WO2007012170A1

WO2007012170A1 - A new method and apparatus to attain and maintain target end tidal gas concentrations

Info

Publication number: WO2007012170A1
Application number: PCT/CA2005/001166
Authority: WO
Inventors: Marat Slessarev; Joel Fisher; George Volgyesi; Eitan Prisman; David Mikulus; Chris Hudson; Cliff Ansel
Original assignee: Marat Slessarev; Joel Fisher; George Volgyesi; Eitan Prisman; David Mikulus; Chris Hudson; Cliff Ansel
Priority date: 2005-07-28
Filing date: 2005-07-28
Publication date: 2007-02-01

Abstract

A method and apparatus is disclosed that induces target 'end tidal' (end of exhalation) gas concentrations, and in particular, end tidal oxygen concentrations and end tidal carbon dioxide concentrations, in a subject independent of one another. Additionally, the establishment of the target may be independent of minute ventilation. The method can, be used to induce rapid sequential changes in both target O2 and CO2. Subjects need not change their minute ventilation to attain changes in target O2 and CO2. In addition, when increases in minute ventilation do occur, the end tidal O2 and CO2 remain at target levels. The methods comprise setting the flow of source gas into a partial rebreathing circuit on which the patient is breathing at a rate equal or greater than the minute ventilation of the patient, and determining prospectively the concentrations of CO2 and O2 in the source gas to achieve the end tidal targets. An apparatus is provided to control the flow of source gases. The source gases are chosen so as to have a safe minimum concentration of O2 .

Description

TITLE OF INVENTION

A NEW METHOD AND APPARATUS TO ATTAIN AND MAINTAIN TARGET END TIDAL GAS CONCENTRATIONS

FIELD OF INVENTION

The invention disclosed herein relates to the field of blood gas control, which further relates to a number of fields of medical diagnostics and treatment. Changes in end tidal CO₂ and/or O₂ can be used to monitor vascular reactivity in retinal vessels and other vascular beds as detected by various retinal blood flow and other vascular flow sensors. Similarly, changes in end tidal CO₂ and/or O₂ can be used to monitor changes on organ or tissue function by measuring such factors as heart rate variability, skin conductivity_s hormone levels, organ temperature, plethysmography and other measurements known to physiologists and others skilled in the art.

BACKGROUND OF THE INVENTION

The present invention relates to a method to control the end tidal CO₂ and end tidal O₂ independently of each other and independently of minute ventilation.

It should be noted that gas concentrations described herein may be referred to as partial pressures (e.g. PCO₂) or as fractional concentrations (e.g FCO₂ ). Those skilled in the art will recognize the relationship between the two in that partial pressure = fractional concentration x ambient pressure.

Ordinarily, when minute ventilation increases, the partial pressure of end tidal CO₂ (PETCO₂) decreases and partial pressure of end tidal O₂ (PETO₂) increases. Fisher [for example, US Patent 6622725)], describes fixing fresh gas flowing into a partial rebreathing circuits such as the sequential gas delivery circuit in order to maintain constant PETCO₂ in the face of increases in minute ventilation on the part of the subject. Fisher [Canadian Application 2,346,517] also describes means of keeping PETO₂ constant at a given attained level despite increases in minute ventilation. None of these patents disclose means to set gas flows and gas concentrations into a circuit to attain a target end tidal fractional concentration of CO₂ (FTETCO₂) and/or target end tidal fractional concentration of O₂ (FTETO₂) for a given minute ventilation ( VE ). This is required for a number of applications as will be enumerated below. For illustrations purposes, will take the example of one such application: measuring cerebrovascular reactivity.

Cerebral blood flow (CBF) is closely regulated by metabolic demands of the brain tissue. CBF also responds to changes in arterial PCO₂ and PO₂. The extent of the change in CBF in response to a stimulus is termed cerebrovascular reactivity (CVR). CVR may be a sensitive indicator of abnormal vessels such as vascular dysplasia or tissue abnormalities such as brain swelling and cancer. Quantitatively mapping CVR throughout the brain using imaging techniques such as magnetic resonance imaging (MRI) could identify areas of abnormal CVR. Brain blood vessel diameter responds to changes in blood PO₂ as well as blood PCO₂. Blood PO₂ and blood PCO₂ are strongly tied to end tidal concentrations of O₂ and CO₂ respectively. Present methods of inducing high PETCO₂ control PETO₂ poorly and do not control PCO₂ and PO₂ independently.

Brief review of current methods of changing blood PCO₂ and PO₂ via control of the lungs:

A: Breath-holding methods:

The simplest method for inducing changes in PCO₂ during Magnetic Resonance Imaging (MRI) is breath-holding. As there is a rapid drift in the baseline MRI signal, changes in MRI signal resulting from changes in brain blood flow can be detected only by rapidly alternating the stimulus between "control" and "test" values. With respect to PCO₂, this requires rapid step changes in PCO₂, preferably maintaining PO₂ constant. Cycle times of 3 min have been reported by Vesely et al (1) to be suitable, but shorter cycle times would be preferred. Breath-holding induces an increase in PCO₂ but it is not well suited to measuring CVR. The rise in blood PCO₂ during breath-holding is very slow as it is dependent on body CO₂ production ( FCO₂ ), which is small compared to body capacitance for CO₂. During breath holding, alveolar PO₂ declines progressively. As CO₂ production, CO₂ capacitance and the tolerable breath-holding time varies from patient to patient, so will the final blood PCO₂ and PETO₂. As there is no gas sampling during breath-holding the blood PCO₂ and PO₂ is unknown for the duration of the breath- hold so it is not possible to relate the MRI signal strength to PCO₂ or PO₂, a requirement for the calculation of CVR.

B: Inhaling CO₂

A second traditional method of changing PCO₂ is inspiring gas mixtures containing CO₂ via a facemask. This is known to result in a highly variable ventilatory response between subjects leading to a large variability in PETCO₂. Furthermore, inhaling CO₂ changes the minute ventilation (VE) resulting also in variability in blood PO₂. Oxygen is a potent vasoconstrictor and confounds the interpretation of the relationship between PCO₂ and brain blood flow. Therefore, neither breath-holding nor inhaling a gas mixture containing CO₂ provide suitable conditions for a consistent, repeatable quantitative test for CVR.

