WO2006092624A1

WO2006092624A1 - Method and apparatus

Info

Publication number: WO2006092624A1
Application number: PCT/GB2006/000781
Authority: WO
Inventors: David Marston Band; Christopher Bancroft Wolff
Original assignee: Lidco Group Plc
Priority date: 2005-03-03
Filing date: 2006-03-03
Publication date: 2006-09-08
Also published as: GB0504469D0

Abstract

Methods for determining the oxygen extraction index (E) of a tissue of interest in a subject include the steps of determining rSO2 in the tissue of interest, determining SaO2 in the subject, taking the rSO2 and SaO2 measured values and using these values in the calculation; E = (p + 1) x (1 - rSO2/SaO2). In the equation, p is a constant. The results of the calculation are displayed and represent the oxygen extraction index for the tissue of interest. Methods for determining whole body oxygen extraction and oxygen consumption are also described. Suitable apparatus, processors and computer programs for carrying out the methods are also provided.

Description

METHOD AND APPARATUS

Field of the Invention

The present invention relates to novel methods and apparatus for determining a physiologically relevant parameter, the oxygen extraction index (E), in a subject. The methods and apparatus have both medical and non-medical applications .

Background to the invention

Cerebral oxygen delivery is sustained in the face of, at least moderate, hypoxia (1) . The measurements required to show this have, in the past, been especially invasive, with a requirement for jugular venous bulb sampling and carotid arterial administration of a marker to allow measurement of flow by dye dilution (2) . With the advent of middle cerebral arterial blood velocity measurement (Doppler) and arterial oxygen saturation measurement (pulse oximetry) the procedure is greatly simplified, at least on a relative basis: SaO₂ multiplied by middle cerebral artery velocity will, arguably, give individual changes in oxygen delivery for, at least, the distribution supplied by the middle cerebral artery. This will, for normal subjects, usually change in proportion to global changes.

Cerebral near infrared spectroscopy (NIRS) provides a measure of the proportion of blood which is oxygenated in a given, mainly cortical, region. It does not, however, distinguish how much is in the arterial or the venous part of that vascular bed. The proportions of blood in the arterial and venous compartments in the brain have been estimated at 28% of the total for the arterial and 72% for the venous value (3) . This gives a relationship between the arterial and venous blood volumes (p = Va/Vv) of 28/72 or 0.39 (so p = 0.39). There will be a range of values above and below this for individual local tissues .

Previous work has examined how well oxygen delivery is sustained with increasing altitude (and/or reduced oxygen saturation) from earlier measurements of middle cerebral artery velocity (MCAV) , and explored how well a model of arterial/venous distribution fits with SaO₂ and NIRS data (rSO₂) from the same experimental series (4-6) .

In a previous study, (7) a model was derived for fractional oxygen concentration in the blood volume described by near- infrared transmission (rSO₂) in terms of

SaO₂, the relative volumes of arterial and venous blood (p = Va/Vv) and the proportional extraction (E) of oxygen from its perfusate. rS0₂ represents the volume of oxygenated blood divided by the total blood volume (i.e. HbO₂ / (Hb + HbO₂) . Hence, rS0₂ = (SaO₂ x Va + SvO₂ x Vv) / (Va + Vv) . From this, rS0₂ can be obtained in terms of p: rSO₂ = (SaO₂ x p + SvO₂) / (p + 1) . E = VO₂ / DO₂ = (SaO₂ - SvO₂) / SaO₂ so SaO₂ x (1 - E) can be substituted for SvO₂. This gives the equation: rS0₂ = (SaO₂ x p + SaO₂ x (1- E) ) / (p + 1) (An alternative is: rS0₂ = SaO₂ x (1 - E x (1 - f) ) , where f = Va / (Va + Vv) ) . Such an equation leaves two unknown variables, E and p. There is, therefore, a requirement for a reliable indication of oxygen delivery to tissues which allow for changes in metabolic rate.

Description

The present invention relies upon the realisation of the clinical value of having a reliable and easily obtainable measure of the proportional extraction of oxygen in a tissue of interest or in the whole body in a subject from its perfusate.

The present invention thus provides a method and apparatus for determining the oxygen extraction index (E) for a tissue of interest in a subject.

By the term "oxygen extraction index" (E) as used herein is meant a numerical value, which represents the proportional extraction of oxygen in a tissue of interest in a subject from its perfusate. It is calculated from the relationship between fractional oxygen concentration in total blood (rS0₂) , oxygen saturation of the arterial system (SaO₂) and the relative volumes of arterial (Va) and venous ■ (Vv) blood (P = Va/Vv) . i The oxygen extraction index (E) is particularly

* beneficial because it takes into account the metabolic rate of the tissue of interest, whereas a measurement of, for example, oxygen delivery (DO₂) does not.

Thus, the advantage of the oxygen extraction index (E) over DO₂ in assessing oxygenation of the brain (or other organs) is that, while DO₂ has been shown to be constant, for moderate cerebral hypoxia in normal subjects, this is due to constancy of the rate of cerebral oxygen consumption (Cerebral metabolic rate for oxygen, CMRO₂) . The primary regulation is the constancy of oxygen extraction (E=CMRO₂/cerebral DO₂) . Where CMRO₂ may vary, clinically, for example in hypothermia used in cardiac operations, the appropriate DO₂ is reduced in proportion to the, unknown, reduction in CMRO₂. However, the appropriate value of E remains the same as at normal temperature (and CMRO₂) .

The ability to readily discover the oxygen extraction index (E) in a specific tissue of a subject has many clinical applications and benefits. For example, during bypass surgery carried out where the heart is stopped and where a pump is, therefore, utilised in order to maintain the flow of blood around the body (referred to as "on pump"), the volume and concentration of blood circulated around the body by the action of the pump is decreased relative to when the heart is active. This, together with debris (possibly formed by initiation of the coagulation pathway upon contact of the subject's blood with the tubes which run through the pump and connect the pump to the patient's vasculature) which accumulates in the blood during the operative procedure can lead to reduced oxygen delivery to the entire body, and importantly to essential organs.

The ability to determine the oxygen extraction index (E) in a specific tissue allows a determination to be made as to whether the levels of oxygen reaching this particular tissue are sufficient to maintain the function and viability of that tissue. If the value of E changes significantly this will alert the appropriate carer (such as a surgeon or nurse, for example) to the problem that there may be a lack of oxygen delivery to the appropriate tissue (with respect to the oxygen requirements of that particular tissue) .

One relatively common complaint from patients following cardiac by-pass surgery carried out "on-pump" is a loss of cognitive function. This may persist for months and even years after the surgical procedure has been completed. It is hypothesised that this impaired cognitive function may be linked to reduced oxygen delivery to the brain during the surgical procedure.

Even when by-pass surgery is carried out "off-pump" so that the heart remains beating, the surgical process still requires that specific regions of the heart are clamped such that they cannot move. Again, this can lead to reduced cardiac output and consequently, decreased oxygen delivery to the tissues of the body.

A similar lack of oxygen during surgery can even lead to necrosis of the gut. The gut is one of the first organs to be sacrificed (in terms of oxygen delivery and consumption) during periods of hypoxia and so it would be beneficial to be able to determine the oxygen extraction index (E) for, this tissue both pre-, during and post- operation period. The nature of the gut as a hollow viscus organ may mean, however, that for this tissue the method may not be as useful as for other, solid, organs such as the liver and kidney.

It has been surprisingly discovered that the value of p will not change unless the value of E also changes. Thus, the relative volumes of arterial and venous blood remain relatively constant whilst oxygen extraction in a tissue remains at a relatively constant level . This has allowed E to be calculated in terms of rSO₂ and SaO₂ only by assuming p is either constant or by effectively not including it in the calculation (which gives "E related") . In the case of E related the value of p can be assumed to be zero.

