Title of Invention

AN APPARATUS TO ASCERTAIN CARDIAC OUTPUT

Abstract

An apparatus to measure cardiac output (Q) and other parameters such as alveolar ventilation (VA), minute CO2 elimination from the lung (VCO2 ), minute oxygen consumption (VO2), oxygenated mixed venous partial pressure of CO2, (PvCO2-oxy), true mixed venous partial pressure of CO2 (Pv CO2), PaCO2, mixed venous oxygen saturation (SvO2), pulmonary shunt, and anatomical dead space, consisting of: a) a breathing circuit with characteristics that: i. on exhalation, exhaled gas is kept substantially separate from inhaled gas; ii. oninhalation, when VE is greater than FGS flow, the subject inhales FGS first and then inhales a gas that is substantially SGS, for the balance of inhalation; b) gas sensor means for monitoring gas concentrations at the patient-circuit interface c) a first gas set (FGS), and a second gas set (SGS), said second gas set which may comprise previously exhaled gases or exogenous gases or both d) a gas flow control means for controlling the rate of FGS flow into the breathing circuit e) means to identify phase of breathing, said means may consist of pressure sensors or analysis of signal generated by gas sensors or other means known to those skilled in the art; f) machine intelligence consisting of a computer or logic circuit capable of controlling the gas flow control means, receiving the output of the gas sensor means and means to identify phased of breathing, and performing the calculations for measuring cardiac output and other parameters as outlined in the disclosure.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & The Patents Rules, 2003 PROVISIONAL / COMPLETE SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION : "METHOD OF MEASURING CARDIAC RELATED PARAMETERS NON-INVASIVELY VIA THE LUNG DURING SPONTANEOUS AND CONTROLLED VENTILATION" 2. APPLICANT (S) (a) NAME (b) NATIONALITY (c) ADDRESS FISHER, JOSEPH, PREISS, David, AZAMI, Takalumi, VESELY, Alex, PRISMAN, Eltan, and ISCOE, Steve Canadians c/o The Toronto General Hospital, Department of Anesthesia, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada 3. PREAMBLE TO THE DESCRIPTION PROVISIONAL The following specification describes the invention COMPLETE The following specification particularly describes the invention and the manner in which it is to be performed. 4. DESCRIPTION (Description shall start from next page) 5. CLAIMS (not applicable for provisional specification. Claims should start with the preamble - "I/we claim" on separate page) 6. DATE AND SIGNATURE (to be given at the end of last page of specification) 7. ABSTRACT OF THE INVENTION (to be given along with complete specification on separate page) WO2004/73482 PCT/CA2004/000234 TITLE OF THE INVENTION A NEW METHOD OF MEASURING CARDIAC RELATED PARAMETERS NON-INVASIVELY VIA THE LUNG DURING SPONTANEOUS AND CONTROLLED 5 VENTILATION HELD Of THE INVENTION This invention, discloses a method that calculates noninvasively, via the lung, the 10 total cardiac output, pulmonary blood flow, shunt flow, anatomical and alveolar deadspace, true mixed venous Q2 saturation, true mixed venous FCO2, and PaCO2. Furthermore the method can be performed in ventilated subjects, subjects breathing spontaneously, even in the presence of variations in their tidal volume and breathing frequency. Subjects need not perform any respiratory manoeuvre such as 15 hyperventilation or breath holding to perform the test BACKGROUND OF THE INVENTION 1. Importance of cardiac output 20 A physician's ability to determine a patient's cardiac output {Q, the volume of blood pumped by the heart each minute) is important in the assessment of critically ill patients. There are various devices and methods that provide a direct or indirect measure of Q (see table 1). The most common method used in clinical practice is 25 theme-dilution, established by Ganz et al (1). Commercially manufactured catheters (referred to as Swan-Ganz catheters, named after the inventors) contain multiple lumina, an embedded thermister, and a balloon at the tip. The method requires the insertion of the catheter through the skin to access a large central vein such as the internal jugular, subclavian, cephalic or femoral. When the balloon at the 30 end of the catheter is inflated, the catheter tip is carried along with the flow of blood to the right ventricle of the heart and then into the pulmonary artery. The part of the catheter that remains outside the body has connections that can be attached to electrical sensors that determine the pressure and temperature in the pulmonary artery where the tip of the catheter is positioned. Calculation of Q requires the 2_ WO 2004/073482 PCT/CA2004/000234 Page 2 injection of a fixed volume of cool liquid of known temperature into a lumen of the catheter that has its opening part way along its length (usually in a part of the catheter in the right atrium). The thermister at the tip of the catheter will register changes in temperature as the cool liquid, carried by the blood, passes. The extent of 5 dilution of the cold bolus of liquid by warm blood win determine the temporal profile of the temperature change at the tip of me catheter. This is referred to as the thermodilution method of measuring cardiac output (TD Q). The popularity of TDΩ stems from ease of use once the catheter is in place. 10 However, the placing and maintenance of the catheter entails considerable risk and expense. Insertion of the Swan-Ganz catheter is associated with complications that are frequency fatal such as puncture of the carotid or subclavian artery with associated internal haemorrhage or stroke/ tension pneumothorax, rupture of the right ventricle, malignant azzhythmias (including fatal ventricular fibrillation), and 15 rupture of the pulmonary artery. As a foreign body violating the skin barrier, a pulmonary artery catheter is a constant threat as a source of blood-bom infection that is the greatest risk to heart valves, artificial joints, and other implants. Such infections are medical disasters leading to severe morbidity and death. Furthermore, the use of pulmonary artery catheters to measure TDQ is very expensive as it 20 requires admission to an intensive care facility where there is continuous presence as it critical care nursing and medical staff. Despite these risks, it is still not the ideal method to measure Q as it tends to overestimate Q by as much as 10% compared to the Pick method (see below) and, for greatest accuracy, requires repeated measurements as its precision is poor. The variability of repeated single 25 measurements is about 22% and can be reduced to 10% by repeated averages of 9 measurements (2). A single thermodilution measurement is considered to be plus or minus 33% the true value.(3) Because of die expense and risks of keeping the catheters in place, (hey are removed as soon as practical, often within 24-48 hours of major heart surgery. Often they are 30 removed while the information they provide can still be clinically useful and well 3, WO 7.004/073482 PCT/CA2004/000234 Page 3 before the patient is no longer at significant risk for relapse. If the patient's health deteriorates, a decision must be made about re-inserting the catheter. An automated non-invasive method of Q monitoring would be very useful in the 5 following clinical scenarios: a) Selected low risk patients now routinely undergoing pulmonary artery catheterization for intra- and postoperative monitoring. b) Patients whose Q would be clinically important to know but in whom the risks and costs of insertion of a pulmonary catheter cannot be justified; this 10 includes ward patients, outpatients or patients in. the emergency department or doctor's office. c) Patients who are too sick to warrant the added risk of pulmonary artery catheter insertion d) High and moderate cardiac risk patients undergoing minor and moderate 15 non-cardiac surgical procedures e) Severely ill patients with non-cardiac disease. f) Relatively healthy patients undergoing major stressful surgery. g) Situations in which Q is clinically indicated but there is no access to the expertise and critical care facilities required for the use of the pulmonary 20 artery catheters. h) Means of monitoring response to cardiovascular therapy such as for hypertension and heart failure, i) As a non-invasive diagnostic test of cardio-pulmonary status. j) As a means of assessing cardiovascular fitness. 25 Despite these many applications, non-invasive methods of Q measurements have not obtained widespread clinical acceptance. The most commonly researched methods include ECG bio-impedance (Imhoff. 2000 (4)), and pulsed-wave Doppler esophageal sonography. These methods have good repeatability (5-12) and good 30 limits of agreement with either thermodilution or Fick-based methods but only in some populations of subjects. Each method fails in certain patients groups with such 4 WO 2004/073482 PCT/CA2004/000234 Page 4 pathologies as very high or low Q states as occur in surgical patients, septic shock, exercise or cardiogenic shock. 2. Background physiology and definition of terms 5 Venous blood returns to the right side of the heart from the muscles and organs with reduced oxygen (O2) and increased carbon dioxide (CO2) levels. Blood from various parts of the body is mixed in the right side of the heart and pumped to me rungs via the pulmonary artery. The blood in the pulmonary artery is known as the mixed 10 venous blood In the lungs the blood vessels break up into a network of small vessels that surround tiny rung sacs known as afoeoli. This network of vessels surrounding the alveoli provides a large surface area for the exchange of gases by diffusion along their partial pressure gradients. After a bream of air is inhaled into the lungs, ft dilutes the CO2 left in the alveoli at the end of the previous expiration, thereby 15 establishing a pressure gradient between the partial pressure of CO2 (PCO2) in the mixed venous blood (PD CO2) arriving at the alveoli and the alveolar PCO2 (PACO2). The CO2 diffuses into the alveoli from the mixed venous blood diminishing the PCO2 in the blood, and increasing the PCO2 in the alveoli until equilibrium is established between the PCO2 in alveolar capillary blood and the PCO2 in the alveoli. The blood 20 then returns to the left side of the heart via the pulmonary vein and is pumped into the arterial system by the left ventricle. The PCO2 in the arterial; blood (PaCO2) is now the same as mat in the alveoli. When the subject exhales, the gas at the very end of exhalation is considered to have come from the alveoli and thus simultaneously reflects the PCO2 in the pulmonary capillaries and the alveoli; the PCO2 in this gas is 25 called me end-tidal PCO2 (PETCO2). The volume of gas breathed per minute, or minute ventilation (VB), is measured at the airway opening (nose and/mouth) and is expressed in L/min. The volume of breathed gas distributed to the alveoli (and thus contributing to gas exchange) is 30 termed the alveolar ventilation (VA) and is also expressed in L/min The part of VB that does not contribute to gas exchange is termed dead space ventilation. This is 5 WO 2004/073482 PCT/CA2004/000234 Page 5 divided into the anatomical dead space that consists of the trachea and other gas-conducting tubes leading from the nose and mouth to the alveoli, and the alveolar dead space mat is collectively the alveoli that are ventilated but not perfused with blood. 5 The VB during normal breathing provides the VA that is required to eliminate the CO2 brought to the lungs. VB is controlled by a feedback system to keep PaCO2 at a set level of approximately 40 mmHg. Under steady state conditions, the rate at which CO2 is exhaled from the lungs {VCO2) is equal to the rate that it is brought to 10 the lungs, which in turn is equal to the metabolic CO2 production. We define steady state as the condition in which the flux of CO2 at the lungs is equal to the CO: production and the VCO2, PvCO2 and FaCO2 remain steady. If-the VCO2 is diminished, the CO2 extraction from the mixed venous blood passing by the alveoli will be reduced resulting in an increase in the PaCQ2 when that blood reaches the 15 arterial system. As the blood traverses the body, it will pick up additional CO2 and will. return to the pulmonary artery with a higher PCO2 than on its previous passage. The time between the change in VCO2 and re reappearance of the blood with raised FCO2 in the mixed venous circulation is termed the recirculation time which is generally taken as 20-30 a in resting subjects. 20 3. The Fick equation The approach for respiratory-based methods for measuring Q non-invasively is described by the Fick equation, a mass balance of any substance across the lungs. 25 The Fick method was originally described for O2 as a method for determining pulmonary blood flow. The Fick relation states that the O2 uptake by the lung is equal to the difference between the pulmonary artery and systemic arterial O2 contents times the Q. The blood contents originally had to be obtained invasively from blood samples. The same relation holds with respect to O2 The advantage of 30 using C O2 as the tracer is that mixed venous and arterial blood contents of C O2 may be determined non-invasively. The Fick mass balance equation for C O2 is: 6 WO 2004/073482 PCT/CA2OO4/O00234 Page 6 where Q is the cardiac output, VC O2 is the rate of elimination of CO* at the lungs, Cv CO2 and CaC O2 are the mixed venous and systemic arterial contents of C O2, 5 respectively. VCO2 can be measured by a timed collection of expired gas and measuring its volume and CO2 concentration. The term CaCO2 can be calculated using an estimate of arterial PCO2 (PaCO2) as derived from the PC O2 of end tidal gas (PETCO2). The hemoglobin concentration (easily obtained from a venous blood sample or a drop of blood from a finger prick) and the relation between blood PCO2 10 and CO2 content (available from standard physiology texts) are then used to calculate CaCO2. However, CvC O2 is difficult to estimate. The PCO2 of mixed venous blood (EVCO2) is difficult to determine as true mixed venous blood is present only in the pulmonary 15 artery, which is inaccessible from the surface. The air in the lungs is in intimate contact with mixed venous blood, but CO2 diffuses rapidly from me mixed venous blood into the alveoli before an equilibrium is established. The PCO2 of the expired gas therefore reflects this equilibrium PCO2 and not the PCO2 of mixed venous blood. The PvCO2 can be determined from expired gas only when there has been 20 full equilibration with continuously replenished mixed venous blood or partial equilibration under controlled conditions that allow for back calculation of PvCO2 from the PCOz in expired gas. Hence during rebreathing, the alveolar gas is not refreshed and the mixed venous blood continuously passes the alveoli such that an equilibrium is established whereby the PBTCOZ reflects the PCOz in mixed venous 25 blood. However, even in this scenario, the PCO2 is not that which exists in the pulmonary artery. Blood in the pulmonary artery has a relatively low PO2. Because of the Haldane effect, the low PO2 allows the COz to be carried by the hemoglobin at a 30 relatively low PCO2. When the mixed venous blood is exposed to gas in the alveoli, 7 WO 2004/073482 PCT/CA2004/000234 Page 7 Oz diffuses into the blood, binds to the hemoglobin and increases the PCQj needed for a given CO* content on the hemoglobin (the complimentary aspect of the Haldane effect). All methods based on full or partial equilibration of alveolar gas with Pv COz take into account that the equilibration is to a virtual PCO2 that would 5 exist if the CO content of the hemoglobin were the same as in mixed venous blood bat the hemoglobin were saturated with Q>. We refer to this as the oxygenated mixed venous PCO2(PvCO2-oxy). Because the relationship between PCO2 and content of C O2 in blood is known, Cv COz can be calculated from both the true PvCO2* (as obtained, for example, from a pulmonary arterial blood sample) and 10 Pv CO2-oxy (as obtained by some of the non-invasive methods described below)*. 4. Rebreathing-equilibration method One method of measuring Pv CO-oxy was introduced by Collier in 1956, and is known as the equilibration method. A bag is pr&-filled with a high concentration of 15 CO2 (-10-13%) and the subject exhales and inhales rapidly to and from the bag and PCO2 is monitored continuously at the mouth. The object of the test is to find the combination of bag volume and bag concentration of CO* such that once the gas in the bag mixes with that in the lungs (the concentration of C O2 in tine residual gas in the lung at the end. of a bream in a healthy person is -5.5%), the partial pressure of 20 COz in the lung is equal to that in mixed venous blood. A flat segment of the FCO2 tracing segment indicates that inspired and expired PCO2 are equal To identify the true Pv C O2-oxy, the flat segment must occur within the first 3-4 breaths, before recirculation raises the Pv CO2-oxy (see Figure 8). 25 4.11 Advantages of the equilibration method: The Pv~COj-oxy does not really exist but is a virtual number created by instantaneously oxygenating mixed venous blood before and diffusion of CO} into 4c alveoli. The CvCO2 is the same in each. 8 WO 2004/073482 PCT/CA2004//000234 Page 8 The capnograph reading is of gas equilibrated with Pv-CO2-oxy and can be considered a directly measured value as opposed to a value obtained from calculation or extrapolation. 5 4.1.2 limitations of the equilibration method: 4.1.2.1 The COz concentration in the bag depends on bag size, the patient's lung volume, and the Pv C02-oxy— the last being the unknown value. Therefore, the concentration of CO2 in the bag must be individualized to the patient and thus found by trial and error. The method is therefore 10 difficult to automate fully. 