AU2008200782A1 - Method and apparatus for measuring cardiac output - Google Patents

Description

S&F Ref: 842231

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Applied Physiology Pty Ltd, an Australian company, ACN 107 608 971, of 119 Willoughby Road, Crows Nest, New South Wales, 2065, Australia William Geoffrey Parkin, Mark Stephen Leaning Spruson Ferguson St Martins Tower Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Method and apparatus for measuring cardiac output Associated Provisional Application Details: [33] Country: [31] Appl'n No(s): [32] Application Date: 2007900851 20 Feb 2007 The following statement is a full description of this invention, including the best method of performing it known to me/us: 5845c(1134912_1) 00 METHOD AND APPARATUS FOR MEASURING CARDIAC

OUTPUT

a, T Technical Field 5 The present invention relates to the field of cardiac output measurement.

C-i Background of the Invention 00 The measurement of cardiac output, that is the flow rate of blood pumped by the heart of a patient, is required for haemodynamic control. Knowledge of cardiac output 00 l o underlies the understanding and use of a wide range of physiological variables in both human and veterinary medicine.

Historically, cardiac output has been measured in various ways. These methods typically utilise the addition of a marker to the bloodstream at a known rate and measuring the concentration of the marker at a downstream location. Examples of markers used with such measurement include heat (applying thermodilution principles), dyes (for example, indocyanine green) and lithium chloride (using an arterial lithium sensing electrode). It is also known to measure cardiac output using various other techniques, such as ultrasound.

A disadvantage of typical marker techniques is the need to introduce invasive cannulae into the bloodstream, resulting in discomfort and risk to the subject, both whilst introducing and measuring the markers. There are also associated relatively significant costs.

A variant of the marker techniques utilises the Fick principle. Utilising the Fick principle it is possible to measure the flow rate of a stream by adding or subtracting a marker to/from the stream at a known rate and measuring the concentration of the marker upstream and downstream of the point of addition/subtraction of the marker. Thus, if the arterial and venous oxygen concentrations and the rate of oxygen uptake by the lung (and thus bloodstream), are known, pulmonary bloodflow rates cardiac output) may be calculated. Similarly cardiac output may be measured by way of a known carbon dioxide uptake by the lung and arterial and venous carbon dioxide concentrations.

Various methods of measuring cardiac output have previously been proposed utilising the Fick principle using carbon dioxide as the marker by adding carbon dioxide to the subject's lung (and thus bloodstream). The carbon dioxide is typically added by having the subject rebreathe a portion of expired (and thus carbon dioxide laden) air.

(I 1284994):PRW 00 Previously proposed carbon dioxide methods utilising rebreathing, however, are C typically relatively inaccurate. The rebreathing methods also require a relatively complicated valving arrangement to cause rebreathing and in-phase flow, and result in

D

Selevated breathing resistance to the patient and resultant discomfort.

Whilst direct injection of known quantities of carbon dioxide has been proposed to partly address these deficiencies of the rebreathing method, inaccuracies in measurement N of expired carbon dioxide volumes still significantly affect the accuracy of the calculated 00 Scardiac output.

00 10 Object of the Invention SIt is the object of the present invention to substantially overcome or at least ameliorate at least one of the above disadvantages.

Summary of the Invention In one aspect, the present invention provides a method of measuring cardiac output of a subject, said method comprising the steps of: a) measuring one or more quantitative characteristics of CO 2 expired by the subject in a steady state breathing condition.

b) delivering a quantifiable total quantity of CO 2 into the airway of the subject during the inspiratory phase of each breath of a series of breaths; c) measuring the duration of each said breath d) measuring one or more quantitative characteristics of CO 2 expired during each said breath e) for each said breath formulating an approximation of a first amount of said total quantity used to increase the quantity of CO 2 in the lungs of the subject; (ii) formulating an approximation of a second amount of said total quantity used to maintain and increase the quantity of CO 2 in the arterial system of the subject, as a function of cardiac output of the subject (CO); (iii) formulating an approximation of a third amount of said total quantity used to increase the quantity of CO 2 expired from the airway of the subject; (iv) calculating a sum comprising said first amount said second amount and said third amount and equating said sum with said total quantity thereby creating a single equation for each said breath and (1128499_4):PRW 0 0 f) solving a series of simultaneous equations defined by said single equation for each Ssaid breath to provide an estimate of said cardiac output (CO).

STypically, said total quantity of CO 2 is delivered into the airway of the subject by Sinjecting a discrete known quantity of C0 2 In a preferred form, the method further comprises, for each said breath, the step of formulating an approximation of a fourth amount being a breath duration irregularity C correction factor, said sum further comprising said fourth amount.

00 Typically, said one or more quantitative characteristics of CO 2 expired by the Ssubject in a steady state condition includes CO 2 partial pressure (pCO 2 00 10 Said one or more quantitative characteristics of CO 2 may be measured utilising inline or off-line capnography.

Typically, said method includes the step of determining end tidal CO 2 partial pressure (PETCO2) in said steady state breathing condition.

Typically, said method further comprises the step of measuring one or more quantitative characteristics of total gas volume expired in said steady state breathing condition.

Where off-line capnography is utilised, said method may further comprise the steps of: directing at least a portion of total gas volume expired during said steady state breathing condition through a mixing box to mix said gas volume expired; and subsequently determining CO 2 partial pressure (PMxC02) of the mixed expired gas.

Typically, said one or more quantitative characteristics of CO 2 expired by the subject during each said breath includes CO 2 partial pressure (pCO2).

Typically, said method includes, for each said breath the step of determining end tidal CO 2 partial pressure (PETCO2) of said breath In one form, said method includes the step of determining a volume of CO 2 expired by the subject during each said breath.

Typically, said method further comprises the step of measuring one or more quantitative characteristics of total gas volume expired during each said breath.

Typically, said first amount is formulated as a function of lung volume (VL) of the subject.

In one form, said first amount is approximated by: AL VL PETCO2(N) PETrCO2N-() ALuN) V L (1)

PAT

(1 1284994):PRW 0 0 where: SAL(N) said first amount (1)

SV

L lung volume at end of expiry phase of breath E pECO,) end tidal CO 2 partial pressure (mmHg) of the Nth breath; and p atmospheric pressure (mmHg).

Typically, said second amount (ABN)) is formulated as a function of the slope of a C CO 2 dissociation curve of the subject.

00 Typically, said slope is approximated as a function of end tidal CO 2 partial pressure O (pETCO2) and haemoglobin concentration Preferably, said haemoglobin 00 0o concentration is determined by analysing a blood sample of said subject.

O Typically, said second amount is formulated as a first component (ABI(N)) of said second amount used to increase the quantity of CO 2 in the arterial system and a second component (AB2(N)) of said second amount used to maintain the quantity of CO 2 in said arterial system above a quantity of CO 2 in the arterial system of the subject in the steady state condition.

In one form, said first component (ABIaN)) of said second amount is approximated by: ABI(N) 0.5 x CO x 60( (ETC2(N) PETCO 2 where: ABI(N) said first component of said second amount CO cardiac output (1/min); t(N) duration of Nth breath (s) slope of CO 2 dissociation curve at an average CO 2 partial pressure (pCO 2 of pCO 2 (ave) PETCO2() pTCO2(N-1) and haemoglobin 2 concentration (Hb) of the subject's blood (mlCO 2 /lblood/mmHg).

In one form, said second component (AB2(N)) of said second amount is approximated by: COx x ETCO2(N pETCO 2(0) xS- S ,o where: (1128499_4):PRW AB2(N) said second component of said second amount PEC02(o) end tidal C0 2 partial pressure in said steady breathing condition (mmHg).

S(N-I)

0 slope of CO 2 dissociation curve at pETCOZ(N-1 pE-CO2(0) pCr2(ave) C2 P 0 2 and prevailing haemoglobin concentration (Hb) of the subject's blood (mlCO 2 /lboood/mmHg).

Alternatively, said second component (AB2(N)) of said second amount may be approximated by: AB2(N) COx- (pETCO2i)- PETCO2(-)x S where:

A

82 said second component of said second amount PE7CO2(o) end tidal CO 2 partial pressure in said steady state breathing condition (mmHg).

slope of CO 2 dissociation curve at pCOO PETC0() and prevailing haemoglobin concentration (Hb) of the subject's blood (mlCO 2 /lboood/mmHg).

The third amount (AEN) may be approximated by: AE(N) VC02M VCO 2 (o) where: AEN) said third amount

VCO

2 total volume of CO 2 expired during Nth breath

VCO

2 total volume of CO 2 expired during a breath in said steady state breathing condition Where inline capnography is utilised, said third amount may be approximated by: S Fx x PXNCO2 _Fx x PxoCO 2 AE(N) J S PAT

PAT

where: FxN instantaneous expiratory total gas flow rate during Nth breath (1/min) (1128499_4):PRW 6 00 Fxo instantaneous expiratory total gas flow rate during a breath in said

O

0 steady state breathing condition (1/min) pXNC02 instantaneous expired CO 2 partial pressure during Nth breath

D

S(mmHg) s pxoCO2 instantaneous expired CO 2 partial pressure during a breath in said steady state breathing condition (mmHg).

