WO2013084159A1

WO2013084159A1 - System for the estimation of cardiac output

Info

Publication number: WO2013084159A1
Application number: PCT/IB2012/056980
Authority: WO
Inventors: Massimiliano Carassiti; Sergio Silvestri; Stefano CECCHINI; Emiliano SCHENA
Original assignee: Università Campus Bio-Medico Di Roma
Priority date: 2011-12-06
Filing date: 2012-12-05
Publication date: 2013-06-13
Also published as: EP2787878A1; ITRM20110650A1

Abstract

The present invention is about an apparatus for the estimation of cardiac output (CO) on mechanically-ventilated patients. The apparatus, according the invention, allows such estimation by inducing a prolonged expiration and without interfering with the normal functioning of the mechanical ventilator.

Description

SYSTEM FOR THE ESTIMATION OF CARDIAC OUTPUT

Field of the invention

The present invention relates to an apparatus and a method for estimating the cardiac output.

The invention is based on the Fick law, which describes the CO₂ exchange at the blood-gas interface into the lungs.

Background of the invention and drawbacks of the prior art

As well known, the cardiac output is the volume of blood pumped by one ventricle per unit of time. Its value provides an indication of the ventricular function, making its monitoring an important component in the haemodynamic management of critically ill patients, patients with suspected cardiovascular disease and patients who underwent cardiac surgery.

The Fick method [2] - which is based upon the principle of mass conservation applied to the alveolar exchange of O₂ or CO₂ - and the thermodilution [4] are considered the gold standards for cardiac output estimation. Both these methods are invasive, since they require the use of a central venous catheter and of Swan-Ganz catheter, respectively, thus exposing the patient to risks of sepsis, pneumothorax, thrombosis or pulmonary artery rupture: this constitutes one of the main drawback of the gold standards. Due to the above-reported risks, these two methods are used rarely and only in particular clinical conditions.

In the last decade, several minimally invasive or non-invasive techniques for cardiac output monitoring in both mechanically ventilated patients and healthy volunteers have been developed and tested. They include, among others: transthoracic bioimpedance, dye-dilution, Doppler ultrasound, arterial pulse contour and acetylene-helium rebreathing. These methods have not achieved widespread use in clinical practice mainly due to: high cost of both devices and disposable components, dependence of the outcome upon the operator experience, non-continuous assessment of cardiac output and concerns about accuracy, precision and reproducibility. Some others techniques have been developed which are based upon a modified, differential application of the Fick method to CO₂ mass conservation at the blood-gas interface into the lungs.

These techniques can be applied to mechanically ventilated patients and require the following two respiratory phases: the first phase involves measurements performed during the steady state, and the second phase starts when a sudden perturbation is introduced into the CO₂ elimination process. Several techniques have been successfully used to induce such perturbation: changing the minute-ventilation [5] or the respiratory rate set on the ventilator [6], breath holding [7] and even adding pure CO₂ to the inspiratory gas [8].

As background of the present invention, the above techniques based on the differential application of the Fick method to the CO₂ are taken into account.

One of these methods, US6402697 [1], describes a device providing an estimated cardiac output based upon gas analysis in collaborative patients. The main concern of this approach is related to its inability in the cardiac output monitoring in mechanically ventilated patients.

Summary of the invention

Therefore, the technical problem solved by the present invention is that of providing an apparatus and a method for the estimation of cardiac output of a patient allowing overcoming the drawbacks mentioned above with reference to the known art.

Such a problem is solved by an apparatus according to claim 1 and by a method according to claim 16.

The invention is also based upon an algorithm for the estimation of physiological parameters through the prolonged expiration.

The invention allows a non-invasive estimation of cardiac output (CO) by inducing a prolonged expiration.

The apparatus and method of the invention can be applied in both mechanically-ventilated patients - without modifying the normal functioning of the mechanical ventilator - and in cooperative patients.

In particular, the system of the invention allows performing a reproducible prolonged expiration, minimizing the interferences with the mechanical ventilator.

The developed apparatus also avoids risks for the patient and allows cardiac output estimation in brief time.

Moreover, the accuracy of the estimation is not dependent upon the operator's experience.

Therefore, the invention improves the medical care of critical patients, allowing more frequently cardiac output measures and overcoming the drawbacks of prior art systems.

Other advantages, features and the operation steps of the present invention will be made apparent in the following detailed description of some embodiments thereof, given by way of example and not for limitative purposes.

