as follows:

'Correction Factor Equation'from the above example Kn = Dcvp : P : R : Dpv : Sp/e2inv : Dco. e3 : DXSHB and note that the value DXSHB in the equation is not calculated for the'Runner', but for the subject under review as has been described earlier in the text of this improved method; g) and substituting the evaluated values from the subject under review for

the notated factors listed in the above'Correction Factor Equation' :

Kan 0. 2 + 0. 006 + 0. 1 + 0. 2-0. 076 + DXSHB h) the-value of the initial correction factor DXSHB as described earlier in this text is given by the equation :

DXSHB = (KcL * (KcH/XCLa)) - (HCLa -XCLa) (K (2H - KlJ..

(HCLa - LCLa) C-ZCZ wherein in the above algorithym, the value of the factors, 1) HCLa, KcH, K : L are values of the measured and evaluated factors from the'Dominant Pupils'which are recorded in the database for a parameter; 2) and XCLa is the value of a measured or evaluated factor from the subject under review in realtime ; i) and the value Kn is applied to the evaluated value of the parameter, as described in Applicant's earlier International Patent Application, WO 01/86474 Al, for a final calibrated result for that parameter.

The database for a parameter is complete when no difference exists between a realtime measurement for a subject under review and the'Runner'with which it has been matched for calibration. The apparatus will be said to function with a 100% accuracy. In the above example of the calibration of a parameter which has been evaluated for a subject under review, the result of the calibration is not expected to be accurate because of the many differences found, which are listed as follows:

'Runner' : Subject Mcp-O. n derived mean capillary pressure Mcp + O. n T + l. ne-03 measured total proteins concentration T + O. On Hgb + 1. ne-03 derived haemoglobin concentration Hgb + O. On h + l. ne-03 measured height h - l. ne-03

Examples of the determination of the various parameters is described in

Applicant's earlier International Patent Application, WO 01/86474 Al (line 16 of page 19, to, line 4 of page 43). A method to increase the sensitivity of the apparatus requires both knowledge of the algorithym from which a parameter is evaluated and, the clinical status of the subject from whom measured and evaluated factors are made. The'Universal Tertiary Key Factor', the'Statement Tertiary Key Factor', the'Lesser Tertiary Key Factor', and the'Correction Factor Equation'modes will be employed in the following text to give examples of the determination of the various parameters by this improved method. It will also be appreciated that the general techniques of calibration described may be used for other parameters, and predictions where the factor occur in nature with measurable predictability, frequency and reproducibility.

With reference to the diagram as shown in Figure 1, the'Dominant Pupils'1 with a higher class pupil (HCP) and lower class pupil (LCP), having been elected according to the principles earlier described in this text, each entered in the database with the following: i) a correction factor kc, the factor by which the evaluated parameter may be modified to calibrate this to the actual value; ii) a list of its'Universal Tertiary Key Factor (UTKF), and each factor with an evaluated kps value, a ratio of the change in the correction factor kc, with respect to the change in the value of the factor (either measured or evaluated) between the lower class pupil and the higher class pupil.

The'Dominant Pupils'create conditions to evaluate a'Runner', and, prepares the evaluated measurement from a subject under review for the calibration unit.

To follow the pathway 2 to a'Runner'in the database with the following: a) its initial correction factor (DXRHB) and correction factor for each of the factors listed in its'Statement Tertiary Key Factor'and'Lesser Tertiary Key Factor'are evaluated according to the principles described in Applicant's earlier International Patent Application WO 01/86474 A1 ; b) the notated values together with the value of the initial correction factor for the evaluated parameter are used to create a correction factor equation (CFQ).

To follow the pathway 3 from the'Dominant Pupils'to a subject under review in realtime has a limited number of actual measurements in realtime 4, entered into the CPU of the microcomputer 6 with the following: i) a'Statement Tertiary Key Factor'and'Lesser Tertiary Key Factor'are created as dictated for the parameter by the'Runners' ; ii) the initial'correction factor (DXSHB) and correction factor for each of the factors listed in its'Statement Tertiary Key Factor'and'Lesser Tertiary Key Factor'are evaluated according to the principles described in Applicant's earlier International Patent Application WO 01/86474 Al ; To follow the pathway 7 the'Statement Tertiary Key Factor'and'Lesser Tertiary Key Factor'from the subject under review in realtime is matched with those of a 'Runner'in the database according to the principles earlier described in this text.