4.1.22 In practice, since the characteristic of a suitable endpoint (the plateau of PCO2) is subjective, identification of a suitable plateau is difficult to automats. 41.23 The manoeuvre of rebreathing from a bag is difficult to perform in 15 mechanically ventilated patients and is therefore not suitable for such patients. 4.1.24 Inhaling 10-13% COz is very uncomfortable and most people cannot tolerate it It is particularly uncomfortable to someone who is short of bream or exercising. 20 4.1.2.5 The method requires an external source of CO2. This makes testing equipment bulky and awkward. 4.1.2.6 The method requires mat the subject hyperventilate in order to mix thoroughly the gas in the bag and the lungs before recirculation of blood takes place. This requirement limits the test to those subjects who 25 can perform this manoeuvre and who can provide this degree of cooperation. The excludes patients who have severe lung disease, those who are too young, too confused or too 31 to cooperate. 4.12.7 The test loads a considerable volume of COz into the subject's lungs and at the same time prevents CO2 from leaving the blood for the duration 30 of the test This has negative consequences for the subject 412.7.1 Following the test, the subject must hyperventilate to eliminate the applied CO2 load as well as the volume of metabolically-produced 9 WO 2004/073482 PCT/CA2004/000234 Page 9 CO2 not eliminated during the test This may pose a considerable burden for some subjects with lung disease or exercising subjects who are already expending considerable effort to cope with their existing metabolic CO2 load. 5 4.1.2.7.2 A period of hyperventilation following the test is required to eliminate the CO2. This may be difficult for some subjects to perform and, consequently, they may experience respiratory distress for some time until their PCO2 is decreased. 4.12.73 Repeated tests must be delayed until the extra CO2 is eliminated 10 and the baseline state re-established. 4.1.2.7.4 The test itself may distress the subject and alter the Q. 5. Rebreathing- Exponential Method In this technique, a small amount of CO2 is placed in a bag and the subject asked to 15 rebreathe from the bag. The PBICO2s of successive breaths will rise exponentially towards PvCO2-oxy. A rising exponential curve is then fit to the PETCO2S of these breams to predict an asymptotic value that is assumed to be the Pv CO2-oxy (See Figure 9). 20 53. Advantages of the exponential method 5.1.1 There is no requirement for respiratory manoeuvres by the patient 5.12 A smaller CO2 load is placed on the subject in order to perform the test 52 Limitations of the exponential method 25 52.1 This is an indirect test in which the PvCO2-oxy is not measured directly but calculated from data generated by a test 522 As the metabolic production of CO2 is small compared to me size of the lung and bag, the rise of PCO2 occurs over a prolonged period. This severely limits the number of useful data points for accurate 30 extrapolation from an exponential curve, before recirculation. 52.3 The most important limitation of this and other methods that use partial equilibration during rebreathing to extrapolate to an asymptote 10 WO 2004/073482 PCT/CA2004/000234 Page 10 using a single exponential is that the assumptions underlying the method are incorrect la fact, the method produces two different mathematical profiles: the one describing the washout of CO2 from me lung into the bag is a decreasing exponential whereas the second 5 describing the build-up of CO2released from Hie blood into the lung- bag mixture is an increasing exponential (13). Only after the gases in the lung-bag system have become well mixed do the two exponentials resolve to a single exponential. By then, very few breaths (if any) that can provide suitable data for extrapolation from a single exponential 10 can be taken before recirculation 5.2.4 A continually rising level of CO2 makes this test unpleasant in conscious patients, especially in those exercising or very ilL 52.5 The manoeuvre of rebreathing from a bag is difficult to perform in mechanically ventilated patients and is therefore not suitable far such 15 patients. 52.6 The method requires an external source of CO2. This makes testing equipment bulky and awkward. 52.7 The test loads a volume of CO2 into the subject's lungs and at the same time prevents CO2 from leaving the blood for the duration of the test 20 Although me extent of the CO* load on the subject is less than with the equilibration method, the negative consequences for the subject; outlined in the section on the equilibration method (discussed above/ must be considered. 52.8 Priming the rebreathing bag with some CO2 improves me predictive 25 qualities of the asymptote since every data point lies closer to the asymptote, but the increased CO2 concentrations increase the discomfort and the limitations approach those outlined above for the equilibration method. 11 WO 2004/073482 ;PCT/CA2004/000234 Page 11 6.0 Calculating Q without first calculating Pv CO2-oxy Gedeon in 1980 described a method of calculating Q in ventilated patients via a differential Pick method that circumvents the need to calculate Pv CO2-oxy. The 5 underlying assumptions of the method are that and Q PvCO2 will remain unchanged during a step change in lung CO2 elimination and alveolar PCO2 (PACQ2) lasting less than a recirculation time (about 30 seconds). Gedeon proposed reducing lung CO2 elimination by reducing either the tidal volume or respiratory frequency setting of the ventilator. As a modification of this method, Orr et al. 10 proposed leaving the ventilator settings unchanged and reducing lung COi elimination by temporarily interposing a dead space between the ventilator and the patient's airway resulting in a transient period of rebreathing previously exhaled gas- 15 6.1 Theoretical basis of Gedeon/Orr method; The method applies to a subject being ventilated under control conditions in which CO2 elimination and PETCO2 are measured A test manoeuvre consisting of a transient alteration in the CO2 elimination fox a time less man a recirculation time is effected and the resulting "equilibrium" PBTCO2 is noted. It is assumed that the Q 20 and Pv CO2-oxy during the test are unchanged from control conditions. The Fick equation for these two conditions can be written as 25 where VCO2 is the CO2 flux at the lungs during the test and CaCO2 'is the corresponding 'new arterial content of CO2. These two equations can be combined to yield the differential form of Fick's equation: 12 WO 0004/073482 PCT/CA2004/000234 Page 12 where A denotes a "difference in". Since the PaCO2 and Pv CO2-owy lie on the same CO2 dissociation curve, partial pressures of CO2 can be substituted for CO2 content to yield the following relation: 5 ' where S is the slope of the CO2 dissociation carve. like the conventional non¬invasive CO2-based Pick method, the differential Pick method relies on predicting PaCO2 through measurements of PETCO2. However, instead of requiring a calculation of PvCO2-oxy, the differential Pick equation assumes no change in 10 Pv CO-oxy over the duration of the test, and uses the measured quantities VCO2 and VCO2 and well as PaCO2 and PaCO2 (from PETCO2) to calculate the remaining unknown value in the equation: Q. 6.2 Advantages of Gedeon/Orr method 15 62.1 The main advantage is that Pv CO* does not need to be calculated. 6.2L2 If the deadspace method is used to alter the VCO2, then no change in breathing pattern is required. 6.23 The method can, theoretically, be fully automated, (In its present commercial form, the size of the interposed deadspace must still be altered manually). 20 63 Limitations of Gedeon/Orr method There are a number of limitations in applying Orr'S method to spontaneously ventilating subjects. 63.1 In spontaneously breathing subjects, there is considerable bream-to-breath 25 variation in breath size and breathing frequency resulting in a variation in PBICO2. This poses problems with respect to: 63.1.1 Identification of FBTCO2 and PEICO1. Long periods of baseline measurements are needed in order to average the end tidal values and 13 WO 2004/073482 PCT/CA2004/000234 Page 13 identify the PETCO2 to be used as the baseline PETCO2 in the differential Fick equation. The test phase cannot last for more than about 30 seconds (due to recirculation), typically 5 breaths. This leaves little time to determine an accurate average PETCO2'. During prolonged baseline periods of observation, 5 the condition of the patient may change. 6.3.L2 Calculation of VCO2. The variations in PBTCO2 are related to variations in CO2 elimination but the relationship is not consistently reflected by the PBTCO2. For example, assuming a subject breathing at rest with an average resting breath size, an interposed smaller breath may result in a lower 10 PETCO2 (due to a smaller contribution of alveolar gas to me end tidal sample) but the CO2 elimination from that breath will be diminished. Conversely, a larger breath may result in the same PETCO2 as the resting breath but a greater volume of CO2 is eliminated. The commercial automated Gedeon method (NICO2, Novametrics Medical Systems, Wallingford, CT, USA.) 15 measures the CO? eliminated breath-by-bream and therefore must continuously average the values to measure VCO2. The NICO2 method of calculating VCO2 by real-time integration of continuous measurements of flow (with a pneumotachymeter) and CO2 concentration (with a capnogxaph) is fraught with potential for errors: a small error in the integration of these 20 two signals with different time delays and time constants results in a much larger error in the calculation of VCO2. In addition, the greater the variability of the breath size and CO2 concentrations, the longer the measurement time required for an accurate estimate of V CO2. 632. Calculation of VCO2'. Stable transient changes in VCO2 can not be achieved in 25 conscious spontaneously ventilating patients: 6.3.2.1 Interposing a deadspace and raising their PCO2 will stimulate spontaneously breathing conscious subjects to increase their VB and VCO2 until the PBTCO2 is restored. 6322 Any change in breath size or frequency during a period of breathing, (a 30 normal occurrence in spontaneously breathing people) changes the VCO2 14 WO 2004/073482 PCT/CA2004/000234 Page 14 during that period. During inspiration, the deadspace gas is inhaled first followed by fresh gas. A decrease in a breath size or frequency diminishes the volume of fresh gas inhaled (and thus the VCO2 for that breath). An increase in breath size or frequency will result in an increased volume of fresh gas 5 delivered to the alveoli 63.25 Each breath is an independent event and there is no inherent method to compensate in a subsequent breath for changes in VCO2 in the preceding breath. For the method to be implemented, therefore, measures must be taken to ensure that breath size and frequency stay absolutely constant 10 during the test The NICD2 method has no such built-in aspects. The method can therefore be used only in patients who have precisely uniform breathing pattern such as those that are paralysed and mechanically ventilated. 15 6.33 Identification of PETCO2PaCO2 gradient The Gedeon and Orr methods assume, ox require the establishment of, a constant gradient between the PBTCO2 and the PaCO2. The variation in PETCO2 is due to variations of distribution of fresh gas to various parts of the lung and any one bream does not reflect the overall state of CO* exchange. On the other hand, such 20 variations are not reflected in the PETCO2 which does reflect the overall exchange of CO2 and remains relatively constant Therefore, variations in PETCO2 also confound the quantification of me PBTCO2-PaCO2 gradient under control conditions. Although Orr provides a number of equations to correct for these limitations, these equations are empirical and do not 25 necessarily apply to a particular patient For example, they are applied whether or not there is irregular breathing. The PETCO2-PaCO2 gradient during the test phase when rebreathing occurs is unknown, hi the presence of large alveolar deadspace (as commonly occurs 30 in many ill patients} the PsrCQrPaCQt gradient will change during the rebreathing phase. Orr provides some equations to correct for this but since 15 WO 200W73482 PCT/CA2004/000234 Page 15 the volume of the alveolar deadspace is unknown, the applicability of the formula to any particular patient is unknown. This further diminishes the accuracy of calculating PaCO2. The manoeuvres required to determine each of the terms required to calculate Q (VCO2, VCO2, PBTCO2, PETCO2' and PaCO2) by the Orr/ Gedeon / NICO2 method is awkward to implement and prone to errors in measurement in the presence of any variation in breath amplitude or breathing frequency as occurs in spontaneously breathing humans or animals. 10 63A The parameter calculated by the differential Fick method as practiced by Gedeon/Orr/Respironics is pulmonary blood flow (Q p). Pulmonary blood flow may be less than the total cardiac output (Q t) when, for example, some of the Q is shunted from the right side of the circulation (superior vena 15 cava, right atrium, right ventricle, pulmonary artery) into the left side of the circulation without passing through the lungs. This is referred to as "shunt" (Qs). About 5% of venous blood bypasses the lungs (termed shunted blood) in healthy adults. Much larger shunts occur in marry medical conditions such as congenital heart disease, surgical repair of some congenital heart diseases, 20 pneumonia, pulmonary edema, asthma, pulmonary atelectasis, adult respiratory distress syndrome, obesity, pregnancy, liver disease and others. The differential Pick method does not include shunted blood in the calculation of Q and other empiric corrections must be made to account for it 25 7.0Kim-Rahn Farhi method 7.1 Theory: A unique maneuver was proposed by Km, Rahn and Farhi, Q. AppL Physiol 21:1388-44.1966.) as a way to calculate the oxygenated mixed venous PCOz (Pv CO2-oxy) as well as the true Pv COz and PaCO2. It is based on a paradigm of taking a breath of 30 O2, holding the breath, and exhaling slowly over a period equal to the recirculation 16 WO 2004/073482 PCT/CA2004/000234 Page 16 time. Over this lime of exhalation, the CO2 from the mixed venous blood will diffuse into the alveoli and Os will be absorbed. The low PO2 in the red blood cells in the mixed venous blood maximizes the volume of CO2 that can be carried by hemoglobin. Oxygen from the alveoli diffuses into the red blood cells, raising the 5 PO2 and decreasing me affinity of hemoglobin for COz (Haldane effect). This releases COz from the binding sites on the hemoglobin, making it available for diffusion into the alveoli. With breath holding, CO2 will accumulate in the alveoli and the alveolar PCO2 (PACO2)will rise until it no longer provides a gradient for diffusion from me blood. (This PCO2 is known as the oxygenated mixed venous PCO2 (PvCO2-oxy).), 10 However, O2 will continue to diffuse as long as the PAO2 is greater man Pv O2. Relatively little CO2 need diffuse into the alveoli to reach Pv CO2-oxy compared to the volume of Oz mat is available for uptake before the PO2 in the pulmonary capillary blood is in equilibrium with the PAO2. In other words, this equilibration of CO: in the alveoli with the mixed venous blood will occur well before mat of O2. 15 Since both O2 and CO2 are contained in the same physical volume, the changes in concentrations of each gas over a short period will reflect the rates of flux of mat gas over the same period. Therefore, over a short period, the ratio of PCO2 to PO» will reflect the respiratory quotient, RQ (denned as the rate of CO2 diffusion from the 20 blood into the alveoli divided by the rate of O2 absorption into the blood from the alveoli). The RQ will initially be highest at the beginning of the breath when the rate of CO2 diffusion into the alveoli is maximal, and will approach 0 when the alveolar PCO2 equals Pv CO2-oxy. In vitro studies have shown that PACO2 equals the true PvCO2 when the RQ = 0.32 and equals PaCO2 when RQ is equal to the patient's 25 steady state RQ (typically -0.8). 72. Test method The method suggested for performing this test would require a subject to take a maximum breath of 100% Oz and exhale very slowly and maximally. Over die course 30 of this exhalation, expired gas is sampled and analyzed continuously for both PO2 and PCO2. PO2 is graphed vs. PCO2 and the RQ is calculated from the instantaneous slope of tangents to the curves at various PCO2 values as follows: 17 WO 2004/073482 PCT/CA2004/000234 Page 17 RQ _ slope ~(FeO2* slope) – FeCO2 (FeO, * slope) – FeCO2, These RQ values are then plotted against their respective PCO2 data points resulting 5 in a linear relation as illustrated in figures 4 and 5 of IS. Kin, H. Rahn, and L. E Farhi cited above. 73 Advantages of the method. 7.3.1 This is the only known non-invasive method by -which true Pv CQj can 10 be calculated. 7.3.2 The method provides an estimate of PaCO2 not based on assuming a gradient between PETCO2 and PaCO2. 7.3.3 Data generated by the method can be used to calculate the d saturation of mixed venous blood. 15 - 7A Limitations of the Kim- Rahn-Farhi breath-hold method. The main limitation of this method is mat it requires the subject to have a large hmg capacity, hold his breath, and exhale over a prolonged duration. Patients with 20 conditions such as pulmonary fibrosis, pneumonia, adult respiratory distress syndrome, chronic obstructive lung disease, asthma, obesity, trauma, abdominal and chest surgery, mental obtundatian, confusion, pregnancy and many others have marked limitations in their ability to take a large breath. Patients ate required to cooperate with their duration of breath holding and rate of exhalation. Many 25 patients who are ill, exercising subjects, children and others are unable to perform this satisfactorily. This method is very awkward to automate or perform on ventilated patients. 