Thus, the prior art teaches a calculation for rSO₂ as presented below (1) rSO₂ = (SaO₂ x p + SaO₂ x (1 - E) ) / (p + 1)

The realisation of the clinical value of being able to determine the oxygen extraction index E leads to a rearrangement of equation (1) as follows: (2) rS0₂ x (p + 1) = SaO₂ x (p + 1 - E)

(3) (p + 1) x rS0₂ / SaO₂ = (p + 1 - E) ;

( 4 ) E = (p + 1 ) ( 1 - rS0₂ / SaO₂ ) . If p = 0 , E = ( 0 + 1 ) ( 1 - rS0₂ / SaO₂ ) . Therefore , E related = 1 - rS0₂ / Sa0₂

Accordingly, the present invention provides a method for determining the oxygen extraction index (E) of a tissue of interest in a subject comprising; determining rS0₂ in the tissue of interest, determining SaO₂ in the subject, taking the rS0₂ and SaO₂ measured values and using these values in the calculation;

E = (p+1) x (1 - rS0₂/Sa0₂) wherein p = a constant; and displaying the result of the calculation which represents the oxygen extraction index (E) for the tissue of interest in the subject. This method and corresponding apparatus of the invention enable rapid and convenient measurement of a physiologically important parameter using non-invasive technologies. The method and apparatus may find application in a number of clinical settings, for example to monitor the effectiveness of oxygen delivery to the tissues before, during and after an operative procedure.

In addition, the method and apparatus may also be used in non-clinical applications, such as for example to monitor oxygen extraction in various tissues of a subject during exercise. This may assist with the development of specific tailored training programs for professional athletes for example.

Furthermore, due to the fact that known non-invasive means can be employed to carry out the invention it is clear that existing equipment can be adapted to measure the oxygen extraction index for a tissue of interest in a subject concurrently with other physiologically important parameters. In practical terms, this may be particularly useful in the clinical setting to reduce costs for new equipment and also to facilitate care for the patient since a single instrument may provide the carer with all the relevant information, and this information may thus be conveniently summarised for the benefit of the carer (such as a doctor or nurse for example) .

In one embodiment p = 0 and so E = 1 - rS0₂/Sa0₂ (also referred to as "E related") . As mentioned above, the value of p represents the relative volumes of arterial (Va) and venous (Vv) blood. Thus, Va/Vv. The prior art has estimated the value of p to be around 0.39. With the realisation that p does not change under normal conditions where oxygen delivery is adequate, it is possible to make p a constant, which can be any value when calculating the oxygen extraction index. The value of p will only be affected under conditions where the subject is in a deteriorating state of health and this will be reflected in the value of E in any case. Thus, for the sake of convenience p is preferably 0.39 in accordance with the estimated values in the art. In an alternative embodiment p is assumed to be zero. As aforementioned, the value of p which is included in the calculation is not of any great importance and may be any value which makes the value of E easy to present and interpret.

The tissue under test may be any tissue of interest in the subject. Particularly preferred tissues are organs or parts thereof, and the method may give a representative measure of oxygen extraction index (E) for the whole organ or may give single or multiple measurements for various parts of the organ. In a preferred embodiment the method is used to determine the oxygen extraction index (E) in the brain. Other embodiments allow determination of the value of E for skeletal muscle, kidney, liver, pancreas, spleen and heart. In addition E may also be determined for stomach, small intestine and large intestine etc. These examples are not intended to be limiting with respect to the present invention. - S -

The subject is, in a most preferred embodiment, a human subject. The human subject will generally be a hospitalised patient. Measurements of E may be taken at pre-determined intervals or on a continuous basis. For example E values may be calculated prior to an operative procedure and may then be monitored throughout and after the operation in order to ensure that the oxygen extraction index (E) does not fall outside a pre-determined range of values. The range may be calculated having regard to the pre-operative value calculated for the particular individual, since this may vary from patient to patient and also from tissue to tissue.

Means for determining fractional oxygen concentration in total blood (rSO₂) in a tissue of interest are well known in the art and are commercially available. Determination of rSO₂ is preferably carried out using near-infrared spectroscopy (NIRS) , which offers a non-ionising and noninvasive means of determining fractional oxygen concentration in the blood volume (rSO₂) . Examples of commercially available NIRS machines include, but which are not intended to be limiting with respect to the present invention: (1) The Critikon 2020 monitor (Johnson and Johnson, Newport, UK) which has four output channels (oxygenated blood, deoxygenated blood, ,total blood and calculated rSO₂ - the ratio of oxygenated to total) ; and

(2) The Invos machine manufactured by Somanetics, which has two output channels (rS0₂ values for two different sites) .

Any method for determining rSO₂ is included within the scope of the present invention, although non-invasive methods are preferred. Generally, NIRS involves the use of optical fibres, which carry the near-infrared light to and from the tissue of interest. These fibres tend to end with prisms, which direct the light normally onto the surface of the tissue. Thus, in most cases there will be a single input and output with a single distance being measured between the two points where the light is shone onto the surface of the tissue. The Criticon 2020 utilises a second shorter path designed to. detect only light passage through the skull. This value can be subtracted from the total from the more distant detector. Thus absorption by the brain alone is obtained.

However, in one alternative embodiment of the invention, the method for determining rSO₂ in the tissue of interest may involve greater than one pairs of contact points with the tissue of interest, in order to measure any variability in the rS0₂ value in different parts of the tissue .

The tissue of interest, for the avoidance of doubt, is the same tissue as that for which the value of E is calculated.

Methods and apparatus for determining arterial oxygen saturation (SaO₂) in a subject are also commercially available. The method generally employed to determine SaO₂ is termed pulse oximetry. Pulse oximetry is a non-invasive method of determining the oxygen saturation of arterial blood. Therefore, in a most preferred embodiment SaO₂ is determined by pulse oximetry. A pulse oximeter generally consists of: (1) A probe which can be attached to any peripheral part of the body (i.e. to the skin) such as, for example, to the nose, an ear lobe, a finger or a toe.

(2) A photodetector; and (3) A processor which displays the calculated oxygen saturation and possibly other parameters such as pulse rate for example. The processor selects out absorbance caused by arterial blood from other causes of absorbance. The probe produces beams of light at two different wavelengths, one in the visible spectrum (approximately 660 nm) and one in the infrared spectrum (approximately 940 nm) , which pass through the tissues to the photodetector.

The amount of absorption of each beam of light is used to calculate, after remaining absorbance due to nonpulsatile flow, the degree of oxygen saturation in the arterial system.

Suitable pulse oximetry apparatus for use in the method of the invention includes the Propac Encore Monitor

(Beaverton, USA) and the NONIN and BCI pulse oximeters (Harrell Medical, Inc, USA) .

A measurement of SaO₂ can be taken at any point on the surface of the body and this does not necessarily have to coincide with the tissue in which the oxygen extraction index (E) is being calculated. For example, if the cerebral oxygen extraction index is being determined, the SaO₂ determination may be made using a probe which contacts the subject on the skin of a finger or toe, or on the nose or ear for example. This is because the value of SaO₂ is thought to be relatively consistent throughout the arterial system and does not vary significantly in different arteries within the body. Arterial blood has been oxygenated at the lungs then neither loses or gains oxygen until it has passed from there through the pulmonary vein, the left side of the heart and the arterial perfusion system to reach the tissues where some of the oxygen is removed. All the arterial blood will therefore have the same oxygen concentration unless there are rapid changes in the access of oxygen to the blood at the lung. For most clinical states that is not a practical problem.

In one embodiment, the determination of SaO₂ will be carried out at the skin surface of the subject which corresponds to the tissue of interest. Thus, for example, if the cerebral oxygen extraction index is to be determined the determination of both SaO₂ and rSO₂ may be carried out using sensors which contact and/or attach to the skin of the head, such as the forehead for example.

The measured values of SaO₂ and rSO₂ are then used as an output which is used to determine the oxygen extraction index (E) for the tissue of interest in the subject, according to the formula E =(P + 1) x (1 - rS0₂/Sa0₂) . The calculation is carried out by a suitable processor unit. The output of the measurements of SaO₂ and rS0₂ may be a digital or analogue output for example .

The processor may be a suitably programmed computer, such as an IBM compatible computer (PC) or a Macintosh computer for example. The computer program which is run on the computer is one which is capable of taking the numerical outputs of SaO₂ and rS0₂ values and using these in the equation:

E = (p + 1) x (1 - rS0₂/Sa0₂) in order to determine the oxygen extraction index (E) for the tissue of interest.