To follow the pathway 8, the matched'Runner'returns its correction factor equation to the CPU of the microcomputer 9, wherein the evaluated values from the subject under review are substituted into the correction factor as dictated by its matched'Runner', to evaluate the correction factor kn for the evaluated parameter, to follow the principles earlier described in this text.

The calibrated value of the evaluated parameter for the subject under review is displayed on an LED of a microcomputer 10.

In has been earlier described in this text (page 5 and 6) that while a list of the 'Universal Tertiary Key Factor'is common to all the parameters of the determination of blood flow, it is possible to find differences in the list for the 'Statement Tertiary Key Factor', the'Lesser Tertiary Key Factor', and the 'Correction Factor Equation'modes for each parameter. For the following: Cardiac Output The algorithyms which are used to evaluate cardiac output are given in Applicant's earlier International Patent Application, WO 01/86474 Al (line 8 of page 20, to, line 13 of page 21) as follows:

the equation used for the adult

CO-kn {DpV. P (S-D). T. (WO. 425) (hO. 725)) 0. 09604. Dw. (3Hgb)

the equation used for children

COk = kn f Dpv. P (S-D). T. U. pH. (wO. 425) (hO. 725)} 72. 38. Dw. (3Hgb)

the equation used for the pregnant female

COpu = kn {Dpv. P (S-D). T. U. us. ( (L+150)/50). pH. (w0425Vh0725 O. 149. fe. Dw. (3Hgb)

adhering to the general principles inherent in the creation and use of the following modes of a parameter: the'Statement Tertiary Key Factor' the'Lesser Tertiary Key Factor' and the'Correction Factor Equation' it can be assumed that the values given and the ordered form of seniority, for each of the measured and evaluated factors, have been adjusted to correlate with the subject's clinical status; i. e. altogether, to form a calibration unit for the subject under review in realtime. In the following example:

the factors from'Statement Tertiary Key Factor' : Dcvp : P : R : Dpv : Sp : Dco factors from the'Lesser Tertiary Key Factors' : Dsr : PaPm : Mcp : m2 : Dw : T : (3Hgb) : w : h : U : Dsv : dOFka : dOFkv : dCOka : DpH 'Correction Factor Equation' : Dcvp/inv : P : R : Dpv/1O : Sp/1Oinv : Dco. e2 : DXSHB There are some modifications to be made to the above modes: for the pregnant female, the factors in the order in which they are listed here, U (maternal blood oxygen saturation), (L+150)/50, (which relates to the age of the

foetus), us (the maternal blood sugar concentration), fe (serum iron concentration of maternal blood) and the maternal blood pH are added to the list of'Lesser Tertiary Key Factors', to be placed between the factors m2 and Dw; and for children, the factors in the order in which they are listed here, U (blood oxygen saturation), and the blood pH are added to the list of'Lesser Tertiary Key Factors', to be placed between the factors m2 and Dw.

Central Venous Presure The algorithyms which are used to evaluate central venous pressure is given in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 14 to 16 of page 21) as follows: the equation used CVP = kn { (20m2/Dco) -C} adhering to the general principles inherent in the creation and use of the following modes of a parameter: the'Statement Tertiary Key Factor' the'Lesser Tertiary Key Factor' and the'Correction Factor Equation' it can be assumed that the values given and the ordered form of seniority, for each of the measured and evaluated factors, have been adjusted to correlate with the subject's clinical status; i. e. altogether, to form a calibration unit for the subject under review in realtime. In the following example: the factors from'Statement Tertiary Key Factor' : (Dcvp+C):m2:Dpv:Sp:Dco

factors from the'Lesser Tertiary Key Factors' : P : R : Dsr : PaPm : Mep : L) w : T.- (3Hgb) : w : h.-U : Dsv : dOFka : dOFkv dCOka : DpH 'Correction Factor Equation' : (Dcvp+ C) : P : R : Dpv/lC : ?/7C : Dec ; DAS

Right Pulmonary artery Systolic Pressure The algorithyms which are used to evaluate cardiac output are given in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 4 to 8 of page 22) as follows: the equation-used for the adult