8.0 Fisher method 30 84 Theory 18 WO 20C4/0734S PCT/CA2004/000234 Page 18 In a steady state, if a subject breathes in a PCO2 equal to Pv CO2-oxy, there will be no gradient for gas exchange and the difference in PCO2 between the inspired PCO2 (PrCO2) and the expired PCO2 (PECO2) will be 0. The volume of CO2 diffusing into the alveoli will be maximal when the difference between PlCO2 and PBCO2 is 5 greatest ie., what the PCO2 is 0. Since the change in alveolar PCO2 (PACO2) varies directly as the volume of CO2 diffusing into the alveoli and the volume diffusing into the alveoli varies directly as the gradient, then the difference between the F1CO2 and PECQZ will vary inversely as P1CQ2. In other words, graphing the difference between the PECO* and PlCQz (PECOI - PlCQz) vs. PICO* will result in a straight line. Since 10 subjects normally breathe room air (PrCQz equals 0 or Ox the control PElCQz provides the first point on the graph. When subjects inhale gas with any constant value of PCQ2, the PHTCOz at the end of an equilibration period not exceeding the time for recirculation will provide a second data point which can be used to. define the straight line which crosses the X axis where PlCQz equals Pv CQ2-oxy. 15. 82 Test method: The subject breathes via a non-rebreathing valve. The inspiratory limb is provided with either fresh gas or test gas with any PCQ2, To perform a test the inspired gas is switched from control gas to test gas for about one recirculation time. The P1CO2 of 20 the test gas, the PETCQZ just before the test (when PiCQ2 was 0), and the PETCO2 of the last breath before recirculation are used to calculate the Pv CQ2-oxy. 8.3 Advantages of the Prior Disclosed Previous Fisher method: 8.3.1 Any low inspired concentration of CQz such as 1% is adequate to 25 generate a data point; therefore the subject need not get a large CO2 load 8.3.2 This Fisher method extrapolates to the Pv CQz-oxy from a linear function and is therefore easier to calculate and snore accurate than with the partial rebreathing test in which data points axe fit to an 30 exponential curve for extrapolation to an asymptote. 8.33 The P1CQ2 can be any value, so accurate mixtures of gases are not required 19 WO 2004/073482 PCT/CA2004/000234 Page 19 83.4 Assuming arterial PCQj values (PaCQ2) can be obtained from arterial blood sample, for example, the method measures total Q, not just pulmonary blood flow. 8.35 The subject need not carry out any respiratory manoeuvre such as breath holding or hyperventilation. 83.6 The method does not entail any rebreathing. "Therefore, O2 levels remain stable throughout the test and supplemental Ox is not needed. 8.4 limitations of the Fisher method. 10 8.4.1 Uniform bream size cannot be guaranteed in spontaneously breaming subjects. A change of breath size or breaming frequency during the latter parts of the test phase will affect the PBTCQ2 and thus the calculation of FvCO2-oxy. Furthermore, as the subjects are inhaling 15 gas that contains CO2 they may be stimulated to take larger or more frequent breams. 8.4.2 The test requires an external source of CO2. This must be supplied via a tank of CO2 and a gas blender or via a tank of pre-mixed gas. If more than one test gas is required, then arrangements to. blend additional 20 gases must be made or more than one additional gas tank is required. This is inconvenient, costly, and adds complexity to the test method and additional bulk and weight to the test apparatus. 8.4.3 It is very complex to configure an automated system that works for both spontaneously breathing and mechanically ventilated patients. 25 8.44 There is no simple method to adapt currently available ventilators, anaesthetic machines or breathing circuits to provide a known and constant P1CO2 for a fixed number of breaths. 8.4.5 The technique is difficult to adapt to anaesthetized patients breaming via a circle circuit in which bom the test gas and the anaesthetic gases 30 enter the circuit, especially in me presence of a COz absorber removing CO* from the circuit 20 WO 2J104/073482 PCT/CA2004/000Z34 Page 20 OBJECT OP THE INVENTION It is therefore a primary object of this invention to provide an improved method and 5 apparatus for the purpose of iion-invasively determining cardiac output (Q) which may be utilized in ventilated subjects, subjects who breath spontaneously or subjects who are under controlled ventilation such as those undergoing surgical procedures under general anesthesia. 10 It is yet a further object of this invention to provide an improved method and the apparatus related thereto for the purposes of non-invasively detamining alveolar ventilation (VA ) and calculating minute CO* production (VCQ2), oxygenated mixed venous PCQ2 (Pv CQ2-oxy), true mixed venous PCO2 ( true Pv CO2), pulmonary shunt, anatomical dead space, arterial PCQ2, at a greater accuracy titan prior known 15 non-invasive methods and apparatuses would provide. It is yet another object of the invention to provide a method of non-invasively calculating the oxygen saturation of mixed venous blood (Sv O2) which may be 20 utilized to reveal heart failure of septic shock in a patient or the like. It is yet a further object of this invention to provide an improved method and Ihe apparatus related thereto for the purposes of determining Q, VA and calculating VCO2, Pv COz-oxy, true Pv COz, pulmonary shunt, anatomical dead space in a non-25 invasive and fully automated manner. Further and other objects of the invention Will become apparent to those skilled in the art when considering the following summary of the invention and the more detailed description of the preferred embodiments illustrated herein. 21 WO 2004/073482 PCT/CA2OO4/O0023* Page 21 SUMMARY Of THE INVENTION This invention discloses a method and apparatus for calculating all of the Q regardless of shunt, calculating the shunt, anatomical and alveolar deadspace, true 5 mixed venous O2 saturation, true mixed venous PCO2, and PaCO2. Furthermore the method and apparatus can be used with ventilated subjects, subjects breathing spontaneously/ even with marked variations in their tidal volume and breathing frequency, or subjects undergoing surgery under anaesthesia. Subjects need not perform any respiratory manoeuvre such as hyperventilation or breath, holding. 10 According to one aspect of the invention there is provided an improved method and apparatus for the purposes of determining Q and VA and calculating VCO2, PvCO2-oxy, true PvCO2, PaCQ2, pulmonary shunt, and anatomical dead space which increases the accuracy of these determinations in relation to known methods 15 and apparatus and allows the full automation of the various methods disclosed herein for these determinations and calculations The new method: 2. is insensitive to changes in minute ventilation (VE), tidal volume and/or 20 respiratory frequency so that the method can be carried out in spontaneously breathing subjects; 2. is simplified and less expensive to construct compared to other non-invasive automated methods of performing the differential Pick technique in that a. it does not necessarily require any mechanically activated valves to 25 be actively engaged in the patient circuit b. does not require a pneumotachygraph to measure flows c. does not require manual adjustment of an interposed dead space (and thus can be totally automated); d. The device will be the same for all sizes of adults (one size fits all) 30 3. is compatible with a number of sequential gas delivery breathing (SGDB) circuits. A SGDB circuit provides for the sequential delivery of two gas sets 22 WO ;.504/073482 PCT/CA2004/00O234 Page 22 to the lungs during inhalation. A gas set is composed of one or more gases and vapors. The first gas set (PCS) is provided from the beginning of inhalation and can terminate at some time during inhalation depending on the FGS flow and the VB, at which time inhalation continues with the 5 delivery of the second gas set (SGS). For the purposes of measuring Q and the other physiologic parameters described herein, it is preferred that there is a distinct transition from FGS to SGS and there is no mixing of the gas sets. A small degree of mixing of FGS with SGS during the latter part of inhalation will reduce accuracy of the measured and calculated results. Mathematical 10 corrections can be made to minimize effect of the mixing of FGS with SGS, but cannot completely negate the effects in all circumstances. Therefore, breathing circuits which separate the FGS from the SGS are preferred. i. the generation and presentation of data will be substantially the same for controlled (mechanical) ventilation and rebreathing so that the algorithms to 15 perform, the tests and analyze the data can be substantially die same; 5. can institute an equnlibrium steady state within one recirculation time so mat the value for FETCO2 will be a true measured value rather than one requiring multiple corrections based on unsubstantiated assumptions; 6. will allow the measurement of a new steady state PETCO2 within one 20 recirculation time and thus actualize the assumption underlying the Differential Pick approach that Pv CO2 is unchanged; 7. will minimize the effect of changes in tidal volume on the alveolar ventilation. 8. maintain the alveolar PQ2 while making pulmonary blood flow 25 measurements; 9. make all calculations without a requirement to measure breath-by-breath volumes of inspired and expired CQ2 or any flows of tidal gases. According to one aspect of the invention there is provided an improved apparatus 30 and method of identifying the alveolar ventilation (VA), substantially as Illustrated and described herein, preferably the VA so determined is utilized to calculate the 23 WO 2004/073432 PCT/CA2004/000234 Page 23 VCO2 as VA x PETCO2. where PETCO2 is the fractional pressure of CO? in end tidal gas. In one embodiment of the improved apparatus and method: 5 a) the Fisher approach is used to determine PvCO2-Oxy (or) b) the Kim Rahn Farhi approach is used to determine i) PvCO2-oxy ii) true Pv CQ2 iii) PaCO2 10 iv) true PVCO2 plus the information from a pulse oximeter to determine mixed venous hemoglobin Q* saturation (or) c) the differential CO2 Pick technique of Gedeon and Orr is utilized to determine any combination of i) PvCO-oxy 15 ii) Q iii) VCO2 iv) VCO2 v) PBTCO2-PaCO2 gradient determined using the PaCQ2 as determined by the Kim Rahn Farhi method from data collected 20 while reducing the VCO2 in order to perform the Differential Pick method, (or) d) Q is determined via the Kan Rahn Farhi method performed during partial rebreathing using a CO2 Pick method where the i) Vi b calculated with or without the new method as disclosed 25 ii) CaCQ2 and Cv CO* are determined from the PaCOa and PvQO2 respectively derived by the Kim Rahn Farhi method; (or) e) calculation of the respiratory quotient (RQ) is determined as PBlCQ2/ (Pl02-PB02);(or) f) PaCO2* is determined directly via analysis of arterial blood sample, 30 arterialized venous sample, transcutaneous PCQ2 electrode, or other methods known to those skilled in the art 24 WO 2004/073482 PCT/CA2004/000234 Page 24 wherein said apparatus or method may be utilized for very accurate non¬invasive determination of Q and the other indicated parameters. 5 According to yet another aspect of the invention there is provided an improved method of apparatus for determining VA, VCO2 and calculating Q, PvCO2- oxy, true Fv 00% PaCO2, pulmonary shunt, anatomical dead space, and Q* saturation in mixed venous blood; which increases the accuracy of these determinations and calculations in relation to known methods and apparatuses and allows for full 10 automation thereof if necessary by using automated means well known to those skilled in the art, to: i) induce a step change in VCO2 by providing a step change in FGS flow to a SGDB circuit to create, with the control data at rest, two sets of data for said determination utilizing the differential Pick equations; (or) ii) change the partial pressure of COz in FGS of a SGDB circuit to create, with the control data at rest, two sets of data for said determination utilizing the Fisher or the differential Pick equations; (or) iii) change FGS flow or change the partial pressure of CO2 in FGS in a SGDB circuit to simulate complete or partial bream holding and utilizing the Kim-Rahn-Farhi technique, wherein the PETCO2 of each breath is equivalent to a sequential alveolar sample; thereby providing more relevant data to calculate desired parameters. 25 In yet another embodiment of the invention a ventilation circuit and method is provided for using sequential delivery of gas sets in order to identify the minute volume of gas entering the anatomical dead space and the minute volume entering the alveoli and thereby available for gas exchange (VA) . Subsequently, setting FGS 30 flow to substantially equal to or less than VA substantially controls VA. A step reduction in VA can then be induced by a step reduction in FGS flow, and resultant 25 WO .20M/073482 PCT/CA2004/Q00234 Page 25 effects on end tidal gases such as CO2 can be used in the to calculate Q and other parameters as previously set out herein in the Background, disclosures and figures. In yet another embodiment there is provided a method and apparatus of 5 determining Q and the other parameters disclosed by utilizing any SGDB circuit for example, the circuits described and illustrated herein by reducing the FGS flow to said circuit or increasing the PCO2 of FGS to said circuit, independent of the breathing rate thereby allowing for calculations to be made via Differential Fick equations, and/or Fisher method, and / or the Kim-Rahn-Farhi method, 10 Preferably the method or apparatus previously described wherein the CQ2 content as calculated from Pv CQ2-oxy and true Pv CQ2, may be utilized to determine me Q2 saturation of mixed venous blood with known relations between CO* content, O2 saturation and PCO2. 15 In one embodiment the method or apparatus disclosed may be utilized wherein the arterial O2 hemoglobin saturation, as determined by a non-invasive pulse oximeter, which makes me measurement by shining infrared light through a finger, is utilized with the Q2 saturation value in the pulmonary artery as calculated by the Kim Rahn 20 Farhi method, to calculate the fraction of shunted blood (assuming fully oxygenated blood in the end pulmonary capillary) thereof. Preferably said method or apparatus is utilized to determine the fraction of shunted blood Qs, which in conjunction with determination of total cardiac output Qr 25 (utilizing PaCO2 as determined by the Kim Rahn Farhi method, or available from analysis or arterial blood or determined by transcutaneous PCQ2 determination or otherwise known to those skilled in the art, as a term in the Pick equation) and pulmonary blood flow Qp (utilizing PBlCOz in the Fick equation) may be used to determine Q a the pulmonary output via the relationship. 30 26 WO 2004/073482 PCT/CA2004/000234 Page 26 Preferably the method or apparatus disclosed wherein the O2 saturation of haemoglobin in mixed venous blood (SaO2), as determined therewith, is utilized to reveal a condition in a patient such as septic shock, or heart failure. 5 BRIEF DESCRIPTION OP THE FIGURES Figure 8: PCO2 vs time tracing during a rebreathing equilibrium test for determining oxygenated mixed venous PCO* 10 Figure 9: PCO2 vs. time tracing during exponential method of finding oxygenated mixed venous FCO2. Figure 2 is a SGDB Circuit as taught by Fisher in US Patent 6,622,725 referred to herein as the Fisher circuit 15 Figure 3 is similar to Figure 2 wherein the reservoir bags are remote from the patient Figure 5 is a new circuit for use with spontaneous ventilation. 20 Figure 3B is similar to Figure 5 wherein bypass limb, bypass valve, and passive expiratory valve are replaced by an active expiratory valve. Figure 3D is similar to Figure 2 wherein an active valve has been added to the inspiratory limb to prevent mixing of FGS with SGS during inhalation. 25 Figure 5A is similar to Figure 5 wherein an active valve has been added to the inspiratory limb to prevent mixing of FGS with SGS during inhalation Figure 3E is similar to Figure 2 wherein an active valve has replaced the passive 30 inspiratory valve. 27 WO 2004/073482 PCT/CA2004/000234 Page 27 Figure 5B is similar to Figure 5 wherein an active valve has replaced the passive inspiratory valve. Figure 3C is similar to Figure 3B wherein an active valve has replaced, the passive 5 inspiratory valve. Figure 4 shows a modification of any of the circuits shown in Figures 2,3-3E, 5-5B for use with a mechanically ventilated patient 10 Figure 4B shows the preferred embodiment modified for use on ventilated, patients. Figure 6 is a modification of the above circuits to include co-axially arranged inspiratory and expiratory limbs between the valves and the patient. 15 Figure 6A shows the preferred embodiment of the cardiac output drcuit where inspiratory and expiratory limbs are co-axially arranged with the circuit of Figure 5A. Figure 7 is a new circuit designed to allow measurement of cardiac output while 20 delivering anesthetics or removing volatile agents from a patient Figure 5C shows a detail of a circuit design where the passive valves are surrounded by the exhaled gas reservoir 25 Figure 10: Apparatus for non-invasive cardiac cardiac output apparatus consisting of a breathing circuit, gas sources, gas flow controllers, gas concentration sensors, and microprocessor capable of receiving and storing analog and digital input from sensors and operators, storing and following a decision tree, and generating output signals to a computer screen and to flow controllers. 