Brief description of the drawings

Reference will be made to the figures of the annexed drawings, wherein:

- Figure 1 shows the trends of P_AO₂ and PACO₂ as a function of time measured during a prolonged expiration of a patient ventilated with

F|O₂=40%; also PAO₂ as a function of PACO₂ is reported - usually, the trends of PAO₂ and PACO₂ present cardiogenic oscillation as visible in Figure 1 ;

- Figure 2 reports PACO₂ VS. PAO₂, during a prolonged expiration of a patient ventilated with F|O₂=40%, obtained by fitting the trends of PAO₂ and PACO₂ with exponential or polynomial curves;

- Figure 3 is a schematic representation of a previously developed device for cardiac output estimation used on collaborative patients;

- Figures 4 and 5 show a previously developed device for cardiac output estimation used on mechanically-ventilated patients;

- Figure 6A is a schematic representation of an apparatus according to a first embodiment of the invention for a collaborative subject;

- Figure 6B is a schematic representation of an apparatus according to a variant of the first embodiment of the invention for a mechanically ventilated patient;

- Figure 7 shows some details of the apparatus of Figure 6B, during use;

- Figure 8 shows perspective views of an inflatable member of the apparatus of Figures 6A and 6B; - Figure 9 is a schematic representation of an apparatus according to a second embodiment of the invention for a mechanically ventilated patient;

- Figure 10 shows the correlation between the values of CO_K and CO_T of all patients;

- Figure 1 1 shows the comparison between the CO values calculated with the proposed method (COK) and the values obtained by thermodilution (COT) using the Bland-Altman plot: all the values of all patient are reported;

- Figure 12 shows the percentage differences (ACO) between COK and COT for each patient.

Detailed description of preferred embodiments

Before describing in detail preferred embodiments of the invention, the Fick method [2] (Eq. 1 ) is explained, together with an overview of a few prior art devices for estimating cardiac output.

* * *

As said above, this method is based upon the principle of mass conservation applied to the alveolar exchange of O2 or CO2 :

CO=F-^- (1 )

AC0₂

wherein CO is the cardiac output, Vco₂ is the amount of carbon dioxide produced by the subject per unit of time, AC0₂ is the difference between the arterial concentration of CO2 and the venous one, and F (shunting factor) is the ratio between shunted blood volume (Qs) and stroke volume (Qt); F takes into account the percentage of blood flow that effectively participates in the alveolar exchange of CO₂.

The approach used to estimate cardiac output in the present invention requires the analysis of the expired gas content during both normal breathing and prolonged expiration. During normal breathing, inspired and expired gases are sampled and respiratory flows are monitored. These data allow calculating the difference between the amount of expired and the inspired CO2, providing a measure of Vco₂ . The evaluation of the denominator of Eq. (1 ) is performed with the use of an approach introduced by Kim [3], which is based upon the analysis of gases during a prolonged expiration.

The conspicuous oscillations of the P_AO₂ and PACO₂ trends (Figure 1 ), during the prolonged expiration, can dramatically decrease the accuracy and repeatability of CO estimation. These trends are fitted by exponential or polynomial curves in order to obtain more regular curves without oscillations, as shown in Figure 2. The introduction of this technical solution makes the algorithm more robust, minimizing the influence of the cardiogenic oscillations on the repeatability and accuracy of the presented method.

As shown in Figure 2, the correlation between the values of PAO₂ and PACO₂, measured during the prolonged expiration, is a means to obtain the difference ACO₂ between the arterial concentration of CO₂ and the venous one.

With reference to Figure 3, the device disclosed in US 6,402,697 provides cardiac output estimation of collaborative patients by a non-invasive approach based on the analysis of the respiratory gases.

In the device, indicated with (10), the patient breaths within a facial mask (12). A flowmeter (14), coupled to the mask by an adapter (16), measures the amount of inspired and expired air. The respiratory gas is sampled from a sampling port (18), connected to a catheter (24) and conducted to a gas sensor (20). A transduction module (22) performs calculations.

The device (10) performs a breath-by-breath estimation of cardiac output, based on Fick method, using the trends of gases as a function of time during the prolonged expiration. The system cannot be used in mechanically ventilated patients.

Considering Figures 4 and 5, a second well-known technique estimates cardiac output in mechanically-ventilated patients with a non-invasive approach and using gas analysis.

The employed system allows partial rebreathing of the expired CO₂ by the patient [9, 10].