C PAT atmospheric pressure (mmHg).

00 The breath duration irregularity correction factor (AD) may be approximated by: 60 0 o A C0 2 (o t( I-) where: V CO 2 0 average volume of CO 2 expired per minute during said steady state breathing condition (1/min), and is t(N) duration of Nth breath Where in-line capnography is utilised, V CO 2 may be approximated as: F x x p CO 2

PAT

where: Fx instantaneous expiratory total gas flow rate (1/min), pxC02 instantaneous expired CO 2 partial pressure (mmHg), PAT= atmospheric pressure (mmHg).

Where off-line capnography is utilised, V CO 2 may be approximated by:

VCO

2 0

(V

0 X PMxCO2(o) where: MV(o)= volume of total gases expired per minute during said steady state breathing condition (1/min).

PMxCO2(o) mixed expired CO 2 partial pressure during said steady state breathing condition (1/min).

(1128499_4):PRW 0 Where off-line capnography is utilised, said third amount may be Sapproximated by: A TV) PMxCO2( PETCO 2

ETCO

2 0 A =TV x x 0 E) PETCO 2

PAT

"1 where: 00 TVg.) total volume of gases expired during Nth breath SPMXC02(O) mixed expired CO 2 partial pressure in said steady state breathing 0 0 condition (mmHg); SC0 2 to alveolar to total ventilation ratio in said steady state breathing

PETCO

2 (o) condition.

Typically, said series of simultaneous equations are solved to provide an estimate of said lung volume.

In a second aspect, the present invention provides an apparatus for estimating cardiac output of a subject, said apparatus comprising: a breathing head defining a flow path and having a breathing interface for communicating said flow path with the airway of a subject; a CO 2 measurement system for measuring one or more quantitative characteristics of CO 2 expired by the subject during a breath; a CO 2 delivery system for delivering a quantifiable total quantity of CO 2 to said flow path; and a data processing and control system communicating with said CO 2 measurement system, and said CO 2 injection system, said data processing and control system being configured to: receive and record signals from said CO 2 measurement system; control said CO 2 delivery system to deliver a quantifiable total quantity of

CO

2 into said flow path during the inspiratory phase of each breath of a series of breaths of the subject; measure duration of each said breath; for each said breath: formulate an approximation of a first amount (AL(N))of said total quantity used to increase the quantity of CO 2 in the lungs of the subject; (1128499 4):PRW 00 (ii) formulate an approximation of a second amount of said total Squantity used to maintain and increase the quantity of CO 2 in the arterial system of the subject, as a function of cardiac output of the subject a)

S(CO);

(iii) formulate an approximation of a third amount of said total quantity used to increase the quantity of CO 2 expired from the airway of the subject; 00 (iv) calculate a sum comprising said first amount said second Samount and said third amount and 00 1o equate said sum with said total quantity thereby creating a single Sequation for each said breath and e) solve a series of simultaneous equations defined by said single equation for each said breath to provide an estimate of said cardiac output (CO) of the subject.

Typically, said apparatus further comprises a flow meter for measuring one or more quantitative characteristics of total gas volume expired by the subject during a breath, said data processing and control system communicating with said flow meter to receive and record signals from said flow meter.

In one form, said CO 2 measurement system comprises an in-line capnograph.

In another form, said CO 2 measurement system comprises an off-line capnograph.

In one form, said CO 2 measurement system further comprises a mixing box located in said flow path, said off-line capnograph being configured to selectively communicate with an output of said mixing box and a region of said flow path upstream of said mixing box.

Brief Description of the Drawings Preferred embodiments of the present invention will now be described, by way of an example only, with reference to the accompanying drawings wherein: Figure 1 is a flow chart of a method of measuring cardiac output of a subject; Figure 2 is a schematic representation of a first embodiment of an apparatus for measuring cardiac output; Figure 3 is a graph depicting a trace of CO 2 partial pressure over a series of breaths in a "steady state" condition; Figure 4 is a graph depicting a trace of total gaseous flow rate over a series of breaths in a "steady state" condition); (1 128499_4):PRW 00 Figure 5 is a graph depicting a trace of CO 2 partial pressure over a series of breaths Sincluding COz injection; SFigure 6 is schematic representation of a second embodiment of an apparatus for d Smeasuring cardiac output; Figure 7 is schematic representation of a third embodiment of an apparatus for measuring cardiac output; N Figure 8 is a schematic representation of a fourth embodiment of an apparatus for 00 measuring cardiac output.

SFigure 9 is a schematic representation of a CO 2 injection system.

00 10to Figure 10 is a schematic representation of an alternate actuator for the CO 2 injection Ssystem of Figure 9; Figure 11 is a schematic representation of a further alternate actuator for the CO 2 injection system of Figure 9; Figure 12 is a schematic representation of an alternate CO 2 injection system.

Figure 13 is a schematic representation of a modified version of the second embodiment apparatus of Figure 6.

Figure 14 is a schematic representation of a further modified version of the second embodiment apparatus of Figure 6.

Detailed Description of the Preferred Embodiments During the inspiratory phase of breathing, gas is drawn in through the trachea and bronchi and into the lungs, reaching the alveoli where the gas inspired is available for gas exchange with the bloodstream in the arterial system. During any breath, only part of the inspired gas will reach the lungs, constituting useful ventilation. The remainder of the inspired gas only reaches the "deadspace" of the trachea and bronchi and is effectively wasted, being expired during the expiratory phase of the breath.

When a subject inspires a quantity of carbon dioxide (C0 2 the basic principles of conservation of mass dictate that the entire quantity of inspired CO 2 is either transferred to the subject's arterial system via the alveoli, inspired into the lungs without subsequent transfer to the arterial system, or only inspired into the "deadspace" of the trachea and bronchi. The inspired CO 2 will thus increase the quantity of CO 2 in the arterial system, in the lungs, and/or expired during the expiratory phase of the breath.

The present inventors have determined that the amount of the inspired CO 2 that is utilised to change the quantity of CO 2 in each of the above three destinations can be approximated from formulae based on various quantitative characteristics of CO 2 expired (I 1284994):PRW o00 by the subject in a steady state condition (without C02 inspiration) and in each breath of a 0 Sseries of breaths during which CO 2 is inspired. If the quantity of CO 2 inspired is known, Sthe values calculated can be added and equated to the known quantity of CO 2 inspired for Seach breath of the series of breaths. This will provide a single equation for each breath.

The amount of inspired CO 2 that is utilised to increase CO 2 in the bloodstream can be expressed in terms of the subject's cardiac output which is the unknown that is i sought to be measured. Depending upon the formulae adopted and measurements taken, 00oO there may be one or more other unknowns in the equation. To enable solution of the equation with multiple unknowns, the measurement and calculation may be repeated over oO o10 a series of breaths so as to provide several simultaneous equations that may be solved by any of various non-linear numerical methods.

The amount of CO 2 inspired during any breath that is utilised to increase the quantity of CO 2 in the lungs can be determined by determining the quantity of CO 2 in the lung at the end of the breath, less the quantity of CO 2 in the lung at the end of the Is previous breath. As the end tidal CO 2 partial pressure (PET C0 2 being the airway CO 2 partial pressure (pCO 2 at the end of a given breath, is representative of the level of CO 2 in the lungs, this value may be approximated by: AL(N) V PETCO2(N) PECO2(N-I) (1)

PAT

where: AL(N) volume of CO 2 utilised to raise CO 2 quantity in lung in Nth breath (1) VL lung volume at end of expiry phase of breath PETCO02 end tidal CO 2 partial pressure (mmHg) of the Nth breath; and PAT atmospheric pressure (mmHg).

Whilst the lung volume (VL) will typically not be known, the end tidal CO 2 partial pressure (PET C0 2 of each breath may be readily measured by capnography as will be discussed below.

The only unknown on the right side of Equation 1 will thus be the lung volume The lung volume of a subject at the end of the expiry phase will, however, be relatively constant over an extended period of time and if it has previously been determined through another application of the present method, or some other analysis, the known lung volume can be readily applied to Equation 1. The lung volume (VL) is treated as a constant in this analysis.

(1 128499_4):PRW 00 The amount of CO 2 inspired during any breath that is utilised to maintain and increase the quantity of CO 2 in the arterial system can effectively be separated into two components. The first component is the amount of inspired CO 2 that is utilised to Sincrease the quantity of CO 2 in the arterial system compared to that of the previous breath.

The second component is the amount of inspired CO 2 utilised to maintain the quantity of

CO

2 in the arterial system at the level of the last breath, above the previous "steady state" level without CO 2 inspiration.

0o The first arterial system component may be approximated by: O AI( 0.5 x CO x x (PETCO2(N) PETCO2(u))x (2) (NN where: AI(N) volume of CO 2 utilised to raise CO 2 quantity in arterial system in Nth breath CO cardiac output (1/min); duration of Nth breath (s) S(N)(NI) slope of CO 2 dissociation curve at an average CO 2 partial pressure (pCO 2 of pCO 2 (ave) PETC2(N) PECO2(N-) and the prevailing 2 haemoglobin concentration (Hb) of the subject's blood (mlCO 2 /lblood/mmHg).