C: Gas forcing

Since the effects of inhaling a Cθ₂-containing gas mixture on increasing PCO₂ can be overcome by increasing minute ventilation, one can introduce a feedback loop to adjust the inhaled PCO₂ to effect a target PETCO₂. This is referred to as "gas forcing"(2) . Gas forcing has been shown to be effective in imposing target PETO₂ and target PETCO₂ independent of minute ventilation. However, it does have some drawbacks with respect to measuring CVR:

1) Gas forcing depends on a feedback loop. Feedback loops can have inherent instability depending on the gain and time constant of the system, and are prone to drift and oscillation of end-tidal values.

2) Gas forcing is usually applied in a chamber or requires a hood over the head. As such, there is a large volume of gas that needs to be replaced rapidly for each change in inspired PCO₂. This necessitates very large flows of gases and very precise flow controllers for each gas (such as N₂, O₂ and CO₂ if only these gases are controlled). This is very expensive and cumbersome, and an error which leads to presentation of pure N₂ or pure CO₂ could be deadly.

3) Gas forcing requires the construction of a special chamber that is not available commercially and has been custom built for research purposes. This is available only in a few places in the world.

4) The requirement for specific air-tight chambers, large gas flow controllers, massive volumes of gases, and complex computer control algorithms makes gas forcing too cumbersome to be suitable for use in a radiology, MRI and ophthalmology suites.

5) The time constant for changes in alveolar gas concentrations is too long to be suitable for use with MRI.

D: Sequential gas delivery method: 1) A more recent method introduced by Vesely et al.(l) solved some of these problems. They used O₂ flow to a sequential gas delivery (SGD) circuit to produce rapid changes in PETCO₂ between two known levels (30-50 mmHg). (A SGD circuit provides (at least) two gases through two limbs. The gas from the first limb (G¹) is provided first, and if the subjects breathing exceeds the available first gas, the balance of that breath is made up of the second gas (G²). The second gas may be previously exhaled gas collected in a reservoir on the second limb.) To reduce PCO₂, they asked their patients to hyperventilate while providing large O₂ flows into the SGD. To raise the PCO₂, they provided a bolus of CO₂ by briefly changing the composition of the gas entering the circuit and then maintained the raised PCO2 by controlling the flow into the SGD. While this allowed transitions to a new PETCO₂, the lowering and raising of O₂ flows into the circuit to control PETCO₂ and the required changes in VE caused alveolar, and thus end tidal, O₂ concentrations to change during the protocol despite near constant inspired O₂ concentration. For example, when O₂ flow was restricted in order to keep the PETCO₂ high, the PETO₂ tended to drift down (as O₂ consumption stays constant in the face of reduced O₂ delivery). When patients hyperventilated to lower the PETCO₂, the increased O₂ flow into the circuit resulted in a rise of PETO₂ (as O₂ consumption stays constant and O₂ delivery is increased). The changes in blood PO₂ have an effect on the MRI signal independent of brain blood flow confounding the interpretation with respect to blood flow.

There are additional practical problems with this method:

1) Subjects must change their VE frequently during the protocol. It may be difficult for most people to comply adequately with this.

2) Not adequately following breathing instructions results in not meeting target PCO₂ values

3) Not responding to breathing instructions quickly enough invalidate the MRI data. 4) The method of Vesely et al uses 2 gases and the manipulation of flow into the circuit to change end tidal CO₂ values. With this method, if the total flow is set, then i) varying the inspired PCO₂ changes the inspired PO₂. ii) PETO₂ cannot be determined independently of PETCO₂. iii) PETO₂ and PETCO₂ cannot be varied independently.

Reference List

(1) Vesely A, Sasano H, Volgyesi G, Somogyi R₉ Tesler J₅ Fedorko L et al. MRI mapping of cerebrovascular reactivity using square wave changes in end-tidal PC02. Magn Reson Med 2001; 45(6):1011-1013.

(2) Robbins PA, Swanson GD₅ Howson MG. A prediction-correction scheme for forcing alveolar gases along certain time courses. J Appl Physiol 1982; 52(5):1353- 1357.

SUMMARY OF THE INVENTION

In one aspect, the invention is directed to a method of inducing a target end tidal concentration, or maintaining the end tidal concentration at a target level, of a gas X in a patient comprising the steps of: a) setting the source gas flow into a partial re-breathing circuit at a rate equal to or less than the patient's minute ventilation; b) setting the concentration of said gas X in the source gas to a predetermined level corresponding to the target end tidal concentration of gas X; c) delivering the source gas to the patient through said circuit. In a second aspect, the invention is directed to a method of inducing target end tidal concentrations, or maintaining end tidal concentrations at a target level, of a plurality of gases in a patient comprising: a) setting the source gas flow into a partial re-breathing circuit at a rate equal to or less than the patient's minute ventilation; b) setting the concentration in the source gas, of each gas whose target is being induced or maintained, to a predetermined level to attain the target end tidal concentration of that gas; c) delivering the source gas to the patient through said circuit.

As further described herein, according to one embodiment of the invention, the concentration in the source gas, of each gas whose end tidal concentration in the patient is being set to or maintained at a target, may be set by using one or more pre-mixed gases as the source gas, the said pre-mixed gas having concentrations so as to provide the required target end tidal concentrations. Alternatively, the concentrations in the source of each gas whose end tidal concentration in the patient is being set to or maintained at a target, may be set by blending the source gas from a set of component gases.

The invention may be employed to simultaneously maintain or change the end tidal concentrations of two gases independently of one another. Alternatively, the invention may be employed to maintain the end tidal concentration of a first gas X, while the end tidal concentration of at least one second gas Y is changed from a first target to a second target, by altering the composition of the source gas so that the concentration of the at least one second gas Y is changed.

As first described above, according to one aspect of the invention the concentration of one of more gases in the source gas may be controlled to achieve a particular target end tidal concentration of those gases when such concentration of such gases in the source are predetermined and set based one or more steps described herein. As described below, to achieve a target end tidal of a gas X that is physiologically produced by the patient's body, the concentration of said gas X is set using one formula: VX

FG¹X = F_xETX --^- ^τ VG¹ where FG¹X is the concentration of gas X in the source gas G¹, VX is the patient's minute production of the physiologically produced gas X, FTETX is the target end tidal concentration of said gas X, and VG¹ is the flow rate of the source gas. An example of one such gas would be CO₂ .