30 28 WO 2004/073482 PCT/CA2004/00O234 Page 28 Figure 11 Flow diagram describing automated sequence of events performed by the non-invasive cardiac output apparatus in order to automatically generate and record data non-invasively and calculate Q and other physiologic parameters. 5 Figure 12 is a schematic of a standard anesthetic circle system herein provided as reference for discussion of disclosed system. Gas entering the anesthetic circuit consisting of oxygen, with the possible addition of air and/or nitrous oxide (N3O), and possibly an anesthetic vapor such as isoflurane, desflurane or sevoflurane enters the fresh gas port (6) at a constant and known flow. The gas concentrations entering 10 the circuit are set by the anesthesiologist The patient inspires through the patient port (1) and draws fresh gas plus gas drawn from the gas reservoir bag (4) through the CO2 absorber (5) up the inspiratory limb (8). During exhalation, the inspiratory valve (7) closes and the fresh gas passes through the CO* absorber (5) towards the gas reservoir bag. Expired gas flows down the expiratory limb (2) displacing gas 15 into the gas reservoir bag (4). When the reservoir bag is full, the pressure in the circuit rises, opening the AFL (airway presslure relief) valve (9), and the rest of the expired gas exits the circuit through the AFL valve. Gas is sampled continuously at the patient port and is analyzed for concentrations of constituent gases. The inspiratory (2) and expiratory (8) limbs consist of tubing (T). 20 Figure 13 A detail of the computer screen output of an automated analysis of test finding VA by progressive reduction in SGF flow method in a subject is illustrated in Figure 13. The figure illustrates that progressive reduction of SGF (labelled "FGF' in the figure) results in a distinct inflection point when either PErCC* or PETO2 is 25 graphed as a function of SGF. DETAILED DESCRIPTION OF THE INVENTION 30 Detailed Description of the Apparatus Referring now to Figure ??, an apparatus is shown with the following components: 29 WO 2004/073482 PCT/CA2004/000234 Page 29 1) a breathing circuit (202), said breathing circuit preferably has the characteristic that, on exhalation, exhaled gas is kept separate from inhaled gas and on inhalation, when VE is greater than the flow of a first gas set (FGS) into the circuit, the subject inhales FGS gas-first and then inhales a 5 second gas set (SGS) gas, preferably said SGS containing COz and where SGS may be mostly previously exhaled gas. Any SGDB circuit can be used to greater or lesser benefit, according to its characteristics. We provide below detailed descriptions of several alternate configurations and outline their particular advantages and drawbacks with respect to measuring Q 10 and related parameters outlined above. 2) a gas sample line (204.1) leading to a gas analyzer (204) that monitors the concentration of gases, for example COz, Qs, at the patient-circuit interface and outputs preferably an electric signal corresponding to the concentrations (204.2) (for example if the gases of interest are O2 and COz, 15 the "#17500 Q2 and CQ2 analyzer set" (Vacurned, Ventura CA, USA)) 3) a precise gas flow controller (200), preferably one that can control Ihe flow of one or more pressurized gases (such as oxygen, air, CQ2) singly or in combination, and that can be set manually or via an automated system such as via machine intelligence (for example, the Voltek gas flow controller by 20 Voltek Enterprises, Toronto, Canada); 4) a source of FGS (201), preferably containing Oz and /or air with or without CO*; 5) means (205) to identify phase of breathing, for example using electronic pressure sensors with tubing to sample pressures at me patient-circuit 25 interface (205.1)or in other locations in the circuit and generating electrical signal corresponding to the sensed pressures. Such means will provide electrical signal (205.2). Phase of breathing can also be determined from analysis of gas sensor output by machine intelligence. 6) a computer or machine intelligence (207) which records, stores, analyzes 30 signals from gas analyzer (204) and pressure transducer (if present), contains a predetermined set of instructions regarding the analysis of data 30 WO 2004/073482 PCT/CA2004/000234 Page 30 such as calculation of Q and physiologic parameters, determination of phase of respiration, display of information on a computer screen, and control of gas flow controller (200) including the tuning, sequence and flow of gas. 5 7) wherein said device may be utilized for non-invasive measurement and determination of Q and other parameters such as VA, VCO2, Pv CO2-oxy, true Pv CO2 PaCO2 pulmonary shunt, and anatomical dead space 10 Detailed Description of Breathing Circuits figure 5 shows a breathing circuit which provides sequential delivery of the PGS followed by the SGS when VE exceeds FGSF, with the manifold containing the valves and the PGS reservoir bag and the expiratory gas reservoir bag remote from 15 the patient This improvement reduces the bulk of the patient manifold, and eliminates ti»a possibility of the SGS mixing with the FGS due to vigorous exhalation. Referring to Figure 5, Patient (38) breathes via a Y connector (40). Valve (31) is an inspiratory valve and valve (33) is an expiratory valve. Valve (35) is a bypass valve 20 in the bypass limb (34) that bypasses the expiratory valve (33) and has an opening pressure greater than inspiratory valve (31). Valves (35,33) may be close to or distal from the patient manifold as desired, as long as they are on the expiratory limb (39). However, in the preferred embodiment, they are distal to the patient to reduce the bulk of the patient manifold. Inspiratory valve (31) may be close to, or distal from, 25 the patient manifold as desired/ as long as it is on the inspiratory limb (32). In the preferred embodiment it is distal to tine patient as well. PGS enters the circuit via port (30). Function: 30 During exhalation, increased pressure in the circuit closes inspiratory valve (31) and bypass valve (35). Gas is directed into the exhalation limb (39), past one-way valve 31 WO 2004/073482 PCT/CA2004/00023 Page 31 (33) into the expiratory gas reservoir bag (36). Excess gas is vented via port (41) in expiratory gas reservoir bag (36). FGS enters via port (30) and fills FGS reservoir (37). During inhalation, inhalation valve (31) opens and FGS from the FGS reservoir (37) and FGS port (30) enter the inspiratory limb (32) and are delivered to the patient 5 If FGSF is less than VB, the FGS reservoir (37) empties before the end of the breath, and continued respiratory effort results in a further reduction in pressure in the circuit When the opening pressure of the bypass valve (35) is reached, it opens and gas from the expiratory gas reservoir (36) passes into the expiratory limb (39) and makes up the balance of the breath with SGS. 10 Thus when FGSF is less than VB, the subject inhales FGS, then SGS, and no contamination of FGS occurs. Figure 36 shows an alternate embodiment of the circuit illustrated in. Figure 5 where 15 the passive expiratory valve (33) and expiratory bypass limb (34), and expiratory limb bypass valve (35) are replaced with a control valve that is triggered by the collapse of the inspiratory reservoir. Referring to Figure 3B, a control valve (401) is placed in the expiratory limb (16) anywhere along its length between the patient port (10) and the expiratory reservoir bag (18). When the patient's VE exceeds the FGSF 20 during inspiration the reservoir bag (20) collapses. This is detected by pressure sensing means (405) through port (406) as an acute reduction in pressure. Pressure sensing means (405) could be an electronic pressure transducer capable of detecting changes 2 cm H2O pressure, for example Immediately afterwards, valve (401) is then opened by control means (403), which could be an electronic signal for activating a 25 solenoid valve, for example, leading to depressurization and collapse of a balloon valve, as is known to those skilled in the art, resulting in SGS is being inhaled for the balance of inhalation. During exhalation, patient exhales through expiratory tube (16) past valve (401) into the SGS reservoir (18). At end of exhalation, as detected by pressure sensing means (405) as a reduction of pressure, valve (401) is closed by 30 control means (403), which could be an electronic signal for toggling a solenoid valve, for example, leading to pressurization and inflation of a balloon valve, as is known to -those skilled in the art 32 WO 2004/073482 PCT/CA2004/000234 Page 32 While the circuits of Figure 5 and Figure 3B present the advantages over the Fisher circuit of reducing the bulk of the patient manifold, and eliminating the possibility of the SGS mixing with the FGS due to vigorous exhalation, they still have the 5 following drawback: When FGS reservoir (20, 37) is emptied and the patient is breathing SGS for the balance of an inspiration, the circuit does not deliver SGS alone but a mixture of SGS and FGS. The FGS continues to flow into the circuit and is drawn by inhalation past one-way inspiratory valve (31,3) and allows FGS gas to be inhaled from the inspiratory limb (32,14). To optimize the generation of data 10 required to measure of cardiac output, it is necessary to redirect the FGS into the FGS reservoir (37,20) for the balance of inhalation after the initial collapse of the FGS reservoir. This would prevent mixing of FGS with SGS during the period of inhalation where the patient breathes SGS. This limitation of circuits illustrated in Figures 5 and 3B with, respect to measuring cardiac output are shared with the Fisher 15 circuit - Figure 3D shows an improved circuit that prevents contamination of the SGS by FGS when SGS is being delivered to the patient Referring to Figure 3D, FGS control valve (400) is added to the inspiratory limb (14) at some point between the FGS port (12) 20 and the inspiratory valve (11). Pop-off valve (425) is connected to the inspiratory limb on the side of the FGS control valve (400) that is proximal to the inspiratory reservoir bag (425). During exhalation, gas passes from the patient port (10), through the expiratory one-way check valve (15) down the expiratory limb (16) into the expiratory reservoir bag (18). Excess gas exits the expiratory reservoir bag (18) at the 25 opening (19) remote from the entrance. FGS enters the circuit at a constant flow via a fresh gas port (12). As the inspiratory one-way check valve (11) is dosed during exhalation, the fresh gas accumulates in the fresh gas reservoir bag (20). During inhalation, FGS entering from the port (12) and the FGS reservoir (20) passes through the inspiratory valve (11) and enters the patient If the FGSF is fess than VE, the 30 FGS reservoir bag (20) collapses, as detected by pressure sensing means (405) connected to pressure sensing port (406). FGS control valve (400) is closed via valve control means (403), and valve (17) in the bypass limb (13) opens, directing 33 WO KM/073482 PCT/CA2004/000234 Page 33 previously exhaled gas to the patient When the FGS control valve (400) is closed, any FGSF entering the circuit during the balance of inspiration is directed only to the SGS reservoir bag (20) and not to the patient, who is receiving SGS for the balance of inspiration. FGS control valve (400) may be ie-opened any time from the beginning 5 of expiration to just before the next inspiration. FGS control valve (400) may be any type of valve, and is preferably an active valve such as a balloon valve, known to those skilled in the art that can be controlled by automated means. The pop-off valve (425) opens when the reservoir bag (20) is full to prevent the reservoir bag (20) from overfilling. 10 The circuit illustrated in Figure 5A is similar to that in Figure 5 but has the addition of a FGS control valve (400), together with pressure sensing means (405) and port (406), and valve control means (403), added to the inspiratory limb of the circuit (32) distal to the one-way inspiratory valve (31) and proximal to tins FGS inflow port (30). 15 Similarly, a FGS control valve, together with pressure sensing means and port, and valve control means, may be added to the inspiratory limb (14) of the circuit illustrated in Figure 3B positioned distal to the one-way inspiratory valve (31) and proximal to the FGS inflow port (12) to achieve me same result, namely, prevention of contamination of SGS by FGS when VE exceeds FGSF and the FGSF reservoir bag 20 is emptied. We present two additional circuits that are configured by adding FGS control valve (400) together with pressure sensing means (405) and port (406), and valve control means (403). to thu Fiaher circuit and the circuit illustrated in Figure 5 and removing 25 the passive one way inspiratory valve (11, 31), as shown in Figure 3E and 5B respectively. These circuits function identically to those illustrated in Figures 3D and 5A with respect to complete separation of FGS and SGS during inhalation. In such a circuit during inspiration, FGS control valve (400) is open until FGSF reservoir bag (20,37) is emptied, then it is dosed so that any additional FGSF 30 entering the circuit during the balance of inspiration is directed only to the reservoir bag £20) and not to the patient As the patient continues to inspire, bypass valve (1735) opens allowing the patient to inhale SGS for the balance of inspiration. 34 WO 2004/073482 PCT/CA2004/000234 Page 34 .Another embodiment of each of the circuits whereby the valves can. be remote from the patient without loss of sequential delivery of FGS and SGS, such as those illustrated in figures 5,3B, 5A, 5B, 3C, 4B, is the replacement of separate inspiratory 5 limbs and expiratory limbs with co-axially arranged inspiratory and expiratory limbs as shown in Figure 6. Figure 6A shows the preferred embodiment of the invention: The circuit valves are configured as in the circuit illustrated in Figure 5A with the improvement of co-axially arranged inspiratory (59) and expiratory (51) limbs. The limbs (51,59) are co-axial so that one limb is contained within the other 10 for some length of tubing, with the limbs separating at some point along its length, such that the expiratory limb (51) leads to the exhaled gas reservoir (54) and the inspiratory limb (59) leads to the FGS reservoir (56). This has two important advantages over the circuit of Figure 5: 1. A single tube is connected to the patient interface making 15 it easier to manage sick patients 2. Tne heat contained in the expiratory limb (51) warms the FGS entering through the inspiratory limb (59). 3. If the inner tube is of a material mat allows moisture to pass through it but not gas, such as Nation, will promote moisture 20 exchange as well, so that FGS will become slightly moisturized and more comfortable for the patient to breathe if the SGS is moist It should be understood that co-axial tubing may be used with any of the SGDB circuits described herein. 25 Description at a Prefered Embodiment Referring to Figure 6A, Patient port (50) opens directly to the inspiratory limb (59) and expiratory limb (51) without a Y connector, where the limbs are arranged co-axially. Valve (31) is an inspiratory valve and valve (33) is an expiratory valve Valve (35) is a bypass valve in the bypass limb (34) mat bypasses the expiratory 30 valve (33) and has an opening pressure greater than inspiratory valve (31). Valves (35,33) are preferably distal from the patient on the expiratory limb (51) to reduce the bulk of the patient interface. Inspiratory valve (31) is also preferably distal from, 3 5 WO 2004/073482 PCT/CA2004/000234 Page 35 the patient on the inspiratory limb (59). FGS enters the circuit via port (30). PGS control valve (400) is on the inspiratory limb (59) between port (30) and inspiratory valve (31). FGS reservoir bag (37) is connected to inspiratory limb (59) distal to the patient past port (37). SGS reservoir bag (36) is distal to the patient on fee expiratory 5 limb (51) past expiratory valve (33) and bypass valve (35). Excess expiratory gas vents to the atmosphere via port (41). Pressure sensing means (405) is connected to pressure sensing port (406) which is connected to the patient port (50), and valve control means (403). Pressure sensing port (406) may be connected to the co-axial inspiratory (59) and expiratory limb arrangement (51) anywhere along its length 10 between the inspiratory valve (31) and the patient port (50) or between the expiratory valve (33) and the patient Pop-off valve (425) is connected to the inspiratory limb on the side of the PGS control valve (400) that is proximal to the inspiratory reservoir bag (425). 