The cardiac output being the volume of blood pumped by the heart in a minute, is unknown and is the characteristic of the subject that is sought to be measured.

The cardiac output will remain relatively constant over a series of breaths, and hence can be treated as a constant in the analysis.

The haemoglobin concentration (Hb) of the subject's arterial system will typically not be known and may be determined by taking a sample of the subject's blood and measuring the haemoglobin concentration by standard methods.

The slope of the CO 2 dissociation curve can be calculated utilising the known equation: 1.34 x Hb +18.34 S (3) 1+ 0.193 x pCO 2 where: (1128499_4):PRW 00 S slope of CO 2 dissociation curve (mlCO 2 /lblood/mmHg) Hb haemoglobin concentration (g/dl) pCO 2

CO

2 partial pressure (mmHg) The only remaining unknown in Equation 2 for any given breath is thus cardiac S 5 output (CO).

The second arterial system component, being the amount of inspired CO 2 utilised to N1 maintain the quantity of CO 2 in the arterial system at the level of the last breath, above the 00 previous "steady state" level, can be approximated by: to A 8 2 =COx x X(PECO2(,)- PETCO2(0))xS(N-1,O (4a) or more accurately, by:

A

2 =COx xL (pCO 2 (i)-PETCO2(i-x

S(

1 (4b) =60 where: AB2(N) volume of CO 2 utilised to maintain CO 2 quantity in arterial system at level of last breath, above steady state level pE7CO2(o) end tidal CO 2 partial pressure in steady state (without CO 2 inspiration) (mmHg).

S(uN-).o slope of CO 2 dissociation curve at pCO2 PETCO 2

PTCO

2 and the prevailing haemoglobin concentration (Hb) of the subject's blood (mlCO 2 /lboood/mmHg).

The amount of CO 2 inspired during any breath that is utilised to increase the quantity of CO 2 expired over and above that expired at the "steady state" level can be approximated by: AE(N) VCO2(N) VCO 2 where: AEN) volume of CO 2 utilised to increase CO 2 expired over and above that expired during "steady state" breath (without CO 2 inspiration) VCO2(N) total volume of CO 2 expired during Nth breath (1128499 4):PRW 0 VC0 2 total volume of CO 2 expired during "steady state" breath (without

CO

2 inspiration) SWhere instantaneous expired CO 2 partial pressure (pxCO2) can be measured along l with instantaneous expired total flow rate such as when inline capnography is utilised as discussed below, the total volume of CO 2 expired during a breath (VCO 2 can be determined by cross multiplying and integrating the expiratory total flow rate (Fx) and N expired CO 2 partial pressure (pxCO2) across the breath, providing: 00

FOCO

VCO

2 p C 2 (6) 00

PAT

010 where:

VCO

2 total volume of CO 2 expired Fx instantaneous expiratory total flow rate (1/min); pxCO 2 instantaneous expired CO 2 partial pressure (mmHg).

1s AEN) may thus be expressed as: AE(N) F x PCO 2 FX x PoC0 2 (7a) E N J nJ PAT PAT where: FXN instantaneous expiratory total flow rate during Nth breath (1/min) Fxo instantaneous expiratory total flow rate during "steady state" breath (1/min) pxNCO instantaneous expired CO 2 partial pressure during Nth breath (mmHg) pxoCO2 instantaneous expired CO 2 partial pressure during "steady state" breath (mmHg).

Where CO 2 partial pressures are measured utilising off-line capnography, alternate equations, that will be discussed below, may be utilised to approximate AE(N).

If the total quantity of CO 2 inspired during the Nth breath is delivered by injecting a discrete, known quantity of C0 2 or otherwise delivering a quantity that may be readily quantified, this known quantity may then be equated with the sum of the various amounts of CO 2 calculated from Equations 1, 2, 4a or 4b, and 7a above, providing: A(N) AL(N) AB(N) AZB(N) AE() (8) (1128499_4):PRW 00 ^O where: AI(N) total quantity of CO 2 inspired during Nth breath.

SAssuming that the lung volume (VL) is not known, this provides a single equation 5 with two unknowns, being lung volume (VL) and cardiac output (CO).

Repeating the measurements over a series of breaths (with CO 2 inspiration) C provides several equations, which may be solved for the two unknowns so as to provide an approximation of the lung volume and (VL) and the cardiac output (CO).

0 A significant portion of the inspired C0 2 will be transferred to the 00 10 bloodstream in the arterial system (ABI(N) AB2(N)). The accuracy of calculation of Scardiac output will be strongly dependent on the accuracy of the inspired quantity of CO 2 If the CO 2 is thus injected into the airway as a discrete, known quantity or otherwise delivered as a quantity that may be readily quantified, cardiac output (CO) may be calculated relatively accurately compared to prior art methods that are highly dependent upon the accuracy of calculation of expired C0 2 volume (VCO 2 which accuracy is typically relatively low.

Figure 1 depicts a flow chart broadly describing a method of measuring cardiac output utilising the above described principles. Firstly, one or more quantitative characteristics of CO 2 expired by the subject are measured in a steady state breathing condition, being a condition without inspiry of CO 2 The quantitative characteristics of

CO

2 expired may include end tidal CO 2 partial pressure. A quantifiable total quantity of CO 2 is then delivered into the airway of the subject during the inspiratory phase of each breath of a series of breaths. The duration of each breath is measured. One or more quantitative characteristics of CO 2 expired during each breath of the series of breaths is measured. The quantitative characteristics of CO 2 expired may include end tidal CO 2 partial pressure.

Approximations of three separate amounts of the total quantity of CO 2 utilised are then formulated. A first amount of the total quantity of CO 2 is that used to increase the quantity of CO 2 in the lungs of the subject. A second amount of the total quantity of CO 2 is used to maintain and increase the amount of CO 2 in the arterial system of the subject as a function of cardiac output of the subject The third amount of the total quantity of CO 2 is used to increase the quantity of CO 2 expired from the airway of the subject. A sum comprising the first amount the second amount and the third amount is then calculated and equated with the quantifiable quantity of CO 2 delivered into the airway, thereby creating a single (I 128499_4):PRW 0 0 equation for each breath The series of simultaneous equations defined by the single Sequation for each breath is then solved to provide an estimate of cardiac output (CO).

When the breath duration of the subject is irregular, the volume of CO 2 delivered to aD the lung will vary. Accordingly, depending upon the irregularity in the breath duration, equation above will be subject to some error. This error may be accounted for by a breath duration irregularity correction factor, approximating the difference in volume of NC CO 2 delivered to the lungs as: 00 V C2Oo A, 0 2 0 (t (9) 00 where: V C0 2 average volume of CO 2 expired per minute during the steady state (1/min), and duration of the Nth breath Equation 8 can then be modified to allow for breath duration irregularities to provide: AIN) ALt(N) ABI(N AB2(N) AE(N) AD Where instantaneously expired CO 2 partial pressure (pCO2) can be measured along with instantaneous expired total flow rate, V CO 2 can be expressed as:

VCO

2 F X p X (11)

PAT

Where CO 2 partial pressures are measured utilising off-line capnography alternate equations, that will be discussed below, may be utilised to approximate V CO 2 The first embodiment of an apparatus for measuring cardiac output is depicted in Figure 2. The apparatus comprises a breathing head 10, CO 2 injection mechanism flow meter 30, CO 2 measurement system 40 and data processing and control system The breathing head 10 is here a handheld device suitable for use by non-entubated subjects breathing spontaneously. The breathing head 10 comprises a single tube 11 defining a single flow path 12. A breathing interface, in the form of a mouthpiece 13, is fitted to the proximal end 1 la of the tube 11 communicating with the flow path 12. The 128499_4):PRW 16 00 distal end 1 lb of the tube 11 is open to the atmosphere. The flow meter 30 is typically a

C

Sbi-directional flow meter of any suitable known form for measuring gaseous flow rates in both inspiration and expiration directions (that is, along the flow path 11 towards the mouthpiece 13 for inspiration and along the flow path 12 towards the trailing end 11 b of the tube 11 for expiration). The flow meter 30 may comprise static and dynamic ports connected to a differential pressure transducer and amplifier.

N, The CO 2 injection system 20 comprises a medical CO 2 supply 21 coupled to a CO 2 00oO injector 22. The CO 2 injector 22 communicates with the flow path 12 by way of a CO 2 delivery line 23.

00 10 The CO 2 measurement system 40 is in the form of an in-line capnograph 40 fitted to the tube 11 for measuring CO 2 partial pressure flowing along the flow path 12 during both expiratory and inspiratory flow. The capnograph 40 will typically be a standard capnograph utilising an infrared beam shining across the airstream for instantaneous recordal of CO 2 partial pressure (pCO2), however, any suitable form of inline capnograph may be utilised as desired. The capnograph 40 will typically be located between the CO 2 injector 22 and the distal end 1 lb of the tube 11 so as to avoid the possibility of contamination of the expired CO 2 signal by injected CO 2 The data processing and control system 50, which may be in the form of a simple handheld laptop or desktop computer system, is coupled to the CO 2 injector 22, flow meter 30 and capnograph 40. The data processing and control system 50 receives flow rate signals from the flow meter 30 and CO 2 partial pressure signals from the capnograph The data processing and control system 50 provides control signals to the CO 2 injector 22 to inject discrete known amounts of CO 2 into the flow path 12 at the appropriate time.