The concentration in the source gas of gases that are physiologically consumed by the patient are set using the formula:

FG¹X = F₁ETX + - ^τ VG¹ where FG¹X is the concentration of gas X in the source gas G¹ , VX is the patient's minute consumption of gas X₉ FTETX is the target end tidal concentration of gas X and VG¹ is the flow rate of the source gas.

The patient's minute production of a physiologically produced gas or minute consumption of a physiologically consumed gas may be estimated based on height and weight, or other parameters, or measured directly.

Whether the source gas is, at any given time, made up of pre-mixed gases delivered individually or a blend of component gases, is a function of the capability of the apparatus (the apparatus may be adapted to accommodate one or both capabilities depending on its intended use) but is otherwise immaterial to the practice of the invention. In either case according to one preferred embodiment of the invention, the source gas flow into me breathing circuit preferably has a minimum safe concentration of O₂ , for example 10%. Where the source gas is made up of blended component gases (examples of sets of components gases for providing a full array of target end tidals are described below), at least the most frequently used and preferably each of the component gases comprises a minimum safe concentration of O₂. In a broader aspect, to achieve one or more changes in the end tidal concentration of a given gas in the source without achieving a pre-determined change, the invention is directed to a method of changing an end tidal concentration of a gas X in a patient comprising setting the source gas flow into a partial rebreathing circuit at a rate equal to or less than the patient's minute ventilation and providing a first concentration of said gas X in the source gas and delivering the source gas to the patient through said circuit in order to effect a first end tidal concentration of said gas X.

In a preferred embodiment of the latter method, the further step of providing at least one second different concentration of said gas X in the source gas and delivering the source gas to the patient through said circuit in order to effect a second end tidal concentration of said gas X conveniently enables a diagnostic assessment to be made by measuring a physiological parameter at two end tidal levels of said gas X.

In other aspects, the invention is directed to diagnostic methods employing any of the aforementioned methods of the invention and the various embodiments of those methods described herein and to apparatus adapted to carry out the method and components thereof, optionally including component gases, assembled to carry out the method.

Preferred embodiments of such diagnostic methods include:

A method to measure cerebrovascular reactivity comprising controlling the end tidal CO₂ and O₂ levels of a subject using one of the aforementioned methods and monitoring a blood oxygen level dependent (BOLD) MRI signal intensity,

A method to measure occulovascular reactivity comprising controlling the end tidal CO₂ and O₂ levels of a subject using one of the aforementioned methods and monitoring occulovascular blood flow.

A method to measure a beneficial level of oxygenation to tissues for the purpose of radiotherapy or chemotherapy, comprising controlling the end tidal CO₂ and O₂ levels of a subject using one of the aforementioned methods and monitoring oxygenation or blood flow in the tumor.

It will be appreciated that in the practice of the aforementioned diagnostic methods the end tidal CO₂ and O₂ levels are controlled independently of each other. For example, the end tidal CO₂ levels may be changed while the end tidal O₂ levels are kept constant or the end tidal O₂ levels may be changed while the end tidal CO₂ levels are kept constant or the end tidal O₂ levels and the end tidal CO₂ levels may be changed simultaneously.

In yet another aspect, the invention is directed to a therapeutic method comprising any of the aforementioned methods for controlling end tidal gas concentrations, for example a therapeutic method comprising using such a method to set the end tidal O₂ and CO₂ levels to pre-determined levels that provide a beneficial oxygenation level or blood flow level to tissues for the purpose of radiotherapy or chemotherapy.

In the practice of one embodiment of one of the aforementioned methods, the partial re- breathing circuit is a sequential gas delivery circuit and the apparatus includes means for controlling the rate of flow of the source gas into the circuit and means for controlling the concentration of said gases in the source gas flow. Optionally, the apparatus further comprises means for monitoring pressure in the breathing circuit and optionally further comprises means for measuring the patient's end tidal gas concentrations.

Optionally, the method above may further comprise measuring the end tidal gas concentrations and using feedback control to increase or decrease the concentrations of a particular gas so as to minimize the difference between the current end tidal concentration and the target end tidal concentration, for example so as to effect a more rapid change in target end tidal levels.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure IA shows a rebreatbing sequential gas delivery circuit. Figure IB shows a non-rebreathing sequential gas delivery circuit.

Figure 2 shows the preferred embodiment of the apparatus.

Figure 3 shows an alternate embodiment of the apparatus.

Figure 4 shows data from a subject using the apparatus and method, with constant P_Eτθ₂ and changes in levels of PETCO₂. Figure 5 shows data from a subject using the apparatus and method, with constant

PETCO₂ and changes in levels of P_ET0₂. Figure 6 shows data from a subject using the apparatus and method, with simultaneous controlled changes in PETCO₂ and PETO₂.

DETAILED DESCRIPTION OF THE INVENTION

In the present invention the subject or patient preferably breathes through a breathing valve manifold with breathing tubes (herein referred to as a breathing circuit) known as a partial rebreathing circuit. Preferably, the subject breathes on a particular type of partial rebreathing circuit known as a sequential gas delivery (SGD) circuit, whose functions will be reviewed briefly.

The non-rebreathing sequential gas delivery circuit was taught by Fisher [US 6354292]. The rebreathing sequential gas delivery circuits were taught by Fisher [US 6622725, US 6612308]. Figure IB illustrates the principles of a non-rebreathing sequential gas delivery circuit. During exhalation, the expiratory one-way valve (30) opens and gas is exhaled to atmosphere; meanwhile, the source gas enters the source gas port (32) and is stored in the source gas reservoir (33). Figure IA illustrates the homologous circuit where exhaled gas is used as reserve gas. With this circuit, during exhalation, exhaled gas is directed into an exhaled gas reservoir (28) and made available to act as reserve gas. During inhalation, the one-way inspiratory valve (31) opens and source gas from the source gas port (32) and the source gas reservoir (33) are inhaled. In both of these circuits, when VE exceeds source gas flow, the difference between VE and source gas flow is made up of reserve gas which is presented through crossover valve (29) in the rebreathing circuit or via demand valve (35) in the non rebreathing circuit. Source gas and reserve gas are inhaled sequentially: at the beginning of inhalation, gas is inhaled from the fresh gas flow inlet and the fresh.gas reservoir. Reserve gas in the non rebreathing circuit is comprised of gas that has similar properties to exhaled gas.

