IDENTIFICATION AND QUANTIFICATION OF THE DEGREE OF TISSUE HYPOXIA

Abstract

The present invention relates to a method for identification of tissue hypoxia from measurements of acid-base and oxygenation status from venous and/or arterial blood.

Claims

1. A computer-implemented method, executed on one or more processors, for determining the degree of tissue hypoxia of a subject, the method comprising: a) determining venous blood values by at least one of measuring and estimating a blood acid-base status in a venous blood sample that has been obtained from the subject; b) providing a value of at least one of measured and estimated arterial oxygenation (SO.sub.2AM, SO.sub.2AE, SpO.sub.2) from the subject; c) converting the venous blood values by applying a venous-to-arterial conversion model for deriving blood acid-base status and oxygenation status into first estimated arterial blood values (1_ABG.sub.C); d) providing second reference acid-base status and oxygenation values of arterial blood (2_ABG) from the subject; e) implementing a tissue hypoxia model using a measure of at least one of a total buffer base concentration (BB) and a measure of the total carbon dioxide content (tCO.sub.2) in the arterial blood, the model having as input, at least the first estimated arterial blood values (1_ABG.sub.C) and the second reference values of arterial blood (2_ABG), f) wherein the tissue hypoxia model calculates at least one of: a. a first measure indicative of the change in the total buffer base concentration (ΔBB.sub.T) between the first estimated arterial blood values (1_ABG.sub.C) and the second reference values of arterial blood (2_ABG); and b. a second measure indicative of the change in the total carbon dioxide content (ΔtCO.sub.2,T) between the first estimated arterial blood values (1_ABG.sub.C) and the second reference values of arterial blood (2_ABG), and g) using the tissue hypoxia model to output a measure indicative of the degree of tissue hypoxia of the subject using at least one of the first and second measures.

2. The method according to claim 1, wherein the output measure in g) comprises the first measure (ΔBB.sub.T), the second measure (ΔtCO.sub.2,T) or any combinations thereof.

3. The method according to claim 1, wherein the tissue hypoxia model is further performs a minimization process of the at least one first measure (ΔBB.sub.T) and the second measure (ΔtCO.sub.2,T).

4. The method according to claim 3, wherein the minimization process of the at least one first measure (ΔBB.sub.T) and second measure (ΔtCO.sub.2,T), or any measures of acid-base included in these measures, is performed by an iteration process, preferably using a combined error function (ERROR) of the first and the second measure, or any measures of acid-base included in these measures.

5. The method according to claim 1, wherein the second reference arterial blood values from the subject are derived from a venous blood sample drawn from a warm, well-perfused bodily extremity.

6. The method according to claim 5, wherein second reference arterial blood values from the subject are derived by: determining venous blood values by at least one of measuring and estimating a blood acid-base status in a blood sample (VBG) drawn from the subject; providing values of at least one measured and estimated arterial oxygenation (SO.sub.2AM, SO.sub.2AE, SpO.sub.2) from the subject; and converting the venous blood values by applying a venous-to-arterial conversion model for deriving blood acid-base status and oxygenation status into second estimated arterial blood values (2_ABG).

7. The method according to claim 1, wherein the second reference arterial blood values from the subject are derived from an arterial blood sample while the subject is receiving oxygen from a ventilator under stable ventilator conditions.

8. The method according to claim 1, wherein the second reference arterial blood values from the subject are derived from an arterial blood sample while the subject is receiving oxygen from a ventilator under unstable ventilator conditions.

9. The method according to claim 1, wherein the tissue hypoxia model further receives third blood acid-base status and oxygenation reference values of arterial blood values (3_ABG) from the subject.