To measure the cardiac output of a non-entubated patient utilising the apparatus of Figure 2, the haemoglobin concentration (Hb) of the subject's arterial system is first determined by taking a sample of the subject's blood and subjecting it to standard analysis so as to determine the haemoglobin concentration. The standard units for haemoglobin concentration is grams per decalitre with typical values being of the order of 15g/dl. The haemoglobin concentration (Hb) is utilised in Equation 3 to determine the slope of the CO 2 dissociation curve.

The mouthpiece 13 is placed in the mouth of the subject and gripped between the subject's teeth. A noseclip may be placed on the subject's nose to occlude the nasal airway, such that all ventilation occurs through the mouthpiece 13.

(I 1284994):PRW 0 The subject then begins to breathe reciprocally through the mouthpiece 13. The

SCO

2 partial pressure (pCO2) in the flow path 12 is then continuously monitored by the ,C capnograph 40 whilst the total gaseous flow rate in the flow path 12 is continuously Smonitored by the flow meter 30. Typical graphs of both total gaseous flow rate over time and CO 2 partial pressure (pCO2) over time, measured in the "steady state" without injection of C0 2 are depicted in Figures 3 and 4. The end tidal CO 2 partial pressure C (PETCO2) is the CO 2 partial pressure (pCO 2 at the end of the expiratory phase of each

OO

r breath. This can be readily identified by the data processing and control system Smonitoring the CO 2 partial pressure (pCO2) as the CO 2 partial pressure (pCO 2 00 to immediately prior to a sudden decrease in CO 2 partial pressure (pCO2) which occurs at Sthe end of the expiratory phase of each breath.

The breath duration can be readily assessed for each breath either by assessing the time between the sudden drop off of CO 2 partial pressure (pCO2) between each subsequent breath, which marks the onset of the inspiratory phase of the next breath, or alternatively by directly measuring the time between the onset of inspiratory phases of subsequent breaths using the flow meter, as the flow direction changes at the onset of inspiration. The expired volume of CO 2

(VCO

2 may also be determined for each breath by cross-multiplying and integrating the flow rate and CO 2 partial pressure (pCO2) during the expiratory phase of each breath (see Equation 6 above).

The steady state end tidal CO 2 partial pressure (pETCO2) will typically be taken as a running average of several breaths, typically about five breaths. While quietly breathing, the end tidal CO 2 partial pressure (PETCO2) will typically be stable in a normal subject at approximately 40 mmHg. While quietly breathing, the breathing rate will typically be stable at about ten to twelve breaths per minute, giving a breath duration of approximately 5-6 seconds. The amount of CO 2 expired per minute V CO 2 may be evaluated by integrating the expired volume of CO 2 per breath over one minute as a running average. While quietly breathing, the amount of CO 2 expired per minute (V CO for a normal subject will typically be about 0.2 1/min. To assist in stabilising the subject's steady state breathing, the data processing and control system 50 may be configured to provide a periodic audio or visual signal to assist in giving regular cadence to the subject's breathing.

The data processing and control system may also be configured to provide real-time displays of the end tidal CO 2 partial pressure (PET CO2), breath duration CO 2 expired per breath (VCO 2 and CO 2 expired per minute (V CO 2 These figures will (1128499_4):PRW 00 also be retained in the memory of the data processing and control system 50 for later Sanalysis.

With the various steady state measurements having been taken, the subject's Sbreathing is pertubated by injecting a discrete known quantity of CO 2 during the inspiration phase of a series of breaths by way of the CO 2 injector 22. The CO 2 injection process is commenced by way of a manual control interfaced with the data processing and C control system 00 The data processing and control system 50, which is monitoring the total flow rate C(F) and CO 2 partial pressure (pCO2) in the flow path 12, controls the injection of each 00 lo dose of CO 2 into the flow path 12. The data processing and control system 50 controls the CO 2 injector 22 to inject the dose of CO 2 during the early part of the inspiratory phase of each breath, as gas inspired during the early part of the inspiratory phase will typically reach the alveoli of the lungs where gas exchange with the arterial system may take place.

Gas inspired during the last part of the inspiratory phase will typically only go to the "deadspace" of the trachea and bronchi. To ensure that the dose of CO 2 is injected at the ideal time, the drop in CO 2 partial pressure (pCO 2 measured by the capnograph 40 may be utilised as a trigger signal. A suitable trigger would be a fall of the CO 2 partial pressure (pCO 2 below approximately 20 mmHg. Alternatively, the flow meter 30 could be utilised to assess when the inspiratory phase of a new breath takes place, when the flow direction changes to the inspiratory direction, perhaps to above a threshold flow rate.

The typical injected volume of CO 2 for each breath would be between 5 and For a subject with a total tidal flow of the order of 500ml per breath, the typical injected volume of CO 2 would be of the order of 10ml. For young, old, and/or small subjects the injected volume of CO 2 may be less than 10ml, whilst for large subjects the injected volume may be in excess of 10ml. A suitable method of assessing appropriate injected volumes of CO 2 is discussed further below.

The capnograph 40 and flow meter 30 continue to continuously measure CO 2 partial pressure (pCO 2 and total flow rate for each subsequent breath during the CO 2 injection process. End tidal CO 2 partial pressure (PETCO2), breath duration CO 2 expired per breath (VCO 2 and CO 2 expired per minute I CO 2 are determined by the data processing and control system 50 as discussed above in relation to the steady state.

The data processing and control system 50 will typically continue to control the

CO

2 injector 22 to inject a dose of CO 2 for each subsequent breath until the earlier of a set time having elapsed or with the end tidal CO 2 partial pressure (PET C0 2 having stabilised.

Typically, the end tidal CO 2 partial pressure (PETCO2) will rise with each subsequent (I 1284994):PRW 19 0 breath during CO 2 injection to a total rise of the order of 5 to 8 mmHg during the course

C

Sof five to eight breaths, by which time the end tidal CO 2 partial pressure (PETCO2) will d have asymptoted to a new steady state value. An appropriate measure as to when the end Stidal CO 2 partial pressure (PETCO2) has stabilised is when three sequential breaths have a measured end tidal CO 2 partial pressure (PETCO2) within 0.3 mmHg. Figure 5 depicts a typical graph of CO 2 partial pressure over time, starting with steady state breathing N, followed by a series of breaths during which CO 2 is injected, elevating the end tidal CO 2 00oO partial pressure (pETCO2) from the steady state value (PETCO2(0)) over several breaths to an elevated stabilised level.

00 io After approximately 30 to 45 seconds, the injected CO 2 will appear in the venous Ssystem, by recirculation throughout the subject's blood system. Such appearance of the injected CO 2 in the venous system will disrupt the mathematical models of the equations discussed above, resulting in potentially erroneous calculations. Accordingly, if the end tidal CO 2 partial pressure (PETCO2) has not already stabilised, the data processing and Is control system 50 should disable the CO 2 injector 22 if approximately 45 seconds has elapsed.

Once the CO 2 injector 22 has been disabled, the end tidal CO 2 partial pressure (PETCO2) will fall back to the initial steady state value over a few breaths.

The various measurements taken and transmitted to the data processing and control system 50 during both the "steady state" breathing and subsequent series of breaths with

CO

2 injection can then be applied to Equation 8 (or Equation 10 if breath duration irregularity is being considered) so as to provide a series of simultaneous equations in which lung volume (VL) and cardiac output (CO) are the only unknowns. These equations may then be solved by the data processing and control system 50 using any suitable non-linear numerical methods such as a least squares fit method. The results will provide an estimate of the cardiac output (CO).

A second embodiment of an apparatus for measuring cardiac output is depicted in Figure 6. The apparatus of Figure 6 incorporates a respirator 160 and is suitable for use by subjects requiring assisted or controlled ventilation. The apparatus comprises a breathing head 110, CO 2 injection mechanism 20, flow meter 30, CO 2 measurement system 40, data processing and control system 50 and the respirator 160. The respirator 160 may also be part of an anaesthetic circuit.

The breathing head 110 is Y-shaped and includes a stem 111 defining a common flow path 112 and having a mouthpiece 113 (or ventilation mask) fitted to the proximal end 11 la of the stem 111. An inspiratory limb 114 of the breathing head 110 defines an (11284994):PRW 00 inspiratory flow path 115 whilst an expiratory limb 116 of the breathing head 110 defines an expiratory flow path 117. The stem 111, inspiratory limb 114 and expiratory limb 116 are joined to define the Y-shape of the breathing head 110 and to communicate the combined flow path 112, inspiratory flow path 115 and expiratory flow path 117. The inspiratory flow path 115 is further defined by an inspiratory line 118 coupled at opposing ends to the inspiratory limb 114 and the inspiratory valve 161 of the respirator 160. The 00 expiratory flow path 117 is further defined by an expiratory line 119 connected at 00 opposing ends to the expiratory limb 116 and the expiratory value 162 of the respirator.

The flow meter 30 may be mounted in the stem 111, for measuring gaseous flow 00 1 rates in both inspiratory and expiratory directions along the common flow path 112.