As the previously introduced methods, also this one is based on the differential application of the Fick method on the CO₂ mass balance:

A Vco₂

CO = F - (2)

ACaCO-

CaC0₂ = (6.957[Hb] + 94.864) · log(l .0 + 0.1933PaC0₂ ) (3) wherein CaC0₂ is the arterial concentration of CO₂, PaC0₂ is the arterial partial pressure of CO₂, which derives from CO₂ concentration measurements in the breathing circuit, and [Hb] is the hemoglobin concentration into the blood.

The partial rebreathing method combines measurements obtained during a non- rebreathing period with the ones obtained during a subsequent rebreathing period: this involves a transitory interruption (about 1 min) of CO₂ elimination by addition of a dead space to the ventilatory circuit, which leads to a progressive increase in end-tidal CO₂. This is functional to the application of the differential Fick method.

In Figures 4 and 5 the partial rebreathing circuit is shown: through a valve an additional dead space (35 ml_) is introduced into the patient circuit for a period of 30-50 s intermittently every 3 min. In Figure 5 the rebreathing valve has the function to exclude (a) the volume rebreathing loop 2 or not (b). In the first case the subject ventilates normally at baseline level, whilst in the second one an amount less than the total CO₂ volume, from the previous expired tidal volume, is rebreathed by the subject.

The values collected during the non-rebreathing period are averaged, whilst those relative to the rebreathing period are plateau values. Having a cycle of 3 min this method does not provide a continuous estimation of the cardiac output.

Absolute and differential pressure sensors 4, a capnometer 3, and a pulse oxymeter are employed to estimate cardiac output (Figure 4).

Anyway, as already mentioned, this system requires, for a correct functioning, a perturbation of the normal ventilatory status of the patient for a very long period.

* * *

With reference to Figure 6A, an apparatus according to a first embodiment of the invention is globally denoted by 1 .

In the example proposed in Figure 6A, apparatus 1 is used for the estimation of cardiac output on a collaborative subject 2.

The apparatus 1 comprises a main duct 3, apt to receive air inspired and expired from the subject 2 and having an inlet 31 and an outlet 32. In the main duct 3 a pneumatic resistance 4 is placed. The apparatus 1 comprises also reversible by-pass means 51 , 52 of the pneumatic resistance 4, associated with the main duct 3. Thus, when the by-pass means are activated, gas flows into the main duct 3 without going through the pneumatic resistance 4. Apparatus 1 comprises also a measurement system of values related to the inspired/expired air flowing into the main duct 3 and calculation means, schematically denoted with the numerical reference 8. In particular, the measurement system comprises a flowmeter 7, placed at the outlet of the main duct 3 and configured so as to measure the gas flowing into the duct, and a first and a second sensor (both denoted by 6) of CO₂ and O₂ content, respectively, into the inspired/expired gas. For an optimal measurement, samples of CO₂ and O₂ should be taken at the subject's mouth 31 . Thus, as indicate din Figure 6A the measurement system comprises an air sampling line 9, which intercepts the main duct 3 substantially at the subject's mouth 31 .

Sensors 6 are placed downstream of sampling line 9 in order to analyze the air sampled at said position of main duct 3. Preferably, line 9 is connected to sensors 6 and calculation means 8 using an anti-saliva filter 1 1 .

Alternatively, sensors 6 can be placed directly on the main duct 3 in proximity of the subject's mouth 31 .

Preferably, the pneumatic resistance 4 comprises a member having an orifice (not visible in the figure).

According to the first embodiment herein described as a non-limiting example, by-pass means comprises a secondary duct 51 , connected to the main duct 3 in such a way to have an inlet and an outlet sections placed upstream and downstream the pneumatic resistance 4, respectively. In the present example by-pass means also comprises a valve 52, preferably of an on-off type, placed into the secondary duct 51 to control the gas flow direction.

Said on-off valve can be of any kind. In particular, in the described example it comprises an obstructing balloon or membrane, inflatable through a syringe 53. The membrane or balloon closes or opens the secondary duct 51 to the expired gas.

Alternatively, the valve can be of any other kind, as for example of a "proportional" type, in order to make only a set amount of gas going through the secondary duct 51 .

During normal breathing the valve 52 is open, making the expired gas flowing freely in the main duct 3 through the secondary duct 51 . During this phase, by sampling the inspired/expired air by the patient, analyzing it with the use of sensors 6, and measuring the gas flow using the flowmeter 7, the calculation means 8 elaborate the numerator Vco₂ of above equation (1 ) for the calculation of the cardiac output.