Sr = kn { (Sqr. (Dpv. P (S-D). T. (w0. 425) (hO. 725). U. (Dcvp+C)) + Dcvp} 800. 705. Dw. (3Hgb)

the equation used for children

Srk = kn Sqr. (Dpv. P (S-D). T. (wO. 425) (hO. 725). U. pH. (Dcvp+C)) + Dcvp} 5957. 25. Dw. (3Hgb) adhering to the general principles inherent in the creation and use of the following modes of a parameter: the'Statement Tertiary Key Factor' the'Lesser Tertiary Key Factor' and the'Correction Factor Equation' it can be assumed that the values given and the ordered form of seniority, for each of the measured and evaluated factors, have been adjusted to correlate with the subject's clinical status; i. e. altogether, to form a calibration unit for the subject under review in realtime. In the following example:

the factors from'Statement Tertiary Key Factor' : Dcvp : Dpv : Sp : Dsr : Dco factors from the'Lesser Tertiary Key Factors' : Sp : PaPm : Dco : P : R : U : m2 : Dw : T : (3Hgb) : w : h 'Correction Factor Equation' : Dcvp/70 : Dpv/e2 : Sp/e2inv : Dsr. inv : Dco. e3inv : DXSHB There are some modifications to be made to the above modes: for children, the factors in the order in which they are listed here, U (blood oxygen saturation), and the blood pH are added to the list of'Lesser Tertiary Key

Factors', to be placed between the factors m2 and Dw.

Right Pulmonary artery Diastolic Pressure The algorithyms which are used to evaluate Right Pulmonary artery Diastolic Pressure are given in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 4 to 8 of page 22) as follows:

the equation used for the adult Papd = -2-yr-2/j Dsr is the derived right pulmonary artery systolic pressure in the adult or pregnant female (substituted for Dsrk for children) as described in the above algorithym, and Sp (Spk for children) is the mean systemic filling pressure (as also described above). Adhering to the general principles inherent in the creation and use of the following modes of a parameter: the'Statement Tertiary Key Factor' the'Lesser Tertiary Key Factor' and the'Correction Factor Equation' it can be assumed that the values given and the ordered form of seniority, for each of the measured and evaluated factors, have been adjusted to correlate with the subject's clinical status; i. e. altogether, to form a calibration unit for the subject under review in realtime. In the following example: the factors from'Statement Tertiary Key Factor' :

Dcvp : Dpv : Spr : Dsr : Dco : DPaPd factors from the'Lesser Tertiary Key Factors' : Sp Sp : PaPm : MCp : m2 : P : R : Dw : T : (3Hgb) : w : h 'Correction Factor Equation' :

Dcvp/70.-D/ < ? 2 : PP.-D/7C ; Dec. 7 ; PP/C.-ZMS Right mean Pulmonary artery Pressure The algorithyms which are used to evaluate Right mean Pulmonary artery Pressure are given in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 18 to 20 of page 23) as follows:

the equation used for the adult Papm = kn (Dsr - 2Sp) Dsr is the derived right pulmonary artery systolic pressure in the adult or pregnant female (substituted for Dsrk for children) as described in the above algorithym, and Sp (Spk for. children) is the mean systemic filling pressure (as also described above). Adhering to the general principles inherent in the creation and use of the following modes of a parameter: the'Statement Tertiary Key Factor' the'Lesser Tertiary Key Factor' and the'Correction Factor Equation' it can be assumed that the values given and the ordered form of seniority, for each of the measured and evaluated factors, have been adjusted to correlate with the subject's clinical status; i. e. altogether, to form a calibration unit for the subject under review in realtime. In the following example:

the factors from'Statement Tertiary Key Factor' : Dcvp : Dpv : Sp : Dsr : Dco : DPaPm factors from the'Lesser Tertiary Key Factors' : Sp : PaPd : Mcp : m2 : P : R : Dw : T : (3Hgb) : w : h 'Correction Factor Equation' : Dcvp/1Oinv : Dp ?lvinv : S 6e2 : Dsr. inv : Deo. e2 : PaPm. inv : DXSHB Left atrial pressure, Yp The algorithyms which are used to evaluate the left atrial pressure are given in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 18 page 22, to, line2 of page 23) as follows: the equation used for the adult Yp = kn. { (Dpv. (3Hgb) S2) / (P (S-D). Dw. T. (wO. 425) (ho. 725) (58. 43))} the equation used for children

Ypk= kn. { (Dpv. (3Hgb) S2)/ (P (S-D). Dw. U. pH. T. (wo. 425) (ho. 725) (58. 43))} Adhering to the general principles inherent in the creation and use of the following modes of a parameter: the'Statement Tertiary Key Factor' the'Lesser Tertiary Key Factor' and the'Correction Factor Equation' it can be assumed that the values given and the ordered form of seniority, for each of the measured and evaluated factors, have been adjusted to correlate with the subject's clinical status; i. e. altogether, to form a calibration unit for the subject under review in realtime. In the following example: the factors from'Statement Tertiary Key Factor' :