The processor may be integrated with other software and hardware for measuring other physiologically relevant parameters. For example, in one embodiment, calibrated cardiac output derived from arterial blood pressure during cardiac by pass operations is also measured, where it will show whether circulation in the body as a whole (cardiac output) is likely to be adequate for cerebral perfusion. This may be in conjunction with oxygen extraction for the whole body, calculated from arterial and mixed venous

(pulmonary artery) or central venous (right atrium) oxygen saturation; and for carrying out other related tasks. This may be useful in practical terms because it results in less items of apparatus being required around a patient ' s hospital bed. Additionally, an integrated unit for calculating related parameters may allow rationalisation of the results in terms of subsequent presentation to the carer of the patient.

For example, in one embodiment, the method of the invention is carried out in conjunction with measurement of middle cerebral arterial velocity (MCAV) . The determination of this value is complementary to that of E and so by measuring both, a suitable cross-check is effectively put in place. For example a reduced value of cerebral oxygen delivery in the face of a constant value of the oxygen extraction index shows that cerebral oxygen metabolic rate (CMRO₂) is reduced but that this is healthy, for example in hypothermia. Calculation of D0₂%control is from 100 x (MCAV x SaO₂) / (Control MCAV x control SaO₂) .

In a further embodiment the method of the invention is combined with a method of determining levels of SlOO protein. Here the use is by cardiac surgeons to indicate the presence of damage to the lining layer (endothelium) of cerebral blood vessels which control adequate blood flow and hence E and oxygen delivery (DO₂) . (8,9) .

The finding of S-IOO protein in the arterial blood signifies permeability of the walls of the brain blood vessels. Not only does this endothelium normally determine the normal constant oxygen extraction but it is normally extremely impermeable to all but oxygen and carbon dioxide. This includes impermeability to ions including hydrogen ions. S-100 protein is normally restricted to the brain; hence, its presence in the blood stream also means there is some brain damage in addition to damage to the blood vessel wall (endothelium) .

The output (E) from the computer program may then be displayed on a suitable display. The display may be an integral part of the processor. Alternatively, the output may be transmitted to another device which is capable of displaying the output of E, such as a separate monitor, which may be, for example, a liquid crystal display (LCD) or plasma screen or cathode ray tube screen. Any suitable display is included within the scope of the invention. The display may present the oxygen extraction index (E) as a numerical value or as a selective indication (such as "increasing" or "decreasing" for example) and may display a suitable warning once the E value falls outside a pre- determined range .

The display may, in one embodiment, comprise the calculated value of E. The user may then monitor the value to ensure that this remains relatively constant, for example during a surgical procedure. If the value displayed falls outside a pre-determined range, a suitable warning may be presented on the display in order to alert the carer to a situation where the subject is not receiving sufficient oxygen in the tissue of interest. The warning may comprise an audible alarm for example or a visual signal.

In an alternative embodiment, the display may display the result in terms of the safety or consistency of the determined E value. Thus, for a particular tissue of interest the oxygen extraction value (E) should remain relatively constant for a particular subject. If the value of E changes such that it falls outside the pre-determined range or "safety zone" the display may present this information such that the user, generally the carer for a patient, will be immediately warned that there is a problem, namely that the oxygen levels in the relevant tissues may r not be sufficient to retain normal functionality. This would then allow the user to make the necessary adjustment in order to attempt to bring the value back to one which is acceptable. The display may for example read "OK" or

"acceptable" whilst E remains in the pre-determined range or "safety zone" . A display such as "warning" or "attention" may be displayed if E falls outside the "safety zone". The pre-determined range may be seen as a "safety zone", outside which the subject may require attention and treatment such as increased blood flow, increased oxygen carrying capacity (haemoglobin or haemoglobin substitutes) or increased oxygen saturation of the blood. The range of values will depend upon the value for E in the subject at rest under the appropriate climatic conditions .

In a preferred embodiment, the pre-determined range allows for about a 20% increase or decrease compared to the resting E value before a suitable warning is given. For example, if prior to an operation a subject has a resting cerebral E value of 0.38 (using p = 0.39) (38%), during the operation the oxygen extraction index would be allowed to increase to 0.456 (45.6%) or decrease to 0.304 (30.5%) before a warning is given on the display. The warning may comprise displaying the numerical value in a different colour or by using a flashing display for example.

Other possible pre-determined ranges include approximately +15%, ±25%, ±30%, ±35%, ±40% etc. Such examples are not intended to be limiting with respect to the present invention. Because each individual is likely to have a different (even if only marginally different) resting value for the oxygen extraction index in a tissue of interest under the climatic conditions, the appropriate range of the "safety zone" will be determined individually for each subject. The processor has the ability to determine this range for each individual by carrying out the appropriate calculation based upon the resting oxygen extraction index (E) . The display may give the output (either number or other appropriate visual or audible indicator) either continuously or at pre-determined time intervals. For example, the display may refresh every 0.1 second, 0.5 second, 1 second, 2 seconds, 3 seconds, 5 seconds, 10 seconds, 30 seconds, 1 minute, 2 minutes, 5 minutes or 10 minutes for example. Again these examples are provided by way of illustration and not limitation.

In one embodiment, the method of the invention may be carried out simultaneously for a number of tissues of interest in the subject. This may effectively provide a global and integrated assessment of the oxygen extraction index for various tissues around the body. For example, a study may be made of oxygen extraction index in various muscle groups around the body. This may be useful to study oxygen delivery to tissues, for example, during exercise. Most preferably, such an integrated system may provide E values for a number of important organs selected, for example, from the brain, heart, kidney, liver, spleen, pancreas, skeletal muscle and, possibly also stomach, and small and large intestines.

The display may provide appropriate indicators of the safety of the oxygen extraction index for each individual tissue of interest or may combine any number, including all, of the values in order to present an aggregate assessment of the oxygen extraction index for the subject. The measurement which can act as supportive here for this aggregate is derivation of the whole body oxygen extraction directly from arterial saturation (SaO₂) and venous saturation where all venous blood is mixed (mixed venous saturation, SmvO₂) . The whole body oxygen extraction is derived from the equation (SaO₂ - SmvO₂) / SaO₂, where SmvO₂ is mixed venous oxygen saturation or, with some reservations, central venous oxygen saturation (ScvO₂) from blood taken using a central venous catheter in the great veins just before or just after the venous blood reaches the right side/atrium of the heart.

In a second aspect, the invention provides an apparatus for carrying out this method of the invention. There is, therefore, provided an apparatus for determining the oxygen extraction index (E) of a tissue of interest in a subject comprising: means for determining rS0₂ in the tissue of interest, means for determining SaO₂ in the subject, a processor which is connected to the means for determining rSO₂ and the means for determining SaO₂ wherein the processor performs the calculation E =(p + 1) x (1 - rS0₂/Sa0₂) wherein p = a constant; and display means for presenting the result of the calculation. i In one preferred embodiment, the apparatus for determining the oxygen extraction index (E) for a tissue of interest in a subject comprises: a near-infrared spectroscopy (NIRS) machine, a pulse oximeter, a processor connected to the NIRS machine and the pulse oximeter wherein the processor performs the calculation

E = (p + 1) x (1 - rSO₂/SaO₂) wherein p = a constant; and display means for presenting the result of the calculation.

The features described above in respect of the method of the invention apply mutatis mutandis to the apparatus of the invention.

In a third aspect, the invention also provides a processing means programmed to perform the calculation:

E = (p + 1) x (1 - rS0₂/Sa0₂) wherein E = oxygen extraction index, p = a constant, rS0₂ = fractional oxygen concentration in the total blood volume,

SaO₂ = oxygen saturation of the arterial system.

In a preferred embodiment the processing means is a suitable programmed computer, for example an IBM compatible computer or a Macintosh computer.

In a fourth aspect of the invention, there is provided a computer program including software arranged to perform the calculation E = (p + 1) x (1 - rS0₂/Sa0₂) wherein E = oxygen extraction index, p = a constant, rS0₂ = fractional oxygen concentration in the total blood volume, SaO₂ = oxygen saturation of the blood in the arterial system. In a fifth aspect of the invention there is provided a carrier containing a computer program including software arranged to perform the calculation E = (p + 1) x (1 - rS0₂/Sa0₂) wherein E = oxygen extraction index, p = a constant, rSO₂ = fractional oxygen concentration in the total blood volume, SaO₂ = oxygen saturation of the arterial system.

The computer program carrier may be any computer readable medium capable of carrying the computer program, such as, a floppy disk, zip disk, compact disc (CD) or digital versatile disk (DVD) for example.