Description of Method to Independently Control End-Tidal Gases

The present invention describes a method for independent control of end tidal (end of exhalation) gas concentrations of a subject. The discussion herein describes the method particularly as it pertains to control of CO₂ and O₂ , although those skilled in the art will recognize that the method can be equally applied to control of other gases in the subject.

The method comprises:

1. determining or estimating the subject's VCO2 and VO2

2. setting the flow rate of the source gas (VG¹) into a partial rebreathing circuit, preferably a sequential gas delivery circuit, on which the subject is breathing, equal to or less than the subject's average VE . This may be . accomplished by adjusting the source gas flow until the source gas reservoir of a sequential gas delivery circuit just empties on each breath, or alternatively, a flowmeter may be interposed between the subject and the circuit.

3. setting the O₂ and CO₂ concentrations in the source gas (FG¹O₂ and FG¹CO₂ respectively) to concentrations determined using the methods described below

A partial rebreathing circuit is required with the method since the end tidal concentrations when breathing on such a circuit become fixed (approximately fixed for most partial rebreathing^' circuits, and reliably fixed with sequential gas delivery circuits) and independent of minute ventilation (VE )₅ provided the gas flow into the circuit is less than or equal to the VE . The end tidal concentrations become a function only of the gas concentrations of the source gas. We will first describe the method for determining FG¹CO₂ . In order to carry out the method, one must first obtain values for the subject's CO₂ production (FCO₂) , which can be done by direct measurement (for example by analyzing a timed collection of exhaled gas for FCO₂) or calculated from standard tables based on other anthropomorphic data such as weight and height.

The method makes use of the relationship known in the art that relates a rate of alveolar ventilation VA to the patient's fractional end tidal CO₂ concentration:

FETC02 Equation (4)

This relationship states that for a given rate of alveolar ventilation, a particular end tidal concentration is produced. Lowering the alveolar ventilation raises FETCO₂ and raising it lowers FETCO₂.

In the present method, we determine what concentration of CO₂ is required in the source gas to keep the FETCO₂ level fixed at the target. Changing the CO₂ level to a new target requires determining the new required CO₂ concentration in the source gas. For example, consider a case where the patient has a resting VA witihi a corresponding resting end tidal

CO₂. If we wish to increase the source gas flow ^ to greater than the subject's resting

VA , and we instruct the subject to breathe at a rate > ^ to assure that all of VG^X reaches the alveoli, then G¹ must have additional CO₂ to prevent a reduction in PETCO₂.

Another way to view this is to split G¹ into a component with a flow rate equal to the resting VA and a component with the balance of the flow which is (G¹ - VA). We call the component that is equal to VA "fresh" gas flow because it contributes to gas exchange, (RJ¹/ ) by virtue of having no CO₂. This gas flow therefore determines the end tidal concentration according to Equation (4). The second component of G¹ consisting of the difference between the desired G¹ and the VA (G¹ - VA) requires a concentration of CO₂ that does not provide a gradient for gas exchange. Thus composed, it is considered a "neutral" gas flow ( VG\ ). FG^! _nCO₂ equal to that of alveolar gas (as approximated by end tidal gas) by definition would be "neutral" with respect to gas exchange.

Since there is no CO₂ in FG¹ _/ , VG^l _n is the source of all of the CO₂ in G¹ (Equation (6).

FG¹ x FG¹CO₂ = VG\ x FG¹HCO₂ Equation (6)

The concentration in the neutral gas must be equal to the target CO₂ concentration to maintain PETCO₂ at the target value

FG¹ x FG¹CO₂ = VG\ x F_TETCO₂ Equation (7)

and the rate of flow of neutral gas is the difference between the rate of flow of the source gas and the rate of his alveolar ventilation, or

VG\ = [ VG¹ - VA ] Equation (7b)

Allows us to rewrite Equation (7) as:

VG¹ x FG¹CO₂= [ FG¹ - VA ] x F_TETCO₂ Equation (7c)

Also, the relationship between his target end tidal and alveolar ventilation is known from Equation (4).

VA = Equation (4)

F_TETCO₂ ^{4 V ;}

Therefore, substituting Equation (4) in equation (7c) we get:

VG¹X FG¹CO₂= [VG¹ - ^VC°² ] x FTETCO₂ Equation (8)

F_TETCO2

Dividing both sides by ^ gives:

FG¹CO₂ = F₁ETCO₂ - ^SQ- Equation (9) This argument should hold generically for any gas that is absorbed by the body as well. In practice, it is preferable to have the patient breathing at a rate greater than their resting breathing rate in order to achieve end tidal CO₂ targets below their resting levels. Additionally, having the patient breathe faster enables more rapid transitions between end tidal levels, particularly when moving from higher to lower CO₂ targets, since the breathing rate becomes the limiting factor when giving the lowest concentration (i.e. 0%) of CO₂ possible.

We now describe the method for determining FG¹O₂ . In order to carry out the method, one must first obtain values for the subject's O₂ consumption (FO₂ ) , which can be done by direct measurement (for example by collecting exhaled gas in a bag and analyzing its concentration), calculated from standard tables based on other physiological data such as weight and height, or determined from FCO₂ and the Respiratory Quotient (RQ) which relates FO₂ to VCΟ2 and is usually estimated as having a value of 0.8 in most people.

The method for determining FG¹O₂ is analogous to determining FG¹CO₂ with the exception that the sign on the FO₂ is reversed in Equation (9) reflecting the fact that O₂ is consumed by the body while CO₂ is produced by the body. Thus the analogous form for Equation (9) as is pertains to O₂ is as follows:

FG¹O₂ = F_xETO₂ +-^- Equation (11)

It will be appreciated by those skilled in the art that Equations 9 and 11 may be generalized to any gas that is physiologically produced (as is CO₂ ) or consumed (as is O₂ ) by the body. The general form of Equation 9 for inducing or maintaining a target end tidal concentration of a gas X that is physiologically produced by the body would thus be to set the concentration of gas X in the source gas (defined as FG¹X ) using

. FG¹X Equation (12)

where VX is the patient's minute production of gas X₅ FJETX is the target end tidal concentration of gas X, and VG¹ is the flow rate of the source gas.