10. A data processing system for determining the degree of tissue hypoxia of a subject, the data processing system comprising one or more processors configured to: a) determine venous blood values by performing at least one of measuring and estimating a blood acid-base status in a venous blood sample that has been obtained from the subject; b) receive or provide a value of at least one of measured and estimated arterial oxygenation (SO.sub.2AM, SO.sub.2AE, SpO.sub.2) from the subject; c) convert the venous blood values by applying a venous-to-arterial conversion model for deriving blood acid-base status and oxygenation status into first estimated arterial blood values (1_ABG.sub.C); d) receive or provide second reference acid-base status and oxygenation values of arterial blood (2_ABG) from the subject; e) implement a tissue hypoxia model using at least one of a measure of the total buffer base concentration (BB) and a measure of the total carbon dioxide content (tCO.sub.2) in the arterial blood, the model having as input, at least the first estimated arterial blood values (1_ABG.sub.C) and the second reference values of arterial blood (2_ABG); f) wherein the tissue hypoxia model calculates at least one of: a. a first measure indicative of the change in the total buffer base concentration (ΔBB.sub.T) between the first estimated arterial blood values (1_ABG.sub.C) and the second reference values of arterial blood (2_ABG) and b. a second measure indicative of the change in the total carbon dioxide content (ΔtCO.sub.2,T) between the first estimated arterial blood values (1_ABG.sub.C) and the second reference values of arterial blood (2_ABG); and g) further wherein the tissue hypoxia model is arranged to output a measure indicative of the degree of tissue hypoxia of the subject using at least one of the first and/O second measures.

11. A computer program product enabling a computer system to carry out the operations of the system of claim 10 when downloaded or uploaded into the computer system.

12. A method of determining a degree of tissue hypoxia of a subject and treating a determined tissue hypoxia in the subject, the method comprising: a) determining venous blood values by at least one of measuring and estimating a blood acid-base status in a venous blood sample that has been obtained from the subject; b) providing a value of at least one of measured and estimated arterial oxygenation (SO.sub.2AM, SO.sub.2AE, SpO.sub.2) from the subject; c) converting the venous blood values by applying a venous-to-arterial conversion model for deriving blood acid-base status and oxygenation status into first estimated arterial blood values (1_ABG.sub.C); d) providing second reference acid-base status and oxygenation values of arterial blood (2_ABG) from the subject; e) implementing a tissue hypoxia model using at least one of a measure of the total buffer base concentration (BB) and a measure of the total carbon dioxide content (tCO.sub.2) in the arterial blood, the model having as input, at least the first estimated arterial blood values (1_ABG.sub.C) and the second reference values of arterial blood (2_ABG); f) wherein the tissue hypoxia model calculates at least one of: a. a first measure indicative of the change in the total buffer base concentration (ΔBB.sub.T) between the first estimated arterial blood values (1_ABG.sub.C) and the second reference values of arterial blood (2_AB G); and b. a second measure indicative of the change in the total carbon dioxide content (ΔtCO.sub.2,T) between the first estimated arterial blood values (1_ABG.sub.C) and the second reference values of arterial blood (2_ABG); g) using the tissue hypoxia model to output a measure indicative of the degree of tissue hypoxia of the subject using said at least one of the first and second measures; and h) treating the subject according to the measure indicative of the degree of tissue hypoxia, the treating comprising at least one of increasing a flow of oxygen to the subject and increasing a ventilation rate to the subject.

13. A device for determining the degree of tissue hypoxia of a subject, the device comprising a processor configured to: a) at least one of measure and estimate values of blood acid-base status in a venous blood sample that has been obtained from the subject; b) at least one of receive and provide a value of at least one of measured and estimated arterial oxygenation (SO.sub.2AM, SO.sub.2AE, SpO.sub.2) from the subject; c) convert the venous blood values by applying a venous-to-arterial conversion model for deriving blood acid-base status and oxygenation status into first estimated arterial blood values (1_ABG.sub.C); d) at least one of receive and provide second reference acid-base status and oxygenation values of arterial blood (2_ABG) from the subject; e) implement a tissue hypoxia model using at least one of a measure of the total buffer base concentration (BB) and a measure of the total carbon dioxide content (tCO.sub.2) in the arterial blood; the model having as input, at least, the first estimated arterial blood values (1_ABG.sub.C), and the second reference values of arterial blood (2_ABG); f) the tissue hypoxia model calculating: a. a first measure indicative of the change in the total buffer base concentration (ΔBB.sub.T) between the first estimated arterial blood values (1_ABG.sub.C) and the second reference values of arterial blood (2_ABG); and b. a second measure indicative of the change in the total carbon dioxide content (ΔtCO.sub.2,T) between the first estimated arterial blood values (1_ABG.sub.C) and the second reference values of arterial blood (2_ABG); and wherein the tissue hypoxia model is arranged to output a measure indicative of the degree of tissue hypoxia of the subject using at least one of the first and second measures to a display of the device.

14. The device according to claim 13, further comprising: g) an associated ventilator for providing ventilation and supplemental oxygen to a subject; and h) a controller for controlling at least one of a ventilation rate and an oxygen flow from the associated ventilator to the subject.