As mentioned above, it is also possible to measure whole body oxygen extraction directly from arterial saturation (SaO₂) and venous saturation where all blood is mixed (mixed venous saturation, SmvO₂) , or possibly also using central venous oxygen saturation (ScvO₂) .

Thus, whole body oxygen extraction (referred to herein as Ewb) = (SaO₂-SmVO₂) /SaO₂ or possibly, whole body oxygen extraction Ewb) = (SaO₂-ScVO₂) /SaO₂.

Prior to the present invention being made, it was not known that this calculation provides a direct indicator of the adequacy of whole body oxygenation. The capability to carry out such a calculation and the realisation of the clinical relevance of this value leads to a number of important applications as discussed above with respect to determination of E in a tissue of interest, for example to determine the adequacy of oxygen supply to the whole body during cardiac by-pass operations. In cardiac by-pass operations, hypothermia can reduce oxygen consumption enough to mean that the whole body oxygen extraction is the only reasonable measurement of adequacy of whole blood oxygen delivery.

Accordingly, the present invention provides, in a sixth aspect, a method for determining whole body oxygen extraction (Ewb) in a subject comprising; determining SaO₂ in the subject, determining SmvO₂ in the subject, taking the determined values of SaO₂ and SmvO₂ and using these values in the calculation; whole body oxygen extraction (Ewb) = (SaO₂-SvO₂)/ SaO₂; and displaying the result of the calculation which represents the whole body oxygen extraction for the subject; wherein SaO₂ = oxygen saturation of the arterial system SmvO₂ = oxygen saturation of the venous system (where all blood is mixed)

An alternative method for determining Ewb comprises; determining SaO₂ in the subject, determining ScvO₂ in the subject, taking the determined values of SaO₂ and ScvO₂ and using these values in the calculation; whole body oxygen extraction (Ewb) = (SaO₂ - SCvO₂) /SaO₂; and displaying the result of the calculation which represents the whole body oxygen extraction for the subject wherein SaO₂ = oxygen saturation of the arterial system ScVO₂ = an estimate of SmvO₂ measured in venous blood immediately before its passage via the right ventricle.

These methods are complementary to that described above for determining the oxygen extraction index (E) of a tissue of interest in a subject, and have similar applications and benefits .

The subject is, in a most preferred embodiment, a human subject. The human subject will generally be a hospitalised patient. Measurements of whole body oxygen extraction may be taken at pre-determined intervals or on a continuous basis. For example whole body oxygen extraction values may be calculated prior to an operative procedure and may then be monitored throughout and after the operation in order to ensure that the whole body extraction index does not fall outside a pre-determined range of values. The range may be calculated having regard to the pre-operative value calculated for the particular individual, since this may vary from patient to patient.

It may be the case that the range of whole body oxygen extraction (Ewb) can be absolute, since the normal values may not vary much.

Methods for determining SaO₂ are described in detail \ above and apply equally with respect to this aspect of the invention.

Methods and apparatus for determining mixed venous saturation (SmvO₂) or central venous oxygen saturation (ScvO₂) are well known and commercially available. For example SmvO₂ and ScvO₂ are commonly determined using pulmonary artery catheters by fibreoptic oximetry, which are capable of measuring SτnvO₂ or ScvO₂ continuously depending on the location of the detector.

In a study by Rivers et al (2001) (10) patients with sepsis were evaluated, for adequacy of whole body oxygenation, within six hours of arrival in the hospital emergency (casualty) department. The criterion was a central venous oxygen saturation (ScvO₂) below 70% taken to mean inadequate whole body oxygenation. The catheter, inserted on the venous side of the circulation was capable, with its spectrophotometric detector in or near the right atrium of the heart, to measure ScvO₂ (Edwards Life Sciences, Irvine, Calif.) . The method produces useful clinical gains but, two disadvantages which reduce its precision:

1. It fails to take into account variations in SaO₂, which have a considerable effect on whole body oxygen extraction (Ewb) . 2. The value of ScvO₂ may be different from the true value for fully mixed venous blood from the whole body which is obtained from the pulmonary artery.

Pulmonary artery sampling of fully mixed venous blood has been undertaken earlier (1994) on a continuous basis, in patients with heart failure using a similar detector attached to a catheter with its tip in the pulmonary artery (11) . The catheter was "a triple lumen flow-directed balloon-tipped thermodilution catheter (7F American Edwards, Baxter, Irvine, Calif.)". The authors calculated Ewb from VO₂/DO₂, therefore including Hb and cardiac output in their calculations, and obtained mean values for normal subjects of 28.2% and for heart failure patients of 38%. Using their SaO₂ and SmvO₂ values gives 30.2% for normal subjects and 36.3% for heart failure patients. The values derived directly are obtained very simply (100 x (SaO₂ - SmvO₂) /SaO₂) and depend only on the accuracy of two measures (SaO₂ and SmvO₂) .

Reservations about ScvO₂ accuracy come from the different assertions in the literature about how much it differs from SmvO₂ (true mixed venous oxygen saturation) 12,13) . ScvO₂ has the great advantage that it can be obtained from routine central venous catheter samples, and the avoidance of the labour intensive and dangerous insertion of a pulmonary artery catheter.

The measured values of SaO₂ and SmvO₂ or ScvO₂ are then used as an output to determine whole body oxygen extraction in the subject. Whole body oxygen extraction = (SaO₂- SmvO₂) /SaO₂ or (Sa0₂-Scv0₂) /SaO₂. The calculation is carried out by a suitable processor unit. The output of the measurement of SaO₂ and SmvO₂ (or ScvO₂) may be a digital or analogue output for example .

The processor may be a suitably programmed computer, as discussed above. The computer program which is run on the computer is one which is capable of taking the numerical outputs of SaO₂ and SmvO₂ or ScvO₂ values and using these in the equation: whole body oxygen extraction = (SaO₂-SmVO₂) /SaO₂ or (SaO₂- ScvO₂) /SaO₂ in order to determine the whole body oxygen extraction (Ewb) for a subject. The processor may be integrated with other software and hardware for measuring other physiologically relevant parameters, as discussed above. The features described above apply mutatis mutandis to this aspect of the invention and, of course, the methods described in this aspect can be integrated with calculation of E for a tissue of interest in a subject.

The description presented in respect of the display in accordance with the first aspect of the invention applies mutatis mutandis to this aspect of the present invention.

In a seventh aspect, the invention also provides an apparatus for carrying out the methods of determining whole body oxygen extraction (Ewb) . Accordingly, there is provided an apparatus for determining whole body oxygen extraction in a subject comprising; means for determining SaO₂ in the subject, means for determining SmvO₂ in the subject, a processor which is connected to the means for determining SaO₂ and the means for determining SmvO₂ wherein the processor performs the calculation: whole body oxygen extraction = (SaO₂-SmVO₂) /SaO₂ or (SaO₂- ScvO₂) /SaO₂; and display means for presenting the result of the calculation.

Similarly, there is also provided an apparatus for determining whole body oxygen extraction (Ewb) in a subject comprising; means for determining SaO₂ in the subject, means for determining ScvO₂ in the subject, a processor which is connected to the means for determining SaO₂ and the means for determining ScvO₂ wherein the processor performs the calculation: whole body oxygen extraction = (SaO₂-SCvO₂) /SaO₂; and display means for presenting the result of the calculation.

The respective apparatus may be the same apparatus and may, therefore, allow both calculations of Ewb to be performed.

In a preferred embodiment the means for determining SaO₂ in the subject comprises a pulse oximeter.

In a further embodiment, the means for determining SmvO₂ or ScvO₂ in the subject comprises a catheter, incorporating a device for measurement of oxygen saturation.

In a further aspect the invention also provides processing means programmed to perform the calculation: whole body oxygen extraction = (SaO₂-SmVO₂) /SaO₂ wherein SaO₂ = oxygen saturation of the arterial system

SmvO₂ = oxygen saturation of the venous system (where all blood is mixed)

Similarly, the invention also provides processing means programmed to perform the calculation: whole body oxygen extraction = (SaO₂-ScVO₂) /SaO₂ wherein SaO₂ = oxygen saturation of the arterial system ScvO₂ = an estimate of the oxygen saturation of the venous system where all blood may be mixed but is sampled from the right atrium of the heart or the great veins close to the heart .