The general form of Equation 11 for inducing or maintaining a target end tidal concentration of a gas X that is physiologically consumed by the body would thus be to set the concentration of gas X in the source gas (defined as FG¹X ) using

FG¹X = F_TETX + ~ Equation (13)

where VX is the patient's minute production of gas X, FjETX is the target end tidal concentration of gas X₅ and VG¹ is the flow rate of the source gas.

Optionally, it will be appreciated by those skilled in the art that the method above may be used to target particular end tidal concentrations, however, the targeting may be fine tuned, or the target may be reached more quickly, by measuring the end tidal gas concentrations and using feedback control to increase or decrease the concentrations of a particular gas so as to minimize the difference between the current end tidal concentration and the target end tidal concentration.

Selection of Source Gases

Another aspect of the present invention is the selection of gases used to carry out the method. It will be appreciated by those skilled in the art that, for a given desired total flow, any combination of concentrations OfCO₂ and O₂ in the source gas may be achieved by mixing source gases consisting of pure O₂, CO₂ and N₂. However, pure CO₂ and pure N₂ contain no O₂ and thus if the gas blending apparatus were to fail and the patient were to inhale just a few breaths of either of these two gases, it would lead to severe hypoxemia and possibly death. One aspect of the present invention is the use of source gases each of which has at least a minimum concentration of O₂ determined to be the safe minimum level. Preferably, this level is at least 10%, but under certain controlled and monitored conditions, levels less than 10% might still be used.

The gas concentrations are chosen subject to the following constraints: i. To achieve the maximum signal / noise ratio for diagnostics, the widest range of FETO2 and FETCO₂ values is desirable. ii. Each gas must have a minimum safe concentration of oxygen, such that if it is the only gas given, the subject will not be severely harmed. This is preferably about 10%. One gas (call it gas "C") should have no more O₂ than this and a low level of CO₂ to achieve the combination of low target FTET¹O₂ and low FTETCO₂. iii. The minimum oxygen concentration of one gas (call it gas "A") must be set so as to achieve the maximum FETO₂ desirable to give the patient, iv. One gas (call it Gas "B") must also contain at least a high enough CO₂ concentration so as to be able to achieve the maximum F_ETCθ₂ desired. The concentration of CO₂ in Gas B is further constrained by the fact that, to get a high FETO₂ and high FETCO₂ simultaneously, a substantial amount of Gas A (high O₂ concentration) must be given, leaving less room for Gas B in the FG¹. For example, to achieve a 7.5% F_EτCO₂ with a 90% F_ETO₂ , Gas A would need over a 90% concentration of O₂ and Gas B would need at least a 60% concentration of CO₂ . v. The O₂ concentration of Gas "B" must be low enough to enable producing in the subject the highest desirable FETCO₂ and the lowest desirable FETO₂. vi. Gas. "A" must have a low CO₂ concentration since it contains a high O₂ concentration, and it may be desirable to have a high FETO₂ and low FETCO₂ , which cannot be achieved any other way once the constraints on gases B and C above are considered. vϋ. Therefore, based on the above constraints, the preferred method includes using gases with relative concentrations as described in Table 1 :

Table 1: Relative concentrations of O₂ and CO₂ in Gas A, Gas B and Gas C

Blending Source Gases to Achieve the Required Total Gas Concentrations of COg and O₂

For the present discussion, we assume that the FO₂ in Gas B and Gas C are set to achieve the lower bound of FTETO₂, and FCO₂ in Gas A and Gas C are both set to achieve the lower bound FTETCO₂. Hence, the greatest range of F_TETO₂ and FTETCO₂ occurs when FBO₂ = FcO₂ and FACO₂ = FcCO₂ . Table 2 is used to defines terns used to designate the O₂ and CO₂ concentrations in Gas A, Gas B and Gas C.

Table 2: Definition of terms used to designate the O₂ and CO₂ concentrations in Gas A, Gas B and Gas C.

The method summarized by Equations 11 and 9 are used to determine fractional concentrations of CO₂ and O₂ that have to be supplied in G¹ to attain target FTETCO₂ and F_τETθ₂, assuming the patient's or subject's VCO2 and VO2 are known. The total flow of source gas G¹ into the apparatus is the sum of the flows of the individual gases A, B and C.

The flow of O₂ in the source gas is equal to the sum of the flows of O₂ from the individual gases. Therefore:

VG¹ x FG¹O₂ = QA X FAO₂ + QB X FBO₂ + Qc x FcO₂ But since FcO₂ = FBO₂ this can be rewritten as

VG¹ x FG¹O₂ = QA X FAO₂ + (FG¹- QA ) x FBO₂ Which simplifies to

_Λ YG¹CFG¹O₂- FBO₂) _ .. ,„

QA = — — Equation (1)

FAO₂ -FBO₂ ^H

The flow of CO₂ in the source gas is equal to the sum of the flows in the individual gases. Therefore:

FG¹X FG¹CO₂ = QA X FACO₂+ QB X FBCO₂ + QC X FCO₂ But since FACO₂ = FcCO₂ this can be rewritten as

VG¹ x FG¹CO₂ = QB X FBCO₂ + (VG¹- QB ) x FACO₂

This simplifies to

_Λ -. ₊. ,„

QB Equation (2)

Finally,

Qc = VG¹- QA - QB Equation (3)

Equations 1, 2 and 3 can be used to calculate flows required from each mixture to obtain a total flow ( VG^ ) with O₂ concentration OfFG¹O₂ and CO₂ concentration FG¹CO₂. It should be appreciated by those skilled in the art that other gas combinations for component gases may be used, and the derivation above may be extended to the general case of any concentration for any gas in the component gas. The same method and approach that is described for O₂ can be applied to any other gas that is absorbed, including, but not limited to acetylene, carbon monoxide, nitrous oxide, anesthetic gases. It is recognized that by defining target PCO₂ and target PO₂, target PN2 is also defined. In the same way, the target partial pressure of any inert gas can be defined, for example, but not limited to argon, helium, and xenon.

