Technical field of the invention

The present invention relates to a method for calibrating the level of oxygen in respiratory gas related to the level of oxygen in the blood circulation of an individual, and a corresponding computer program product.

Background of the invention

In clinical practice, measurement of pulmonary gas exchange is limited to simple single parameter measurements such as the Pa02/Fi02 ratio or effective pulmonary shunt which have been criticized for providing insufficient descriptive detail (Karbing et al. 2007). In contrast, detailed experimental methods have been applied to improve physiological understanding, for instance the multiple inert gas elimination technique (MIGET) (Wagner, Saltzman & West 1974), but these methods have not found their way into routine clinical practice. Recently, a new method based on measurements of arterial oxygenation at varied inspired oxygen fractions and a physiological mathematical model, has been developed . The method known as ALPE (acronym for Automatic Lung Parameter Estimator system) provides the clinician with estimates of pulmonary shunt, and ventilation perfusion mismatch (Rees et al. 2002), which can be used to determine optimal inspired oxygen fraction (Karbing et al. 2010). To describe a patient's gas exchange ALPE conducts a 3 to 5 step maneuver taking 10 to 15 minutes, where inspired oxygen (Fi02) is changed and the resulting end-tidal (Fet02) and pulse oximetry arterial oxygenation (Sp02) measured. Figure 1 illustrates an example of data collected during an ALPE maneuver, with raw data shown as points and the drawn curve is the best fit of the mathematical model of pulmonary gas exchange included in ALPE (Karbing et al. 2011).

Clinical studies have evaluated the use of ALPE in post-operative hypoxaemia (Rasmussen et al. 2006, Rasmussen et al. 2007, Kjaergaard et al. 2001,

Kjaergaard et al. 2004), to describe a range of intensive care patients (Karbing et al. 2007, Kjaergaard et al. 2003) and in patients with left-sided heart failure (Moesgaard et al. 2009). The model has been compared to MIGET (Rees et al. 2006, Rees et al. 2010).

The mathematical model included in ALPE describes transport of oxygen from inspired gas to the blood and includes conservation of mass equations at steady state. This dictates that measurements of arterial oxygenation and Fet0 ₂ must be at steady state conditions following a change in Fi0 ₂ level. During an ALPE maneuver, steady-state is evaluated by monitoring changes in breath by breath Fet0 ₂ where a continuous low variation (plateau) over a period of time is defined as a steady state, typically achieved within 2 to 4 minutes.

The assumption of steady state may be insufficient in some cases: 1) In patients with severe lung disease, for example chronic obstructive pulmonary disease (COPD), 2 to 4 minutes may be insufficient to reach steady state. Indeed several studies have shown that this can take as long as 30 minutes (Woolf 1976, Sherter et al. 1975); 2) The ALPE system evaluates steady state by a constant Fet0 ₂ value, however arterial oxygenation may have a slower time course, taking longer to equilibrate than Fet0 ₂ ; and 3) The ALPE system approximates arterial oxygen saturation using pulse oximetry measurement of Sp0 ₂ at the fingertip which is delayed in relation to arterial values due to circulation time of blood and sensor averaging (Young et al. 1992, Zubieta-Calleja et al. 2005). Circulation can for example be compromised at the pulse oximeter site due to well-known

mechanisms such as vasoconstriction. The delay is patient specific as it depends on local blood flow in the fingers (Ding et al. 1992) and is affected by hypothermia (MacLeod et al. 2005).

Hence, improved methods for obtaining respiratory parameters relating to an individual would be advantageous.

Summary of the invention

Since a steady state may not be achieved in 2 to 4 minutes in all individuals, a method is presented inhere wherein breath by breath measurements of oxygen parameters such as Fet02 and Sp02 are determined to e.g. rapidly estimate one or more respiratory parameters relating to an individual. Thus, the need for steady state levels of oxygen levels in the blood are eliminated, which otherwise slows the method. This method is based on that the delay due to e.g. pulse oximetry can be calibrated for, on an individual patient basis.

Thus, an object of the present invention relates to a method for calibrating the level of oxygen in respiratory gas related to the level of oxygen in the blood circulation of an individual.