During the prolonged expiration phase, the by-pass means are disabled. The valve 52 is closed by inflating air into the balloon or membrane. In this way, the pneumatic resistance 4 induces a prolonged expiration. The air sampling during this phase allows calculating the denominator of the equation (1 ), and finally the estimated value of cardiac output. Preferably, calculation means 8 are based upon an algorithm using exponential and/or polynomial curves to fit measured data from sensors 6. Such fitting allows neglecting the influence of cardiogenic oscillation. Preferably, a data-reduction procedure, preferably performed by calculation means 8, allows rejecting all the said measured data where the gas coming predominantly from the dead space, which procedure allows to correctly calculate the exponential and/or polynomial fitting curves.

In the example of Figure 6A, the flowmeter is based on the turbine principle and is connected at the outlet 32 of the main duct 3 through a wrinkled tube 10. However, the flowmeter could also be directly positioned at the outlet 32.

In Figure 6B, the apparatus 1 is shown as associated with a breathing support system.

In this example, the breathing support system comprises a ventilation unit, globally denoted by 100. Such ventilation unit 100 is connected to the main duct 3 at its outlet 32, and comprises an inspiratory duct 30, placed between the ventilation unit 100 and the main duct 3.

In case the apparatus comprises also the breathing support system, unit 100 closes, using a valve (not represented), the duct 3 at its outlet 32 and forces air toward patient 2 through the inspiration duct 30.

During the expiration phase, similarly, the ventilation unit 100 closes the inspiratory duct 30 and opens the section 32, previously closed, in order to make the patient expiring only through the main duct 3.

During the normal ventilation, the by-pass means are active the valve 52 is open. During this phase, as reported above, gas flowing into the apparatus is analyzed in its content and quantity.

During the prolonged expiration phase, the medical operator pushes an 'expiratory pause hold' key of the ventilator (or performs an equivalent command), to avoid the delivery of an inspiratory act: thanks to the apparatus, the expiration phase is prolonged and, after about fifteen seconds, normal breathing is restored. Thanks to the pneumatic resistance the patient can expire more slowly and at a lower flowrate.

Prolonged expiration can be obtained by a pneumatic resistor purposively arranged at the main duct, as in the previous examples, or by means of a mechanical ventilator expiratory valve operating as a pneumatic resistor.

Figure 7 shows positioning and details of the by-pass means 51 , 52 belonging to the first embodiment considered so far. In Figure 8, it is shown a pneumatic resistance 200 according a second preferred embodiment of the invention. In particular, the pneumatic resistance 200 has an inflatable membrane 201 , which has, preferably in central position, an orifice 202. The membrane 201 is supported by an annular support system 203.

The membrane 201 is configured so as to leave the main duct (not represented) free when deflated (situation in Figure 8A), and to place the orifice along the duct when inflated (situation in Figure 8B).

In this second embodiment, the by-pass means of the first embodiment can be associated with a device (not represented) for the supply/exhaust of pressurized gas to/from the membrane 201 . In particular, such device comprises a pressurized gas source connected to the membrane 201 through a feeding line 210 (partly represented in Figure 8). When the membrane 201 must be deflated, to restore the normal breathing the feeding line can be equipped with a three-way valve, having one way connected with the external environment, at atmospheric pressure. Opening this way and closing the way supplying pressurized gas, the gas contained in the membrane 201 is passively released in the external environment thanks to the pressure gradient: thus, the membrane deflates.

Figure 9 shows an apparatus 1 ' according the second embodiment of the invention, comprising said membrane 201 . In particular, the apparatus V is shown when coupled to the breathing support system 100.

In this embodiment, the membrane 201 is preferably placed along the main duct 3 in that part in common with the inspiration duct 30, therefore substantially between the ramification and the patient's mouth. In this way the effect of an additional deadspace into the breathing circuit is drastically reduced respect on the first embodiment.

In Figure 9, the device for the supply/exhaust of pressurized gas is schematically denoted by the numerical reference 500.

The description of embodiment V is completely analogous to the description of embodiment 1 and it will not be repeated. In conclusion, the invention can be used on both mechanically-ventilated patients, as a monitoring tool, and collaborative subject, as a diagnostic tool. * * *

With the aim of further justifying the patentability of the invention under discussion, a preliminary clinical experimentation has been conducted in the Intensive Care Unit of the General Hospital (Policlinico Universitario Campus Bio-Medico, Rome, Italy). The results of this study are reported below for exemplificative purposes only.