Another aspect of this invention is the use of the independent control of end tidal CO₂ and O₂ , N₂ or other gas levels to carry out diagnostic and therapeutic tests or carry out research in physiology. What follows are examples that are not meant to be an exhaustive list of applications for instituting targeted blood gases. For example, the CO₂ levels may be rapidly transitioned from low to high targets and back repeatedly while the subject's brain blood flow is measured using the Blood Oxygen Level Dependent (BOLD) MRI imaging technique. This produces a map of cerebrovascular reactivity. BOLD and transcranial Doppler, for example can be used to measure the physiology of brain and other tissue blood flow response to changes in blood concentrations of CO₂, O₂, with or without the presence of other gases or substances in the blood. Similarly, occulovascular reactivity may be measured by measuring blood flow in the retinal vessels with Doppler ultrasound, MRI or other devices known to those skilled in the art, at target concentrations of CO₂, O₂ and other gases, with and without the presence of other substances in the blood. Another test involves manipulating O₂ levels in tumors and measuring beneficial oxygenation levels in the tumor using BOLD MRI signal or other methods known to those skilled in the art. This would identify blood gasses providing beneficial levels of blood flow and oxygenation to tumors, sensitizing them to destruction by radiotherapy or chemotherapy. This may additionally be combined with using the method during radiotherapy so as to reproduce the determined level of oxygenation. It is obvious that similar studies may be performed in any of the other responsive vascular beds in the body including but not limited to the skin, kidney, heart, lung and various abnormal congenital and acquired conditions such as tumours and vascular malformations. Being able to achieve target end tidal PO₂ and PCO₂ allows the reproducibility of test conditions. This in turn allows the comparison of tests on one subject from one time to the next and between subjects. This reproducibility of the test enables the doctor, for the first time, to follow the progress of an abnormality, or a response to treatment. For example, in a patient with Moyamoya disease, an area of the brain develops abnormalities in blood vessels which can be identified by abnormal response to changes in PCO₂. Repeated standardized tests to the same target PCO₂ allows the doctor to identify changes in strength of response. In cranial artery stenosis, an area of the brain may lose its vascular reactivity as seen by response to BOLD imaging with MRI in response to changes in PCO₂. The test can be repeated after surgery to identify the extent of recovery of vascular reactivity. If there are still areas of loss of reactivity, further surgery may be indicated.

A standardized test allows the study of the normal physiology of control of blood flow to a tissue or organ that responds to CO₂ or O₂. For example, trans cranial Doppler, BOLD MRI, spin labeling, with MRI, Positron Emission Tomography or many other • ^• measurements known to those skilled in the art can be used to measure blood flow, oxygenation or metabolism of tissues and organs in response to known, reproducible changes in PO₂ and PCO₂ or other gases with this method.

In summary, this invention provides the ability to provide standard, reproducible stimuli via the lung to vascular beds and other tissues. When combined with any of a long list of sensors, known to those skilled in the art, a standard set of stimuli allows the comparison of results in a subject over time, between patients or subjects in a group, of a group over time, and between groups being studied by different researchers. None of these advantages can be obtained from known methods that do not reliably provide reproducible stimuli.

Alternate Method Using Premixed Gases

Equations 9 and 11 above disclose the method for determining the fractional concentrations of CO₂ and O₂ in the source gas based on the target end tidal concentrations and the patient's rate OfO₂ consumption and CO₂ production. It may be desirable for performance of certain diagnostic tests to assume that a particular patient population has a small range of values for CO₂ production and O₂ consumption, or to ignore the small variations that the differences in these values might make to the resulting end tidal concentrations. It would then be possible to use a plurality of gas mixtures with predetermined concentrations of gas to achieve particular sets of targets. For example, assuming all patients had a VO₂ of 300 ml/min , VCO₂ of 250 rtύVmin, and breathed at a rate of VE = 10 lpm, and given the following set of target end tidal concentrations of CO₂ O₂ , one might provide the following premixed gases each of which corresponded to one pair of targets. These gases may be provided to the patient in a predetermined sequence to perform a diagnostic test, for example.

Table: Sample Premixed Gases to Achieve Desired set of Targets

End Tidal Control Apparatus

Another aspect of the present invention is the apparatus used to carry out the method. The apparatus consists of source gases chosen to provide the maximum range of combinations of targets for the end tidal gases, a gas blending device and a partial rebreathing circuit. In the preferred embodiment, the gases to be controlled are O₂ and CO₂. With reference to Figure 2, three pressurized gases A, B and C are connected to the gas blending apparatus (1). When the method is conducted, gases A, B and C are delivered to the blender (1) at flows QA , QB and Qc that are regulated by flow controllers (6A), (6B) and (6C) via control inputs (3A), (3B) and (3C) respectively. These flow controllers may be of many types known in the art, but are preferably mass flow controllers to enhance precision. Flows of QA , QB and Qc are determined according to the present method for target FETCO₂ and FETO_Ϊ at each phase in the sequence. The blend of QA , QB and Qc results in FG¹. The resulting mixture, G¹, leaves the blender (l).yia an output hose (7) and is delivered to the gas inlet (8) of the partial rebreathing circuit (9). In the preferred embodiment shown, the partial rebreathing circuit is a sequential gas delivery circuit. During inhalation, inspiratory one-way valve (10) opens and the first part of the breath comes from the gas inlet (8) and G¹ reservoir (11). IfVE >exceeds VG¹ , the G¹ reservoir

(11) collapses during the breath and the balance of the breath comes from the exhaled gas G² reservoir (12) via the crossover valve (13) or in the case of a non-rebreathing SGD from stored exogenous gas that approximates exhaled gas.

During exhalation, expiratory one-way valve (14) opens and expired gases are either collected in the exhaled gas reservoir (12), or in the case of a non-rebreathing SGD, they are vented. Meanwhile, G¹ collects in the G¹ source gas reservoir (11). Optional pressure sampling line (15) and pressure transducer (17) can be inserted at the patient-circuit . interface to aid in synchronization of changes in gas flows with the breath. Optionally, gas may be sampled via line (16) connected to an optional CO₂/O₂ analyzer (18). Peak detection algorithm can use signals from pressure transducer (17) or gas analyzer to detect breaths and pick end-tidal values for O2 and CO₂. Data can be analyzed on- or offline and displayed on a computer screen (4).

Optionally, if it is desired to give the patient air during a stand by phase, three-way solenoid valve (2) is electronically controlled by connection (3S) from machine intelligence (4) and is either open to air source (5) or to the manifold (82) collecting gas from gas sources A, B and C. When the apparatus is in the standby mode, the patient receives air flow which is regulated by flow controller (6) via control input (84).