DYp Yp : Dpv : S2 : Sp : P : R : Dca factors from the'Lesser Tertiary Key Factors' : Dcvp : Dsr : DPaPm : P : R : U : m2 : Dw : T : (3Hgb) : w : h 'Correction Factor Equation' : D?.-Opv : S2 : Sp : P : R : Dca : DXSHB There is a modification to be made to the above modes: for children, the factor the blood pH is added to the list of'Lesser Tertiary Key Factors', to be placed between the factors m2 and Dw.

Stroke Volume The algorithym which is used to evaluate stroke volume is given in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 10 to 15 of page 23) as follows: SV = kn (P (S-D) (Dcvp + C)/IOS2 adhering to the general principles inherent in the creation and use of the following modes of a parameter: the'Statement Tertiary Key Factor' the'Lesser Tertiary Key Factor' and the'Correction Factor Equation'

it can be assumed that the values given and the ordered form of seniority, for each of the measured and evaluated factors, have been adjusted to correlate with the subject's clinical status; i. e. altogether, to form a calibration unit for the subject under review in realtime. In the following example:

the factors from'Statement Tertiary Key Factor' : Dcvp.-Dpv ; : ?.- P.-.-Dec.-D.-D factors from the'Lesser Tertiary Key Factors' : Dsr : DPaPm : R : U.-2.-Dw. T.-3Hgb) : w.-h : dO972 -37v. COka.

DpH 'Correction Factor Equation': Dcvp : Dpv.- ; 5 ?. P. 7.-Dec.-Dp.-D.-TS Pain Index One indication of pain that a subject is in, is the'Pain Response Index', PAr, which in Applicant's earlier International Patent Application, WO 01/86474 Al (line 18 of page 34), is given by the algorithym: PAr = DsvI/Dsv2 where Dsvl is the derived stroke volume measurement when the pain patient is pain free, and Dsv2 is the derived stroke volume measurement when the pain patient is in pain. In both cases the derived stroke volume measurement is evaluated as expressed as above.

When compilling the database for pain index, a trained observer scores the value of the degree of pain of the'Dominant Pupils'and'Runners', in accordance with a special protocol, and this is stored as the Kc value. The factors that are used in assessing the pain response index, namely the pulse rate (P), pulse pressure ( [SD]), the derived central venous pressure (Dcvp + C), the systolic blood pressure (S2), and the pain response index itself are also stored. And, Pain index (%) = CFQ + DXSHBPAr = kn' Mean Pulmonary Capillary Pressure

The algorithym which is used to evaluate mean pulmonary capillary pressure is given in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 14 to 17 of page 24) as follows: Mcp = kn { (m. (Dcvp + C). T)/ (m. (Dcvp + C). 8)} adhering to the general principles inherent in the creation and use of the following modes of a parameter: the'Statement Tertiary Key Factor' the'Lesser Tertiary Key Factor' and the'Correction Factor Equation' it can be assumed that the values given and the ordered form of seniority, for each of the measured and evaluated factors, have been adjusted to correlate with the subject's clinical status ; i. e. altogether, to form a calibration unit for the subject under review in realtime. In the following example: the factors from'Statement Tertiary Key Factor' : DMcp : m : (Dcvp +C) : Dpv : T : Sp : Dca factors from the'Lesser Tertiary Key Factors' : Dsr : DPaPm : R : P : (3Hgb).- : : U : Dsv : w : h.- dOFka : dOFkv : dCOka : DpH 'Correction Factor Equation' : DMcp : m : (Dcvp +C) : Dpv : T : Sp : Dcc.- DXSHB Plasma Osmolarity The algorithym which is used to evaluate plasma osmolarity is given in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 15 of page 25) as follows: W = kn f (142 (100- (3Hgb)))/ (56.8 (In [3Hgb/T]))} adhering to the general principles inherent in the creation and use of the following modes of a parameter: the'Statement Tertiary Key Factor'

the'Lesser Tertiary Key Factor' and the'Correction Factor Equation' it can be assumed that the values given and the ordered form of seniority, for each of the measured and evaluated factors, have been adjusted to correlate with the subject's clinical status; i. e. altogether, to form a calibration unit for the subject under review in realtime. In the following example: the factors from'Statement Tertiary Key Factor' :