Thus, one aspect of the invention relates to a method for calibrating the level of oxygen in respiratory gas related to the level of oxygen in the blood circulation of the individual, comprising providing a level of oxygen in the gas flow passing into, or out, of the respiratory system of the individual and producing a corresponding first output,

- providing a level of oxygen in the blood circulation of the individual and producing a corresponding second output,

providing a computer for receiving and storing at least two measurements, each measurement being the concurrent output of said first output and said second output within a data structure, in which the two stored outputs are mutually related, in data storage means associated with the computer, the at least two measurements being conducted at respective levels of oxygen in the gas flow passing into the respiratory system, and

- calibrating the level of oxygen in the gas value in response to a delay

between the level of oxygen in the blood circulation of the individual and the level of oxygen in the gas flow passing into, or out, of the respiratory system of the individual.

The invention is particularly, but not exclusively, advantageous for obtaining an improved method which provides significantly reliable and/or faster

measurements of respiratory parameters of patients as compared to previous methods applied, such as the so-called ALPE. For example measurements performed on patients suffering from chronic obstructive pulmonary disease (COPD) may be performed an order of magnitude quicker and also more reliable because the required assumption of steady state may be uncertain and/or difficult to validate. In the context of the present invention, the concept of 'calibrating the level of oxygen in the gas value' is to be understood in the broadest sense. Thus, the term 'calibrating' may alternatively be replaced, or having synonyms meaning, with adjusting, compensating, regulating, bringing into line, correcting, adapting, and so forth, as the skilled person will understand once the general teaching and principle of the present invention has been appreciated, in particular when realizing the origin and meaning of the delay between the level of oxygen in the blood circulation of the individual and the level of oxygen in the gas flow passing into, or out, of the respiratory system of the individual. Notice that the delay as such may be caused by a number of factors, the physiological delay typically being the dominating source without being limited to this particular type of delay.

In one embodiment of the invention, the provided values of the level of oxygen in the blood circulation of the individual (e.g. Sp02) are shifted in time (either positive or negative depending on the reference) according to the delay. In another embodiment, the provided values of the level of respiratory oxygen of the individual (e.g. FE02) are shifted in time (either positive or negative depending on the reference) according to the delay.

In one alternative embodiment of the invention, the actual values of the level of blood circulation of the individual (e.g. Sp02) and/or the level of respiratory oxygen of the individual (e.g. FE02) are calibrated, or adjusted, according to the delay in order to provide faster and/or more reliable measurement of respiratory parameters. This could be done by using an appropriate physiological model as the skilled person will appreciate, this could be performed as an alternative or addition to the said shifting in time.

In one embodiment, wherein the computer may be further adapted for estimating least two respiratory parameters relating to the individual, the two respiratory parameters descriptive of the pulmonary gas exchanges. The computer may specifically be adapted for determining at least two respiratory parameters chosen from the list consisting of: Rdiff, shunt, ^ -distribution, Q -distribution, H- shift, V-shift, or C02-shift, or any combination thereof, or equivalents or derived parameters thereof as the skilled person will appreciate once the general principle and teaching of the present invention has been fully comprehended.

In particular, the present invention may be implemented in connection with a device for determining respiratory parameters as described in US patent

7,008,380 (assigned to Mermaid Care A/S), which is hereby incorporated by reference in its entirety. Cf. also Rees et al., 2002. In a separate aspect, the present invention can accordingly be implemented in a device for determining one or more respiratory parameters, particularly at least two parameters, relating to an individual, comprising

a gas flow device having means for conducting a flow of inspiratory gas from an inlet opening to the respiratory system of the individual and a flow of expiratory gas from the respiratory system of the individual to an outlet opening, a gas-mixing unit for supplying a substantially homogeneous gas to the inlet opening of the gas flow device,

first supply means for supplying a first gas to an inlet of the gas mixing unit and having first control means for controlling the flow of the first gas,

second supply means for supplying a second gas having an oxygen fraction different to the gas supplied from the first supply means to an inlet of the gas mixing unit and having second control means for controlling the flow of the second gas,

a computer for determining said one or more respiratory parameters, first detection means for detecting the level of oxygen (Sa02, Sp02, Pa02, Pp02) in the blood circulation of the individual and producing an output to the computer accordingly, and