SAlternatively, if fitted, an integral flow meter within the respirator 160 or other equipment associated with the respirator circuit may be utilised to measure flow rates. As another alternative, separate flow meters could be fitted to the inspiratory limb 114 and expiratory limb 116.

The CO 2 measurement system 40 is in the form of an in-line capnograph 40 which is again mounted on the stem I 11, or alternatively, on the expiratory limb 116 or expiratory line 119 to enable measurement of CO 2 partial pressures in the expiratory phase of each breath. Locating the capnograph 40 on the expiratory limb 116 or expiratory line 119 will avoid contamination of the expired CO 2 signal by the injected

CO

2 If the respirator 160 or other equipment associated with the respirator circuit is fitted with an integral in-line capnograph, there will be no need for an additional in-line capnograph on the breathing head 110 or expiratory line 119.

The CO 2 injection system 20 comprises a medical CO 2 supply 21 coupled to a CO 2 injector 22 as per the apparatus of the first embodiment depicted in Figure 2. The CO 2 injector 22 communicates with the common flow path 112, or alternatively with the inspiratory flow path 115, by way of the CO 2 delivery line 23.

The data processing and control system 50 is in the same basic form as that described above in relation to the apparatus of the first embodiment and will be coupled to the respirator 160 if the integral flow meter and/or capnograph of the respirator 160 are utilised. Operation of the apparatus to measure cardiac output is also essentially the same as discussed above in relation to the apparatus of the first embodiment, although no separate noseclip will typically be utilised.

Whilst the use of an in-line capnograph is ideal, given that it allows for direct integration of measured flow rates and measured CO 2 partial pressures (pCO 2 so as to provide expired volumes of CO 2

(VCO

2 it is envisaged that the present methods may (I 1284994):PRW also be carried out with the use of off-line (sidestream) capnographs, which may be the Sonly type of capnograph available to the medical practitioner carrying out the method.

A third embodiment of an apparatus for measuring cardiac output, utilising off-line Scapnography, is depicted in Figure 7. This apparatus comprises a breathing head 210,

CO

2 injection mechanism 20, flow meter 30, CO 2 measurement system 240 and data processing and control system 250.

The breathing head 210 is here a handheld device suitable for use by non-entubated 00oO subjects breathing spontaneously. The breathing head 210 is Y-shaped and includes a Sstem 211 defining a common flow path 212 and having a mouthpiece 213 fitted to the oO lo proximal end 211 a of the stem 211. An inspiratory limb 214 of the breathing head 210 Sdefines an inspiratory flow path 215 whilst an expiratory limb 216 of the breathing head 210 defines an expiratory flow path 217. The stem 211, inspiratory limb 214 and expiratory limb 216 are joined to define the Y-shape of the breathing head 210 and to communicate the combined flow path 212, inspiratory flow path 215 and expiratory flow is path 217.

The distal end of the inspiratory limb 214 is fitted with a one-way inspiratory valve 218 which allows air to be inspired from atmosphere into the breathing head 210 during the inspiratory phase of breathing, but prevents expiry of gases back through the one-way inspiratory valve 218 to atmosphere during the expiratory phase. A one-way expiratory valve 219 is fitted to the distal end of the expiratory limb 116 to allow expired gases to pass therethrough whilst preventing gases being inspired into the breathing head 210 during inspiration.

The CO 2 injection system 20 comprises a medical CO 2 supply 21 coupled to a CO 2 injector 22 as per the apparatus of the first embodiment depicted in Figure 2. The CO 2 injector 22 communicates with either the common flow path 212 or inspiratory flow path 215 by way of the CO 2 delivery line 23.

The flow meter 30 will typically be mounted in the stem 211, for measuring gaseous flow rates in both inspiratory and expiratory directions. Alternatively, separate flow meters could be mounted in the inspiratory limb 214 and expiratory limb 216.

The CO 2 measurement system 240 comprises an off-line capnograph 241, mixing box 242 and solenoid valve 243. The mixing box 242 is fitted with a series of baffles 248 that interrupt the flow path through the mixing box 242 so as to effectively homogenise gases passing through.

The inlet 242a of the mixing box 242 communicates with the expiratory flow path 217 by way of an expiratory line 244. The outlet 242b of the mixing box 242 (I 1284994):PRW 22 0 communicates with the atmosphere and with a first inlet 243 of the solenoid valve 243 by way of a mixing box sampling line 245. A second inlet 243b of the solenoid valve 243 Scommunicates with the expiratory flow path 217 (or alternatively the combined flow path S212 by way of an expiratory flow path sample line 246. The inlet 241a of the s capnograph 241 communicates with the outlet 243c of the solenoid valve 243 by way of a capnograph input line 247. The outlet 241 b of the capnograph 241 communicates with the 00 atmosphere.

00 To measure the cardiac output of a non-entubated subject utilising the apparatus of O Figure 7, the haemoglobin concentration (Hb) of the subject's arterial system is first 00 10 determined in the same manner as discussed above.

0 The mouthpiece 213 is placed in the mouth of the subject and gripped between the subject's teeth and a noseclip placed on the subject's nose as discussed above.

The subject then begins to breathe reciprocally through the mouthpiece 213.

During the inspiratory phase, air is inspired from atmosphere through the one-way is inspiratory valve 218. During the expiratory phase, expired gases are expired through the one-way expiratory valve 219 and into the mixing box 242. The gaseous flow rate in the combined flow path 212 is continuously monitored by the flow meter The data processing and control system 250 switches the solenoid valve 243 to alternatively communicate the mixing box sample line 245 and the expiratory flow path sample line 246 with the capnograph inlet line 247. Accordingly, the off-line capnograph 241 samples gases from the mixing box 242 and directly from the expiratory flow path 217 via the expiratory flow path line 246. The gaseous sample taken directly from the expiratory flow path 217 is analysed by the capnograph 241 for instantaneous CO 2 partial pressures (pCO2). However, given that the off-line capnograph 241 is well downstream of the flow meter 30, there is a transport delay in expired gases before they reach the offline capnograph 241 as compared to when they reach the flow meter 30. Accordingly, the

CO

2 partial pressure (pCO2) readings taken by the off-line capnograph 241 from the expiratory flow path 217 cannot be directly multiplied and integrated with the measured flow rates to determine expired volumes of CO 2

(VCO

2 The CO 2 partial pressure (pCO2) measured by the off-line capnograph 241 from the expiratory flow path samples are only used to determine end tidal CO 2 partial pressure (PETCO2) and breath duration (t0N)) in the same manner as described above in relation to the apparatus of the first embodiment depicted in Figure 2.

The mixing box 242 effectively homogenises the expired gas passing through the mixing box 242 over several breaths. The resultant CO 2 partial pressure measured by the (1128499_4):PRW 00 0 off-line capnograph 241, termed the mixed expired CO 2 partial pressure (pMxCO2), is thus N, effectively an average of the CO 2 partial pressure over time. The mixed expired CO 2 Spartial pressure (pMxCO2) will remain relatively constant in the steady state condition and Swill gradually rise during and immediately following breaths during which CO 2 is s injected.

During "steady state" breathing, with CO 2 injection, the "steady state" end tidal 00 CO 2 partial pressure (pETCO2) is taken as a running average over several breaths. Expired 00 volume of CO 2 per breath (VCO 2 is not evaluated in the steady state when using off-line capnography. Instead, the mixed expired CO 2 partial pressure (PMxCO2) is measured.

00 00 0 It will take some time for the mixed expired CO 2 partial pressure (PMx CO 2 to drop Sback down to the steady state value after any period of CO 2 inspiration. Accordingly, when determining steady state mixed expired CO 2 partial pressure (pMxCO2(o)) after a period of CO 2 inspiration, sufficient time should be allowed after the end of the CO 2 inspiration to allow the mixed expired CO 2 partial pressure to drop back down to the is steady state level before commencing measurement. A delay period of approximately four time constants of the mixing box will typically be suitable, with one time constant being equal to the volume capacity of the mixing box 242 divided by the minute volume For a typical mixing box capacity of 4 litres and minute volume of 5 litres/min, this gives a time constant of 48 seconds. Thus, a delay period of about 3 minutes should be provided after any CO 2 inspiration before taking any steady state mixed expired CO 2 measurements.

Once steady state measurements have been taken, the subject's breathing is perturbated by injecting a discrete known quantity of CO 2 during the inspiration phase of each of a series of breaths by way of the CO 2 injector 22 as described above in relation to the first embodiment depicted in Figure 2. The CO 2 injection process is first commenced by a manual control, and is then controlled by the data processing and control system 250.

The CO 2 is again injected during the early part of the inspiratory phase. Given that the expired CO 2 partial pressure (pCO 2 measurements taken by the off-line capnograph 241 are transport delayed, the sudden drop off in CO 2 partial pressure is not a suitable trigger for CO 2 injection. Instead, the flow rate signals from the flow meter 38 are utilised as a trigger signal, when a reverse in flow indicating the onset of the inspiratory phase of a new breath is detected. During the series of breaths involving CO 2 injection, the data processing and control system 250 switches the solenoid valve 243 to communicate the expiratory flow path sample line 246 with the capnograph inlet line 247, allowing measurement of the end tidal CO 2 partial pressure (PETCO2) for each breath.