15 Function: During exhalation, increased pressure in the circuit closes inspiratory valve (31) and bypass valve (35). Gas is directed into the exhalation limb (51), past one-way valve (33) into the expiratory gas reservoir bag (36). Excess gas is vented via port (41) in expiratory gas reservoir bag (36). FGS enters via port £30) and fills FGS reservoir 20 (37). During inhalation, inhalation valve (31) opens and FGS from the FGS reservoir (37) and FGS port ^0) enter the inspiratory limb (59) and are delivered to the patient If FGSF is less than VE , the FGS reservoir (37) empties before me end of the breath, and continued respiratory effort results in a further reduction in pressure in the circuit When the opening pressure of the bypass valve (35) is reached, it opens and 25 gas from the expiratory gas reservoir (36) passes into the expiratory limb (39) and makes up the balance of the bream with SGS. The emptying of FGS reservoir bag (37) is detected by pressure sensing means (405) such as an electronic pressure transducer, known to those skilled in the art, connected to pressure sensing port (406), and FGS control valve (400) such as a balloon valve known to those skilled in 30 the art, is closed via valve control means (403) such as access to gas pressure controlled by an electronically toggled solenoid valve known to those skilled in me art When the FGS control valve (400) is closed, any additional FGSF entering the 36 ^■O ?0tM/073482 PCT/CA2004/000234 Page 36 circuit during the balance of inspiration is directed only to the PCS reservoir bag p20) and not to the patient, who is inhaling only SGS for the balance of inspiration. FGS control valve (400) may be re-opened any time from the beginning of expiration, as sensed by the reverse of pressure by the pressure sensing means (405), to just before 5 the next inspiration, also sensed by pressure changes in the breathing circuit Pop-off valve (425) prevents the FGS reservoir bag (20) from overfilling when FGS exceeds VE. Thus when FGSF is less than VB, the subject inhales FGS, then SGS, and no 10 contamination of SGS with FGS occurs. Use of Circuits for Ventilated Patients Any of the SGDB circuits disclosed herein as well as the Fisher circuit can. be used for a patient tinder controlled ventilation by enclosing the FGS reservoir (20) and 15 exhaled gas reservoir (18) within a rigid container (21) with exit ports for the inspiratory limb of the circuit (24) and expiratory limb of the circuit (25) and port for attachment to a patient interface of a ventilator (22) as illustrated in Figure 4. In Figure 4, the inspiratory limb (500) represents the inspiratory limb of any of the SGDB circuits herein described, and expiratory limb (501) corresponds to the 20 expiratory limb of any of the SGDB circuits herein described. The FGS reservoir bag (20) and expiratory gas reservoir bag (18) are enclosed in a rigid air-tight container such mat the inspiratory limb (500) enters the container via port (24) and expiratory limb (501) enters the container via port (25) such that the junctions of the outside of the limbs form an air-tight Beal with the inside surface of the ports. A further port 25 (22) 1B provided for attachment of the Y piece of any ventilator (23). Detachment from the ventilator allows the circuit to be used with a spontaneously breathing patient During the inspiratory phase of the ventilator, the pressure inside the container (21) rises putting the contents of the FGS reservoir bag (20) and the expiratory gas reservoir bag (18) under the same pressure. Since the opening 30 pressure of the inspiratory valve is less than that of the bypass valve for circuits using passive bypass valves (for example those shown in Figures 2,3,5,5B, 5A, 3B, and 3D), the FGS reservoir (20) will be emptied preferentially. "When the FGS 37 WO 2004/073497. PCT/CA2004/000234 Page 37 reservoir (20) is empty, the pressure in the container (21) and inside the expiratory gas reservoir (18) will open the bypass valve (35,17, 206) and begin emptying exhaled gas reservoir (18) delivering SGS to the patient For circuits using an actively engaged control valve (400) in the inspiratory limb of the circuit a valve 5 opening detection means (407) such as an electronic circuit that is broken by the opening of the valve when the valve is part of a closed electronic circuit, not shown, detects opening of the one way valve (35,17,206) in the exhalation bypass limb. The FGS control valve (400) is then dosed, directing FGS into the FGS reservoir bag until the collapse of the FGS reservoir during the next inspiratory phase. 10 During the exhalation phase of the ventilator, the ventilator's expiratory valve is opened and contents of the container (21) are opened to atmospheric pressure, allowing the patient to exhale into the expiratory gas reservoir (18) and the FGS to flow into the FGS reservoir bag (20). Thus, the FGS and SGS are inhaled sequentially 15 during inhalation with controlled ventilation without mixing of FGS with SGS at any time. Figure 4B shows the ventilator configuration described above as used with the preferred circuit shown in Figure 6A. This is the preferred embodiment for 20 ventilated patients. The primary difference between the standard anesthetic circle circuit of the prior art (Figure 12) and the circuits disclosed herein is that with the circuits disclosed herein, both a SGS reservoir (18) and a FGS reservoir (20) are in the rigid box. With the valve 25 configurations disclosed herein, there will be sequential delivery of the FGS, men the SGS, when VB exceeds the FGSF. This does not occur with the standard anesthetic circle circuit even; if the CO* absorber is removed from the circuit 30 CIRCUIT FOR CALCULATION OF Q AND RELATED PHYSIOLOGIC PARAMETERS WHLE MODIFYING SECOND GAS SET 38 WO 2004/073482 PCT/CA2004/000234 Page 38 Figure 7 shows the preferred circuit for measuring cardiac output while maintaining the ability to modify the SGS. The circuit consists of the following components: 200 patient port 201 three-port connector 5 202 expiratory limb 203 expiratory valve 204 canister on bypass conduit that may be switched to be empty, contain CQ2 absorbing crystals, zeolyte, charcoal or similar substance mat filters anesthetic agents, or hopcalite for filtering carbon monoxide 10 205 bypass conduit 206 one-way bypass valve with opening pressure slightly greater than mat of the inspiratory valve (219) 207 SGS reservoir bag 208 port in rigid container for entrance of expiratory limb of circuit in an air- 15 tight manner 209 exit port for expired gas from expired gas reservoir 210 a 2-way manual valve that can be turned so that me gas in the rigid box (216) is continuous with either the ventilator Y piece (211) or the manual ventilation assembly consisting of ventilating bag (212) and APL valve (213) 20 211 the ventilator Y piece 212 the ventilation bag 213 APL valve 214 ventilation port in rigid box (216) 215 FGS reservoir 25 216 rigid box 217 port in rigid container for entrance of inspiratory limb of circuit (220) in an air-tight manner 218 FGS inlet port 219 inspiratory valve 30 220 inspiratory limb 221 bypass limb proximal to canister (204) 400 active FGS Control valve 39 WO 2004/073482 PCT/CA2004/000234 Page 39 403 valve control means 407 bypass valve opening sensing means , Function of the circuit as an anesthetic circuit: 5 For spontaneous ventilation, 3-way valve (210) is open between rigid container (216) and manual ventilation assembly consisting of ventilation bag (212) and APL valve (213). When the patient exhales, increased pressure in the circuit doses inspiratory valve (219) and bypass valve (206). Exhaled gas is directed into the exhalation limb (202), past one-way valve (203) into the expiratory reservoir bag (207). FGS enters via 10 port (218) and fills the FGS reservoir (215). During inhalation, inhalation valve (219) opens and FGS from the FGS reservoir (215) and FGS port (218) enter the inspiratory limb (220) and are delivered to patient If FGSF is less than VB, the FGS reservoir (215) empties before the end of the breath; continued respiratory effort results in a further reduction ia. pressure in the circuit When the opening pressure of the bypass 15 valve (206) is exceeded, it opens and gas from the expiratory gas reservoir (207) passes through the canister (204) into the rebreathing limb (221) and makes up the balance of the breath with SGS. The opening of bypass valve (206) is detected by valve opening sensing means (407) signals are sent to dose FGS control valve (400) by activating valve control means (403). When the FGS control valve (400) is dosed, 20 any additional FGSF entering the circuit during the balance of inspiration is directed only to the FGS reservoir bag (215) and not to the patient When valve (400) is dosed patient receives only SGS for the balance of inspiration. FGS control valve (400) may be re-opened -any time from the beginning of expiration to just before the next inspiration. Phase of ventilation is sensed by sensor (407). 26 For the purposes of functioning as an anesthetic delivery circuit,, part of the FGS entering the circuit would be the anesthetic vapor, for example Desflurane, and the canister (204) would contain CO2 absorbent material. The SGS passes through the canister (204) but still contains expired O2 and anesthetic, which can both be safely 30 rebreathed by the patient In this respect, the circuit in Figure 7 functions like a circle anesthetic circuit in which the FGSF containing Q2 and anesthetic can be reduced to 40 WO 2004/073482 FCT/CA2004/000234 Page 40 match the consumption or absorption by the patient However, by bypassing the canister (204), the circuit can be used for measuring cardiac output. If the canister (204) is filled with hopcalite it can be used to remove carbon monoxide 5 from the patient since the SGS still contains expired O2 and CO*. LE the caruster (204) is filled with zeolite it can. be used to remove volatile agents such as anesthetics from the patient Advantages of circuit over previous art 10 1. It is comparable to the circle anesthesia circuit with reaped: to efficiency of delivery of anesthesia, and ability to conduct anesthesia with spontaneous ventilation as well as controlled ventilation. 2) It is often important to measure tidal volume and VE during anesthesia. With a 15 circle circuit a pneumotach with attached tubing and cables must be placed at the patient interface, increasing the dead-space, bulk and clutter at the head of the patient With our circuit the pneumotach (or a spirometer if the patient is breaming spontaneously) can be placed at port (214) and thus; remote from the patient 20 3) Sasano (Anesth Analg 2001; 93:1188-1191) taught a circuit that can be used to accelerate the elimination of anesthesia. However that circuit required additional devices such as an external source of gas (reserve gas), a demand regulator, self-inflating bag or other manual ventilating device, 3-way stopcock and additional tubing. Furthermore, Sasano did not disclose a. method whereby 25 mechanical ventilation can be used. In fact it appears mat it cannot be used- patients must be ventilated by hand for that method. With the apparatus and method disclosed herein, there is no requirement for an additional external source of gas or demand regulator; 4) the patient can be ventilated with the ventilation bag (212) already on the circuit 30 or the circuit ventilator, or any ventilator; no other tubing or devices are required. 41 WO 2004/073482 PCT/CA2004/000234 Page 41 5) Circle circuits cannot deliver FGS and then SGS sequentially- Such control is required to make physiological measurements such as cardiac output during anesthesia. 5 With the circuit of Figure 7, if the canister (204) is bypassed, the circuit becomes the equivalent of the one described in Figure 5 with the addition of the ventilator apparatus shown in Figure 4. With the circuit of Figure 7, box (216) could be opened to atmosphere instead of connected to a ventilator, and the circuit could be used with spontaneously breathing patients for measuring cardiac output white 10 modifying SGS. It should be recognized to those skilled in the art that various embodiments of the invention disclosed in this patent application are possible without departing from the scope including, but not limited to: 15 a) using multiple inspiratory and expiratory limbs in combination provided that i) the inspiratory and expiratory limbs are kept separate except at a single point prior to reaching the patient where they are joined ii) each limb has the corresponding valves as in the arrangement above, and 20 iii) the valves have the same relative pressures so as to keep the inspired gas delivery sequential as discussed above. b) using active valves, for example electronic, solenoid, or balloon valves, instead of passive valves, provided said valves are capable of occluding the limbs, and means is provided for triggering and controlling said active 25 valves. The advantage of active valves is more precise control. The disadvantage is that they are more costly. c) replacing reservoir bags with extended tubes or other means for holding gases d) surrounding valves in exhalation limb and/or in the inspiratory limb of 30 circuit with the exhaled gas reservoir causing them to be surrounded by warm exhaled air and prevent freezing and sticking of valves in cold environments. 42 WO 2004/073482 PCT/CA2004/000234 Page 42 e) Changing the composition of FGS and SGS to change alveolar concentrations of gases other than CQ2, for example O2. By analogy to CQ2, with respect to Q2: alveolar PO2 is determined by FGS flow and the PQ2 of FGS. When PC* of SGS is the same as the PQ2 in the alveoli, inhaling SGS does not change 5 flux of O2 in the alveoli. Therefore, those skilled in the art can arrange the partial pressure of component gases in FGS and SGS and the flows of FGS such that they can achieve any alveolar concentration of component gases independent, of VE as long as VB exceeds sufficiently flow of FGS. 10 As many changes can be made to the various embodiments of the invention without departing from the scope thereof; it is intended that all matter contained herein be interpreted as illustrative of the invention but not in a limiting sense. 15 To clarify the function of the automated cardiac output device, we will contrast it to a standard anaesthetic machine which has the same configuieation of listed components. 20 1) The preferred SGDB circuits we describe differ from any anaesthetic circuit The SGDB circuit first provides the FGS, men the SGS. This allows Are circuit to compensate for changes in CO2 elimination on any particular breath. For example, during a small breath, the unused FGS remains in the FGS reservoir and is available to provide the exact additional V'A for each gas in the set when a 25 larger breath is taken or frequency of breaming increases subsequently. As a result changes in "VCO2 can be instituted independent of breaming pattern. 2) Anesthetic machines do not automatically alter the fresh gas flows. Fresh gas flows are manually controlled by the anesthesiologist 3), Anesthetic machines do not calculate VA and cannot calculate VCC*, and Q. 43 WO 2004/073482 PCT/CA2004/000234 Page 43 4) Anesthetic machines cannot generate the data required to make the calculations for Q and its associated parameters because the circuit is inappropriate and the gas flows are not configured to be controlled by a computer. 5) The flowmeters on commonly used anesthetic machines are too imprecise and 5 inaccurate to perform these teste and calculations. There is no need for such precision and accuracy of flow for routine clinical anesthetic care. 9.0 Method of generating data required to make calculations of Q and related physiologic parameters (see Figure 11): 10 Cardiac Output can be measured in several ways according to the methods and apparatus disclosed herein. These include: 9.1 Set-up phase 9.1.1 Set Plow of FGS > VB 9.12 Access default values 15 9.1.3 Check pressure sensor, or PCO2 sensor during inhalation. If fresh gas reservoir collapsed or CO2 is detected during inhalation, increase FGS flow until the reservoir until reservoir does not collapse fully and no CQ2 is detected during inhalation 91.4 Identify TEICO2 from the CQz gas analyzer 20 92 Find VA via one of two methods: 9.2.1 Calculate VA by inducing two reductions in FGS flow below VA without first identifying VA by following the following steps: 9.2.1.1 Calculate a preliminary minimum VA for the subject based on body weight, temperature, sex and other parameters known to those 25 skilled in the art 92.12 Provide luxuriant FGS flow greater than the patient's resting VB until steady state PETCO2 is reached 9.2.1.3 Impose a VA by setting FGS Flow below assumed VA, to VA* preferably just below the calculated preliminary VA, for a time less 30 than or equal to a recirculation time, and measure PerCO2, the end tidal CO2 concentration during equilibrium if an equilibrium end tidal value is reached within a recirculation time, otherwise it is me equilibrium value of end tidal CO* as extrapolated from the 44 WO 2004/073482 PCT/CA2004/000234 Page 44 exponential rise in end tidal CQz values within, the recirculation time. 92.1.4 Set FGS flow above VB until steady state PEICO2 is reached as identified by a less than a threshold change in PETCO2 over a 5 designated time period. The actual thresholds and time periods are user defined according to the circumstances of the test and can be determined by those skilled in the art 92.15 Impose a VA by setting FGS How below assumed VA, to VA where VA y is less than calculated preliminary minimum VA and not equal 10 to VA *, for a time approximately equal to a recirculation time, about 30s at rest Measure PETCO2 , the end tidal CQz concentration during equilibrium if an equilibrium end tidal value is reached within a recirculation time, otherwise it is the equilibrium value of end tidal CO* as extrapolated from the exponential rise in end tidal CQz 15 values within the recirculation time. 9.2.1.6 On a graph of PETCO2 vs PGS flow, plot the points (PsrCO2y, VAl) and (PETCOA VA X). Extrapolate the line formed by connecting these two point to intersect a horizontal line at PurCQ2- resting PBICQ2 . The FGS flow at the intersection point is determined to be VA. 20 922 Progressive Reduction of FGS flow method of finding VA: 922.1 Use FGS that preferably has no CO2 9222 Wait for steady state as indicated by less man a threshold change in PETCQ2 over a designated time period. The actual thresholds and time periods are user defined according to me circumstances of the 25' test and can be determined by those skilled in the art 922.3 When in steady state, reduce FGS flow by a small fixed flow, for example 0.1 L/min, preferably at regular intervals of time or after each breath. Alternate flow reduction rates could be used, and the reduction need not be linear in time. 30 92.2.4 When PETCQ2 begins to rise above a threshold value which is approximately the mean steady state PETCO2 continue the reduction 45 WO 2004/073482 PCT/CA2004/0G0234 Page 45 in the FGS flow for a time approximately equal to one recirculation time. 9.2.25 After approximately one recirculation time, usually about 30 8, raise FGS flow above resting VB . A relation of PHICQI VS PGS flow is 5 calculated and two lines of best fit are calculated/ one for the set of steady state PmCOz values, and one for the set of raised PEICQZ values above the mean of the steady state values. The FGS flow corresponding to the intersection of said lines corresponds to ™. Figure 13 illustrates that progressive reduction of SGF (labelled 10 "FGF' in tine figure) results in a distinct inflection point when either PETCQ2 or PETO2 is graphed as a function of SGF. We define the SGF corresponding to this inflection point as equal to VA. 922.6 These two methods of finding YA are physiologically equivalent and 15 one may have some advantages over the other in particular clinical or research circumstances. The Progressive Reduction method should be contrasted with the method for calculating VA taught by Preiss et al (Canadian Patent Application 2346517). In that method, while fresh gas flow into a sequential gas delivery circuit was 20 reduced stepwise, after each reduction, the subject was observed for several breaths looking for an exponential rise in PETCO2. The Preiss method requires continued breathing at each fresh gas flow looking for development of a new steady when fresh gas flow falls below VA. This process is very time consuming and is unlikely to be 25 tolerated by most patients. If, in the attempt to shorten the time for finding the fresh gas flow below VA the fresh gas flow reduction are large, resolution of critical fresh gas flow is lost If the steps are small, when the fresh gas flow is just barely less than VA, it will be difficult to discern the small rise in PETCQ2 from the normal 30 variation in PETCO2. The progressive breath-by-breath reduction in FGS flow disclosed herein results in a rapid linear rise in PETCQ2 46 2U«M/073482 PCT/CA2004/000234 Page 46 and fall in PETO2 , both of which can be used to identify the FGS flow corresponding to VA as illustrated in Figure 13. 