second detection means for detecting the level of oxygen (FI02, FE'02, FE

02, PI02, ΡΕΌ2, PE02) in the gas flow passing into or out of the respiratory system of the individual and producing an output to the computer accordingly, the computer being adapted for retrieving and storing at least two measurements being the concurrent output produced by the first detection means and the second detection means within a data structure, in which the two stored outputs are mutually related, in data storage means associated with the computer, the at least two measurements being conducted at respective levels of oxygen in the gas flow passing into the respiratory system, the computer further being adapted for determining at least one respiratory parameter (Rdiff, shunt, V/Q , H-shift, V- shift) being descriptive of the condition of the individual, the determination being based on the at least two measurements. Additionally, or alternatively , the present invention may be implemented in connection with another device for determining respiratory parameters as described in international patent application WO 2012/069051 (assigned to Mermaid Care A/S), which is also hereby incorporated by reference in its entirety. The latter device may estimate pulmonary parameters indicative of gas exchange of both 02 and C02 in an individual. Thus, the present invention may be implemented in a device for determining at least two respiratory parameters relating to an individual, comprising

a gas flow device having means for conducting a flow of inspiratory gas from an inlet opening to the respiratory system of the individual and a flow of expiratory gas from the respiratory system of the individual to an outlet opening, a gas-mixing unit for supplying a substantially homogeneous gas to the inlet opening of the gas flow device,

first supply means for supplying a first gas to an inlet of the gas mixing unit and having first control means for controlling the flow of the first gas,

second supply means for supplying a second gas having an oxygen fraction different to the gas supplied from the first supply means to an inlet of the gas mixing unit and having second control means for controlling the flow of the second gas,

a computer for determining said two or more respiratory parameters, first detection means for detecting the level of oxygen in the blood circulation of the individual and producing an output to the computer accordingly, and

second detection means for detecting the level of oxygen in the gas flow passing into or out of the respiratory system of the individual and producing an output to the computer,

first carbon dioxide detection means for detecting the level of carbon dioxide in the blood circulation of the individual and producing an output to the computer accordingly, and second carbon dioxide detection means for detecting the level of carbon dioxide in the gas flow passing into or out of the respiratory system of the individual and producing an output to the computer accordingly,

the computer being adapted for retrieving and storing at least two oxygen measurements and one carbon dioxide measurement,

the oxygen measurements being the concurrent output produced by the first detection means and the second detection means within a data structure, in which the two stored outputs are mutually related and related to a stored oxygen measurement at a corresponding level of oxygen in the gas flow passing into the respiratory system,

the carbon dioxide measurement being the concurrent output produced by the first carbon dioxide detection means and the second carbon dioxide detection means within a data structure, in which the two stored outputs are mutually related and related to a stored carbon dioxide measurement at a corresponding level of oxygen in the gas flow passing into the respiratory system, and

the computer further being adapted for determining at least two respiratory parameters being descriptive of the pulmonary gas exchange of oxygen and/or carbon dioxide of the individual, the determination being based on the at least two oxygen measurements and one carbon dioxide measurement.

Both of the above-mentioned devices may beneficially exploit that the calibration the level of oxygen in the gas value in response to a delay between the level of oxygen in the blood circulation of the individual and the level of oxygen in the gas flow passing into, or out, of the respiratory system of the individual, may result in much improved measurement time and/or reliability.

Another aspect of the present invention relates a computer program product comprising software code adapted to enable the computer to calibrating the level of oxygen in respiratory gas related to the level of oxygen in the blood circulation of the individual according to the preceding aspect. This aspect of the invention is particularly, but not exclusively, advantageous in that the present invention may be accomplished by a computer program product enabling a computer system to carry out the operations of the apparatus/ system of the first aspect of the invention when down- or uploaded into the computer system. Such a computer program product may be provided on any kind of computer readable medium, or through a network.

The individual aspects of the present invention may each be combined with any of the other aspects. These and other aspects of the invention will be apparent from the following description with reference to the described embodiments.

Brief description of the figures

The method according to 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.