(I 128499.4):PRW 24 0 Utilising the off-line capnographic system, Equation 7a, approximating the amount Sof CO 2 inspired during any breath that is utilised to increase the quantity of CO 2 expired

(VCO

2 over and above that expired at the "steady state" level, may be replaced by an AC equation based on the alveolar to total ventilation ratio as follows: AE) TV(N) PMxCO 2 0

PETCO

2

PETCO

2 (0) AE(N) -V x x (7b) C PET 2(0) PAT 00 where: 0 0 TV(N tidal volume of the Nth breath, being the total volume of gases expired during the Nth breath; pMxC02(0) mixed expired CO 2 partial pressure in steady state condition; PMxC02(0) alveolar to total ventilation ratio in steady state condition.

PETCO

2 (0) The above equation 7b assumes that the alveolar to total ventilation ratio remains constant at the steady state level, even during CO 2 inspiration. In general, this assumption should be relatively accurate.

Tidal volume of the Nth breath can be readily determined by integrating the expiratory flow rate (Fx) measured by the flow meter 30 over the duration of the breath as follows: TV,, Fx(, (12) Equations 1, 2 and 4a or 4b are used to calculate ALtN), ABI(N) and AB2() in the same manner as described above in relation to the apparatus of the first embodiment depicted in Figure 1. Equation 7(b) above is used to calculate AE(N) for each of the series of breathes for which CO 2 is inspired.

Equation is then again applied to equate the total quantity of CO 2 inspired during the Nth breath to the sum of the various amounts of CO 2 calculated from Equations 1, 2, 4a or 4b, and 7b and the simultaneous equations resulting are again solved for the two unknowns of lung volume (VL) and cardiac output (CO) in the same manner as described above in relation to operation of the apparatus of the first embodiment depicted in Figure 1.

If the breath duration of the subject is irregular, and the resulting variance in volume of CO 2 delivered to the lungs is to be accounted for, Equation 10 is again applied.

(1128499_4):PRW 00 o The average volume of CO 2 expired per minute during the steady state, CO 2 used in Equation 9 can be estimated by: SC0 20 MV(o x pC0 2 0 (13) where: oO MV(o)= steady state minute volume, being the volume of total gases expired Sper minute during steady state (1/min).

0 The volume of gas expired per minute, referred to as the minute volume, may be oO 1o readily determined by integrating the expiratory flow rate (Fx) over time.

SEquation 10 is then utilised to allow for the breath duration irregularities in the same manner as described above in relation to the operation of the apparatus of the first embodiment depicted in Figure 2.

Off-line capnography can also be utilised for subjects requiring assisted or Is controlled ventilation. Figure 8 depicts a fourth embodiment of an apparatus for measuring cardiac output which incorporates a respirator 160, breathing head 110, CO 2 injection system 20 and flow meter 30, as described above in relation to the second embodiment depicted in Figure 6. The apparatus also incorporates a CO 2 measurement system 240 as described above in relation to the third embodiment depicted in Figure 7.

The fourth embodiment is thus effectively a combination of the second and third embodiments. Features of the apparatus of Figure 8 that are common to the second or third embodiments are thus indicated with common reference numerals in Figure 8.

In the apparatus of Figure 8 the inlet 242a of the mixing box 242 communicates with the outlet valve 163 of the respirator 160 rather than the one-way expiratory valve 219 utilised in the third embodiment of Figure 6. The expiratory valve 161 of the respirator 160 otherwise effectively replaces the one-way expiratory valve 219.

Similarly, the one-way inspiratory valve 218 of the third embodiment of Figure 7 will effectively be replaced by the inspiratory valve 161 of the respirator 160. The expiratory flow path sample line 246 is communicated with the expiratory line 119 or alternatively the expiratory limb 116 of the breathing head 110. The apparatus of Figure 8 is operated in much the same way as the third embodiment depicted in Figure 7 but utilising the respirator 160 to assist ventilation.

The CO 2 injection system 22 used in each of the above described embodiments may take any of various forms. Referring to Figure 9, the CO 2 injector 22 may be in the form of an injector cylinder 24 housing a longitudinally displaceable injector piston 25. The (I 128499_4):PRW 0 injector cylinder cavity 26 communicates with an atmospheric pressure reservoir 27 that Sis filled with medical CO 2 from the medical CO 2 supply 21 via a pressure regulator 28. A first non-return or on/off valve 29a is located between the reservoir 27 and the injector Scylinder cavity 28. A second non-return or on/off valve 29b is located in between the cylinder cavity 26 and the relevant flow path 12, 112, 212 in the breathing head.

The injector piston 25 is here actuated by a linear actuator in the form of an 00 electromagnetic actuator 80 coupled to the injector piston 25 by a piston rod 81. The 00 electromagnetic actuator 80 is controlled by the data processing and control system S250 to withdraw the injector piston 25 during the expiratory phase of the subject's breath, 00 io thereby drawing a dose of CO 2 into the cavity 26, and to advance the injector piston Sduring the expiratory phase to inject the fixed quantity of CO 2 A stop 82 engages a flange 83 extending from the piston rod during withdrawal of the piston 25, so as to control the precise quantity of CO 2 drawn into the cavity 26, and thus control the quantity of CO 2 injected into the flow path. The stop 82 may be controlled by the data processing and control system 50, 250, being displaceable to a position that provides the desired quantity of CO 2 Rather than employing a separate stop 82, the data processing and control system 50, 250 may directly control the electromagnetic actuator 80 to stop at a pre-set position corresponding to the required quantity of CO 2 in the injector cylinder cavity 26.

An alternative to the electromagnetic actuator 80 is a double-ended pneumatic actuator 180 as depicted in Figure 10. The pneumatic actuator 180 has an actuator cylinder 181 housing an actuator piston 182 that is connected to the injector piston 25 by way of the piston rod 81. The upper actuator cavity 183a of the cylinder 181 communicates with a pneumatic pressure supply 184 by way of a first solenoid valve 185 whilst the lower actuator cavity 183b of the cylinder 181 communicates with the pneumatic pressure supply 184 by way of a second solenoid valve 186. The first and second solenoid valves 185, 186 are controlled by the processing and control system 250 to drive the actuator piston 182 towards the injector cylinder 24 for CO 2 injection and away from the injector cylinder 24 for reloading of the injector cavity 26 with CO 2 during the expiratory phase of breathing. The rate of delivery of CO 2 may be regulated via a variable pneumatic resistor 187, controlling the rate at which the actuator piston 182 is driven towards the injector cylinder 24. The variable pneumatic resistor 187 will also be controlled by the data processing and control system 50, 250.

A further alternative actuator, depicted in Figure 11, is in the form of a rack and pinion drive 280, comprising a linear rack 281 driven by a rotating pinion 282.

(I 128499.4):PRW 00 An alternative CO 2 injector 322 is depicted in Figure 12. The CO 2 injector 322 is

C

Sin the form of a pneumatic capacitor 323 and resistor 324 coupled to a regulated pressurized CO 2 supply 21 (for example in the form of a gas cylinder) by a solenoid valve S325. The data processing and control system 50 controls the solenoid valve 325 so as to precisely control the timing and amount of CO 2 injected.

Rather than actively injecting a fixed quantity of CO 2 with a CO 2 injector, it is 00 envisaged that CO 2 laden air expired during the expiratory phase of any given breath may oO be utilised during the inspiratory phase of the next breath so as to deliver required CO 2 to the subject's airways. Utilising the expired gases in a subsequent breath would be 00 1o acceptable, so long as the quantity of CO 2 contained in the volume of expired gases that are subsequently inspired is readily quantifiable.

This may be achieved by inspiring a portion of the expired gases from a given breath having a known fixed volume and known or quantifiable CO 2 partial pressure. A modified version of the apparatus of the second embodiment configured to utilise expired gases in such a manner is depicted in Figure 13. Features of the apparatus of Figure 13 that are common with the apparatus of the second embodiment depicted in Figure 6 are provided with identical reference numerals. The apparatus of Figure 13 is identical to the apparatus of Figure 6, apart from the omission of the CO 2 injection mechanism 20 which is effectively replaced by a CO 2 delivery system 420. The CO 2 delivery system 420 comprises a two-way valve 422 which is mounted in line with the inspiratory line 118 of the inspiratory flow path 115. The two outlets of the two-way valve 422 are respectively coupled to the inspiratory line 118 and a transfer line 433 which communicates with the expiratory line 119. The two-way valve 422 is controlled by the data processing and control system 50. During the expiratory phase of each breath, CO 2 laden expired air passes along the expiratory flow path 117 through the expiratory line 119 and into the respirator 162. At the end of the expiratory phase of the breath, and commencement of the inspiratory phase of the next breath, the expiratory valve 162 is closed such that the expiratory flow path 117 remains filled with CO 2 laden expired air. With this portion of the expired breath representing the last portion of the expired breath, it has a CO 2 partial pressure approximately equal to the end tidal CO 2 partial pressure (PETCO2). Whilst there will be some variation in the CO 2 partial pressure at this portion of the expired breath, given that the CO 2 partial pressure asymptotes toward the end tidal CO 2 partial pressure (PETCO2), the end tidal CO 2 partial pressure (PETCO2) is a good approximation of the average CO 2 partial pressure of this portion of the expired breath, which will typically have a volume of 200 to 300 mis in typical respirator circuits. For breaths where CO 2 (I 1284994):PRW 0 inspiry is desired, the two-way valve 422 is switched at the commencement of the inspiratory phase to communicate the respirator end of the inspiratory line 118 with the Sexpiratory line 119 via the transfer line 423 such that the effective inspiratory flow path is d Sthrough the expiratory flow path 117. Accordingly, the CO 2 laden air located in the Sexpiratory flow path between the outlet of the transfer line 433 and the Y-junction of the breathing head 110 is inspired by the patient during the initial phase of inspiry. With the CI volume of the expiry flow path 117 between the transfer line 433 and Y-junction of the 00 breathing head 110 being known, the volume of additional C02 being inspired per breath can be determined as:

CI

00 1 Al PETCO2(N-I) (14) cA (14)

PAT

where: AIoN) volume of CO 2 inspired during nth breath VE volume of expiry line between transfer line and Y-junction PEPC02(N- end tidal partial pressure (mmHg) of the (nth 1 breath); PAT= atmospheric pressure (mmHg).