Alternate Embodiment

If it is desired to "hardwire" a particular sequence of target end tidal concentrations, premixed gases with concentrations to achieve the desired targets can be used with an alternative apparatus described in Figure 3. For any given pattern of transitions and steady states, individual concentrations of O₂ and CO2 in the G¹ gas measured among different patients will depend on patient's VO₂ and VCO₂ . In order to accommodate for these differences, apparatus described in Figure 3 allows precise control of FG¹ according to the patient's VO₂ and FCO₂ or estimate thereof.

With reference to Figure 3 a set of premixed gases (5 are shown, but one is needed for each set of target end tidal concentrations) D, E, F, G and H containing premixed mixtures of O₂, CO₂ and N₂ equal to those required in the G¹ gas during each phase of the sequence, are connected to gas blender (1). Two-way solenoid valves (25D₅ 25E₅ 25F, 25G₅25H) control the flow of gases D, E, F₅ G and H. The two-way solenoid valves (25) are controlled by machine intelligence (4), which contains pre-programmed information about the order and duration of opening of each individual valve. Gas flow to the circuit (9) is regulated by a flow controller (26). Optional three-way solenoid valve (23) is electronically controlled via machine intelligence (4) and may be open to optional air_. source (5) during an optional stand by phase or to the gases coming through solenoids (25). The rest of the apparatus is the same as in Figure 2 .

Figures 4-6 show experimental data obtained from a subject whose end tidal values were controlled and set to target levels.

Claims

What is claimed is:

1. A method of inducing a target end tidal concentration of a gas X in a patient comprising: a) setting the source gas flow into a partial rebreathing circuit at a rate equal to or less than the patient's minute ventilation b) setting the concentration of said gas X in the source gas to a predetermined level corresponding to the target end tidal concentration of gas X c) delivering the source gas to the patient through said circuit

2. The method of claim 1 wherein said gas X is a gas produced by the patient, and the

VX concentration of said gas X (FG¹X) is set according to FG¹X = F_xETX — _: — _j- , where

VX is the patient's minute production of gas X₅ FTETX is the target end tidal concentration of gas X, and VG¹ is the flow rate of the source gas,

3. The method of claim 1 wherein said gas X is a gas consumed by the patient, and the

concentration of said gas X ( FG¹X ) is set according to FG¹X = F₁ETX + -^ — γ , where

VX is the patient's minute consumption of gas X, F_TETX is the target end tidal concentration of gas_. X and VG¹ is the flow rate of the source gas.

4. A method of simultaneously inducing target end tidal concentrations of a plurality of gases in patient, where said target end tidal concentrations are independent of each other, comprising: a) setting the source gas flow into a partial rebreathing circuit at a rate .equal to or less than the patient's minute ventilation b) setting the concentration of each gas in the source gas to attain the target end tidal concentration of that gas c) delivering the source gas to the patient through said circuit

5. The method of claim 4 wherein at least one of the gases X whose end tidal concentration is being induced, is a gas produced by the patient, and the concentration VX of said gas X in the source gas is set according to FG¹X = F_xETX - -7 — 7- , where VX

VG is the patient's minute production of gas X₅ F_TETX is the target end tidal concentration of gas X and G¹ is the flow rate of the source gas.

6. The method of claim 4 wherein at least one of the gases X whose end tidal concentration is being induced, is a gas consumed by the patient, and the

VX concentration said gas X is set according to FG X = FETX + -. — 7- , where VX is the

patient's minute consumption of gas X₅ FTETX is the target end tidal concentration of gas X₅ and VG¹ is the flow rate of the source gas.

7. A method of changing an end tidal concentration of a gas X in a patient comprising: a) setting the source gas flow into a partial rebreathing circuit at a rate equal to or less than the patient's minute ventilation b) providing a first concentration of said gas X in the source gas and delivering the source gas to the patient through said circuit in order to effect a first end tidal concentration of said gas X c) providing a second concentration of said gas X in the source gas and delivering the source gas to the patient through said circuit in order to effect a second end tidal concentration of said gas X

8. A method of changing between target end tidal concentrations of a first gas X in a patient comprising inducing the first target end tidal concentration using any of the methods of Claim 1- 7, then inducing the second target end tidal concentration using any of the methods of Claim 1- 7.

9. The method of Claim 8 further comprising keeping end tidal concentration of a second gas Y at a fixed target level using any of the methods of Claim 1- 7.

10. The method of simultaneously changing between target end tidal concentrations of two or more gases in a patient comprising inducing the first target end tidal gas concentrations using any of methods of claims 1- 7, then inducing the second target end tidal gas concentrations using any of methods of claims 1- 7.

11. The methods. of Claims 1- 10 where, for each set of target end tidal gas concentrations, the gas flow into the breathing circuit is comprised of a premixed gas

12. The methods of Claims 1- 10 where, for each set of target end tidal gas concentrations, the gas flow into the breathing circuit is comprised of a blend of at least two component gases, said component gases being blended to achieve the desired concentrations in the source gas flow of the gases whose end tidal concentrations are being targeted.

13. The method of Claims 11 or 12 where each of the component gases has a minimum safe concentration OfO₂ .

14. The method of Claims 1 lor 12 where the source gas flow into the breathing circuit has a minimum safe concentration of O₂ .

15. The method of Claims 13 or 14 where the minimum safe level Of O₂ concentration is 10%.

16. The method of Claims 13 or 14 where the minimum safe level of O₂ concentration is 10%.

17. The method of Claims 13 - 16 using 3 component gases.

18. The method of any of claims 1- 17 wherein the partial rebreathing circuit is a sequential gas delivery circuit.

19. The method of any of claims 1- 17 wherein the gas whose end tidal concentration target is being induced is O₂ .

20. The method of any of claims 1- 17 wherein the gas whose end tidal concentration target is being induced is CO₂ .

21. The method of Claim 17 where the component gases have the following relative concentrations: a) Gas^' A: High O₂ , Low CO₂ b) Gas B: Low O₂ , High CO₂ c) Gas C: Low O₂ , Low CO₂

22. The method of Claim 16 where the source gases have the following concentrations: a) Gas A: 50-100% O₂ , 0-20% CO₂ b) Gas B: 10-30% O₂ , 20-80% CO₂ c) Gas C: 10-30% O₂ , 0-20% CO₂

23. The method of Claim 16 where the source gases have the following concentrations: a) Gas A: 100% O₂ , 0% CO₂ b) Gas B: 10% O₂ , 20-80% CO₂ c) Gas C: 10% O₂ , 0% CO₂