Sp : P : R : Pp : Dpv : (3Hgb) : Dw factors from the'Lesser Tertiary Key Factors' : Dsr : DPaPm : Dco : Dcvp : T : w : h : dOFka : dOFkv : dCOka : DpH 'Correction Factor Equation' : Sp : P : R : Pp : Dpv : ).-D.-Dec ; ZMS' Erythrocyte sedimentation Rate The algorithym which is used to evaluate the erythrocyte sedimentation rate is given in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 16 to 18 of page 25) as follows: Ed = kn In (3Hgb/T) adhering to the general principles inherent in the creation and use of the following modes of a parameter: the'Statement Tertiary Key Factor' the'Lesser Tertiary Key Factor' and the'Correction Factor Equation' it can be assumed that the values given and the ordered form of seniority, for each of the measured and evaluated factors, have been adjusted to correlate with the subject's clinical status; i. e. altogether, to form a calibration unit for the subject under review in realtime. In the following example: the factors from'Statement Tertiary Key Factor' : Sp : P : R : Pp : Dw : (3Hgb) : DEd

factors from the'Lesser Tertiary Key Factors' : Dsr : DPaPm : Dco : Dcvp : T : w : h : dOFka : dOFkv : dCOka : DpH 'Correction Factor Equation' : .-P.-P ; Pp ; Zv ; ).-D.-Dec ; DS' The value given by the correction factor equation for the erythrocyte sedimentation rate is then converted to a calibrated sedimentation rate, E, using the equation as given in Applicant's earlier International Patent Application, WO 01/86474 Al

(line I of page 26), as follows : E = (Ed -1. 625)/0. 00426 The Blood Haematocrit The algorithym which is used to evaluate the haematocrit is given in Applicant's earlier International Patent Application, WO 01/86474 Al (line 12 of page 36, to, line 2 of page 37) as follows: A = kn. ZA. InT adhering to the general principles inherent in the creation and use of the following modes of a parameter: the'Statement Tertiary Key Factor' the'Lesser Tertiary Key Factor' and the'Correction Factor Equation' it can be assumed that the values given and the ordered form of seniority, for each of the measured or evaluated factors, have been adjusted to correlate with the subject's clinical status; i. e. altogether, to form a calibration unit for the subject under review in realtime. In the following example: the factors from'Statement Tertiary Key Factor' :

Sp : Dcvp : Dco : P (S-D) : Dsr factors from the'Lesser Tertiary Key Factors' : Dsr : PaPm : Mp 2 m P.-P : R. D v : U : T : Dwx : w : h

'Correction Factor Equation' :

Sple2 + Ppe4 + Ax] + + Lr C : DXSHB Volume Change of the Circulation The algorithym which is used to evaluate the volume change of the circulation is given in Applicant's earlier International Patent Application, WO 01/86474 Al (line 18 of page 26), as follows: Fd = kn. 8. {((Dcvp12.Dco1 . P1) / 10S12) - ((Dcvp22.Dco2 . P2) / 10S22) adhering to the general principles inherent in the creation and use of the following modes of a parameter: the'Statement Tertiary Key Factor' the'Lesser Tertiary Key Factor' and the'Correction Factor Equation' it can be assumed that the values given and the ordered form of seniority, for each of the measured and evaluated factors, have been adjusted to correlate with the subject's clinical status; i. e. altogether, to form a calibration unit for the subject under review in realtime. In the following example:

the factors from'Statement Tertiary Key Factor' : Dcvp : Dco : Sp : P : R : Pp : Dpv factors from the'Lesser Tertiary Key Factors' : Dsr : DPaPm : :Dw : (3Hgb) : T : w : h : dOFka : dOFkv : dCOka : DpH 'Correction Factor Equation' : Dcvp : Dco : Sp : P : R : Pp : Dpv : DXSHB

Cation and Anion Concentration The algorithym which is used to evaluate of the electrolytes and products of metabolism, Cs, is given in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 15 of page 25) as follows: Cs = kn { (Nv. 142 (1 00 - (3Hgb))) 1 (56.8 (In [3Hgb/T]))} adhering to the general principles inherent in the creation and use of the following modes of a parameter: the'Statement Tertiary Key Factor' the'Lesser Tertiary Key Factor' and the'Correction Factor Equation' it can be assumed that the values given and the ordered form of seniority, for each of the measured and evaluated factors, have been adjusted to correlate with the subject's clinical status; i. e. altogether, to form a calibration unit for the subject under review in realtime. In the following example:

the factors from'Statement Tertiary Key Factor' : Nv : Sp : P : R : Pp : Dpv : (3Hgb) : D & factors from the'Lesser Tertiary Key Factors' : Dsr : DPaPm :Dec.: Dcvp : Dw : T : w : h : dOFka : dOFkv : dCOka : DpH 'Correction Factor Equation' :