The volume of expiratory line utilised in Equation 14 does not include the volume of the stem 111 downstream of the Y-junction of the breathing head 110, given that any

CO

2 in the stem would be inspired by the patient whether the effective inspiratory line is through the expiratory line 117 or inspiratory line 115, so use of the two-way valve 422 does not result in any further addition of CO 2 through the stem.

This apparatus as depicted in Figure 13 thus avoids the need for a separate CO 2 supply and injection mechanism, although it does becomes more reliant on the accuracy of the CO 2 partial pressure measurements during the expiratory phase.

A further alternate modified version of the apparatus of the second embodiment is depicted in Figure 14. Again, features of the apparatus of Figure 14 that are common with the apparatus of Figure 6 are provided with identical reference numerals. In the apparatus of Figure 14, the CO 2 injection system 20 is replaced with a CO 2 continuous flow delivery system 520. The CO 2 continuous flow delivery system 520 is here in the form of a pressurised CO 2 supply 21 coupled to a mass flow controller 522. The mass flow controller 522 communicates with the inspiratory line 118 by way of a CO 2 delivery line 23. The mass flow controller is controlled by the data processing and control system to provide a constant delivery of CO 2 to the inspiratory line 118 at a constant known flow rate during the period over which CO 2 inspiry is desired. During the expiratory phase of any breath, whilst the inspiratory valve 161 of the respirator 160 is closed, CO 2 (11284994):PRW 00 delivered by the mass flow controller 522 into the inspiratory line 118 will gradually build up in the inspiratory line 118, whilst expired breath expired by the patient will pass Sthrough the expiratory flow path 117 and into the respirator 160 by way of the expiratory Svalve 162 in the usual manner. To ensure that CO 2 delivered to the inspiratory line 118 by the mass flow controller 522 does not migrate through the breathing head into the expiratory line 119, it is preferred that the mass flow controller 522 be positioned on the N inspiratory line 118 toward the inspiratory valve 161. The volume of CO 2 accumulated in 00 the inspiratory line during the expiratory phase of any given breath would typically only Sbe of the order of 5 ml, such that there would only be a negligible pressure build up in the to inspiratory line 118 which would have a volume of 200 to 300 mls in a typical respiratory Scircuit. During the inspiratory phase of the next breath, the CO 2 delivered to the inspiratory line 118 by the mass flow controller would be inspired by the patient, along with the additional volume of CO 2 delivered by the mass flow controller during the inspiratory phase. The total volume of CO 2 inspired during any given breath can thus be Is quantified as the known CO 2 delivery flow rate multiplied by the total time of the inspiratory phase and the previous expiratory phase.

As described above, the volume of CO 2 injected may be determined based on one or more physiological characteristics of the subject such as, for example, age, height, mass and/or sex. If only a small quantity of CO 2 is injected per breath, the end tidal CO 2 partial pressure (pETCO2) will rapidly stabilise at a fixed elevated amount perhaps after only 2 or 3 breaths, such that no further CO 2 will be added to the lungs resulting in Equation 1, defining the amount of CO 2 inspired to increase the quantity of CO 2 in the lungs, to be equal to 0. With no CO 2 being added to the lungs, no additional CO 2 will be transferred to the bloodstream to further elevate the quantity of CO 2 in the arterial system, resulting in equation 2 equating to 0. Accordingly, a sufficient quantity of CO 2 should be injected per breath to provide a significant increase in the new elevated end tidal CO 2 partial pressure equilibrium, such that CO 2 will continue to be transferred to the bloodstream over several breaths, further elevating the quantity of CO 2 in the arterial system.

Assuming a regular respiratory rate, and at fixed total expiratory volume per breath fixed ventilation) and ignoring the increased expiratory volume of CO 2 that results from the elevated end tidal CO 2 partial pressure (PET C0 2 the required amount of CO 2 injected per breath to raise the end tidal CO 2 partial pressure by a desired amount, may be approximated by: (I 128499_4):PRW 00 t A,(N =CO x 0 ETC2(E) -ETCO2))x S(o Swhere: AI() volume of CO 2 injected per breath CO estimated cardiac output (1/min); C t) duration of breath 00 l. pE7CO2(E) desired elevated end tidal CO 2 partial pressure equilibrium S(mmHg); 00 pE7CO2(o) end tidal partial pressure at "steady state" level (mmHg); S o S slope of CO 2 dissociation curve at an average end tidal CO 2 partial pressure of pCO 2 ave PETC2(N) PETC2(0) and the prevailing haemoglobin 2 concentration (Hb) of the subject's blood (mlCO 2 /lblood/mmHg).

If this equation is applied to a subject aged forty years, having a height of 182cm and a mass of 80kgs, a respiratory rate of ten breaths per minute, a "steady state" end tidal

CO

2 partial pressure (PET CO 2 of 40 mmHg, and (haemoglobin concentration (Hb) of 12g/dl) the amount of CO 2 that will need to be injected in each breath to raise the end tidal CO 2 partial pressure (PET CO 2 to a new stabilised equilibrium level or 45 mmHg may be calculated as follows: Firstly, the body surface area may be estimated as: BSA M725x 0.007184 (16) where: BSA body surface area (m2); M mass H= height This example provides BSA 2.01 m 2 The normal resting cardiac output, based on age and body surface area, may be estimated from the following equation: CO CI, x BSA (17) where: (1 128499_4):PRW SClage normal resting cardiac index 4.5 x (0.

9 9 )(age For the example, this provides an estimated cardiac output (CO) of 7.03 1/min.

These figures can then be applied to equation (14) above to provide a required Cvolume of CO 2 injected per breath of approximately 13.1 mls per breath.

5 In a second example of a subject aged 80 years with a height of 150 cm and mass of 48 kg, again breathing at a respiratory rate of ten breaths/min, a "steady state" C1 end tidal CO 2 partial pressure (PET CO 2 of 40 mmHg and a haemoglobin concentration 00 (Hb) of 12 g/dl, an injected volume of only 6.1 mis. CO 2 per breath will be required to 0 raise the "steady state" end tidal pCO 2 (PET CO 2 to 00 10 This equation may thus be utilised to estimate the quantity of inspired CO 2 required 0 to raise the end tidal CO 2 partial pressure (PET C0 2 to a desired new elevated "steady state" end tidal CO 2 partial pressure (PET C0 2 As discussed above, an increase of the order of 5 8 mmHg would typically be suitable.

Various other modifications of the methods and specific apparatus in embodiments described will be readily apparent to the person skilled in the art.

(1128499_4):PRW

Claims (22)

1. A method of measuring cardiac output of a subject, said method comprising the steps of: a) measuring one or more quantitative characteristics of CO 2 expired by the subject in s a steady state breathing condition. b) delivering a quantifiable total quantity (AIN)) of CO 2 into the airway of the subject oO during the inspiratory phase of each breath of a series of breaths; c) measuring the duration (t0N)) of each said breath 00 d) measuring one or more quantitative characteristics of CO 2 expired during each said lo breath N e) for each said breath formulating an approximation of a first amount of said total quantity used to increase the quantity of CO 2 in the lungs of the subject; (ii) formulating an approximation of a second amount of said total quantity used to maintain and increase the quantity of CO 2 in the arterial system of the subject, as a function of cardiac output of the subject (CO); (iii) formulating an approximation of a third amount of said total quantity used to increase the quantity of CO 2 expired from the airway of the subject; (iv) calculating a sum comprising said first amount said second amount and said third amount and equating said sum with said total quantity thereby creating a single equation for each said breath and f) solving a series of simultaneous equations defined by said single equation for each said breath to provide an estimate of said cardiac output (CO).