93 Calculations with the Differential lick equation There are two methods of calculating cardiac output with the Differential Fick 5 equation. (It is understood that the general methods are disclosed without the details well known to those skilled in the art of the multiple standard corrections for temperature, moisture, barometric pressure and the like.): 9.3.1 Find VA by the Progressive Reduction of FGS flow method of finding VA: 10 93.1.1 Find VA 93.1.2 Set FGS Flow = VA and calculate VCO2 using the equation VCO2= VA x FETCO2. 9.3.1.3 Impose a transient step change in VA to VA' for a time approximately equal to a recirculation time, about 30s at rest, by changing FGS flow to a value below VA. To fully automate the process, select a VA' that will be below the VA. Calculate VCO2 ° VA' x FH1CO2'. Where FETCO2 is the fractional end tidal CQ2 concentration during equilibrium if an equilibrium end tidal value is readied within a recirculation time, otherwise it is the equilibrium value of end tidal C(>2 as extrapolated from the exponential rise in end tidal CO* values within the recirculation time. .14, 'Calculate « according to the differential Fick equation using VCO2, VCO2, and CCO2 and CCO2 where CCQ2 and CCO2' are the contents of COz of end capillary blood as calculated from PBTCQ2 , and PBTCO2 using known relationships between PETCO2, and other characteristics related to the blood such as hemoglobin concentration, temperature oxygen partial pressure and other parameters that are accessible or can be used as default values by these skilled in the art 47 WO 2004/07348: PCT/CA2004/000234 Page 47 9.3.1.5 Calculate Q according to the differential Fids equation using VCQ2 and PETCO2 data from steady state phase and step change phase and the PaCO2 from, the Kim Rahn Farhi method. This allows fee identification of the PETCO2-PaCO2 gradient without an arterial 5 blood sample. 932 Generate required data by inducing two reductions in FGS flow below VA without first identifying VA by following the following steps: 9.3.2.1 Calculate a preliminary minimum VA for the subject based on body weight, temperature, sex and other parameters known to those 10 skilled in the art 9322 Provide luxuriant FGS flow greater man the patient’s resting VE until steady state PETCO2 is reached 9.3.Z3 Impose a VA and hence a VCO2 by setting FGS Flow below preliminary calculated VA, to VA* preferably just below the 15 preliminarily calculated VA, for a time less than or equal to a recirculation time, and calculate VCO2* using the equation VC02*= VA * x FErCQe' where FETCO** is the fractional end tidal CO2 concentration during equilibrium, if an equilibrium end tidal value is reached within, a recirculation time, otherwise it is the 20 equilibrium value of end tidal CQz as extrapolated from the exponential rise in end tidal CO2 values within, the recirculation time 9.3.Z4 Set FGS flow above VB until steady state PETCO2 is reached as identified by a less than a threshold change in PETCO2 over a 25 designated time period. The actual thresholds and time periods are user defined according to the circumstances of me test and can be determined by those skilled in the art 9325 Impose a transient step change in VA to VAy where VAv is less titan calculated VA and not equal to VA *, for a time approximately equal 48 WO 2004/0734*2 PCT/CA2004/000234 Page 48 to a recirculation time, about 30s at rest Calculate VCO2 •» VA * x FETCO^. FETCO2y is the end tidal CO2 concentration during equilibrium if an equilibrium end tidal value is reached -within a recirculation time, otherwise it is the equilibrium value of end tidal 5 CQz as extrapolated from the exponential rise in end tidal CQz values within the recirculation tune. |932.6 Calculate; Q according to the differential Fick equation using VCO2x , VCO2y, and and CCQ2" and CCO2y where CCQ2* and CCC2 are the contents of CO2 of end capillary blood as calculated from PxrCCv , 10 " and PHrCQ2y using known relationships between PBlCCfc, and other characteristics related to the blood such as hemoglobin concentration, temperature oxygen partial pressure and other parameters that are accessible or can be used as default values by those skilled in the art 15 93.2.7 Calculate Q according to the differential Eck equation using VCO2 and PETCO2 data from steady state phase and step change phase and the PaCQ2 from the. Kim Rahn Farhi method to identify the PBTCQ2 PaCO2 gradient This allows the identification of the PBTCQ2-PaCO2 gradient without an arterial blood sample. 20 Difference between this method and previous methods to perform the differential Pick: (a) With the new method, the decrease in VCO2 is performed by reducing the FGF to a SGDB circuit as opposed to insertion of a 25 deadspace at the patient-circuit interface. As a result, if the subject increases his breathing rate or breath size, there is no change in VCO2 and the calculations via the differential Pick equation are not affected. (b) The VCO2 is known using the VA (identified by one of the new 30 or the previously disclosed method) and the PBTCQ2. two robust 49 WO 2004/073482 PCT/CA2004/000234 Page 49 and highly reliable measures. This is unlike the need for a pneumotachymeter and the error-prone breath-by-breath analysis of VCO2 required by previous art (c) VA is notideritified with the previous differential Pick methods. 5 (d)The PBTCO2 to PaCO2 gradient is calculated from two independently derived values in the same subject In the previous art, this gradient is calculated from empirical formulae derived from averaged values and do not necessarily apply to the subject Therefore our method provides more accurate values for VCO2, V 10 CQ2 and PaCO2 than the previous art. 9.4 Kim-Rahn -Farlu 9.4.1 A period of reduced FGS flow simulates complete or partial breath holding. The PETCQ2 of each breath is equivalent to a sequential 15 alveolar sample in the KRF prolonged exhalation method. The substitution of sequential PETCO2 values for sequential samples from a single exhalation is used to calculate true Pv CO?/ Pv CQ2-oxy, PaCQ2 and hemoglobin O2 saturation in mixed venous blood SvO2 using the Kim Kahn Farhi method. 20 9.4.2 Q can be calculated using the Fick approach where the Pv COz-oxy and PaCQ. as calculated by the Bom Palm Farhi method are used to calculate the respective CQ2 contents using methods well known to those skilled in the art, and the VCO2 is as calculated from VA and FBTCO2 as derived in the sequence of steps described above. 25 9.43 Mixed venous O* hemoglobin saturation are calculated as follows. VO2 is calculated from VO2= VA x (F1O2 - FElQz) where F1Q2 and PETO2 are the fractional concentration of inspired and end tidal O2 respectively. Using VO2, & as calculated by Differential Fick or Kim Rahn Farhi or Fisher Method, end capillary O2 oxygen content 30 (assuming end capillary blood is folly saturated with oxygen), Mixed 50 WO 200V073482 PCT/CA2004/000234 Page 50 venous Q2 saturation can be calculated from the standard Pick equation. 9.4.4 Infonnation regarding the arterial Q* hemoglobin saturation (SaO2) (as read from a. non-invasive commonly available pulse oximeter that makes the 5 measurement by shining an infrared light through a finger), and the Sv02 can be used to calculate the fraction of shunted blood {Qs) (assuming fully oxygenated blood in the end pulmonary capillary) by using tine following equation ^JSpO2)Qt-(Sa02a)Qp SvQ2 10 Our method of performing the Kim Rahn Farhi is an improvement over the previous art in that (a) Test is performed simultaneously with a test for differential Pick in spontaneously breaming subject 15 (b) Data are pooled with the test as outlined above so calculation of VCOi, is simultaneous to the other calculations. In the previous art, the VCOi, calculation cannot be done during a breath hold or simulated breath hold by rebreathing. (c) VCOi, measurement does not require a pneumotachymeter 20 which is expensive, cumbersome and error-prone, hi the previous art, VCOi, required for me calculation of Q required additional apparatus such as pneumatchymeter or gas collection and volume measuring apparatus. 25 9.5 Fisher E-I test 9.5,1 Calculate VA from the calibration phase, set FGS flow *• VA. 9.52. With FGS Flow at VA , the FCO2 in the FGS is changed to any value and held at that value for a time approximately equal to a recirculation 30 time, about 30s at rest 51 WO 2004/073482 PCT/CA2004/000234 Page 51 9.53 Pv CO2-oxy is calculated using the PETCQ2 – PlCO2 method described by Fisher. Our method of the Fisher E-I test is an improvement over the previous art in 5 that the effect of change in breath size on the equilibrium value of FETCO2 is minimized by the SGDB circuit such that a larger breath delivers physiologically neutral previously expired gas instead of additional test gas. 10.0 Method of finding VE using progressive reduction of FGS HOW: 10 10.1 Use FGS that preferably has no COz 10.2 Wait for steady state as indicated by less than a threshold change in FETCO2 over a designated time period. The actual thresholds and time periods are user defined according to the circumstances of the test and can be determined by those skilled in the art 15 103 When in steady state, reduce FGS flow by a small fixed flow, for example 0.1 L/min, preferably at regular intervals of time or after each breath. Alternate flow reduction rates could be used, and the reduction need not be linear in time. 10.4 Using a means for measuring pressure within the FGS reservoir in the 20 breaming circuit, for example a pressure transducer, monitor when the FGS reservoir bag first collapses. VE is the FGS flow rate when the reservoir bag first collapses. 11.0 Method for Measuring Anatomical Dead Space 11.1 Measure VB and VA using any of the methods disclosed above 25 112 Measure the respiratory rate, preferrably using the apparatus for cardiac output disdosed herein. 11.3 Calculate Anatomical Dead Space VDAN *={VB-VA)/ respiratory rate 52_ WO 2004/073482 PCT/CA2004/Q00234 Page 52 As many changes can be made to the various embodiments of the invention without departing from the scope thereof; it is intended that all matter contained herein be interpreted as illustrative of the invention but not in a limiting sense. 5 53 54 We claim: 1. A breathing circuit for use with a first gas set (FGS) and a second gas set (SGS), said circuit comprising means for keeping separate the FGS and SGS, an FGS reservoir, 5 and a means for sequentially delivering to a patient on inspiration, first the FGS, and, when FGS reservoir is emptied, subsequently delivers substantially SGS for the balance of inspiration. 2. The breathing circuit of claim 1 comprising: 10 a. an inspiratory limb with a port for entry of FGS, a FGS reservoir and FGS flow control means, whereby the FGS control means directs FGS into the FGS reservoir during the portion of inspiration after the FGS reservoir is emptied preventing FGS flow to the patient prior to the beginning of the next inspiration, 15 b. an expiratory limb containing an exit port for exhaled gas, an SGS reservoir, and exhalation valve for directing the flow towards the SGS reservoir during exhalation, c. a bypass limb connecting the inspiratory and expiratory limbs, containing a bypass flow control means which directs flow of the SGS from the SGS 20 reservoir to the patient through the inspiratory limb during the portion of inspiration from when the FGS reservoir is emptied until the end of inspiration. 3. The circuit of claim 1 comprising: a. an inspiratory limb with a port for entry of FGS, a FGS reservoir and FGS flow control means; b. an expiratory limb containing an exit port for exhaled gas, SGS reservoir, and SGS flow control means for directing the flow towards the SGS reservoir during exhalation, and for directing the flow of SGS in the expiratory limb towards the patient during a portion of inspiration. 4. The circuit of claim 2 or claim 3 where the FGS flow control means comprises at least one uni-directional valve that opens toward the patient. 54 55 5. The circuit of claim 2 or claim 3 where the FGS flow control means comprises a FGS controlled valve activated by a FGS valve control means, which allows FGS to flow to the subject during inspiration until the FGS reservoir has been emptied and then 5 prevents FGS from flowing to the subject until the next inspiration begins. 6. The circuit of claim 5 where the FGS flow control means additionally comprises at least one uni-directional valve that opens toward the patient, located between the controlled valve and the patient. 10 7. The circuits of claims 4, 5 or 6 wherein the SGS flow control means comprises an exhalation valve on the expiratory limb, and a bypass valve on a bypass limb connected to the expiratory limb, said bypass limb bypassing said exhalation valve, whereby said bypass valve is opened during inspiration only once the FGS reservoir has been emptied. 15 8. The circuit of claims 4, 5 or 6 wherein the SGS control means comprises a SGS controlled valve activated by a SGS valve control means, said SGS valve control means which opens said SGS controlled valve to allow SGS to be inspired by the subject during inspiration once the inspiratory reservoir has been emptied and closes it after expiration. 20 9. The circuits of claim 1 or claim 2 whereby the inspiratory and expiratory limbs are co-axial. 10. The circuits of claim 9 whereby one of the limbs is comprised of a material that 25 allows passage of moisture to the other but keeps the gases in the limbs separate. 11. The circuits of claim 1 or claim 2 whereby the reservoirs are contained in a sealed container with openings for the inspiratory and expiratory limbs, and with opening for connection to a ventilator. 30 12. The circuits of claim 1 or claim 2 additionally comprising means for detecting when SGS is being delivered to the patient, with FGS control means using said detecting 55" 56 means to determine when to direct FGS to the FGS reservoir and prevent FGS from being delivered to the patient. 13. The circuits of claim 1 or claim 2 whereby the FGS consists of one or more gases 5 in combination and in varying concentrations. 14. The circuits of claim 1 or claim 2 whereby the FGS consists of air. 15. The circuits of claim 1 or claim 2 whereby the FGS consists of O2. 10 16. The circuits of claim 1 or claim 2 whereby the FGS consists of air and O2 mixed. 17. The circuits of claim 1 or claim 2 whereby the FGS contains CO2. 15 18. The circuits of claim 1 or claim 2 whereby the SGS consists of one or more gases in combination and in varying concentrations. 19. The circuits of claim 1 or claim 2 whereby the SGS comprises previously exhaled gas. 20 20. The circuits of claim 1 or claim 2 whereby the SGS comprises a mixture of previously exhaled gas and an exogenous set of gases. 21. The circuits of claim 1 or claim 2 further comprising means for altering the 25 composition of SGS delivered to the patient. 22. The circuits of claim 21 wherein said SGS altering means comprises CO2 absorbing material. 30 23. The circuits of claim 21 wherein said SGS altering means comprises Zeolite for elimination of anesthetics or vapour anaesthetic agents. 