The respective processing means may be the same processing means and may, therefore, allow both calculations of Ewb to be performed.

In a preferred embodiment, the processing means is a suitably programmed computer as discussed above.

In a still further aspect of the invention there is provided a computer program including software arranged to perform the calculation; whole body oxygen extraction = (SaO₂-SmVO₂) /SaO₂ wherein SaO₂ = oxygen saturation of the arterial system

SmvO₂ = oxygen saturation of the venous system (where all blood is mixed)

Similarly, there is provided a computer program including software arranged to perform the calculation; whole body oxygen extraction = (SaO₂-SCvO₂) /SaO₂ wherein SaO₂ = oxygen saturation of the arterial system Scv0₂ = an estimate of the oxygen saturation of the venous system where all blood may be mixed but is sampled from the right atrium of the heart or the great veins close to the heart.

The respective computer programs may be the same computer program and may, therefore, allow both calculations of Ewb to be performed. In a further aspect of the invention there is provided a carrier containing a computer program including software arranged to perform the calculation; whole body oxygen extraction (Ewb) = (SaO₂-SmVO₂) /SaO₂ wherein SaO₂ = oxygen saturation of the arterial system

SmvO₂ = oxygen saturation of the venous system (where all blood is mixed) .

In similar fashion, the invention provides a carrier containing a computer program including software arranged to perform the calculation; whole body oxygen extraction = (SaO₂-SCvO₂) /SaO₂ wherein SaO₂ = oxygen saturation of the arterial system ScvO₂ is an estimate of the oxygen saturation of the venous system where all blood may be mixed but is sampled from the right atrium of the heart or the great veins close to the heart .

The respective carriers may be carrying the same computer program capable of both calculations and may, therefore, allow both calculations of Ewb to be performed.

As described above, a major advantage of the oxygen extraction index (E) over DO₂ in assessing oxygenation of the brain (or other organs) is that, while DO₂ has been shown to be constant, for moderate cerebral hypoxia in a normal subject, this is due to constancy of rate of cerebral oxygen consumption (Cerebral metabolic rate for oxygen, CMRO₂) . The primary regulation is the constancy of oxygen extraction (E = CMRO₂/cerebral DO₂) . Where CMRO₂ may vary, clinically, for example in hypothermia used in cardiac operations, the appropriate DO₂ is reduced in proportion to the, unknown, reduction in CMRO₂. However, the appropriate value of E remains the same as at normal temperature (and CMRO₂) .

Thus, there is value in being able to determine oxygen consumption as a percentage of control (at rest) oxygen consumption whilst the E value, which includes Ewb, remains constant since this will reflect any changes occurring in metabolic rate.

Hence, during transition from normal to low body temperature, or from low body temperature to normal, it will be possible to both see proportional CMRO₂ changes as well as assessing (from E) whether cerebral oxygen delivery is keeping pace with the changes. If cerebral oxygen delivery keeps pace with the changes in CMRO₂ then cerebral E will remain constant in the normal range. If E changes one will know the adequacy of oxygen delivery has altered. This will prompt therapeutic manoeuvres to correct E.

Accordingly, in addition to and complementary to the methods and products described above there is also provided a method for determining oxygen consumption as a percentage of control in a tissue of interest in a subject comprising: determining DO₂ at an initial (or first) time point to give control DO₂ and at a further point in time to give measured DO₂ in the tissue of interest and using these values in the calculation: percentage oxygen consumption = 100 x (measured D0₂/control DO₂) with the proviso that the calculation is carried out when the value of E is the same at the initial time point and also at the further point in time and displaying the results of the calculation which represent oxygen consumption as a percentage of control; wherein DO₂ = oxygen delivery.

The method can be used for whole body calculations for the subject also, by using Ewb and DO₂ for the whole body. E is most preferably calculated utilising the methods and/or apparatus of the present invention, as described herein.

In a most preferred embodiment, the initial time point represents a value for oxygen delivery while the subject is at rest, for example prior to an operative procedure.

Calculation of percentage of control oxygen consumption can also be undertaken when oxygen extraction changes; from the initial and final oxygen extraction (E_a and E₂) and initial and final oxygen delivery related values (DO_2,i and

DO₂,₂) :

Percentage oxygen consumption = 100 x (E₂ZE₁) x (DO₂,₂/DO_2,i)

E may preferably be calculated according to any of the methods described above, for example.

The further point in time can be any time at which it is desired to determine DO₂. For example DO₂ may be measured prior to an operative procedure to give the initial "control" DO₂ and then monitored during the operative procedure, in conjunction with determination of E, to ensure that oxygen extraction remains constant. Similarly, "final" oxygen extraction (E₂) , as referred to above can be taken at any suitable further point in time, as can the final oxygen delivery values (DO₂, 2) ■

An apparatus for carrying out either, or both, of these methods is also provided by the invention. There is thus provided an apparatus for determining oxygen consumption as a percentage of control in a tissue of interest in a subject comprising; means for determining E in the subject at an initial time point and at a further time point, means for determining DO₂ in the subject at the initial time point and at the further time point, a processor which is connected to the means for determining E and the means for determining DO₂ wherein the processor performs the calculation: percentage oxygen consumption = 100 x (measured D0₂/control DO₂) with the proviso that the calculation is carried out when the value of E is the same at the first time point and also at the further point in time; and display means for presenting the result of the calculation.

i Also provided is an apparatus for determining oxygen consumption as a percentage of control in a tissue of, interest in a subject comprising; means for determining E in the subject at an initial time point E₁ and at a further time point E₂, means for determining DO₂ in the subject at the initial time point DO₂,1 and at the further time point DO_{2, 2}, a processor which is connected to the means for determining E and the means for determining DO₂ wherein the processor performs the calculation:

Percentage oxygen consumption = 100 x (E₂ZE₁)X(DO₂₁₂ZDO₂,_!); and display means for presenting the result of the calculation.

The means for determining E are set out above; any suitable means can be utilised.

Similarly DO₂ can be calculated by any suitable means examples of which are well known and commercially available. By way of example, for the brain, the apparatus for noninvasive DO₂ includes measurement of middle cerebral artery velocity (MCAV) by means of, for example, a Logidop 3 TCD monitor (SciMed Bristol, UK) and SaO₂ measurement, for example, using a Propac Encore Monitor (Beaverton, USA) . DO₂ can be obtained on a comparative basis, as a percentage of control (D0₂%) . The calculation is: D0₂% = 100 x MCAV x SaO₂ Z (MCAVcontrol x SaO₂ control) .

For the whole body:

DO₂ = Arterial O₂ content x cardiac output . The apparatus requires measurement of Cardiac output, haemoglobin (Hb) and SaO₂.

Means for measurement of whole body oxygen delivery include the PulseCO apparatus made by LiDCO. Here Hb is entered prior to lithium dilution and SaO₂ then or at other times, and DO₂ is displayed. Any of the means referred to above can be incorporated into the apparatus according to this aspect of the invention.

The tissue of interest can be any tissue (see above) . The method, however, is most preferably carried out to determine cerebral oxygen consumption as a percentage of control, very simply, when the oxygen extraction index is unchanged, or in a slightly more complex manner when the oxygen extraction index changes.

The methods and apparatus can also be used in a whole body context by measuring overall E (Ewb) and overall DO₂ at appropriate time points.

Ewb (Oxygen extraction for the whole body) , as described supra, requires measurement of SmvO₂ or ScvO₂. For true mixed venous oxygen saturation (SmvO₂) measurement is from a catheter with its sensor in the pulmonary artery. An example is an Opticath (PA Catheter P 7110, 7.5 Abbot Laboratories) . For ScvO₂ either a blood sample may be obtained from a central venous catheter, or continuous ScvO₂ can be obtained from an optical catheter, for example, a standard central venous catheter with a custom fibre optic probe with its tip at the tip of the central venous catheter and the outer end connected to a SAT2 -Oximeter (Baxter Health-care, Irvine Calif., USA).

The display for the apparatus may be any suitable display, examples of which are provided in respect of other aspects of the invention (above) . As for the other aspects of the invention, the description of which apply equally to this aspect, the subject is most preferably a human subject.

In a further aspect there is also provided a computer program including software arranged to perform the calculation: percentage oxygen consumption = 100 x (measured D0₂/control DO₂) x (Measured E/control E) which reduces to 100 x (measured D0₂/control DO₂) ; if the value of E is the same at measured DO₂ and DO₂ control .