2. The method of claim 1 wherein said total quantity of CO 2 is delivered into the airway of the subject by injecting a discrete known quantity of CO 2

3. The method of either of claims 1 and 2 wherein said one or more quantitative characteristics of CO 2 expired by the subject in a steady state condition includes CO 2 partial pressure (pCO 2

4. The method of claim 3, wherein said method includes the step of determining end tidal CO 2 partial pressure (PETCO2) in said steady state breathing condition. (11284994):PRW 00 The method of claim 3, wherein said method further comprises the steps of: Sdirecting at least a portion of total gas volume expired during said steady state Sbreathing condition through a mixing box to mix said gas volume expired; and subsequently determining CO 2 partial pressure (pMxCO2) of the mixed expired gas.

6. The method of any one of claims 1 to 5, wherein said method further 00 comprises the step of measuring one or more quantitative characteristics of total gas O volume expired in said steady state breathing condition. 00 ,0 S7. The method of any one of claims 1 to 6, wherein said one or more quantitative characteristics of CO 2 expired by the subject during each said breath includes CO 2 partial pressure (pCO2).

8. The method of claim 7, wherein said method includes, for each said breath the step of determining end tidal CO 2 partial pressure (PETCO2) of said breath

9. The method of any one of claims 1 to 8, wherein said method includes the step of determining a volume of CO 2 expired by the subject during each said breath. The method of any one of claims 1 to 9, wherein said method further comprises the step of measuring one or more quantitative characteristics of total gas volume expired during each said breath.

11. The method of any one of claims 1 to 10, wherein said first amount is formulated as a function of lung volume (VL) of the subject.

12. The method of claim 11, when appended to claim 8, wherein said first amount is approximated by: AL)= VL PETCO2(N) PETC02(N-1) AL(N) ~L PAT where: AL(N) said first amount (1) V, lung volume at end of expiry phase of breath PETCO 2 N) end tidal CO 2 partial pressure (mmHg) of the Nth breath; and (1128499_4):PRW 34 00 PA atmospheric pressure (mmHg). d. 13. The method of any one of claims 1 to 12, wherein said second amount (AB(N)) is formulated as a function of the slope of a CO 2 dissociation curve of the subject.

14. The method of claim 13, when appended to claim 8, wherein said slope is 00 approximated as a function of end tidal CO 2 partial pressure (PETCO2) and haemoglobin 00 concentration (Hb). 00 0o 15. The method of claim 14, wherein said haemoglobin concentration is 0 determined by analysing a blood sample of said subject.

16. The method of either of claims 14 and 15, wherein said second amount is formulated as a first component (ABIaN)) of said second amount (ABM) used to increase the quantity of CO 2 in the arterial system and a second component (AB2(N)) of said second amount used to maintain the quantity of CO 2 in said arterial system above a quantity of CO 2 in the arterial system of the subject in the steady state condition.

17. The method of claim 16, wherein said first component (ABI)) of said second amount is approximated by: ABI) 0.5 x CO X X (ETCO 2 PETCO(N-I))x S where: ABIN) said first component of said second amount CO cardiac output (1/min); duration of Nth breath (s) slope of CO 2 dissociation curve at an average CO 2 partial pressure (pCO 2 of pCO 2 (ae) PETCO2(N) pCO 2 and haemoglobin 2 concentration (Hb) of the subject's blood (mlCO 2 /lblood/mmHg).

18. The method of either of claims 16 and 17, wherein said second component (AB2(N)) of said second amount is approximated by: (1128499_4):PRW 00 0 AB(N) COx i xE60 T N- j PETC2(0))x S(-I),o 0(N) I Swhere: i AB2) said second component of said second amount SpEICO2(o) end tidal CO 2 partial pressure in said steady breathing condition (mmHg). SS(N_, 1 slope of CO 2 dissociation curve at 00 PETC02(N-) PEC02(0, pCO, PETCO 2 PETCO2() and prevailing haemoglobin pCO 2 2 Sconcentration (Hb) of the subject's blood (mlCO 2 /lboood/mmHg). 00 0 0 10 19. The method of either of claims 16 and 17, wherein said second component (AB2(N)) of said second amount is approximated by: AB 2 CO X I (pETCO2 PET CO) 2 x S where: AB2(N) said second component of said second amount pE7C02(o) end tidal CO 2 partial pressure in said steady state breathing condition (mmHg). slope of CO 2 dissociation curve at pCPETCO 2 PETCO2() and prevailing haemoglobin concentration (Hb) of the subject's blood (mlCO 2 /lboood/mmHg). The method of any one of claims 1 to 19, wherein said third amount is approximated by: AE(N) VCO 2 VC0 2 (o) where: AEN) said third amount VCO 2 N) total volume of CO 2 expired during Nth breath VCO 2 total volume of C0 2 expired during a breath in said steady state breathing condition

21. The method of any one of claims 1 to 19, wherein said third amount is approximated by: (1128499_4):PRW 36 00 rF x PXNCO, Fxo x pxCOC2 SAE-(N) A J PAT PAT Swhere: instantaneous expiratory total gas flow rate during Nth breath Fxo instantaneous expiratory total gas flow rate during Nth breath in said SFxo instantaneous expiratory total gas flow rate during a breath in said Ssteady state breathing condition (1/min) C, pxvCO2 instantaneous expired CO 2 partial pressure during Nth breath 00 (mmHg) 0pxoCO2 instantaneous expired COz partial pressure during a breath in said 00 steady state breathing condition (mmHg). PAT atmospheric pressure (mmHg).

22. The method of claim 8, when appended through claim 5, wherein said one or more characteristics of CO 2 is/are measured utilising off-line capnography and said third amount is approximated by: STV CO 2 0 PETCO 2 PETCO 2 0 E(N) T(N) xI jx PET CO2( 0 PAT where: TV(N) total volume of gases expired during Nth breath pMxCO2() mixed expired CO 2 partial pressure in said steady state breathing condition (mmHg); PUX C02(0 alveolar to total ventilation ratio in said steady state breathing PETCO 2 (O) condition.

23. The method of any one of claims 1 to 22, wherein said method further comprises, for each said breath, the step of formulating an approximation of a fourth amount being a breath duration irregularity correction factor, said sum further comprising said fourth amount.

24. The method of claim 23, wherein said breath duration irregularity correction factor (AD) is approximated by: (1128499_4):PRW 00 0 V C02(0) 8AD N, Swhere: SC0 2 0 average volume of CO 2 expired per minute during said steady state breathing condition (1/min), and t(N) duration of Nth breath 00 The method of claim 24, wherein V CO 2 is approximated as: 00 SFx PX CO 2 VCO2 N PAT where: Fx instantaneous expiratory total gas flow rate (1/min), pxC02 instantaneous expired CO 2 partial pressure (mmHg), PAT atmospheric pressure (mmHg).

26. The method of claim 24, when appended through claim 5, wherein VCO 2 is approximated by: VCO0 2 MV"IO pMxCO0 2 where: MV(o)= volume of total gases expired per minute during said steady state breathing condition (1/min). PuxC02(o) mixed expired CO 2 partial pressure during said steady state breathing condition (/min).

27. The method of any one of claims 1 to 26, wherein said series of simultaneous equations are solved to provide an estimate of said lung volume.

28. An apparatus for estimating cardiac output of a subject, said apparatus comprising: a breathing head defining a flow path and having a breathing interface for communicating said flow path with the airway of a subject; a CO 2 measurement system for measuring one or more quantitative characteristics of CO 2 expired by the subject during a breath; (1128499_4):PRW a CO 2 delivery system for delivering a quantifiable total quantity of CO 2 to said flow path; and a data processing and control system communicating with said CO 2 measurement system, and said CO 2 injection system, said data processing and control system being configured to: receive and record signals from said CO 2 measurement system; control said CO 2 delivery system to deliver a quantifiable total quantity of CO 2 into said flow path during the inspiratory phase of each breath of a series of breaths of the subject; measure duration of each said breath; for each said breath: formulate an approximation of a first amount (AL(N))of said total quantity used to increase the quantity of CO 2 in the lungs of the subject; (ii) formulate an approximation of a second amount of said total quantity used to maintain and increase the quantity of CO 2 in the arterial system of the subject, as a function of cardiac output of the subject (CO); (iii) formulate an approximation of a third amount of said total quantity used to increase the quantity of CO 2 expired from the airway of the subject; (iv) calculate a sum comprising said first amount said second amount and said third amount and equate said sum with said total quantity (AIM), thereby creating a single equation for each said breath and solve a series of simultaneous equations defined by said single equation for each said breath to provide an estimate of said cardiac output (CO) of the subject.

29. The apparatus of claim 28, wherein said apparatus further comprises a flow meter for measuring one or more quantitative characteristics of total gas volume expired by the subject during a breath, said data processing and control system communicating with said flow meter to receive and record signals from said flow meter. The apparatus of either of claims 28 and 29, wherein said CO 2 measurement system comprises an in-line capnograph. (I 128499_4):PRW 00 0 N, 31. The apparatus of either of claims 28 and 29, wherein said CO 2 measurement Ssystem comprises an off-line capnograph.

32. The apparatus of claim 31, wherein said CO 2 measurement system further comprises a mixing box located in said flow path, said off-line capnograph being 0 configured to selectively communicate with an output of said mixing box and a region of 00 said flow path upstream of said mixing box. 00 Dated 19 February, 2008 SAPPLIED PHYSIOLOGY PTY LTD Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON (1128499_4):PRW