15. Use of the device according to claim 13 for treating tissue hypoxia, in which the device adjusts at least one of a ventilation rate and oxygen flow of an associated ventilator based on measurements output by the tissue hypoxia model to the device.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0076] The invention will now be described in more detail with regard to the accompanying figures. The figures show one way of implementing the present invention and is not to be construed as being limiting to other possible embodiments falling within the scope of the attached claim set.

[0077] FIG. 1 depicts the effects of tissue hypoxia on blood CO.sub.2 and BB at the tissue site.

[0078] FIG. 2 is an example of the method, including, but not limited to, the preferential embodiment for the second input, i.e. calculation of reference arterial values from a specific venous, in this case a peripheral venous expected to have little or no tissue hypoxia.

[0079] FIG. 3 outlines a simulated patient case illustrating the calculation of level of tissue hypoxia

[0080] FIG. 3b shows a sample pair presented on their individual buffer lines.

[0081] FIGS. 4 and 5 illustrate situations where the method may be of potential advantage in relation to state of the art.

[0082] FIG. 4 illustrates the situation where the method may be of potential advantage when separating the effects of tissue hypoxia from the level of aerobic metabolism.

[0083] FIG. 5 illustrates the situation where the method may be of potential advantage when separating the effects of tissue hypoxia from transient changes in ventilation.

[0084] FIG. 6 illustrates an example of a mathematical model of acid-base chemistry, modified from a previous publication (5).

DETAILED DESCRIPTION OF AN EMBODIMENT

[0085] This invention is a method and a corresponding computer system for identifying the degree to which tissue hypoxia has modified measures of arterial acid-base chemistry. An element of the invention is a comparison of calculated and measured values of acid-base chemistry.

[0086] FIG. 2 is a schematic drawing of the method of the invention. The method, illustrated on the figure, includes input from a previous method using specified and unspecified venous blood samples to obtain “calculated arterial” values of acid-base and oxygenation status (cf. WO 2004/010861 (to OBI Medical Aps, Denmark) (5) as defined in steps a, b, and c of the first aspect of the invention. In this context, the term “unspecific” venous blood is used to denote a venous sample in which there is no understanding as to whether the sample has been modified by mechanisms other than aerobic metabolism during its transit through the tissues. As such, it is not understood whether this sample has been modified by either tissue hypoxia, or by any other mechanism, as described in the background to this method. This input is, in effect, arterial values calculated as if aerobic metabolism is the only mechanism for modification of oxygenation and acid-base across the tissue, with these arterial values called “calculated arterial” on the figure.

[0087] The second input is that describing “reference arterial” values. The source of these reference arterial values can be of three types, and therefore represents three embodiments of this method. Preferentially, the source includes input from the previous method calculating arterial acid-base and oxygenation status from a specific venous blood sample. This source is labelled A in the figure, and in this context, the term “specific” venous blood is used to denote a venous sample drawn from a warm, well-perfused extremity, as identified from routine clinical practice, and as such is unlikely to have been modified by anaerobic metabolism its transit through the tissues. This input is, in effect, arterial values calculated as if aerobic metabolism is the only mechanism but in a situation where tissue hypoxia is unlikely.

[0088] Generally, the calculated arterial values are defined as an embodiment of the first estimated arterial blood values, and the measured arterial values are defined as an embodiment of the second reference acid-base status and oxygenation values of arterial blood in the first, second and third aspect of the present invention

[0089] Alternatively, the source can be measured from an arterial sample in stable ventilator conditions, labelled B on the figure, such as in mechanically ventilated patients without spontaneous breathing activity.

[0090] Another alternative could be an arterial sample where ventilation might have been unstable, labelled C on the figure, where it is not understood whether this sample has been modified by a transient change in ventilation. For any of these three sources this input is called “reference arterial” on the figure.

[0091] Using the calculated arterial and reference arterial as input, enables calculation of the differences between these two. Calculated arterial values are first transformed to concentrations using standard mathematical models of acid-base chemistry as illustrated in FIG. 7, so as to calculate the total buffer base concentration (BB) and the total CO.sub.2 (tCO.sub.2) in the calculated arterial blood.

[0092] Differences between calculated arterial values and reference arterial values can then be calculated as the CO.sub.2 content (ΔtCO.sub.2,T) and/or buffer base (ΔBB.sub.T) required to be added to or removed from the blood such that modified calculated arterial values of pH and PCO.sub.2 minimize the error function shown. As an alternative to buffer base (ΔBB.sub.T), base excess (ABET) in combination with CO.sub.2 content (ΔtCO.sub.2,T) can be used. Here the subscripts ‘T’ are used to denote changes due to the effects of tissue hypoxia.