Nv : Sp : P : R : Pp : DpV : (3Hgb). DG : Dco : DXSHB Surface Area of the body Surface Area of the body The surface area may be calculated using the Dubois equation, namely : SA = (wO. 425) (ho 725) (0. 00718) It has been disclosed to use a hydraulic bed device to determine the surface area of a subject by determining the pressure induced (Pid) by the weight (w) of the subject on the hydraulic bed and the temperature (Thf) of the fluid within the

hydraulic bed based on the gas laws.

It is possible to determine the weight of a subject from the correction factors DXw and know, as described in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 3 to 5 of page 33). Further, that the evaluated weight, w, is proportional to the correction factor DX, and equal to the factor knw.

Earlier in this text a description is made on the application of the correction factor DX in this improved method. To adhere to those principles outlined, which incorporates the use of the'Correction Factor Equation' (CFQ), it is possible to make the following expressions:

w = = CFQ + DXR, for the'Runner', and w = know = CFQ + DXSHB w, for a subject under review, and

DX = (wh (wh/Xh))- (YHh-Xh) (wh-wl)) the preferred algorythym for the (Xh-Hh) initial correction factor equation There are some deviations to be described before a'Correction Factor Equation'is established for the'Runners'.

In the creation of the'Dominant Pupils'for use in the evaluation of the surface area of a subject in this improved method, the table 3 as shown on page 33 in Applicant's earlier International Patent Application, WO 01/86474 Al is subjected to some modifications. The'Schools'as defined in the aforementioned table become, for want of description, Pseudo-Parameters, which in the following examples : a pseudo-parameter in this improved method is the age, GE, of less than eighteen months; another pseudo parameter in this improved method is the age, GE, equal to eighteen months, but less than five years;

and, to reach an upper limit (to follow the table in this example), a pseudo-parameter in this improved method is the age, GE, of greater than fifty years.

To adhere to the principles inherent in the creation of'Schools'as described in Applicant's earlier International Patent Application, WO 01/86474 Al (line 18 of page 6, to, line 6 of page 7) The'Schools'for a pseudo-parameter described above may be defined, as in the example of the less than eighteen months old pseudo parameter, by the following:

School 1........... born three weeks before term School 2 born one week before term School 3........... born at term School 4........... born at term, but less than six weeks old School 5........... six weeks old, but less than three months old School 6........... three months old, but less than six months old School 7........... six months old, but less than one year old School 8........... one year old, but less than eighteen months old It is possible to define the'Dominant Pupils'elected for a pseudo-parameter as described earlier in this text, by the following: a) a'Primary Key Factor', the factor Sp (or Spk for children) with a value which is equal to or lower than some 0.01 units; b) a'Secondary Key Factor', the factor height (length in babies and neonates), h, which as described earlier in this text may have a value which is in the range of the (statistical) mode for the pseudo-parameter ; i. e. 80cm for the newborn.

The following is a preferred list of those factors for the'Dominant Pupils'which may contribute to the'Universal Tertiary Key Factor'mode: weight (w), height (h), age (GE), the pressure induced by weight of the subject (Pid), the temperature of the fluid within the hydraukic bed (Thf), the Sp (or Spk for children) value, derived central venous pressure (Dcvp), derived cardiac output (Dco), derived sodium ion concentration (Na+), derived potassium ion concentration (K+), the measured plasma total proteins concentration (T),

temperatue of the subject (Th), and the respiratory rate of the subject (Rf) ; i The correction factor kps are evaluated for each factor in the list of the'Universal Tertiary Key Factor'mode, using the equation as described in Applicant's earlier International Patent Application, WO 01/86474 Al (line 18 of page 34), as follows: kps- (wh-wl)/ (QuH-QuL) The'Dominant Pupils'fully described for the evaluation of the body surface area, in this improved method, it is possible to create the calibration unit, and, collect and process the required measured and evaluated factors for a subject under review, to enter the evaluated pseudo-parameter for calibration, according to the principles which have been described earlier in this text. It is possible to create for both the'Runner'and the subject under review, the following'Statement Tertiary Key Factor', 'Lesser Tertiary Key Factor', and the'Correction Factor Equation' (the factors are listed without their notated value or evaluated value, respectively, for the'Runner'and the subject under review):