Figure 1

Figure 1 shows an ALPE model representation, curve, of end-tidal oxygen fraction (Fet02) versus pulse oximetry arterial oxygenation (Sp02) measured at steady state for different inspired oxygen fractions (Fi02). Circle, Fi02=21%; square, Fi02= 18%; triangle, Fi02= 15%; tipped triangle FiO2=30%. Figure 2

Figure 2 shows pulse oximetry arterial oxygenation (Sp02), solid line, left axis, and inspired oxygen fraction (Fi02), dashed line, right axis, plotted against time. The label A marks the first change in Fi02. The grey vertical dashed line marked B shows the beginning of response of Sp02. Duration from A to B is the estimate of delay in Sp02.

Figure 3

Figure 3 shows breath-by-breath Fet02 (or FE02) versus Sp02 raw data (top) and calibrated for Sp02 delay (bottom) for a representative patient included in the study (grey). Steady state oxygen levels for each inspired oxygen fraction (Fi02) step are marked in black by: Circle = 21%, Square = 18%, Triangle = 15%, Diamond = 25%, Flipped triangel = 30%, Pentagram = 35%. The present invention will now be described in more detail in the following.

Detailed description of the invention The invention relates a method for calibrating the level of oxygen in respiratory gas related to the level of oxygen in the blood circulation of the individual.

The method comprises providing a level of oxygen in the gas flow passing into, or out, of the respiratory system of the individual, such as FE02, and producing a corresponding first output.

The method further comprises providing a level of oxygen in the blood circulation of the individual, such as Sp02, and producing a corresponding second output, A computer is provided for receiving and storing the at least two measurements, each measurement being the concurrent output of said first output and said second output within a data structure, in which the two stored outputs are mutually related, in data storage means associated with the computer, the at least two measurements being conducted at respective levels of oxygen in the gas flow passing into the respiratory system. Further, the invention comprises the step of calibrating, or adjusting, the level of oxygen in the gas value in response to a delay between the level of oxygen in the blood circulation of the individual and the level of oxygen in the gas flow passing into, or out, of the respiratory system of the individual.

Advantageously, the level of oxygen in respiratory gas may be provided by measurements of Fi0 ₂ , Pi0 ₂ , FE'0 ₂ , FE'02, PE'0 ₂ and/or PE0 ₂ , or other equivalent measures available to the skilled person. Advantageously, the level of oxygen in the blood circulation of the individual is provided by measurements of Sa0 ₂ , Ca0 ₂ , Pa0 ₂ , Sp0 ₂ , and/or Pp0 ₂ , or other equivalent measures available to the skilled person. Typically, wherein the level of oxygen is in the gas flow passing into the respiratory system may be different in the at least two measurements. In a particular embodiment, the level of oxygen in at least one measurement may be the level natural present in air measured at sea level, such as around 21%.

The delay may be measured, estimated or fitted, possibly a combination of these ways of finding the delay may be applied.

In one embodiment, the provided values of the level of oxygen in the blood circulation of the individual (Sp02) are shifted in time according to the delay, e.g. for the delay of 28 seconds for patient number 1, the patient data for oxygen in the blood being depicted in Figure 3 top are shifted by 28 seconds in the bottom of Figure 3. Alternatively, the provided values of the level of respiratory oxygen of the individual (FE02) may be shifted in time according to the delay, corresponding to negative shift of 28 seconds for patient number, this is however not shown in Figure 3, but the result would have been the same. Alternatively or additionally, the delay may be estimated for a specific patient condition, such as sex, age, diagnosis, disease history, weight, a local perfusion level, a temperature change, and/or an average based on a patient group.

Alternatively or additionally, the delay may be obtained by a fitting by minimizing deviation from a predefined curve, such as a function or a polynomial, and/or a physiological/mathematical model of oxygen transport. Appropriate minimization techniques are ready available to the skilled person once the general teaching of the present invention is comprehended. As seen in Figure 3 (bottom), the calibrated values can be fitted to a relatively smooth or continuous function.

Typically, the at least two measurements may be provided from measurements obtained at different time points. The different time points being preferably shifted in time by at least one breath of the individual from which the measurements have been obtained, optionally two breaths, three breaths, fours breaths, etc. In particular, the at least two measurements at different time points may be obtained at non-steady state conditions for the respiratory state of the individual yielding faster measurement time. The measurements may be obtained after inhaling or exhaling. Advantageously, further measurements may also be shifted in time by at least one breath of the subject from which the data points have been obtained, e.g. 3 measurements, 4 measurements, 5 measurements, 6

measurements, etc.