56 57 24. The circuits of claim 21 wherein said SGS altering means comprises Hopcalite for elimination of carbon monoxide. 25. The circuits of claim 1 or claim 2 whereby the portion of the inspiratory limbs and expiratory limbs that contain the valves or flow control means are contained within the 5 SGS reservoir. 26. The circuits of claim 1 or claim 2 wherein said SGS reservoirs are bags or extended tubes sufficiently large to provide the functions of SGS. 10 27. An apparatus to measure cardiac output (Q) and other parameters such as alveolar ventilation (VA), minute ventilation (VE), minute CO2 elimination from the lung (VCO2), minute oxygen consumption (VO2), oxygenated mixed venous partial pressure of CO2, (PvCO2)-oxy), true mixed venous partial pressure of CO2 (PvCO2), PaCO2, mixed venous oxygen saturation (SVO2), pulmonary shunt, and anatomical dead space, comprises: 15 a) any breathing circuit wherein when the subject's minute ventilation exceeds a first gas set (FGS) flow into the circuit, the balance of his/her ventilation is supplied from a second gas set (SGS); b) gas analyser means for monitoring gas concentrations of the patient's breath; c) a gas flow control means for controlling the rate of FGS flow into the 20 breathing circuit; and d) optionally wherein FGS is provided to the patient first followed by SGS. 28. The apparatus of claim 27 further comprising a first gas set (FGS), and a second gas set (SGS), said second gas set which may comprise previously exhaled gases or 25 exogenous gases or both. 29. The apparatus of claim 27 further comprising means to identify phase of breathing. 30. The apparatus of claim 27 further comprising machine intelligence capable of 30 controlling the gas flow control means, receiving the output of the gas sensor means and means to identify phased of breathing, and performing the calculations for measuring cardiac output and other parameters. 57 58 31. The apparatus of claim 27 wherein the breathing circuit is the circuit of claim 1 or claim 2. 32. The apparatus of claim 27 wherein the breathing circuit is that described by Fisher in US Patent 6,622,725. 5 33. The apparatus of claim 27,28, or 30 where said gas flow control means is capable of controlling and mixing the flows of several component gases to constitute FGS. 34. The apparatus of claim 27,28 or 30 where FGS comprises O2. 10 35. The apparatus of claim 27,28 or 30 where FGS comprises air. 36. The apparatus of claim 27, 28 or 30 where FGS comprises O2 and air in any proportion. 15 37. The apparatus of claim 34, 35, or 36 where FGS further comprises any proportion of CO2, anesthetic or other gas or vapour. 38. The method of using the apparatus of claims 27, 28 or 30 for determining Q, VA, 20 VE, VC02, V02, PvCO2-oxy, true PvCO2, PaCO2, Sv02, pulmonary shunt, and anatomical dead space. 39. A method of identifying the alveolar ventilation (VA) using the apparatus of claim 27 comprising: 25 a. setting the FGS flow into the circuit at a rate greater than the subject's minute ventilation VE; b. measuring one or more end tidal CO2 concentrations (PETCO2 ) in a steady state; c. progressively lowering the FGS flow into the circuit, either breath by breath 30 or continuously while measuring PETCO2 of the subject; d. identifying a rise in PETCO2 above a threshold; and 58 59 e. determining VA as the rate of FGS flow into the circuit at the beginning of the rise in PETO2 above said threshold. 40. The method of claim 39 wherein the beginning of the rise in PETCO2 is determined by: 5 a. after identifying the rise in PETCO2 above said threshold, collecting one or more successive PETCO2 values prior to a recirculation time; b. fitting a straight line to said values of PETCO2 on a graph of PETCO2 vs FGS flow; and c. determining the FGS flow at which the PETCO2 of said line equals one of, or 10 the average of several of, the PETCO2 values at steady state, said FGS flow being equal to VA. 41. A method of measuring the alveolar ventilation (VA) using the apparatus of claim 27 comprising: a. estimating a preliminary minimum VA for the subject based on body 15 weight, temperature, and sex; b. providing FGS flow greater than the patient's resting VE until steady state PETCO2 is reached; c. setting FGS flow below said estimated VA, to a flow VA X for a time less than or equal to a recirculation time, and measure PBTCO2 , the end tidal 20 CO2 concentration during equilibrium if an equilibrium end tidal value is reached within a recirculation time, otherwise measuring PETCO2X the equilibrium value of end tidal- CO2 as extrapolated from the exponential rise in end tidal CO2 values within the recirculation time; d. setting FGS flow above VE until steady state PETCO2 is reached; 25 e. setting FGS Flow below estimated VA, to flow Vy where VA* is not equal to Vx , for a time less than or equal to a recirculation time, and measuring PETCO2, the end tidal CO2 concentration during equilibrium if an equilibrium end tidal value is reached within a recirculation time, otherwise measuring PETCO2 as the equilibrium value of end tidal CO2 as 30 extrapolated from the exponential rise in end tidal CO2 values within the recirculation time; 59 60 f. on a graph of PETCO2 VS FGS flow, plot the points (PETCO2, V3) and (PEICO2X, Vx) extrapolate the line formed by connecting these two points to intersect a horizontal line at PETCO2 - resting PEICO2 ; and g. determining VA to be the FGS flow corresponding to the intersection point. 5 42. The method of claims 39, 40, or 41 wherein the VA SO determined is utilized to determine the VCO2 as VAX FETC02 during the steady state. 43. The method of claims 39 or 40, wherein 02 is used instead of CO2 and the PETO2 10 level drops below a threshold value, instead of PETCO2 rising above a threshold value. 44. The method of claim 41 wherein PETO2 values are measured instead of PETCO2 values. 15 45. A method for measuring VCO2 of a subject breathing on any breathing circuit wherein when the subject's minute ventilation exceeds a first gas set (FGS) flow into the circuit, the balance of his/her ventilation is supplied from a second gas set (SGS) comprising: a. setting the FGS flow into the circuit at a rate equal to or above the subject's 20 VA; b. measuring the average CO2 concentration of gas exiting the circuit; and determining said VC02 to be the average CO2 concentration x FGS flow rate. 25 46. A method for determining VA of a subject comprising measuring VCO2 using the method of claim 45, measuring the subjects FETCO2 and determining VA as VCO2 / FETC02. 47. A method for measuring VO2 of a subject breathing on any breathing circuit 30 wherein when the subject's minute ventilation exceeds a first gas set (FGS) flow into the 60 61 circuit, the balance of his/her ventilation is supplied from a second gas set (SGS) comprising: a. setting the FGS flow into the circuit at a rate equal to or above the subject's vA; 5 b. measuring the average O2 concentration of gas exiting the circuit; and c. determining said VO2 to be the FGS flow rate x [average O2 concentration of FGS - average O2 concentration of gas exiting the circuit]. 48. The method of claim 45 wherein the circuit is a SGDB circuit. 10 49. The method of claim 47 wherein the circuit is a SGDB circuit. 50. A method of measuring cardiac output in a subject using the apparatus of any of claims 27,28 or 30 comprising: 15 i. measuring VCO2 and PETCO2 in a first state; ii. changing VCO2 for a time less than or equal to a recirculation time to a new VCO2, designated as VCO2'.; iii. determining a new PETCO2 at VCO2' designated as PETCO2 wherein said PETCO2 is the steady state end tidal PCO2 after a change in 20 VCO2 to VCO2', or if no steady state is reached, then it is the extrapolated steady state end tidal PCO2 from the exponential rise in end tidal PCO2 within the recirculation time; and iv. determining Q using the Differential Fick relationship. 25 51. The method of claim 50 wherein VCO2 in the first state is measured using the method of claim 42. 52. The method of claim 50 wherein VCO2 in the first state is measured using the method of claim 45. 30 61 62 53. The method of claim 50 wherein VC02 in the first state is measured using the method of claim 48. 54. The method of claim 50 wherein the FGS flow during the first state is equal to the 5 subject's VA- 55. The method of claim 50 wherein the FGS flow during the second state is less than the subject's VA- 10 56. The method of claim 54 or 55 wherein the VA is determined according to the method of claim 39 or claim 40 or claim 41. 57. The method of claim 50 wherein the VCO2 is changed to VCO2' by changing the concentration of CO2 in FGS. 15 58. The method of any one of claims 50 to 56 wherein VCO2' is determined as FETCO2 x FGS flow, where FETC02 is the end tidal CO2 of the subject either at equilibrium or as extrapolated to equilibrium from the exponential rise in end tidal CO2 values. 20 59. A method of measuring cardiac output in a subject using the apparatus of any of claims 27,28 or 30 comprising: i. estimating the subject's VA (denoted VA PRELIM) based on weight, height, temperature, and sex; ii. setting the FGS flow into the circuit at a rate greater than the subjects 25 minute ventilation (VE); iii. for a time less than or equal to a recirculation time, changing FGS flow to a value V1 which is below VA PRELIM; iv. calculating VC02l = VA1 X FETCC^1, whereby FETCO21 is the fractional end tidal CO2 concentration during equilibrium if an equilibrium end tidal value 30 is reached within a recirculation time, otherwise it is the equilibrium value 62 63 of end tidal CO2 as extrapolated from the exponential rise in end tidal CO2 values within the recirculation time; v. setting the FGS flow into the circuit at a rate greater than VE and waiting for a steady state PETCO2 to be reached; 5 vi. for a time less than or equal to a recirculation time, changing FGS flow to a value V2 which is below V A PRELIM and not equal to V1; vii. calculating VC022 = V2 x FETC022, whereby FETC022 is the fractional end tidal CO2 concentration during equilibrium if an equilibrium end tidal value is reached within a recirculation time, otherwise it is the equilibrium value 10 of end tidal CO2 as extrapolated from the exponential rise in end tidal CO2 values within the recirculation time; viii. determine PETCO2 from FETCO2 X ambient pressure, and PETCO22 from FETCO22 x ambient pressure; and ix. using the values of VC02', VCO22 , PETCCV, and PETC022 in the 15 Differential Fick equation to determine cardiac output. 60. The method of claim 50 or 59 whereby the PETCO2 values in the Fick equation are replaced by the PaCO2 using the Kim Rahn Farhi method to identify the PETCO2-PaCO2 gradient. 20 61. The method of determining PvCO2-oxy in a subject using the apparatus of any of claims 27,28 or 30 comprising: i. determining VA according to any of the methods in claims method of claims 45,46, or 47; 25 ii. setting the FGS flow in the circuit equal to VA and measuring inspired concentration of CO2 and PETCO2; hi. for a series of breaths no longer man a recirculation time changing the CO2 concentration in the FGS and measuring inspired concentration of CO2 and PETCO2; and 30 iv. using the values of inspired and expired concentrations as described by Fisher to calculate PvCO2-oxy. 63 64 62. The method of any one of claims 39 to 41 wherein the VA so determined is utilized to determine the V02 as VAx [F1O2 - FETO2 ] during the steady state where FiO2 is the O2 concentration in FGS. 5 63. The method of identifying the minute ventilation (VE) using any breathing circuit wherein when the subject's minute ventilation exceeds a first gas set (FGS) flow into the circuit, the balance of his/her ventilation is supplied from a second gas set (SGS) comprising i. setting the FGS flow into the circuit at a rate greater than the subject's 10 minute ventilation (VE); and ii. progressively lowering the FGS flow into the circuit, either breath by breath or continuously, until the FGS reservoir bag in the breathing circuit first collapses. The FGS flow when the bag first collapses is determined to be Vg. 15 64. A method of determining the anatomical dead space comprising: a. measuring V A using any of the methods of claims 3 9,40 or 41; b. measuring VE; c. measuring the respiratory rate; and d. determining anatomical dead space = (VE-VA) / respiratory rate. 20 65. The method of determining physiological parameters in a subject using the apparatus of claims 27, 28 or 30 wherein the Kim Rahn Farhi approach is used to determine i) PvCO2-oxy 25 ii) true PvCO2 iii) PaCO2 iv) Q iv) true P\?C02 plus the information from a pulse oximeter to determine mixed venous hemoglobin 02 saturation. 30 64 65 66. The method of determining physiological parameters in a subject using the apparatus of claim 27,28 or 30 wherein the differential C02 Fick technique of Gedeon and Orr is utilized to determine any combination of i) Pv-C02-oxy 5 ii) Q ii) VC02 iii) VC02' iv) PETCO2-PaCO2 gradient determined using the PaCO2 as determined by the Kim Rahn Farhi method from data collected while reducing the 10 V CO2 in order to perform the differential Fick method. 67. An improved method for determining Q , VA , VCO2, PvCO2-oxy, true PvCO2, PaCO2, pulmonary shunt, anatomical dead space, and O2 saturation in mixed venous blood in a subject breathing on any breathing circuit wherein when the subject's minute 15 ventilation exceeds a first gas set (FGS) flow into the circuit, the balance of his/her ventilation is supplied from a second gas set (SGS) comprising i) setting the flow of FGS to the circuit to create two sets of data for said determination utilizing the Fick equations; (or) 20 ii) determining the PETCO2 - PaCO2 gradient from two independently derived values in the same subject; (or) iii) utilizing the Kim-Rahn-Farhi technique a series of reduced FGS flows simulates complete or partial breath holding, wherein the PETCO2 of each breath is equivalent to a sequential alveolar sample. 25 68. The method of claim 27, 28 or 30 used to measure Q wherein Q is used to determine Sv02 using the relationship Sv02 = SaO2 -VO-J [Hb x CC x Q], where Hb is haemoglobin, and CC (in ml O2 / gm Hb) is the capacity of haemoglobin to carry oxygen. 30 69. The method of claim 68 wherein the arterial O2 hemoglobin saturation, is utilized with the O2 saturation value in the pulmonary artery to calculate the fraction of shunted blood (assuming fully oxygenated blood in the end pulmonary capillary) thereof. 65 66 70. The method of claim 69 utilized to determine the fraction of shunted blood Qs, which in conjunction with determination of cardiac output Qy may be used to determine Q? • » # the pulmonary output via the relationship Q T =Q p +g s- 5 71. The method of claim 27, 28 or 30 wherein the O2 saturation of haemoglobin in mixed venous blood, as determined therewith, is utilized to reveal a condition in a patient such as septic shock, or heart failure. 10 72. The method of claims 38, 39, 41, 45, 47, 50, 63, 64 or 67 which is automated by gauges, controls, and computer assisted devices in conjunction with at least one computer in order to control, activate and measure the variables and determinates thereof. 73. The method of claims 38, 39,41,45,47,50,63, 64, or 67 which is automated with 15 at least one computing device. 74. A breathing circuit for use with a first gas set (FGS) and a second gas set (SGS); a breathing circuit; an apparatus to measure cardiac output and other parameters; a method of identifying and measuring the alveolar ventilation; a method for determining V2A , VC02, C02, FETC02 of a subject breathing of ay breathing circuit a method of measuring cardiac output in a subject using the apparatus; a method of identifying the minute ventilation using any breathing circuit; a method of determining the anatomical dead space; a method of determining the physiological parameters, and an improved method for determining Q, VA, VC02, PvCO2y, true PvC02, PaC02, pulmonary shunt, anatomical dead space and 02 saturation in mixed venous blood in a subject breathing on any breathing circuit substantially as herein described with reference to the foregoing examples and accompanying drawings. Dated this 14th day of September 2005 66 ABSTRACT An apparatus to measure cardiac output (Q) and other parameters such as alveolar ventilation (VA), minute C02 elimination from the ling (VC02), minute oxygen consumption (V02), oxygenated mixed venous partial pressure of C02, (PvC02-oxy), true mixed venous partial pressure of C02, (PvC02), PaC02, mixed venous oxygen saturation (Sv02), pulmonary shunt, and anatomical dead space, consisting of: a) a breathing circuit with characteristics that: i. on exhalation, exhaled gas is kept substantially separate from inhaled gas; ii. on inhalation, when VE is greater than FGS flow, the subject inhales FGS first and then inhales a gas that is substantially SGS, for the balance of inhalation; b) gas sensor means for monitoring gas concentrations at the patient-circuit interface; c) a first gas set (FGS), and a second gas set (SGS), said second gas set which may comprise previously exhaled gases or oxogenous gases or both; d) a gas flow control means for controlling the rate of FGS flow into the breathing circuit; e) means to identify phase of breathing, said means may consist or pressure sensors or analysis of signal generated by gas sensors or other means known to those skilled in the art; f) machine intelligence consisting of a computer or logic circuit capable of controlling the gas flow control means, receiving the output of the gas sensor means and means to identify phased of breathing, and performing the calculations for measuring cardiac output and other parameters as outlined in the disclosure. 67