the factors from'Statement Tertiary Key Factor' : Sp : Pid. Thf : Th : h : GE factors from the'Lesser Tertiary Key Factors' : Dco : Dcvp : DNa+ : DK+ : T : Th : Rf 'Correction Factor Equation' : Sp : Pid : Thf : Th : h : GE : DXSHB A correction factor kc w, as described in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 1 to 17 of page 6), for the'lower class pupil' and the'higher class pupil', from the'Dominant Pupils', are stored in the database for a pseudo-parameter ; the value kc W for the'higher class pupil'is wh (the weight of the pupil), and, the value kcw for the'lower class pupil'is wl.

The initial correction factor DXRHB for each of the'Runners'for the pseudo-

parameters are evaluated, according the principles inherent in the creation of a 'Runner'as given earlier in this text, by using the equation which in this example is for a'Runner'whose measurements fall within a given'Class'as defined in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 4 to 12 of page 34):

The value of the'Correction Factor Equation'is the result knw, is the true evaluated weight of the subject under review. This result may then be used to determine the surface area of the subject in accordance with the Dubois equation.

Foetal Distress Index Similar principles used for those for determining Pain Index can be used for the determination of foetal distress, Ftd, during pregnancy and parturition.

Foetal distress index measurements range from a value of 0, indicating that the foetus is in no distress, to 5, indicating foetal death. Foetal distress is determined by a trained observer who scores the value of the degree of foetal distress based on observations. When compilling the database for pain index, a trained observer scores the degree of foetal distress of the subject in accordance with a special protocol, and this stored as the kc value for the'Dominant Pupils', and as the (CFQ

+ DXRHB) for the'Runner'.

An indication of foetal distress may be determined using the equation, which in Applicant's earlier International Patent Application, WO 01/86474 Al (line 9 of page 39), is given by the algorithym: Ftr = { (Pm (Sm-Dm) (Dcvpm + C))/ (lOPf. Sm2)} where Sm is the maternal systole blood pressure, Dm is the maternal diastole blood pressure, Dcvpm is the maternal derived central venous pressure and Pf is the foetal heart rate. The'Dominant Pupils'are elected using maternal Sp and Pp factors according to the principles earlier described in this text:

adhering to the general principles inherent in the creation and use of the following modes of a parameter: the'Statement Tertiary Key the'Lesser Tertiary Key Factor' and the'Correction Factor Equation' it can be assumed that the values given and the ordered form of seniority, for each of the measured or evaluated factors, have been adjusted to correlate with the subject's clinical status; i. e. altogether, to form a calibration unit for the subject under review in realtime. In the following example wherein all factors are maternal except for the foetal heart rate (Ftr): the factors from'Statement Tertiary Key Factor' :

P : Ftr.- (Dcvp + C) : Deo.- (S-D) : Sp factors from the'Lesser Tertiary Key Factors' : Dsr : PaPm : Mcp : Dpv : Dw : T : (3Hgb) : w : h : U : dOFka : COka : DpH 'Correction Factor Equation' : P : Ftr : (Dcvp + C) : R : Dpv/10 : Sp/10 : Dc.: DXSHB It will be appreciated that for pain index and foetal distress index, there is no general equation to give the kc value for a'Runner' (i. e. with kc = 1). Then in the determination of the index, the index equals kn (i. e. the"equation"modified by the kn value is 1), as described in Applicant's earlier International Patent Application, WO 01/86474 Al (lines 12 to 15 of page 40).

It will be appreciated that when in this text the factor Sp is applied for adults, the Spk value will apply for children while not in some cases specified.

Apparatus Suitable apparatus for the implementation of the present invention is based around a microcomputer with a memory storing the database for the parameters to be

determined. Preferably there are databases for each of the parameters to be determined, although these may be combined.

The measurements from the subject under review are input to the microcomputer.

This may either be by manual imput of the measured parameters, for example through a keyboard. However, it is preferred that the measurements are input directly from the measuring apparatus. For example, an electronic sensor may be provided that determines the pulse rate and blood pressure measurements, and outputs these directly to the computer for processing. Another machine, including a hydraulic bed. may determine the weight and height of the subject, and again can output these determinations to the computer directly. The measurements that come from a sample of the subject's blood may also be analysed by a machine that outputs the results in an electronic form directly to the computer.