[0093] As illustrated in the figure, the values of ΔtCO.sub.2,T and ΔBB.sub.T can be calculated by iteratively searching through possible values, until values of ΔtCO.sub.2,T and ΔBB.sub.T are found which minimize the error function. One potential error function is illustrated in the figure. Calculated values of ΔtCO.sub.2,T or ΔBB.sub.T can be understood differently depending upon the difference sources of input 2: A, B or C on the figure.

[0094] For source A, i.e. reference arterial values from a specific venous sample, the differences between reference arterial and calculated arterial are solely due to anaerobic metabolism. Values of ΔtCO.sub.2,T and ΔBB.sub.T, therefore describe the CO.sub.2 and strong acid added due to tissue hypoxia.

[0095] For source B, i.e. reference arterial values from measured arterial at stable ventilation, the differences between reference arterial and calculated arterial are solely due to anaerobic metabolism. Values of ΔtCO.sub.2,T and ΔBB.sub.T, therefore describe the CO.sub.2 and strong acid added due to tissue hypoxia.

[0096] For source C, i.e. reference arterial values from measured arterial at potentially unstable ventilation, the differences between reference arterial and calculated arterial can be due to either ventilation disturbance or anaerobic metabolism.

[0097] Values of ΔtCO.sub.2,T therefore describes the net CO.sub.2 added due to both these effects, with an addition of strong acid, ΔBB.sub.T, being strongly suggestive of tissue hypoxia.

[0098] FIG. 3 is an example of the method, including the preferential embodiment for the second input, i.e. calculation of reference arterial values from a specific venous sample, in this case a peripheral venous sample expected to have little or no tissue hypoxia. In addition to this example, the unspecific venous is a central venous sample. Calculated arterial values of acid-base and oxygen status are modified by removal of CO.sub.2 (ΔtCO.sub.2,T) and addition of buffer base (ΔBB.sub.T) so as to account for anaerobic metabolism. Values of ΔtCO.sub.2,T and ΔBB.sub.T are selected so as to minimize the shown error function, such that the modified values of calculated arterial are as close to the reference arterial values as possible. The example illustrates a possible first step in minimization of the error function and hence estimation of ΔtCO.sub.2,T and ΔBB.sub.T. It can be concluded that these additions cannot be accounted for by aerobic metabolism or transient ventilation, and as such are indicative of tissue hypoxia.

[0099] A common way of describing CO.sub.2 and BB modification is through buffer lines illustrating the relationship between pH and PCO.sub.2 in the blood. Two such buffer lines are illustrated in FIG. 3b, illustrating this case. The specific venous blood, in this case peripheral venous (shown as dot [A]), has higher PCO.sub.2 and lower pH than the reference arterial (dot [B]) but lies on the same buffer line. If all transport of CO.sub.2 over the tissues were due to aerobic metabolism, as can be expected in a peripheral venous sample taken from a warm well perfused site, then the reference arterial calculated from this venous represents the true arterial undisturbed by changes in ventilation. The unspecific venous blood, in this case central venous (shown as dot [C]), has higher PCO.sub.2 and lower pH than the calculated arterial (dot [D]) but lies on the same buffer line. The difference between the calculated and reference arterial represents the need for change in both CO.sub.2 and BB so as to move along and between buffer lines, with these changes due to tissue hypoxia.

[0100] FIG. 4 illustrates a situation where the method may be advantageous in relation to existing methods. In particular, it illustrates an example showing the sensitivity of current methods to the level of aerobic metabolism. Two examples are shown, the first with reduced aerobic metabolism (Case A—left), and increased aerobic metabolism (Case B—right). Standard ratios used in current clinical practice to identify tissue hypoxia are used to describe both these situations; the situation for aerobic metabolism alone is illustrated in the top half of the figure for both these cases. The situation for the presence of tissue hypoxia is illustrated in the bottom half of both figures with the addition of 1 mmol/l ΔtCO.sub.2,T to the venous sample. In doing so, it is shown how the same 1 mmol/l ΔtCO.sub.2,T addition to two different cases with different aerobic conditions can have a very different clinical interpretation. In doing so it is shown that the calculation of ΔtCO.sub.2,T proposed by the method in this patent may be advantageous in relation to current clinical indices. The details are as follows:

[0101] Case A, on the left of the figure, illustrates a simulated situation of reduced aerobic metabolism. The reference arterial blood gas values, shown in the middle of the figure on the left hand side include an oxygen saturation of 90% and a relatively low value of blood haemoglobin concentration (6 mmol/l). This means that the total oxygen concentration of arterial blood is similarly low, i.e. taO.sub.2=5.4 mmol/l. In addition, the level of oxygenation in the unspecific venous values, in this case central venous, remain high, at a saturation of 80% such that central venous oxygen concentration (tcvO.sub.2) is 4.8 mmol/l. This means that little oxygen has been utilised in the tissue, and the ΔtO.sub.2 is small (ΔtO.sub.2=5.4−4.8=0.6 mmol/l).

[0102] In contrast, Case B on the right of the figure illustrates a situation of elevated aerobic metabolism. Arterial oxygen saturation is 90% and the value of haemoglobin is high (11 mmol/l). This means that the total oxygen concentration of arterial blood is elevated taO.sub.2=9.9 mmol/l. In addition, venous values of oxygenation are low at 45% such that central venous oxygen concentration is 4.95 mmol/l. As such, substantial oxygen is utilised in the tissue, and the ΔtO.sub.2 is large ΔtO.sub.2=9.9−4.95=4.95 mmol/l.

[0103] Applying a clinical ratio seen as current best practice to these two situations provides a similar clinical interpretation in the case of aerobic metabolism alone. The value of this ratio, labelled RATIO on the figure and described as the ratio of ΔtCO.sub.2(v−a)/ΔtO.sub.2(a−v), is shown for the case of aerobic metabolism alone, with the low aerobic metabolism case (case A) and the high aerobic metabolism case (case B) having a value of 0.80 and 0.83, respectively. These values are below the value of 1.02 used as a cut-off to identify sepsis or tissue hypoxia (1).

[0104] At the bottom of the figure, the same indices are calculated following a simulated addition of ΔtCO.sub.2,T=1 mmol/l to the central venous values, so as to approximate the effects of CO.sub.2 addition due to tissue hypoxia. The resulting central venous values for case A and case B are shown. Applying the same clinical ratio to compare arterial and central venous samples after addition of ΔtCO.sub.2,T=1 mmol/l to both central venous samples provides a dramatically different clinical interpretation. The low aerobic metabolism case (A) has a value of the ratio of 2.50; and the high aerobic metabolism case having a value of 1.00. In this case only the low aerobic metabolism case (case A) would result in a ratio above the value of 1.02 used to identify sepsis or tissue hypoxia (1), despite the same CO.sub.2 concentration change due to tissue hypoxia.

[0105] This clearly shows that the identification of ΔtCO.sub.2,T, possible from the method presented here, is not equivalent to current methods and may be advantageous in identifying tissue hypoxia separate from the underlying aerobic metabolism.

[0106] FIG. 5 illustrates a second situation where the method may be advantageous in relation to existing methods. In particular, it illustrates a simulated situation where a ventilation disturbance can lead to a ΔtCO.sub.2(v−a)/ΔtO.sub.2(a−v) ratio which would classify the patient as having tissue hypoxia or sepsis despite this clearly not being the case.

[0107] Illustrated at the top of the figure, and surrounded by a box, is an example of the preferential embodiment of the method with the unspecific venous measurements as a central venous and the specific venous measurement as a peripheral venous. The calculated values of ΔCO.sub.2,T and ΔBB.sub.T in this case are both zero, indicating no tissue hypoxia.

[0108] Also included on the figure are the values of a simultaneous arterial sample in the presence of a transient increase in ventilation. As arterial acid-base values respond rapidly to changes in ventilation, CO.sub.2 values are substantially lower than both the reference and calculated arterial values. However, current indices classifying sepsis and tissue hypoxia based on arterial and venous difference ratios do not make the distinction between differences due to increases in ventilation and tissue hypoxia and could therefore lead to erroneous conclusions. This is illustrated by calculating the value of the ΔtCO.sub.2(v−a)/ΔtO.sub.2(a−v) ratio for the relationship between arterial and central venous blood, and this is shown at the bottom of the figure. The value for this ratio in this instance is 1.81, substantially higher that the 1.02 threshold used to identify sepsis or tissue hypoxia ((ref 1), potentially resulting in information indicating tissue hypoxia in a situation where a transient increase in ventilation was the only cause.