Documents:

1027-mumnp-2005-abstract(24-03-2008).doc

1027-mumnp-2005-abstract(24-03-2008).pdf

1027-MUMNP-2005-ABSTRACT(GRANTED)-(15-5-2008).pdf

1027-mumnp-2005-abstract.doc

1027-mumnp-2005-abstract.pdf

1027-mumnp-2005-cancelled page(24-03-2008).pdf

1027-MUMNP-2005-CANCELLED PAGES(24-3-2008).pdf

1027-mumnp-2005-claim(granted)-(24-03-2008).doc

1027-mumnp-2005-claim(granted)-(24-03-2008).pdf

1027-MUMNP-2005-CLAIMS(AMENDED)-(3-8-2010).pdf

1027-MUMNP-2005-CLAIMS(GRANTED)-(15-5-2008).pdf

1027-MUMNP-2005-CLAIMS(MARKED COPY)-(3-8-2010).pdf

1027-mumnp-2005-claims.doc

1027-mumnp-2005-claims.pdf

1027-mumnp-2005-correspondence(24-03-2008).pdf

1027-MUMNP-2005-CORRESPONDENCE(3-8-2010).pdf

1027-mumnp-2005-correspondence(ipo)-(29-04-2008).pdf

1027-MUMNP-2005-CORRESPONDENCE(IPO)-(5-9-2008).pdf

1027-mumnp-2005-correspondence-received-ver-131005.pdf

1027-mumnp-2005-correspondence-received-ver-150905.pdf

1027-mumnp-2005-correspondence-received-ver-240106.pdf

1027-mumnp-2005-correspondence-received-ver-300606.pdf

1027-mumnp-2005-descripiton (complete).pdf

1027-MUMNP-2005-DESCRIPTION(GRANTED)-(15-5-2008).pdf

1027-mumnp-2005-drawing(24-03-2008).pdf

1027-MUMNP-2005-DRAWING(GRANTED)-(15-5-2008).pdf

1027-mumnp-2005-drawings.pdf

1027-mumnp-2005-form 1(14-03-2008).pdf

1027-mumnp-2005-form 1(16-09-2005).pdf

1027-mumnp-2005-form 1(24-03-2008).pdf

1027-MUMNP-2005-FORM 13(3-8-2010).pdf

1027-MUMNP-2005-FORM 13(7-10-2005.pdf

1027-mumnp-2005-form 18(30-01-2006).pdf

1027-MUMNP-2005-FORM 2(GRANTED)-(15-5-2008).pdf

1027-mumnp-2005-form 2(granted)-(24-03-2008).doc

1027-mumnp-2005-form 2(granted)-(24-03-2008).pdf

1027-MUMNP-2005-FORM 2(TITLE PAGE)-(GRANTED)-(15-5-2008).pdf

1027-MUMNP-2005-FORM 26(14-3-2008).pdf

1027-MUMNP-2005-FORM 26(16-9-2005).pdf

1027-mumnp-2005-form 26(20-09-2005).pdf

1027-mumnp-2005-form 26(24-03-2008).pdf

1027-MUMNP-2005-FORM 26(24-3-2008).pdf

1027-mumnp-2005-form 3(14-03-2008).pdf

1027-MUMNP-2005-FORM 3(14-3-2008).pdf

1027-MUMNP-2005-FORM 3(16-9-2005).pdf

1027-mumnp-2005-form 3(20-09-2005).pdf

1027-mumnp-2005-form 3(24-03-2008).pdf

1027-MUMNP-2005-FORM 3(24-1-2006).pdf

1027-MUMNP-2005-FORM 3(24-3-2008).pdf

1027-mumnp-2005-form 3(30-01-2006).pdf

1027-mumnp-2005-form 5(14-03-2008).pdf

1027-mumnp-2005-form 5(20-09-2005).pdf

1027-mumnp-2005-form 5(24-03-2008).pdf

1027-mumnp-2005-form-1.pdf

1027-mumnp-2005-form-13.pdf

1027-mumnp-2005-form-18.pdf

1027-mumnp-2005-form-2.pdf

1027-mumnp-2005-form-3-ver-150905.pdf

1027-mumnp-2005-form-3-ver-300606.pdf

1027-mumnp-2005-form-5.pdf

1027-mumnp-2005-form-pct-ipea-237.pdf

1027-mumnp-2005-form-pct-isa-210(20-09-2005).pdf

1027-mumnp-2005-form-pct-separate sheet-237.pdf

1027-mumnp-2005-pct-search report.pdf

1027-mumnp-2005-petition under rule 137(14-03-2008).pdf

1027-MUMNP-2005-SPECIFICATION(AMENDED)-(14-3-2008).pdf

1027-MUMNP-2005-SPECIFICATION(AMENDED)-(24-3-2008).pdf

abstract1.jpg