In a still further aspect, there is provided a computer program arranged to perform the calculation of percentage of control oxygen consumption from the initial and final oxygen extraction (E₁ and E₂) and initial and final oxygen delivery related values (DO₂,i and DO₂,₂) :

Percentage oxygen consumption = 100 x (E₂/Ei)x(Dθ2,2/DO₂,i)

Depending upon whether E or E_Wb is being calculated, the computer programs may be combined with the appropriate computer programs described above which calculate E or E_Wb respectively .

The present invention will be further described, by way of example, with reference to the accompanying drawings in which:

Figure 1 is, in diagram form, a simple model of the cerebral circulation. In the upper panel the total blood volume is partitioned as arterial and venous volumes (Va and Vv) . Hence, these have concentrations of SvO₂ and SaO₂ respectively. The lower panel shows the effect detected by NIRS of pooling all the blood but detecting the amount of oxygenated blood and the total blood volume; hence there is a single (NIRS) value for the concentration of oxygenated blood, rSO₂.

Figure 2 is a graph of Oxygen delivery (DO₂) as a percentage of the sea level value (mean of two values) . A regression line has been fitted to values at all altitudes (0) other than 5050m (o) in A and the slope of the regression line is not significant (the equation of the linear regression is: D0₂%sea = 102 - 0.011 x altitude) . The 5050m point and the data point recorded at sea level on 12.5% O₂ (■) show reduced oxygen delivery. In graph B, DO₂ values are plotted against SaO₂.

Figure 3A shows the values from table 1 in graphical form. Isobars for E appear as a grid on a plot of rS0₂ against p. The measured rS0₂ value (at sea level) - rSO2

(sea) - is also plotted as a horizontal bar and crosses E = 0.4 and 0.5 E isobars around p values of 0.4 to 0.8.

Figure 3B. The measured values of rSO₂ here are also represented by a horizontal line on four individual graphs of the theoretical values of oxygen extraction at the different individual values of SaO₂. (In 3B,A 2400m; 3B,B 3549m; 3B,C at sea level breathing 12.5% oxygen and in 3B,D at 5050m. ) The measured rSO₂ crosses the same E isobars as at sea level (figure 3A) in 3B,A and 3B,B, modest hypoxia.

In severe hypoxia, 3B,C and 3B,D measured rSO₂ crosses lower E values . Figure 4 shows values for E calculated from rS0₂, SaO₂ and an assumed p value of 0.39. These are for the same experimental data as appear in figure 3 with two additional points (from sea level and high altitude; Chamlang base camp; 5000m) . The equation used was: E = (p + 1) x (1 - rS0₂/Sa0₂) . In the figure this equation has been represented in abbreviated form on the Y axis as 'E' (1.39 x (1- r/Sa) ) .

Figure 5 shows the value referred to elsewhere as E related for 14 subjects having SaO₂ and rS0₂ values calculated at sea level and at altitude (Chamlang base camp; 5000 m) .

Figure 6 shows three histograms of rSO₂ , SaO₂ and E related (1 - rSO₂ /SaO₂) , closely related to putative E (CerE) by a factor of 1.39. Across subjects there is variation in the sea level and altitude values of the E related variable. Although this could suggest that it would not be useful in individuals the initial value prior to intervention might well work as an adequate control .

Experimental Section

Measurements

Methods of measurement for rS0₂, SaO₂ and MCAV are outlined in the studies quoted. (4-6) SaO₂ was measured using a Propac Encore Monitor (Beaverton, USA) , rSO₂, a Critikon 2020 monitor (Johnson and Johnson, Newport, UK) and middle cerebral artery velocity (MCAV) , a Logidop 3 TCD monitor (SciMed, Bristol, UK) . The SaO₂ (arterial oxygen saturation) measurement was made with a standard finger probe; this includes red and infra-red light sources and, on the opposite side of the finger, a suitable photodetector . The Criticon 2020 sensor also utilises emitted light to obtain rSO₂ (oxygenated blood / total blood, in cerebral tissue) but utilises four wavelengths (776.5 nM, 8190.0 nM, 871.4 nM and 908.7 nM) . The light emitter unit and detectors are incorporated in a probe unit applied to the skin of the forehead; in this instance, one detector is located at 10 mm, the other at 37 mm from the light source. The absorption registered by the nearer detector is due to non-cerebral brain tissue (skin and bone of the skull) and subtraction from the absorption value detected by the more distant detector allows calculation of the absorption, largely, by cerebral tissue. For MCAV the Doppler probe is manually applied over the middle cerebral artery, requiring careful positioning aided by auditory control. The correct insonation depth is found by a gradual increase from an initial value of 50 mm to identify the optimal signal. Oxygen delivery is calculated here as a percentage of the putative sea level value:

100 x (MCAVtest x Saθ₂test) / (MCAVsea x Saθ₂sea) . Studies were carried out under various conditions (breathing normal air versus 12.5% oxygen) and at various altitudes (sea level through to 5010 m) .

Derivation of oxygen extraction index (E)

Previous studies have failed to look at the functional relationships between the measurements made by ordinary oximeters and NIRS. Estimates of how the arterial and blood volumes are distributed (see figure 1) are available in the literature and are equivalent to an arterial volume of around 39% of the venous value.

A model has been proposed previously (7) for fractional oxygen concentration in the blood volume described by infrared transmission (rSO₂) in terms of SaO₂, the relative volumes of arterial and venous blood (p = Va/Vv) and the proportional extraction (E) of oxygen from its perfusate. rSO₂ represents the volume of oxygenated blood divided by the total blood volume (i.e. HbO₂ / (Hb + HbO₂) . Hence, rS0₂ = (SaO₂.Va + SvO₂.Vv) / (Va + Vv) . From this rS0₂ can be obtained in terms of p: rS0₂ = (SaO₂.\p + SvO₂) / (p + 1) .

Since, E = VO₂ / DO₂ = (SaO₂ - SvO₂) / SaO₂ it is possible to substitute SaO₂ x (1 - E) for SvO₂. This gives the equation: rS0₂ = (SaO₂ x p + SaO₂ x (1 - E) ) / (p + 1) (the model) (An alternative is: rSO₂ = SaO₂ x (1 - E(I - f)), where f = Va / (Va + Vv) )

The alternative equation is given because the estimates of cerebral blood volumes in the literature are in terms of ^λf (the ratio of oxygenated to total blood volumes) rather than 'p' , which is Va/Vv.

An example of a set of values for rSO₂ obtained from this model for a sea level SaO₂ of 97% is shown in table 1 below:

Table 1. Values of rSO₂ calculated from the model for a range of p and E values at sea level (SaO₂ = 97%) . Mean measured rS0₂ is given in the last column. Values in bold are nearest to measured values.

Values are calculated (as in table 1 for normal sea level SaO₂) for each measured SaO₂ (at sea level on air, at altitudes 2400m, 3549m and 5050m and at sea level with subjects breathing 12.5% oxygen). Each set is presented graphically (figure 3A shows the sea level values, the rest are in figure 3B) each depicted as a plot of rSO₂ against p, with isobars for E. The value of each measured rSO₂ is drawn as a horizontal line across the theoretical plot.

Oxygen delivery

Oxygen delivery is shown in figure 2 as a percentage of the sea level value. It is constant over the range from sea level to 3549m (A) and is lower at 5050m and at sea level in subjects breathing 12.5% oxygen. The DO₂ values are also related to SaO₂ in figure 2B.

The Model and Measured SaQ₂ and rSO₂ Values

Figure 3A shows the values from table 1 in graphical form. Isobars for E appear as a grid on a plot of rSO₂ against p. The measured rSO2, referred to as rS0₂ (sea) , represents the rSO₂ value measured at sea level. This value is plotted as a horizontal bar. The curved isobars are theoretical plots derived from equation 1 for the specified values of E (cerebral oxygen extraction) . The horizontal line for the measured rSO₂ value crosses only the 0.4 and 0.5 isobars for oxygen extraction and the corresponding p values are around 0.4 to 0.8.