[0109] This example clearly indicates the advantageous nature of the method presented here in relation to current practice in separating the effects of transient increase in ventilation and tissue hypoxia.

[0110] FIG. 6 illustrates a mathematical model of the acid-base chemistry of blood, published previously (5). This model, or similar, is required to perform simulations of modifications of the acid-base chemistry in the blood as illustrated where it states “Calculate from model” in FIGS. 2-5. These models are readily available, with this particular model included here as an example only, hence, the skilled person will understand that other models may be implemented in the context of the present invention once the principle and teaching of the present invention is understood.

Glossary

[0111] 1_ABG.sub.C First estimated or calculated arterial value [0112] 2_ABG Second reference arterial value [0113] BB Buffer Base [0114] BE Base Excess [0115] DPG 2,3-disphosphoglycerate [0116] FCOHb Fraction of Carboxyhaemoglobin [0117] FMetHb Fraction of Methaemoglobin [0118] GUI Graphical User Interface [0119] Hb Haemoglobin [0120] HCO.sub.3.sup.− Bicarbonate ion [0121] PCO.sub.2 Partial pressure of carbon dioxide in the blood [0122] PO.sub.2 Partial pressure of oxygen in the blood [0123] RQ Respiration Quotient [0124] SO.sub.2AE Oxygen saturation in estimated arterial blood [0125] SO.sub.2AM Oxygen saturation in measured arterial blood [0126] SpO.sub.2 Oxygen saturation measured by pulse oximetry [0127] tCO2 Total carbon dioxide content [0128] tO2 Total oxygen content [0129] VBG Venous blood gas [0130] ΔtCO.sub.2,T Change in total CO.sub.2 in blood related to tissue hypoxia [0131] ΔBB.sub.T Change in total Buffer Base related to tissue hypoxia

REFERENCES

[0132] 1. J. Mallat et al., “Ratios of central venous-to-arterial carbon dioxide content or tension to arteriovenous oxygen content are better markers of global anaerobic metabolism than lactate in septic shock patients,” Ann. Intensive Care, vol. 6, no. 1, pp. 1-9, 2016. [0133] 2. G. A. Ospina-Tascón, G. Hernendez, and M. Cecconi, “Understanding the venous-arterial CO2 to arterial-venous O2 content difference ratio,” Intensive Care Med., vol. 42, pp. 1801-1804, 2016. [0134] 3. G. A. Ospina-Tascón et al., “Combination of arterial lactate levels and venous-arterial CO.sub.2 to arterial-venous O.sub.2 content difference ratio as markers of resuscitation in patients with septic shock,” Intensive Care Med., vol. 41, no. 5, pp. 796-805, 2015. [0135] 4. X. Monnet et al., “Lactate and venoarterial carbon dioxide difference/arterial-venous oxygen difference ratio, but not central venous oxygen saturation, predict increase in oxygen consumption in fluid responders,” Crit. Care Med., vol. 41, no. 6, pp. 1412-1420, 2013. [0136] 5. WO 2004/010861 (to OBI Medical Aps, Denmark) [0137] 6. S. E. Rees et al., A method for calculation of arterial acid-base and blood gas status from measurements in the peripheral venous blood, 2006

[0138] All of the above patent and non-patent literature are hereby incorporated by reference in their entirety.

[0139] The invention can be implemented by means of hardware, software, firmware or any combination of these. The invention or some of the features thereof can also be implemented as software running on one or more data processors and/or digital signal processors i.e. data processing on one, or more, computers

[0140] The individual elements of an embodiment of the invention may be physically, functionally and logically implemented in any suitable way such as in a single unit, in a plurality of units or as part of separate functional units. The invention may be implemented in a single unit, or be both physically and functionally distributed between different units and processors.

[0141] Although the present invention has been described in connection with the specified embodiments, it should not be construed as being in any way limited to the presented examples. The scope of the present invention is to be interpreted in the light of the accompanying claim set. In the context of the claims, the terms “comprising” or “comprises” do not exclude other possible elements or steps. Also, the mentioning of references such as “a” or “an” etc. should not be construed as excluding a plurality. The use of reference signs in the claims with respect to elements indicated in the figures shall also not be construed as limiting the scope of the invention.

[0142] Furthermore, individual features mentioned in different claims, may possibly be advantageously combined, and the mentioning of these features in different claims does not exclude that a combination of features is not possible and advantageous.