24. The method of Claim 16 where the source gases have the following concentrations: a) Gas A: 100% O₂ , 0% CO₂ b) Gas B: 10% O₂ , 20-40% CO₂ c) Gas C: 10% O₂ , 0% CO₂

25. The method of Claim 16 where the source gases have the following concentrations: a) Gas A: 100% O₂ , 0% CO₂ b) Gas B: 10% O₂ , 40% CO₂ c) Gas C: 10% O₂ , 0% CO₂

26. The method of Claim 16 where the source gases have the following concentrations: a) Gas A: 100% O₂ , 0% CO₂ b) Gas B: 10% O₂ , 20% CO₂ c) Gas C: 10% O₂ , 0% CO₂

27. A diagnostic method comprising any method according to claims 1 to 26.

28. A method to measure cerebrovascular reactivity comprising: a) controlling the end tidal CO₂ and O₂ levels of a subject using the methods of claims 20 or 21. b) monitoring a blood oxygen level dependent (BOLD) MRI signal intensity

29. The method of Claim 28 where the end tidal CO₂ and O₂ levels are controlled independently of each other.

30. The method of Claim 28 or 29 where the end tidal CO₂ levels are changed while the end tidal O₂ levels are kept constant.

31. The method of Claim 28 or 29 where the end tidal PO₂ levels are changed while the end tidal PCO₂ levels are kept constant

32. The method of Claim 28 or 29 where the end tidal PO₂ levels and the end tidal PCO₂ levels are changed simultaneously

33. A method to measure occulovascular reactivity comprising: a) controlling the end tidal CO₂ and O₂ levels of a subject using the methods of claims 20 or 21. b) monitoring occulovascular blood flow

34. The method of Claim 33 where the end tidal CO₂ and O₂ levels are controlled independently of each other.

35. The method of Claim 33 or 34 where the end tidal CO₂ levels are changed while the end tidal O₂ levels are kept constant.

36. The method of Claim 33 or 34 where the end tidal PO₂ levels are changed while the end tidal PCO₂ levels are kept constant

37. The method of Claim 33 or 34 where the end tidal PO₂ levels and the end tidal PCO₂ levels are changed simultaneously.

38. A method to standardize measurement of occuloVasciilar reactivity.

39. A method to measure a beneficial level of oxygenation to tissues for the purpose of radiotherapy or chemotherapy, comprising: a) controlling the end tidal CO₂ and O₂ levels of a subject using the methods of claims 20 or 21. b) monitoring oxygenation or blood flow in the tumor

40. The method of Claim 39 where the end tidal CO₂ and O₂ levels are controlled independently of each other.

41. The method of Claim 39 or 40 where the end tidal CO₂ levels are changed while the ^• end tidal O₂ levels are kept constant.

42. The method of Claim 39 or 40 where the end tidal PO₂ levels are changed while the end tidal PCO₂ levels are kept constant

43. The method of Claim 39 or 40 where the end tidal PO₂ levels and the end tidal PCO₂ levels are changed simultaneously

44. A therapeutic method comprising any method according to claims 1 to 26.

45. A therapeutic method comprising: a) using any of the methods of claims 39 to 44 to determine end tidal O₂ and CO₂ levels that provide a beneficial oxygenation or blood flow level to tissues for the purpose of radiotherapy or chemotherapy b) using any of the methods of claims 1 to 26 to set the end tidal O₂ and CO₂ levels to said levels during radiotherapy or chemotherapy

46. An apparatus for inducing target end tidal gas concentrations in a patient simultaneously, and independently of each other comprising: a) a partial rebreatbing circuit b) a source gas flow into said breathing circuit c) means for controlling the rate of said source gas flow into the circuit d) means for controlling the concentration of said gases in the source gas flow independently of each other

47. The apparatus of Claim 46 further comprising means for monitoring end tidal CO₂ and O₂ concentrations

48. The apparatus of Claim 46 further comprising means for monitoring pressure in the breathing circuit ^• ._.

49. The apparatus of Claim 46 where the breathing circuit is a sequential gas delivery circuit.

50. The apparatus of Claims 46 to 49 where, for each set of target end tidal gas concentrations, the gas flow into the breathing circuit is comprised of a premixed gas

51. The apparatus of Claims 46 to 49 where, for each set of target end tidal gas concentrations, the gas flow into the breathing circuit is comprised of a blend of at least two component gases, said component gases being blended to achieve the desired concentrations in the source gas flow of the gases whose end tidal concentrations are being targeted.

52. The apparatus of Claims 46 to 51 with 3 component gases.

53. The apparatus of Claim 52 where the component gases have the following relative concentrations: a) Gas A: High O₂ , Low CO₂ b) Gas B: Low O₂ , High CO₂ c) Gas_. C: Low O₂ , Low CO₂

54. The apparatus of Claim 53 where the component gases have the following concentrations: a) Gas A: 50-100% O₂ , 0-20% CO₂ b) Gas B: 10-30% O₂ , 20-80% CO₂ c) Gas C: 10-30% O₂ , 0-20% CO₂

55. The apparatus of Claim 53 where the component gases have the following concentrations: a) Gas A: 100% O₂ , 0% CO₂ b) Gas B: 10% O₂ , 20-80% CO₂ c) Gas C: 10% O₂ , 0% CO₂

56. The apparatus of Claim 53 where the component gases have the following concentrations: a) Gas A: 100% O₂ , 0% CO₂ b) Gas B: 10% O₂ , 20-40% CO₂ c) Gas C: 10% O₂ , 0% CO₂

57. The apparatus of Claim 53 where.the component gases have the following concentrations: a) Gas A: 100% O₂ , 0% CO₂ b) Gas B: 10% O₂ , 40% CO₂ c) Gas C: 10% O₂ , 0% CO₂

58. The apparatus of Claim 53 where the source gases have the following concentrations: a) Gas A: 100% O₂ , 0% CO₂ b) Gas B: 10% O₂ , 20% CO₂ c) Gas C: 10% O₂ , 0% CO₂

59. The method of claims 1 to 45 further comprising the steps of: a) monitoring the end tidal gas concentration of the patient for a particular gas b) increasing or decreasing the concentration of said gas so as to decrease the difference between the patient's end tidal concentration of said gas and the target end tidal concentration of said gas.