Twenty patients were recruited in this prospective study, underwent cardiac surgery under general anesthesia, and had to be mechanically ventilated after surgery (Clinical experimentation: N. Prot. 19/201 1 ComEt CBM). Values of CO obtained with the proposed method (COK) have been compared to values of CO obtained with the thermodilution method (CO_T), which represents the gold- standard in the CO assessment.

20 estimations of COx and 10 of COT have been obtained for each patient.

The results are represented in figure 10, 1 1 , and 12.

The percentage error is defined as follow:

CO - CO

A CO [%] = ^{K 1} · 100

CO T,

(4)

From an analysis of the pictures, it is possible to see that estimated and measured values are very close. In the linear correlation we obtain a correlation coefficient very close to 1 (Figure 10). In the Bland-Atman representation (Figure 1 1 ) a slight underestimation of the measured value: the average difference between the two methods is about -0.2 L/min.

In Figure 12 this underestimation is confirmed: the mean percentage difference (equation 4) is -6 % and, in the 90 % of the cases the underestimation is lower than 15 %.

Repeatability of the method is defined as:

R [%] = 2 - CF- ^=^ - 100 (5)

CO '

being CO the average of all the estimated CO_K, CF a cover factor equal to 2.09, and SEM the normalized standard deviation. The repeatability of the proposed method is about 29 %. This value is slightly higher than that obtained for the thermodilution in the same patients (20 %) and comparable with values calculated, in analogous surveys, for other non-invasive and less-invasive methods. The present invention has been hereto described with reference to preferred embodiments thereof. It is understood that other embodiments might exist, all falling within the concept of the same invention, and all comprised within the protective scope of the claims hereinafter.

Bibliography

[1 ] Calkins, J. M. and T. M. Drzewicki. "Non-invasive cardiac output and pulmonary function monitoring using respired gas analysis techniques and physiological modeling". United States Patent, No. 6,402,697 B1 (Jun 2002).

[2] Fick, A. Ueber die messung des blutquantums in den hertzventhkeln.

Sitzungsbehchte der Physiologisch- Medizinosche Gesellschaft zu Wuerzburg 2:16, 1870.

[3] Kim, T. S., H. Rahn, and L. E. Fahh. Estimation of true venous and arterial PCO₂ by gas analysis of a single breath. J. Appl. Physiol. 21 (4):1338-

1344, 1966.

[4] Faddy, S. C. Cardiac output, Fick technique for. In: Encyclopedia for medical devices and instrumentation, J. G. Webster. New York: Wiley- Interscience, 1988, pp. 12-21 .

[5] Gedeon, A., L. Forslund, G. Hedenstierna, and E. Romano. A new method for noninvasive bedside determination of pulmonary blood flow. Med. Biol. Eng. Comput. 18:41 1 -418, 1980.

[6] Peyton, P. J., D. Thompson, and P. Junor. Non-invasive automated measurement of cardiac output during stable cardiac surgery using a fully integrated differential CO₂ Fick method. J. Clin. Monit. Comput. 22(4):285-

292, 2008.

[7] Gedeon, A., P. Krill and B. Osterlund. Pulmonary blood flow (cardiac output) and the effective lung volume determined from a short breath hold using the differential Fick method. J. Clin. Monit. Comput. 17(5):313-321 , 2002.

[8] Linnarson, D. and H. Larsson. Pulmonary blood flow determination with selective rebreathing of CO₂. Clin. Physiol. 5:39-48, 1985.

[9] Jaffe, M. B. Partial CO₂ rebreathing cardiac output-operating principles of the NICO™ system. J. Clin. Monit. Comput. 15(6):387-401 , 1999.

[10] Orr, J. A., S. A. Kofoed, D. Westenskow, and M. B. Jaffe. "Apparatus for non-invasively measuring cardiac output' United States Patent, No. 7,686,012 B2 (Mar 2010).

Claims

1. An apparatus (1 ; 1 ') for the estimation of a patient's cardiac output, comprising:

- a main duct (3), apt to receive air expired by the patient;

- a pneumatic resistor (4; 200), placed within said main duct (3);

- means (51 , 52; 500) for selectively activating said pneumatic resistor (4;

200) upon the flow of expired air;

- a system (6, 7) for measuring data associated with inspired and/or expired air; and

- calculation means (8), apt to receive as input said measured data and to return as output an estimation of the patient's cardiac output (CO) based

Vco

upon Fick's equation CO= F — ,

AC0₂ wherein Vco₂ is a measured quantity of CO2, AC0₂ is the artero-venous difference of CO₂ and F is a pre-determined factor, and

wherein the arrangement is such that said pneumatic resistor (4; 200) is apt to induce a prolonged expiratory act by the patient and said calculation means (8) are configured so as to estimate the patient's cardiac output based upon data measured during said prolonged expiratory act taken as a perturbation of the normal breathing for calculating the denominator of said equation.