Advantageously, the time between the first measurement and the second measurement is less than 2 minutes, such as less than 1 minute such as less than 30 seconds. The present invention is particularly advantageous in that an equilibrium or steady state condition is not necessary.

The present invention may be beneficially applied when the individual is a normal person, or suffers from one or more respiratory diseases or abnormalities, including primary and secondary lung diseases, such as chronic obstructive pulmonary disease (COPD), acute lung injury, acute respiratory distress

syndrome, pulmonary edema, asthma, pleural disease, or airway disease. Other related or similar diseases/conditions for which the present invention may be advantageously applied are also contemplated.

In a particular aspect, the invention relates to a computer program product comprising software code adapted to enable the computer to calibrating the level of oxygen in respiratory gas related to the level of oxygen in the blood circulation of the individual according to any of preceding claims. Thus, advantageously the invention may be implemented on a computer having appropriate software and relevant patient data stored in connection with the computer

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.

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.

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. 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.

It should be noted that embodiments and features described in the context of one of the aspects of the present invention also apply to the other aspects of the invention.

All patent and non-patent references cited in the present application, are hereby incorporated by reference in their entirety.

The invention will now be described in further details in the following non-limiting examples.

Example 1

Pulse oximetry Sp0 ₂ delay was evaluated and individual patient calibration explored in 16 patients diagnosed with COPD.

Patients

Sixteen patients admitted to the local pulmonary out-patient clinic all suffering from mild to very severe COPD entered in this study. Patients, 31% women, where 68±11 years and had a FEVi% of 56±24. All patients gave their informed consent and the study was approved by the local Ethics Committee. An ALPE manoeuvre was performed for each patient (Mermaid Care A/S, DK9400

N0rresundby, Denmark). During the investigation the equipment continuously records Fet02, and Sp02.

Data analysis

For each patient delay in Sp02 is estimated using a plot of Sp02 and Fi02 over time for the entirety of the ALPE experiment (Figure 2). Delay is estimated as the duration from the first change in Fi02 (A) to the beginning of response of Sp02 (B, dashed vertical line). To perform this calibration is was necessary that a sufficiently large signal was seen in Sp02 so as to determine the start of Sp02 change from noise. In 8 of the 16 patients this was not the case for the first step change in Fi02 and a subsequent step was therefore used. To explore whether Fet02 versus Sp02 data lie on a single continuous curve and to examine the effect of Sp02 delay, two plots were then made for each patient, with Fet02 plotted against Sp02 for both raw data and with Sp02 data corrected for delay. Expirations shorter than one second were excluded in these plots to prevent error in measurements of Fet02 due to lack of alveolar plateau.

Results

Table 1 gives values for Sp02 delay for all patients. The average delay was 39.6 seconds, a value which is within range of the 30 seconds reported for finger probe pulse oximeters (MacLeod et al. 2005) where hyperthermia was absent.

Patient no Delay

1 28

2 23

3 38

4 38

5 41

6 42

7 31

8 29

9 37

10 47

11 45

12 40

13 37 14 40

15 55

16 70

Average 39.6

Standard deviation 11.2

Minimum 23

Maximum 70

Figure 3 shows Fet02 versus Sp02 raw data (top) and calibrated for Sp02 delay (bottom) for one patient included in the study, the lower graph being derived from the upper graph as indicated by the arrow connecting the upper and lower graph. Typical profiles of Fet02 versus Sp02 change during Fi02 steps can be seen in patient 1 both for calibrated and un-calibrated data. The start points for oxygen steps are marked with black symbols and are numbered to illustrate the order of steps. For patient 1, the ALPE experiment starts at a Fi02 = 21 % (black circle), followed by a reduction in Fi02 to 18%. For the un-calibrated data in this patient, immediately following the change in Fi02, Sp02 remains constant while Fet02 reduces. After approximately 6 breaths Sp02 reduces with a relatively constant Fet02. The first step change in Fi02 ends at the data point marked with a black square. The subsequent reduction Fi02 from 18% to 15% has a similar profile with an initial drop in Fet02 followed by a reduction in Sp02. In the last step Fi02 is increased from 15% to 25%. Once again Fet02 changes occur first followed by change in Sp02. The errors are such that on reducing Fi02 data is shifted up and to the left, and on increasing Fi02 data is shifted down and to the right. Similar patterns are seen in all patients. Following calibration or adjustment, data lie on a single continuous curve including both breath by breath data and the final ALPE equilibrium points, illustrating that difference in dynamics between Fet02 and Sp02 could be explained by the Sp02 delay.