The computer is then able to take the measurements, derive the derived parameters and calculate the values of the desired parameters using the equations and methods as described above.

In general, a parameter which is elected for calibration must have a history and, notably, to highlight its mode of frequency reproducibility and predictability. For an example, the measure of reproducibility of the following: i) for blood flow it is the measurement of cardiac output; ii) for an earthquake it is the measurement on the Richter scale; ii) for a rainfall it is the measurement of the height of fluid collected in a standardized container.

Therefore, it is possible to apply this improved method of calibration and, or prediction broadly. It is said that a coat cannot be cut without some material and, better still, that the material is fashioned for a service. In the calibration or the prediction of a factor, it is preferred that a matrix algorithym (the material) is created which not only relates to, but will give near enough real values for the measurement. Instruments may be required to measure factors which make up the matrix algorithym for the parameter in question; i. e. the'Statement Tertiary Key Factor'. It is also possible that when a parameter is measured, the measurement has to be qualified, and, these factors can be listed for it as the'Lesser Tertiary Key Factor'. The calibration or prediction is completed by a designed'Correction Factor

Equation', by adhering to the principles which have been described in the foregoing text.

Claims

CLAIMS 1. A method of determining a parameter related to blood flow or the blood carrying organs of a subject from one or more measurements, comprising the steps of : forming a database by obtaining a set of measurements for each of a plurality of test subjects, each set of measurements including the measurements required to determine the parameter using an algorithym, and each set of measurements having an associated correction facto (Kc) related to the deviation between the calculated value of the parameter using the algorithym and the actual value of the parameter, the sets of measurements being divided into classes based on a Class Index (CLa) value, each class having a lower class pupil (LCP) and a higher class pupil (HCP) each with an associated set of measurements; and, determining of the parameter for the subject by: taking measurements for the subject including those required for the determination of the parameter by the algorithym; determining a Class Index from the set of measurements; identifying the class within which the set of measurements falls based on the determined Class Index, the class being that for which the Class Index for the subject is between the respective Class Index for the subject is between the respective Class Index values of the lower class pupil and higher class pupil; determining a correction factor (kn) based on an interpolation of the correction factors for the lower class pupil and the higher class pupil that define the class within which the set of measurements falls and using this to determine the correct value of the parameter kn. <Desc/Clms Page number 46> CLAIMS

1. A method of determining a parameter related to blood flow or the blood carrying organs of a subject from one or more measurements, comprising the steps of : forming a database by obtaining a set of measurements for each of a plurality of test subjects, each set of measurements including the measurements required to determine the parameter using an algorithym, and each set of measurements having an associated correction factor (Kc) related to the deviation between the calculated value of the parameter using the algorithym and the actual value of the parameter, each from the set being divided by its collection of factors that are listed in an ordered form based upon their physiological or pathophysiological significnce to the parameter entering first into a list of the Statement Tertiary Key Factors (STKF) which are those factors carried in the algorithym to evaluate the parameter, secondly into a list of the Lesser Tertiary Key Factors which are those factors which contribute directly or indirectly to the physiological or patho-physiological change, and thirdly into the Correction Factor Equation (CFQ) a value equivalent to the correction factor (Kc) a total of the initial correction factor DXRHB and those factors collected from the the list of the statement tertiary key factors and lesser tertiary key factors the value of each factor in the list adjusted to meet with its physiological or patho-physiological significance of the evaluated parameter; and, determining of the parameter for the subject by: taking measurements for the subject including those required for the determination of the parameter by the algorithym ; determining the correction factors for each factor required by the parameter for its list as defined by the Statement Tertiary Key Factors and Lesser Tertiary Key Factors modes; identifying within the database for the measurement a calibration unit with Statement Tertiary Key Factors and Lesser Tertiary Key Factors which is its blueprint based upon the ordered form in the listing of and value of these factors which have defined a range; determining a correction factor (kn) based on the sum total of the correction factor for each of the factors which have been measured or evaluated from the subject

and have been adjusted to meet with the values as dictated by the Correction Factor Equation of its match in the database that total added to the initial correction factor DXSHB for the evaluated parameter from the subject.

2. An apparatus for use with the method of the preceding claim, the apparatus including a memory for storing the measurements of test subjects in a database, an input means for in putting the measurements for a test subject, and a prosessing means for evaluating the or each parameter based on the input measurements from a subject to be monitored with reference to the measurements stored in the database.