2. The apparatus (1 ; 1 ') according to claim 1 , wherein said pneumatic resistor (4; 200) comprises an element having an orifice (202).

3. The apparatus (1 ') according to claim 1 or 2, wherein said pneumatic resistor (200) comprises an inflatable body (201 ), preferably an inflatable membrane.

4. The apparatus (1 ') according to the preceding claim, wherein said pneumatic resistor (200) comprises an annular support (203) inside which said inflatable body (201 ) is placed.

5. The apparatus (1 ') according to claim 3 or 4, wherein said means for selectively activating said pneumatic resistor comprises means for feeding (500) and/or discharging pressurized gas to/from said inflatable body (201 ).

6. The apparatus (1 ') according to the preceding claim, comprising a source of pressurized gas (500) connected or connectable to said inflatable body (201 ).

7. The apparatus (1 ') according to claim 5 or 6, wherein said feeding and/or discharging means (500) comprises a three-way valve.

8. The apparatus (1 ) according to any of the preceding claims, wherein said means for activating said pneumatic resistor comprises bypass means (51 , 52) for bypassing said pneumatic resistor (4).

9. The apparatus (1 ) according to the preceding claim, wherein said bypass means comprises a secondary duct (51 ) connected or connectable to said main duct (3) so as to have an inlet section and an outlet section placed respectively upstream and downstream of said pneumatic resistor (4), said secondary duct (51 ) comprising there inside a valve (52), preferably of an on/off type.

10. The apparatus (1 ) according to the preceding claim, wherein said on/off valve (52) comprises an inflatable body, preferably an inflatable membrane.

11. The apparatus (1 ; 1 ') according to any one of the preceding claims, wherein said measuring system (6, 7) comprises:

- a flowmeter (7), apt to measure data relating to the flow of inspired and/or expired air and preferably placed downstream of said main duct (3); and/or

- a first sensor (6) of CO2 content and a second sensor (6) of O2 content of the inspired and/or expired air.

12. The apparatus (1 ; 1 ') according to the preceding claim, wherein said first (6) and/or second (6) sensor are positioned substantially at a mouth-piece of said main duct (3).

13. The apparatus (1 ; 1 ') according to any of the preceding claims, wherein said measuring system (6, 7) comprises an air sampling line (9), preferably intercepting said main duct (3) substantially at a mouth-piece thereof.

14. The apparatus (1 ; 1 ') according to the preceding claim and to claim 1 1 or 12, wherein said first (6) and second (6) sensors are placed downstream of said sampling line (9).

15. The apparatus (1 ; 1 ') according to any of the preceding claims, further comprising an assisted ventilation system, said system comprising a ventilation unit (100) connected downstream of said main duct (3) and an inspiration duct (30) interposed between said ventilation unit (100) and said main duct (3).

16. A method for the estimation of a patient's cardiac output, comprising the steps of:

- inducing a prolonged expiratory act by the patient by means of a pneumatic resistor (4; 200) placed in a main duct (3) apt to receive air expired by the patient, or by means of mechanical ventilator expiratory valve;

- measuring data associated with inspired and/or expired air; and

- calculating, from said measured data, an estimation of the patient's

Vco

cardiac output CO based upon Fick's equation CO = F — ,

AC0₂ wherein Vco₂ is a measured quantity of CO2, AC0₂ is the artero-venous difference of CO2 and F is a pre-determined factor,

and wherein the denominator of said equation is calculated based upon data measured during said prolonged expiratory act taken as a perturbation of the normal breathing.

17. The method according to the preceding claim, wherein exponential and/or polynomial curves are used to fit said measured data in order to neglect the influence of cardiogenic oscillation.

18. The method according to the preceding claim, wherein a data-reduction procedure allows to reject all the said measured data where the gas coming predominantly from the dead space, which procedure allows to correctly calculate the exponential and/or polynomial fitting curves.

19. The method according to any of claims 16 to 18, using an apparatus (1 ; 1 ') according to any of claims 1 to 15.