Figure 3B. The measured values rS0₂ here are, again, each represented by a horizontal line. For 3B,A altitude was

2400 m and SaO₂ was 94.6%; for 3B,B altitude was 3549m and SaO₂ was 91.3%. The measured rS0₂ line crosses the same isobars as at sea level and at the same range of p values . For 3B,C and 3B,D hypoxia is more severe, SaO₂ values being 79% and 73.6% respectively. You can see that for these two grossly hypoxic situations the measured values of rSO₂ cross much higher up the grid of E isobars, corresponding with much lower values for E .

A. At 2400 m: SaO₂ = 94.6% (rS0₂ was 68.5%)

B. At 3549 m: SaO₂ 91.3% (rSO₂ was 65.7%) C. Hypoxic, 12.5 % O₂ at sea level: Sa = 79%; (rSO₂ was 63.7%) D. At 5050 m: SaO₂ = 73.6% (rSO₂ was 62.1%).

However, above 5000m the measured value of rSO₂ crossed much higher up (a much lower E value; figure 3B,D) .

100 x the MCAV x SaO₂ product / (the sea level value) (i.e. DO₂ index, D0₂% sea) was the same for all altitudes except above 5000 m where it was only 85% (figure 2A) . A sea level value done with 12.5% inspired O₂ with a low SaO₂ also showed a reduced DO₂ index (figures 2A and 2B) .

Figure 2 shows Oxygen delivery as a percentage of the sea level value (mean of two values) . A regression line has been fitted to values at all altitudes (0) other than 5050m (o) in A and the slope of the regression line is not significant (the equation of the linear regression is: D0₂%sea = 102 - 0.011 x altitude) . The 5050m point and the data point recorded at sea level on 12.5% O₂ (■) show reduced oxygen delivery, in part B of figure 2, DO₂ values are plotted against SaO₂. Since the linear regression of DO₂ was lost at the same altitude as both oxygen extraction and p (derived from NIRS) the realisation was made that it was therefore possible to use the NIRS machine on its own by inverting the formula to give an equation for E.

From the original equation: rSO₂ = (SaO₂ x p + SaO₂ x (1 - E) ) / (p + 1) by rearrangement: rS0₂ x (p + 1) = SaO₂ x (p + 1 - E) Hence: (p + 1) x rSO₂ / SaO₂ = (p + 1 - E) ; So E = (p + l) x (l - rSO₂ / SaO₂) .

p is still an unknown but it is realised that this will not change until E changes.

Sea level values for E, based upon measured SaO₂ and rS0₂ values were also calculated from SaO₂ and rS0₂ values at intervening altitudes and at 5000m, as well as the value of E for sea level in subjects breathing 12.5% oxygen. E was calculated assuming p is normally 0.39. Once the value of E is affected in the grossest hypoxia, so is the value of p. However, that only means the values for E calculated in gross hypoxia are not correct yet they nevertheless still show there is an error in cerebral oxygenation. This is the value of being able to determine E readily.

Figure 4 illustrates how this putative E value (CerE) changes with SaO₂. Shown are putative E values calculated from rSO₂, SaO₂ and an assumed p value of 0.39. The equation used was: E = (p + 1) (1 - rS0₂/Sa0₂) . In the figure this equation has been represented in abbreviated form on the Y axis as ^VE' (1.39 x (1 - r/Sa) ) . As SaO₂ falls from the normal sea level value there is no change in ^λE' until SaO₂ falls below the low 90%s. The next value in the mid 80%s is the mean from Chamlang base camp, the next is from a study involving breathing 12.5% oxygen at sea level and the lowest point is from a rapid ascent to 5010 m.

All altitudes below 5000 m with subjects breathing air gave the same CerE values as at sea level. With measurements at 5000 m or on 12.5% O₂ at sea level values for SaO₂ were all below 90% and CerE was progressively lowered as SaO₂ went down. Furthermore, this decrease occurred in a linear manner .

The clear picture from the average values in the various situations indicates that an individual value is indicative where an internal control for each individual can be used (a resting value for E) .

A set of 14 subjects had measurements of both SaO₂ and rSO₂ taken at sea level and at altitude (Chamlang, 2003) . The SaO₂ and rSO₂ values and calculated E related variable (this time without the "x 1.39") are shown in figure 5.

It is clear that SaO₂ falls, rSO₂ falls and, with one exception, the E related variable (calculated simply as 1 - rSO₂/ SaO₂) also falls, although only by a modest amount (as for CerE in figure 5) .

Figure 6 shows histograms of SaO₂, rSO₂ and E related (1 - rSO₂ / SaO₂) which is related to putative Cerebral E (CerE) by a factor of 1.39. Across subjects there is variation in the sea level and altitude values of the E related variable. However, a clear trend is seen for a reduced CerE value at altitude compared to the sea level value. This suggests that the initial value prior to intervention is useful to determine the base value of CerE prior to an intervention with a patient.

A protocol for the assessment of cerebral oxygenation in patients having cardiac operations would thus take a form such as : 1) Pre-operative measurement of SaO₂, rS0₂ and optionally MCAV (middle cerebral artery velocity) .

2) Continuous measurement of SaO₂, rS0₂ and MCAV from the time of induction and throughout the operation.

3) The apparatus would compute CerE from SaO₂ and rS0₂ and optionally may also calculate a cerebral DO₂ related variable, cDO₂%, from SaO₂ and MCAV.

Thus, CerE = 1.39 x (1 - rS0₂/ SaO₂) and CerE% = 100 x CerE / preopCerE. cDO₂ = SaO₂ x MCAV (strictly CDO₂ related, i.e. proportional to cerebral oxygen delivery) and CDO₂% = 100 x CDO₂ / preop. CDO₂.

Ideally CerE% and cD0₂% are displayed continuously. If either or both fall an alarm sounds alerting the clinician to the situation. There is a need to allow cD0₂% to fall during hypothermia since cerebral tissue oxygen consumption falls, under which circumstance it is appropriate for CDO₂ to fall proportionately, without any change in rS0₂. Based upon the values for E shown in the altitude study of Figures 4, 5 and 6, the mean value at altitude was just over 80% of the normal value (horizontal section in figure 4) . The subjects (Chamlang, 2003; slow ascent to 5000m in 2003, figures 5 and 6) all appeared to be in no immediate danger which suggests that measurements following a trend downwards to values around 80% of control would be monitored carefully and any fall below this "safety zone" would lead to positive action in order to attempt to return the E value back to safe levels .

MCAV requires much more skill to measure and so may not be as advantageous as use of E; in addition, it fails to give the information in hypothermia about the adequacy or otherwise of cerebral blood flow and oxygenation. However, the techniques may complement one another and so both could be used on the same individual to cross-check and confirm the status of oxygen delivery. Combining the measurements would allow assessment of cerebral oxygen consumption compared with baseline. Should cerE% be normal and CDO₂ be falling one can assume cerebral oxygen consumption is falling in the same proportion. Cerebral oxygen consumption can be calculated as a percentage of control from:

100 x (measured D0₂%/control DO₂%) x (measured E/ control E) .

Measurement of SlOO (S-100) protein shows whether there is damage to cerebral vascular endothelium (8,9). SlOO proteins are involved in the synthesis and release of cerebral neurotransmitters. If they are released into the blood stream this signifies cerebral damage as well as permeability of the endothelial lining of the cerebral blood vessels. The endothelial lining of the cerebral blood vessels is normally extremely impermeable (except to oxygen and carbon dioxide) . It normally functions to sustain constant ion concentrations in the fluid bathing the brain and the normal oxygen delivery and blood flow. Increase in permeability signifies it is damaged so one expects correlation between finding SlOO protein in the blood and indicators of cerebral injury and impaired oxygenation.

References

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Claims

1. A method for determining the oxygen extraction index (E) of a tissue of interest in a subject comprising; determining rS0₂ in the tissue of interest, determining SaO₂ in the subject, taking the rSO₂ and SaO₂ measured values and using these values in the calculation; E = (p + 1) x (1 - rS0₂/Sa0₂) wherein p = a constant; and displaying the result of the calculation which represents the oxygen extraction index for the tissue of interest of the subject.

2. The method of claim 1 wherein the value of p is 0.

3. The method of claim 1 wherein the value of p is 0.39.

4. The method according to any one of claims 1 to 3 wherein tissue of interest is skeletal muscle.

5. The method according to any one of claims 1 to 3 wherein the tissue of interest is an organ or a part thereof.

6. The method according to claim 5 wherein the organ is any one or more of brain, heart, kidney, liver, spleen, pancreas, small intestine, large intestine or stomach.