Conclusion In this example it is shown that data describing breath by breath Fet02 and Sp02 corrected for delay lie on a single curve. This illustrates that, even in patients with COPD, Fet02 and Sa02 may have similar time constants and complete oxygen equilibration can be avoided in order to draw an Fet02 versus Sp02 curve suitable for estimating pulmonary gas exchange. COPD patients were studied here as these reflect those expected to have greater duration of oxygen equilibration than normal. Despite this selection the patients studied here had FEV1% level in the more moderate range of COPD and only four could be classified as severe COPD according to the GOLD criteria.

Thus, this example study has shown that a lack of equilibrium between Fet02 and Sp02 may not be a limitation when step changes in Fi02 and mathematical models are used as a tool for estimating pulmonary gas exchange.

Glossary

Fi02 Fraction of oxygen in inspired gas.

Pi02 Pressure of oxygen in inspired gas.

Sa02 Oxygen saturation of arterial blood, measured from a blood sample. Ca02 Oxygen concentration in arterial blood.

Pa02 Pressure of oxygen in arterial blood, measured from a blood sample.

Sp02 Oxygen saturation of arterial blood, measured transcutaneously.

Pp02 Pressure of oxygen in arterial blood, measured transcutaneously.

FE'02 Fraction of oxygen in expired gas at the end of expiration.

FE02 Fraction of oxygen in the mixed expired gas.

ΡΕΌ2 Pressure of oxygen in expired gas at the end of expiration.

PE02 Pressure of oxygen in the mixed expired gas.

Non-limiting list of respiratory parameters descriptive of the pulmonary gas exchange: shunt Respiratory parameter representing the fraction of blood not

involved in gas exchange.

Rdiff Respiratory parameter representing a resistance to oxygen diffusion across the alveolar lung capillary membrane.

V Ventilation.

Q Perfusion. Respiratory parameter representing the balance between ventilation and perfusion of a homogeneous region of the lung.

V -distribution Respiratory parameter representing fraction of ventilation going to different regions of the lungs or fraction of ventilation going to different ventilated compartments of a model of pulmonary gas exchange.

Q -distribution Respiratory parameter representing fraction of perfusion going to different regions of the lungs or fraction of perfusion going to different ventilated compartments of a model of pulmonary gas exchange.

V-shift Respiratory parameter representing a vertical shift in plots of Fi02 against Sa02 , Fi02 against Sp02, FE'02 against Sa02, or FE'02 against Sp02.

H-shift Respiratory parameter representing a horizontal shift in plots of Fi02 against Sa02 , Fi02 against Sp02, FE'02 against Sa02, or FE'02 against Sp02.

C02-shift Respiratory parameter representing the C02-level shift in plots of

FiC02 against PaC02 , FiC02 against PtcC02, FE'C02 against PaC02, or FE'C02 against PtcC02.

In short, the present invention relates to a method for calibrating, or adjusting, the level of oxygen in respiratory gas related to the level of oxygen in the blood circulation of the individual, comprising providing a level of oxygen in the gas flow passing into, or out, of the respiratory system of the individual and producing a corresponding first output, providing a level of oxygen in the blood circulation of the individual and producing a corresponding second output, providing a computer for receiving and storing at least two measurements, each measurement being the concurrent output of said first output and said second output within a data structure, in which the two stored outputs are mutually related, in data storage means associated with the computer, the at least two measurements being conducted at respective levels of oxygen in the gas flow passing into the respiratory system, and calibrating the level of oxygen in the gas value in response to a delay between the level of oxygen in the blood circulation of the individual and the level of oxygen in the gas flow passing into, or out, of the respiratory system of the individual.

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