7. The method according to claim 5 or 6 wherein the organ is brain.

8. The method according to any preceding claim wherein the subject is a human.

9. The method according to any preceding claim wherein the determination of rSO₂ in the tissue of interest comprises use of near-infrared spectroscopy (NIRS) .

10. The method according to any preceding claim wherein the determination of SaO₂ in the subject comprises use of pulse oximetry.

11. The method according to any preceding claim wherein the result of the calculation is displayed as a numerical value.

12. The method according to any preceding claim wherein a warning signal is presented if the calculated value for E falls outside of a pre-determined range.

13. The method of claim 12 wherein the warning signal is an audible alarm or a visual warning or both.

14. The method of claim 12 or 13 wherein the pre-determined range is determined from the value of E taken from a subject at rest.

15. The method of claim 14 wherein the resting value of E is taken prior to a surgical procedure.

16. The method of claim 14 or 15 wherein the pre-determined range allows for a 20% increase or decrease compared to the resting value.

17. The method of any preceding claim wherein E is determined continuously.

18. The method of any one of claims 1 to 16 wherein E is determined at regular intervals .

19. The method of claim 18 wherein E is determined every 0.1 second, 0.2 second, 1 second, 10 seconds, 30 seconds, 1 minute, 2 minutes, 5 minutes or 10 minutes.

20. An apparatus for determining the oxygen extraction index (E) of a tissue of interest in a subject comprising; means for determining rS0₂ in the tissue of interest, means for determining SaO₂ in the subject, a processor which is connected to the means for determining rS0₂ and the means for determining SaO₂ wherein the processor performs the calculation:

E = (p + 1) x (1 - rS0₂/Sa0₂) wherein p = a constant; and display means for presenting the result of the calculation.

21. The apparatus of claim 20 wherein the means for determining rSO₂ in the tissue of interest comprises a near- infrared spectroscopy (NIRS) machine.

22. The apparatus if claim 20 or 21 wherein the means for determining SaO₂ in the subject comprises a pulse oximeter.

23. The apparatus of any one of claims 20 to 22 wherein the processor is a computer programmed to perform the calculation:

E = (p + 1) x (1 - rS0₂/Sa0₂)

24. The apparatus of any one of claims 20 to 23 wherein the display means comprises a liquid crystal display, plasma screen or cathode ray tube screen.

25. The apparatus of any one of claims 20 to 24 which is used in the method of any one of claims 1 to 19.

26. A processing means for use in the method of any one of claims 1 to 19 programmed to perform the calculation: E = (p + 1) x (1 - rS0₂/Sa0₂) wherein E = oxygen extraction index; p = a constant; rS0₂ = fractional oxygen concentration in the total blood volume; and SaO₂ = oxygen saturation of the arterial system.

27. A computer program including software arranged to perform the calculation:

E = (p + 1) x (1 - rSO₂/SaO₂)

28. A carrier containing the computer program of claim 27.

29. A method for determining whole body oxygen extraction (Ewb) in a subject comprising; determining SaO₂ in the subject, determining SmvO₂ or ScvO₂ in the subject, taking the determined values of SaO₂ and SmvO₂ or ScvO₂ and using these values in the calculation; whole body oxygen extraction (Ewb) = (SaO₂ - SmvO₂) / SaO₂ or (SaO₂ - ScvO₂)/ SaO₂; and displaying the result of the calculation which represents the whole body oxygen extraction for the subject wherein SaO₂ = oxygen saturation of the arterial system

SmvO₂ = oxygen saturation of the venous system (where all blood is mixed) and ScvO₂ = an estimate of SmvO₂.

30. The method according to claim 29 wherein the determination of SaO₂ in the subject comprises use of pulse oximetry.

31. The method according to claim 29 or 30 wherein the determination of SmvO₂ or ScvO₂ comprises use of a catheter.

32. The method according to any one of claims 29 to 31 wherein the result of the calculation is displayed as a numerical value .

33. The method according to any one of claims 29 to 32 wherein a warning signal is presented if the calculated value for Ewb falls outside of a pre-determined range.

34. The method of claim 33 wherein the warning signal is an audible alarm or a visual warning or both.

35. The method of claim 33 or 34 wherein the pre-determined range is determined from the value of Ewb taken from a subject at rest.

36. The method of claim 35 wherein the resting value of Ewb is taken prior to a surgical procedure.

37. The method of claim 33 or 34 wherein the pre-determined range allows for a 20% increase or decrease compared to the resting value.

38. The method of any one of claims 30 to 37 wherein whole body oxygen extraction is determined continuously.

39. The method of any one of claims 30 to 37 wherein whole body oxygen extraction is determined at regular intervals.

40. The method of claim 39 wherein whole body oxygen extraction (Ewb) is determined every 0.1 second, 0.2 second, 1 second, 10 seconds, 30 seconds, 1 minute, 2 minutes, 5 minutes or 10 minutes.

41. An apparatus for determining whole body oxygen extraction in a subject comprising; means for determining SaO₂ in the subject, means for determining SmvO₂ or ScvO₂ in the subject, a processor which is connected to the means for determining SaO₂ and the means for determining SmvO₂ or ScvO₂ wherein the processor performs the calculation: whole body oxygen extraction = (SaO₂ - SmvO₂) / SaO₂ or (SaO₂ -

display means for presenting the result of the calculation.

42. The apparatus according to claim 41 wherein the means for determining SaO₂ in the subject comprises a pulse oximeter.

43. The apparatus according to claim 42 wherein the means for determining SvO₂ in the subject comprises a catheter.

44. A processing means programmed to perform the calculation: whole body oxygen extraction (Ewb) = (SaO₂. SmvO₂) / SaO₂

wherein SaO₂ = oxygen saturation of the arterial system SmvO₂ = oxygen saturation of the venous system

(where all blood is mixed) and ScvO₂ = an estimate of SmvO₂.

45. A computer program including software arranged to perform the calculation; whole body oxygen extraction (Ewb) = (SaO₂ - SmvO₂) / SaO₂ or (SaO₂ - SCvO₂)/ SaO₂ wherein SaO₂ = oxygen saturation of the arterial system

SmvO₂ = oxygen saturation of the venous system (where all blood is mixed) and

ScvO₂ = an estimate of SmvO₂.

46. A carrier containing the computer program of claim 45.

47. A method for determining oxygen consumption as a percentage of control in a tissue of interest in a subject comprising: determining DO₂ at an initial time point (DO₂, i) and at a further point in time to give DO₂, ₂ in the tissue of interest and using these values in the calculation: percentage oxygen consumption = 100 x (DO₂,₂/DO_2>1) with the proviso that the calculation is carried out when the value of E is the same at the initial time point (DO_2/1) and also at the further point in time (DO₂, ₂) and displaying the results of the calculation which represent oxygen consumption as a percentage of control; wherein DO₂ = oxygen delivery.

48. A method for determining oxygen consumption as a percentage of control in a tissue of interest in a subject comprising: determining DO₂ at an initial time point to give

DO₂,i and at a further point in time to give DO₂, ₂ and E at the initial time point to give Ei and at the further time point to give E₂ in the tissue of interest and using these values in the calculation: Percentage oxygen consumption = 100 x (E₂ZE₁)X(DO₂₁₂ZDO₂,_!) and displaying the results of the calculation which represent oxygen consumption as a percentage of control.

49. The method according to claim 47 or 48 wherein E is calculated by the method of any one of claims 1 to 16

50. The method according to any one of claims 47 to 49 wherein the tissue of interest is brain.

51. A computer program including software arranged to perform the calculation: percentage oxygen consumption = 100 x (DO₂,2/DO₂, 1) with the proviso that the calculation is only carried out when the value of E is the same at DO₂,_x and DO₂,₂ and wherein DO₂,₁ is taken at an initial time point and DO₂,2 is taken at a further point in time.

52. A computer program including software arranged to perform the calculation;

Percentage oxygen consumption = 100 x (E₂ZE₁) x (DO₂, ₂/DO₂, ₁) wherein Ei = initial value for oxygen extraction E₂ = final oxygen extraction DO₂,1 = initial oxygen delivery value and DO₂,2 = final oxygen delivery value.

53. A computer program according to claim 51 or 52 also incorporating the computer program of claim 27 for calculating E.